fumarates and aliskiren

Aliskiren is an oral antihypertensive medication that acts by directly inhibiting renin. High levels of circulating renin and prorenin activate the pathological signaling pathway of fibrosis. This drug also reduces oxidative stress. Thus, the aim of this systematic review is to analyze experimental studies that show the actions of aliskiren on fibrosis. PubMed and LILACS databases were consulted using the keywords aliskiren and fibrosis within the period between 2005 and 2017. Fifty-three articles were analyzed. In the heart, aliskiren attenuated remodeling, hypertrophy, inflammatory cytokines, collagen deposition, and oxidative stress. In the kidneys, there was a reduction in interstitial fibrosis, the infiltration of inflammatory cells, apoptosis, proteinuria, and in the recruitment of macrophages. In diabetic models, an improvement in the albumin/creatinine relationship and in the insulin pathway in skeletal muscles was observed; aliskiren was beneficial to pancreatic function and glucose tolerance. In the liver, aliskiren reduced fibrosis, steatosis, inflammatory cytokines, and collagen deposition. In the lung and peritoneal tissues, there was a reduction in fibrosis. Many studies have reported on the beneficial effects of aliskiren on endothelial function and arterial rigidity. A reduction in fibrosis in different organs is cited by many authors, which complies with the results found in this review. However, studies diverge on the use of the drug in diabetic patients. Aliskiren has antifibrotic potential in several experimental models, interfering with the levels of fibrogenic cytokines and oxidative stress. Therefore, its use in diseases in which fibrosis plays an important pathophysiological role is suggested.

Topics: Amides; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Drug Repositioning; Endomyocardial Fibrosis; Fibrosis; Fumarates; Humans; Nephritis, Interstitial; Oxidative Stress

Aliskiren is a newly developed medicine. As one of the effective renin-angiotensin-aldosterone system inhibitors, its role in lowering blood pressure has been recognised. However, its safety and tolerability still remain controversial. The aim of the paper is to systematically summarise the published studies about the clinical efficacy and side effects of aliskiren monotherapy.. A comprehensive review of PubMed, Embase and Cochrane Library databases published from inception until June 2019 will be conducted. The selected articles are meta-analyses that integrated the randomised controlled studies, which evaluated efficacy, safety and tolerability of aliskiren monotherapy. Two people will select eligible articles and extract data independently. Any disputes will be resolved by discussion or the arbitration of a third person. The quality of reporting evidence will be assessed using the AMSTAR 2 tool. Study selection process will be presented using a flowchart. We will re-analyse each outcome with the random effect methods if necessary. If possible, we will also calculate 95% prediction intervals for each random effect estimate, by using Egger's test to evaluate if the reporting bias existed.. Ethical approval is not required for the study, as we only collected data from available published materials. This umbrella review will be also submitted to a peer-reviewed journal for publication after completion.. CRD42019142141.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Drug Tolerance; Fumarates; Humans; Hypertension; Treatment Outcome

Aliskiren is a newly developed drug. Its role in lowering BP has been recognized. However, the role of aliskiren in treating heart and renal diseases are still controversial.. To evaluate the existing evidence about clinical efficacy, safety and tolerability of aliskiren monotherapy (AM).. An umbrella review of systematic reviews of interventional studies. We searched Pubmed, Embase and Cochrane Library up to June 2019. Two reviewers applied inclusion criteria to the select potential articles independently. The extract and analyze of accessible data were did by two reviewers independently too. Discrepancies were resolved with discussion or the arbitration of the third author.. Eventually, our review identified 14 eligible studies. Results showed that for essential hypertension patients, aliskiren showed a great superiority over placebo in BP reduction, BP response rate and BP control rate. Aliskiren and placebo, ARBs or ACEIs showed no difference in the number or extent of adverse events. For heart failure patients, AM did not reduce BNP levels (SMD -0.08, - 0.31 to 0.15) or mortality rate (RR 0.76, 0.32 to 1.80), but it decreased NT-proBNP (SMD -0.12, - 0.21 to - 0.03) and PRA levels (SMD 0.52, 0.30 to 0.75), increased PRC levels (SMD -0.66, - 0.8 to - 0.44). For patients who are suffered from hypertension and diabetes and/or nephropathy or albuminuria at the same time, aliskiren produced no significant effects (RR 0.97, 0.81 to 1.16).. We found solid evidence to support the benefits of aliskiren in the treatment of essential hypertension, aliskiren can produce significant effects in lowering BP and reliable safety. However, the effects of aliskiren in cardiovascular and renal outcomes were insignificant.. Study has been registered in PROSPERO (CRD42019142141).

Topics: Albuminuria; Amides; Antihypertensive Agents; Blood Pressure; Diabetic Nephropathies; Essential Hypertension; Fumarates; Heart Failure; Humans; Renin; Systematic Reviews as Topic; Treatment Outcome

COVID-19, caused by infection with SARS-CoV-2, is a disease characterised by cough, fever and fatigue, which progresses to life-threatening lung injury in approximately 5% of patients. The SARS-CoV-2 virus enters the cell via ACE2. ACE2 is a component of the renin-angiotensin system (RAS) which has an important counterregulatory effect on the classical ACE-dependent pathway. Several antihypertensives increase ACE2 expression or activity, leading to concern that this may facilitate SARS-CoV-2 entry and worsen COVID-19 disease. However, ACE2 is protective against lung injury while ANG II (which is catabolised by ACE2) is associated with lung injury both in mice and humans. We propose that medications which inhibit the RAS ACE-dependent pathway may be beneficial in treating COVID-19 and should be explored in animal models and clinical trials. Here we give an overview of the RAS pathway with respect to COVID-19 and argue that strategies which manipulate this pathway might reduce the destructive lung manifestations of COVID-19 and improve patient outcomes.

Topics: Amides; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Betacoronavirus; Coronavirus Infections; COVID-19; Fumarates; Humans; Lung Injury; Mice; Pandemics; Peptidyl-Dipeptidase A; Pneumonia, Viral; Renin-Angiotensin System; SARS-CoV-2; Virus Internalization

Fibrosis is characterized by excessive deposition of extracellular matrix components such as collagen in tissues or organs. Fibrosis can develop in the heart, kidneys, liver, skin or any other body organ in response to injury or maladaptive reparative processes, reducing overall function and leading eventually to organ failure. A variety of cellular and molecular signaling mechanisms are involved in the pathogenesis of fibrosis. The renin-angiotensin-aldosterone system (RAAS) interacts with the potent Transforming Growth Factor β (TGFβ) pro-fibrotic pathway to mediate fibrosis in many cell and tissue types. RAAS consists of both classical and alternative pathways, which act to potentiate or antagonize fibrotic signaling mechanisms, respectively. This review provides an overview of recent literature describing the roles of RAAS in the pathogenesis of fibrosis, particularly in the liver, heart, kidney and skin, and with a focus on RAAS interactions with TGFβ signaling. Targeting RAAS to combat fibrosis represents a promising therapeutic approach, particularly given the lack of strategies for treating fibrosis as its own entity, thus animal and clinical studies to examine the impact of natural and synthetic substances to alter RAAS signaling as a means to treat fibrosis are reviewed as well.

Topics: Amides; Angiotensins; Animals; Benzimidazoles; Biphenyl Compounds; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Fumarates; Gene Expression Regulation; Humans; Kidney; Liver; Molecular Targeted Therapy; Myocardium; Pyridones; Renin-Angiotensin System; Signal Transduction; Skin; Tetrazoles; Transforming Growth Factor beta

The renin-angiotensin-aldosterone system (RAAS) is a hormonal system that has a critical role in maintaining the normotensive state and electrolyte balance of the organism. The RAAS also has an important influence in the development of various pathophysiological conditions especially those concerning the renal system, cardiovascular system and hypertension. One of the consequences of the RAAS system is an increase in the generation of the reactive oxygen species (ROS) that causes an increase in oxidative stress, which may play a role in the development or exacerbation of such pathological conditions. Blocking this system at multiple points has been advantageous in the clinical management of these disorders. The key blockers that had gained predominant clinical use for such manifestations were angiotensin receptor blockers and angiotensin-converting enzyme (ACE) inhibitors. However, their prolonged use caused a compensatory increase in renin and angiotensin I levels. The blocking of the system at the initial stages by blocking renin was of advantage to overcome such compensation. Such a renin blocker that gained widespread use was aliskiren. It is the first oral renin inhibitor that was approved for use in 2007. Although the opinions are varied about the use and future of renin inhibitors as antihypertensive agents, aliskiren has been well documented to have antioxidant effects. Aliskiren functions as an antioxidant by lowering the increase in ROS that are produced by the RAAS system at doses independent of decreasing the blood pressure. In the present review we discuss the antioxidant properties of aliskiren independent of its blood pressure lowering property.

Topics: Amides; Animals; Antihypertensive Agents; Antioxidants; Blood Pressure; Fumarates; Humans; Hypertension; Reactive Oxygen Species

Renin inhibitors (RIs) reduce blood pressure more than placebo, with the magnitude of this effect thought to be similar to that for angiotensin converting enzyme (ACE) inhibitors. However, a drug's efficacy in lowering blood pressure cannot be considered as a definitive indicator of its effectiveness in reducing mortality and morbidity. The effectiveness and safety of RIs compared to ACE inhibitors in treating hypertension is unknown.. To evaluate the benefits and harms of renin inhibitors compared to ACE inhibitors in people with primary hypertension.. The Cochrane Hypertension Group Information Specialist searched the following databases for randomized controlled trials up to August 2020: the Cochrane Hypertension Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also contacted authors of relevant papers about further published and unpublished work. The searches had no language restrictions.. We included randomized, active-controlled, double-blinded studies (RCTs) with at least four weeks follow-up in people with primary hypertension, which compared renin inhibitors with ACE inhibitors and reported morbidity, mortality, adverse events or blood pressure outcomes. We excluded people with proven secondary hypertension.. Two review authors independently selected the included trials, evaluated the risks of bias and entered the data for analysis.. We include 11 RCTs involving 13,627 participants, with a mean baseline age from 51.5 to 74.2 years. Follow-up duration ranged from four weeks to 36.6 months. There was no difference between RIs and ACE inhibitors for the outcomes: all-cause mortality: risk ratio (RR) 1.05, 95% confidence interval (CI) 0.93 to 1.18; 5 RCTs, 5962 participants; low-certainty evidence; total myocardial infarction: RR 0.86, 95% CI 0.22 to 3.39; 2 RCTs, 957 participants; very low-certainty evidence; adverse events: RR 0.98, 95% CI 0.93 to 1.03; 10 RTCs, 6007 participants;  moderate-certainty evidence; serious adverse events: RR 1.21, 95% CI 0.89 to 1.64; 10 RTCs, 6007 participants; low-certainty evidence; and withdrawal due to adverse effects: RR 0.85, 95% CI 0.68 to 1.06; 10 RTCs, 6008 participants; low-certainty evidence. No data were available for total cardiovascular events, heart failure, stroke, end-stage renal disease or change in heart rate. Low-certainty evidence suggested that RIs reduced systolic blood pressure: mean difference (MD) -1.72, 95% CI -2.47 to -0.97; 9 RCTs, 5001 participants;  and diastolic blood pressure: MD -1.18, 95% CI -1.65 to -0.72; 9 RCTs, 5001 participants,  to a greater extent than ACE inhibitors, but we judged this to be more likely due to bias than a true effect.  AUTHORS' CONCLUSIONS: For the treatment of hypertension, we have low certainty that renin inhibitors (RI) and angiotensin converting enzyme (ACE) inhibitors do not differ for all-cause mortality and myocardial infarction. We have low to moderate certainty that they do not differ for adverse events. Small reductions in blood pressure with renin inhibitors compared to ACE inhibitors are of low certainty.  More independent, large, long-term trials are needed to compare RIs with ACE inhibitors, particularly assessing morbidity and mortality outcomes, but also on blood pressure-lowering effect.

Topics: Aged; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Cause of Death; Female; Fumarates; Heart Rate; Humans; Irbesartan; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Myocardial Infarction; Patient Dropouts; Ramipril; Randomized Controlled Trials as Topic; Renin

Aliskiren might be beneficial for heart failure. However, the results of various studies are controversial. We conducted a systematic review and meta-analysis to explore the efficacy of aliskiren supplementation for heart failure.. PubMed, Embase, Web of Science, EBSCO, and the Cochrane Library databases were systematically searched. Randomized controlled trials (RCTs) assessing the efficacy of aliskiren for heart failure were included. Two investigators independently searched for articles, extracted data, and assessed the quality of included studies. The meta-analysis was performed using the random-effect model.. Five RCTs comprising 1973 patients were included in the meta-analysis. Compared with control interventions in heart failure, aliskiren supplementation was found to significantly reduce NT-proBNP levels (standardized mean difference [SMD] = -0.12; 95% CI = -0.21 to -0.03 pg/ml; p = 0.008) and plasma renin activity (SMD = -0.66; 95% CI = -0.89 to -0.44 ng/ml.h; p < 0.00001) while increasing plasma renin concentration (SMD = 0.52; 95% CI = 0.30-0.75 ng/l; p < 0.00001); however, it demonstrated no significant influence on BNP levels (SMD = -0.08; 95% CI = -0.31-0.15 pg/ml; p = 0.49), mortality (RR = 0.97; 95% CI = 0.79-1.20; p = 0.79), aldosterone levels (SMD = -0.09; 95% CI = -0.32-0.14 pmol/l; p = 0.44), adverse events (RR = 3.03; 95% CI = 0.18-49.51; p = 0.44), and serious adverse events (RR = 1.34; 95% CI = 0.54-3.33; p = 0.53).. Aliskiren supplementation was found to significantly decrease NT-proBNP levels and plasma renin activity and to improve plasma renin concentration in the setting of heart failure.

Topics: Amides; Antihypertensive Agents; Dietary Supplements; Female; Fumarates; Heart Failure; Humans; Male; Randomized Controlled Trials as Topic

The role of the direct renin inhibitor aliskiren in hypertension is not fully established and use of aliskiren in diabetic patients is especially controversial. A systematic review investigating both short-term diastolic and systolic blood pressure (DBP and SBP) reduction and long-term cardiovascular outcomes has not been conducted. Therefore, we aimed to fill this gap by investigating BP reduction, major cardiovascular outcomes, and mortality of aliskiren compared to other antihypertensive therapy. We searched PubMed and Embase databases for relevant randomized controlled trials (RCTs). Using a random-effects model, weighted mean difference (WMD) and relative risk (WRR) with 95% confidence interval (CI) were used to measure the effect of aliskiren therapy in the management of hypertension and major cardiovascular outcomes. Thirty seven RCTs with a total of 35,916 patients were included. Aliskiren induced slightly greater DBP and SBP reductions than other antihypertensive agents (WMD -0.77 mmHg, 95% CI [-2.01;0.46 mmHg] and WMD -1.14 mmHg, 95% CI [-2.78;0.50 mmHg], respectively). Aliskiren did not reduce total mortality or cardiovascular death. In patients with diabetes, aliskiren add-on therapy may have the potential to increase total mortality and cardiovascular death (WRR 1.06, 95% CI [0.88;1.28] and WRR 1.09, 95% CI [0.94;1.24], respectively). Despite superior BP-reducing effect, aliskiren is not recommended as first-line treatment in hypertensive patients as it does not reduce mortality and major cardiovascular outcomes. Dual renin-angiotensin-aldosterone system inhibition with aliskiren should be avoided in diabetic patients, while the use of aliskiren monotherapy remains to be investigated.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System; Risk Factors; Signal Transduction; Treatment Outcome

Even mild abnormalities of the renal structure or function can increase the risk of mortality and complications in other organs. Therefore, safe and effective treatments are necessary in order to influence the progression of renal disease. We used 2 methods to assess the renoprotective effects of aliskiren: 1) a statistical analysis of clinical trials that investigated aliskiren-induced renoprotection, in terms of changes in serum creatinine concentration (sCr) or estimated glomerular filtration rate (eGFR), and, 2) clinical trials that investigated the renoprotective effects of aliskiren with respect to changes in albuminuria or proteinuria. In the forest plot, the overall risk ratio (%) for renal impairment with respect to changes in sCr or eGFR was 0.97 (0.88-1.06; overall p=0.48). The tabulation of data from clinical trials included 10 entries for monotherapy with aliskiren and 6 entries for add-on aliskiren. All of the clinical trials, except one, showed a decrease in proteinuria or albuminuria following aliskiren treatment. In conclusion, inhibiting renin and prorenin with aliskiren is a more promising renoprotective treatment compared with blocking the renin/prorenin receptors (RPR). One of the main mechanisms by which aliskiren may confer renoprotection is by decreasing albuminuria and proteinuria. However, it does not seem to change sCr and eGFR in patients at risk of developing renal disease. Furthermore, co-administration of an angiotensinconverting- enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) and aliskiren was shown to decrease albuminuria and proteinuria to a greater extent compared with monotherapy with these agents.

Topics: Albuminuria; Amides; Animals; Clinical Trials as Topic; Fumarates; Glomerular Filtration Rate; Humans; Kidney; Kidney Diseases; Renal Agents; Renin; Renin-Angiotensin System; Treatment Outcome

Hypertension is a chronic condition associated with an increased risk of mortality and morbidity. Renin is the enzyme responsible for converting angiotensinogen to angiotensin I, which is then converted to angiotensin II. Renin inhibitors are a new class of drugs that decrease blood pressure (BP) by preventing the formation of both angiotensin I and angiotensin II.. To quantify the dose-related BP lowering efficacy of renin inhibitors compared to placebo in the treatment of primary hypertension.To determine the change in BP variability, pulse pressure, and heart rate and to evaluate adverse events (mortality, non-fatal serious adverse events, total adverse events, withdrawal due to adverse effects and specific adverse events such as dry cough, diarrhoea and angioedema).. The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials (RCTs) up to February 2017: the Cochrane Hypertension Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 2), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. There was no restriction by language or publication status. We also searched the European Medicines Agency (EMA) for clinical study reports, the Novartis Clinical Study Results Database, bibliographic citations from retrieved references, and contacted authors of relevant papers regarding further published and unpublished work.. We included randomized, double-blinded, placebo-controlled studies evaluating BP lowering efficacy of fixed-dose monotherapy with renin inhibitor compared with placebo for a minimum duration of three to 12 weeks in adult patients with primary hypertension.. This systematic review is a comprehensive update which includes four additional studies and extensive detail from nine clinical study reports (CSRs) of previously included studies obtained from EMA. The remaining three CSRs are not available.Two review authors independently assessed study eligibility and extracted data. In all cases where there was a difference between the CSR and the published report, data from the CSR was used. Dichotomous outcomes were reported as risk ratio (RR) with 95% confidence intervals (CIs) and continuous outcomes as mean difference (MD) with 95% CIs.. 12 studies (mean duration of eight weeks) in 7439 mostly Caucasian patients (mean age 54 years) with mild-to-moderate uncomplicated hypertension were eligible for inclusion in the review. Aliskiren was the only renin inhibitor evaluated. All included studies were assessed to have high likelihood of attrition, reporting and funding bias.Aliskiren has a dose-related systolic/diastolic blood pressure (SBP/DBP) lowering effect as compared with placebo MD with 95% CI: aliskiren 75 mg (MD -2.97, 95% CI -4.76 to -1.18)/(MD -2.05, 95% CI -3.13 to -0.96) mm Hg (moderate-quality evidence), aliskiren 150 mg (MD -5.95, 95% CI -6.85 to -5.06)/ (MD -3.16, 95% CI -3.74 to -2.58) mm Hg (moderate-quality evidence), aliskiren 300 mg (MD -7.88, 95% CI -8.94 to -6.82)/ (MD -4.49, 95% CI -5.17 to -3.82) mm Hg (moderate-quality evidence), aliskiren 600 mg (MD -11.35, 95% CI -14.43 to -8.27)/ (MD -5.86, 95% CI -7.73 to -3.99) mm Hg (low-quality evidence). There was a dose-dependent decrease in blood pressure for aliskiren 75 mg, 150 mg and 300 mg. The blood pressure lowering effect of aliskiren 600 mg was not different from 300 mg (MD -0.61, 95% CI -2.78 to 1.56)/(MD -0.68, 95% CI -2.03 to 0.67). Aliskiren had no effect on blood pressure variability. Due to very limited information available regarding change in heart rate and pulse pressure, it was not possible to meta-analyze these outcomes.Mortality and non-fatal serious adverse events were not increased. This review found that in studies of eight week duration aliskiren may not increase withdrawal due to adverse events (low-quality evidence). Diarrhoea was increased in a dose-dependent manner (RR 7.00, 95% CI 2.48 to 19.72) with aliskiren 600 mg (low-quality evidence). The most frequent adverse events reported were headache, nasopharyngitis, diarrhoea, dizziness and fatigue.. Compared to placebo, aliskiren lowered BP and this effect is dose-dependent. This magnitude of BP lowering effect is similar to that for angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). There is no difference in mortality, nonfatal serious adverse events or withdrawal due to adverse effects with short term aliskiren monotherapy. Diarrhoea was considerably increased with aliskiren 600 mg.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Diarrhea; Fumarates; Humans; Middle Aged; Randomized Controlled Trials as Topic; Renin

Aliskiren was shown to increase adverse events in patients with diabetes and concomitant renin-angiotensin blockade. We aim to investigate the efficacy and safety of aliskiren in patients with diabetes and increased cardiovascular risk or established cardiovascular disease.. MEDLINE and Embase were searched for prospective studies comparing addition of aliskiren to standard medical therapy in patients with diabetes and cardiovascular disease, or ⩾1 additional cardiovascular risk factor (hypertension, abnormal lipid profile, microalbuminuria/proteinuria, chronic kidney disease). Relative risk for efficacy (all-cause mortality, combined cardiovascular mortality and hospitalisation) and safety (hyperkalaemia, hypotension, renal impairment) outcomes was calculated.. Of 2151 studies identified in the search, seven studies enrolling 13,395 patients were included. Aliskiren had no effect on all-cause mortality (relative risk: 1.05, 95% confidence interval: 0.90 to 1.24, p = 0.53), or combined cardiovascular mortality or heart failure hospitalisation (relative risk: 1.07, 95% confidence interval: 0.81 to 1.40, p = 0.64). Patients receiving aliskiren had a greater risk of developing hyperkalaemia (relative risk: 1.32, 95% confidence interval: 1.14 to 1.53, p = 0.0003) and renal impairment (relative risk: 1.15, 95% confidence interval: 1.02 to 1.30, p = 0.03), but not hypotension.. Patients with diabetes and cardiovascular disease or cardiovascular risk do not benefit from the addition of aliskiren to standard medical therapy. Detrimental safety profile in pooled analysis supports current warnings.

Topics: Amides; Cardiovascular Agents; Cardiovascular Diseases; Chi-Square Distribution; Diabetes Mellitus; Fumarates; Humans; Odds Ratio; Renin-Angiotensin System; Risk Assessment; Risk Factors; Treatment Outcome

There have been few major breakthroughs in heart failure (HF) drug therapies in recent years yet HF morbidity and mortality remain high, and there is a clear need for further research. Several newer agents that appear promising in Phase I and II trials do not progress to show clinical benefit in later trials. Part of the failure to find new therapies may lie in flawed trial design compounded by the need for ever-increasing patient numbers in order to prove outcome benefit. We summarize some of the most recent and promising medical therapies for HF.

Topics: Amides; Cardiotonic Agents; Chronic Disease; Diuretics; Forecasting; Fumarates; Heart Failure; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Myocardial Contraction; Naphthyridines; Oligopeptides; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Vasodilator Agents

Non-diabetic glomerulonephritis is a frequent cause of end-stage renal disease. The use of renin-angiotensin-aldosterone system blockers is a fundamental therapeutic approach. However, converting enzyme inhibitors (ACE-is) and angiotensin receptor blockers do not always achieve the desired target of proteinuria. The induction of the prorenin and renin up-regulation is a possible explanation. Aliskiren is the first drug acting as direct inhibitor of plasmatic renin activity, also able to interfere with the prorenin and renin profibrotic escape. We aimed at reviewing the literature for the assessment of potential efficacy and safety of aliskiren in the treatment of non-diabetic glomerulonephritis. The data on this topic are limited; however, we concluded for a possible usefulness of aliskiren. The renal safety profile appears potentially acceptable in non-diabetic patients although extreme carefulness, particularly with respect to long-term renal and cardiovascular tolerability, is recommended.

Topics: Amides; Diabetes Mellitus; Fumarates; Glomerulonephritis; Humans; Kidney Failure, Chronic; Renin; Treatment Outcome

The Renin-Angiotensin-Aldosterone System (RAAS) is profoundly involved in the pathogenesis of renal and cardiovascular organ damage, and has been the preferred therapeutic target for renal protection for over 30 years. Monotherapy with either an Angiotensin Converting Enzime Inhibitor (ACE-I) or an Angiotensin Receptor Blocker (ARB), together with optimal blood pressure control, remains the mainstay treatment for retarding the progression toward end-stage renal disease. Combining ACE-Is and ARBs, or either one with an Aldosterone Receptor Antagonist (ARA), has been shown to provide greater albuminuria reduction, and to possibly improve renal outcome, but at an increased risk of potentially severe side effects. Moreover, combination therapy has failed to provide additional cardiovascular protection, and large prospective trials on hard renal endpoints are lacking. Therefore this treatment should, at present, be limited to selected patients with residual proteinuria and high renal risk. Future studies with novel agents, which directly act on the RAAS at multiple levels or have a more favourable side effect profile, are greatly needed to further explore and define the potential for and the limitations of profound pharmacologic RAAS inhibition.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Drug Therapy, Combination; Fumarates; Humans; Hypertension, Renal; Prospective Studies; Proteinuria; Renal Insufficiency, Chronic; Renin-Angiotensin System

The kallikrein kinin system has cardioprotective actions and mediates in part the cardioprotection produced by angiotensin converting enzyme inhibitors and angiotensin type 1 receptor blockers. Additional approaches to exploit the cardioprotective effects of the kallikrein kinin system include the administration of tissue kallikrein and kinin receptor agonists. The renin inhibitor aliskiren was recently shown to increase cardiac tissue kallikrein expression and bradykinin levels, and to reduce myocardial ischemia-reperfusion injury by bradykinin B2 receptor- and angiotensin AT2 receptor-mediated mechanisms. Thus, aliskiren represents a prototype drug for the modulation of tissue kallikrein expression for therapeutic benefit.

Topics: Amides; Animals; Drug Design; Fumarates; Gene Expression Regulation, Enzymologic; Humans; Molecular Targeted Therapy; Tissue Kallikreins

An estimated 5.1 million Americans have chronic heart failure and this is expected to increase 25% by 2030. Heart failure is a clinical syndrome that evolves from either functional or structural changes to the ventricles that lead to filling or ejection abnormalities. Thus far, pharmacotherapy has been show to be beneficial in patients only with reduced ejection fraction; however, new therapies have been developed in hopes of reducing the burden of heart failure. In this review, we will discuss current pharmacotherapies recommended in American College of Cardiology/American Heart Association guidelines, the evidence behind these recommendations as well as new and emerging therapies that have been developed.

Topics: Adrenergic beta-Antagonists; American Heart Association; Amides; Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Anticoagulants; Antihypertensive Agents; Atrial Natriuretic Factor; Benzazepines; Biphenyl Compounds; Calcium Channel Blockers; Cardiology; Cardiotonic Agents; Cardiovascular Agents; Digoxin; Diuretics; Drug Combinations; Erythropoietin; Evidence-Based Medicine; Fumarates; Heart Failure; Hematinics; Humans; Hydralazine; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Iron; Isosorbide Dinitrate; Ivabradine; Mineralocorticoid Receptor Antagonists; Peptide Fragments; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Societies, Medical; Stroke Volume; Tetrazoles; United States; Valsartan; Vasodilator Agents

Early phase studies of novel interventions for hypertension, such as renal sympathetic denervation, are sometimes single-armed (uncontrolled). We explored the wisdom of this by quantifying the blood pressure fall in the placebo arms of contemporary trials of hypertension. We searched Medline up to June 2014 and identified blinded, randomized trials of hypertension therapy in which the control arm received placebo medication or a sham (placebo) procedure. For nonresistant hypertension, we have identified all such trials of drugs licensed by the US Food and Drug Administration since 2000 (5 drugs). This US Food and Drug Administration-related restriction was not applied to resistant hypertension trials. This produced 7451 patients, who were allocated to a blinded control from 52 trials of nonresistant hypertension and 694 patients from 8 trials of resistant hypertension (3 drugs and 2 interventions). Systolic blood pressure fell by 5.92 mm Hg (95% confidence interval, 5.14-6.71; P<0.0001) in the nonresistant cohort and by 8.76 mm Hg (95% confidence interval, 4.83-12.70; P<0.0001) in the resistant cohort. Using metaregression, the falls were larger in trials that did not use ambulatory blood pressure monitoring as an inclusion criterion (z=2.84; P=0.0045), in those with higher baseline blood pressures (z=-0.3; P=0.0001), and in those where the patients were prescribed a continuous background of antihypertensives (z=-2.72; P=0.0065). The nontrivial magnitude of these apparent blood pressure reductions with perfectly ineffective intervention (placebo) illustrates that efficacy explorations of novel therapies for hypertension, once safety is established, should be performed with a randomized, appropriately controlled, and blinded design.

Topics: Amides; Antihypertensive Agents; Benzimidazoles; Benzopyrans; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Control Groups; Double-Blind Method; Drug Resistance; Eplerenone; Ethanolamines; Fumarates; Humans; Hypertension; Imidazoles; Kidney; Nebivolol; Oxadiazoles; Placebo Effect; Placebos; Randomized Controlled Trials as Topic; Regression Analysis; Research Design; Spironolactone; Sympathectomy; Tetrazoles; Treatment Outcome

Aliskiren is a widely used therapy for patients with hypertension, however, the effect of aliskiren on major cardiovascular outcomes is a matter of debate. The aim of this study is to evaluate the effects of aliskiren therapy on major cardiovascular outcomes by this meta-analysis of randomized controlled trials.. We searched PubMed, EmBase, and the Cochrane Central Register of Controlled Trials for relevant literature. All eligible studies were randomized controlled trials assessing the effect of aliskiren therapy compared with patients without aliskiren therapy. Relative risks (RRs) with 95% confidence intervals (CIs) were used to measure the effect of aliskiren therapy on major cardiovascular outcomes with a random-effect model.. We included six trials reporting data on 12,465 patients. These studies reported 1,886 occurrences of major cardiovascular events, 1,074 events of total mortality, 739 events of cardiac death, 366 events of myocardial infarction, and 319 events of stroke. Aliskiren therapy had no effect on major cardiovascular events (RR, 0.93; 95% CI: 0.77-1.13; P=0.47), total mortality (RR, 1.00; 95% CI: 0.77-1.29; P=1.00), cardiac death (RR, 1.01; 95% CI: 0.79-1.29; P=0.95), myocardial infarction (RR, 0.71; 95% CI: 0.36-1.38; P=0.31), or stroke (RR, 0.87; 95% CI: 0.48-1.58; P=0.64).. Aliskiren therapy does not have an effect on the incidence of major cardiovascular events, total mortality, cardiac death, myocardial infarction, or stroke.

Topics: Amides; Cardiovascular Diseases; Fumarates; Humans; Prehypertension; Randomized Controlled Trials as Topic; Treatment Outcome

Heart failure (HF) can rightfully be called the epidemic of the 21(st) century. Historically, the only available medical treatment options for HF have been diuretics and digoxin, but the capacity of these agents to alter outcomes has been brought into question by the scrutiny of modern clinical trials. In the past 4 decades, neurohormonal blockers have been introduced into clinical practice, leading to marked reductions in morbidity and mortality in chronic HF with reduced left ventricular ejection fraction (LVEF). Despite these major advances in pharmacotherapy, our understanding of the underlying disease mechanisms of HF from epidemiological, clinical, pathophysiological, molecular, and genetic standpoints remains incomplete. This knowledge gap is particularly evident with respect to acute decompensated HF and HF with normal (preserved) LVEF. For these clinical phenotypes, no drug has been shown to reduce long-term clinical event rates substantially. Ongoing developments in the pharmacotherapy of HF are likely to challenge our current best-practice algorithms. Novel agents for HF therapy include dual-acting neurohormonal modulators, contractility-enhancing agents, vasoactive and anti-inflammatory peptides, and myocardial protectants. These novel compounds have the potential to enhance our armamentarium of HF therapeutics.

Topics: Amides; Aminobutyrates; Atrial Natriuretic Factor; Biphenyl Compounds; Digoxin; Drug Combinations; Fumarates; Heart Failure; Humans; Natriuretic Peptides; Peptide Fragments; Snake Venoms; Tetrazoles; Valsartan

The two major classes of drugs that target the RAS are the angiotensin-converting enzyme (ACE) inhibitors and the selective AT1 receptor blockers (ARBs). Although both of these drug classes target angiotensin II, the differences in their mechanisms of action have implications for their effects on other pathways and receptors that may have therapeutic implications. Both ACEIs and ARBs are effective antihypertensive agents that have been shown to reduce the risk of cardiovascular and renal events. Direct inhibition of renin -the most proximal aspect of the RAS -became clinically feasible from 2007 with the introduction of aliskiren. This latter drug has been shown to be efficacious for the management of hypertension. Combined therapy of direct renin-inhibitors with ACEIs or ARBs has been tested in some clinical situations as congestive HF and proteinuria with diverse results. This article tries to offer an updated review of current knowledge on the use of RAS blocking drugs in clinical settings.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

Aliskiren, a direct renin inhibitor, is effective for reducing blood pressure (BP) in patients with hypertension when combined with amlodipine or hydrochlorothiazide (HCTZ). However, the efficacy and tolerability of the 2 combinations are unclear. We performed a meta-analysis of randomized controlled trials of aliskiren/amlodpine and aliskiren/HCTZ for hypertension.. The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and the Novartis clinical trial database were searched through December 2012 for reports of randomized controlled trials of aliskiren/amlodpine and aliskiren/HCTZ vs. monotherapy in patients with hypertension. The main outcome measures were reduction in systolic BP and diastolic BP from baseline and rates of therapeutic response and BP control. Tolerance of aliskiren/amlodipine and aliskiren/HCTZ was also analyzed. Outcomes were initially pooled by standard random-effects methods, producing a weighted mean difference (WMD) or risk ratio (RR) and 95% confidence intervals (CIs). The pooled estimates were then used for adjusted indirect comparisons.. We selected 19 reports of trials involving 13,614 participants. Aliskiren/amlodpine and aliskiren/HCTZ were more effective than monotherapy in controlling BP. Aliskiren/amlodipine was significantly more effective than aliskiren/HCTZ in reducing systolic BP (WMD = -3.36 mm Hg; 95% CI = -4.64 to 2.07 mm Hg) and diastolic BP (WMD = -3.49 mm Hg; 95% CI = -4.34 to 2.63 mm Hg). As compared with aliskiren/HCTZ, alikiren/amlodipine was associated with higher rate of therapeutic response (RR = 1.23; 95% CI = 1.14-1.33) and BP control (RR = 1.24; 95% CI = 1.11-1.39). Number of adverse events and withdrawals due to adverse events were similar with aliskiren/amlodipine and aliskiren/HCTZ.. BP control is better with aliskiren combined with amlodipine or HCTZ than with monotherapy, with aliskiren/amlodipine being more effective than aliskiren/HCTZ.

Topics: Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Renin

This article provides a review of the role of aliskiren, a direct renin inhibitor, in pediatric hypertension and kidney diseases. Among the many mechanisms involved in regulating blood pressure, the renin-angiotensin-aldosterone system (RAAS) plays a major role. Additionally, the RAAS has been identified as a contributing factor to cardiovascular and renal diseases for more than three decades. The potential benefits of inhibiting the RAAS by aliskiren alone or in combination with other RAAS blockers (ACEIs, ARBs) seem to be theoretically promising. However, caution should be exercised in treating children, especially in those with significant chronic kidney disease until there is more evidence regarding the safety and efficacy of this new drug in the pediatric population from ongoing clinical trials.

Topics: Adolescent; Amides; Child; Child, Preschool; Fumarates; Humans; Hypertension; Infant; Infant, Newborn; Kidney Diseases; Renin; Renin-Angiotensin System

The European Society of Cardiology held their annual congress in Amsterdam between the 31st of August and 4 September 2013 to discuss the latest developments in the field. The meeting included an update of the latest treatments currently under investigation for the treatment of heart failure. Updates were provided on the RELAX-AHF study that had, for the first time, demonstrated an improvement in post-discharge outcome in patients with acute heart failure treated with seralaxin. The meeting also gave the opportunity to highlight the latest goings on from the promising agent omecamtiv mecarbil as shown in the ATOMIC-AHF study. Indeed, its unique inotropic effect showed a potential to improve dyspnea without increasing myocardial oxygen consumption. Other presentations at the meeting included: a recent study evaluating ultrafiltration in the treatment of acute HF with renal impairment and the effects of the vasodilator cinaciguat. The unremarkable results from the recent ASTRONAUT study with aliskiren were also touched upon. It is important to note that while the data from seralaxin and omecamtiv mecarbil has been promising, the long term benefits of these therapies in heart failure still need to be evaluated. The authors also highlight the need for these promising agents to be further evaluated in women and other ethnic groups.

Topics: Amides; Benzoates; Cardiac Resynchronization Therapy; Cardiotonic Agents; Fumarates; Heart Failure; Humans; Recombinant Proteins; Relaxin; Ultrafiltration; Urea

Renin-angiotensin-system (RAS) is an enzymatic cascade that plays a pivotal role in the development of arterial hypertension, kidney disease and cardiovascular disease. Inhibition of the RAS with angiotensin converting enzyme (ACE) inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) has proved to be a successful strategy for the treatment of hypertension and related cardiovascular disorders. However, by reducing feedback inhibition of renin release, the effects of ACE-Is and ARBs lead to an increase in plasma renin concentration (PRC) and activity (PRA), limiting a complete inhibition of the RAS. Consequently the effects of a different pharmacological strategy that completely blocks the RAS upstream has been assessed in the last years. In this context, aliskiren is the first representative of a new class of non-peptide orally active renin inhibitor that blocks the RAS at its rate-limiting step and induces a net reduction in PRA, angiotensin II and aldosterone levels. Aliskiren effectively reduces blood pressure as a monotherapy as well in combination therapy. In addition, aliskiren has a placebo-like tolerability profile at the licensed doses of 150 mg and 300 mg. Aliskiren also exhibits additive effects on blood pressure reduction when combined with drugs that lead to a reactive increase in the PRA, such as diuretics, ACE-Is or ARBs. In previous studies, aliskiren showed beneficial effects in patients with arterial hypertension and associated clinical conditions. However, later trials indicated that the use of aliskiren should be avoided in patients with renal failure or receiving ACE-Is or ARBs. The main aim of this review is to summarize the available data on its efficacy and safety profile, highlighting clinical implications from recent trials.

Topics: Amides; Animals; Antihypertensive Agents; Atherosclerosis; Blood Pressure; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Hypertrophy, Left Ventricular; Renin

Soon after the emergence of the renin-angiotensin-aldosterone system (RAAS) blocking treatment as the cornerstone of renoprotective treatment in the prevention and treatment of diabetic and nondiabetic CKD, it was investigated if a higher degree of achievable RAAS blockade by combining more than one compound is feasible and advantageous. Regardless of the benefits from using monotherapy for diabetic kidney disease, there is still much improvement to wish for in terms of kidney prognosis in these populations. A great deal of research has gone into evaluating combinations of the RAAS blocking treatments in different populations and with different drugs and doses. Studies have mostly been short-term and use surrogate endpoints such as albuminuria. Side effects have been well known and expected in terms of increasing potassium levels and hypotension, but to an acceptable extent. With recent disappointing results from major hard endpoint trials using dual RAAS blockade the concept is now under scrutiny. In this review we will discuss the pros and cons of dual RAAS blockade, with facts and findings from smaller studies, endpoint trials, and meta-analyses.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diabetic Nephropathies; Drug Therapy, Combination; Fumarates; Humans; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Risk Assessment; Treatment Outcome

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD). Renin-angiotensin-aldosterone system (RAAS) plays a critical role in the development of DKD with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) being the mainstay of treatment. Systemic RAAS activity has been implicated in the pathogenesis of DKD, but lately interest has shifted to intrarenal RAAS effect. With the discovery of the (pro)renin receptor and ACE independent pathways of angiotensin II production, our understanding of role of renin in end organ damage has improved significantly.. We summarize our current understanding of ACE dependent and independent pathways in the development of DKD and the preclinical models demonstrating renal effects of direct renin inhibitors (DRIs). We then review clinical studies and trials performed so far evaluating the efficacy of aliskiren on renal outcomes and safety in DKD.. At present, there is little evidence for renal benefit of aliskiren in DKD beyond that offered by ACEIs or ARBs. Combining aliskiren with ACEI or ARB in DKD did not significantly improve renal outcomes in comparison with ACEI or ARB monotherapy in clinical trials. Slightly more adverse events including hyperkalemia, acute kidney injury and hypotension were observed in the combination therapy as compared to the monotherapy. Thus, current evidence suggests that aliskiren, because of its antihypertensive and antiproteinuric effects, maybe used as monotherapy in DKD and considered an equivalent alternative to ACEIs or ARBs. Careful monitoring for renal adverse effects would allow safe clinical use of DRI.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Diabetic Nephropathies; Fumarates; Humans; Renin; Renin-Angiotensin System

A case of probable drug-induced liver injury (DILI) attributed to use of the antihypertensive agent aliskiren is reported.. A 61-year-old woman undergoing routine liver function monitoring in conjunction with long-term antiepileptic therapy was noted to have an asymptomatic acute hepatic cytolysis 1 month after the initiation of concomitant aliskiren therapy (150 mg/day). Liver enzyme testing showed dramatically elevated aspartate transaminase (AST) and alanine transaminase (ALT) concentrations, with substantial rises also noted in γ-glutamyltransferase (GGT) and alkaline phosphatase (ALP) levels. The calculated ALT:ALP value indicated hepatocellular injury. On discontinuation of aliskiren use, rapid biological improvement occurred, including normalization of serum AST and a sharp decline in serum ALT within one week and the return of GGT and ALP levels to baseline a few weeks later; the patient's AST and ALT concentrations remained normal during 18 months of subsequent monitoring. Using the algorithm of Naranjo et al. and a DILI-specific causality assessment instrument, it was determined that aliskiren use was the probable cause of the patient's liver injury. While this is believed to be the first report of aliskiren-associated DILI in the professional literature, a review of information from several European and North American pharmacovigilance databases (through October 2012) identified 117 reports of suspected aliskiren hepatotoxicity, including 6 reports of liver failure and 12 reports of deaths.. Asymptomatic acute hepatic cytolysis was observed in a 61-year-old woman approximately one month after initiation of aliskerin for treatment of hypertension. Improvement in AST and ALT concentrations was observed shortly after the drug was discontinued.

Topics: Acute Disease; Alanine Transaminase; Amides; Antihypertensive Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Databases, Factual; Female; Fumarates; Humans; Liver Function Tests; Middle Aged; Pharmacovigilance

Unlike the prolonged benefit produced by the treatment of chronic heart failure, newer drugs tested for the treatment of acute heart failure in the last decade have failed to provide evidence of clinical benefit beyond some improvement in symptom relief. In particular, no drug has shown the ability to reduce the higher medium- and long-term risk of morbidity and mortality in these patients after an episode of decompensation. Current understanding of the pathophysiology of acute heart failure and its consequences has led to the hypothesis that, beyond symptom control, effective therapies for this syndrome should target not only the hemodynamic changes of the initial phase of the syndrome but should also "protect" the organism from the activation of neurohumoral and inflammatory pathways triggered by the decompensation episode, which persist in time and confer a risk of deleterious effects in several organs and tissues. Serelaxin, a new drug related to the peptidic endogenous hormones of the relaxin family, has recently been shown to provide multiple beneficial effects in terms of "organ protection" - not only in the cardiovascular and renal systems - from these acute heart failure-related deleterious changes. This drug has already been tested in acute heart failure patients with encouraging results in terms of medium-term clinical benefit, rendering serelaxin as a serious candidate for first-line, prognosis-modifying therapy in this syndrome.

Topics: Acute Disease; Amides; Benzazepines; Cardio-Renal Syndrome; Dobutamine; Fumarates; Heart Failure; Humans; Hydrazones; Inflammation; Kaplan-Meier Estimate; Multicenter Studies as Topic; Natriuretic Peptide, Brain; Prognosis; Pyridazines; Randomized Controlled Trials as Topic; Recombinant Proteins; Relaxin; Simendan; Therapies, Investigational; Tolvaptan

The renin-angiotensin system (RAS) affects vascular tone, cardiac output and kidney function. By these means the RAS plays a key role in the pathogenesis of arterial hypertension. As a result, RAS inhibition is highly effective not only in lowering blood pressure but also in reducing kidney disease progression (particularly when associated with proteinuria) and cardiovascular events. Among RAS blocking agents, direct renin inhibitors have shown not only excellent efficacy in hypertension control but also pharmacologic tolerance that is comparable with other renin-angiotensin suppressors. Indeed, aliskiren, the only direct renin inhibitor available is effective in controlling blood pressure as monotherapy or in combination with other antihypertensive drugs, irrespective of patient's age, ethnicity or sex. It is also effective in patients with metabolic syndrome, obesity and diabetes. Long-term studies comparing 'hard endpoints' of aliskiren therapy versus treatment with other RAS inhibitors, including cardiac and kidney protection, are currently ongoing. Combined with other antihypertensive agents, aliskiren not only improves their hypotensive response but may also lessen the adverse effects of other drugs. In high-risk patients, however, precautions should be taken when combining two or more renin-angiotensin inhibiting agents, as tissue perfusion may be highly renin-dependent in these patients and serious adverse side effects could take place.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Kidney Diseases; Renin; Renin-Angiotensin System

In the last few years, a number of important clinical trials have been completed that have investigated the inhibition of the renin-angiotensin system. New drugs, focusing on this system, have now emerged as a result.. The authors review the most relevant information available, reported from the last 5 years, pertaining to the most important clinical trials on renin-angiotensin system blockers (ARBs). The authors' data review includes the trials of aliskiren, telmisartan, olmesartan and azilsartan. The authors also review the possible risk of cancer with ARBs.. The results of ASPIRE and ALTITUDE trials strongly suggested that dual inhibition of aliskiren with either ARBS or angiotensin converting enzyme inhibitors (ACEi) should be avoided. Olmesartan is an effective and safe antihypertensive agent, but special attention should be paid to high-risk patients, such as those with coronary disease, to avoid an excessive reduction in blood pressure. The authors also note that while azilsartan is probably the most potent ARB, there is still a lack of data regarding potential organ damage and the incidence of cardiovascular events. Lastly, recent evidence has shown a lack of a relationship between ARB therapy and the occurrence of cancer.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Blood Pressure; Clinical Trials as Topic; Drug Evaluation; Fumarates; Humans; Imidazoles; Meta-Analysis as Topic; Neoplasms; Oxadiazoles; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Risk Factors; Telmisartan; Tetrazoles

The renin-angiotensin-aldosterone system (RAAS) has long been established as a key pathway in the regulation of blood pressure and body fluid volume. The aspartic protease renin is responsible for the initial and rate-limiting step of the RAAS; hence inhibition of renin would favor an upstream blockade or modulation of the RAAS. Direct renin inhibitors (DRIs) are therefore considered attractive agents for the treatment of hypertension. However, the identification of orally bioavailable, efficacious and safe low molecular weight DRIs has proven very challenging. To date, aliskiren is the only DRI that has reached FDA approval as a hypertension therapy option.. The present review summarizes the recent scientific accounts describing the design of new non-peptidic DRIs published between 2009 and 2012. The author also presents a number of chemical structures in addition to preclinical ADMET obtained from public scientific literatures and patent filings. Furthermore, the author discusses the results of early clinical trials of new candidate DRIs.. The vast medicinal chemistry efforts on structure-based design of non-peptidic DRIs, over the past 10 years, have presented new chemical spaces for tight binding to renin as well as gaining a proper balance between the physicochemical properties, potency, efficacy and safety. However, the criteria for candidate selection has become increasingly demanding; and new antihypertensives are expected to demonstrate a clear difference in their clinical profile beyond lowering blood pressure compared with established drug treatment paradigms.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Drug Design; Drug Discovery; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

Activation of the renin-angiotensin-aldosterone system (RAAS) plays a key role in the progression of chronic kidney disease (CKD). RAAS inhibitors, such as angiotensin converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs), decrease the rate of progression of diabetic and non-diabetic nephropathies and are first-line therapies for CKD. Although these agents are highly effective, current therapeutic strategies are unable to sufficiently suppress the RAAS and stop CKD progression. Aliskiren, the first in a new class of RAAS-inhibiting agents (direct renin inhibitors) has been approved to treat hypertension. Aliskiren exerts renoprotective, cardioprotective, and anti-atherosclerotic effects in animal models that appear to be independent of its blood pressure lowering activity. Early clinical studies using urinary protein excretion as a marker of renal involvement suggest a possibly novel role for aliskiren in treating CKD. This review discusses the antiproteinuric efficacy and safety of aliskiren and considers the evidence for its potential renoprotection.

Topics: Amides; Animals; Fumarates; Humans; Kidney; Proteinuria; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System

Numerous clinical studies have been conducted to analyse the ability of renin-angiotensin system blockade to lower blood pressure and to reduce end-organ damage. In addition to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, direct renin inhibitors emerged as an attractive option to inhibit the renin-angiotensin system and thus to prevent cardiovascular damage. Based on the publication of the most recent available results of ALTITUDE and ASTRONAUT, we review the data with respect to the direct renin inhibitor aliskiren given as an antihypertensive drug, in monotherapy and combination therapy, and the most recent publication analysing the effects of aliskiren on end-organ protection.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Clinical Trials as Topic; Endpoint Determination; Fumarates; Humans; Renin; Treatment Outcome

Topics: Amides; Animals; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

It is increasingly necessary to analyze data from multiple sources when conducting public health safety surveillance or comparative effectiveness research. However, security, privacy, proprietary, and legal concerns often reduce data holders' willingness to share highly granular information. We describe and compare two approaches that do not require sharing of patient-level information to adjust for confounding in multi-site studies.. We estimated the risks of angioedema associated with angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and aliskiren in comparison with beta-blockers within Mini-Sentinel, which has created a distributed data system of 18 health plans. To obtain the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs), we performed (i) a propensity score-stratified case-centered logistic regression analysis, a method identical to a stratified Cox regression analysis but needing only aggregated risk set data, and (ii) an inverse variance-weighted meta-analysis, which requires only the site-specific HR and variance. We also performed simulations to further compare the two methods.. Compared with beta-blockers, the adjusted HR was 3.04 (95% CI: 2.81, 3.27) for ACEIs, 1.16 (1.00, 1.34) for ARBs, and 2.85 (1.34, 6.04) for aliskiren in the case-centered analysis. The corresponding HRs were 2.98 (2.76, 3.21), 1.15 (1.00, 1.33), and 2.86 (1.35, 6.04) in the meta-analysis. Simulations suggested that the two methods may produce different results under certain analytic scenarios.. The case-centered analysis and the meta-analysis produced similar results without the need to share patient-level data across sites in our empirical study, but may provide different results in other study settings.

Topics: Adrenergic beta-Antagonists; Amides; Angioedema; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Comparative Effectiveness Research; Computer Simulation; Confounding Factors, Epidemiologic; Databases, Factual; Fumarates; Humans; Logistic Models; Multivariate Analysis; Pharmacoepidemiology; Propensity Score

Aliskiren is a novel renin-angiotensin aldosterone system (RAAS) inhibitor, the combination therapy of aliskiren and amlodipine for blood pressure control have been reported recently. The primary objective of this analysis is to review recently reported randomized controlled trials (RCTs) to compare antihypertensive effects and adverse events between mono (amlodipine or aliskiren alone) and combination therapy of both medicines.. Databases for the search included Pubmed, Embase and the Cochrane Central Register of Controlled Trials. Revman v5.0 statistical program was used to analyze the data. Weighted mean differences (WMD) with a 95% confidence interval (CI) were used for the calculation of continuous data, and relative risk (RR) with a 95% CI was used for dichotomous data.. We analyzed the data from 7 RCTs for a total of 6074 participants in this meta-analysis. We found that the aliskiren/amlodipine combination therapy had a stronger effect in lowering blood pressure as compared with the monotherapy using aliskiren (SBP: WMD = -10.42, 95% CI -13.03∼-7.82, P<0.00001; DBP: WMD = -6.60, 95% CI -7.22∼-5.97, P<0.00001) or amlodipine (SBP: WMD = -4.85, 95% CI -6.88∼-2.81, P<0.00001; DBP: WMD = -2.91, 95% CI -3.85∼-1.97, P<0.00001). No differences were found in terms of adverse events between combination therapy and monotherapy, except for the rates of peripheral edema and hypokalaemia which were significantly lower in the combination therapy than in the amlodipine monotherapy (RR = 0.78, 0.66∼0.92, P = 0.004; RR = 0.51, 0.27∼0.97, P = 0.04). Similar antihypertensive effects were found in both obese (body mass index > = 30 kg/m(2)) hypertensive and non-obese (body mass index <30 kg/m(2)) hypertensive patients. Moreover, there was no difference with the blood pressure lowering or adverse effects with regards to the combination therapy in both subgroups.. We found that aliskiren/amlodipine combination therapy provided a more effective blood pressure reduction than monotherapy with either drug without increase in the occurrence of adverse events.

Topics: Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hypertension; Obesity; Publication Bias; Randomized Controlled Trials as Topic

Renin-angiotensin system (RAS) blockade with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) has become a major therapeutic approach in medicine since the end of the 1970's. Although these molecules were the first RAS blockers to be developed, it would have been physiologically and pharmacologically more pertinent to selectively inhibit renin itself. Indeed, the reaction between renin and its unique substrate, angiotensinogen, is the highly regulated and rate-limiting step of the RAS. The development of direct renin inhibitors (DRI) has been a slow and complex process and the synthesis of the first orally active DRI, aliskiren, was only achieved in the 2000's. Its pharmacological profile in patients with hypertension, diabetic nephropathy or heart failure, in addition to experimental evidence, suggests that aliskiren may be of value for the management of cardiovascular and renal diseases. However, the long-term, randomized, placebo-controlled, morbidity/mortality trial, ALTITUDE, which included 8,600 patients with type 2 diabetes, proteinuria and a high cardiovascular risk already treated with ACE inhibitors or ARBs was terminated in December 2011 because of futility and an increased incidence of serious adverse events in the aliskiren 300 mg arm. Other long-term studies are still ongoing to demonstrate the safety and efficacy of aliskiren to reduce cardiovascular morbidity and mortality in patients with heart failure and in elderly individuals (≥65 years) with systolic blood pressure of 130 to 159 mmHg, no overt cardiovascular disease, and a high cardiovascular risk profile. In the meantime, according to the European Medicines Agency recommendations, aliskiren should not be prescribed to diabetic patients in combination with ACE inhibitors or ARBs.

Topics: Amides; Animals; Cardiovascular Diseases; Fumarates; Humans; Kidney Diseases; Protective Agents; Renin

The renin-angiotensin-aldosterone system (RAAS) plays pivotal roles in the pathogenesis of progression of arterial hypertension, chronic kidney disease (CKD) and cardiovascular disease (CVD). Previous studies suggested that a direct renin inhibitor, aliskiren, may be effective for blood pressure lowering, renoprotection and cardiovascular protection. This review focuses on the effects of aliskiren for arterial hypertension, CKD and CVD.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Fumarates; Humans; Hypertension; Renal Insufficiency, Chronic; Renin

To investigate the antihypertensive effects and tolerability of aliskiren in comparison with other antihypertensive drugs and placebo in patients with hypertension, a meta-analysis was performed of studies published between 1950 and 2012. A systematic literature search of MEDLINE and the Cochrane Library was conducted for randomized controlled trials. Weighted mean differences and relative risk with 95% confidence intervals were calculated for continuous and dichotomous data, respectively. In all, 14 studies with 6741 participants were included in the present meta-analysis. Nine studies included trial arms with placebo, four included angiotensin (Ang) AT1 receptor blockers (ARBs), three included Ang-converting enzyme inhibitors (ACEIs), two included calcium channel blockers (CCBs), one included a β-blocker, and one included hydrochlorothiazide (HCTZ). We found that aliskiren, which lowered blood pressure (BP) effectively in patients with mild-to-moderate hypertension, was similar to HCTZ but inferior to CCBs in BP reduction, response rates and control rates. Furthermore, aliskiren was superior to ACEIs in lowering diastolic BP (DBP), while it had similar effects to ACEIs on systolic BP (SBP) reduction, response rates and control rates. Additionally, the present meta-analysis showed the superiority of atenolol over aliskiren in DBP reduction and BP response but showed that atenolol was inferior in SBP reduction and BP control. No difference was found in the rates of therapeutic response between aliskiren and ARBs, while more patients achieved BP control with aliskiren. Further studies will be needed to determine the antihypertensive effects and tolerability of aliskiren in comparison with other antihypertensive drugs.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Fumarates; Humans; Hypertension; Treatment Outcome

For approximately 6 years, the only commercially available direct renin inhibitor, aliskiren, which inhibits the renin-angiotensin-aldosterone system at the initial rate limiting step, has been marketed for the treatment of hypertension. Concurrently, much attention has been given to the possibility that renin inhibition could hold potential for improved treatment in patients with chronic kidney disease, with diabetic nephropathy as an obvious group of patients to investigate, as the activity of the renin-angiotensin-aldosterone system is enhanced in these patients and as there is an unmet need for improved treatment and prognosis in these patients. Several short term studies have been performed in diabetic nephropathy, showing a consistent effect on the surrogate endpoint lowering of albuminuria, both as monotherapy and in combination with other blockers of the renin-angiotensin-aldosterone system. In addition, combination treatment also seemed safe and effective in patients with impaired kidney function. These initial findings formed the basis for the design of a large morbidity and mortality trial investigating aliskiren as add-on to standard treatment. The study has just concluded, but was terminated early as a beneficial effect was unlikely and there was an increased frequency of side effects. Also in non-diabetic kidney disease a few intervention studies have been carried out, but there is no ongoing hard outcome study. In this review we provide the current evidence for renin inhibition in chronic kidney disease by reporting the studies published so far as well as a perspective on the future possibilities.

Topics: Amides; Angiotensin Receptor Antagonists; Animals; Clinical Trials as Topic; Diabetic Nephropathies; Drug Therapy, Combination; Fumarates; Humans; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Treatment Outcome

Inhibition of the RAAS (renin-angiotensin-aldosterone system) plays a pivotal role in the prevention and treatment of diabetic nephropathy and a spectrum of other proteinuric kidney diseases. Despite documented beneficial effects of RAAS inhibitors in diabetic patients with nephropathy, reversal of the progressive course of this disorder or at least long-term stabilization of renal function are often difficult to achieve, and many patients still progress to end-stage renal disease. Incomplete inhibition of the RAAS has been postulated as one of reasons for unsatisfactory therapeutic responses to RAAS inhibition in some patients. Inhibition of renin, a rate-limiting step in the RAAS activation cascade, could overcome at least some of the abovementioned problems associated with the treatment with traditional RAAS inhibitors. The present review focuses on experimental and clinical studies evaluating the two principal approaches to renin inhibition, namely direct renin inhibition with aliskiren and inhibition of the (pro)renin receptor. Moreover, the possibilities of renin inhibition and nephroprotection by interventions primarily aiming at non-RAAS targets, such as vitamin D, urocortins or inhibition of the succinate receptor GPR91 and cyclo-oxygenase-2, are also discussed.

Topics: Amides; Animals; Cyclooxygenase 2 Inhibitors; Diabetic Nephropathies; Fumarates; Humans; Kidney Failure, Chronic; Prorenin Receptor; Receptors, Calcitriol; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Renin; Renin-Angiotensin System; Urocortins; Vitamin D

Main pharmacovigilance updates in 2012 are reviewed here. Dabigatran: elderly patients with renal failure are at higher risk of bleeding. Dual renin-angiotensin-aldosterone system blockade comprising aliskiren is harmful. Incretins: low risk of acute pancreatitis. Interaction between fusidic acid and statins: many reports of rhabdomyolysis. Interactions between boceprevir/telaprevir and antiretroviral therapies: complex, but manageable. Citalopram, ondansetron: maximum recommended doses are reduced. Atomoxetine: significant increase in blood pressure and heart rate in a fraction of exposed patients. Agomelatine: elevated liver enzymes are common. Fingolimod: bradycardia and heart blocks after first dose - stronger safety recommendations regarding use in patients with heart conditions and strengthened cardiovascular monitoring.

Topics: Adrenergic Uptake Inhibitors; Age Factors; Aged; Amides; Antihypertensive Agents; Atomoxetine Hydrochloride; Benzimidazoles; beta-Alanine; Cardiovascular Diseases; Dabigatran; Drug-Related Side Effects and Adverse Reactions; Fibrinolytic Agents; Fumarates; Hemorrhage; Humans; Pharmacovigilance; Propylamines

The renin-angiotensin-aldosterone-system (RAAS) plays a central role in the pathophysiology of heart failure and cardiorenal interaction. Drugs interfering in the RAAS form the pillars in treatment of heart failure and cardiorenal syndrome. Although RAAS inhibitors improve prognosis, heart failure-associated morbidity and mortality remain high, especially in the presence of kidney disease. The effect of RAAS blockade may be limited due to the loss of an inhibitory feedback of angiotensin II on renin production. The subsequent increase in prorenin and renin may activate several alternative pathways. These include the recently discovered (pro-) renin receptor, angiotensin II escape via chymase and cathepsin, and the formation of various angiotensin subforms upstream from the blockade, including angiotensin 1-7, angiotensin III, and angiotensin IV. Recently, the direct renin inhibitor aliskiren has been proven effective in reducing plasma renin activity (PRA) and appears to provide additional (tissue) RAAS blockade on top of angiotensin-converting enzyme and angiotensin receptor blockers, underscoring the important role of renin, even (or more so) under adequate RAAS blockade. Reducing PRA however occurs at the expense of an increase plasma renin concentration (PRC). PRC may exert direct effects independent of PRA through the recently discovered (pro-) renin receptor. Additional novel possibilities to interfere in the RAAS, for instance using vitamin D receptor activation, as well as the increased knowledge on alternative pathways, have revived the question on how ideal RAAS-guided therapy should be implemented. Renin and prorenin are pivotal since these are at the base of all of these pathways.

Topics: Amides; Antihypertensive Agents; Cardio-Renal Syndrome; Fumarates; Heart Failure; Humans; Renin; Renin-Angiotensin System

To examine the safety of using aliskiren combined with agents used to block the renin-angiotensin system.. Systematic review and meta-analysis of randomised controlled trials.. Medline, Embase, the Cochrane Library, and two trial registries, published up to 7 May 2011.. Published and unpublished randomised controlled trials that compared combined treatment using aliskiren and angiotensin converting enzyme inhibitors or angiotensin receptor blockers with monotherapy using these agents for at least four weeks and that provided numerical data on the adverse event outcomes of hyperkalaemia and acute kidney injury. A random effects model was used to calculate pooled risk ratios and 95% confidence intervals for these outcomes.. 10 randomised controlled studies (4814 participants) were included in the analysis. Combination therapy with aliskiren and angiotensin converting enzyme inhibitors or angiotensin receptor blockers significantly increased the risk of hyperkalaemia compared with monotherapy using angiotensin converting enzymes or angiotensin receptor blockers (relative risk 1.58, 95% confidence interval 1.24 to 2.02) or aliskiren alone (1.67, 1.01 to 2.79). The risk of acute kidney injury did not differ significantly between the combined therapy and monotherapy groups (1.14, 0.68 to 1.89).. Use of aliskerin in combination with angiotensin converting enzyme inhibitors or angiotensin receptor blockers is associated with an increased risk for hyperkalaemia. The combined use of these agents warrants careful monitoring of serum potassium levels.

Topics: Acute Kidney Injury; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Hyperkalemia; Randomized Controlled Trials as Topic

Diabetic patients are at risk of macro- and micro-vascular complications, including diabetic nephropathy, and have difficulties in achieving blood pressure (BP) goals. Aliskiren, a direct renin inhibitor, inhibits the first step of the renin angiotensin aldosterone system. We aimed to systematically address the relevant evidence on the effects of aliskiren in diabetic individuals.. We considered randomized controlled trials (RCTs) evaluating aliskiren in diabetic patients. Information was recorded independently by 2 investigators. We were limited to trials published in English.. PubMed search retrieved 16 items. After excluding 12, we ended with 4 eligible studies with 1488 participants. Mean baseline BP levels were 143/82 mmHg and median follow up was 2 months. Aliskiren was compared against angiotensin converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB) or aliskiren plus ACE inhibitor/ARB in 2 studies and against placebo in the other 2. The most frequent indication for aliskiren therapy was diabetes plus hypertension and albuminuria. Aliskiren seems to be effective in reducing BP levels, albuminuria in diabetics, either as monotherapy (compared with placebo), or in addition to ACE inhibitors/ARB (compared with monotherapy), without any major safety considerations.. There are promising results on the effect of aliskiren in diabetic patients, but the available evidence is limited so far. This is a poorly investigated field with few RCTs and new studies focusing on "hard" outcomes are needed.

Topics: Albuminuria; Amides; Antihypertensive Agents; Blood Pressure; Diabetes Complications; Diabetes Mellitus; Fumarates; Humans; Randomized Controlled Trials as Topic; Renin

Cardiovascular-related morbidity and mortality is linked to hypertension with proportional gains in cardiovascular risk factor reduction with the lowering of blood pressure. Clinical trial data has shown that attaining goal blood pressure requires, for most patients, at least two antihypertensive medications, with a significant proportion requiring regimens of three or more medications. Single-pill triple combinations have returned to the market following results of increased efficacy and adherence over dual- and mono-therapy. The combination of aliskiren, amlodipine and hydrochlorothiazide is a rational choice for combination therapy and recent studies suggest that it is safe and effective in lowering blood pressure in patients who fail dual combination therapy.

Topics: Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Treatment Outcome

Angio-oedema is a rare, but potentially life-threatening side effect to medication that interferes with the renin-angiotensin-aldosterone system. Clinically controlled trials were reviewed and the incidence assessed. We conclude, that treatment with an angiotensin receptor blocker can be tried after angiotensin-converting enzyme inhibitor (ACE-I) induced angio-oedema. The assessment should be individually based and take the severity of the previous attack and the weight of the indication into account. The risk on ACE-I might be greater in persons that have had angio-oedema for other reasons.

Topics: Amides; Angioedema; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Fumarates; Humans; Renin-Angiotensin System; Risk Factors

Topics: Albuminuria; Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Calcium Channel Agonists; Catheter Ablation; Cerebrovascular Circulation; Chronic Disease; Diabetic Nephropathies; Drug Therapy, Combination; Evidence-Based Medicine; Fumarates; Humans; Hypertension; Imidazoles; Kidney; Kidney Diseases; Randomized Controlled Trials as Topic; Tetrazoles; Valine; Valsartan

High blood pressure (BP) is a major risk factor for cardiovascular and renal complications. A majority of treated hypertensive patients still complain of high BP. The renin-angiotensin aldosterone system (RAAS) has been a centre-stage target for all the cardiovascular and cardio-renal complications. Aliskiren, is the first direct renin inhibitor (DRI) to be approved by the US FDA. Renin controls the rate-limiting step in the RAAS cascade and hence is the most favorable target for RAAS suppression.. This review article strives to summarize the pharmacokinetic, preclinical and clinical studies done so far pertaining to the efficacy of aliskiren. Further, the pharmacology of aliskiren has been comprehensively dealt with to enhance understanding so as to further research in this unfathomed area in the multitude of cardiovascular disorders and renal diseases.. Aliskiren has been shown to have comparable BP-lowering effects to other RAAS inhibitors. Recent clinical trials have indicated that it might contribute significantly in combination with other agents for the protection of end-organ diseases.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Fumarates; Humans; Hypertension; Kidney Diseases; Renin; Renin-Angiotensin System

Topics: Amides; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Heart Failure, Systolic; Humans; Renin-Angiotensin System

The overactivation of the renin-angiotensin-aldosterone system (RAAS) is associated with cardiovascular and renal abnormalities, which can be mitigated by angiotensin converting enzyme inhibitors (ACEIs) and angiotensin-II (Ang-II)-AT(1) receptor blockers (ARBs). Both prorenin and renin bind to the (pro)renin receptor (PRR) to activate Ang-II-dependent and -independent signaling cascades. Renin cleaves angiotensinogen to Ang-I, which is subsequently converted into Ang-II leading to cardiovascular and renal compensatory responses and eventually dysfunction. This initial step is blocked by renin inhibitor aliskiren, thus explaining its anti-hypertensive effect. Aliskiren is approved for the treatment of hypertension either as monotherapy or in combination with amlodipine, hydrochlorothiazide, or valsartan. Several clinical trials have suggested an organoprotective potential of aliskiren beyond its anti-hypertensive action, but the mechanism by which this might occur is less clear. Like ACEIs and ARBs, aliskiren increases plasma renin concentration; however, aliskiren reduces plasma renin activity. Intriguingly, aliskiren has additional abilities to downregulate the expression of the PRR and the AT(1) receptor, adding novel mechanistic insights to our current knowledge. Importantly, a few questions remain unresolved, such as the potential effects of aliskiren on (i) prorenin and its receptor-mediated Ang-II-independent pathways, and (ii) the signal network that comprises of PRR-associated vacuolar-H(+)-ATPase-linked Wnt/Frizzled signal transduction, including canonical-β-catenin and non-canonical Wnt-JNK-Ca(2+) signals. Discrepant outcomes in ALTITUDE study make more complex understanding aliskiren's therapeutic potential in treating cardio-renal disorders. This review attempts to address some of the remaining questions regarding aliskiren's action in cardiovascular and renal disorders.

Topics: Amides; Animals; Cardiovascular Diseases; Fumarates; Humans; Kidney Diseases; Signal Transduction

Aliskiren is the first known representative of a new class of non-peptide orally active renin inhibitors that blocks the renin-angiotensin-aldosterone-system (RAAS) at its rate-limiting step. It induces a net reduction in plasma renin activity (PRA), angiotensin II and aldosterone levels. Aliskiren is effective in reducing blood pressure (BP) and is well tolerated. The incidence of adverse events and the number of study discontinuations as a result of adverse events during aliskiren treatment were relatively low and generally not dissimilar from placebo. In placebo-controlled studies, aliskiren showed a dose-related systolic/diastolic BP lowering effect at doses between 75 and 300 mg/day. When compared to active treatments, aliskiren was generally as effective as hydrochlorothiazide, angiotensin-converting-enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and beta-blockers, in reducing BP. Aliskiren exhibits synergistic effects when combined with drugs that lead to a reactive increase in the PRA, such as diuretics, ACE inhibitors or ARBs. Although in clinical studies aliskiren proved to reduce proteinuria, the early termination of the Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (ALTITUDE) confirms previous concerns about the full suppression of the RAAS, in this case with aliskiren combined with ACE-inhibitors or ARBs, in patients with diabetes and concomitant renal impairment. This review summarizes the available data on its safety profile and its clinical development for treatment of arterial hypertension, diabetes and nephropathy.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Drug Synergism; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Kidney Diseases; Renin; Renin-Angiotensin System

Topics: Amides; Blood Pressure; Fumarates; Humans; Kidney; Renal Insufficiency, Chronic; Renin

Aliskiren is the first orally active direct renin inhibitor approved for the treatment of hypertension. Aliskiren's inhibitory effect on angiotensin I generation, through renin blockade, is highly specific and long-lasting (24 hours). This feature differentiates aliskiren from traditional antihypertensive drugs.. This paper reviews the results of various clinical trials which investigate the safety and efficacy of aliskiren on blood pressure (BP) reduction and clinical end points.. Aliskiren is suitable for once-daily administration. Its antihypertensive effect is comparable or superior to that of other antihypertensive agents at recommended doses. The tolerability profile of aliskiren is placebo-like at the licensed doses of 150 and 300 mg. In particular, the discontinuation of therapy due to clinical adverse events occurs similarly among patients treated with either aliskiren or placebo. Aliskiren is not recommended in association with ACE-inhibitors or angiotensin II receptor blockers in patients with type 2 diabetes and renal impairment. Pending disclosure of full results, the early termination of the ALTITUDE seems to confirm previous concerns about the safety of the dual pharmacological blockade of the renin-angiotensin system in these patients. Aliskiren is a well-tolerated antihypertensive drug that may help to achieve the recommended targets of BP control.

Topics: Amides; Antihypertensive Agents; Clinical Trials as Topic; Drug Costs; Drug Therapy, Combination; Fumarates; Humans; Hypertension

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Disease Progression; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fumarates; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Kidney Function Tests; Phosphates; Predictive Value of Tests; Prognosis; Randomized Controlled Trials as Topic; Risk Assessment

Hypertension is a leading cause of cardiovascular morbidity and mortality, and uncontrolled hypertension remains common despite the availability of several classes of effective antihypertensive medications. Combination therapy with antihypertensive agents of complementary actions has been advocated in the management of hypertension to maximize efficacy and minimize side effects.. This review summarizes the current data on the triple combination therapy of aliskiren with amlodipine and hydrochlorothiazide, and discusses the clinical use of single pill triple combination of aliskiren, amlodipine and hydrochlorothiazide in the treatment of hypertension and associated cardiovascular conditions.. Combination therapy with antihypertensive agents of complementary actions is more effective than monotherapy in the management of hypertension. Combining an agent in renin-angiotensin blockade with a dihydropyridine calcium channel blocker (CCB) and a thiazide diuretic has plausibility in maximizing blood pressure reduction and minimizing side effects. The combination of aliskiren with amlodipine and hydrochlorothiazide has shown effective blood pressure lowering and noteworthy tolerability. The single pill triple combination of aliskiren, amlodipine, and hydrochlorothiazide offers five different formulations of escalating dosages of the three agents, allowing dosing flexibility. The decreased pill burden and simplified treatment options with the single pill triple combination provide an opportunity to improve blood pressure control through improved adherence and reduced treatment inertia.

Topics: Amides; Amlodipine; Antihypertensive Agents; Drug Combinations; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Treatment Outcome

Aliskiren is a novel antihypertensive agent and the first direct renin inhibitor (DRI) in clinical use. Several clinical trials have compared DRI with angiotensin receptor blockers (ARBs) in the management of essential hypertension. However, systematic comparison of efficacy and safety between DRIs and ARBs is still lacking. We reviewed randomized controlled trials (RCTs) comparing aliskiren with ARBs for net reduction of blood pressure from baseline, achieved rate of control, and incidences of common and serious adverse events. Weighted mean differences (WMD) and relative risk (RR) with 95% confidence intervals (CI) were calculated for continuous and dichotomous data, respectively. Seven RCTs with 5488 patients were included in this meta-analysis. We compared the efficacy of aliskiren and ARBs in reducing systolic blood pressure (SBP) and diastolic blood pressure (DBP). No differences were found between the two groups. Aliskiren combined with ARBs was superior to aliskiren monotherapy at the maximum recommended dose on SBP and DBP reduction. (WMD -4.80, 95% CI -6.22-- -3.39, p < 0.0001; WMD -2.96, 95% CI -4.63-- -1.28, p = 0.0001; respectively). Similar results were found with aliskiren combined with ARBs versus ARB monotherapy (WMD -4.43, 95% CI -5.91-- -2.96, p < 0.0001; WMD -2.40; 95% CI -3.41-- -1.39, p < 0.0001; respectively). No differences were found in adverse events between the aliskiren and ARB groups. Similar results were found with aliskiren and ARB combination therapy and its respective monotherapy. We conclude that aliskiren's BP-lowering capabilities were comparable to those of ARBs. Aliskiren and ARB combination therapy provided more effective BP reduction than each respective monotherapy without increasing adverse events.

Topics: Amides; Angiotensin Receptor Antagonists; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fumarates; Humans; Hypertension

Aliskiren, a drug which inhibits the initial and rate-limiting step of the renin angiotensin aldosterone system (RAAS), recently approved for the treatment of hypertension, may become a reasonable therapeutic choice in a broad number of clinical conditions sharing an increased cardiovascular risk, where the inhibition of the RAAS has been shown to be beneficial.. The present review summarizes the pharmacokinetic and pharmacodynamic properties of aliskiren along with the clinical trials that took into account the effects of aliskiren on blood pressure control and on a number of renal and cardiovascular end points. The specific effects of aliskiren on different populations (e.g., elderly hypertensives, patients with diabetes and hypertension, patients with hypertension and renal impairment) are discussed.. The review discusses the most recent discoveries of the cardiovascular and renal effects of aliskiren, including a comprehensive discussion of the ongoing trials and of the areas of remaining uncertainty.. Aliskiren is a promising drug that may become a convenient choice in several clinical conditions. The full spectrum of the beneficial effects of aliskiren will be fully elucidated when the results of the large ongoing trials become available.

Topics: Amides; Antihypertensive Agents; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus; Drug Evaluation; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Fumarates; Humans; Hypertension; Kidney Diseases; Renin; Renin-Angiotensin System

Hypertension is one of the most important risk factor and cause of cardiovascular diseases (CVD). Chronic activation of the renin-angiotensin-aldosterone system (RAAS) plays a key role in the development of hypertension, cardiac and renal diseases. RAAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs), improve cardiovascular and renal outcomes. However, studies have shown that residual morbidity and mortality remains high, despite current optimal treatment. More comprehensive control of the RAAS might provide additional reductions in morbidity and mortality. Direct renin inhibitors such aliskiren offer the potential for enhanced RAAS control as they target the system at the point of activation, thereby reducing plasma renin activity; by contrast, ACEI and ARBs increase plasma renin activity. The efficacy of aliskiren in the reduction of major clinical events is being tested in large ongoing clinical trials. This review examines the efficacy, safety, and tolerability of aliskiren, and considers the evidence for the potential organ protection benefits of this treatment.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Drug Therapy, Combination; Fumarates; Heart; Humans; Hypertension; Kidney; Renin; Renin-Angiotensin System

Inhibition of the renin-angiotensin system has been a highly successful therapeutic approach for the prevention of hypertension-related end organ damage. Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers lower blood pressure and reduce morbidity and mortality in patients with cardiovascular and kidney disease. However, progression to end-stage disease remains common in these patient populations. A compensatory increase in plasma renin activity occurs with the use of either angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, thus causing increased levels of angiotensin II, which may limit the therapeutic effectiveness of these agents. The direct renin inhibitor, aliskiren, suppresses the renin-angiotensin system by inhibiting its first and rate-limiting step. This early inhibition reduces the production of all downstream components of the system. In this review, recent clinically relevant advances in the understanding of renin-angiotensin system biology are explored as a rationale for combining aliskiren with other blockers of the renin-angiotensin system. These combinations more fully inhibit the renin-angiotensin system, with the goal of providing additional therapeutic benefits in diseases associated with chronic activation of the renin-angiotensin system.

Topics: Amides; Animals; Clinical Trials as Topic; Drug Synergism; Drug Therapy, Combination; Fumarates; Humans; Renin; Renin-Angiotensin System

Aliskiren, a newly discovered renin inhibitor, blocks the renin-angiotensin system (RAS) from the top of the enzyme cascade and therefore, might provide comparable or even superior clinical efficacy of blood pressure (BP) control than angiotensin receptor blockers (ARBs). With this meta-analysis, we aimed to compare the efficacy and tolerability of aliskiren and ARBs in the treatment of hypertension in the short-term treatment period.. Reports of randomized controlled trials (RCTs) comparing aliskiren and ARBs in patients with hypertension were selected by a search of the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE. The main outcome measures were reduction in diastolic BP (DBP) and systolic BP (SBP) and rates of therapeutic response and BP control. We also compared the tolerability of aliskiren and ARBs. Revman v5.0 was used to obtain the pooled estimates.. We analyzed data from 10 reports of trials involving 3,732 participants. DBP and SBP reduction did not differ between aliskiren and ARBs (weighted mean difference (WMD), -0.18; 95% confidence interval (CI), -1.07 to 0.71, and WMD, 0.15; 95% CI, -1.38 to 1.69, respectively). Aliskiren and ARB treatment did not differ in rates of BP control or therapeutic response. Moreover, aliskiren and ARB treatment led to a similar number of adverse events, severe adverse events, and withdrawal due to adverse events.. Aliskiren is as effective as ARBs (losartan, valsartan, and irbesartan) in controlling BP and does not differ from ARBs in risk of adverse events.

Topics: Amides; Angiotensin Receptor Antagonists; Blood Pressure; Fumarates; Humans; Hypertension; Randomized Controlled Trials as Topic

Peripheral edema is a common adverse effect of calcium channel blockers. The addition of a renin-angiotensin system blocker, either an angiotensin-converting enzyme inhibitor or an ARB, has been shown to reduce peripheral edema in a dose-dependent way.. We performed a MEDLINE/COCHRANE search for all prospective randomized controlled trials in patients with hypertension, comparing calcium channel blocker monotherapy with calcium channel blocker/renin-angiotensin system blocker combination from 1980 to the present. Trials reporting the incidence of peripheral edema or withdrawal of patients because of edema and total sample size more than 100 were included in this analysis.. We analyzed 25 randomized controlled trials with 17,206 patients (mean age 56 years, 55% were men) and a mean duration of 9.2 weeks. The incidence of peripheral edema with calcium channel blocker/renin-angiotensin system blocker combination was 38% lower than that with calcium channel blocker monotherapy (P<.00001) (relative risk [RR] 0.62; 95% confidence interval [CI], 0.53-0.74). Similarly, the risk of withdrawal due to peripheral edema was 62% lower with calcium channel blocker/renin-angiotensin system blocker combination compared with calcium channel blocker monotherapy (P=.002) (RR 0.38; 95% CI, 0.22-0.66). ACE inhibitors were significantly more efficacious than ARBs in reducing the incidence of peripheral edema (P<.0001) (ratio of RR 0.74; 95% CI, 0.64-0.84) (indirect comparison).. In patients with hypertension, the calcium channel blocker/renin-angiotensin system blocker combination reduces the risk of calcium channel blocker-associated peripheral edema when compared with calcium channel blocker monotherapy. ACE inhibitor seems to be more efficacious than ARB in reducing calcium channel blocker-associated peripheral edema, but head-to-head comparison studies are needed to prove this.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Drug Therapy, Combination; Edema; Female; Fumarates; Humans; Hypertension; Incidence; Male; Middle Aged; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System; Research Design; Treatment Refusal

Optimal antihypertensive therapy requires a multimodal approach based on lifestyle modification and, for most individuals, combination drug therapy. Recommendations from experts suggest that a combination of an agent that blocks the renin-angiotensin system (RAS), together with a vasodilator (generally a calcium-channel blocker or a thiazide-type diuretic), is most likely to control blood pressure and provide the widest overall cardiovascular protection. Understanding the opportunities afforded by the combination of RAS blockade with a calcium-channel blocker requires a discussion of basic and clinical science data. One new concept is that of 'global' or total RAS blockade. The impact of the RAS can be diminished or blocked by several different classes of drugs (central sympatholytics, β-blockers, renin inhibitors, ACE inhibitors or ARBs); what is most important is how effectively the overall impact of angiotensin II is blunted. A second new concept is that the complementary actions of RAS blockers and calcium-channel blockers are best explained on the basis of diminished intracellular calcium availability in excitable tissue (sympathetic neurons and vascular smooth muscle cells) via parallel actions that reduce angiotensin II type-1 receptor stimulation and L-channel-mediated calcium flux. Aliskiren is the first of the direct renin inhibitors, the newest subclass of RAS blockers. In both short- and long-term studies, aliskiren has been shown to be similar in efficacy and tolerability compared with other RAS blockers, with the added benefit that its effects persist longer. Outcome studies with aliskiren are currently underway.

Topics: Amides; Amlodipine; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Treatment Outcome

The renin–angiotensin–aldosterone system (RAAS) plays a pivotal role in regulating blood pressure, volume, and electrolytes. The final product of RAAS cascade is angiotensin II, which exerts diverse biological activities via binding to one of three known receptor types, with different binding consequences. Despite the success with conventional strategies to limit angiotensin II production and action, these agents promote a reflex rise in plasma renin activity, which is thought to be associated with an increased incidence of cardiovascular events. Several renin inhibitors have been synthesized in order to counteract deleterious consequences of renin activity and RAAS activation; aliskiren is the first of these new non-peptide direct renin inhibitors to be approved for the treatment of hypertension. The paper reviews pharmacokinetics of aliskiren and its role in hypertension, with particular regard to those studies that compared clinical efficacy of aliskiren in comparison and in addition to other antihypertensive drug strategies.

Topics: Amides; Cardiovascular Agents; Cardiovascular Diseases; Fumarates; Humans; Renin; Renin-Angiotensin System

Topics: Amides; Amlodipine; Animals; Drug Approval; Drug Combinations; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Tablets; United States

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Female; Fumarates; Humans; Hypertension; Hypertension, Pregnancy-Induced; Pregnancy

To provide an educational update for the nurse practitioner (NP) on the care of patients with hypertension, particularly in high-risk populations. Barriers to reaching blood pressure goals are reviewed in the context of identifying and addressing the sequelae of uncontrolled hypertension. Available antihypertensive agents are reviewed, including a description of direct renin inhibition with aliskiren, the newest agent and antihypertensive class available. Treatment recommendations are discussed in light of recent clinical trial data demonstrating improved cardiovascular (CV) outcomes, including myocardial infarction, stroke, and death.. Clinical studies and state-of-the-art articles indexed on PubMed. Current hypertension guidelines provide detailed management strategies, particularly for patients at high risk for CV events. NPs may help improve CV outcomes through careful diagnosis, risk stratification, and disease management, including improved patient education of the benefits of rational and sustained management of hypertension.. Early diagnosis, evidence-based treatment, and ongoing disease management of hypertension can be expected to improve CV outcomes. Treatment initiation with combination therapy, preferably with single-pill combinations that incorporate an agent that modulates the renin-angiotensin-aldosterone system, provides an approach that is safe, effective, and well tolerated and which can be tailored to the needs of the individual patient.

Topics: Amides; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Practice Guidelines as Topic; Renin; Renin-Angiotensin System; United States

In the current context of renin-angiotensin-aldosterone system (RAAS) blockade, angiotensin (Ang) converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), or their combination, have proved to be effective in providing cardiovascular and renal protection. However, renin inhibition has long been recognized as the preferred site for blockade of the RAAS because renin represents the first, highly-regulated and rate-limiting step of the system. Up to now, the first orally active renin inhibitors initially tested in humans did not meet the necessary all the criteria (specificity, potency, and pharmacokinetic profile) to become clinically useful drugs. The synthesis of aliskiren, a potent alkane carboxamide renin inhibitor, now provides an orally active compound which, according to its pharmacological profile in normotensive subjects and in patients with hypertension, diabetic nephropathy or heart failure suggests that this drug may be of value for the treatment of patients with cardiovascular and renal disorders. However, long-term studies are needed to demonstrate the efficacy of aliskiren in these clinical settings. The results of the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Disease Endpoints (ALTITUDE) trial which has already included 8600 patients with type 2 diabetes, proteinuria and a high cardiovascular risk and compared the effects of aliskiren vs. a placebo on a composite endpoint including renal and cardiovascular morbidity and mortality should be provided in 2012.

Topics: Amides; Animals; Antihypertensive Agents; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fumarates; Heart Failure; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System

While it may seem at first that antihypertensive drug combinations run counter to the desire to 'personalize' the management of hypertension, the best combinations have predictable efficacy in different individuals and subpopulations. Race is probably not a valid surrogate for clinically meaningful genetic variation or guide to therapy. Most guidelines suggest similar blood pressure goals for different races but drug treatment recommendations have diverged. In the United States, race is not considered to be a major factor in drug choice, but in England and other countries, initial therapy with renin-angiotensin system blocking drugs is not recommended in Blacks. In this review we: (1) examine new trends in race-based research; (2) emphasize the weaknesses of race-based treatment recommendations; and (3) explore the effects of a new combination, renin inhibition (aliskiren) and amlodipine, in African Americans.

Topics: Amides; Amlodipine; Antihypertensive Agents; Black or African American; Blood Pressure; Calcium Channel Blockers; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Patient Selection; Practice Guidelines as Topic; Precision Medicine; Treatment Outcome; United States

It is widely acknowledged that activation of the renin-angiotensin system impairs insulin sensitivity. Pharmacological inhibition of the (pro)renin receptor-dependent system has shown beneficial effects in diabetic nephropathy, retinopathy and hypertensive cardiac damage in animal models. Previously, we showed that fructose feeding stimulated nonproteolytic activation of prorenin and subsequent production of angiotensin II in skeletal muscle in rats, and that inhibition of the (pro)renin receptor-dependent system improved the development of fructose feeding-induced insulin resistance. In addition, our current preliminary study suggests that local angiotensin II generation in skeletal muscle and adipose tissues induced by nonproteolytic activation of prorenin is involved in the development of spontaneous insulin resistance in type 2 diabetic rats. In this review, we will briefly summarize the possible contribution of the (pro)renin receptor-dependent system to the pathogenesis of insulin resistance, with a focus on how the nonproteolytic activation of prorenin contributes to the development of insulin resistance.

Topics: Adipose Tissue; Amides; Animals; Fumarates; Glucose; Insulin Resistance; Male; Muscle, Skeletal; Prorenin Receptor; Rats; Rats, Inbred OLETF; Receptors, Cell Surface; Renin; Renin-Angiotensin System

The safety of angiotensin II receptor blockers (ARBs) for the treatment of hypertension and cardiovascular and renal diseases has been well documented in numerous randomized clinical trials involving thousands of patients. However, recent concerns have surfaced about possible links between ARBs and increased risks of myocardial infarction and cancer. Less is known about the safety of the direct renin inhibitor aliskiren, which was approved as an antihypertensive in 2007. This article provides a detailed review of the safety of ARBs and aliskiren, with an emphasis on the risks of cancer and myocardial infarction associated with ARBs. Safety data were identified by searching PubMed and Food and Drug Administration (FDA) Web sites through April 2011. ARBs are generally well tolerated, with no known class-specific adverse events. The possibility of an increased risk of myocardial infarction associated with ARBs was suggested predominantly because the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial reported a statistically significant increase in the incidence of myocardial infarction with valsartan compared with amlodipine. However, no large-scale, randomized clinical trials published after the VALUE study have shown a statistically significant increase in the incidence of myocardial infarction associated with ARBs compared with placebo or non-ARBs. Meta-analyses examining the risk of cancer associated with ARBs have produced conflicting results, most likely due to the inherent limitations of analyzing heterogeneous data and a lack of published cancer data. An ongoing safety investigation by the FDA has not concluded that ARBs increase the risk of cancer. Pooled safety results from clinical trials indicate that aliskiren is well tolerated, with a safety profile similar to that of placebo. ARBs and aliskiren are well tolerated in patients with hypertension and certain cardiovascular and renal conditions; their benefits outweigh possible safety concerns.

Topics: Amides; Angiotensin Receptor Antagonists; Antihypertensive Agents; Fumarates; Humans; Hypertension; Myocardial Infarction; Neoplasms

Combinations of the direct renin inhibitor aliskiren with angiotensin receptor blockers (ARBs) or diuretics are effective therapeutic regimens for the treatment of hypertension. A large database of safety information has become available during the past several years with aliskiren in combination trials. Data were pooled from 9 short-term (8-week) and 4 longer-term (26- to 52-week) randomized controlled trials of aliskiren in patients with hypertension. Adverse event (AE) rates were assessed for aliskiren combination therapy compared with component monotherapies. In short-term studies, overall AE rates were similar for patients receiving aliskiren/valsartan or aliskiren/diuretic combinations (32.2%-39.8%) and those receiving the component monotherapies (30.0%-39.6%). In longer-term studies, AE rates with aliskiren/losartan (55.5%) and aliskiren/diuretic (45.0%) combination therapy were similar to those with losartan (53.9%) and diuretic (48.9%) alone. Angioedema and hyperkalemia occurred in similar proportions of patients taking combination therapies vs monotherapy. The safety and tolerability profile of aliskiren in combination with the ARBs valsartan or losartan, or diuretic, is similar to aliskiren, ARBs, or diuretics alone.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Aged; Amides; Angiotensin Receptor Antagonists; Antihypertensive Agents; Biological Availability; Blood Pressure; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Randomized Controlled Trials as Topic; Renin; Sodium Chloride Symporter Inhibitors; Treatment Outcome

The renin-angiotensin system (RAS) is the most important mechanism leading to cardiovascular and renal damage in diabetic patients. Studies conducted until now have unequivocally demonstrated that antihypertensive treatment with RAS blockers (angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers) improve the prognosis of patients with diabetes, by reducing rates of cardiovascular events and preventing or delaying the progression of diabetic nephropathy. However, despite the benefits of such treatment, cardio-renal events are still very frequent in diabetics. Several strategies for reducing this cardiovascular and renal risk have been proposed, but among them, a more complete blockade of the RAS seems the most attractive. Direct renin inhibitors are RAS blockers with some particularities, such as their ability to reduce plasma renin activity or the possibility to modulate tissue and intracellular RAS, which could represent a theoretical advantage when treating diabetic patients. In experimental and clinical studies conducted until now, aliskiren is able to reduce blood pressure in diabetics, alone or in combination with ACE inhibitors or angiotensin-receptor blockers. Moreover, aliskiren reduces markers of cardiac and renal disease, such as left ventricular hypertrophy or post-infarction ventricular remodeling, as well as proteinuria in diabetics already treated with other RAS blockers. The translation of these promising results to the clinical arena is currently being investigated in the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE), where more than 8600 diabetic patients with chronic kidney disease and at high-risk of cardio-renal events are treated with aliskiren or placebo added to the current treatment consisting of another RAS blocker. If positive, aliskiren will be the treatment of choice in the prevention of cardiorenal disease in diabetics.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Diabetes Complications; Diabetic Nephropathies; Fumarates; Humans; Hypertension; Renin

KEY POINTS AND PRACTICAL RECOMMENDATIONS: •  Aliskiren, the sole oral renin inhibitor approved by the US Food and Drug Administration, is indicated for the treatment of hypertension, either as monotherapy or in combination, with reductions in blood pressure similar to other agents. •  Early evidence suggests that aliskiren confers additional benefit in patients with diabetic nephropathy. Data are not yet available to determine whether protection will extend to cardiovascular disease. •  No initial dosage adjustment is required in elderly patients or for patients with mild to severe renal impairment; however, clinical experience is limited in patients with significant renal impairment, and with renal artery stenosis. •  It appears rational to combine aliskiren with agents that otherwise increase plasma renin activity, including thiazide diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers. •  While there is a reactive rise in renin in response to aliskiren, probably larger than that induced by angiotensin receptor blockers and angiotensin-converting enzyme inhibitors, there is no evidence that this rise is harmful. •  In placebo-controlled studies, the incidence of edema anywhere in the body was 0.4% with aliskiren compared with 0.5% with placebo. It is unknown whether angioedema rates are higher in blacks with aliskiren. •  Aliskiren is associated with a slight increase in cough, with rates of about one third to one half seen with angiotensin-converting enzyme inhibitors. •  Increases in serum potassium >5.5 meq/L were infrequent in patients with essential hypertension treated with aliskiren alone (0.9% compared with 0.6% with placebo).

Topics: Amides; Antihypertensive Agents; Cough; Edema; Fumarates; Humans; Hypertension; Renin; Treatment Outcome

Nowadays, social and economic burden related to cardiovascular and renal diseases still remains extremely high, although there has been a dramatic improvement of diagnostic options and therapeutic strategies reported in the last 30 years. The progressively higher attention towards integrated pharmacological strategies, which are able to interfere with different pathophysiological mechanisms, has certainly led to better control of cardiovascular and renal diseases. In view of the large involvement of the renin-angiotensin system (RAS) in the vast majority of pathophysiological mechanisms leading to the development and progression of cardiovascular and renal diseases, it can be easily understood why it has been long viewed as the 'ideal' target for the pharmacological treatment of several clinical conditions. Recently, besides the well known therapeutic approaches for RAS blockade, based on the use of ACE inhibitors, angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) and aldosterone antagonists, both the scientific and medical community have focused their attention on a novel therapeutic option. In 2007, aliskiren, the first compound of a new drug class, the direct renin inhibitors (DRIs), has become available for clinical use, being a novel and innovative therapeutic option. Aliskiren is able to interfere with the enzymatic activity of renin by blocking the catalytic site of the molecule and inducing an 'upstream' RAS blockade. This leads to a modulation of the biological properties of renin, thus resulting in the missed cleavage of angiotensinogen to angiotensin I. Aliskiren has demonstrated antihypertensive efficacy comparable or even superior to that of other classes of antihypertensive drugs, both in monotherapy and in combination therapies. Its safety and tolerability are comparable with those of other antihypertensive drug classes and almost similar to placebo. In addition, it has been demonstrated to reduce progression of cardiac and renal organ damage in addition to ACE inhibitors or ARBs. An ambitious and large clinical trial programme specifically designed for this innovative antihypertensive drug will evaluate the efficacy of aliskiren in terms of reduced incidence of major cardiovascular and renal outcomes in patients with hypertension and cardiovascular disease, besides the use of optimal (standard) therapeutic strategies, including ACE inhibitors and ARBs.

Topics: Amides; Animals; Antihypertensive Agents; Diabetes Mellitus; Diffusion of Innovation; Drug Design; Fumarates; Heart Diseases; Humans; Hypertension; Kidney Diseases; Renin; Renin-Angiotensin System; Translational Research, Biomedical

Hypertension (HTN) affects an estimated 76.4 million US adults. Despite improvements in blood pressure (BP) control rates and the availability of effective antihypertensive agents, only 50% of these individuals achieve BP control. It is now recognized that many patients will require ≥ 2 antihypertensive agents to achieve BP control. Both the current US and reappraisal of the 2007 European guidelines include dual-combination regimens among recommended treatments for initial HTN therapy. For patients requiring 3 drugs, the combination of agents with complementary mechanisms of action (ie, renin-angiotensin-aldosterone system blocker, calcium channel blocker, and diuretic) has been recognized as rational and effective. Three single-pill triple-drug combinations have recently been approved for use in HTN in the United States: valsartan (VAL)/amlodipine (AML)/hydrochlorothiazide (HCTZ); olmesartan medoxomil (OM)/AML/HCTZ; and aliskiren (ALI)/VAL/HCTZ. Triple-combination regimens have resulted in a greater proportion of patients achieving BP control compared with dual-combination regimens, with significantly lower BP levels documented after only 2 weeks at maximum doses. Single-pill combinations offer convenience to address barriers to BP control such as poor adherence to therapy and therapeutic inertia. Additional benefits of combining antihypertensive agents from different classes include improved efficacy, safety, and reduction of cardiovascular risk. In patients with essential HTN for whom dual therapy is inadequate, single-pill triple-drug therapy can offer a simplified and effective treatment strategy.

Topics: Amides; Amlodipine; Antihypertensive Agents; Drug Combinations; Drug Design; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Imidazoles; Medication Adherence; Olmesartan Medoxomil; Practice Guidelines as Topic; Practice Patterns, Physicians'; Tetrazoles; Valine; Valsartan

Renin inhibitors, similar to all renin-angiotensin system (RAS) blockers, increase the plasma concentration of renin because they attenuate the negative feedback effect of angiotensin (Ang) II on renin release. The increase in renin has been suggested to be higher than that during other types of RAS blockade. This could potentially limit the effectiveness of renin inhibition, either because Ang II generation might occur again ('Ang II escape'), possibly even at the levels above baseline, as has been described before for angiotensin-converting enzyme inhibitors, or because high levels of renin will stimulate the recently discovered (pro)renin receptor, and thus induce effects in an Ang-independent manner. This review shows first that the cause(s) of the renin increase during treatment with the renin inhibitor aliskiren is the consequence of a combination of factors, including an assay artifact, allowing the detection of prorenin as renin, and a change in renin half-life. When correcting for these phenomena the increase is unlikely to be as excessive as originally thought. The review then critically describes the consequence(s) of such a increase, concluding (i) that an Ang II escape is highly unlikely, given the [aliskiren]/[renin] stoichiometry, and (ii) that renin and prorenin downregulate their receptor (similar to many agonists). On the basis of the latter, one could even speculate that this will be more substantial when the renin and prorenin levels are higher. Thus, from this point of view the larger increase in renin during renin inhibition will cause a stronger reduction in (pro)renin receptor expression, and a greater suppression of (pro)renin receptor-mediated effects than other renin-Ang blockers.

Topics: Amides; Angiotensin II; Animals; Antihypertensive Agents; Fumarates; Humans; Prorenin Receptor; Receptors, Cell Surface; Renin

Angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and diuretics all cause reactive rises in plasma renin concentration, but particularly high levels have been reported with aliskiren. This prompted speculation that blockade of plasma renin activity with aliskiren could be overwhelmed, leading to paradoxical increases in blood pressure. This meta-analysis of data from 4877 patients from 8 randomized, double-blind, placebo- and/or active-controlled trials examined this hypothesis. The analysis focused on the incidence of paradoxical blood pressure increases above predefined thresholds, after > or =4 weeks of treatment with 300 mg of aliskiren, angiotensin receptor blockers (300 mg of irbesartan, 100 mg of losartan, or 320 mg of valsartan), 10 mg of ramipril, 25 mg of hydrochlorothiazide, or placebo. There were no significant differences in the frequency of increases in systolic (>10 mm Hg; P=0.30) or diastolic (>5 mm Hg; P=0.65) pressure among those treated with aliskiren (3.9% and 3.1%, respectively), angiotensin receptor blockers (4.0% and 3.7%), ramipril (5.7% and 2.6%), or hydrochlorothiazide (4.4% and 2.7%). Increases in blood pressure were considerably more frequent in the placebo group (12.6% and 11.4%; P<0.001). None of the 536 patients with plasma renin activity data who received 300 mg of aliskiren exhibited an increase in systolic pressure >10 mm Hg that was associated with an increase in plasma renin activity >0.1 ng/mL per hour. In conclusion, the incidence of blood pressure increases with aliskiren was similar to that during treatment with other antihypertensive drugs. Blood pressure rises on aliskiren treatment were not associated with increases in plasma renin activity. This meta-analysis found no evidence that aliskiren uniquely causes paradoxical rises in blood pressure.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hypertension; Middle Aged; Randomized Controlled Trials as Topic; Renin; Treatment Outcome

Direct renin inhibition is a new means for blocking the renin-angiotensin system at the rate-limiting step of the cascade of events triggered by renin release--the interaction of renin with its physiological substrate angiotensinogen. The remarkable success of angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers in the management of cardiovascular and renal disease has led to great interest in the potential of direct renin inhibitors. This Review focuses on the evidence that suggests that direct renin inhibitors might block the renin-angiotensin system in the kidney more completely than either angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers. The therapeutic implications of this evidence are also reviewed, as well as the possible mechanistic routes by which direct renin inhibition might exert its influence on the kidney.

Topics: Amides; Animals; Antihypertensive Agents; Diabetic Nephropathies; Fumarates; Humans; Hypertension, Renal; Renin; Renin-Angiotensin System

Chronic activation of the renin-angiotensin-aldosterone system (RAAS) plays a key role in the development of hypertension, and cardiac and renal diseases. RAAS inhibitors, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), improve cardiovascular and renal outcomes. However, studies have shown that residual morbidity and mortality remains high, despite current optimal treatment. More comprehensive control of the RAAS might provide additional reductions in morbidity and mortality. Direct renin inhibitors offer the potential for enhanced RAAS control as they target the system at the point of activation, thereby reducing plasma renin activity (PRA); by contrast, ARBs and ACE inhibitors increase PRA. Elevated PRA is independently associated with cardiovascular morbidity and mortality. A single-pill combination of the direct renin inhibitor, aliskiren, and the ARB, valsartan, at once-daily doses of 150/160 mg and 300/320 mg, has recently been approved by the US FDA for the treatment of hypertension in patients not adequately controlled on aliskiren or ARB monotherapy, and as initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals. This article examines the efficacy, safety and tolerability of aliskiren/valsartan combination therapy, and considers the evidence for the potential organ-protection benefits of this treatment.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Drug Combinations; Fumarates; Humans; Kidney Diseases; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan

Arterial hypertension is an important risk factor for the development and progression of cardiovascular disease (CVD). The renin angiotensin aldosterone system (RAAS) plays a crucial role in the pathophysiology of hypertension and associated complications. Direct renin inhibitors (DRIs) are novel antihypertensive drugs which inhibit the first step of RAAS. Aliskiren is the first orally active DRI approved as monotherapy or in combination with other antihypertensive agents for the treatment of hypertension.. This article reviews the efficacy and safety of aliskiren as monotherapy and in combination with other antihypertensive agents and comments on its potential role in clinical practice.. Relevant articles were identified through a PubMed search (up to 17 August 2009).. Aliskiren, used alone or in combination with other antihypertensive agents, has a favourable effect on blood pressure (BP). Specifically, aliskiren is equally effective with other RAAS inhibitors and probably superior to hydrochlorothiazide in the reduction of systolic and diastolic BP. The combination of aliskiren with other antihypertensive drugs seems to be an effective and safe therapeutic option. In addition, aliskiren may have favourable effects in terms of ameliorating several microvascular and macrovascular complications of hypertension and diabetes.. Aliskiren appears to be an effective and safe antihypertensive drug. Whether the BP lowering effect of aliskiren is associated with improvements in cardiovascular outcomes remains to be elucidated.

Topics: Amides; Animals; Antihypertensive Agents; Clinical Trials as Topic; Fumarates; Humans; Hypertension; Renin; Signal Transduction; Treatment Outcome

Hypertension is a major risk factor for cardiovascular disease, which is the leading cause of mortality in women in developed countries. This pooled analysis assessed the antihypertensive efficacy, safety and tolerability of monotherapy with the direct renin inhibitor aliskiren (150 mg and 300 mg) over 8-12 weeks in women with mild-to-moderate hypertension (mean sitting diastolic blood pressure (msDBP) ≥95 and <110 mm Hg) across eight randomized and double-blind trials. Safety and tolerability were assessed in the five placebo-controlled trials in the analysis. In the 1527 women enrolled in these studies, aliskiren 150 mg and 300 mg produced significantly greater blood pressure (BP) reductions (14.1/11.0 and 16.1/12.3 mm Hg, respectively) compared with placebo (7.2/7.6 mm Hg; P<0.0001). BP reductions with aliskiren monotherapy in women were similar to those observed in men, and consistent across subgroups of age, metabolic syndrome and obesity. The overall incidence of adverse events in women was similar with aliskiren treatment (150 mg, 42.3%; 300 mg, 46.0%) and placebo (39.0%); adverse events with aliskiren were more frequent in women than in men, consistent with previous studies of gender differences in drug tolerability. In conclusion, aliskiren monotherapy at 150 mg and 300 mg doses provided effective, dose-dependent BP-lowering in women with mild-to-moderate hypertension, and it was well tolerated.

Topics: Aged; Amides; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Female; Fumarates; Humans; Hypertension; Middle Aged; Randomized Controlled Trials as Topic; Renin; Sex Factors; Time Factors; Treatment Outcome

The renin-angiotensin-aldosterone system (RAAS) has a central function in the regulation of blood pressure. Aliskiren, the first direct renin inhibitor to be approved for the treatment of hypertension, blocks the RAAS at its point of activation. As renin inhibition acts at the top of the RAAS cascade, this mechanism has been proposed to offer advantages over existing modes of RAAS blockade. The RAAS is also considered to be a major factor in the pathogenesis of many renal diseases, especially diabetic nephropathy (DN), the main cause of end-stage renal disease. Existing therapies to block the RAAS slow the progression of DN, but they do not halt the disease. Therefore, more effective modes of interventions are needed. Studies to determine the efficacy of aliskiren in human renal disease are in progress. This review summarizes in vivo studies in which the efficacy of aliskiren was tested in experimental models of renal disease, and presents in vitro studies that provide insights into the possible mechanisms by which aliskiren confers renoprotection in animals. These works are discussed in the framework of the intrarenal RAAS and suggest that aliskiren may act by unique renoprotective mechanisms.

Topics: Amides; Animals; Drug Evaluation, Preclinical; Fumarates; Humans; Kidney Diseases; Renin; Renin-Angiotensin System

The role of renin-angiotensin-aldosterone system (RAAS) in regulating the volume and composition of extracellular fluid, blood pressure (BP) as well as onset and progression of cardiovascular and renal diseases has been studied for more than 150 years. The compounds that block the vital stages of the RAAS cascade, such as ACE-inhibitors (ACEI), AT1-receptor blockers (ARB) and aldosterone receptor antagonists, importantly extended our treatment options. However, the positive therapeutic effects of these compounds also have certain negative consequences. Administration of ACEIs and ARBs interrupts physiological feedback for renal renin release and leads to reactive elevation of circulating active renin and greater production of angiotensin I and angiotensin II with subsequent return of aldosterone secretion to the pre-treatment levels ('escape' phenomenon). These possible adverse effects of the intermediary products of incomplete RAAS blockade leading to organ complications have facilitated the efforts to develop compounds blocking the initial stages of renin-angiotensin cascade--i.e. direct renin blockers. After several years of unsuccessful attempts, the recent years have seen development of the first non-peptide, orally long-term effective renin inhibitor, aliskiren fumarate. In monotherapy or in combination with other antihypertensives (hydrochlorothiazide, ARB, ACEI), aliskiren reduces BP in a dose-dependent manner (75-600 mg/den). Aliskiren reduces plasma renin activity (PRA) and neutralises hydrochlorothiazide-induced RAAS activation. Once daily administration of the drug leads to longer than 24-hour activity and its prolonged blocking effects on the kidneys are the basis for its renoprotectivity. In addition to the significant antihypertensive effect, clinical studies also showed a range of organoprotective properties in patients with left ventricle hypertrophy (ALLAY study), heart failure (ALOFT study) and diabetic nephropathy (AVOID study). Similar to other AT1-blockers, aliskiren has a minimum of adverse side effects. Aliskiren for hypertension therapy was launched in clinical practice in USA in 2007 (Tekturna and combination formulation TekturnaHCl, respectively) and shortly after that in European Union as Rasilez. In the Czech Republic, aliskiren (Rasilez) was released for clinical use by diabetologists and nephrologists in patients with hypertension and concomitant diabetes, nephropathy and proteinuria in doses of 150-300 mg per day on 1. 8. 2

Topics: Amides; Animals; Cardiovascular Diseases; Fumarates; Humans; Kidney Diseases; Renin; Renin-Angiotensin System

The renin-angiotensin-aldosterone system (RAAS) is a key regulator of blood pressure (BP), as well as volume and electrolytes, in both hypertensive and normotensive individuals. Inappropriate activation of the RAAS is important in hypertension-induced cardiovascular disease (CVD) and chronic kidney disease (CKD). Renin is the rate-limiting step in the RAAS cascade, which makes direct renin inhibitors (DRIs) an attractive target for RAAS suppression and treatment of hypertension. Current regimens using either angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) result in feedback upregulation of renin and aldosterone breakthrough, which contribute to incomplete suppression of the RAAS. Thereby, aliskiren - alone or in combination - might offer a novel therapeutic intervention to improve suppression of the RAAS, with potential to translate to improved CVD and CKD outcomes.. Herein, we present the current state of knowledge of DRIs in the preclinical and clinical realm and their antihypertensive efficacy in relation to cardiovascular and renal risk. Recent clinical trials (2007 - 2009) support the efficacy of aliskiren, and studies suggest the potential for improved CVD and CKD outcomes.. An understanding of the mechanism of action of DRIs and a perspective of recent clinical trials.. The DRI aliskiren is an effective antihypertensive agent that preliminary data suggests has a beneficial effect in CVD and CKD. Combination of aliskiren with an ACEi or ARB may be better tolerated than the ACEi-ARB combination. Future work is needed to further quantify aliskiren's impact on hard CVD and CKD end points.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Drug Design; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Kidney Diseases; Renin; Renin-Angiotensin System

Topics: Amides; Animals; Antihypertensive Agents; Fumarates; Humans; Hypertension; Male; Rats

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Fumarates; Humans; Hypertension; Kidney Diseases; Prorenin Receptor; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptor, Angiotensin, Type 1; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Renin; Renin-Angiotensin System

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Chronic Disease; Clinical Trials as Topic; Drug Therapy, Combination; Evidence-Based Medicine; Fumarates; Kidney Diseases; Losartan; Tetrazoles; Valine; Valsartan

Aliskiren is an orally active direct renin inhibitor which inhibits the synthesis of angiotensin I by linking to active renin on a deep cleft of its molecular structure, the site of hydrolysis of the Leu10-Val11 bond of angiotensinogen. At variance with angiotensin-converting enzyme (ACE) inhibitors, aliskiren eliminates the main substrate for the 'escape' phenomenon (synthesis of angiotensin II from angiotensin I through alternative enzymatic pathways). The possibility that the antihypertensive effect of aliskiren differs from that of ACE inhibitors needs to be proved in specifically designed clinical trials. Over the past 2 years, three studies have been published which directly compared aliskiren with ramipril, in patients with hypertension. We made a pooled analysis of these studies. In order to avoid interference with additional drugs, analysis was restricted to trial periods when the two drugs were given as monotherapy. In each individual study, systolic blood pressure (BP) was slightly lower with aliskiren. Overall, systolic BP was lower with aliskiren than with ramipril (weighted mean difference between the treatments 1.84 mmHg; fixed effect model; p < 0.0001; and 1.87 mmHg; random effect model; p = 0.0055). The standardized mean difference between the treatments was 2.58 (fixed effect model; p < 0.0001) and 2.92 (random effect model; p = 0.0017) in favor of aliskiren. Compared with ramipril, aliskiren may have induced a more complete 'upstream' inhibition of the renin-angiotensin-aldosterone system, with consequent greater suppression of angiotensin II. Another potential explanation may be the longer terminal elimination halflife of aliskiren (about 40 hours) compared with ramiprilat (13-17 hours). These data provide further evidence that aliskiren monotherapy provides a sustained BP reduction over the 24 hours.

Topics: Aging; Amides; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Diabetic Angiopathies; Fumarates; Half-Life; Humans; Hypertension; Ramipril; Renin-Angiotensin System

ACE inhibitors and angiotensin receptor blockers confer renal protection in proteinuric nephropaties, but recently worsening of renal outcomes has been reported in non-proteinuric patients treated with a combination of ramipril and telmisartan, compared to ramipril only. In view of these apparently contradictory data, the review wants to shed light on treatment modalities of patients with hypertension and chronic kidney disease.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diuretics; Fumarates; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Kidney Diseases; Kidney Failure, Chronic; Meta-Analysis as Topic; Natriuresis; Proteinuria; Randomized Controlled Trials as Topic; Water-Electrolyte Imbalance

Interruption of the Renin-Angiotensin-Aldosterone System (RAAS) with Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin-Receptor Blockers (ARBs), alone or in combination, has become a leading therapeutic strategy to slow down the progression of chronic kidney disease. Nevertheless, a considerable proportion of patients progress despite this therapy. New alternative arms are available today to treat hypertension in uncontrolled patients that might have a role in renoprotection. The role of aliskiren, the recently available renin inhibitor may be assumed, based on the pathophysiology of RAAS related renal damage and from data derived on experimental and clinical studies in-patient with type 2 diabetes related nephropathy. The review focuses on the potential consequences of (pro)renin blockade in glomerular hypertension and renal scarring along with some patented treatment methods. The benefit of this additional therapy is still only hypothetical. Ad hoc clinical trials have been conducted to confirm the expected results. Finding that prolonged inhibition of renin vasoconstrictor effect, suppression of plasma renin activity and a more effective RAAS blockade, in patients with chronic RAAS inhibition may help to achieve a sustained reduction of proteinuria, would suggest that renin inhibitors may represent a new weapon to fight progressive nephropathies.

Topics: Amides; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Chronic Disease; Fumarates; Humans; Kidney Diseases; Rats; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Treatment Outcome

Diabetic nephropathy is the most common and most rapidly growing cause of end-stage renal failure in developed countries. Diabetic nephropathy results from complex interactions between genetic, metabolic and hemodynamic factors. Improvements in our understanding of the pathogenesis of fibrosis associated with diabetic kidney disease have led to the identification of several novel targets for the treatment of diabetic nephropathy. Albuminuria is a useful clinical marker of diabetic nephropathy, as it can be used to predict a decline in renal function. A reduction in albuminuria might not, however, be reflective of a protective effect of therapies focused on ameliorating renal fibrosis. Although new strategies for slowing down the progression of several types of renal disease have emerged, the challenge of arresting the relentless progression of diabetic nephropathy remains. In this Review, we discuss novel pharmacological approaches that aim to improve the renal outcomes of diabetic nephropathy, including the use of direct renin inhibitors and statins. We also discuss the promise of using antifibrotic agents to treat diabetic nephropathy. The need for novel biomarkers of diabetic nephropathy is also highlighted.

Topics: Albuminuria; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antihypertensive Agents; Biomarkers; Clinical Trials as Topic; Diabetic Nephropathies; Disease Progression; Fumarates; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Protein Kinase C; Pyridones; Renin; Transforming Growth Factor beta

Hypertension is the most prevalent and important risk factor for cardiovascular and renal disease worldwide. Despite the large armamentarium of available blood pressure-lowering agents, the need remains for safer and more effective antihypertensive treatment. Based on current target levels of < 140/90 mm Hg, only one-third of hypertensive Americans have achieved goal blood pressure. Several strategies can help address these challenges, including increasing public awareness, and improving physician awareness of evidence-based therapeutic guidelines. There also remains a need for new therapeutic options. This review examines new developments among those agents having inhibitory activity on the renin-angiotensin-aldosterone system (RAAS). All currently available RAAS blockers cause a reactive increase in plasma renin concentration. However, the direct renin inhibitors are the only class that diminishes plasma renin activity, an effect that may provide additional cardiovascular and/or renoprotective benefit. Aliskiren is the first clinically available direct renin inhibitor that has been shown to be effective and well tolerated both as monotherapy and in combination with other established agents in hypertensive patients. Randomized clinical trials are underway to explore the extent to which direct renin inhibition provides additive protection against cardiovascular and renal disease events.

Topics: Aged; Amides; Antihypertensive Agents; Diabetes Complications; Drug Therapy, Combination; Fumarates; Healthy People Programs; Heart Failure; Humans; Hypertension; Middle Aged; Obesity; Renin; Renin-Angiotensin System

The renin-angiotensin-aldosterone system (RAAS) is a major factor for the development and maintenance of hypertension and a major cause for cardiovascular remodeling and cardiovascular complications through its active peptide angiotensin (Ang) II. Blockade of RAAS with ACE inhibitors (ACEIs) results in suppression of Ang II levels, which eventually return to baseline levels after prolonged ACEI administration. This leads to an escape phenomenon through generation of Ang II from enzymes other than ACE and led to the hypothesis that dual blockade of RAAS with an ACEI/Ang receptor blocker (ARB) combination could lead to total blockade of RAAS, since ARBs block the action of Ang II at the AT1 receptor level, irrespective of the mechanism of Ang II generation and will have an additive blood pressure (BP)-lowering effect. However, this hypothesis has not materialized clinically, as the ACEI/ARB combination produces modest BP reductions that are not significantly greater than monotherapy with the component drugs, and is frequently associated with higher incidence of side effects. A new dual RAAS blockade with the direct renin inhibitor aliskiren and the ARB valsartan produces greater BP reductions than monotherapy with the component drugs and is safe and well tolerated. The combination of aliskiren with valsartan, and with other antihypertensive drugs is discussed.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Drug Interactions; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan

The renin-angiotensin system (RAS) or the renin-angiotensin-aldosterone system (RAAS) is a major endocrine/paracrine system that regulates blood pressure (BP) via angiotensin release and fluid and electrolyte homoeostasis via aldosterone release. RAAS should be constantly suppressed and any degree of activity may lead to hypertension (HTN) and associated target organ damage. Activation of the RAAS in the pathogenesis of HTN, CVD and renal disease is well documented. Also benefits of inhibition of RAAS, as an effective way to intervene in pathogenesis HTN, CVD and CRF, has been well recognized. RAAS may be blocked by drugs at various points and is important target site for five distinctive classes of hypertensive drugs; beta blockers, renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and aldosterone inhibitors. Inhibition of renin activity and the blocked of RAAS cascade at its primary steps, has long been proposed as the optimal means of RAAS Inhibition. Renin inhibitor provides more effective means of RAAS Inhibition. Aliskiren is the first in a new class of orally active, non-peptide, low molecular weight direct renin inhibitor (DRI) available for clinical use and potential new approach to the blockade of the RAAS. An average plasma half-life of 23.7 hours (range 20-45 hours), makes drug suitable for once daily administration. BP-lowering affect of aliskiren is associated with a decreased, not increased, generation of Ang I, as it blocks generation of Ang I from angiotensinogen, by inhibiting the active enzymatic site of renin. Aliskiren has generally been well tolerated with adverse events and discontinuation rates similar to placebo in most clinical trials. Aliskiren has the potential to be useful in this wide spectrum of conditions and may provide organ protection independent of BP reductions.

Topics: Aldosterone; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Fumarates; Mineralocorticoid Receptor Antagonists; Renin-Angiotensin System

The renin-angiotensin system plays an important role in various physiological and pathophysiological regulatory mechanisms. Within the past few years, the classical concept of a linear enzymatic cascade has experienced substantial changes. A parallel counterregulatory axis has been identified which involves the angiotensin converting enzyme homologue ACE2, angiotensin (1-7), and receptors Mas. The research in prorenin and its non-proteolytic activation has greatly advanced after the discovery of cellular receptors (P)RR; binding of renin or prorenin to these receptors not only facilitates angiotensin generation, but at the same time activates specific signal transduction pathways. The long-term search for clinically useful direct renin inhibitors has recently succeeded with the new antihypertensive drug aliskiren. While beneficial effects of aliskiren on some markers of cardiovascular and renal diseases have been proved in large clinical studies, important questions remain to be solved.

Topics: Amides; Animals; Antihypertensive Agents; Enzyme Activation; Fumarates; Humans; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Vacuolar Proton-Translocating ATPases

Since renin inhibition interferes with the first and rate-limiting steps in the renin-angiotensin system, the renin step is a very attractive target for lowering blood pressure and minimizing target-organ damage. The newly developed direct renin inhibitor aliskiren has several attractive characteristics: it definitively reduces plasma renin activity among inhibitors of the renin-angiotensin system, is remarkably specific for human renin, exhibits a long half-life in plasma comparable to that of amlodipine, and has a high affinity for renal glomeruli and vasculature. Although these characteristics suggest the clinical usefulness and safety of aliskiren, several problems remain unsolved. Why does aliskiren have beneficial effects on the heart and kidneys of patients treated with angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II type 1-receptor blockers (ARBs)? Is the blood-pressure-lowering effect of aliskiren dependent on the plasma renin activity? Does aliskiren exert a possible adverse effect via (pro)renin receptor-dependent intracellular signals? Here, we review the characteristics and usefulness of aliskiren and discuss the current issues associated with this direct renin inhibitor.

Topics: Amides; Antihypertensive Agents; Fumarates; Half-Life; Humans; Renin; Renin-Angiotensin System

The renin-angiotensin-aldosterone system (RAAS), an important regulator of blood pressure and mediator of hypertension-related complications, is a prime target for cardiovascular drug therapy. Angiotensin-converting enzyme inhibitors (ACEIs) were the first drugs to be used to block the RAAS. Angiotensin II receptor blockers (ARBs) have also been shown to be equally effective for treatment. Although these drugs are highly effective and are widely used in the management of hypertension, current treatment regimens with ACEIs and ARBs are unable to completely suppress the RAAS. Combinations of ACEIs and ARBs have been shown to be superior than to either agent alone for some, but certainly not all, composite cardiovascular and kidney outcomes, but dual RAAS blockade with the combination of an ACEI and an ARB is sometimes associated with an increase in the risk for adverse events, primarily hyperkalemia and worsening renal function. The recent introduction of the direct renin inhibitor, aliskiren, has made available new combination strategies to obtain a more complete blockade of the RAAS with fewer adverse events. Renin system blockade with aliskiren and another RAAS agent has been, and still is, the subject of many large-scale clinical trials and furthermore, is already available in some countries as a fixed combination.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Kidney; Renin; Renin-Angiotensin System

Chronic kidney failure remains a major health problem worldwide. Although current treatment is focused on the renin-angiotensin system, it is essential that new treatments targeted toward novel pathophysiological mechanisms are developed if we are to make significant progress in this area. In this review, we have outlined several promising new areas while emphasizing that large, randomized, well-controlled clinical trials are essential to reach a meaningful conclusion about the efficacy and safety of novel treatment.

Topics: Amides; Anticoagulants; Antihypertensive Agents; Bicarbonates; Chronic Disease; Enzyme Inhibitors; Fumarates; Glycosaminoglycans; Humans; Indoles; Iron Chelating Agents; Kidney Diseases; Kidney Failure, Chronic; Maleimides; Pentoxifylline; Phosphodiesterase Inhibitors; Protein Kinase C; Pyridones; Renin; Renin-Angiotensin System

Hypertension is one of the most important risk factors and causes of cardiovascular disease (CVD). From some years, renin-angiotensin-aldosterone system (RAAS) inhibitors such angiotensin converting enzyme (ACE) and angiotensin receptor blockade (ARB) have been of interest, not only for better blood pressure (BP) control but also for their involvement in the mechanisms of various organ functions.. The aim of this review is to focus on the effectiveness and safety of aliskiren beyond the treatment of hypertension.. Aliskiren, the first approved renin inhibitor to reach the market, is a low-molecular-weight, orally active, hydrophilic non-peptide molecule that blocks angiotensin I generation. Because of its mechanism of action, aliskiren may offer the additional opportunity to inhibit progression of atherosclerosis at tissue level and the potential to be useful in a wide spectrum of conditions. However, we will discuss how it might become a reasonable therapeutic choice also in a broad number of clinical conditions, sharing an increased cardiovascular risk as stable coronary artery disease (CAD), microvascular and cardio-renal disease, diabetes, and peripheral arterial disease (PAD).. Therapy of hypertension through a better blockade of RAAS may be the first step in also achieving interesting results in the complications that hypertension causes in several organs.

Topics: Amides; Animals; Antihypertensive Agents; Clinical Trials as Topic; Disease Progression; Drug Evaluation, Preclinical; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Rats; Renin; Renin-Angiotensin System

Renin-angiotensin aldosterone system (RAAS) activation is a key neurohormonal contributor to the progression of chronic heart failure. Strategies that block this activation have consistently demonstrated major beneficial impacts on morbidity and mortality in this setting. Direct renin inhibitors (DRIs) present a novel opportunity to block at an additional or alternative step in this pathway, that being conversion of angiotensinogen to angiotensin I. Theoretical benefits of blocking at the level of renin include: inhibition of the reflex activation of plasma renin activity induced by conventional downstream RAAS blockers. Minimization of angiotensin II and/or aldosterone escape and blocking upstream at the rate-limiting step of angiotensin I production. Preclinical and early-phase clinical studies have largely supported this hypothesis. In the Aliskiren Observation of Heart Failure Treatment study, patients with systolic chronic heart failure receiving background angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers and β-blockers benefited from aliskiren in reduction vs placebo of plasma levels of brain natriuretic peptide, the primary efficacy endpoint of that study. Large-scale outcome trials are, however, required to definitively determine the benefits of a DRI strategy additional to, or as an alternative to, conventional approaches such as ACE inhibitors in the systolic chronic heart failure setting. Copyright © 2010 Wiley Periodicals, Inc.The authors have no funding, financial relationships, or conflicts of interest to disclose.

Topics: Adrenergic beta-Antagonists; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Disease Progression; Fumarates; Heart Failure; Humans; Natriuretic Peptide, Brain; Prognosis; Renin; Renin-Angiotensin System

Combination therapy is necessary for most patients with hypertension, and agents that inhibit the renin-angiotensin-aldosterone system (RAAS) are mainstays in hypertension management, especially for patients at high cardiovascular and renal risk. Single blockade of the RAAS with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) confers some cardiorenal protection; however, these agents do not extinguish the RAAS as evidenced by a reactive increase in plasma renin activity (PRA), a cardiovascular risk marker, and incomplete cardiorenal protection. Dual blockade with an ACE inhibitor and an ARB offers no additional benefit in patients with hypertension and normal renal and left ventricular function. Indeed, PRA increases synergistically with dual blockade. Aliskiren, the first direct renin inhibitor (DRI) to become available has provided an opportunity to study the merit of DRI/ARB combination treatment. By blocking the first and rate-limiting step in the RAAS, aliskiren reduces PRA by at least 70% and buffers the compensatory increase in PRA observed with ACE inhibitors and ARBs. The combination of a DRI and an ARB or an ACE inhibitor is an effective approach for lowering blood pressure; available data indicate that such combinations favorably affect proteinuria, left ventricular mass index, and brain natriuretic peptide in patients with albuminuria, left ventricular hypertrophy, and heart failure, respectively. Ongoing outcome studies will clarify the role of aliskiren and aliskiren-based combination RAAS blockade in patients with hypertension and those at high cardiorenal risk.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan

Aliskiren is an orally administered, nonpeptide direct renin inhibitor indicated for the management of hypertension. Aliskiren was effective in controlling blood pressure (BP) as monotherapy and in combination with other antihypertensives, in large, randomized trials. Aliskiren 150-300 mg/day as monotherapy was effective in lowering BP across short- (≤12 weeks) and longer-term (up to 54 weeks) periods, providing sustained and consistent effects with 24-hour BP control. Compared with other antihypertensives, aliskiren was generally as effective as hydrochlorothiazide (HCTZ), valsartan, losartan, irbesartan and lisinopril in reducing BP. Furthermore, short-term aliskiren was noninferior to ramipril in reducing BP, but with a longer treatment duration, a greater efficacy of aliskiren-based therapy over ramipril-based therapy was demonstrated. Additional BP-lowering effects occurred when aliskiren was coadministered (as a fixed-dose combination or separate tablets) with other antihypertensives, including HCTZ, valsartan and amlodipine, according to large, randomized trials of short- (≤12 weeks) and longer-term (up to 54 weeks) duration. Combination therapy with aliskiren plus HCTZ was effective in hypertensive patients when administered as initial therapy or to patients previously treated with HCTZ or aliskiren monotherapy. Aliskiren-based therapy was also effective in lowering BP in obese patients, patients with type 1 or 2 diabetes mellitus, patients with metabolic syndrome and the elderly. Aliskiren efficacy was observed irrespective of patient age, sex or ethnicity. Aliskiren monotherapy or combination therapy was generally well tolerated over short- and longer-term study durations in large, randomized clinical trials. Clinical trials to evaluate the effects of aliskiren on clinical outcomes, including renoprotective and cardioprotective effects, are currently ongoing. Thus, aliskiren is a useful option for the treatment of patients with stage 1 to stage 2 (mild to moderate) hypertension, alone or in combination with other antihypertensives, including HCTZ, valsartan or amlodipine.

Topics: Amides; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Randomized Controlled Trials as Topic

Aliskiren, the first orally active direct renin inhibitor, is an effective antihypertensive drug with distinctive characteristics, including good blockade of the renin-angiotensin system, a prolonged duration of action, pharmacologic effects that persist after drug discontinuation, and favorable tolerability comparable with placebo. The blood pressure-lowering effect of aliskiren monotherapy is similar, if not superior, to that of other first-line antihypertensive agents, and is greatly enhanced when aliskiren is combined with various other antihypertensive medications, without any adverse drug interactions. Aliskiren is also an effective and well tolerated therapy in special populations, including diabetic, obese, and elderly hypertensives. Beyond its blood pressure-lowering efficacy, results from experimental and clinical trials suggest that aliskiren has positive effects on markers of cardiovascular and renal damage. The ASPIRE (Aliskiren Study in Post-MI patients to Reduce rEmodelling) HIGHER clinical trials program is further assessing whether the promising pharmacologic properties of aliskiren translate into reduced risk of adverse cardiovascular and renal outcomes.

Topics: Amides; Animals; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

Agents that block the renin-angiotensin-aldosterone system (RAAS) are the cornerstones of antihypertensive therapy in patients at high risk for cardiovascular or renal disease. Recently, it was shown that activation of RAAS may occur through alternate pathways not inhibited by angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), or mineralocorticoid receptor antagonists (MRAs), and that ACEIs, ARBs, or MRAs may actually cause a reactive increase in plasma renin concentration and activity. While these agents, alone or in combination, decrease blood pressure and cardiovascular events to varying degrees, the direct renin inhibitor is a new class of RAAS blocking agent. Aliskiren is the first US Food and Drug Administration-approved direct renin inhibitor with good oral bioavailability. ASPIRE HIGHER is an ongoing series of clinical trials designed to investigate the effect of aliskiren on cardiovascular/renal surrogate endpoints and morbidity/mortality in patients with hypertension and high risk for cardiovascular or renal disease.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Biological Availability; Fumarates; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Renin; Renin-Angiotensin System

The paper covers current problems in the treatment of arterial hypertension. Renin is an important and promising therapeutic target. The direct renin inhibitor aliskiren (Rasilez) is a promising current effective antihypertensive agent that has cardio- and nephroprotective effects. The paper considers a number of clinical studies that have proven the antihypertensive effect of aliskiren and revealed its benefits versus other drugs recommended for blood pressure lowering. It is assumed that this agent may be used in combinations with angiotensin-converting enzyme inhibitors, thiazide or thiazide-like diuretics, and calcium antagonists. Moreover, aliskiren neutralizes the effect of feedback in the compensatory increase in the activity of plasma renin.

Topics: Amides; Antihypertensive Agents; Clinical Trials as Topic; Fumarates; Humans; Hypertension; Renin; Treatment Outcome

Reninangiotensinaldosterone system is a key link in regulation of blood pressure and causes the target organ damage in hypertensive patients. For many years is not lost interest in the pharmacological blockade of RAAS in order to achieve target levels of BP and prevent damage target organs, particularly kidneys. Most recently recommended for clinical application of direct rennin inhibitor--aliskiren, a number of researcher have proven expressed nephroprotective effect. However, at present there is no unequivocal answer to the question whether there are advantages in combined RAAS blockade in hypertensive patients with use of aliskiren and angiotensinconverting enzyme inhibitor or angiotensin receptor blocker.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hypertension; Kidney; Kidney Diseases; Renin-Angiotensin System

Angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists (angiotensin receptor blockers) have been shown to be effective drugs in the management of hypertension and to have beneficial effects along the cardiovascular continuum. However, due to compensatory mechanisms, both of these types of agent increase plasma renin activity, which has been reported to have deleterious effects on patient outcomes. Aliskiren is the first nonpeptide orally administered direct renin inhibitor available on the market. Reported data have shown that aliskiren effectively reduces BP alone or in combination with other antihypertensive agents, and has a good tolerability profile. Moreover, this agent reduces plasma renin activity, which in theory could have additional clinical benefits. However, clinical trials analyzing the effects of aliskiren on mortality are still ongoing.

Topics: Amides; Antihypertensive Agents; Cardiovascular Diseases; Clinical Trials as Topic; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

Suppressed baseline plasma renin activity (PRA) levels or large reactive increases in renin secretion are two possible reasons for treatment failure with antirenin system drugs.. To investigate their prevalence we reanalyzed data from three published clinical trials of the renin inhibitor aliskiren.. Aliskiren failed to lower systolic blood pressure (SBP) by at least 10 mm Hg in half of all patients. It was very effective in two-thirds of medium- to high-renin patients (-19 mm Hg). But BP did not fall in most low-renin patients, or in 30% of medium- to high-renin patients. BP actually rose by >10 mm Hg in 5% of patients taking aliskiren and in >10% of patients when aliskiren was added to an angiotensin receptor blocker (ARB) or angiotensin converting enzyme inhibitor (ACEI). PRA changed in parallel with BP. Although PRA fell in most patients, it actually rose in 5% and in up to 30% when aliskiren was added to an ARB or ACEI.. There are two reasons for treatment failure with aliskiren. Many hypertensive patients have large BP falls. But, BP does not fall in most low-renin patients or in medium- to high-renin patients whose PRA levels do not fall sufficiently. If the concept of that treatment resistance is caused by excessive reactive increases in renin secretion is confirmed, then a PRA determination during treatment could be used to guide subsequent addition or subtraction of either natriuretic or antirenin drug types, to thereby correct BP and reduce cardiovascular risk.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hypertension; Renin; Treatment Failure

We conducted a systematic review and meta-analysis of double-blind randomized controlled trials to quantify the dose-related systolic (SBP) and diastolic blood pressure (DBP) lowering efficacy of renin inhibitors vs placebo in the treatment of adults with primary hypertension. Databases searched were Medline (1966-March 2008), EMBASE (1988-March 2008) and Cochrane Central Register of Controlled Trials (CENTRAL). Six trials in 3694 patients met the inclusion criteria. All examined aliskiren, the only renin inhibitor licensed for marketing in Canada and the United States. Aliskiren caused a dose-related SBP/DBP lowering effect compared to placebo: weighted mean difference with 95% CI: aliskiren 75 mg, -2.9 (-4.6, -1.3)/-2.3 (-3.3, -1.3) mm Hg; aliskiren 150 mg, -5.5 (-6.5, -4.4)/-3.0 (-3.7, -2.3) mm Hg; aliskiren 300 mg, -8.7 (-9.7,-7.6)/-5.0 (-5.6, -4.3) and aliskiren 600 mg, -11.4 (-13.5, -9.2)/-6.6 (-7.9, -5.2) mm Hg. Aliskiren 300 mg significantly lowered both SBP -3.0 (-4.0, -2.0) and DBP -1.7 (-2.3, -1.0) as compared to aliskiren 150 mg. Aliskiren has no effect on blood pressure variability. No data were available to assess the effect of aliskiren on heart rate or pulse pressure. This review found weak evidence that during 4- to 8-week use, aliskiren did not increase withdrawals due to adverse effects as compared to placebo. We concluded that aliskiren has a dose-related blood pressure lowering effect better than placebo and magnitude of effect is similar to that determined for angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

Topics: Adult; Amides; Angioedema; Antihypertensive Agents; Blood Pressure; Cough; Dose-Response Relationship, Drug; Fumarates; Heart Rate; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin; Treatment Outcome; Young Adult

Aliskiren is the first member of the new class of orally active direct renin inhibitors to receive approval from the United States Food and Drug Administration for the treatment of hypertension. In patients with hypertension, aliskiren can be used either as monotherapy or in combination with other antihypertensive agents. By inhibiting renin, aliskiren blocks the conversion of angiotensinogen to angiotensin I, which subsequently results in a reduction in angiotensin II concentrations. Unlike the angiotensin-converting enzyme inhibitors and the angiotensin II receptor blockers (ARBs), which reactively stimulate an increase in plasma renin activity, aliskiren suppresses the effects of renin and leads to a reduction in plasma renin activity. In clinical trials involving patients with mild-to-moderate hypertension, aliskiren provided antihypertensive efficacy that was comparable to that of an ARB. Combination therapy with aliskiren and an ARB may provide additional blood pressure-lowering effects compared with the respective monotherapies with each of the agents. The results from surrogate outcome studies have also alluded to the potential for aliskiren to prevent target organ damage. Because aliskiren does not significantly affect the cytochrome P450 system, it has been associated with few drug interactions. In clinical studies, aliskiren was well tolerated, and its adverse-effect profile was similar to that of placebo. Fatigue, headache, dizziness, diarrhea, nasopharyngitis, and back pain were the most commonly reported adverse events. Overall, aliskiren appears to be a reasonable treatment option for patients with mild-to-moderate hypertension who are intolerant of first-line antihypertensive therapies. Aliskiren may also be a promising renoprotective strategy in patients with concomitant hypertension and diabetes mellitus. Its potential as a first-line antihypertensive agent will have to be further examined once studies evaluating its effects on long-term clinical outcomes are completed.

Topics: Administration, Oral; Amides; Antihypertensive Agents; Clinical Trials as Topic; Diabetes Complications; Drug Approval; Drug Interactions; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin; United States

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Evidence-Based Medicine; Fumarates; Humans; Hypertension; Proteinuria; Treatment Outcome

Diabetes mellitus is an independent risk factor for cardiovascular disease (CVD) and current opinion holds that hyperglycemia directly damages smaller blood vessels, resulting in microvascular complications of nephropathy, retinopathy, and neuropathy. In a patient with diabetes, hypertension compounds and greatly increases the risk of microvascular complications, and thus the risk of end-stage kidney disease, vision loss, and nontraumatic limb amputations. Hypertension and hyperglycemia directly damage the microvasculature, leading to small vessel dysfunction that manifests as the clinical disease states of diabetic retinopathy and nephropathy. Early recognition and treatment of both hyperglycemia and hypertension may prevent vision loss and chronic kidney disease, the devastating outcomes of these microvascular complications. One of the pathogenic mechanisms for microvascular dysfunction is upregulation of the angiotensin II type 1 receptor, the most physiologically common receptor for the vasoconstrictor properties of angiotensin II. In patients with diabetic retinopathy and nephropathy, tight control of blood pressure (BP) (< 130/80 mm Hg) delays the progression of retinopathy and nephropathy in addition to reducing cardiovascular morbidity and mortality. Aggressive treatment with 2 or more antihypertensive agents, selected from different drug classes, is often needed to reach the optimal BP target level. A PubMed search was conducted to identify randomized controlled trials that evaluated hypertension control and microvascular outcomes in patients with diabetes. Several clinical trials have yielded promising data with renin-angiotensin-aldosterone system (RAAS) inhibitors (the direct renin inhibitor aliskiren, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers). Attainment of BP control with RAAS inhibitors reduces the risk for CVD, nephropathy, and retinopathy. In addition, RAAS inhibitors have demonstrated renoprotective effectiveness independent of the BP reduction achieved. This review will examine the results of clinical trials in the context of BP control, diabetes, and the microvascular complications of retinopathy and nephropathy.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diabetes Mellitus; Diabetic Nephropathies; Diabetic Retinopathy; Disease Progression; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Microvessels

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Fumarates; Heart Failure; Humans; Hypertension; Hypertrophy, Left Ventricular; Renin; Renin-Angiotensin System; Treatment Outcome

Chronic kidney disease (CKD) is a common condition that is increasing in prevalence in developed nations. The economic and psychosocial costs of CKD are considerable, and are associated with high levels of morbidity and mortality. Specific treatments do not exist for many causes of CKD. Therefore, treatment is reliant on the introduction of therapies that retard progression of structural renal damage and renal impairment. At present, aside from judicious use of antihypertensive agents to lower blood pressure, and possibly low-protein diets and statin therapy, blockade of the renin-angiotensin-aldosterone system (RAAS) with angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) are the only widely available treatments. Although these measures attenuate the inexorable progression to renal failure, they do not halt it. One limiting factor may be feedback effects of ACEis and ARBs, such as increased plasma renin activity. Aliskiren is a newer agent that inhibits renin, the rate-limiting step in the RAAS. There are several theoretical reasons to suggest that aliskiren may have renoprotective actions superior to those of ACEis and ARBs. In this paper the available evidence regarding renoprotective effects of aliskiren is reviewed, with an emphasis on comparison with ACEis and ARBs.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Clinical Trials as Topic; Dose-Response Relationship, Drug; Forecasting; Fumarates; Humans; Male; Molecular Structure; Protective Agents; Renin; Renin-Angiotensin System; Time Factors; Treatment Outcome

Current therapies proven to slow the progression of diabetic nephropathy include blockade of the renin-angiotensin system (RAS) with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Given our better understanding of the pathophysiology of diabetic nephropathy, newer therapies to treat this condition are slowly emerging.. Animal studies and a single clinical trial demonstrate efficacy of the renin inhibitor, aliskiren, to decrease a marker of nephropathy progression, that is albuminuria. On the basis of animal study results, pyridoxamine, an inhibitor of advanced glycation and ruboxistaurin, a protein kinase C inhibitor showed promise as new agent to treat nephropathy. The clinical trial results were less than gratifying, however. Sulodexide, a glycosaminoglycan, works to reduce proteinuria presumably by restoring the already reduced glycoproteins present in the glomerular basement membrane. Like other agents, sulodexide also looked promising in animal studies, but failed to demonstrate albuminuria reduction in a large multicentre clinical trial (SUN-Micro-Trial).. This review summarizes newer therapies for slowing the progression of diabetic nephropathy. Aliskiren shows promise from small clinical studies, but we await the results of the multicentre, international ALTITUDE trial in about 2012. On the basis of the results of trials only, pyridoxamine may have a chance at further evaluation, but that is also unclear.

Topics: Amides; Animals; Diabetic Nephropathies; Fumarates; Humans; Indoles; Maleimides; Pyridoxamine; Superoxides

The renin-angiotensin-aldosterone system (RAAS) is an important mediator of blood pressure (BP) and volume regulation in both normotensive and hypertensive persons and is a major contributor to hypertension-related target organ damage. The concept of renin inhibition for managing hypertension by blocking the RAAS pathway at its point of activation is very attractive since the renin-angiotensinogen reaction is the first and rate-limiting step in the generation of angiotensin II (Ang II). Aliskiren, the first in a new class of orally effective direct renin inhibitors (DRIs), is approved for the treatment of hypertension. It is effective in reducing BP in the general population of hypertensive patients and in special patient groups such as obese persons, and has a tolerability and safety profile similar to placebo. Aliskiren has renoprotective, cardioprotective and anti-atherosclerotic effects in animal models that appear to be independent of BP lowering. It reduces proteinuria in diabetic patients and has favorable neurohumoral effects in patients with symptomatic heart failure. Additional outcome trials are needed to establish the role of this novel class of antihypertensive medication in the therapeutic armamentarium.

Topics: Administration, Oral; Amides; Animals; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Fumarates; Humans; Hypertension; Kidney Diseases; Renin; Renin-Angiotensin System; Risk Assessment; Treatment Outcome

Cardiovascular (CV) and renal complications associated with diabetes can be attenuated with antihypertensives that work on the renin-angiotensin-aldosterone system (RAAS),particularly angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and possibly direct renin inhibitors (DRIs). Cardioprotective and renoprotective benefits are independent of the blood pressure-lowering effect of the RAAS inhibitor. Given more complete RAAS blockade, evidence has suggested that the use of ACE inhibitor/ARB combination therapy may provide greater target organ protection. However, recent data have challenged this assumption. Although advances have been made in reducing diabetic nephropathy progression through use of ACE inhibitors and ARBs, improvement in organ protection is needed because diabetes remains the leading cause of end-stage renal disease. Despite the use of these agents in patients with CV disease and diabetes, CV adverse events remain high, suggesting the need for improved outcomes. Newer agents such as DRIs may have the potential to offer similar target organ protection. The first DRI, aliskiren, administered alone or in combination with other RAAS inhibitors, has been shown to confer renoprotective and cardioprotective benefits in human and animal studies that have measured surrogate endpoints. An ongoing outcomes study (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints [ALTITUDE]), which is assessing renal and CV morbidity and mortality, will further define whether aliskiren provides additional benefits beyond RAAS inhibition and lowering of blood pressure.

Topics: Amides; Cardiovascular Diseases; Diabetes Mellitus; Fumarates; Humans; Renin; Renin-Angiotensin System

Aliskiren is the first direct renin inhibitor for the treatment of hypertension. Clinical experience from studies in over 14,000 patients has shown that aliskiren, alone or in combination with other antihypertensive therapies, provides effective blood pressure lowering with a good safety and tolerability profile.The ultimate aim of antihypertensive therapy, however, is to reduce the risk of adverse cardiovascular and renal outcomes.The effect of aliskiren on surrogate markers of organ damage and clinical outcomes is being assessed in the ongoing ASPIRE HIGHER programme, the largest clinical trials programme in the cardio-renal disease area. Results from the ALOFT, AVOID and ALLAY studies suggest that aliskiren has positive effects on markers of cardiovascular and renal damage in patients with type 2 diabetes and nephropathy, heart failure and left ventricular hypertrophy.ASPIRE HIGHER also includes four large-scale studies assessing the potential outcome benefits of aliskiren, and the results of these trials will help define the clinical utility of aliskiren in the treatment of cardiovascular and renal diseases. In this article, we review the antihypertensive efficacy of aliskiren and explore its potential in the management of cardiovascular and renal risk.

Topics: Amides; Antihypertensive Agents; Cardiovascular Diseases; Clinical Trials as Topic; Fumarates; Humans; Hypertension; Hypertrophy, Left Ventricular; Renin; Renin-Angiotensin System

The overall purpose of hypertension treatment is 2-fold. First, patients often have symptoms that are related to their high blood pressure and although subtle in many instances may be improved dramatically by blood pressure control. The main reason for blood pressure treatment, however, is to reduce the burden of cardiovascular complications and end organ damage related to the condition. This may be considered the ultimate goal of blood pressure treatment. In this respect, actual blood pressure measurements may be seen as surrogate end points as the organ protective effects of two antihypertensive agents may differ significantly even though their blood pressure lowering effects are similar. Thus beta-blockers, once seen as first-line treatment of hypertension for most patients, now are considered as third- or fourthline agents according to the latest NICE guidelines (National Institute for Health and Clinical Excellence, www.nice.org.uk/CG034). On the other hand, agents that inhibit the activity of the renin-angiotensin-aldosterone system (RAAS) system are being established as safe, effective and end organ protective in numerous clinical trials, resulting in their general acceptance as first-line treatment in most patients with stage 2 hypertension. This shift in emphasis from beta-blockers and thiazide diuretics is supported by numerous clinical trials and has proven safe and well tolerated by patients. The impact of this paradigm shift will have to be established in future long-term randomized clinical trials. The optimal combination treatment with respect to end organ protection has yet to be determined. Most combinations will include either a RAAS active agent and calcium channel blocker or two separate RAAS active agents working at different levels of the cascade. In this respect direct renin inhibitors and angiotensin receptor blockers seem particularly promising but the concept awaits evaluation in upcoming randomized clinical trials. Although safety data from the randomized clinical trials to date have been promising, we still lack data on the long-term effect of aliskiren on mortality and there still are patient groups where the safety of aliskiren is unexplored.

Topics: Aged; Aged, 80 and over; Amides; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin-Angiotensin System; United States

The number of well-controlled hypertensives is unacceptably low worldwide. Respecting the circadian variation of blood pressure, nontraditional antihypertensives, and treatment in early stages of hypertension are potential ways to improve hypertension therapy. First, prominent variations in circadian rhythm are characteristic for blood pressure. The revolutionary MAPEC (Ambulatory Blood Pressure Monitoring and Cardiovascular Events) study, in 3000 adult hypertensives investigates, whether chronotherapy influences the cardiovascular prognosis beyond blood pressure reduction per se. Second, melatonin, statins and aliskiren are hopeful drugs for hypertension treatment. Melatonin, through its scavenging and antioxidant effects, preservation of NO availability, sympatholytic effect or specific melatonin receptor activation exerts antihypertensive and anti-remodeling effects and may be useful especially in patients with nondipping nighttime blood pressure pattern or with nocturnal hypertension and in hypertensives with left ventricular hypertrophy (LVH). Owing to its multifunctional physiological actions, this indolamine may offer cardiovascular protection far beyond its hemodynamic benefit. Statins exert several pleiotropic effects through inhibition of small guanosine triphosphate-binding proteins such as Ras and Rho. Remarkably, statins reduce blood pressure in hypertensive patients and more importantly they attenuate LVH. Addition of statins should be considered for high-risk hypertensives, for hypertensives with LVH, and possibly for high-risk prehypertensive patients. The direct renin inhibitor, aliskiren, inhibits catalytic activity of renin molecules in circulation and in the kidney, thus lowering angiotensin II levels. Furthermore, aliskiren by modifying the prorenin conformation may prevent prorenin activation. At present, aliskiren should be considered in hypertensive patients not sufficiently controlled or intolerant to other inhibitors of renin-angiotensin system. Third, TROPHY (Trial of Preventing Hypertension) is the first pharmacological intervention for prehypertensive patients revealing that treatment with angiotensin II type 1 receptor blocker attenuates hypertension development and thus decreases the risk of cardiovascular events.

Topics: Amides; Animals; Antihypertensive Agents; Chronotherapy; Circadian Rhythm; Fumarates; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Melatonin

Hypertension is one of the most important risk factors for, and causes of, cardiovascular disease. The difficulty in achieving a normal blood pressure range in some patients makes the rate of cardiovascular disease high. For some years renin-angiotensin system inhibitors such as angiotensin-converting enzyme (ACE) and angiotensin receptor blockade have been objects of interest for treatment of cardiovascular disease. Aliskiren, the first approved renin inhibitor to reach the market, is a low molecular weight, orally active, hydrophilic nonpeptide molecule, which blocks angiotensin I generation. However it might also become a reasonable therapeutic choice in a broad number of clinical conditions, as stable coronary artery disease, cerebrovascular and cardiorenal disease, diabetes, and peripheral arterial disease. The aim of this review is to describe the effectiveness and safety of aliskerin in the treatment of hypertension.

Topics: Amides; Animals; Antihypertensive Agents; Drug Interactions; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System

The renin-angiotensin-aldosterone system (RAAS), an important regulator of blood pressure as well as fluid and electrolyte balance, plays an important role in the pathophysiology of cardiovascular and kidney diseases. Blockade of the RAAS with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-II (ANG-II) receptor blockers (ARBs) lowers blood pressure, decreases morbidity and mortality in patients with chronic heart failure, and decreases proteinuria and the rate of decline in renal function in patients with chronic kidney disease. Although these drugs are highly effective and are widely used in the management of cardiovascular and kidney diseases, current treatment regimens with ACEIs and ARBs may not completely suppress the RAAS. Combinations of ACEIs and ARBs have been shown to be superior to either agent alone for some, but certainly not all, composite cardiovascular and kidney outcomes. With the growing appreciation of the role of aldosterone in the pathogenesis of cardiorenal diseases and the recent approval of the direct renin inhibitor (DRI), aliskiren, additional combination strategies have emerged that may offer novel ways to more fully suppress the RAAS. This review examines what is presently known about ACEI/ARB combination therapy and explores alternative combination strategies that include DRIs and mineralocorticoid receptor blockers (MRBs).

Topics: Aldosterone; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fumarates; Humans; Kidney Diseases; Receptors, Mineralocorticoid; Renin-Angiotensin System

Despite the last three decades of progress in improving cardiovascular outcomes via renin-angiotensin-aldosterone system (RAAS) blockade in hypertensive patients, substantial residual morbidity/mortality remains. Attempts to improve clinical outcomes by combining angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have yielded mixed results. Adverse effects of RAAS blockade with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may relate to compensatory increases in plasma renin activity (PRA). The first-in-class direct renin inhibitor, aliskiren, blocks the RAAS at its point-of-activation, suppressing PRA and attenuating increases associated with other antihypertensives. Aliskiren (with or without other agents) provides significant and prolonged blood pressure reductions in a broad range of hypertensive patients and is well tolerated. Initial results from organ-protection studies are promising. Long-term outcomes studies should yield valuable information regarding the significance of direct renin inhibition in clinical practice.

Topics: Amides; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

Aliskiren, the first orally effective direct renin inhibitor, is an effective antihypertensive agent with distinctive properties including placebo-like tolerability, pharmacologic effects that persist after drug discontinuation, and a unique mechanism of action. When combined with agents that inhibit the renin-angiotensin-aldosterone system (RAAS), such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or beta-blockers, additional blood pressure reduction reflects more complete RAAS blockade. Concern that marked elevation in plasma renin concentration following aliskiren administration might lead to RAAS-induced paradoxical blood pressure increases appears unfounded, based upon analyses of patients participating in clinical trials. Studies in animals and humans indicate that aliskiren accumulates in renal tissue, blocks the intrarenal RAAS, and interferes with deleterious cellular effects of angiotensin II by mechanisms that may include enzymatic blockade of renin and prorenin at the site of the (pro)renin receptor. In patients with diabetic nephropathy, adding aliskiren to losartan resulted in an additional 20% reduction in urinary protein excretion. In patients with heart failure, aliskiren reduced brain natriuretic peptide levels when added to other RAAS inhibitors, suggesting an additional hemodynamic effect. The ASPIRE HIGHER clinical trials program is assessing whether the promising pharmacologic properties of aliskiren translate into long-term clinical benefits.

Topics: Amides; Animals; Antihypertensive Agents; Disease Models, Animal; Fumarates; Humans; Hypertension; Rats; Renin

The renin-angiotensin system (RAS) is a prime target for cardiovascular drug therapy. Inhibition of the RAS lowers blood pressure and confers protection against cardiovascular and renal events. These latter benefits cannot be entirely attributed to blood pressure lowering. Angiotensin-converting enzyme (ACE)-inhibitors and angiotensin receptor blockers (ARBs) have been studied extensively and, while there is irrefutable evidence that these agents mitigate the risk for cardiovascular and renal events, their protection is incomplete. In outcomes studies that have employed ACE-inhibitors or ARBs there has been a relatively high residual event rate in the treatment arm and this has been ascribed, by some, to the fact that neither ACE-inhibitors nor ARBs completely repress RAS. For this reason, combined RAS blockade with an ACE-inhibitor and ARB has emerged as a therapeutic option. In hypertension, combined RAS blockade elicits only a marginal incremental drop in blood pressure and it does not further lower the risk for cardiovascular events. In chronic heart failure and proteinuric renal disease, combining these agents in carefully selected patients is associated with a reduction in clinical events. Irrespective of the setting, dual RAS blockade is associated with an increase in the risk for adverse events, primarily hyperkalemia and worsening renal function. The emergence of the direct renin inhibitor, aliskiren, has afforded clinicians a new strategy for RAS blockade. Renin system blockade with aliskiren plus another RAS agent is the subject of ongoing large-scale clinical trials and early studies suggest promise for this strategy. Currently, combined RAS blockade with an ACE-inhibitor and an ARB should not be routinely employed for hypertension; however, the combination of an ACE-inhibitor or ARB with aliskiren might be considered in some patients given the more formidable blood pressure-lowering profile of this regimen. In carefully selected patients with heart failure or kidney disease, combination therapy with two RAS inhibitors should be considered.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Drug Therapy, Combination; Fumarates; Heart Failure; Humans; Hypertension; Kidney Diseases; Renin; Renin-Angiotensin System

After discovery of the first direct renin inhibitor, aliskiren, which blocks the renin-angiotensin-aldosterone system in the first rate limiting step, in addition to angiotensin-converting enzymes (ACE) and angiotensin-receptor blockers (ARB), renin has become an important target nowadays. The scope of this review is to give a detailed information regarding renin which has an important regulatory function in the body. It is crucial to understand renin and related structures in order to understand its functions in the organ systems. It is for sure that the ongoing trials will enlighten us more regarding the beneficial effects of renin inhibition in terms of morbidity and mortality.

Topics: Amides; Antihypertensive Agents; Fumarates; Humans; Renin; Renin-Angiotensin System

Arterial hypertension is an independent risk factor for cardiovascular diseases and one of the major causes for mortality worldwide. Drugs, that control hypertension effectively are therefore needed to reduce hypertension induced morbidity and mortality. The inhibition of the renin-angiotensin-aldosterone-system (RAAS) is one target to control blood pressure in these patients. The new direct renin inhibitor aliskiren is one new substance on the market to inhibit the RAAS effectively by suppression of the plasma renin activity, which inhibits the RAAS at its rate-limiting step. Therefore, aliskiren in monotherapy and in combination might yield beneficial effects for the patients. Nevertheless, blood pressure lowering has to be combined with a reduction of target organ damage for all drug classes prescribed to patients with hypertension. Therefore, we review here the major effects of this new drug not only in regard to hypertension but also in regard to target organ damage reduction and possible changes in morbidity and mortality, which future trials will investigate.

Topics: Amides; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Biphenyl Compounds; Cardiovascular Diseases; Diabetic Nephropathies; Diuretics; Drug Therapy, Combination; Europe; Fumarates; Germany; Heart Failure; Humans; Hydrochlorothiazide; Hypertension; Irbesartan; Japan; Prevalence; Prorenin Receptor; Protein Precursors; Randomized Controlled Trials as Topic; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Risk Factors; Tetrazoles; Time Factors; World Health Organization

The three main causes of Chronic Kidney Diseases [CKD] are diabetes mellitus, chronic glomerulonephritis and hypertension. CKD is an increasing burden in the community as more patients fall prey to kidney failure. Both dialysis and renal transplantation are expensive modalities of treatment for end stage renal failure [ESRF]. Through the years many clinical trials have been performed to retard the progression of CKD to ESRF. Most of the trials focus on three main strategies which aim at renal retardation, namely, control of hypertension, treatment of proteinuria and control of hypercholesterolaemia. More recently, investigators have been exploring the role of high dose ARBs as well as the use of Aliskiren, a renin inhibitor. Early therapeutic intervention is necessary as it will contribute to better chances of minimising glomerular damage and in the case of some, even lead to the improvement of renal function with regression of glomerulosclerosis.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Clinical Trials as Topic; Combined Modality Therapy; Drug Therapy, Combination; Fumarates; Humans; Hypercholesterolemia; Hypertension; Kidney Failure, Chronic; Losartan; Proteinuria; Renal Replacement Therapy

The importance of renin-angiotensin aldosterone system (RAAS) in cardiovascular and renal diseases has long ago been recognized. However despite the availability of many effective drugs, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers, RAAS blockade is incomplete in several patients with consequent uncontrolled high blood pressure and not efficacy cardiovascular and renal protection. Aliskiren is a new renin inhibitor that block the RAAS at its origin. Recent studies suggest that Aliskiren reduces blood pressure, inhibits plasma renin activity and attenuates renal damage in diabetic patients with nephropathy. This review summarized the results of the more important studies performed in hypertensive and diabetic patients in which Aliskiren showed to be a safe and effective antihypertensive agent that can be used in monotherapy or in combination with other drugs to provide additional options to improve blood pressure control.

Topics: Aldosterone; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Clinical Trials as Topic; Diabetic Nephropathies; Double-Blind Method; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Drug Combinations; Drug Interactions; Fumarates; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin; Tetrazoles; Valine; Valsartan

The renin-angiotensin system (RAS) plays a crucial role in development of hypertension, heart failure, as well as in the whole process of nephropathy, particularly of diabetic nephropathy, with or without proteinuria. Blockade of RAS plays the key role in the management of hypertension and other cardiovascular diseases. Angiotensin-converting enzyme (ACE) inhibitors do not provide the full blockade of angiotensin II because it is produced through alternative pathways. Angiotensin receptor blockers (ARBs) also block the negative feedback of angiotensin II upon renin like ACE inhibitors, leading to a several fold increase in angiotensin II levels. Aliskiren is an orally-active, nonpeptidic, direct inhibitor of renin which simultaneously reduces angiotensin I, angiotensin II and plasma renin activity (PRA). This is the main point of action of aliskiren, making it completely different from ACE inhibitors and ARBs. Aliskiren introduces a new concept into the management of hypertension. However, the question concerning its real role in the management of heart failure and its place in the existing therapeutic schemes with ACE inhibitors, ARBs, beta blockers and antagonists of aldosterone receptor, will be answered by numerous ongoing studies and clinical trials. Aliskiren shows renoprotective and antiproteinuric effects similar to those of ACE inhibitors and ARBs. The available results demonstrate that aliskiren provides a new approach to the antagonism of the RAS, offering possibilities of a more efficacious and effective treatment of hypertension, heart failure and proteinuria in diabetic patient.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin-Angiotensin System

The US Food and Drug Administration (FDA) has approved several new drugs in the past 2 years. This article provides an overview of some of the newer drugs that are likely to find wider use in the future. The drugs reviewed in this article can be used to treat cardiovascular system problems, diabetes mellitus, multiple sclerosis, hepatitis B infection, hyponatremia, Parkinson's disease, rheumatoid arthritis, pain, constipation, and insomnia. Another drug discussed can be used to help a patient stop smoking. The article also discusses Gardasil, the recombinant vaccine against human papilloma virus (types 6, 11, 16, and 18).

Topics: Abatacept; Acetanilides; Amides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antiparkinson Agents; Antirheumatic Agents; Antiviral Agents; Apomorphine; Benzazepines; Cardiovascular Agents; Fumarates; Hepatitis B; Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18; Humans; Hypoglycemic Agents; Immunoconjugates; Multiple Sclerosis; Natalizumab; Nucleosides; Papillomavirus Vaccines; Pharmacology, Clinical; Piperazines; Pyrazines; Pyrimidinones; Quinoxalines; Ranolazine; Sitagliptin Phosphate; Smoking Cessation; Telbivudine; Thymidine; Triazoles; Varenicline; Viral Vaccines

The pharmacology, bioavailability and pharmacokinetics, clinical efficacy, adverse effects and toxicity, drug interactions, and dosage and administration of aliskiren as well as safety and economic issues related to its use are reviewed.. Aliskiren is the first of a new class of antihypertensive agents, direct renin inhibitors, that act by blocking the rate- limiting step of the renin-angiotensin- aldosterone system (RAAS). It was approved by the Food and Drug Administration in 2007 for use as monotherapy or in combination with other antihypertensives. Clinical studies comparing aliskiren monotherapy with placebo indicated a dose-dependent reduction in both systolic and diastolic blood pressure (BP). Greater reductions in BP have been achieved when aliskiren was used in combination with hydrochlorothiazide or an angiotensin-receptor blocker. The most common adverse effects reported in clinical trials were headache, fatigue, dizziness, diarrhea, and nasopharyngitis. Aliskiren has not been studied in patients with moderate renal dysfunction; as a RAAS-acting drug, it should be prescribed for such patients only with caution.. Aliskiren at a dosage of 150 or 300 mg daily may be a good option for control of mild-to-moderate hypertension in patients with or without diabetes in whom first-line antihypertensives have failed to adequately control BP; comparative studies with other antihypertensives are needed to determine which patients can most benefit from aliskiren therapy.

Topics: Amides; Antihypertensive Agents; Biological Availability; Drug Interactions; Fumarates; Humans; Treatment Outcome

Aliskiren is the first orally bioavailable direct renin inhibitor approved for the treatment of hypertension. It acts at the point of activation of the renin-angiotensin-aldosterone system, or renin system, inhibiting the conversion of angiotensinogen to angiotensin I by renin and thereby reducing the formation of angiotensin II by angiotensin-converting enzyme (ACE) and ACE-independent pathways. Aliskiren is a highly potent inhibitor of human renin in vitro (concentration of aliskiren that produces 50% inhibition of renin 0.6 nmol/L). Aliskiren is rapidly absorbed following oral administration, with maximum plasma concentrations reached within 1-3 hours. The absolute bioavailability of aliskiren is 2.6%. The binding of aliskiren to plasma proteins is moderate (47-51%) and is independent of the concentration. Once absorbed, aliskiren is eliminated through the hepatobiliary route as unchanged drug and, to a lesser extent, through oxidative metabolism by cytochrome P450 (CYP) 3A4. Unchanged aliskiren accounts for approximately 80% of the drug in the plasma following oral administration, indicating low exposure to metabolites. The two major oxidized metabolites of aliskiren account for less than 5% of the drug in the plasma at the time of the maximum concentration. Aliskiren excretion is almost completely via the biliary/faecal route; 0.6% of the dose is recovered in the urine. Steady-state plasma concentrations of aliskiren are reached after 7-8 days of once-daily dosing, and the accumulation factor for aliskiren is approximately 2. After reaching the peak, the aliskiren plasma concentration declines in a multiphasic fashion. No clinically relevant effects of gender or race on the pharmacokinetics of aliskiren are observed, and no adjustment of the initial aliskiren dose is required for elderly patients or for patients with renal or hepatic impairment. Aliskiren showed no clinically significant increases in exposure during coadministration with a wide range of potential concomitant medications, although increases in exposure were observed with P-glycoprotein inhibitors. Aliskiren does not inhibit or induce CYP isoenzyme or P-glycoprotein activity, although aliskiren is a substrate for P-glycoprotein, which contributes to its relatively low bioavailability. Aliskiren is approved for the treatment of hypertension at once-daily doses of 150 mg and 300 mg. Phase II and III clinical studies involving over 12,000 patients with hypertension have demonstrated that

Topics: Administration, Oral; Amides; Antihypertensive Agents; Biological Availability; Drug Interactions; Fumarates; Humans; Hypertension; Renin

The US Food and Drug Administration's approval in March 2007 of aliskiren, the first commercially available direct renin inhibitor, for the treatment of hypertension met with great enthusiasm. Clinical trials have demonstrated it to be as effective as other commonly prescribed antihypertensive agents with few side effects. Preclinical studies in genetically manipulated rats have shown it to be effective in reversing angiotensin II-induced cardiac and renal damage. Despite the notable absence of human clinical data for this agent, many clinicians have touted aliskiren as the ideal agent to achieve additional suppression of the renin-angiotensin-aldosterone system (RAAS) as a means to reduce the morbidity and mortality of chronic diseases of the cardiovascular and renal systems. Clinical studies are ongoing and future studies are planned to prove its effectiveness in several chronic diseases known to be related to RAAS activation.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Drug Evaluation, Preclinical; Fumarates; Humans; Hypertension; Prorenin Receptor; Receptors, Cell Surface; Renin; Renin-Angiotensin System

Aliskiren, an antihypertensive drug approved in the United States and Europe, is the first in a new class known as direct renin inhibitors. Aliskiren has been evaluated for safety and tolerability in more than 6400 patients. It has demonstrated a favorable safety and tolerability profile alone or in combination with other drugs.. This article reviews the currently available safety and tolerability data for aliskiren.. Using the search term aliskiren, MEDLINE (no timeframe set) and major cardiovascular congresses (2005-2008) were searched. Articles and abstracts with safety and drug interaction data were included.. Aliskiren may share common adverse effects observed with angiotensin-converting enzyme (ACE)-inhibitor and angiotensin receptor blocker (ARB) therapy. In placebo-controlled trials, those commonly reported for aliskiren at the approved dosage were headache, diarrhea, for personal and fatigue, with incidences similar to those of placebo. Aliskiren has been well tolerated in black, geriatric, diabetic, or obese patients and patients with renal or hepatic impairment. Aliskiren neither inhibits nor induces the cytochrome P450 system; it does not inhibit P-glycoprotein, but is a substrate for this drug transporter. Adding a direct renin inhibitor to another renin-angiotensin-aldosterone system (RAAS) inhibitor may further improve cardiovascular outcomes, renal outcomes, or both, without increasing the incidence of adverse effects.. Aliskiren is well tolerated, has an adverse effect profile comparable to that of placebo, and has a low potential for drug interactions. Data from ongoing trials evaluating the effects of aliskiren on surrogate markers, morbidity, and mortality will further define the role of direct renin inhibition in the antihypertensive armamentarium.

Topics: Amides; Antihypertensive Agents; Clinical Trials as Topic; Fumarates; Humans; Placebos; Renin

The direct renin inhibitor aliskiren has recently been approved for the treatment of hypertension in humans. The potential for these newer agents having an advantage over the existing renin-angiotensin-aldosterone system (RAAS) antagonists in the treatment of hypertension and related target organ damage has drawn the interest of several investigators. In this review, we discuss the potential advantages and disadvantages of this newest antihypertensive class over other available RAAS antagonists.. The antihypertensive efficacy of aliskiren monotherapy has been compared with that of other RAAS antagonists and combinations of aliskiren with these agents. These studies have shown that aliskiren is equally effective as angiotensin receptor blockers and may be slightly more effective than angiotensin converting enzyme inhibitors in lowering blood pressure. In contrast to the other RAAS antagonists, aliskiren shuts down the entire downstream RAAS cascade. This results in greatly increased plasma renin concentration due to removal of angiotensin II-mediated feedback inhibition of renin release, which has raised concerns about whether direct renin inhibition adds anything to inhibition of downstream components of the RAAS cascade.. The potential advantages and disadvantages of aliskiren therapy versus existing RAAS antagonists in treating hypertension and target organ damage are under investigation.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin; Risk Factors

Direct renin inhibitors such as aliskiren offer a novel way of treating hypertension and its co-morbidities, conditions with a considerable prevalence, morbidity, and mortality worldwide.. The burden of hypertension worldwide and the role of the renin-angiotensin-aldosterone system in this disease will be reviewed. Current treatments for hypertension and its co-morbidities that work by manipulating this system will be discussed. The development of, and clinical trials involving, direct renin inhibitors will be reviewed, with a focus on aliskiren.. PubMed was utilized to search the most recent literature on the topics of the renin-angiotensin-aldosterone system, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone and aliskiren.. The direct renin inhibitors, including aliskiren, are new agents with great promise for the treatment of hypertension and its co-morbid conditions, including renal and cardiovascular disease.

Topics: Amides; Antihypertensive Agents; Cardiovascular Diseases; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

Aliskiren is the first renin inhibitor to be licensed for use as an antihypertensive drug in both the United States and Europe. Opinions vary considerably concerning the future of aliskiren and renin inhibition. Some experts argue that renin inhibitors should only be prescribed when less expensive blockers of the renin-angiotensin system (RAS), with established effects on morbidity and mortality, are not tolerated or have failed to reduce blood pressure effectively. Others propose that because renin is a highly specific catalyst for the rate-limiting step of the RAS, renin inhibitors have the potential to supersede angiotensin-converting enzyme inhibitors and angiotensin receptor blockers as the preferred inhibitors of the cascade in patients with particular pathologies and/or genotypes. It has also been suggested that dual blockade of the RAS might be particularly advantageous. This review discusses the currently available evidence, and concludes with speculation concerning the future of direct renin inhibition.

Topics: Amides; Antihypertensive Agents; Fumarates; Humans; Hypertension; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Vacuolar Proton-Translocating ATPases

To systematically analyze the efficacy and safety of aliskiren for the treatment of hypertension in comparison to placebo, other monotherapy, and various combination therapies.. A PubMed database (1966-June 2008) search was conducted with aliskiren as a search term with limits of humans, written in English, and in title only. Phase III pivotal clinical studies retrieved by PubMed database and resources such as printed labeling, approval letter, pharmacology reviews, and medical reviews posted in Drug@FDA website were evaluated with regard to study design and outcomes of efficacy and safety.. Six Phase III pivotal clinical studies compared various doses of aliskiren to placebo and some studies compared aliskiren to treatment with other monotherapies or combinations. Aliskiren in doses of 300 mg showed a statistically significant reduction in both systolic and diastolic blood pressure versus placebo. Comparison to other antihypertensive treatments suggest that aliskiren doses of 150 and 300 mg may induce blood pressure changes similar to those seen with moderate doses of hydrochlorothiazide or angiotensin receptor blockers. Aliskiren in combination with angiotensin receptor blockers or hydrochlorothiazide showed additional blood pressure reduction only when higher doses of aliskiren were used. Aliskiren appears to be well tolerated, with diarrhea being the only statistically significant adverse event.. Aliskiren is a novel antihypertensive that exerts its effects through the direct inhibition of renin. Although the drug is well tolerated, its modest effects on blood pressure and the present lack of evidence of impact on objective cardiovascular outcomes appear to limit its utility in the general treatment of hypertension at this time.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Clinical Trials, Phase III as Topic; Diarrhea; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin

Hypertension is a chronic condition associated with an increased risk of mortality and morbidity. The renin-angiotensin-aldosterone system is an important target site for five antihypertensive drug classes: beta blockers, renin inhibitors, ACE inhibitors, angiotensin receptor blockers (ARBs) and aldosterone inhibitors. Renin is the enzyme responsible for converting angiotensinogen to angiotensin I, which is then converted to angiotensin II. Renin inhibitors prevent the formation of both angiotensin I and angiotensin II . Renin inhibitors do not affect kinin metabolism and may produce fewer adverse effects than ACE inhibitors such as dry cough or angioedema.. To quantify the dose-related blood pressure lowering efficacy of renin inhibitors versus placebo in the treatment of primary hypertension.. We searched the following databases for randomised, double blind, placebo-controlled trials of renin inhibitors: Medline (1966-March 2008), EMBASE (1988-March 2008), Cochrane CENTRAL, and bibliographic citations from retrieved references. No language restrictions were applied.. Study design had to meet the following criteria: double-blinded, placebo-controlled; random allocation to a specific dose of renin inhibitor group and parallel placebo group; duration of follow-up of at least three weeks.. Two reviewers independently extracted data and assessed trial quality using risk of bias tables. Disagreements were resolved by discussion or a third reviewer. Data synthesis and analyses were done using the Cochrane Review Manager software, RevMan 5. Data for continuous variables were combined using a weighted mean difference method. Dichotomous variables were analysed using relative risk.. Six trials (N=3694) met the inclusion criteria for this review. Aliskiren was the only renin inhibitor studied in these studies. The meta-analysis shows that aliskiren has a dose-related both systolic/diastolic blood pressure lowering effect as compared to placebo: aliskiren 75 mg -2.9/-2.3 mmHg, aliskiren 150 mg -5.5/-3.0 mmHg, aliskiren 300 mg -8.7/-5.0, aliskiren 600 mg -11.4/-6.6 mmHg. Aliskiren 300 mg significantly lowered both SBP and DBP as compared to aliskiren 150 mg (SBP:-2.97 (95% CI -3.99, -1.95) and DBP: -1.66 (95% CI -2.32, -1.0). Aliskiren has no effect on blood pressure variability. No data was available to assess the effect of aliskiren on heart rate and pulse pressure. This review found weak evidence that with short- term use, aliskiren does not increase withdrawals due to adverse effects as compared to placebo.. Aliskiren has a dose-related blood pressure lowering effect better than placebo. This effect is similar to that determined for ACE inhibitors and ARBs.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin

Arterial hypertension is one of the major risk factors for the development of cardiovascular diseases such as heart failure, ischemic heart disease, chronic kidney disease and cerebrovascular events. Adequate blood pressure control is vital for the management of patients with vascular disease. New therapeutic alternatives are appearing on the horizon to improve the degree of blood pressure control in these patients, such as direct renin inhibitors, beta-blockers with additional properties, carotid receptor- stimulating devices and vaccination against arterial hypertension. Direct renin inhibitors are a new family of antihypertensive drugs that have so far shown a good antihypertensive effect and an additive effect on reduction of proteinuria in patients with diabetic nephropathy. Recent meta-analyses suggest that betablockers used as first-line treatment for uncomplicated arterial hypertension could have a less beneficial effect on the development of cardiovascular disease than other antihypertensive drugs. However, the emergence of new subtypes of beta-blockers with other hemodynamic and metabolic properties could change this conception. Carotid receptor-stimulating devices and vaccination against arterial hypertension, although not totally new therapies, are being revitalized, with preliminary results that suggest that they could be used for the treatment of arterial hypertension in patients with a specific profile. Although scientifically stimulating, the long-term beneficial effects of these new therapeutic alternatives on target-organ protection still need to be confirmed.

Topics: Adrenergic beta-Antagonists; Amides; Angiotensin II; Antihypertensive Agents; Baroreflex; Carotid Sinus; Electric Stimulation Therapy; Electrodes, Implanted; Fumarates; Humans; Hypertension; Immunotherapy, Active; Oligopeptides; Randomized Controlled Trials as Topic; Renin; Vaccines, Synthetic

Aliskiren, the first in a new class of orally effective direct renin inhibitors (DRIs) was recently approved for the treatment of hypertension. In this review, we discuss the history of the development of DRIs and available data regarding the effects of DRIs in the treatment of hypertension and related target organ damage.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin

Topics: Amides; Animals; Fumarates; Humans; Kinetics; Prorenin Receptor; Protein Binding; Receptors, Cell Surface; Renin; Signal Transduction

An association has been shown between plasma renin activity (PRA) and the risk of cardiovascular disease. There is also evidence that angiotensin II exerts detrimental effects on progression and instabilization of atherosclerotic plaque. The renin-angiotensin system (RAS) can be inhibited through inhibition of angiotensin I (Ang I) generation from angiotensinogen by direct renin inhibitors, inhibition of angiotensin II (Ang II) generation from angiotensin I by angiotensin-converting enzyme inhibitors and finally by direct inhibition of the action of Ang II receptor level. Aliskiren, the first direct renin inhibitor to reach the market, is a low-molecular-weight, orally active, hydrophilic nonpeptide. Aliskiren blocks Ang I generation, while plasma renin concentration increases because the drugs blocks the negative feed-back exerted by Ang II on renin synthesis. Because of its long pharmacological half-life, aliskiren is suitable for once-daily administration. Its through-to-peak ratio approximates 98% for the 300 mg/day dose. Because of its mechanism of action, aliskiren might offer the additional opportunity to inhibit progression of atherosclerosis at tissue level. Hypertension is an approved indication for this drug, which is also promising for the treatment of heart failure. The efficacy of this drug in reducing major clinical events is being tested in large ongoing clinical trials.

Topics: Amides; Angiotensinogen; Antihypertensive Agents; Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Drug Administration Schedule; Fumarates; Humans; Prorenin Receptor; Protein Precursors; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Treatment Outcome; Vacuolar Proton-Translocating ATPases

Hypertension is a major risk factor for the development of cardiovascular and renal disease. The incidence of hypertension is increasing globally and the rate of blood pressure control remains inadequate. Renin-angiotensin-aldosterone system (RAAS) plays a crucial role in volume regulation and maintenance of blood pressure. Pathological activation of RAAS results in chronic hypertension and consequent end organ damage. Most patients with hypertension require combination therapy using agents with complimentary mechanisms of action. Hydrochlorothiazide (HCTZ) together with an agent blocking the RAAS such as an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) are widely used effective anti-hypertensive therapy. Aliskiren is an orally effective direct renin inhibitor that blocks the generation of angiotensin I from angiotensinogen, the rate limiting step of RAAS activation. Studies have shown equivalent antihypertensive efficacy of aliskiren when compared to existing medications such as HCTZ, ACE inhibitors and ARBs. Aliskiren has also been tested in combination therapies. The current review aims to look at the efficacy of aliskiren therapy in hypertension and the evidence for using aliskiren in combination with HCTZ.

Topics: Amides; Animals; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Renin; Renin-Angiotensin System; Treatment Outcome

Topics: Amides; Angiotensins; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin

Aliskiren represents the first member in a new class of antihypertensive drugs. Inhibiting the renin-angiotensin system at its rate-limiting step is an idea that has been pursued for >30 years; however, earlier compounds failed because of problems related to efficacy, bioavailability, and/or side effects. Aliskiren, a 610 Da nonpeptide molecule, has exceptional affinity for the human renin enzymatic site and a half-life of about 40 h, which make its 3% bioavailability clinically unimportant with continued administration. The drug is not metabolized by CYP P450 enzymes and is excreted >90% unchanged by the fecal route. No adjustments are necessary for renal function, liver function, age, ethnicity, or other prescribed drugs. Blood pressure reductions are similar to those provided by other monotherapies. Interestingly, aliskiren combined with angiotensin receptor blocker or angiotensin-converting enzyme inhibitor therapy leads to a further blood pressure reduction as does combination with a diuretic or calcium channel blocker. The fact that plasma renin activity is reduced to low levels with aliskiren could provide a theoretical advantage over other treatments, while increases in total renin (prorenin) after the drug poses additional food for thought. Studies with primary cardiovascular and renal end points to address these possibilities are in progress.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Fumarates; Humans; Kidney Failure, Chronic; Renin-Angiotensin System

Fifty years ago, investigators identified renin inhibition as the preferred pharmacologic approach to blockade of the renin-angiotensin system. Renin is a monospecific enzyme that catalyzes the rate-limiting step in the synthesis of angiotensin II. Amplified enzymatic activity and additional physiological effects occur when renin and pro-renin bind to the (pro)renin receptor. Until very recently, development of clinically effective renin inhibitors remained elusive. Molecular modeling was used to develop aliskiren, a potent, low-molecular-weight, nonpeptide, direct renin inhibitor with sufficient bioavailability to produce sustained suppression of plasma renin activity after oral administration. In patients with hypertension, aliskiren produces dose-dependent blood pressure (BP) reduction and 24-h BP control up to a dose of approximately 300 mg once daily; at these doses, aliskiren shows placebo-like tolerability. Its antihypertensive potency is approximately equivalent to that of angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and diuretics. After abrupt withdrawal, persistent BP reduction and prolonged suppression of plasma renin activity is observed. When combined with diuretics, fully additive BP reduction is seen. When given with an angiotensin receptor blocker, aliskiren produces significant additional BP reduction indicative of complimentary pharmacology and more complete renin-angiotensin system blockade. Clinical trials are currently underway assessing the effects of aliskiren combined with an angiotensin receptor blocker on intermediate markers of end organ damage, and long-term end point trials are planned. The results of these studies will ultimately determine the place of renin inhibition and aliskiren in the treatment of hypertension and related cardiovascular disorders. The effect of aliskiren on receptor-bound renin and pro-renin is the subject of active investigation.

Topics: Amides; Animals; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Molecular Structure; Renin; Renin-Angiotensin System

The development of aliskiren, the first orally effective renin inhibitor, utilized molecular modeling based upon X-ray crystallographic analysis of renin's active site to design a potent, low molecular weight renin inhibitor with improved bioavailability (approximately 2.6%). In patients with hypertension, dose-dependent BP reduction occurs with aliskiren 75-300 mg once daily; at these doses, the safety and tolerability profile is comparable to placebo. In direct comparison studies, BP reduction with aliskiren is equivalent to commonly used antihypertensive agents including diuretics, ACE inhibitors, and ARBs. Persistent BP reduction and prolonged suppression of plasma renin activity (PRA) is observed after aliskiren withdrawal. Aliskiren suppresses PRA when given either as monotherapy or in combination with other agents. When added to an ARB, aliskiren blocks compensatory RAS activation and produces significant additional BP reduction. In patients with diabetic nephropathy, addition of aliskiren to losartan, 100 mg resulted in a 20% greater reduction in proteinuria. Ongoing studies evaluating the long-term renal protective effects of aliskiren and its effects on ventricular remodeling are currently planned or underway.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Clinical Trials as Topic; Dose-Response Relationship, Drug; Fumarates; Humans; Hypertension; Renin

Hypertension is a major risk factor for cardiovascular morbidity and mortality and currently has been estimated at 30% of the US population. Of these, only 36.8% have their blood pressure reduced to recommended levels of lower than 140/90 mmHg for uncomplicated hypertension, or less than 130/80 mmHg for patients with diabetes mellitus or renal disease. Since monotherapy controls blood pressure in less than 50% of treated hypertensive patients, combination therapy is often required to bring blood pressure to the recommended levels of the 7th Joint National Committee report. One of the most effective and widely used combinations is the combination of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker with hydrochlorothiazide (HCTZ). Aliskiren, a new blocker of the renin-angiotensin system has been developed and approved by the US FDA on 18th January 2008 for the treatment of hypertension. Aliskiren is a direct inhibitor of renin, the rate-limiting enzyme for the production of angiotensin II, a powerful vasoconstrictive peptide. Several randomized clinical trials have demonstrated that aliskiren administered in single daily doses of 150, 300 or 600 mg alone and in combination with HCTZ 12.5 and 25 mg is effective in lowering blood pressure, and is safe and well tolerated. In this article, the pharmacokinetic and pharmacodynamic profile and the clinical application of aliskiren alone and in combination with HCTZ will be discussed.

Topics: Amides; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Approval; Drug Interactions; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Randomized Controlled Trials as Topic; Renin; Risk Assessment; Severity of Illness Index; Survival Rate; Treatment Outcome; United States; United States Food and Drug Administration

The first evidence of the existence of renin was presented over 100 years ago. However, the importance of renin and the renin-angiotensin system in the pathogenesis of cardiovascular disease was only fully realized in the 1970s. It was another 20 years before the first inhibitors of renin were available for clinical research. Here, we describe the discovery and development of aliskiren, an orally active renin inhibitor, which became the first drug in its class to receive regulatory approval. In 2007, it was approved for the treatment of hypertension by the US Food and Drug Administration and the European Medicines Agency.

Topics: Amides; Antihypertensive Agents; Cardiovascular Diseases; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

The renin-angiotensin-aldosterone system (RAAS) has long been recognized to play a significant role in hypertension pathophysiology. Certain agents that modify the RAAS can control blood pressure and improve cardiovascular outcomes. Aliskiren is the first of a new class of antihypertensive agents known as renin inhibitors.. The goal of this article was to discuss the clinical pharmacology of aliskiren and its use in the management of hypertension, as well as potential uses in other cardiovascular disorders.. Peer-reviewed articles and abstracts were identified from the MEDLINE and Current Contents databases (both 1966-October 1, 2007) using the search terms aliskiren, drug interaction, pharmacokinetics, and pharmacology. Citations from available articles were reviewed for additional references. Abstracts presented at recent professional meetings were also examined.. Nine published clinical studies have evaluated the effect of aliskiren in lowering blood pressure in hypertensive patients, either alone or in combination with other antihypertensive agents. This review summarizes those studies. Patients treated with aliskiren had significantly lower blood pressure compared with patients with mild to moderate hypertension (systolic blood pressure [SBP] 140-180 mm Hg and diastolic blood pressure [DBP] 95-110 mm Hg) who received placebo. Aliskiren in doses of 75 to 300 mg daily produced reductions of SBP (-5.3 to -15.8 mm Hg) and DBP (-5.8 to -12.3 mm Hg); placebo produced reductions of SBP that ranged from -2.85 to -10.0 mm Hg and DBP reductions from -3.26 to -8.6 mm Hg (P < 0.05 in all studies between aliskiren and placebo). Aliskiren's blood pressure-lowering effect at doses of 75 to 300 mg daily was comparable to irbesartan 150 mg daily and valsartan 80 to 360 mg daily alone. When aliskiren was added to ramipril, hydrochlorothiazide, amlodipine, irbesartan, or valsartan, significant additive blood pressure-lowering effects were reported (P < 0.05 in all clinical trials). The total incidence of adverse events was similar to placebo and other comparative agents, including irbesartan, valsartan, losartan, ramipril, and hydrochlorothiazide. The overall adverse-event rates were 22%, 35% to 52%, 25% to 52%, 34% to 55%, and 33% to 52% for aliskiren 37.5, 75, 150, 300, and 600 mg, respectively. The most commonly reported adverse events included headache, dizziness, and fatigue. Studies with cardiovascular outcomes as end points have not been performed with aliskiren.. Aliskiren is an effective alternative agent for blood pressure management. Before aliskiren can be recommended as a routine first-line agent, however, clinical studies must explore if the blood pressure-lowering effect will translate into improvement in cardiovascular outcomes.

Topics: Amides; Antihypertensive Agents; Clinical Trials as Topic; Drug Interactions; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

Aliskiren, the first renin inhibitor with sufficient bioavailability for oral use, is now available to clinicians treating hypertension.. The novel mechanism by which aliskiren works was used to provide understanding of its therapeutic and adverse effects.. After reviewing physiology and preclinical studies, human studies of aliskiren in hypertension were reviewed. Effects of aliskiren on serum levels and enzymatic activity of renin were explored.. Aliskiren has antihypertensive efficacy similar to existing medications such as thiazide diuretics, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, and can be used in drug combinations. Preclinical studies indicate possible cardioprotective and renoprotective effects, similar to other inhibitors of the renin-angiotensin cascade, but future studies are needed in humans.

Topics: Administration, Oral; Amides; Animals; Antihypertensive Agents; Biological Availability; Drug Evaluation, Preclinical; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin

Initial attempts to inhibit renin in humans have faced numerous difficulties. Molecular modeling and X-ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors such as aliskiren. Aliskiren has a low bioavailability (2.6% to 5%) compensated by its high potency to inhibit renin and a long plasma half-life (24 to 40 h), which makes it suitable for once-daily dosing. The once-daily administration of aliskiren to hypertensive patients lowers blood pressure as strongly as standard doses of established AT1 receptor blockers (losartan, valsartan, and irbesartan), angiotensin-converting enzyme inhibitors (ramipril and lisnopril), hydrochlorothiazide, or long-acting calcium channel blockers (amlodipine). In combination therapy, aliskiren further decreases blood pressure when combined with either hydrochlorothiazide, amlodipine, valsartan, irbesartan, or ramipril. However, the biochemical consequences of renin inhibition differ from those of angiotensin I-converting enzyme inhibition and angiotensin II antagonism, particularly in terms of angiotensin profiles and interactions with the bradykinin-NO-cGMP pathway. Blockade of the renin-angiotensin system with angiotensin I-converting enzyme inhibitors, AT1 receptor blockers, or a combination of these drugs has become one of the most successful therapeutic approaches in medicine. However, it remains unclear how to optimize renin-angiotensin system blockade to maximize cardiovascular and renal benefits. In this context, renin inhibition to render the renin-angiotensin system fully quiescent is a new possibility requiring further study. Preliminary results show that short-term administration of aliskiren has beneficial anti-albuminuric effects in diabetic patients with chronic nephropathy and favorable neurohormonal effects in patients with chronic heart failure.

Topics: Amides; Clinical Trials as Topic; Drug Therapy, Combination; Fumarates; Humans; Renin; Renin-Angiotensin System

The first oral direct renin inhibitor, aliskiren, recently received approval for the treatment of hypertension. This article addresses the premise, promise, and potential limitations of this new class of renin-angiotensin system inhibitor. Although aliskiren adds to a list of more than 100 drugs approved for the treatment of hypertension, its introduction into clinical medicine is of particular interest because of the novel mechanism of action: inhibition of renin's catalytic activity, the most proximal and rate-limiting step in renin-angiotensin system activation. By producing more complete renin-angiotensin system inhibition than with existing agents, direct renin inhibitors may afford greater protection from hypertensive complications. Other potential advantages include additional blood pressure reduction when used in combination therapy, a placebo-like side-effect profile, avid renal concentration, and long duration of action. Potential limitations include modest levels of blood pressure reduction that are equivalent to but not greater than angiotensin receptor blockers, reduced gastrointestinal absorption with a high-fat meal, and large reactive increases in renin secretion--the functional importance of which is under intense investigation. The results of outcomes trials are eagerly awaited.

Topics: Administration, Oral; Amides; Blood Pressure Determination; Drug Approval; Female; Follow-Up Studies; Fumarates; Humans; Hypertension; Male; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System; Severity of Illness Index; Treatment Outcome; United States; United States Food and Drug Administration

Hypertension is one of the major health care problems worldwide since it markedly increases the risk for development of heart disease, stroke, generalized vascular disease, and renal failure. The renin-angiotensin system (RAS) with its major end-product angiotensin II (Ang II) plays a fundamental role in blood pressure regulation through direct and indirect mechanisms. Pharmacologically, we can inhibit the RAS using angiotensin-converting enzyme inhibitors and AT1 receptor blocker. Inhibiting renin directly with a clinically useful drug eluded pharmacologists until recently. However, the once-daily, orally effective, small-molecule, direct renin inhibitor aliskiren has recently changed this state of affairs. Aliskiren, with its 40-h half-life and ideal pharmacokinetics, can now address angiotensin production directly at its rate-limiting step. A novel transgenic rat model outfitted with the human renin and angiotensinogen genes allowed the testing of aliskiren in an animal model. Preclinical data demonstrated that aliskiren prolonged survival, decreased cardiac hypertrophy and the inducibility of arrhythmias, proteinuria, and attenuated inflammation. All these features might result in improved target-organ damage. Studies in humans attest to an effective blood pressure-lowering action, a largely side effect-free profile, and the option of several combination therapies. Aliskiren is the first of a novel antihypertensive drug class. The preclinical data is very promising. Nevertheless, for the evaluation of its potency in humans, we have to wait for more clinical data.

Topics: Amides; Animals; Drug Evaluation, Preclinical; Fumarates; Humans; Renin

Aliskiren, a renin inhibitor, is the first in a new class of drugs interfering with the renin angiotensin system. Aliskiren was approved by the US Food and Drug Administration (FDA) in March 2007, and in Europe in August 2007 for the treatment of hypertension (marketed as Tekturna and Rasilez, respectively). Several clinical trials demonstrated effective blood pressure reduction due to aliskiren treatment. Whether aliskiren exhibits morbidity and mortality benefits for patients beyond its blood pressure reduction capability, can only be judged after realization of comparative long-term clinical trials. Furthermore, it remains to be seen, whether the use of aliskiren will be indicated for treatment of additional diseases, as it was the case for other inhibitors of the renin angiotensin system. In fact, recent and ongoing clinical trials regarding heart failure and diabetic nephropathy demonstrated first beneficial effects of aliskiren in these conditions (reduction of urinary albumin/creatinine-ratio and NTproBNP, respectively).

Topics: Amides; Animals; Antihypertensive Agents; Cardiovascular Diseases; Contraindications; Fumarates; Gastrointestinal Diseases; Humans; Hypertension; Kidney Diseases; Renin

To review the safety, efficacy, pharmacology, pharmacokinetics, and drug interactions of aliskiren for the treatment of mild-to-moderate hypertension.. A literature search was conducted using MEDLINE (1966-January 2007), International Pharmaceutical Abstracts (1970-January 2007), and Cochrane database (2006) for the key words aliskiren or SPP100. References of selected articles were also reviewed. Abstract data were included only in the absence of significant published data.. Available English-language data from reviews, abstracts, and clinical trials were selected. For review of efficacy, randomized controlled trials were preferred.. Aliskiren is a renin inhibitor, the first in a new class of antihypertensives. As renin catalyzes the rate-limiting step of the renin-angiotensin system (RAS), renin inhibition may offer a theoretical advantage over other RAS inhibitors, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). In short-term clinical trials (< or =8 wk) of subjects with mild-to-moderate hypertension, single daily doses of aliskiren 150-300 mg produced significant systolic and diastolic blood pressure reduction similar to that achieved with ACE inhibitors and ARBs, with placebo-like tolerability, without an elevation in heart rate or evidence of tolerance.. Aliskiren appears to be a safe and effective treatment option in mild-to-moderate hypertension. Although long-term outcome data have not been published, aliskiren is a promising option for RAS inhibition.

Topics: Amides; Antihypertensive Agents; Clinical Trials as Topic; Drug Interactions; Fumarates; Humans; Hypertension; Renin

This editorial considers the use of the first selective oral renin inhibitor, aliskiren, in reducing angiotensin (Ang) II reactivation or aldosterone (ALDO) escape during renin-angiotensin-aldosterone system (RAAS) inhibition. RAAS blockade with angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor AT(1) blockers (ARBs) is very useful for the treatment of arterial hypertension, chronic heart failure (CHF), atherosclerosis and diabetes. 'Ang II reactivation' and 'ALDO escape' or 'breakthrough' have been observed during either ACEI or ARB treatment, and may attenuate the clinical benefit of RAAS blockade. Renin and Ang I accumulate during ACE inhibition, and might overcome the ability of an ACEI to effectively suppress ACE activity. There is also data suggesting that 30 - 40% of Ang II formation in the healthy human during RAAS activation is formed via renin-dependent, but ACE-independent, pathways. Moreover, ACE gene polymorphisms contribute to the modulation and adequacy of the neurohormonal response to long-term ACE inhibition, at least in patients with CHF (up to 45% of CHF patients have elevated Ang II levels despite the long-term use of an ACEI) or diabetes. The reactivated Ang II promotes ALDO secretion and sodium reabsorption. ALDO breakthrough also occurs during long-term ARB therapy, mainly by an AT(2)-dependent mechanism. This was related to target-organ damage in animal models. Oral renin inhibition with aliskiren has showed excellent efficacy and safety in the treatment of hypertension. Aliskiren can be co-administered with ACEIs, ARBs or hydrochlorothiazide. Furthermore, there is evidence suggesting that aliskiren reduces Ang II reactivation in ACE inhibition and ALDO escape during treatment with an ACEI or an ARB, at least to the degree that this is associated with the RAAS. For RAAS-independent ALDO production, the combination of aliskiren with eplerenone might prove useful.

Topics: Administration, Oral; Aldosterone; Amides; Angiotensin II; Animals; Antihypertensive Agents; Enzyme Activation; Enzyme Reactivators; Fumarates; Heart Failure; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System; Vasoconstrictor Agents

The previous dogma that the renin-angiotensin system exerts its effects entirely through angiotensin II is now under challenge as scientists explore the properties of the prorenin/renin receptor and start to study local vascular actions of renin independent of its production of angiotensin in the plasma. The demonstrated blood pressure effects of the first clinically developed renin inhibitor, aliskiren, have confirmed the validity of this new class of drugs. Future research, exploring effects on the renin-angiotensin system that perhaps cannot be provided by the currently used blockers of this system, will test whether enhanced clinical benefits might result from this new pharmacologic strategy in patients at risk of cardiovascular events.

Topics: Amides; Fumarates; Heart Failure; Humans; Hypertension; Renin; Renin-Angiotensin System; Treatment Outcome

Aliskiren is a potent, highly specific renin inhibitor with better oral bioavailability than earlier renin inhibitors and a long plasma half-life that makes it suitable for once-daily dosing. The efficacy and safety of aliskiren in treating hypertension has been studied in clinical trials both as monotherapy, comparing it with existing antihypertensive therapies, and in combination with other antihypertensive agents, including the diuretic hydrochlorothiazide, the angiotensin-converting enzyme inhibitor ramipril, and the calcium channel blocker amlodipine. From the extensive database acquired to date, it is clear that aliskiren is an effective antihypertensive agent, with once-daily administration resulting in dose-dependent systolic and diastolic blood pressure reductions. Combinations with existing antihypertensives are producing promising additional blood pressure-lowering effects.

Topics: Administration, Oral; Amides; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Fumarates; Humans; Hypertension; Renin; Treatment Outcome

Topics: Adult; Amides; Antihypertensive Agents; Fumarates; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin

A review of six clinical trials of aliskiren involving >5,000 patients with mild to moderate hypertension indicated that this first of a new class of orally active antihypertensive drugs is no more effective than angiotensin-converting enzyme inhibitors (CEIs), angiotensin receptor blockers (ARBs), or diuretics for lowering blood pressure. The starting dose is 150 mg; 300 mg is usually more effective, but 600 mg is no better than 300 mg. Aliskiren in combination with a diuretic appeared to lower blood pressure more than an aliskiren-ARB combination, but still failed to control blood pressure (<140/90) in 50% of the patients. Although aliskiren suppresses plasma renin activity, it causes much greater reactive rises in plasma renin concentration than does any other antihypertensive class tested. Because aliskiren, like CEIs and ARBs, only blocks 90% to 95% of plasma renin, the pressor consequences of its greater reactive increases in plasma renin concentration appear to offset its net ability to lower blood pressure, especially with higher doses. Patients with hyperreactive renin systems (renovascular, advanced, and malignant hypertension) were excluded from all of the trials. Until the possibility is eliminated of inducing increases in blood pressure with aliskiren in patients with highly reactive renin levels, it seems safe and simple to stick to the less expensive, equally effective and widely available generic CEI drugs for treating the renin factor in hypertension.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Clinical Trials as Topic; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Male; Renin

The renin-angiotensin-aldosterone system (RAAS) plays an important part in the pathogenesis of arterial hypertension and the complications it causes in organs (the heart, the circulatory system, the brain, the kidneys), heart failure and kidney diseases. Materials that block the most upstream point of the RAAS cascade (ACE inhibitors - ACEI, AT1,-receptor (AT1R) blockers, aldosterone receptor blockers) have greatly expanded our options in the treatment and primary and secondary prevention of cardiovascular and renal diseases. ACEI and AT1R blockers interrupt the normal feedback provided by the release of renin into the circulatory system from the kidneys. After they are applied the reactive increase in active circulating renin leads to increased creation of angiotensin I and angiotensin II and the subsequent return of aldosterone secretions to pre-treatment values ("escape" phenomenon). The possible negative effect of these intermediary products of an incomplete blockade of RAAS on organ complications lead to an effort to develop a material that could block the renin-angiotensin cascade at its first stage--i.e. a renin blocker. The first efforts with renin antibodies or peptide analogues of renin prosegments failed to satisify the basic requirements for long-term medication--effectiveness when used orally. In recent years the first non-peptidic, oral renin ihibitor providing sustained effects has been developed, aliskiren fumarate. Aliskiren reduces BP depending on the dose (50-300 mg/day) in monotherapy or in combination with hydrochlorothiazide. Aliskiren lowers plasma renin activity (PRA) and neutralises the activation of the RAAS triggered by hydrochlorothiazide. Ambulatory BP monitoring has shown that taking the medicine once a day has a 24-hour effect and its continued residence in the kidneys suggests renoprotective effects. The compound is in the third stage of clinical tests as a monotherapy or in combination for the treatment of hypertension. It has also been shown to have an influence on the regression of cardiac hypertrophy (Aliskiren in Left-Ventricular Hypertrophy trial - ALLAY), the treatment of heart failure (Aliskiren Observation of Heart Failure Treatment trial - ALOFT) and diabetic (Aliskiren in the Evaluation of Proteinuria in Diabetes trial - AVOID). In April 206, the FDA permitted the use of aliskiren in the USA for the treatment of high BP and it is currently undergoing testing in Europe. The renin inhibitor has minimal undesirable

Topics: Amides; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

Aliskiren (Tekturna) is an orally active, nonpeptidic inhibitor of renin, the enzyme involved in the initial and rate-limiting step of the renin-angiotensin system (RAS). In the US, aliskiren is approved for the treatment of hypertension and may be used alone or in combination with other antihypertensive agents. Monotherapy with aliskiren 150-300mg once daily was effective in lowering blood pressure (BP) and providing 24-hour BP control; it was generally well tolerated when administered for up to 1 year to patients with mild to moderate hypertension. In the short term (1-3 months), the BP-lowering effect of aliskiren 150-300mg once daily was significantly greater than that of hydrochlorothiazide (HCTZ) 12.5-25mg once daily and noninferior to, or significantly greater than, that of ramipril 5-10mg once daily. It was similar to that of valsartan 160-320mg once daily and losartan 100mg once daily, and similar to, or significantly greater than, that of irbesartan 150mg once daily. Aliskiren provided significant additional BP-lowering effects when combined with HCTZ 12.5-25 mg/day, ramipril 5-10 mg/day, amlodipine 5mg once daily or valsartan 160-320 mg/day; combination therapy was well tolerated. Long-term administration of aliskiren-based therapy was superior to HCTZ- and ramipril-based therapies in lowering BP after 6 months, and was similarly well tolerated. The ultimate role of aliskiren will be determined by the results of target organ protection studies, which are ongoing, and a cardiovascular outcome trial, which is planned. Nonetheless, by offering a new approach to the blockade of the RAS, aliskiren provides a useful addition to the therapeutic options available to treat patients with mild to moderate hypertension.

Topics: Amides; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

The first renin inhibitor, aliskiren, will soon enter the clinical arena. This review summarizes the potential differences between renin inhibitors and the currently existing blockers of the renin-angiotensin system (RAS) [ie, the ACE inhibitors and the angiotensin II type 1 (AT(1)) receptor antagonists], taking also into consideration the recently discovered (pro)renin receptor. This receptor not only activates the inactive precursor of renin, prorenin, but it also exerts direct renin/prorenin-induced effects, independently of angiotensin. The review ends with a brief overview of the available (pre)clinical aliskiren data and a description of its safety profile.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Drug Delivery Systems; Fumarates; Humans; Hypertension; Prorenin Receptor; Receptors, Cell Surface; Renin; Renin-Angiotensin System

As an important cascade involved in the regulation of blood pressure and volume homeostasis, the renin-angiotensin system (RAS) has been targeted for blood pressure control. In the last decades, the most successful strategy to control the RAS has been the inhibition of the angiotensin-converting enzyme (ACE) and the angiotensin type 1 (AT(1)) receptor. Small-molecule inhibitors targeting these steps have been widely used clinically. However, complete inhibition of the RAS is not achievable by blocking the ACE or the AT(1) because of the compensatory rise in plasma renin activity, which limits the efficacy of many RAS drugs. Direct inhibition of renin, the first and rate-limiting step in the RAS cascade, is the preferred strategy for controlling the RAS, and much progress has been made in the research and development of renin inhibitors. This review covers the evolution of renin inhibitors and discusses the advantages of renin inhibition at the enzymatic and biosynthetic levels for blood pressure control.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antibodies; Antihypertensive Agents; Blood Pressure; Drug Design; Enzyme Inhibitors; Fumarates; Humans; Hypertension; Molecular Structure; Peptides; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Vacuolar Proton-Translocating ATPases; Vitamin D

The suppression of the renin-angiotensin system by angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has been proven in many studies to treat hypertension and reduce cardiovascular events; however, reducing angiotensin I receptor stimulation results in the loss of the negative-feedback signal, leading to increased plasma renin activity. Numerous direct renin inhibitors were synthesized, but abandoned owing to low potency, poor bioavailability and short half-life. Aliskiren, a direct renin inhibitor of a novel structural class, inhibits the activity of the renin produced and, thus, its capacity to form angiotensin I, as measured by plasma renin activity. Aliskiren has been recently shown to be efficacious in hypertensive patients at once-daily oral dosing with favorable pharmacokinetics and the potential to improve end-organ protection.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Cardiovascular System; Drug Interactions; Fumarates; Humans; Hypertension; Kidney; Renin; Renin-Angiotensin System

Despite the availability of many effective, well-tolerated drugs, a significant proportion of treated hypertensive patients still have uncontrolled high blood pressure (BP) and thus face serious morbidity and mortality. The renin-angiotensin aldosterone system (RAAS) is a key target for BP control and for cardiovascular and renal protection. Renin controls the rate-limiting step in the RAAS cascade and hence is the optimal target for RAAS suppression. Aliskiren is the first direct renin inhibitor (DRI) to be approved by the U.S. Food and Drug Administration and the European Medicines Agency for treating hypertension.. To provide an overview of the pharmacology, pharmacokinetics, preclinical, and clinical efficacy and safety data on the DRI aliskiren.. Approximately 70% of essential hypertension is associated with elevated renin levels. Aliskiren is a potent and highly specific inhibitor of renin, with oral bioavailability of 2.6% and an elimination half-life of 40 hours, making it suitable for once-daily oral administration. Aliskiren dose-dependently reduced BP, inhibited plasma renin activity (PRA), attenuated renal damage in animal models, and showed efficient and longer- lasting blockade of the RAAS in normotensive human subjects compared with other RAAS inhibitors. The clinical efficacy and safety of aliskiren have been evaluated both as monotherapy and in combination with other antihypertensive agents in phase II and phase III trials of patients with mild to severe hypertension. When used as monotherapy, aliskiren led to significant dose-dependent reductions in BP from baseline that were greater than those obtained with placebo and comparable with those achieved with an angiotensin II receptor blocker (ARB). The combination of aliskiren with a diuretic, a calcium channel blocker (CCB), an angiotensin-converting enzyme inhibitor (ACEI), or an ARB generally had greater and longer-lasting BP-lowering efficacy than did single agents alone. Aliskiren also countered the reactive increase in PRA caused by diuretic, CC B, ACEI, and ARB therapy. Once-daily treatment with aliskiren was well tolerated.. As a DRI, aliskiren blocks the RAAS more completely than do other current downstream RAAS inhibitors. When used once daily, aliskiren is a safe and effective antihypertensive agent that can be used as monotherapy or in combination with other agents to provide additional options to improve BP control.

Topics: Amides; Animals; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin

At Ciba-Geigy (now Novartis), the clinical development of the CGP38560 renin inhibitor was halted due to insufficient pharmacokinetics. This indicated that the peptidomimetic approach to the development of antihypertensive agents was improper. Real non-peptide drug candidates were then expected to provide the necessary framework for obtaining the desired properties. For this purpose a homology model of the enzyme was used to characterize the binding mode of CGP38560 in complex with the renin model and served as a basis for the four chemistry laboratories that were assigned to this project. The renin team worked in a full structure-based perspective with this model, and four chemically-unrelated non-peptide series were discovered acting as renin inhibitors at the 1-3 nanomolar level. One of these leads was selected for further development and led to Aliskiren, which has been just approved by the FDA. Here is presented the successful structure-based strategy that enabled the discovery of several non-peptide inhibitors and the recent launch of a new drug that will be commercialized in the United States under the name Tekturna (for the treatment of high blood pressure as monotherapy or in combination with other high blood pressure medications).

Topics: Amides; Animals; Biomimetic Materials; Drug Approval; Drug Design; Enzyme Inhibitors; Fumarates; Humans; Hypertension; Models, Molecular; Renin; Structure-Activity Relationship; United States; United States Food and Drug Administration

Aliskiren is the first member of a novel class of antihypertensive agents, the renin inhibitors, that has been approved by the US Food and Drug Administration for the treatment of hypertension. This review discusses its potential differences compared with existing renin-angiotensin-aldosterone system blockers, focusing also on the inactive precursor of renin, prorenin, and the recently discovered (pro)renin receptor. The review summarizes the findings from all clinical trials with aliskiren published so far, and provides an overview of the safety and tolerability of the new drug.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hypertension; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Vacuolar Proton-Translocating ATPases

Topics: Amides; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin

Topics: Amides; Cardiovascular Agents; Etiocholanolone; Fumarates; Heart Failure; Humans; Neovascularization, Physiologic; Ventricular Remodeling

Activation of the renin-angiotensin system (RAS) plays an important role in the pathogenesis of heart failure. Thus, strategies for the treatment of heart failure have focused on agents that block the RAS. More recently, the role of angiotensin receptor blockers (ARBs) in heart failure therapy has been better defined. This article examines the rationale and role of ARBs in the treatment of patients with heart failure on the basis of evidence from clinical trials.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Fumarates; Heart Failure; Humans; Losartan; Randomized Controlled Trials as Topic; Renin; Tetrazoles; Treatment Outcome; Valine; Valsartan

Aliskiren (CGP-60536 or SPP100) is the first oral direct renin inhibitor and the first new class of antihypertensive agents to be introduced in more than a decade. Aliskiren taken once a day, alone or in combination with other antihypertensive agents, has been shown to be effective in reducing blood pressure and is generally well tolerated. Based on an extensive clinical trials program, aliskiren was approved for the treatment of hypertension in March 2007 (as Tekturna; Novartis Pharmaceuticals, East Hanover, NJ, USA) by the U.S. Food and Drug Administration and in August 2007 (as Rasilez, Enviage, Sprimeo, Tekturna and Riprazo, all from Novartis) for the treatment of essential hypertension by the European Commission. Although the indication for aliskiren is treatment of essential hypertension, benefits similar to those demonstrated with certain angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) are anticipated for aliskiren. Some of the 44 trials with aliskiren are listed in Table II. Inhibition of renin, which is the first and rate-limiting step in the renin-angiotensin pathway has theoretical advantages over either ACE inhibitors or ARBs.

Topics: Administration, Oral; Amides; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin

The importance of renin-angiotensin-aldosterone system (RAAS) in diseases such as hypertension, congestive heart failure and chronic renal failure has long ago been recognized. It has also been established that inhibition of RAAS, using inhibitors of the angiotensin-converting enzyme (ACE) or angiotensin II receptor blockers (ARB), is an effective way to intervene with the pathogenesis of these disorders. Renin inhibitors block the RAAS at the highest level, at its origin, and might thus offer a new exciting approach for pharmacotherapy of arterial hypertension. Aliskiren is the first in a new class of orally active, non-peptide, low molecular weight renin inhibitors, and so far the only renin inhibitor that has progressed to phase III clinical trials. This review summarizes the available data on the pharmacokinetic and pharmacodynamic properties of aliskiren and its clinical development for treatment of arterial hypertension.

Topics: Amides; Antihypertensive Agents; Drug Interactions; Fumarates; Humans; Hypertension; Renin

With the development of aliskiren, blockade of the renin-angiotensin-aldosterone system (RAAS) at the level of the interaction of renin with a substrate has become a clinical reality. This review covers the specific features of the first agent likely to achieve widespread clinical exposure, aliskiren. The potential of renin inhibition must be viewed in the context of the remarkable efficacy of both angiotensin-converting enzyme (ACE) inhibition and angiotensin receptor blockers (ARBs). The implications of blockade of the renin system at its rate-limiting step are reviewed, with the therapeutic implications for both the renin inhibitor employed alone or the renin inhibitor combined with an ACE inhibitor or ARB. The relevant and necessary studies are ongoing.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Clinical Trials as Topic; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Vacuolar Proton-Translocating ATPases

In the Hungarian population, there is also a growing number of patients with hypertension. In order to prevent the target organ's damage or in order to slow down the process, it is indispensable to reach the therapeutic target blood pressure. An opportunity for reducing the cardiovascular morbidity and mortality is the inhibition of the renin-angiotensin-aldosterone system. So far, we have had three large families, the angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and aldosterone antagonists, to our disposal. The above are the key molecules for the hypertension treatment, but their application is accompanied by plasma renin level elevations, and thus, increase of plasma renin activation. The protection against increased plasma renin activation is helped by the renin inhibitors. Several decades were needed for their clinical introduction, till a non-peptide, safety medicament was successfully produced, which can be administered orally in small once-per-day doses. Their most promising representative is aliskiren. Still an open question is the mapping of the advantage of the angiotensin-converting enzyme inhibitor and angiotensin receptor blockers combination with aliskiren. The morbidity and mortality investigations are still missing and we curiously await them.

Topics: Amides; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Antihypertensive Agents; Eplerenone; Fumarates; Heterocyclic Compounds, 3-Ring; Humans; Mineralocorticoid Receptor Antagonists; Spironolactone

Topics: Adipocytes; Amides; Angiotensin-Converting Enzyme 2; Antihypertensive Agents; Biphenyl Compounds; Fumarates; Hypertension; Insulin Resistance; Irbesartan; Metabolic Syndrome; Peptidyl-Dipeptidase A; Prorenin Receptor; Receptors, Angiotensin; Receptors, Cell Surface; Renin-Angiotensin System; Tetrazoles; Vacuolar Proton-Translocating ATPases

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Antihypertensive Agents; Aspartic Acid Endopeptidases; Benzimidazoles; Biphenyl Compounds; Drug Combinations; Drug Design; Endothelin Receptor Antagonists; Endothelin-Converting Enzymes; Fumarates; Humans; Hypertension; Immunotherapy, Active; Metalloendopeptidases; Mineralocorticoid Receptor Antagonists; Phenylpropionates; Pyrimidines; Randomized Controlled Trials as Topic; Renin; Tetrazoles

Angiotensin (Ang) II plays important roles in the development of hypertension and cardiovascular and renal injury. Pharmaceutical approaches to block its activity led to the development of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Numerous trials have documented their efficacy in controlling blood pressure, minimising left ventricular remodelling, preventing progression to heart failure, ameliorating proteinuria and retarding renal disease progression. Although they are considered safe in general, there remain concerns about the potential for adverse events in certain target populations. Recently, several novel, low molecular weight renin inhibitors without the extended peptide-like backbone of previous renin inhibitors were developed with favourable pharmacokinetic properties. They have been shown to successfully reduce Ang II levels in normal volunteers and to lower blood pressure in patients with mild-to-moderate hypertension. In this review, the authors summarise current knowledge about these renin inhibitors.

Topics: Abnormalities, Drug-Induced; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Clinical Trials as Topic; Fumarates; Humans; Hyperkalemia; Hypertension; Hypotension; Inappropriate ADH Syndrome; Male; Mice; Renin

Initial attempts to inhibit renin in humans have faced numerous difficulties. Molecular modeling and X-ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors, such as aliskiren. Recent preclinical and clinical data suggest that this drug may be of value for treating patients with cardiovascular and renal disorders.. The once-daily administration of aliskiren to hypertensive patients lowers blood pressure as strongly as, or more strongly than, standard doses of established angiotensin II type 1 receptor blockers. It further decreases blood pressure in combination with hydrochlorothiazide. The biochemical consequences of renin inhibition differ from those of angiotensin I-converting enzyme inhibition and angiotensin II antagonism, particularly in terms of angiotensin profiles and interactions with the bradykinin-nitric oxide-cGMP pathway and possibly the (pro)renin receptor.. Blockade of the renin-angiotensin system with angiotensin I-converting enzyme inhibitors, angiotensin II type 1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine. It remains unclear, however, as to how to optimize the renin-angiotensin system blockade to maximize cardiovascular and renal benefits. In this context, renin inhibition to render the renin-angiotensin system fully quiescent is a new possibility requiring further study.

Topics: Amides; Animals; Fumarates; Prorenin Receptor; Protein Precursors; Receptors, Cell Surface; Renin; Renin-Angiotensin System

The renin-angiotensin system (RAS) plays a pivotal role in the progression of some forms of hypertension and cardiovascular disease. The development of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) has provided physicians with effective and well-tolerated inhibitors of the RAS. However, it remains open to question whether ACE inhibitors and ARBs have fully delivered the reductions in cardiovascular risk that we might have expected. There is little doubt that in conditions such as chronic and acute heart failure or diabetic nephropathy these drugs have provided significant protection. But, in patients with high-risk hypertension, for instance, the anticipated benefits of RAS blockade have been less obvious. This article provides a critical assessment of the results of clinical trials of ACE inhibitors and ARBs across a variety of clinical conditions and assesses the potential need for new methods for blocking the renin system, including the use of renin inhibitors.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Clinical Trials as Topic; Fumarates; Humans; Hypertension; Meta-Analysis as Topic; Renin; Renin-Angiotensin System; Terminology as Topic

A new drug might make a positive contribution to existing therapies for hypertension by: 1) reducing blood pressure (BP) via a novel pharmacologic mechanism; 2) possessing pharmacologic or pharmacokinetic properties that make it superior to other members of its class; or 3) facilitating BP control in refractory patients. In this paper, we review four experimental agents that promise to advance therapeutics by one of these mechanisms. Aliskiren is the first in a new class of potent, orally effective renin inhibitors. Aliskiren produces dose-dependent BP reduction with few side effects and constitutes a novel pharmacologic approach to renin-angiotensin-aldosterone inhibition. Nebivolol is a third-generation, cardioselective beta-blocker that produces vasodilation and improves endothelial function via the l-arginine/nitric oxide pathway. Clevidipine is an ultra-short-acting, vascular-selective, dihydropyridine calcium antagonist that is being developed for intravenous use in acute hospitalized patients. Darusentan is an endothelin(A) selective endothelin receptor antagonist that is effective in achieving BP control in a significant percentage of patients who remain uncontrolled despite treatment with three or more antihypertensive drugs.

Topics: Adrenergic beta-Antagonists; Amides; Antihypertensive Agents; Benzopyrans; Blood Pressure; Calcium Channel Blockers; Drugs, Investigational; Endothelin A Receptor Antagonists; Ethanolamines; Fumarates; Humans; Hypertension; Nebivolol; Phenylpropionates; Pyridines; Pyrimidines; Renin; Treatment Outcome

In recent years, the renin-angiotensin-aldosterone system has been shown to be crucial not only in blood pressure haemostasis but also in the evolution of atherosclerosis, which ultimately determines morbidity and mortality. The angiotensin-converting enzyme inhibitors and, recently, the angiotensin receptor blockers (with their low adverse-effect profile) have added a new dimension to the drug treatment of hypertension. Just a decade after the introduction of angiotensin receptor blockers, physicians treating hypertension are now offered another exciting approach to achieving blockade of the renin-angiotensin-aldosterone system through the inhibition of renin. This review outlines the background evidence for aliskiren, the first orally active renin inhibitor.

Topics: Amides; Animals; Antihypertensive Agents; Drugs, Investigational; Fumarates; Humans; Hypertension; Renin

Use of drugs that inhibit the renin-angiotensin system is an effective way to intervene in the pathogenesis of cardiovascular and renal disorders. The idea of blocking the renin system at its origin by inhibition of renin has existed for more than 30 years. Renin inhibition suppresses the generation of the active peptide angiotensin II. The first generation of orally active renin inhibitors were never used clinically because of low bioavailability and weak blood-pressure-lowering activity. At present, aliskiren is the first non-peptide orally active renin inhibitor to progress to phase-III clinical trials. It might become the first renin inhibitor with indications for the treatment of hypertension and cardiovascular and renal disorders. Novel compounds with improved oral bioavailability, specificity, and efficacy are now in preclinical development. This Review summarises the development of oral renin inhibitors and their pharmacokinetic and pharmacodynamic properties, with a focus on aliskiren.

Topics: Administration, Oral; Adult; Aged; Amides; Animals; Biological Availability; Blood Pressure; Female; Fumarates; Half-Life; Humans; Hypertension; Kidney; Male; Middle Aged; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System; Structure-Activity Relationship

The Joint National Committee and the World Health Organization are in agreement that hypertension in most patients who are treated is controlled inadequately and that rates of cardiovascular morbidity remain high. Additional pharmacologic treatments could ameliorate this situation. The renin-angiotensin-aldosterone system has been a highly successful pharmacologic target, as the system is strongly implicated in the development of hypertension-related target organ damage. However, compensatory increases in plasma renin levels that lead to adjustments in angiotensin production and conversion present limitations for existing renin-angiotensin-aldosterone system inhibitors. A once-daily, orally effective, small-molecule renin inhibitor, aliskiren, is now available to address angiotensin production directly at its rate-limiting step. Studies in humans attest to an effective BP-lowering effect, a side effect profile no different from AT1 receptor blockers, and the option of combination therapies. A novel animal model of high human renin hypertension in the rat attest to target organ protection. Because angiotensin receptor blockade, angiotensin-converting enzyme inhibition, calcium channel blockade, and diuretic therapy all lead to sharp increases in plasma renin activity, aliskiren offers a novel circumvention.

Topics: Amides; Animals; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

The renin-angiotensin aldosterone system (RAAS) plays a key role in the regulation of blood pressure, acting via the effects of the hormone angiotensin (Ang) II. Ang II increases blood pressure and can exert growth-promoting effects leading to end-organ damage. Excess RAAS activity has been shown to be a major underlying cause of hypertension, heart failure, and related cardiovascular disorders. Inhibitors of renin block the RAAS at its first and rate-limiting step and thus appear to offer an excellent opportunity for blood pressure control. In the past two decades various potential renin inhibitors have been developed but have not been clinically useful. This review discusses a recent patent in the development of a novel class of non-peptide renin inhibitors: an alkanecarboxamide, aliskiren (SPP-100; Novartis). Aliskiren is effective in animal models, while recent results from studies in humans indicate that aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Renin; Renin-Angiotensin System

Speedel Pharma is developing aliskiren (formerly CGP-60536), a renin inhibitor under license from Novartis, for the potential treatment of several cardiovascular disorders. By October 2001, a phase IIb study in hypertension had been completed, and phase III studies for this indication were anticipated for 2002; at this time, phase II studies in congestive heart failure and chronic renal failure were ongoing.

Topics: Amides; Animals; Antihypertensive Agents; Clinical Trials as Topic; Fumarates; Humans; Renin

We tested the hypothesis that chronic treatment with the direct renin inhibitor aliskiren improves vascular function in resistance and conduit arteries of type two diabetic and hypertensive patients.. Sixteen patients with mild essential hypertension and with a previous diagnosis of noninsulin-dependent diabetes mellitus were included in the study. Patients were then randomized to aliskiren (150 mg once daily, n = 9), or ramipril (5 mg once daily, n = 7). Each patient underwent a biopsy of the subcutaneous tissue and small arteries were dissected and mounted on a pressurized micromyograph to evaluate endothelium dependent vasorelaxation in response to acetylcholine ± N omega-nitro-L-arginine methyl ester hydrochloride in vessels precontracted with norepinephrine. Endothelial function has been quantified also in large conduit arteries by flow-mediated dilation.. A similar office blood pressure-lowering effect was observed with the two drugs, although changes in DBP were not statistically significant in the ramipril group. Aliskiren significantly improved endothelium-dependent relaxation in subcutaneous resistance arteries, as well as increased flow-mediated dilation in conduit arteries, whereas the effects induced by ramipril did not reach statistical significance. Only aliskiren significantly increased the expression of p1177-endothelial nitric oxide synthase in the endothelium. Both aliskiren and ramipril had a negligible effect on markers of oxidative stress.. Aliskiren restored endothelial function and induced a more prompt peripheral vasodilation in hypertensive and diabetic patients possibly through the increased production of nitric oxide via the enhanced expression and function of the active phosphorylated form of endothelial nitric oxide synthase.

Topics: Amides; Blood Pressure; Diabetes Mellitus; Endothelium, Vascular; Fumarates; Humans; Hypertension; Nitric Oxide; Renin; Vasodilation

Topics: Aged; Amides; Antihypertensive Agents; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Fumarates; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Risk Assessment

Heart failure (HF) trials initiated in the last century highlighted many differences between men and women. Of particular concern was undertreatment of women compared with men, but much has changed during the past 20 years.. This study sought to identify these changes, which may give a new perspective on the management of, and outcomes in, women with HF.. The study analyzed 12,058 men and 3,357 women enrolled in 2 large HF with reduced ejection fraction (HFrEF) trials with near identical inclusion and exclusion criteria and the same principal outcomes. Outcomes were adjusted for other prognostic variables including N-terminal pro-B-type natriuretic peptide.. Women were older and more often obese than men were, had slightly higher systolic blood pressure and heart rate, and were less likely to have most comorbidities, except hypertension. Women had more symptoms and signs (e.g., pedal edema 23.4% vs 19.9%; p < 0.0001) and worse quality of life-median Kansas City Cardiomyopathy Questionnaire Clinical Summary Score 71.3 (interquartile range: 53.4 to 86.5) versus 81.3 (interquartile range: 65.1 to 92.7; p < 0.0001)-despite similar left ventricular ejection fraction and N-terminal pro-B-type natriuretic peptide. However, women had lower mortality (adjusted hazard ratio: 0.68; 95% confidence interval: 0.62 to 0.74; p < 0.001) and risk of HF hospitalization (hazard ratio: 0.80; 95% confidence interval: 0.72 to 0.89; p < 0.001). Diuretics and anticoagulants were underutilized in women. Device therapy was underused in both men and women, but more so in women (e.g., defibrillator 8.6% vs. 16.6%; p < 0.0001).. Although women with HFrEF live longer than men, their additional years of life are of poorer quality, with greater self-reported psychological and physical disability. The explanation for this different sex-related experience of HFrEF is unknown as is whether physicians recognize it. Women continue to receive suboptimal treatment, compared with men, with no obvious explanation for this shortfall.

Topics: Adult; Aged; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Female; Follow-Up Studies; Fumarates; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Quality of Life; Sex Factors; Stroke Volume

Because of concerns about the safety of aliskiren in patients with diabetes, study treatment was stopped prematurely in the Aliskiren Trial of Minimizing OutcomeS for Patients with HEart failuRE (ATMOSPHERE). We examined outcomes and treatment effect in these patients compared with those without diabetes.. ATMOSPHERE included 7016 patients with heart failure and a reduced ejection fraction (HFrEF) randomly assigned to enalapril plus aliskiren, aliskiren alone, or enalapril. At baseline, 1944 (27.7%) patients had diabetes. Median follow-up was shorter in patients with diabetes compared with those without (24 months vs. 46 months). Among patients with diabetes, the primary endpoint of cardiovascular death or hospitalization for heart failure occurred in 216 patients (33.1%) in the enalapril group (reference), 172 (27.4%) in the aliskiren group [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.67-1.00; P = 0.053], and 196 (29.5%) in the combination group (HR 0.86, 95% CI 0.71-1.04; P = 0.13). The effects of the treatments studied did not differ significantly compared with patients without diabetes. In patients with diabetes, aliskiren monotherapy was associated with a lower risk of symptomatic hypotension compared to enalapril [42 (6.7%) vs. 65 (10.0%); P = 0.04], whereas other adverse events were generally balanced between the three groups.. In patients with HFrEF and diabetes, there was no signal of harm and a trend towards benefit when direct renin inhibition monotherapy was compared with an angiotensin-converting enzyme inhibitor, whereas combined aliskiren and enalapril treatment led to more adverse events with no improvement in outcomes. Treatment effects did not differ in patients with diabetes compared with those without. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00853658.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cause of Death; Diabetes Mellitus; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Enalapril; Europe; Female; Follow-Up Studies; Fumarates; Heart Failure; Humans; Male; Middle Aged; Prospective Studies; Stroke Volume; Survival Rate

The self-administered Michigan Neuropathy Screening Instrument (MNSI) is used to diagnose diabetic peripheral neuropathy. We examined whether the MNSI might also provide information on risk of death and cardiovascular outcomes.. In this post hoc analysis of the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) trial, we divided 8463 participants with type 2 diabetes and chronic kidney disease (CKD) and/or cardiovascular disease (CVD) into independent training (n = 3252) and validation (n = 5211) sets. In the training set, we identified specific questions that were independently associated with a cardiovascular composite outcome (cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction/stroke, heart failure hospitalisation). We then evaluated the performance of these questions in the validation set.. In the training set, three questions ('Are your legs numb?', 'Have you ever had an open sore on your foot?' and 'Do your legs hurt when you walk?') were significantly associated with the cardiovascular composite outcome. In the validation set, after multivariable adjustment for key covariates, one or more positive responses (n = 3079, 59.1%) was associated with a higher risk of the cardiovascular composite outcome (HR 1.54 [95% CI 1.28, 1.85], p < 0.001), heart failure hospitalisation (HR 1.74 [95% CI 1.29, 2.35], p < 0.001), myocardial infarction (HR 1.81 [95% CI 1.23, 2.69], p = 0.003), stroke (HR 1.75 [95% CI 1.20, 2.56], p = 0.003) and three-point major adverse cardiovascular events (MACE) (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) (HR 1.49 [95% CI 1.20, 1.85], p < 0.001) relative to no positive responses to all questions. Associations were stronger if participants answered positively to all three questions (n = 552, 11%). The addition of the total number of affirmative responses to existing models significantly improved Harrell's C statistic for the cardiovascular composite outcome (0.70 vs 0.71, p = 0.010), continuous net reclassification improvement (+22% [+10%, +31%], p = 0.027) and integrated discrimination improvement (+0.9% [+0.4%, +2.1%], p = 0.007).. We identified three questions from the MNSI that provide additional prognostic information for individuals with type 2 diabetes and CKD and/or CVD. If externally validated, these questions may be integrated into the clinical history to augment prediction of CV events in high-risk individuals with type 2 diabetes.

Topics: Aged; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Fumarates; Humans; Male; Prognosis; Renal Insufficiency, Chronic; Surveys and Questionnaires

The direct renin inhibitor, aliskiren, is known to reduce plasma renin activity (PRA), but whether the efficacy of aliskiren varies based on an individual's baseline PRA in patients hospitalized for heart failure (HF) is presently unknown. We characterized the prognostic value of PRA and determined if this risk is modifiable with use of aliskiren.. This pre-specified neurohormonal substudy of ASTRONAUT analysed all patients hospitalized for HF with ejection fraction (EF) ≤40% with available baseline PRA data (n = 1306, 80.9%). Risk associated with baseline PRA and short-term changes in PRA from baseline to 1 month was modelled with respect to 12-month clinical events. Median baseline PRA was 3.0 (interquartile range 0.6-16.4) ng/mL/h. Aliskiren significantly reduced PRA early after treatment initiation through 12-month follow-up compared with placebo (P < 0.001). The lowest baseline PRA quartile (<0.6 ng/mL/h) was independently predictive of lower all-cause mortality [adjusted hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.31-0.81] and the composite of cardiovascular mortality and HF hospitalization (adjusted HR 0.57, 95% CI 0.40-0.79). Delta log-normalized PRA (from baseline to 1 month) was not predictive of either primary endpoint at 12 months (P ≥ 0.43). The prognostic value of baseline PRA and short-term changes in PRA did not vary by randomization to aliskiren or placebo (interaction P ≥ 0.13).. Plasma renin activity is reduced early and durably by aliskiren, but this did not translate into improved clinical outcomes in ASTRONAUT. Baseline PRA or short-term reduction in PRA do not identify a subgroup who may preferentially benefit from direct renin inhibition. Clinical Trial Registration ClinicalTrials.gov Unique Identifier: NCT00894387.

Topics: Aged; Amides; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Fumarates; Heart Failure; Humans; Inpatients; Male; Middle Aged; Prospective Studies; Renin; Renin-Angiotensin System; Stroke Volume; Treatment Outcome

The aim of this study was to evaluate the effect of aliskiren on aortic stiffness in patients with Marfan syndrome (MS).. Twenty-eight MS patients (mean age ± standard deviation: 32.6 ± 10.6 years) were recruited from November 2009 to October 2014. All patients were receiving atenolol as standard beta-blocker therapy. A prospective randomization process was performed to assign participants to either aliskiren treatment (150-300mg orally per day) or no aliskiren treatment (negative control) in an open-label design. Central aortic distensibility and central pulsed wave velocity (PWV) by magnetic resonance imaging (MRI), peripheral PWV, central aortic blood pressure and augmentation index by peripheral tonometry, and aortic dilatation by echocardiography were examined initially and after 24 weeks. The primary endpoint was central aortic distensibility by MRI.. In analyses of differences between baseline and 24 weeks for the aliskiren treatment group vs the negative control group, central distensibility (overall; P = .26) and central PWV (0.2 ± 0.9 vs 0.03 ± 0.7 [m/s]; P = .79) by MRI were not significantly different. Central systolic aortic blood pressure tended to be lower by 14mmHg in patients in the aliskiren treatment group than in the control group (P = .09). A significant decrease in peripheral PWV (brachial-ankle PWV) in the aliskiren treatment group (-1.6 m/s) compared with the control group (+0.28 m/s) was noted (P = .005).. Among patients with MS, the addition of aliskiren to beta-blocker treatment did not significantly improve central aortic stiffness during a 24-week period.

Topics: Adrenergic beta-1 Receptor Antagonists; Adult; Amides; Aorta, Thoracic; Atenolol; Blood Pressure; Dose-Response Relationship, Drug; Echocardiography; Electrocardiography; Female; Follow-Up Studies; Fumarates; Humans; Male; Marfan Syndrome; Prospective Studies; Pulse Wave Analysis; Renin; Treatment Outcome; Vascular Stiffness; Vasodilation

The (pro)renin receptor is important in the regulation of the tissue renin-angiotensin-aldosterone system. The benefits and safety of single-aliskiren treatment without other renin-angiotensin-aldosterone system inhibitors remain unclear. The serum level of the soluble form of the (pro)renin receptor is thought to be a biomarker reflecting the activity of the tissue renin-angiotensin-aldosterone system. We investigated the effects of single renin-angiotensin-aldosterone system blockade with aliskiren on renal and vascular functions and determined if serum level of the soluble (pro)renin receptor was a predictor of aliskiren efficacy in hypertensive patients with chronic kidney disease. Thirty-nine essential hypertensive patients with chronic kidney disease in our outpatient clinic were randomly assigned to receive either aliskiren or amlodipine. The parameters associated with renal and vascular functions and indices of renin-angiotensin-aldosterone system components, including serum levels of the soluble form, were evaluated before and after 12-week and 24-week treatment. Blood pressure was not significantly different between the groups. No significant changes in serum levels were observed in the soluble (pro)renin receptor in either group. Urinary albumin, protein excretion, and cardio-ankle vascular index significantly decreased in the aliskiren group. In the aliskiren group, there was a significant negative correlation between the basal level of the soluble (pro)renin receptor and the change in plasma aldosterone concentration. Single renin-angiotensin-aldosterone system blockade with aliskiren showed renal and vascular protective effects independent of blood pressure reduction. Serum levels of the soluble (pro)renin receptor may indicate aldosterone production via the (pro)renin receptor in the adrenal gland.

Topics: Aged; Aldosterone; Amides; Antihypertensive Agents; Blood Pressure; Female; Fumarates; Humans; Hypertension; Kidney; Kidney Function Tests; Male; Middle Aged; Receptors, Cell Surface; Renal Insufficiency, Chronic; Renin-Angiotensin System; Vacuolar Proton-Translocating ATPases; Vascular Stiffness

Sodium retention and volume overload are the main determinants of poor response to renin-angiotensin-aldosterone system (RAAS) inhibition in patients with diabetes. As volume excess can exist without symptoms, biomarkers are needed to identify a priori which patients are volume overloaded and may experience less benefit from RAAS inhibition. N-terminal pro-brain natriuretic peptide (NT-proBNP) is released in the setting of increased cardiac wall stress and volume overload. We conducted a post hoc analysis among 5081 patients with type 2 diabetes mellitus participating in the ALTITUDE trial to investigate whether NTproBNP can predict the effects of additional therapy with aliskiren on cardio-renal endpoints. Aliskiren compared to placebo reduced the risk of the primary cardio-renal endpoint events by 20% (95% confidence interval [CI] 16 to 61) and 2% (95% CI -42 to 30) in the two lowest NT-proBNP tertiles, and it increased the risk by 25% (95% CI -4 to 96) in the highest NT-proBNP tertile (P value for trend = 0.009). Similar trends were observed for the cardiovascular and end-stage renal disease endpoints. Effects of aliskiren compared to placebo on safety outcomes (hyperkalaemia and hospitalization for acute kidney injury) were independent of NT-proBNP. In conclusion, baseline NT-proBNP may be used as a marker to predict the response to aliskiren with regard to cardio-renal outcomes when added to standard therapy with RAAS inhibition.

Topics: Aged; Amides; Antihypertensive Agents; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hypoglycemic Agents; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Renin-Angiotensin System; Risk Factors; Treatment Outcome

Aliskiren penetrates adipose and skeletal muscle in hypertensive patients with abdominal obesity and reduces renin-angiotensin-aldosterone system activity. After discontinuation, blood pressure-lowering effects are observed possibly through drug-tissue binding. We performed microdialysis evaluation of adipose tissue and skeletal muscle before and during an insulin-modified frequently sampled intravenous glucose tolerance test (IM-FSIGT). Aliskiren 300 mg (n = 8) or amlodipine 5 mg (n = 8) once daily were administered during a 12-week randomized treatment period. Aliskiren elicited variable changes in median interstitial angiotensin II (Ang II) in adipose (2.60-1.30 fmol/mL) and skeletal muscle (2.23-0.68 fmol/mL); amlodipine tended to increase adipose and skeletal muscle Ang II (P = .066 for skeletal muscle treatment difference). Glucose/insulin increased median plasma Ang II 1 hour after glucose injection (1.04-2.50 fmol/mL; P = .001), which was markedly attenuated by aliskiren but not amlodipine. Aliskiren increased glucose disposition index (P = .012) and tended to increase acute insulin response to glucose (P = .067). Fasting adipose glycerol (-17%; P = .064) and fasting muscle glucose dialysate (-17%; P = .025) were decreased by aliskiren but not amlodipine. In summary, aliskiren decreased Ang II production in response to glucose/insulin stimulus and elicited metabolic effects in adipose and skeletal muscle suggestive of increased whole-body glucose utilization.

Topics: Adipose Tissue; Adult; Amides; Amlodipine; Angiotensin II; Antihypertensive Agents; Blood Glucose; Double-Blind Method; Female; Fumarates; Glucose; Humans; Hypertension; Insulin; Lipolysis; Male; Microdialysis; Middle Aged; Muscle, Skeletal; Obesity; Renin; Renin-Angiotensin System

Topics: Aged; Amides; Antihypertensive Agents; Diabetes Mellitus, Type 2; Drug Prescriptions; Female; Fumarates; Humans; Hypertension; Male; Ontario; Retrospective Studies

The combination of weight excess and hypertension significantly contributes to cardiovascular risk and progressive kidney damage. An unfavorable renal hemodynamic profile is thought to contribute to this increased risk and may be ameliorated by direct renin inhibition (DRI). The aim of this trial was to assess the effect of DRI on renal and systemic hemodynamics and on RAAS activity, in men with weight excess and hypertension.. A randomized, double-blind, cross-over clinical trial to determine the effect of DRI (aliskiren 300 mg/day), with angiotensin converting enzyme inhibition (ACEi; ramipril 10 mg/day) as a positive control, on renal and systemic hemodynamics, and on RAAS activity (n = 15).. Mean (SEM) Glomerular filtration rate (101 (5) mL/min/1.73m2) remained unaffected by DRI or ACEi. Effective renal plasma flow (ERPF; 301 (14) mL/min/1.73m2) was increased in response to DRI (320 (14) mL/min/1.73m2, P = 0.012) and ACEi (317 (15) mL/min/1.73m2, P = 0.045). Filtration fraction (FF; 34 (0.8)%) was reduced by DRI only (32 (0.7)%, P = 0.044). Mean arterial pressure (109 (2) mmHg) was reduced by DRI (101 (2) mmHg, P = 0.008) and ACEi (103 (3) mmHg, P = 0.037). RAAS activity was reduced by DRI and ACEi. Albuminuria (20 [9-42] mg/d) was reduced by DRI only (12 [5-28] mg/d, P = 0.030).. In men with weight excess and hypertension, DRI and ACEi improved renal and systemic hemodynamics. Both DRI and ACEi reduced RAAS activity. Thus, DRI provides effective treatment in weight excess and hypertension.. Dutch trial register, registration number: 2532 www.trialregister.nl.

Topics: Albuminuria; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Cross-Over Studies; Double-Blind Method; Fumarates; Glomerular Filtration Rate; Hemodynamics; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Overweight; Ramipril; Renal Circulation; Renin; Renin-Angiotensin System

The aim of this study was to compare an aliskiren/amlodipine combination with high-dose amlodipine monotherapy on ambulatory blood pressure monitoring (ABPM) and organ protection. The study was a prospective, randomized, multicenter, open-label trial in elderly essential hypertensive patients. A total of 105 patients with clinic BP (CBP) ≥140/90 mm Hg with amlodipine 5 mg were randomly allocated to aliskiren (150-300 mg)/amlodipine (5 mg) (ALI/AML group, n=53) or high-dose amlodipine (10 mg) (h-dAML group, n=52) and treated for 16 weeks. Each patient's CBP, ABPM, urine albumin-to-creatinine ratio (UACR), and brachial-ankle pulse wave velocity (baPWV) were measured at baseline and at the end of the study. The ALI/AML and h-dAML groups showed similarly reduced mean 24-hour SBP, daytime SBP, nighttime SBP, and baPWV. However, UACR reduction was significantly greater in the ALI/AML group (P=.02). ALI/AML was significantly less effective in reducing early-morning BP (P=.002) and morning BP surge (P=.001) compared with h-dAML.

Topics: Aged; Aged, 80 and over; Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Creatinine; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Japan; Male; Organ Sparing Treatments; Prospective Studies; Renin; Serum Albumin

To investigate whether the degree of albuminuria reduction observed in the ALTITUDE trial is associated with renal and cardiovascular protection, and secondly, whether the reduction in albuminuria was too small to afford clinical benefit.. In a post hoc analysis of the ALTITUDE trial in 8561 patients with type 2 diabetes and chronic kidney disease or cardiovascular disease we examined the effect of albuminuria changes at 6 months on renal and cardiovascular outcomes using Cox proportional hazard regression.. The median change in albuminuria in the first 6 months in the aliskiren arm of the trial was -12% (25th to 75th percentile: -48.7_to_ +41.9%) and 0.0% (25th to 75th percentile: -40.2_to_55%) in the placebo arm. Changes in albuminuria in the first 6 months were linearly associated with renal and cardiovascular endpoints: a >30% reduction in albuminuria in the first 6 months was associated with a 62% reduction in renal risk and a 25% reduction in cardiovascular risk compared with an increase in albuminuria. The association between changes at 6 months in albuminuria and renal or cardiovascular endpoints was similar in the two treatment groups (p for interaction >0.1 for both endpoints).. The addition of aliskiren to angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy resulted in albuminuria changes that were associated with renal and cardiovascular risk changes. This did not translate into renal or cardiovascular protection because the overall reduction in albuminuria in the aliskiren arm was too small and nearly similar to that in the placebo arm.

Topics: Aged; Albuminuria; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Fumarates; Humans; Hypertension; Male; Middle Aged; Practice Guidelines as Topic; Renal Insufficiency, Chronic; Renin; Risk Factors

The authors investigated the long-term effectiveness and safety of aliskiren (ALIS) with particular attention on its association with dual blockade of the renin-angiotensin system (RAS). The open, prospective 3A Registry (N=8723) in Germany assigned patients in a 4:1:1 ratio to ALIS, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), or non-RAS drugs. Patients taking ALIS compared with those taking ACE inhibitors/ARBs or non-RAS had more comorbidities and risk factors, were taking more antihypertensive agents, and had higher blood pressure (BP) values at entry. At 2 years, BP reduction from baseline was similar in all groups (mean, -20.5/-9.9 mm Hg). A total of 2.3% of patients died, 0.5% had myocardial infarction, 0.6% had stroke, 2.9% were hospitalized, and 5.5% had any event (not significant between groups). ALIS alone or combined with another RAS inhibitor was well tolerated and effective in lowering BP in typical unselected patients with hypertension. Given the methodical limitations of the design, the study cannot be used to confirm or refute safety concerns for dual RAS blockade as suggested by the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) trial.

Topics: Aged; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Treatment Outcome

The primary results of the ALTITUDE trial showed no benefit of aliskiren on renal outcomes (doubling of serum creatinine and end-stage renal disease) when used as an adjunct to angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease. We did a prespecified analysis of the ALTITUDE trial to analyse the effects of aliskiren on surrogate renal outcomes in all patients and on primary renal outcomes in subgroups of patients.. In the double-blind, randomised, controlled ALTITUDE trial, 8561 patients with type 2 diabetes and chronic kidney disease or cardiovascular disease were randomly assigned (1:1) to receive aliskiren 300 mg per day or placebo as an adjunct to ACE inhibitors or ARBs. Randomisation was stratified on the basis of baseline urinary albumin-to-creatinine ratio and presence of cardiovascular disease history, and treatment assignments were masked to all patients and study staff. Patients were followed up for a median of 2·6 years (IQR 2·0-3·2). In our secondary analysis, we investigated prespecified intermediate renal outcomes of transitions in albuminuria stages (ie, transitions between normoalbuminuria, microalbuminuria, and macroalbuminuria) and rate of change of estimated glomerular filtration rate (eGFR). We investigated all outcomes in the intention-to-treat population. The primary composite renal outcome of ALTITUDE was defined as a sustained doubling of serum creatinine, end-stage renal disease, or renal death. The ALTITUDE trial is registered with ClinicalTrials.gov, number NCT00549757.. Aliskiren significantly decreased progression (hazard ratio [HR] 0·83, 95% CI 0·75-0·93) and increased regression (HR 1·29, 95% CI 1·19-1·39) of transitions in albuminuria classes. The annual rate of change of eGFR was -3·1 mL/min/1·73 m(2) per year (95% CI -2·9 to -3·3) in the aliskiren group and -3·0 mL/min/1·73 m(2) per year (-2·8 to -3·2) in the placebo group (p=0·52). eGFR change during the first 6 months was significantly larger with aliskiren than with placebo (-2·5 mL/min/1·73 m(2), 95% CI -2·9 to -2·2 vs -1·4 mL/min/1·73 m(2), 95% CI -1·7 to -1·0; p<0·0001). Subsequent eGFR change did not differ significantly between groups (-2·8 mL/min/1·73 m(2) per year, 95% CI -3·0 to -2·6 with aliskiren vs -3·1 mL/min/1·73 m(2) per year, 95% CI -3·3 to -2·8 with placebo; p=0·068). The absence of a benefit of aliskiren on the primary composite renal endpoint in the overall population was also seen in various subgroups.. Aliskiren showed no beneficial effect on hard renal outcomes in the overall population or in various subgroups, but delayed progression to microalbuminuria and macroalbuminuria, and improved regression to microalbuminuria and normoalbuminuria. Whether the chosen intermediates are poor surrogates for clinical outcomes or whether off-target effects disrupt the association between the surrogate and clinical outcomes requires further study.. Novartis.

Topics: Aged; Albuminuria; Amides; Angiotensin Receptor Antagonists; Antihypertensive Agents; Creatinine; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Follow-Up Studies; Fumarates; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Netherlands; Prevalence; Prognosis; Survival Rate

Renin inhibition with aliskiren induced the largest increases in renal plasma flow (RPF) in salt-depleted healthy volunteers of all renin-angiotensin system (RAS) blockers. However, given its side-effects at doses higher than 300 mg, no maximum effect of renin inhibition could be established. We hypothesized that VTP-27999, a novel renin inhibitor without major side-effects at high doses, would allow us to establish this.. The effects of escalating VTP-27999 doses (75-600 mg) on RPF, glomerular filtration rate (GFR), and plasma RAS components were compared with those of 300 mg aliskiren in 22 normal volunteers on a low-sodium diet. VTP-27999 dose-dependently increased RPF and GFR; its effects on both parameters at 600 mg (increases of 18 ± 4 and 20 ± 4%, respectively) were equivalent to those at 300 mg, indicating that a maximum had been reached. The effects of 300 mg aliskiren (increases of 13 ± 5 and 8 ± 6%, respectively; P < 0.01 vs. 300 and 600 mg VTP-27999) resembled those of 150 mg VTP-27999. VTP-27999 dose-dependently increased renin, and lowered plasma renin activity and angiotensin II to detection limit levels. The effects of aliskiren on RAS components were best comparable to those of 150 mg VTP-27999.. Maximum renal renin blockade in healthy, salt-depleted volunteers, requires aliskiren doses higher than 300 mg, but can be established with 300 mg VTP-27999. To what degree such maximal effects (exceeding those of angiotensin-converting enzyme inhibitors and AT1-receptor blockers) are required in patients with renal disease, given the potential detrimental effects of excessive RAS blockade, remains to be determined.

Topics: Adolescent; Adult; Aged; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Carbamates; Double-Blind Method; Female; Fumarates; Glomerular Filtration Rate; Healthy Volunteers; Humans; Male; Middle Aged; Piperidines; Prospective Studies; Renin; Renin-Angiotensin System; Young Adult

Among patients with chronic heart failure, angiotensin-converting-enzyme (ACE) inhibitors reduce mortality and hospitalization, but the role of a renin inhibitor in such patients is unknown. We compared the ACE inhibitor enalapril with the renin inhibitor aliskiren (to test superiority or at least noninferiority) and with the combination of the two treatments (to test superiority) in patients with heart failure and a reduced ejection fraction.. After a single-blind run-in period, we assigned patients, in a double-blind fashion, to one of three groups: 2336 patients were assigned to receive enalapril at a dose of 5 or 10 mg twice daily, 2340 to receive aliskiren at a dose of 300 mg once daily, and 2340 to receive both treatments (combination therapy). The primary composite outcome was death from cardiovascular causes or hospitalization for heart failure.. After a median follow-up of 36.6 months, the primary outcome occurred in 770 patients (32.9%) in the combination-therapy group and in 808 (34.6%) in the enalapril group (hazard ratio, 0.93; 95% confidence interval [CI], 0.85 to 1.03). The primary outcome occurred in 791 patients (33.8%) in the aliskiren group (hazard ratio vs. enalapril, 0.99; 95% CI, 0.90 to 1.10); the prespecified test for noninferiority was not met. There was a higher risk of hypotensive symptoms in the combination-therapy group than in the enalapril group (13.8% vs. 11.0%, P=0.005), as well as higher risks of an elevated serum creatinine level (4.1% vs. 2.7%, P=0.009) and an elevated potassium level (17.1% vs. 12.5%, P<0.001).. In patients with chronic heart failure, the addition of aliskiren to enalapril led to more adverse events without an increase in benefit. Noninferiority was not shown for aliskiren as compared with enalapril. (Funded by Novartis; ATMOSPHERE ClinicalTrials.gov number, NCT00853658.).

Topics: Aged; Amides; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Follow-Up Studies; Fumarates; Heart Failure; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Renin; Stroke Volume; Treatment Failure

In patients with diabetes, albuminuria is a risk marker of end-stage renal disease and cardiovascular events. An increased renin-angiotensin system activity has been reported to play an important role in the pathological processes in these conditions. We compared the effect of aliskiren, a direct renin inhibitor (DRI), with that of angiotensin receptor blockers (ARBs) on albuminuria and urinary excretion of angiotensinogen, a marker of intrarenal renin-angiotensin system activity.. We randomly assigned 237 type 2 diabetic patients with high-normal albuminuria (10 to <30 mg/g of albumin-to-creatinine ratio) or microalbuminuria (30 to <300 mg/g) to the DRI group or ARB group (any ARB) with a target blood pressure of <130/80 mmHg. The primary endpoint was a reduction in albuminuria.. Twelve patients dropped out during the observation period, and a total of 225 patients were analyzed. During the study period, the systolic and diastolic blood pressures were not different between the groups. The changes in the urinary albumin-to-creatinine ratio from baseline to the end of the treatment period in the DRI and ARB groups were similar (-5.5% and -6.7%, respectively). In contrast, a significant reduction in the urinary excretion of angiotensinogen was observed in the ARB group but not in the DRI group. In the subgroup analysis, a significant reduction in the albuminuria was observed in the ARB group but not in the DRI group among high-normal albuminuria patients.. DRI and ARB reduced albuminuria in hypertensive patients with type 2 diabetes. In addition, ARB, but not DRI, reduced albuminuria even in patients with normal albuminuria. DRI is not superior to ARB in the reduction of urinary excretion of albumin and angiotensinogen.

Topics: Albuminuria; Amides; Angiotensin Receptor Antagonists; Angiotensinogen; Antihypertensive Agents; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fumarates; Humans; Hypertension; Kidney Failure, Chronic; Prospective Studies; Renin; Renin-Angiotensin System; Treatment Outcome

The objective of this paper is to study the effect of aliskiren on metabolic parameters and micro- and macrovascular reactivity in individuals diagnosed with or at high risk for developing type 2 diabetes mellitus (T2DM).. We studied 47 T2DM and 41 at-risk individuals in a randomized, double-blinded, placebo-controlled trial. All subjects were treated with 150 mg aliskiren or placebo daily for 12 weeks. Twenty-six (55%) of T2DM and four (8%) at-risk subjects were also treated with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers.. Aliskiren treatment was associated with improvement in systolic and diastolic blood pressure and endothelium-independent vasodilation at the skin microcirculation in those with T2DM but not in those at risk. There were no incidences of hypotension and no significant changes in serum potassium or creatinine levels with aliskiren treatment in either study group.. Aliskiren improves blood pressure and vascular smooth muscle function in the skin microcirculation of T2DM patients.

Topics: Amides; Biomarkers; Biopsy; Demography; Diabetes Mellitus, Type 2; Female; Forearm; Fumarates; Humans; Inflammation; Kidney Function Tests; Male; Microcirculation; Middle Aged; Muscle, Smooth, Vascular; Skin; Vasodilation

The aim of this study was to assess the antihypertensive efficacy and safety of aliskiren versus ramipril or losartan in hypertensive patients with type 2 diabetes mellitus, microalbuminuria and uncontrolled hypertension, despite the use of optimal conventional antihypertensive therapy.. In this open-label active comparator study, 126 patients were randomly assigned to receive 24 weeks of additional therapy with aliskiren (Group A) or either losartan or ramipril (Group B), according to whether a patient was already treated with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, respectively.. After 24 weeks, both treatment groups experienced a significant reduction of systolic blood pressure (-11.37% and -8.47%, respectively; both p <0.001 vs. baseline) and diastolic blood pressure levels (-10.67% and -9.28%, respectively; both p <0.001 vs. baseline), with a greater reduction of mean systolic values in Group A compared with Group B (p <0.001). Furthermore, after six months microalbuminuria was significantly decreased in both treatment groups (-67.62% and -49.1%, respectively; both p <0.001), with a reduction rate in Group A significantly higher than in Group B (p<0.001).. The addition of aliskiren to optimal conventional therapy provided a higher reduction of blood pressure and urinary albumin excretion when compared with the addition of losartan or ramipril.

Topics: Aged; Albuminuria; Amides; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diastole; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Losartan; Male; Potassium; Ramipril; Systole

We examined the effect of the renin inhibitor, aliskiren, on renal blood flow (RBF) in patients with heart failure with reduced ejection fraction (HFREF) and decreased glomerular filtration rate (GFR). Renal blood flow is the main determinant of GFR in HFREF patients. Both reduced GFR and RBF are associated with increased mortality. Aliskiren can provide additional renin-angiotensin-aldosterone system inhibition and increases RBF in healthy individuals.. Patients with left ventricular ejection fraction ≤45% and estimated GFR 30 to 75 mL/min per 1.73 m(2) on optimal medical therapy were randomized 2:1 to receive aliskiren 300 mg once daily or placebo. Renal blood flow and GFR were measured using radioactive-labeled (125)I-iothalamate and (131)I-hippuran at baseline and 26 weeks. After 41 patients were included, the trial was halted based on an interim safety analysis showing futility. Mean age was 68 ± 9 years, 82% male, GFR (49 ± 16 mL/min per 1.73 m(2)), RBF (294 ± 77 mL/min per 1.73 m(2)), and NT-proBNP 999 (435-2040) pg/mL. There was a nonsignificant change in RBF after 26 weeks in the aliskiren group compared with placebo (-7.1 ± 30 vs +14 ± 54 mL/min per 1.73 m(2); P = .16). However, GFR decreased significantly in the aliskiren group compared with placebo (-2.8 ± 6.0 vs +4.4 ± 9.6 mL/min per 1.73 m(2); P = .01) as did filtration fraction (-2.2 ± 3.3 vs +1.1 ± 3.1%; P = .01). There were no significant differences in plasma aldosterone, NT-proBNP, urinary tubular markers, or adverse events. Plasma renin activity was markedly reduced in the aliskiren group versus placebo throughout the treatment phase (P = .007).. Adding aliskiren on top of optimal HFREF medical therapy did not improve RBF and was associated with a reduction of GFR and filtration fraction.

Topics: Aged; Amides; Blood Pressure; Drug Therapy, Combination; Female; Fumarates; Glomerular Filtration Rate; Heart Failure; Humans; Male; Middle Aged; Renal Circulation; Renin; Renin-Angiotensin System; Stroke Volume

Combination therapy of aliskiren and an angiotensin II receptor blocker (ARB) has been reported to be effective for reducing the level of proteinuria. However, it remains unclear whether this combination therapy contributes to suppression of kidney disease progression. The aim of this study was to investigate the effect of aliskiren on hard renal endpoints, when added to an ARB, in patients with advanced chronic kidney disease (CKD).. The study design was a prospective, randomized open-label design. 83 CKD patients (52 men and 31 women) were enrolled and assigned randomly to an aliskiren add-on group (n = 42) or control group (n = 41). Entry criteria included elevated serum creatinine ≥ 1.5 mg/dl, urine protein excretion (≥ 1+ on urine dipstick test), and hypertension. All participants were treated with an ARB. The follow-up period was 12 months. 12 participants were withdrawn during the study period and the study was terminated in January 2012 as a consequence of the results of the interim analysis of the ALTITUDE study.. Nine patients in the aliskiren group and seven patients in the control group started dialysis. Doubling of the serum creatinine level occurred in one patient in the control group. A Cox proportional hazards test showed that dual blockade of the renin-angiotensin-aldosterone system with aliskiren and ARB was not associated with improvement in hard renal endpoints.. We conclude that aliskiren add-on therapy to an ARB may not give any benefit and, therefore, should not be recommended in CKD patients.

Topics: Aged; Amides; Angiotensin Receptor Antagonists; Female; Fumarates; Humans; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renin; Treatment Outcome

In hypertension, changes in small arterial structure are characterized by an increased wall-to-lumen ratio (WLR). These adaptive processes are modulated by the rennin-angiotensin system. It is unclear whether direct renin inhibitors exert protective effects on small arteries in hypertensive patients.. In this double-blind, randomized, placebo-controlled study (http://www.clinicaltrials.gov: NCT01318395), 114 patients with primary hypertension were randomized to additional therapy with either placebo or aliskiren 300 mg for 8 weeks after 4 weeks of standardized open-label treatment with valsartan 320 mg (run-in phase). Parameter of arteriolar remodelling was WLR of retinal arterioles (80 - 140 μm) assessed noninvasively and in vivo by scanning laser Doppler flowmetry (Heidelberg Engineering, Germany). In addition, pulse wave analysis (SphygmoCor, AtCor Medical, Australia) and pulse pressure (PP) amplification were determined.. In the whole study population, no clear effect of additional therapy with aliskiren on vascular parameters was documented. When analyses were restricted to patients with vascular remodelling, defined by a median of WLR more than 0.3326 (n = 57), WLR was reduced after 8 weeks by the treatment with aliskiren compared with placebo (-0.044 ± 0.07 versus 0.0043 ± 0.07, P = 0.015). Consistently, after 8 weeks of on-top treatment with aliskiren, there was an improvement of PP amplification compared with placebo (0.025 ± 0.07 versus -0.034 ± 0.08, P = 0.013), indicative of less stiff arteries in the peripheral circulation.. Thus, our data indicate that treatment with aliskiren, given on top of valsartan therapy, improves altered vascular remodelling in hypertensive patients.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Arterioles; Blood Pressure; Double-Blind Method; Essential Hypertension; Female; Fumarates; Humans; Hypertension; Laser-Doppler Flowmetry; Male; Middle Aged; Pulse Wave Analysis; Retinal Vessels; Valsartan; Vascular Remodeling

The purpose of the present study was to compare the direct renin inhibitor aliskiren to the diuretic hydrochlorothiazide (HCTZ) in their ability to modulate renal tissue oxygenation in hypertensive patients.. 24 patients were enrolled in this randomized prospective study and 20 completed the protocol. Patients were randomly assigned to receive either aliskiren 150-300 mg/d or HCTZ 12.5 - 25 mg/d for 8 weeks. Renal oxygenation was measured by BOLD-MRI at weeks 0 and 8. BOLD-MRI was also performed before and after an i.v. injection of 20 mg furosemide at week 0 and at week 8. BOLD-MRI data were analyzed by measuring the oxygenation in 12 computed layers of the kidney enabling to asses renal oxygenation according to the depth within the kidney and by the classical method of regions of interest (ROI).. The classical ROI analysis of the data showed no difference between the groups at week 8. The analysis of renal oxygenation according to the 12 layers method shows no significant difference between aliskiren and HCTZ at week 8 before administration of furosemide. However, within group analyses show that aliskiren slightly but not significantly increased oxygenation in the cortex and decreased medullary oxygenation whereas HCTZ induced a significant overall decrease in renal tissue oxygenation. With the same method of analysis we observed that the response to furosemide was unchanged in the HCTZ group at week 8 but was characterized by an increase in both cortical and medullary oxygenation in aliskiren-treated patients. Patients responding to aliskiren and HCTZ by a fall in systolic blood pressure of >10 mmHg improved their renal tissue oxygenation when compared to non-responders.. With the classical method of evaluation using regions no difference were found between aliskiren and HCTZ on renal tissue oxygenation after 8 weeks. In contrast, with our new method that takes into account the entire kidney, within group analyses show that aliskiren slightly increases cortical and medullary renal tissue oxygenation in hypertensive patients whereas HCTZ decreases significantly renal oxygenation at trough.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Kidney; Male; Middle Aged; Oxygen Consumption; Prospective Studies; Renin; Single-Blind Method

To: (i) describe the baseline characteristics of patients in ATMOSPHERE and the changes in the planned analysis of ATMOSPHERE resulting from the mandated discontinuation of study treatment in patients with diabetes; (ii) compare the baseline characteristics of patients in ATMOSPHERE with those in the Prospective comparison of Angiotensin Receptor neprilysin inhibitors with Angiotensin converting enzyme inhibitors to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF); and (iii) compare the characteristics of patients with and without diabetes at baseline in ATMOSPHERE.. A total of 7063 patients were randomized into ATMOSPHERE April 2009-April 2014 at 755 sites in 43 countries. Their average age was 63 years and 78% were men. ATMOSPHERE patients were generally similar to those in PARADIGM-HF although fewer had diabetes, renal dysfunction, and were treated with a mineralocorticoid receptor antagonist. In ATMOSPHERE, patients with diabetes differed in numerous ways from those without. Patients with diabetes were older and had worse heart failure status but a similar left ventricular ejection fraction (mean 28%); they had a higher body mass index and more co-morbidity, especially hypertension and coronary heart disease. Mean estimated glomerular filtration rate was slightly lower in those with diabetes compared with those without.. ATMOSPHERE will determine whether patients with HF and reduced ejection fraction (particularly those without diabetes) benefit from the addition of a direct renin inhibitor to standard background therapy, including an angiotensin-converting enzyme inhibitor, beta-blocker, and a mineralocorticoid receptor antagonist. ATMOSPHERE will also determine whether aliskiren alone is superior to, or at least non-inferior to, enalapril.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Diabetes Mellitus; Drug Therapy, Combination; Enalapril; Female; Fumarates; Heart Failure; Humans; Male; Middle Aged; Renin; Stroke Volume; Ventricular Dysfunction, Left

Aliskiren previously was found to have potentially harmful effects in diabetic individuals prescribed concomitant angiotensin converting enzyme inhibitors (ACEI) or angiotenisn receptor antagonists (ARB). We explored potential effects of aliskiren on coronary atheroma progression and major adverse cardiovascular events (MACE: death/non-fatal MI/non-fatal stroke/hospitalization for heart failure/hospitalization for ACS/arterial revascularization) in patients with and without diabetes mellitus (DM).. AQUARIUS employed serial intravascular ultrasound measures of coronary atheroma volume in coronary artery disease patients randomized to receive daily aliskiren 300 mg or placebo for 104 weeks. This post hoc analysis compared changes in plaque volume [percent atheroma volume (PAV) and total atheroma volume (TAV)] and MACE in patients with (n = 115) and without (n = 343) DM stratified by treatment allocation.. In multivariable propensity-weighted analyses, which included controlling for baseline and concomitant ACEI/ARB therapy and duration of aliskiren therapy, aliskiren-treated non-DM patients demonstrated the greatest PAV and TAV regression, whereas aliskiren-treated DM patients demonstrated the greatest TAV progression and greater PAV. Aliskiren-treated non-DM patients appeared at significantly lower risk of MACE compared with their aliskiren-treated DM counterparts [HR 95% CI 0.28 (0.10, 0.80)]. Statistical interactions were noted between DM status and treatment allocation for both changes in PAV (p < 0.001), TAV (p = 0.010) and MACE (p = 0.057).. Aliskiren appears to be relatively anti-atherosclerotic in non-diabetic patients. Due to the limited number MACE and low numbers of diabetic patients in AQUARIUS, the pro-atherosclerotic effects of aliskiren in this population are inconclusive, and these results should be thus considered hypothesis generating. Further outcome studies are required in non-diabetic patients to confirm the possible favorable effects of aliskiren.

Topics: Aged; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Chi-Square Distribution; Coronary Artery Disease; Coronary Vessels; Diabetic Angiopathies; Disease Progression; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Fumarates; Humans; Logistic Models; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Plaque, Atherosclerotic; Prehypertension; Propensity Score; Proportional Hazards Models; Risk Assessment; Risk Factors; Stroke; Time Factors; Treatment Outcome; Ultrasonography, Interventional

The aim of this study was to compare the effects of direct renin inhibitor, aliskiren, and amlodipine combination therapy with those of high-dose amlodipine monotherapy on endothelial function in elderly hypertensive patients.. Participants included 105 patients (mean age 77 years) who had receive 5mg amlodipine for 4 weeks. Patients were allocated to the aliskiren/amlodipine group (AL/AM) or the high-dose amlodipine (AM) group. The AL/AM group received 150mg aliskiren in addition to 5mg amlodipine for 8 weeks; then the dose of aliskiren was doubled to 300mg for another 8 weeks. The AM group received 10mg amlodipine for 16 weeks. Of the 105 patients, 87 who underwent measurements of brachial flow-mediated vasodilation (FMD) and nitroglycerin-mediated vasodilation (NMD) before and after the study were included in the analysis.. Blood pressure-lowering effects were similar in the 2 groups. Plasma renin activity significantly decreased in the AL/AM group (P < 0.001) but increased in the AM group (P < 0.001). Improvement of FMD was found in the AL/AM group (2.6% to 3.7%, P = 0.001) but not in the AM group, while NMD did not change in either group. The changes in 24-hour systolic blood pressure (r = -0.60, P < 0.001) and diastolic blood pressure (r = -0.46, P = 0.004) were significantly correlated with improvement of FMD in the AL/AM group but not in the AM group.. Addition of aliskiren improved endothelial function in elderly hypertensive patients treated with amlodipine.. UMIN000010163.

Topics: Aged; Aged, 80 and over; Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Drug Therapy, Combination; Endothelium, Vascular; Female; Fumarates; Humans; Hypertension; Japan; Male; Renin; Time Factors; Treatment Outcome; Vasodilation; Vasodilator Agents

Antihypertensive agents may, even within the same class, exert variable effects on arterial stiffness variables. Nebivolol could have a better impact than atenolol on arterial stiffness, by increasing the bioavailability of endothelium-derived nitric oxide. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) increase plasma renin activity (enhancing the production of angiotensin II via non-ACE-related pathways) whereas aliskiren does not, potentially affecting central hemodynamics differently. We compared the effects of two renin-angiotensin-aldosterone system (RAAS) inhibitors (quinapril and aliskiren) and 2 beta-blockers (atenolol and nebivolol) on arterial stiffness variables. Treatment-naïve patients (n = 72; 68.1% males; age, 47.6 ± 10.6 years) with uncomplicated stage I-II essential hypertension were randomly assigned to quinapril, aliskiren, atenolol, or nebivolol for 10 weeks. Central systolic and diastolic blood pressure (BP), central pulse pressure (PP), augmentation index (AIx), and pulse wave velocity (PWV) were measured at baseline, 2, and 10 weeks. The same measurements were performed in 20 normotensive subjects (65.0% males; age, 40.0 ± 8.9 years). Peripheral and central systolic and diastolic BP, peripheral PP, and PWV were significantly and similarly reduced by all agents. However, PWV continued to decline between the second and last visit in patients on quinapril and aliskiren but did not change in those on nebivolol or atenolol. Central PP and AIx decreased in patients on quinapril, aliskiren, and nebivolol but did not change in those taking atenolol. The decrease in central PP and AIx did not differ between patients on quinapril, aliskiren, and nebivolol. Despite similar reductions in peripheral BP, atenolol is less effective than nebivolol and RAAS inhibitors in improving central pulsatile hemodynamics. Aliskiren exerts similar effects on markers of arterial stiffness as quinapril. The clinical relevance of these differences remains to be established.

Topics: Adrenergic beta-Antagonists; Adult; Amides; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Drug Monitoring; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Nitric Oxide; Pulse Wave Analysis; Quinapril; Renin-Angiotensin System; Tetrahydroisoquinolines; Treatment Outcome; Vascular Stiffness

Recent trials with inhibition of the renin-angiotensin-aldosterone system (RAAS) in patients with established atherosclerosis have been equivocal. MicroRNAs (miRs) are known to affect multiple pathways relevant to atherosclerosis, including RAAS. We postulated that the use of a direct renin antagonist would result in differential regulation of miRs. We examined monocyte miR expression before and after treatment with renin antagonist, Aliskiren, in patients with established cardiovascular disease as part of a prospective, single-center, randomized, double-blind and placebo-controlled clinical trial (NCT01417104). After screening, patients (mean age 62±3 years) were randomized to placebo or Aliskiren. Three-dimensional dark-blood magnetic resonance imaging assessment of atherosclerosis in the thoracic and abdominal aorta was conducted at baseline and at study completion (19-36 weeks). MiR expression arrays were performed on RNA from peripheral blood mononuclear cells collected at baseline and 12 weeks following randomization to placebo or Aliskiren and showed that hsa-miR-106b-5p, 27a-3p and 18b-5p were significantly downregulated with Aliskiren. Baseline expression of these miRs positively correlated with normalized total wall volume in subjects taking Aliskiren (miR-106b, R=0.62; miR-27a, R=0.63; miR-18b, R=0.77; P<0.05). Hsa-miR-106b-5p, 27a-3p and 18b-5p may represent pathway-specific adaptations to renin inhibition relevant to atherosclerosis.

Topics: Amides; Antihypertensive Agents; Disease Progression; Double-Blind Method; Down-Regulation; Female; Fumarates; Humans; Hypertension; Magnetic Resonance Imaging; Male; MicroRNAs; Middle Aged; Plaque, Atherosclerotic; Prospective Studies; Renin; Signal Transduction

Applying a direct renin inhibitor (DRI) to advanced stage chronic kidney disease (CKD) patients is a matter of controversy. The purpose of this study was to evaluate the effect of the DRI, aliskiren, in patients with therapy-resistant hypertension undergoing hemodialysis (HD).. The study was a prospective, randomized multicenter trial exploring the antihypertensive effect of aliskiren in comparison with amlodipine, a calcium channel blocker, in patients undergoing HD. A total of 83 participants whose blood pressure (BP) had previously been treated with more than one antihypertensive agent and not having achieved the BP goal of <140/90 mmHg were randomly assigned to either aliskiren 150 mg or amlodipine 5 mg as an add-on therapy.. A significant decrease in pre-dialysis clinic BP and home BP was found only in the amlodipine group and not in the aliskiren group. In contrast, there was a significant decrease in atrial natriuretic peptide (ANP) in the aliskiren group but not in the amlodipine group. N-terminal pro-B-type natriuretic hormone remained unchanged in both groups. Aliskiren significantly reduced angiotensin I and II, plasma renin activity, and increased plasma renin content. However, such changes were not observed in the amlodipine group.. Amlodipine, not aliskiren, effectively reduces BP in CKD patients with refractory hypertension undergoing HD. Aliskiren suppresses the renin-angiotensin system and reduces ANP. Whether the DRI is beneficial in improving cardiovascular events in patients undergoing HD remains to be elucidated in future studies.

Topics: Aged; Amides; Amlodipine; Antihypertensive Agents; Calcium Channel Blockers; Female; Fumarates; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Dialysis

A direct renin inhibitor (DRI), aliskiren, may be effective for blood pressure (BP) control in hemodialysis patients. However, it is unclear whether aliskiren has a greater beneficial effect on BP and humoral factors than angiotensin II receptor antagonists (ARBs) in hypertensive patients on hemodialysis.. Eighteen hemodialysis patients (58 ± 14 years) on the recommended dose of an ARB were prospectively randomized into two groups: ARB and DRI groups. Patients in the ARB group continued taking their previous ARB, whereas those in the DRI group switched to aliskiren (150 mg/day) for 12 weeks. Baseline measurements of BP and humoral factors such as plasma renin activity (PRA), plasma aldosterone concentration (PAC) and brain natriuretic peptide (BNP) were performed. Measurements were repeated every 4 weeks.. At baseline, no differences were observed in age, gender or BP between the two groups. Systolic BP was unaffected by treatment in either groups (group effect, p = 0.26; time effect, p = 0.38; group × time effect, p = 0.24). PRA decreased in DRI (p ≤ 0.02, group effect, p = 0.65; time effect, p = 0.13; group × time effect, p = 0.048), but not in ARB (p ≥ 0.94). PAC increased only in DRI (p ≤ 0.03), whereas BNP was unaffected in either group.. Aliskiren at a dose of 150 mg/day had a similar effect on BP compared with ARBs, but significantly lowered PRA.

Topics: Adult; Aged; Aldosterone; Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Blood Pressure; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Renal Dialysis; Renin

Aim of the present study was to compare the effectiveness of two renin-angiotensin-aldosterone system inhibitors in arterial stiffness reduction in previously untreated hypertensive patients.. In this open label study, 154 naïve, or not treated in the last six months hypertensive patients were randomly assigned to receive aliskiren 300 mg or ramipril 5 mg daily. Six weeks after the initiation of treatment, patients were evaluated for blood pressure (BP) control. Patients with SBP ≥140 and/or DBP ≥90 mmHg were assigned to an adjunct of 25 mg hydrochlorothiazide as combination treatment. A re-evaluation of BP control was done after another 6 weeks. Individuals with BP ≥140/90 mmHg were further administered amlodipine 5 mg. The final evaluation was performed six months after the start of the study. Twenty four-hour ambulatory blood pressure monitoring was carried out and the ambulatory arterial stiffness index (AASI) was calculated at baseline and after 6 months of treatment.. Aliskiren-based therapy, as compared with ramipril-based therapy reduced BP to a similar degree: 13±11 vs. 12±11 mmHg reduction in systolic (P=0.34) and 8±7 vs. 7±7 mmHg reduction in diastolic BP (P=0.44). AASI was reduced by 0.04±0.1 in the aliskiren group and by 0.02±0.2 in the ramipril group. AASI reduction did not differ significantly in the two groups (P=0.13).. In hypertensive patients, aliskiren-based treatment as well as ramipril-based treatment appears to have a beneficial effect on arterial stiffness. As arterial stiffness is an important modifiable risk factor, our findings highlight the value of aliskiren beyond BP lowering properties.

Topics: Adult; Aged; Amides; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Drug Therapy, Combination; Fumarates; Greece; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Predictive Value of Tests; Ramipril; Renin-Angiotensin System; Sodium Chloride Symporter Inhibitors; Time Factors; Treatment Outcome; Vascular Stiffness; Vasodilator Agents

Some patients with acute myocardial infarction (AMI) have a poor prognosis due to left ventricular remodeling (LVR), resulting in the recurrence of congestive heart failure even when therapy with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs) has been initiated. We investigated the effect of early administration of the direct renin inhibitor (DRI) aliskiren in combination with an ACEI or an ARB on LVR using cardiac magnetic resonance (CMR) imaging in patients with AMI.Twenty-one consecutive patients were treated with an ACEI or an ARB (non-DRI group), and another 21 consecutive patients received aliskiren 150 mg/day combined with an ACEI or an ARB (DRI group). CMR imaging was performed 7 days after AMI and 10 months later.CMR imaging revealed no significant changes in LV end-systolic volume, LV end-diastolic volume, or LV ejection fraction between the patients with and without DRI aliskiren. In the DRI group, plasma renin activity was significantly lower in both the acute and chronic phases; however, aldosterone levels were significantly lower in the acute but not the chronic phase.A low dose of aliskiren may be insufficient to maintain suppression of aldosterone under current standard therapies with an ACEI or an ARB and β-blocker in patients with primary AMI, and results in no attenuation of LVR.

Topics: Aged; Aldosterone; Amides; Angiotensin II Type 2 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Female; Fumarates; Humans; Male; Middle Aged; Myocardial Infarction; Renin; Ventricular Remodeling

This study compared the pharmacodynamic/pharmacokinetic profile of the new renin inhibitor VTP-27999 in salt-depleted healthy volunteers, administered once daily (75, 150, 300, and 600 mg) for 10 days, versus placebo and 300 mg aliskiren. VTP-27999 was well tolerated with no significant safety issues. It was rapidly absorbed, attaining maximum plasma concentrations at 1 to 4 hours after dosing, with a terminal half-life of 24 to 30 hours. Plasma renin activity remained suppressed during the 24-hour dosing interval at all doses. VTP-27999 administration resulted in a dose-dependent induction of renin, increasing the concentration of plasma renin maximally 350-fold. This induction was greater than with aliskiren, indicating greater intrarenal renin inhibition. VTP-27999 decreased plasma angiotensin II and aldosterone. At 24 hours and later time points after dosing on day 10 in the 600-mg group, angiotensin II and aldosterone levels were increased, and plasma renin activity was also increased at 48 and 72 hours, compared with baseline. VTP-27999 decreased urinary aldosterone excretion versus placebo on day 1. On day 10, urinary aldosterone excretion was higher in the 300- and 600-mg VTP-27999 dose groups compared with baseline. VTP-27999 decreased blood pressure to the same degree as aliskiren. In conclusion, excessive intrarenal renin inhibition, obtained at VTP-27999 doses of 300 mg and higher, is accompanied by plasma renin rises, that after stopping drug intake, exceed the capacity of extrarenal VTP-27999 to block fully the enzymatic reaction. This results in significant rises of angiotensin II and aldosterone. Therefore, renin inhibition has an upper limit.

Topics: Adolescent; Adult; Aldosterone; Amides; Angiotensin II; Blood Pressure; Carbamates; Dose-Response Relationship, Drug; Female; Fumarates; Hemodynamics; Humans; Kidney; Male; Middle Aged; Piperidines; Renin; Young Adult

We studied the unclear question whether blood pressure (BP) lowering reduces cardiovascular disease (CVD) in elderly individuals with systolic BP <160 mm Hg.. We initiated a randomized placebo-controlled stratified 2 × 2 factorial clinical trial evaluating the effects of BP lowering in 11 000 elderly individuals with systolic blood pressure (SBP) between 130 and 159 mm Hg, for 5 years. Following 5-week active run-in, participants were randomized to aliskiren (300 mg) or placebo, and to an additional antihypertensive [hydrochlorothiazide (25 mg) or amlodipine (5 mg)], or their respective placeboes. Study was terminated by sponsor after 1759 subjects (age 72.1 ± 5.2 years, 88% receiving at least one antihypertensive) were randomized and followed for 0.6 year. Study drugs were well tolerated with few serious adverse events during run-in and after randomization, with no significant differences between treatment groups. By design, three levels of BP reductions were achieved, adjusted mean BP reductions of 3.5/1.7 mm Hg (P < 0.001) by aliskiren, 6.8/3.3 mm Hg (P < 0.001) by hydrochlorothiazide or amlodipine, and 10.3/5.0 mm Hg (P < 0.001) by double therapy compared with placebo. Twenty-five major CVD events occurred. Non-significant trends towards fewer CVD events with greater BP reductions are evident: hazard ratios (HR) 0.82 [95% confidence interval (CI): 0.37-1.81] for 3.5 mm Hg SBP reduction; HR 0.45 (95% CI: 0.19-1.04) for 6.8 mm Hg; and HR 0.25 (0.05-1.18) for 10.3 mm Hg reduction for primary composite of CV death, MI, stroke, or significant heart failure.. Sizeable reductions in BP, with potential for substantial CVD reduction, can be safely achieved using combinations of BP drugs in the elderly with normal high and Stage 1 hypertension.. NCT01259297.

Topics: Aged; Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Medication Adherence; Potassium; Treatment Outcome

Arterial stiffness and endothelial dysfunction are important determinants of cardiovascular events in patients with arterial hypertension. There are few data regarding the role of aliskiren on the central hemodynamics and endothelial function in patients with uncontrolled arterial hypertension. The aim of this study was to assess the addition of aliskiren to other antihypertensive drug treatment for arterial stiffness and endothelial function. Thirty uncontrolled hypertensive patients (mean age, 60.4±12.2 years), without any other cardiovascular risk factors, were enrolled. Augmentation index (AIx) and carotid-femoral pulse wave velocity (cfPWV) by applanation tonometry and reactive hyperemia peripheral arterial tonometry (RH PAT) index using peripheral arterious tonometry at baseline and after 6 months of aliskiren titrated to 300 mg once a day was evaluated. The addition of aliskiren had no effect on values of central AIx (33.26±10.74% vs 28.86±10.74%; P=.36) but did significantly improve values of cfPWV (9.36±2.65 m/s vs 8.72±2.48 m/s; P=.04) and RH PAT index (1.64±0.57 vs 1.75±0.45; P=.05). In addition to improving systolic and diastolic blood pressure, the addition of aliskiren to concomitant antihypertensive drugs in uncontrolled hypertensive patients may be effective in improving aortic stiffness and endothelial function. These results encourage further studies to evaluate the use of aliskiren for cardiovascular prevention.

Topics: Aged; Amides; Antihypertensive Agents; Blood Pressure; Body Mass Index; Drug Therapy, Combination; Endothelium, Vascular; Female; Fumarates; Hemodynamics; Humans; Hypertension; Male; Manometry; Middle Aged; Pulse Wave Analysis; Renin; Treatment Outcome; Vascular Stiffness

Although serum and plasma are the biological fluids of choice for pharmacokinetic determination of drugs in adults, it is desirable to elucidate noninvasive methods which can be used for investigations in vulnerable groups such as children. If the drug properties grant sufficient penetration of the drug from blood into saliva, the latter is a useful matrix for noninvasive investigations. Concerning the known physicochemical properties, the direct renin inhibitor aliskiren is one of the substances of which saliva concentrations could substitute blood concentrations for pharmacokinetic investigations in children. Therefore, a reliable bioanalytical method was successfully developed and validated according to the criteria of current international bioanalytical guidelines to enable the comparison of blood and saliva concentrations of aliskiren. After purification of the fluid by solid-phase extraction the chromatographic separation was conducted by using Xselect™ C18 CSH columns. Applying a mobile phase gradient of acidified methanol and acidified water at a flow rate of 0.4ml/min the column effluent was monitored during a total run time of 7.5min by tandem mass spectrometry with electrospray ionization. Running in positive mode the following transitions were investigated: 552.2-436.2m/z for aliskiren and 425.3-351.2m/z for benazepril (internal standard). Calibration curves were constructed in the range of 0.586-1200ng/ml and were analyzed utilizing 1/x(2) weighted linear regression. Intra-run and inter-run precision were 3.8-8.1% and 3.4-8.9%. The method provides selectivity, linearity and accuracy. The validated method was then applied to determine aliskiren concentrations in saliva and blood of three healthy volunteers after oral administration of 300mg aliskiren.

Topics: Administration, Oral; Adult; Amides; Antihypertensive Agents; Calibration; Chromatography, Liquid; Female; Fumarates; Humans; Linear Models; Male; Middle Aged; Reproducibility of Results; Saliva; Solid Phase Extraction; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

This is a report of a clinical trial on the therapeutic efficacy and safety of combined aliskiren and losartan (an angiotensin II receptor blocker (ARB)) versus aliskiren alone and ARB alone in non-diabetic chronic kidney disease (CKD) over a 3-year period.. This was a randomised trial in 155 patients with non-diabetic CKD comparing aliskiren (150 mg/day) (n=52) versus losartan (100 mg/day) (n=52) and the third group aliskiren (150 mg/day) combined with losartan (100 mg/day) (n=51). The trial utilised primary renal end points of eGFR <15 ml/min or end-stage renal failure.. All three groups had significant reduction of proteinuria (p<0.001 for all). The changes in eGFR, total urinary protein from baseline to each year were not significantly different between the three therapeutic groups.. This study in non-diabetic CKD patients showed that combination therapy with aliskiren and ARB was as efficacious as aliskiren alone and ARB alone. There was one patient who developed a non-fatal stroke in the combined aliskiren and ARB group while the other two groups had none.

Topics: Amides; Blood Pressure; Comorbidity; Demography; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fumarates; Glomerular Filtration Rate; Humans; Hyperkalemia; Losartan; Male; Middle Aged; Proteinuria; Renal Insufficiency, Chronic; Systole

Structural alterations of subcutaneous small-resistance arteries are associated with a worse clinical prognosis in hypertension and non-insulin-dependent diabetes mellitus. The effects of the direct renin inhibitor aliskiren on microvascular structure were never previously evaluated. Therefore, we investigated the effects of aliskiren in comparison with those of an extensively used angiotensin-converting enzyme inhibitor, ramipril, on peripheral subcutaneous small-resistance artery morphology, retinal arteriolar structure, and capillary density in a population of patients with non-insulin-dependent diabetes mellitus. Sixteen patients with mild essential hypertension and with a previous diagnosis of non-insulin-dependent diabetes mellitus were included in the study. Patients were then randomized to 1 of the 2 active treatments (aliskiren 150 mg once daily, n=9; or ramipril 5 mg once daily, n=7). Each patient underwent a biopsy of the subcutaneous fat from the gluteal region, an evaluation of retinal artery morphology (scanning laser Doppler flowmetry), and capillary density (capillaroscopy), at baseline and after 1 year of treatment. Subcutaneous small arteries were dissected and mounted on a pressurized micromyograph, and the media-to-lumen ratio was evaluated. A similar office blood pressure-lowering effect and a similar reduction of the wall-to-lumen ratio of retinal arterioles were observed with the 2 drugs. Aliskiren significantly reduced media-to-lumen ratio of subcutaneous small-resistance arteries, whereas ramipril-induced reduction of media to lumen ratio was not statistically significant. No relevant effect on capillary density was observed. In conclusion, treatment with aliskiren or ramipril was associated with a correction of microvascular structural alterations in patients with non-insulin-dependent diabetes mellitus.

Topics: Aged; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arteries; Blood Pressure; Diabetes Mellitus, Type 2; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Ramipril; Skin; Time Factors; Treatment Outcome; Vascular Resistance

The aim of this study was to evaluate the add-on effect of aliskiren to valsartan on endothelial-dependent vasodilation in hypertensive patients with ischemic heart disease (IHD). After 4 weeks of treatment with 80 mg of valsartan, 28 patients were allocated to either continued treatment with valsartan or an add-on treatment with valsartan plus 150 mg of aliskiren. Aliskiren significantly decreased plasma renin activity, whereas endothelium-dependent vasodilation measured by flow-mediated dilation (FMD) did not change. In contrast, heart rate significantly decreased (73.1 ± 9.8 to 66.3 ± 7.0 beats per minute at baseline and 24 weeks, respectively [P = .009]) and the standard deviation of the R-R intervals (SDNN) significantly increased in the aliskiren group. The add-on aliskiren to valsartan therapy may not improve endothelial functions, although it significantly reduced resting heart rate via regulation of the autonomic nervous system in hypertensive patients with IHD.

Topics: Aged; Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Autonomic Nervous System; Comorbidity; Drug Therapy, Combination; Endothelium, Vascular; Female; Fumarates; Heart Rate; Humans; Hypertension; Male; Middle Aged; Myocardial Ischemia; Renin; Tetrazoles; Treatment Outcome; Valine; Valsartan; Vasodilation

Systolic hypertension is the most common form of hypertension in elderly patients. There is increasing evidence that measurement of central aortic pressure (CAP) better accounts for cardiovascular risk than brachial blood pressure (BP). The Aliskiren for GEriatric LowEring of SyStolic hypertension (AGELESS) study in elderly patients with systolic hypertension showed that aliskiren-based therapy provided greater reductions in peripheral BP than ramipril-based therapy over 12 and 36 weeks of treatment. Here, we present CAP results in a substudy of elderly patients from the AGELESS study.. This was a post hoc analysis of a 36-week, randomized, double-blind, parallel-group, active-controlled, optional-titration study in patients ≥65 years of age with systolic BP ≥140 mmHg. Changes in both central and peripheral BP and pulse pressure (PP) and changes in systolic and PP amplification ratios from baseline to the week 36 end point with aliskiren-based versus ramipril-based therapy were analyzed.. Of the 901 patients randomized in the overall study, 154 patients (aliskiren, n=78; ramipril, n=76) had CAP data. Numerically comparable reductions were seen for central aortic systolic pressure (CASP) in aliskiren-based therapy (baseline: 143.7±15.0; week 36: -20.3±16.2) compared with ramipril-based therapy (baseline: 147.9±11.9; week 36: -20.7±14.6). However, for the change in central aortic diastolic pressure, the least squares mean between-treatment difference (-3.6 mmHg [95% confidence interval, -6.76, -0.43; P=0.0263]) was in favor of aliskiren, while the other changes were comparable between the two groups with a trend in favor of aliskiren for CASP as well (-2.6 mmHg [95% confidence interval, -7.38, 2.19; P=0.2855)]. Correlation coefficients for change from baseline between CASP and systolic BP and between central aortic pulse pressure and PP (r=0.8, P<0.0001) were highly significant.. Aliskiren-based therapy provides comparable reductions in CASP to ramipril-based therapy. Although the results did not reach statistical significance, these findings, when coupled with those of the main study, suggest that aliskiren may offer effective control of central BP in elderly patients with systolic hypertension and may be a good alternative to ramipril.

Topics: Aged; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Aorta; Arterial Pressure; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Male; Ramipril; Systole; Time Factors; Treatment Outcome

Pharmacological inhibition of the renin-angiotensin-aldosteron system (RAAS) may have a beneficial impact on proteinuria and chronic kidney diseases (CKD) progression. Despite recent progress by means of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB), there is still no optimal therapy which can stop progression of the nephropathy. Recently introduced aliskiren is the first orally bioavailable direct renin inhibitor approved for the treatment of hypertension. The purpose was to evaluate the extent of oxidative stress and tubular injury after the direct renin inhibitor, aliskiren compared with placebo and perindopril in patients with non-diabetic chronic kidney disease (NDCKD).. A randomized, double-blind, cross-over trial was performed in 14 patients receiving 300mg aliskiren, 10mg perindopril and placebo in random order. The end point was a change in the urinary excretion of N-acetyl-β-D-glucosaminidase (NAG) and α1-microglobulin (α1m) and 15-F(2α)-isoprostane.. Aliskiren reduced excretion of 15-F(2α)-isoprostane (p=0.03) and α1m (p=0.01) as compared to placebo. There were no differences between aliskiren and perindopril in this regard. NAG urine excretion did not change after aliskiren and perindopril.. Aliskiren attenuates oxidative stress and may improve functional status of tubules in patients with NDCKD.

Topics: Adult; Amides; Antihypertensive Agents; Cohort Studies; Cross-Over Studies; Double-Blind Method; Female; Fumarates; Humans; Kidney Tubules; Male; Oxidative Stress; Renal Insufficiency, Chronic; Renin

It has been suggested that aliskiren has a long half-life and maintains a blood pressure (BP)-lowering effect following a missed dose. We tested the hypothesis that every other day (eod) administration of aliskiren has the same effects as the once daily (od) dosing in albuminuric hypertensive patients.. Fifteen hypertensive patients, after a 4-week wash-out period on clonidine, received 300 mg aliskiren od as the sole treatment. In patients who remained out of target, other nonrenin-angiotensin system blockers were added. Patients who completed a 24-week (w24) treatment period were switched to eod administration of aliskiren for an additional period of 24 weeks (w48).. Thirteen patients completed the full study protocol. The mean office BP was reduced at the end of w24 (-9/3 mmHg), a reduction that continued to be observed at w48 (-11/1 mmHg). At the end of the study, the 48 h ambulatory BP monitoring was divided into two 24 h periods. The mean 24 h systolic BP, and the mean daytime systolic and diastolic BP were significantly lower (P<0.05) in the first 24 h (when aliskiren was taken) compared with the second period. Central hemodynamics showed no significant differences at any time during monitoring. Administration of aliskiren resulted in a median reduction of urine albumin/creatinine ratio of 103 mg/g (od) and 102 mg/g (eod). Differences in plasma renin activity, plasma renin concentration, and aldosterone-level measurements were not significant.. The BP-lowering effect of eod aliskiren administration, although adequate, is less efficient compared with od administration, despite the fact that in terms of reducing albuminuria, it appears to be effective.

Topics: Adult; Aged; Albuminuria; Amides; Antihypertensive Agents; Blood Pressure; Creatinine; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Pilot Projects; Prospective Studies; Renin; Time Factors

The combination therapy of aliskiren and renin-angiotensin-aldosterone system (RAAS) blocker in chronic kidney disease (CKD) is controversial. Whether such dual blockade can effectively apply to patients with CKD irrespective of stage and amount of proteinuria remains uncertain.. We added aliskiren at a dosage of 150 mg/day for six months in 103 Chinese CKD patients who had been treated with angiotensin converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) and still had significant proteinuria or uncontrolled hypertension. Blood pressure, serum creatinine, estimated glomerular filtration rate (eGFR), potassium, and spot urine protein-to-creatinine ratio (UPCR) were measured at three and six months after aliskiren add-on therapy and compared with baseline.. The combination of aliskiren and ACEi or ARB significantly reduced UPCR by 23% (p=0.001) and mean arterial pressure by 7.9 ± 13.8 mmHg (p<0.001) at six months. Twenty-five percent of subjects had a greater than 50% reduction in UPCR. No significant changes in eGFR and serum potassium level were noted at six months.. Adding aliskiren on ACEi or ARB in CKD patients, both in diabetes and non-diabetes, has a favorable effect on reducing residual proteinuria and inadequately controlled blood pressure.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Creatinine; Demography; Female; Fumarates; Glomerular Filtration Rate; Humans; Male; Middle Aged; Prospective Studies; Proteinuria; Renal Insufficiency, Chronic; Treatment Outcome

We attempted to test the hypothesis that the direct renin inhibitor aliskiren can improve diastolic dysfunction, glucose, and insulin metabolism (GIM) in overweight and obese hypertensive patients.. Seventy-eight hypertensive patients were divided into two groups: 38 treated with aliskiren for six months, and 40 treated without aliskiren but with only traditional anti-hypertensive therapy, as controls. Doppler mitral flow velocity patterns were assessed before and after aliskiren during a six-month period. GIM (three-hour intravenous glucose tolerance test) was measured after four to six weeks of washout and six months of treatment. The mitral E/A ratio increased from 0.65 ± 0.11 to 0.75 ± 0.19. None of the indexes changed in the control group. In the control group, GIM parameters, fasting glucose levels (5.3 ± 0.9 to 6.0 ± 1.5 mmol/l; p = 0.003), fasting insulin levels (121 ± 121 to 189 ± 228 pmol/l; p = 0.03), and most other relevant metabolic measures (p < 0.05 for all) significantly worsened. Aliskiren did not affect GIM. In the control group LVM/height was not affected (119 ± 12 to 120 ± 17 g/m; p = 0.8), whereas aliskiren significantly reduced LVM/height (120 ± 13 to 111 ± 19 g/m; p = 0.04).. Optimal target BP was achieved in the group as a whole and in both obese patient groups, while benefits to cardiac structure were of a smaller magnitude. In high-risk, overweight/obese patients with hypertension, traditional therapy provides significantly greater BP- versus aliskiren-lowering throughout the 24-hour dosing interval. Therefore in obese, hypertensive individuals, adequate and similar blood pressure control was achieved with aliskiren; however, the aliskiren group and not the control group was associated with a more favorable GIM profile and led to a significant regression of LVM; overall aliskiren-based treatment offers sustained control of PRA.

Topics: Aged; Amides; Antihypertensive Agents; Biomarkers; Blood Glucose; Female; Fumarates; Humans; Hypertension; Insulin; Male; Middle Aged; Obesity; Overweight; Renin; Renin-Angiotensin System; Ultrasonography; Ventricular Function, Left

The aim was to compare the antiproteinuric effect of aliskiren and ramipril in hypertensive patients with type 2 diabetes and microalbuminuria.. A total of 138 patients were treated with aliskiren 300 mg/day or ramipril 10 mg/day for 12 weeks and checked after 1, 2, 4, 8 and 12 weeks and 2 and 4 weeks after treatment withdrawal.. Clinic and ambulatory BP, urinary albumin excretion rate (UAER) and plasma aldosterone were measured.. Both aliskiren and ramipril induced a similar lowering in clinic and ambulatory BP (p < 0.001 vs baseline). However, such a lowering persisted longer after stopping aliskiren than after stopping ramipril regimen. Both treatments reduced UAER, but the decrease in UAER associated with aliskiren was more pronounced, the difference vs ramipril being maximal at week 12 (-42 vs -15%, p < 0.01). Two weeks after stopping therapy, UAER remained below baseline values with aliskiren, but not in the ramipril group. Plasma aldosterone decreased in the aliskiren group, whereas in the ramipril group it decreased until week 8 and thereafter increased toward baseline values.. Aliskiren has a greater and more prolonged antiproteinuric effect than R; it might partly be related to a higher degree of intrarenal renin-angiotensin-aldosterone system blockade.

Topics: Adult; Aged; Albumins; Albuminuria; Aldosterone; Amides; Antihypertensive Agents; Arterial Pressure; Biomarkers; Blood Pressure Monitoring, Ambulatory; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Ramipril; Renin; Single-Blind Method; Treatment Outcome

Renin inhibitors like aliskiren not only block renin but also bind prorenin, thereby inducing a conformational change (like the change induced by acid) allowing its recognition in a renin-specific assay. Consequently, aliskiren can be used to measure prorenin. VTP-27999 is a new renin inhibitor with an aliskiren-like IC50 and t1/2, and a much higher bioavailability. This study addressed (pro)renin changes during treatment of volunteers with VTP-27999 or aliskiren. Both drugs increased renin immunoreactivity. Treatment of plasma samples from aliskiren-treated subjects with excess aliskiren yielded higher renin immunoreactivity levels, confirming the presence of prorenin. Unexpectedly, this approach did not work in VTP-27999-treated subjects, although an assay detecting the prosegment revealed that their blood still contained prorenin. Subsequent in vitro analysis showed that VTP-27999 increased renin immunoreactivity for a given amount of renin by ≥ 30% but did not unfold prorenin. Yet, it did bind to acid-activated, intact prorenin and then again increased immunoreactivity in a renin assay. However, no such increase in immunoreactivity was seen when measuring acid-activated prorenin bound to VTP-27999 with a prosegment-directed assay. The VTP-27999-induced rises in renin immunoreactivity could be competitively prevented by aliskiren, and antibody displacement studies revealed a higher affinity of the active site-directed antibodies in the presence of VTP-27999. In conclusion, VTP-27999 increases renin immunoreactivity in renin immunoassays because it affects the affinity of the active site-directed antibody. Combined with its lack of effect on prorenin, these data show that VTP-27999 differs from aliskiren. The clinical relevance of these results needs to be established.

Topics: Adult; Amides; Carbamates; Dose-Response Relationship, Drug; Female; Fumarates; Half-Life; Humans; Immunoassay; Male; Piperidines; Protein Binding; Protein Unfolding; Renin

Central blood pressure (CBP) is superior to brachial blood pressure as a predictor of cardiovascular risk in patients with hypertension. There is currently no consensus regarding whether a direct renin inhibitor (DRI) selectively acts on CBP.. Thirty subjects with essential hypertension who showed a CBP of 140 mm Hg or higher after 12 weeks of treatment with a standard dose of a DRI (150 mg) were analyzed. The patients were randomly divided into 2 groups: the high-dose DRI group (n=15) received 300 mg of DRI per day, and the combination group (n=15) received both the standard dose of the DRI and a diuretic (12.5 mg of hydrochlorothiazide). The systolic blood pressure (SBP), CBP, and the augmentation index (AI) were determined before treatment and after 12 and 24 weeks of treatment.. The SBP, CBP and AI were significantly decreased after 12 weeks of treatment with standard dose of the DRI (p<0.05). From 12 to 24 weeks after assignment the SBP and CBP were also significantly decreased in both the high-dose DRI group and the combination group. The high-dose DRI group showed a greater decrease in the CBP, but not in the SBP, than did the combination group (p<0.05). The AI decreased significantly from 12 to 24 weeks in the high-dose DRI group (p<0.05) but not in the combination group (p=0.14).. Treatment with a DRI contributes to a decrease in the CBP and AI, and high-dose DRI therapy leads to a further decrease in the CBP and AI.

Topics: Adult; Amides; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Prospective Studies; Renin; Time Factors; Treatment Outcome

Hospitalizations for heart failure (HHF) represent a major health burden, with high rates of early postdischarge rehospitalization and mortality.. To investigate whether aliskiren, a direct renin inhibitor, when added to standard therapy, would reduce the rate of cardiovascular (CV) death or HF rehospitalization among HHF patients.. International, double-blind, placebo-controlled study that randomized hemodynamically stable HHF patients a median 5 days after admission. Eligible patients were 18 years or older with left ventricular ejection fraction (LVEF) 40% or less, elevated natriuretic peptides (brain natriuretic peptide [BNP] ≥ 400 pg/mL or N -terminal pro-BNP [NT-proBNP] ≥ 1600 pg/mL), and signs and symptoms of fluid overload. Patients were recruited from 316 sites across North and South America, Europe, and Asia between May 2009 and December 2011. The follow-up period ended in July 2012.. All patients received 150 mg (increased to 300 mg as tolerated) of aliskiren or placebo daily, in addition to standard therapy. The study drug was continued after discharge for a median 11.3 months. MAIN OUTCOME MEASURES Cardiovascular death or HF rehospitalization at 6 months and 12 months.. In total, 1639 patients were randomized, with 1615 patients included in the final efficacy analysis cohort (808 aliskiren, 807 placebo). Mean age was 65 years; mean LVEF, 28%; 41% of patients had diabetes mellitus, mean estimated glomerular filtration rate, 67 mL/min/1.73 m2. At admission and randomization, median NT-proBNP levels were 4239 pg/mL and 2718 pg/mL, respectively. At randomization, patients were receiving diuretics (95.9%), β-blockers (82.5%), angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (84.2%), and mineralocorticoid receptor antagonists (57.0%). In total, 24.9% of patients receiving aliskiren (77 CV deaths, 153 HF rehospitalizations) and 26.5% of patients receiving placebo (85 CV deaths, 166 HF rehospitalizations) experienced the primary end point at 6 months (hazard ratio [HR], 0.92; 95% CI, 0.76-1.12; P = .41). At 12 months, the event rates were 35.0% for the aliskiren group (126 CV deaths, 212 HF rehospitalizations) and 37.3% for the placebo group (137 CV deaths, 224 HF rehospitalizations; HR, 0.93; 95% CI, 0.79-1.09; P = .36). The rates of hyperkalemia, hypotension, and renal impairment/renal failure were higher in the aliskiren group compared with placebo.. Among patients hospitalized for HF with reduced LVEF, initiation of aliskiren in addition to standard therapy did not reduce CV death or HF rehospitalization at 6 months or 12 months after discharge.. clinicaltrials.gov Identifier: NCT00894387.

Topics: Aged; Amides; Antihypertensive Agents; Double-Blind Method; Female; Follow-Up Studies; Fumarates; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Patient Readmission; Renin; Stroke Volume; Treatment Outcome; Ventricular Dysfunction, Left

Aliskiren is a novel blood pressure-lowering agent acting as an oral direct renin inhibitor. The aim of this study was to assess the effect of aliskiren on arterial stiffness, compared with that of ramipril in mild to moderate essential hypertensive patients.. Following a two week placebo run-in period, patients with a mean sitting diastolic blood pressure (ms-DBP) ≥ 95 and < 110 mmHg (1 mmHg = 0.133 kPa), and a mean sitting systolic blood pressure (ms-SBP) < 180 mmHg were randomly allocated to treatment with aliskiren (150 mg/d, n = 20) or ramipril (5 mg/d, n = 20) for eight weeks. Blood pressure, plasma renin activity, and the brachial-ankle pulse wave velocity (ba-PWV) were measured before and after eight weeks of treatment.. Eight weeks of treatment significantly decreased systolic blood pressure and diastolic blood pressure in both the aliskiren group and ramipril group. The hypotensive effect did not differ between the two groups. Plasma renin activity decreased after aliskiren treatment and increased after ramipril treatment. There was no significant difference in baseline ba-PWV between the aliskiren and ramipril groups (P = 0.892). The ba-PWV was significantly reduced in both the aliskiren group (1535 (1405 - 1666) vs. 1464 (1360 - 1506) cm/s) (P < 0.01) and the ramipril group (1544 (1433 - 1673) vs. 1447 (1327 - 1549) cm/s) (P < 0.01). No statistically significant difference was found in the decline of ba-PWV between the two groups (P = 0.766).. The current study revealed that aliskiren (150 mg/d) could ameliorate arterial stiffness and its effect was similar to ramipril (5 mg/d) in mild to moderate hypertensive patients, indicating that in addition to lowering blood pressure, aliskiren had beneficial effect on vascular protection.

Topics: Adult; Amides; Antihypertensive Agents; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Ramipril; Vascular Stiffness

To assess the pharmacokinetics (PK) and safety profile of aliskiren in pediatric patients (6-17 years old) with hypertension.. Patients were randomized to a single weight-based dose of either 2 mg/kg (n = 19) or 6 mg/kg (n = 20) of aliskiren daily for 8 days. The PK, pharmacodynamics, safety profile, and efficacy of aliskiren were assessed.. Of the 39 randomized patients, 37 (94.9%) completed the study. Aliskiren plasma concentration (maximum plasma concentration and area under the plasma concentration-time curve) increased dose dependently, achieving peak concentrations in 1 to 2 hours, and t(max) was comparable across the dose and age groups. Treatment-emergent adverse events (AEs) were reported in 18 (46.2%) patients, with headache, abdominal pain, and nausea being the most frequent.. Aliskiren 2 mg/kg and 6 mg/kg daily showed dose-dependent increases in the plasma concentration. The drug was well tolerated in hypertensive children aged 6 to 17 years. AEs were generally mild and not related to either the drug or the dose.

Topics: Administration, Oral; Adolescent; Age Factors; Amides; Analysis of Variance; Antihypertensive Agents; Child; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fumarates; Humans; Hypertension; Male; Regression Analysis; Tablets; Treatment Outcome

Various methods of combination renin-angiotensin-aldosterone system blockade help achieve more potent antiproteinuric effects, but may be associated with higher risk of side effects. Therapies involving direct renin inhibitor, aliskiren, may promote renal fibrosis by stimulating (pro)renin receptor due to increased renin levels.. The aim of the study was to compare the effects of combination treatment with angiotensin receptor blockers, telmisartan (80 mg/d) and aliskiren (300 mg/d) with those of combination treatment with 80 mg/d telmisartan and mineralocorticoid receptor blocker (50 mg/d eplerenone) and telmisartan (160 mg/d) alone on the urinary excretion of transforming growth factor β1 (TGF‑β1), renal function, and serum potassium levels.. A randomized open-label controlled cross-over study was performed in 18 white patients (7 women and 11 men; mean age, 42.4 ±1.9 years) with proteinuric nondiabetic chronic kidney disease and estimated glomerular filtration rate of 85.2 ±4.6 ml/min.. The urinary excretion of TGF‑β1 was stable despite a significant increase in plasma renin levels after treatment with telmisartan and aliskiren. There were no differences in renal function and serum potassium levels between the compared treatments. Moreover, there were no episodes of hypotension or acute renal impairment.. Combination therapy with telmisartan and aliskiren may be safe in young nondiabetic patients with normal renal function at low vascular risk. This treatment may be an alternative for a subset of patients in whom standard RAA system blockade is ineffective.

Topics: Adult; Amides; Angiotensin II Type 1 Receptor Blockers; Benzimidazoles; Benzoates; Chronic Disease; Diuretics; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fumarates; Humans; Kidney Diseases; Male; Middle Aged; Patient Safety; Renin-Angiotensin System; Severity of Illness Index; Telmisartan; Treatment Outcome

Elevated brachial blood pressure (BP) is associated with increased cardiovascular risk and predicts morbidity and mortality in humans. Recently, 24-hour ambulatory BP monitoring and assessment of central aortic BP have been introduced to improve BP phenotyping. The Ambulatory Central Aortic Pressure (AmCAP) study combines these approaches and describes, for the first time, the diurnal patterns of simultaneously measured 24-hour ambulatory brachial and central pressures in a prespecified substudy embedded within a clinical trial of BP lowering in patients with hypertension. Twenty-four-hour ambulatory brachial and central pressure measurements were acquired using a tonometer mounted into the articulating strap of a wristwatch-like device (BPro) in 171 participants with hypertension recruited into the ASSERTIVE (AliSkiren Study of profound antihypERtensive efficacy in hyperTensIVE patients) trial. Participants were randomly assigned to BP lowering with either aliskiren 300 mg QD or telmisartan 80 mg QD for 12 weeks. Ambulatory brachial and central BP was measured in all participants both at baseline and at study end. Brachial and central BP both demonstrated typical diurnal patterns with lower pressures at night. However, night time was associated with smaller reductions in central relative to brachial pressure and decreased pulse pressure amplification (P<0.0001 for both). These effects were not modulated after BP lowering and were maintained after adjustment for day and night-time BP and heart rate (P=0.02). This study demonstrates that brachial and central pressure show different diurnal patterns, which are not modulated by BP-lowering therapy, with relatively higher night-time central pressures. These novel data indicate that night-time central BP may provide prognostic importance and warrants further investigation. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00865020.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Aorta, Thoracic; Benzimidazoles; Benzoates; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Brachial Artery; Circadian Rhythm; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Fumarates; Humans; Hypertension; Male; Middle Aged; Prognosis; Prospective Studies; Renin; Reproducibility of Results; Telmisartan

Laboratory research and previous study suggest that aliskiren, a direct renin inhibitor, has anti-proteinuric effects. We conducted a randomized crossover study to evaluate the anti-proteinuric effect of aliskiren in patients with immunoglobulin A (IgA) nephropathy.. We studied 22 patients with biopsy-proven IgA nephropathy and persistent proteinuria despite angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). Patients were randomized to either oral aliskiren 300 mg/day or placebo for 16 weeks and then crossed over to the other treatment arm after a washout period. Proteinuria, estimated glomerular filtration rate (eGFR), blood pressure, and serum potassium were monitored.. After aliskiren treatment, there was a significant reduction in proteinuria in 4 weeks (1.76±0.95 to 1.03±0.69 g:g-Cr, p<0.0001), which remained at a low level throughout the treatment period. There was a significant difference in proteinuria between the aliskiren and placebo groups from 4 to 16 weeks after treatment (p<0.01 for all comparisons). After aliskiren treatment, there were modest but statistically significant reductions in eGFR (57.2±29.1 to 54.8±29.3 ml/min/1.73 m(2), p = 0.013) and diastolic blood pressure (72.6±12.3 to 66.2±11.2 mmHg, p<0.0001). None of the patient developed severe hyperkalemia (serum potassium ≥6.0 mmol/l) during the study period.. Aliskiren has anti-proteinuric effect in patients with IgA nephropathy and persistent proteinuria despite ACE inhibitor or ARB. Further studies are needed to confirm the renal protecting effect of direct renin inhibition in chronic proteinuric kidney diseases.. ClinicalTrials.gov NCT00870493.

Topics: Adult; Amides; Antihypertensive Agents; Blood Pressure; Cross-Over Studies; Female; Fumarates; Glomerular Filtration Rate; Glomerulonephritis, IGA; Humans; Hyperkalemia; Male; Middle Aged; Proteinuria; Renin; Treatment Outcome

Currently there is no consensus regarding which add-on therapy to use in resistant hypertension. We have conducted an open observational study of the use of aliskiren in resistant hypertensive patients. Forty-three patients with resistant hypertension were included in the study. The inclusion criteria were as follows: 1) office blood pressure (BP) > 140/90 mmHg despite treatment with at least three or more antihypertensive drugs; 2) no prior therapy with aliskiren; and 3) no renal insufficiency. Follow-up BP was determined at 1 and 3 months. Baseline BP was 153 ± 12/79 ± 12 mmHg. After 3 months, systolic BP (SBP) and diastolic BP (DBP) dropped significantly: 140 ± 19/73 ± 13 mmHg (P < 0.0001). Twenty-one patients (49%) had an office BP < 140/90 mmHg, and these patients were assigned to the good BP control group. Another 22 were placed into the poor BP control group. BP reductions from baseline in the good BP control group (SBP/ DBP: 19 ± 11/8 ± 7 mmHg) were larger than those in the poor BP control group (5 ± 15/3 ± 9 mmHg, P < 0.05). Mean BP (MBP) values at baseline, 1, and 3 months were higher in the poor BP control group. There was no significant difference in pulse pressure at baseline between the 2 groups. In multivariate analysis, only MBP at baseline correlated with lack of BP control. Aliskiren administration to resistant hypertensive patients was effective in reducing BP. The present findings suggest aliskiren may be useful as a fourth-line or fifth-line treatment added to other drugs in the treatment of resistant hypertension.

Topics: Adult; Aged; Aged, 80 and over; Amides; Antihypertensive Agents; Female; Fumarates; Humans; Hypertension; Logistic Models; Male; Middle Aged; Renin; Salvage Therapy; Treatment Outcome

The renin-angiotensin system is well recognized as a mediator of pathophysiological events in atherosclerosis. The benefits of renin inhibition in atherosclerosis, especially when used in combination with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) are currently not known. We hypothesized that treatment with the renin inhibitor aliskiren in patients with established cardiovascular disease will prevent the progression of atherosclerosis as determined by high-resolution magnetic resonance imaging (MRI) measurements of arterial wall volume in the thoracic and abdominal aortas of high-risk patients with preexisting cardiovascular disease.. This was a single-center, randomized, double-blind, placebo-controlled trial in patients with established cardiovascular disease. After a 2-week single-blind placebo phase, patients were randomized to receive either placebo (n=37, mean ± SD age 64.5 ± 8.9 years, 3 women) or 150 mg of aliskiren (n=34, mean ± SD age 63.9 ± 11.5 years, 9 women). Treatment dose was escalated to 300 mg at 2 weeks and maintained during the remainder of the study. Patients underwent dark-blood, 3-dimensional MRI assessment of atherosclerotic plaque in the thoracic and abdominal segments at baseline and on study completion or termination (up to 36 weeks of drug or matching placebo). Aliskiren use resulted in significant progression of aortic wall volume (normalized total wall volume 5.31 ± 6.57 vs 0.15 ± 4.39 mm(3), P=0.03, and percentage wall volume 3.37 ± 2.96% vs 0.97 ± 2.02%, P=0.04) compared with placebo. In a subgroup analysis of subjects receiving ACEI/ARB therapy, atherosclerosis progression was observed only in the aliskiren group, not in the placebo group.. MRI quantification of atheroma plaque burden demonstrated that aliskiren use in patients with preexisting cardiovascular disease resulted in an unexpected increase in aortic atherosclerosis compared with placebo. Although preliminary, these results may have implications for the use of renin inhibition as a therapeutic strategy in patients with cardiovascular disease, especially in those receiving ACEI/ARB therapy.. URL: http://ClinicalTrials.gov Unique identifier: NCT01417104.

Topics: Amides; Atherosclerosis; Cardiovascular Diseases; Disease Progression; Double-Blind Method; Female; Fumarates; Humans; Imaging, Three-Dimensional; Magnetic Resonance Imaging; Male; Middle Aged; Plaque, Atherosclerotic; Prospective Studies; Renin; Single-Blind Method

To evaluate whether the direct renin inhibitor, aliskiren, has a more favorable effect compared to amlodipine on atherosclerotic biomarkers in patients with stable coronary artery disease and diabetes currently receiving standard secondary prevention therapy.. A total of 38 patients were randomly assigned initially to either aliskiren (150 mg daily) or amlodipine (5 mg daily) for 2 weeks after which the dose of either medication was increased to its maximum daily dose for 4 additional weeks. Baseline and 6-week blood samples were analyzed for changes from baseline and between treatment groups for vascular and intracellular cell adhesion molecule, C-reactive protein, nitric oxide, plasminogen activator inhibitor 1, 8-isoprostane, and thiobarbituric acid reactive substances.. Thirty-one patients completed the study. More of the dropouts occurred in patients receiving aliskiren. Systolic blood pressure decreased in both treatment arms with no differences between the groups being noted. Plasminogen activator inhibitor 1, nitric oxide, and C-reactive protein concentrations increased in both groups from baseline but changes from baseline or between groups were not significant. Vascular and intracellular cell adhesion molecule, thiobarbituric acid reactive substances, and isoprostane concentrations decreased in each treatment arm from baseline, but these changes were not significant and no differences were noted between the groups.. Treatment with either aliskiren or amlodipine did not significantly alter surrogate biomarkers of atherosclerosis in patients with both diabetes and established cardiovascular disease already receiving appropriate secondary cardiovascular prevention therapy. The study is limited in its size and duration to see an effect.

Topics: Aged; Amides; Amlodipine; Atherosclerosis; Biomarkers; Blood Pressure; Coronary Artery Disease; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Fumarates; Humans; Male; Middle Aged; Prospective Studies; Renin

Urinary levels of renin-angiotensin-aldosterone system (RAAS) components may reflect renal RAAS activity and/or the renal efficacy of RAAS inhibition. Our aim was to determine whether urinary angiotensinogen and renin are circulating RAAS-independent markers during RAAS blockade.. Urinary and plasma levels of angiotensinogen, renin, and albumin were measured in 22 patients with type 2 diabetes, hypertension, and albuminuria, during 2-month treatment periods with placebo, aliskiren, irbesartan, or their combination in random order in a crossover study.. Aliskiren and irbesartan both increased plasma renin 3-4-fold, and above 10-fold when combined. Irbesartan decreased plasma angiotensinogen by approximately 25%, and no changes in plasma angiotensinogen were observed during the combination. Urine contained aliskiren at micromolar levels, blocking urinary renin by above 90%. Both blockers reduced urinary angiotensinogen, significant for irbesartan only. Combination blockade reduced urinary angiotensinogen even further. Reductions in urinary angiotensinogen paralleled albuminuria changes, and the urine/plasma concentration ratio of angiotensinogen was identical to that of albumin under all conditions. In contrast, urinary renin did not follow albumin, and remained unaltered after all treatments. Yet, the urine/plasma concentration ratio of renin was more than 100-fold higher than that of angiotensinogen and albumin, and approximately 4-fold reduced by single RAAS blockade, and more than 10-fold by dual RAAS blockade.. Aliskiren filters into urine and influences urinary renin measurements. The urine/plasma renin ratio, but not urinary renin alone, may reflect the renal efficacy of RAAS blockade. Urinary angiotensinogen is a marker of filtration barrier damage rather than intrarenal RAAS activity.

Topics: Adult; Aged; Aged, 80 and over; Albumins; Amides; Angiotensinogen; Angiotensins; Antihypertensive Agents; Biphenyl Compounds; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Fumarates; Humans; Irbesartan; Male; Middle Aged; Renin; Renin-Angiotensin System; Tetrazoles

Longitudinal study aimed to evaluate the antihypertensive efficacy, safety and the effect on cardiac damage of Aliskiren, administered to a group of high-risk hypertensive patients with mild impairment of renal function and uncontrolled blood pressure (BP) despite a two-drug antihypertensive treatment.. One hundred and six patients (56 men and 50 females) aged 61.9±12.7 years, were assigned to receive Aliskiren 150-300 mg once-daily for 12 months. Clinic BP measurements were taken at every follow-up visit (1st, 6th and 12th month), while biochemical tests, estimated glomerular filtration rate (eGFR), 24-hours ambulatory BP measurements (ABMP) and echocardiography were evaluated at baseline and at the end of follow-up. Analysis of variance for repeated measures compared BP, left ventricular mass index (LVMI) and eGFR values changes.. A significant reduction (all P<0.0001) of clinic systolic (-28.6 mmHg) and diastolic (-12.8 mmHg) BP values, mean 24h-systolic (-12.3 mmHg) and 24h-diastolic (-6.5 mmHg), day-time systolic (-11.5 mmHg) and diastolic (-6.4 mmHg), night-time systolic (-11.9 mmHg) and diastolic (-7 mmHg) ABPM values and in the use of antihypertensive drugs was observed (3.0±0.9 vs. 2.0±0.7, p=0.01). LVMI was significantly reduced (130.2±36.1 vs. 115.9±33.4 g/m2, P<0.0001); eGFR was steady (75.3±17.3 vs. 73.1±21.5 ml/min/1.73m2, P>0.05). Putative adverse events caused withdrawal of 7 subjects (6 for gastrointestinal disturbances, 1 for alopecia).. Aliskiren was effective in decreasing both clinical and ABPM values and in reducing LVMI in both genders without any influence on eGFR. The treatment resulted safe, even in combination with ACE-inhibitors and angiotensin II receptor blockers. A significant reduction in the use of concomitant antihypertensive drugs was observed.

Topics: Aged; Alopecia; Amides; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Diarrhea; Female; Fumarates; Glomerular Filtration Rate; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Prospective Studies; Renin; Renin-Angiotensin System; Risk; Ventricular Remodeling

We have reported observing aldosterone breakthrough in the course of relatively long-term treatment with renin-angiotensin (RA) system inhibitors, where the plasma aldosterone concentration (PAC) increased following an initial decrease. Aldosterone breakthrough has the potential to eliminate the organ-protective effects of RA system inhibitors. We therefore conducted a study in essential hypertensive patients to determine whether aldosterone breakthrough occurred during treatment with the direct renin inhibitor (DRI) aliskiren and to ascertain its clinical significance. The study included 40 essential hypertensive patients (18 men and 22 women) who had been treated for 12 months with aliskiren. Aliskiren significantly decreased blood pressure and plasma renin activity (PRA). The PAC was also decreased significantly at 3 and 6 months; however, the significant difference disappeared after 12 months. Aldosterone breakthrough was observed in 22 of the subjects (55%). Urinary albumin excretion differed depending on whether breakthrough occurred. For the subjects in whom aldosterone breakthrough was observed, eplerenone was added. A significant decrease in urinary albumin excretion was observed after 1 month, independent of changes in blood pressure. In conclusion, this study demonstrated that aldosterone breakthrough occurs in some patients undergoing DRI therapy. Aldosterone breakthrough affects the drug's ability to improve urinary albumin excretion, and combining a mineralocorticoid receptor antagonist with the DRI may be useful for decreasing urinary albumin excretion. When the objective is organ protection in hypertensive patients, a two-pronged approach using combination therapy to inhibit both the RA system and aldosterone may be highly effective.

Topics: Aged; Albuminuria; Aldosterone; Amides; Blood Pressure; Dose-Response Relationship, Drug; Drug Therapy, Combination; Eplerenone; Female; Fumarates; Humans; Hypertension; Incidence; Longitudinal Studies; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Renin; Renin-Angiotensin System; Spironolactone; Time Factors

Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used for reducing pain and other symptoms in osteoarthritis (OA). NSAIDs have been associated with an increase in blood pressure (BP) in both normotensive and hypertensive individuals and a blunting effect on various anti-hypertensive medications. Acetaminophen effects on anti-hypertensive treatment, instead, are still a matter of debate.. To assess the effect of naproxen versus acetaminophen on ramipril, valsartan and aliskiren therapy in hypertensive patients with OA in a double-blind, cross-over study, by measuring clinic, ambulatory BP and heart rate (HR).. One hundred seventy four patients were randomly treated with ramipril, valsartan or aliskiren for 8 weeks and 135 patients with normalized BP were randomized to receive naproxen or acetaminophen for 2 weeks. Naproxen significantly increased clinic and ambulatory systolic/diastolic BP (SBP/DBP) values in patients treated with ramipril (p < 0.01) or valsartan (p < 0.05), but did not affect aliskiren effects. Also acetaminophen slightly but significantly affected clinic and ambulatory SBP/DBP in all three groups and, surprisingly, it also produced a slight increase in HR (+3.1, +3.3 and +3.4 b/min day-time HR values, for ramipril, valsartan and aliskiren, respectively; p < 0.05).. Both naproxen and acetaminophen can affect anti-hypertensive therapy with ramipril, valsartan or aliskiren with a different extent. When acetaminophen is chosen for OA management in subjects with hypertension, patients should be evaluated as carefully as when traditional NSAIDs are given.

Topics: Acetaminophen; Adult; Aged; Amides; Anti-Inflammatory Agents, Non-Steroidal; Antihypertensive Agents; Blood Pressure; Cross-Over Studies; Double-Blind Method; Drug Interactions; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Naproxen; Ramipril; Tetrazoles; Valine; Valsartan

An altered ambulatory blood pressure (BP) and heart rate (HR) profile is related to chronic kidney disease (CKD) and cardiorenal syndrome. In this study, we examined the effects of aliskiren, when added to angiotensin II type 1 receptor blockers, on ambulatory BP and cardiorenal function in CKD. Thirty-six hypertensive CKD patients were randomly assigned to the aliskiren add-on group (n = 18) or the benazepril add-on group (n = 18). Ambulatory BP and cardiorenal function parameters were measured at baseline and 24 weeks after treatment. Compared with the benazepril group, nighttime systolic BP variability in the aliskiren group was lower after treatment. Albuminuria was decreased in the aliskiren group, but not in the benazepril group. In addition, left ventricular mass index (LVMI) was significantly lower in the aliskiren group than in the benazepril group after treatment. In the aliskiren group, multivariate linear regression analysis showed an association between changes in albuminuria and changes in nighttime systolic BP. Furthermore, there were associations between changes in LVMI and changes in daytime HR variability, as well as between changes in LVMI and changes in plasma aldosterone concentration. These results suggest that aliskiren add-on therapy may be beneficial for suppression of renal deterioration and pathological cardiac remodeling through an improvement that is effected in ambulatory BP and HR profiles.

Topics: Aged; Albuminuria; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzazepines; Blood Pressure; Cardio-Renal Syndrome; Female; Fumarates; Heart Function Tests; Heart Rate; Humans; Hypertrophy, Left Ventricular; Kidney Function Tests; Male; Oxidative Stress; Renal Insufficiency, Chronic

Acute clamped hyperglycaemia activates the renin-angiotensin-aldosterone system (RAAS) and increases the urinary excretion of inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus. Our objective was to determine whether blockade of the RAAS would blunt the effect of acute hyperglycaemia on urinary cytokine/chemokine excretion, thereby giving insights into potentially protective effects of these agents prior to the onset of clinical nephropathy.. Blood pressure, renal haemodynamic function (inulin and para-aminohippurate clearances) and urinary cytokines/chemokines were measured after 6 h of clamped euglycaemia (4-6 mmol/l) and hyperglycaemia (9-11 mmol/l) on two consecutive days in patients with type 1 diabetes mellitus (n = 27) without overt nephropathy. Measurements were repeated after treatment with aliskiren (300 mg daily) for 30 days.. Before aliskiren, clamped hyperglycaemia increased filtration fraction (from 0.188 ± 0.007 to 0.206 ± 0.007, p = 0.003) and urinary fibroblast growth factor-2 (FGF2), IFN-α2 and macrophage-derived chemokine (MDC) (p < 0.005). After aliskiren, the filtration fraction response to hyperglycaemia was abolished, resulting in a lower filtration fraction after aliskiren under clamped hyperglycaemic conditions (p = 0.004), and none of the biomarkers increased in response to hyperglycaemia. Aliskiren therapy also reduced levels of urinary eotaxin, FGF2, IFN-α2, IL-2 and MDC during clamped hyperglycaemia (p < 0.005).. The increased urinary excretion of inflammatory cytokines/chemokines in response to acute hyperglycaemia is blunted by RAAS blockade in humans with uncomplicated type 1 diabetes mellitus.

Topics: Adult; Amides; Chemokines; Cytokines; Diabetes Mellitus, Type 1; Female; Fumarates; Humans; Hyperglycemia; Insulin; Male; p-Aminohippuric Acid; Proteomics; Young Adult

The objective of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was to determine whether aliskiren, a direct renin inhibitor, would improve post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction. Pre-specified subgroup analyses suggested potential heterogeneity in post-discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM).. ASTRONAUT included 953 patients without DM (aliskiren 489; placebo 464) and 662 patients with DM (aliskiren 319; placebo 343) (as reported by study investigators). Study endpoints included the first occurrence of cardiovascular death or HHF within 6 and 12 months, all-cause death within 6 and 12 months, and change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 1, 6, and 12 months. Data regarding risk of hyperkalaemia, renal impairment, and hypotension, and changes in additional serum biomarkers were collected. The effect of aliskiren on cardiovascular death or HHF within 6 months (primary endpoint) did not significantly differ by baseline DM status (P = 0.08 for interaction), but reached statistical significance at 12 months (non-DM: HR: 0.80, 95% CI: 0.64-0.99; DM: HR: 1.16, 95% CI: 0.91-1.47; P = 0.03 for interaction). Risk of 12-month all-cause death with aliskiren significantly differed by the presence of baseline DM (non-DM: HR: 0.69, 95% CI: 0.50-0.94; DM: HR: 1.64, 95% CI: 1.15-2.33; P < 0.01 for interaction). Among non-diabetics, aliskiren significantly reduced NT-proBNP through 6 months and plasma troponin I and aldosterone through 12 months, as compared to placebo. Among diabetic patients, aliskiren reduced plasma troponin I and aldosterone relative to placebo through 1 month only. There was a trend towards differing risk of post-baseline potassium ≥6 mmol/L with aliskiren by underlying DM status (non-DM: HR: 1.17, 95% CI: 0.71-1.93; DM: HR: 2.39, 95% CI: 1.30-4.42; P = 0.07 for interaction).. This pre-specified subgroup analysis from the ASTRONAUT trial generates the hypothesis that the addition of aliskiren to standard HHF therapy in non-diabetic patients is generally well-tolerated and improves post-discharge outcomes and biomarker profiles. In contrast, diabetic patients receiving aliskiren appear to have worse post-discharge outcomes. Future prospective investigations are needed to confirm potential benefits of renin inhibition in a large cohort of HHF patients without DM.

Topics: Administration, Oral; Amides; Cardiotonic Agents; Death, Sudden, Cardiac; Diabetic Cardiomyopathies; Double-Blind Method; Female; Fumarates; Heart Failure; Hospitalization; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Prospective Studies; Renin; Treatment Outcome

Blood pressure reduction and renin-angiotensin-aldosterone system inhibition are targets for treatment of atherosclerosis. The effect of renin inhibition on coronary disease progression has not been investigated.. To determine the effects of renin inhibition with aliskiren on progression of coronary atherosclerosis.. A double-blind, randomized, multicenter trial (Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study) comparing aliskiren with placebo in 613 participants with coronary artery disease, systolic blood pressure between 125 and 139 mm Hg (prehypertension range), and 2 additional cardiovascular risk factors conducted at 103 academic and community hospitals in Europe, Australia, and North and South America (enrollment from March 2009 to February 2011; end of follow-up: January 31, 2013).. Participants underwent coronary intravascular ultrasound (IVUS) imaging and were randomized to receive 300 mg of aliskiren (n = 305) or placebo (n = 308) taken orally daily for 104 weeks. Disease progression was measured by repeat IVUS examination after at least 72 weeks of treatment.. The primary efficacy parameter was the change in percent atheroma volume (PAV) from baseline to study completion. Secondary efficacy parameters included the change in normalized total atheroma volume (TAV) and the percentage of participants with atheroma regression. Safety and tolerability were also assessed.. Evaluable imaging data were available at baseline and follow-up for 458 participants (74.7%). The primary IVUS efficacy parameter, PAV, did not differ between participants treated with aliskiren (-0.33%; 95% CI, -0.68% to 0.02%) and placebo (0.11%; 95% CI, -0.24% to 0.45%) (between-group difference, -0.43% [95% CI, -0.92% to 0.05%]; P = .08). The secondary IVUS efficacy parameter, TAV, did not differ between participants treated with aliskiren (-4.1 mm3; 95% CI, -6.27 to -1.94 mm3) and placebo (-2.1 mm3; 95% CI, -4.21 to 0.07 mm3) (between-group difference, -2.04 mm3 [95% CI, -5.03 to 0.95 mm3]; P = .18). There were no significant differences in the proportion of participants who demonstrated regression of PAV (56.9% vs 48.9%; P = .08) and TAV (64.4% vs 57.5%; P = .13) in the aliskiren and placebo groups, respectively.. Among participants with prehypertension and coronary artery disease, the use of aliskiren compared with placebo did not result in improvement or slowing of progression of coronary atherosclerosis. These findings do not support the use of aliskiren for regression or prevention of progression of coronary atherosclerosis.. clinicaltrials.gov Identifier: NCT00853827.

Topics: Aged; Amides; Antihypertensive Agents; Blood Pressure; Coronary Artery Disease; Coronary Vessels; Disease Progression; Double-Blind Method; Female; Fumarates; Humans; Male; Middle Aged; Prehypertension; Renin; Renin-Angiotensin System; Risk Factors; Ultrasonography, Interventional

Cardiovascular risk remains high in patients with hypertension even with adequate blood pressure (BP) control. One possible mechanism may be sympathetic activation via the baroreflex. We tested the hypothesis that chronic inhibition of renin reduces BP without sympathetic activation, but diuresis augments sympathetic activity in elderly hypertensives. Fourteen patients with stage-I hypertension (66 ± 5 (SD) years) were treated with a direct renin inhibitor, aliskiren (n = 7), or a diuretic, hydrochlorothiazide (n = 7), for 6 months. Muscle sympathetic nerve activity (MSNA), BP, direct renin and aldosterone were measured during supine and a graded head-up tilt (HUT; 5 min 30° and 20 min 60°), before and after treatment. Sympathetic baroreflex sensitivity (BRS) was assessed. Both groups had similar BP reductions after treatment (all P < 0.01), while MSNA responses were different between hydrochlorothiazide and aliskiren (P = 0.006 pre/post × drug). Both supine and upright MSNA became greater after hydrochlorothiazide treatment (supine, 72 ± 18 post vs. 64 ± 15 bursts (100 beats)(-1) pre; 60° HUT, 83 ± 10 vs. 78 ± 13 bursts (100 beats)(-1); P = 0.002). After aliskiren treatment, supine MSNA remained unchanged (69 ± 13 vs. 64 ± 8 bursts (100 beats)(-1)), but upright MSNA was lower (74 ± 15 vs. 85 ± 10 bursts (100 beats)(-1); P = 0.012 for pre/post × posture). Direct renin was greater after both treatments (both P < 0.05), while upright aldosterone was greater after hydrochlorothiazide only (P = 0.002). The change in upright MSNA by the treatment was correlated with the change of aldosterone (r = 0.74, P = 0.002). Upright sympathetic BRS remained unchanged after either treatment. Thus, chronic renin inhibition may reduce upright MSNA through suppressed renin activity, while diuresis may evoke sympathetic activation via the upregulated renin-angiotensin-aldosterone system, without changing intrinsic sympathetic baroreflex function in elderly hypertensive patients.

Topics: Aged; Amides; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Muscles; Peroneal Nerve; Posture; Renin; Sodium Chloride Symporter Inhibitors; Sympathetic Nervous System

The renin-angiotensin-aldosterone system is not necessarily suppressed in end-stage renal disease patients undergoing dialysis. Of all the inhibitors of this system, the clinical efficacy of the renin inhibitor, aliskiren, has not been well demonstrated in dialysis patients. We evaluated the antihypertensive effect of aliskiren, administered as a single daily dose of 150 mg for 24 weeks, in 23 chronic hemodialysis patients (age 65 ± 12 years, 15 men and eight women) with blood pressure ≥140/90 mm Hg, and assessed the factors relating to blood pressure reduction. At 4 weeks, the average systolic blood pressure before the dialysis session was insignificantly reduced from 163 ± 10 mm Hg to 160 ± 15 mm Hg, while it was significantly lowered at 12 (154 ± 13 mm Hg) and 24 weeks (155 ± 10 mm Hg), although the pulse rate was not significantly altered. Serum K increased at 24 weeks from 4.9 ± 0.6 mEq/L to 5.2 ± 0.8 mEq/L. Only 10 out of 23 patients showed systolic blood pressure reduction by ≥10 mm Hg. Naturally, plasma renin immunoreactivity increased, while plasma renin activity, along with angiotensin II and aldosterone levels decreased. Basal levels of the components of the renin-angiotensin-aldosterone system were not significantly different in patients showing systolic blood pressure reduction by ≥10 mm Hg (n = 10) vs. those with <10 mm Hg changes (n = 13). The reduction in systolic blood pressure in all 23 patients taken as a whole correlated with changes in plasma renin activity (r = -0.432, P < 0.05) and angiotensin II (r = 0.467, P < 0.05). In chronic hemodialysis patients, aliskiren modestly lowers blood pressure over the long term, although the antihypertensive effect seems dependent on the changes, but not on the basal levels of plasma renin activity and angiotensin II.

Topics: Aged; Amides; Angiotensin II; Antihypertensive Agents; Blood Pressure; Female; Fumarates; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Renin; Renin-Angiotensin System; Time Factors; Treatment Outcome

We aimed to assess the effect of aliskiren treatment on blood pressure, albuminuria, and kidney function in patients with chronic kidney disease (CKD). We conducted a prospective, open-label study of 67 patients with CKD who were already being treated with other antihypertensives. Inclusion criteria were blood pressure (BP) ≥130/80 mmHg, albuminuria ≥30 mg/g, and estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m(2). Subjects were treated with 150 mg/day aliskiren, which was increased to 300 mg/day for the 24-week study period. Aliskiren effectively reduced both systolic and diastolic BP, plasma renin activity (PRA), serum aldosterone concentration, albuminuria, urinary N-acetyl-glucosaminidase, and urinary β2-microglobulin levels. Although eGFR was significantly decreased after 4 weeks of aliskiren treatment, it recovered to a pretreatment level within 12 weeks of treatment initiation. There were no significant differences in the percent reduction of albuminuria or changes of eGFR levels when the subjects were divided into three groups on the basis of baseline eGFR (stages 1/2, 3, and 4) and the presence or absence of diabetes mellitus (DM group and non-DM group). Furthermore, in patients not treated with renin-angiotensin-aldosterone-system (RAAS) inhibitors, including angiotensin receptor blockers or angiotensin-converting enzyme inhibitors at baseline, changes in eGFR were significantly increased compared with those already treated with RAAS inhibitors at baseline. Aliskiren administration reduced BP, PRA, serum aldosterone levels, and albuminuria, while maintaining eGFR, regardless of the presence or absence of DM or the degree of eGFR.

Topics: Aged; Albuminuria; Aldosterone; Amides; Antihypertensive Agents; Biomarkers; Blood Pressure; Diabetic Nephropathies; Drug Therapy, Combination; Female; Fumarates; Glomerular Filtration Rate; Humans; Hypertension; Japan; Kidney; Male; Middle Aged; Prospective Studies; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Time Factors; Treatment Outcome

The renin-angiotensin-aldosterone system (RAAS) and autonomic nervous system regulate the cardiovascular system. Blockade of the RAAS may slow the progression of end-organ damage. Direct renin inhibition offers a means for blocking the RAAS. The objective of this study was to examine the effect of direct renin inhibition on cardiovascular autonomic function.. In this double-blind, placebo-controlled trial, 60 individuals with diabetes were randomly assigned to 300 mg of aliskiren or placebo once daily for 6 weeks. The primary end point was a change in tests of cardiovascular autonomic function. Autonomic function was assessed by power spectral analysis and RR-variation during deep breathing [i.e. mean circular resultant (MCR), expiration/inspiration (E/I) ratio]. The MCR and E/I ratio assess parasympathetic function. Secondary measures included change in biochemical parameters [e.g. plasma renin activity, leptin and interleukin-6]. Change in cardiovascular autonomic function and blood analytes were analysed by a mixed effects model for repeated measures.. Baseline characteristics were similar between treatment groups. In response to aliskiren compared with placebo, blood pressure was reduced as well as plasma renin activity [from 2.4 ± 3.8 (mean ± standard deviation) to 0.5 ± 0.4 µg/l/h, p < 0.001]. There was a significant interaction (aliskiren × visit) for MCR (p = 0.003) and E/I ratio (p = 0.003) indicating improvement in MCR and E/I ratio for those on aliskiren. MCR means, baseline vs. follow-up, were 41.8 ± 19.7 vs. 50.8 ± 26.1 (aliskiren) and 38.2 ± 23.6 vs. 37.5 ± 24.1 (placebo).. Parasympathetic function (i.e. MCR and E/I ratio) was enhanced by downregulation of the RAAS.

Topics: Amides; Cardiovascular Diseases; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Follow-Up Studies; Fumarates; Humans; Interleukin-6; Male; Middle Aged; Parasympathetic Nervous System; Parasympatholytics; Renin; Renin-Angiotensin System

The effect of two different strategies for renin-angiotensin-aldosterone system (RAAS) blockade; direct renin inhibition (DRI) versus angiotensin receptor blockade (ARB) on blood pressure (BP) and plasma renin activity (PRA) was compared during exercise.. Hypertensive adults were randomised to aliskiren (300 mg once daily, n=33) or valsartan (320 mg once daily, n=35). BP and PRA were measured during treadmill exercise (Bruce protocol), at baseline, end of treatment (eight weeks), and after treatment withdrawal (48 hours after last dose).. After eight weeks treatment, Aliskiren inhibited PRA (>80%) at rest and during exercise, with inhibition remaining undiminished 48 hours after treatment withdrawal. In contrast, valsartan increased PRA at rest, and more-so during exercise (>400%). Angiotensin receptor blockade, as indicated by PRA increase, was reduced, 48 hours after valsartan treatment withdrawal, suggesting more sustained RAAS blockade with aliskiren. Despite divergent effects on PRA, similar exercise-induced changes in BP were seen. The primary outcome, the rise in systolic BP from rest to peak exercise (baseline to after treatment withdrawal) did not differ between treatments (p=0.25).. Measurement of PRA is a more sensitive index of RAAS blockade than the BP response during exercise. Furthermore, after treatment withdrawal, aliskiren provides more sustained RAAS inhibition than valsartan at rest and during exercise.

Topics: Adult; Aged; Amides; Arginine; Blood Pressure; Demography; Endpoint Determination; Exercise; Female; Fumarates; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Renin; Renin-Angiotensin System; Systole; Tetrazoles; Valine; Valsartan

Most patients with hypertension need more than one drug to achieve blood pressure (BP) control. This randomized, double-blind, multifactorial study evaluated whether combinations of aliskiren and amlodipine provided superior BP reductions to component monotherapies in patients with hypertension (mean sitting diastolic BP (msDBP) 95-<110 mm Hg). Overall, 1688 patients were randomized to once-daily monotherapy with aliskiren 150 or 300 mg or amlodipine 5 or 10 mg, combination therapy with one of four corresponding aliskiren/amlodipine doses, or placebo for 8 weeks. At week 8 end point, aliskiren/amlodipine combinations provided significant msDBP reductions from baseline of 14.0-16.5 mm Hg, compared with reductions of 8.0 and 10.2 mm Hg for aliskiren 150 and 300 mg, respectively (P<0.001), and 11.0 and 13.8 mm Hg for amlodipine 5 and 10 mg, respectively (P<0.05). Aliskiren/amlodipine combinations provided reductions in mean sitting systolic BP 20.6-23.9 mm Hg, compared with decreases of 10.7 and 15.4 mm Hg for aliskiren 150 and 300 mg, respectively (P<0.001), and 15.8 and 21.0 mm Hg for amlodipine 5 (P< or =0.001) and 10 mg (P=NS), respectively. Aliskiren/amlodipine combination therapy provides greater BP lowering than either agent alone, hence offering an effective treatment option for patients with hypertension.

Topics: Adult; Aged; Amides; Amlodipine; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Renin

Blockade of the renin-angiotensin system (RAS) is a critical approach to the management of hypertension, especially in proteinuric patients. It is well proven that the direct renin inhibitor aliskiren shows comparable clinical efficacy to the angiotensin II receptor blocker valsartan on blood pressure control and albuminuria. However, there is only limited data on the hand-to-hand effectiveness of these two RAS blockers in improving arterial stiffness. We tested whether aliskiren or valsartan would improve arterial stiffness in hypertensive patients with albuminuria who are already on antihypertensive therapy.. Thirty-four patients with hypertension and albuminuria < 1 g, after a wash-out period of three weeks, were randomized to aliskiren or valsartan in a 24-week randomized parallel-group study.. A nonsignificant difference in blood pressure was seen between the two treatment groups. Albuminuria was significantly reduced in both groups (56% for the aliskiren group, p < 0.05, and 38% for the valsartan group, p < 0.05). Only valsartan but not aliskiren significantly reduced carotid-femoral pulse wave velocity (-1.1 ± 0.8 m/s (p = 0.02) for valsartan and +0.1 ± 0.7 m/s (ns) for aliskiren).. The results of our study showed that valsartan improves arterial stiffness to a significantly greater extent than aliskiren, despite a similar antihypertensive and antiproteinuric effect.

Topics: Albuminuria; Amides; Antihypertensive Agents; Demography; Female; Fumarates; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Pulse Wave Analysis; Tetrazoles; Treatment Outcome; Valine; Valsartan

The aim of this study was to investigate the antialbuminuric and antihypertensive effects of aliskiren by monitoring home blood pressure (BP) in comparison with the effects of the angiotensin receptor blocker (ARB) valsartan in patients with hypertensive nephrosclerosis and albuminuria.. We conducted an open-label, randomized trial to compare the effects of aliskiren with those of valsartan. Patients with BP <150/90 mmHg, an estimated glomerular filtration rate of 90-30 mL/min/1.73 m(2), and albuminuria >30 mg/g, despite treatment with a 160 mg daily dose of valsartan, were randomly assigned to the following two groups: the aliskiren group, who switched from 160 mg/day valsartan to 150 mg/day aliskiren, which was later increased to 300 mg/day (n = 20); and the valsartan group, who continued with 160 mg/day valsartan (n = 20).. After 12 weeks of treatment, although there was no significant difference in clinic BP between groups, a significant reduction in morning and evening systolic BP was observed in the aliskiren group. The decrease in albuminuria in the aliskiren group was significantly better than that in the valsartan group, and a significant correlation was noted between the change in morning systolic BP and the change in albuminuria in the aliskiren group (r = 0.564, P = 0.0084).. We showed that aliskiren treatment leads to a greater reduction in albuminuria and home systolic BP values than valsartan in patients with nephrosclerosis. We propose that aliskiren therapy should be considered as a therapeutic modality to complement ARBs in hypertensive patients with nephrosclerosis.

Topics: Adult; Aged; Albuminuria; Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Female; Fumarates; Humans; Hypertension; Hypertension, Renal; Male; Middle Aged; Nephritis; Nephrosclerosis; Tetrazoles; Valine; Valsartan

Poor adherence to antihypertensive drug treatment is common and is often associated with marked prolongations of the dosing interval. Hence, selecting a treatment that has the potential to provide a sustained blood pressure (BP)-lowering effect is important. The objective of this analysis is to compare the sustained efficacy of aliskiren with telmisartan after a single missed dose. This is part of a 12-week double-blind study conducted in patients with mild to moderate hypertension randomized to once-daily aliskiren 150 mg or telmisartan 40 mg for 2 weeks, force-titrated to double the doses for 10 weeks, followed by placebo for 1 week. The changes in BP from the end of active treatment (EOA) to 48 hours after treatment withdrawal (day 2) were analyzed. Demographic and baseline characteristics were comparable between the treatment groups. Aliskiren continued to show significantly greater reductions in mean sitting systolic BP (-0.7 vs +1.3 mm Hg; P<.05), 24-hour mean ambulatory systolic BP (-3.6 vs +2.6 mm Hg; P<.01), and 24-hour mean ambulatory diastolic BP (-3.7 vs +0.4 mm Hg; P<.01) compared with telmisartan from EOA to day 2, despite the similar BP reductions from randomization to EOA. In conclusion, aliskiren sustained the BP-lowering efficacy better than telmisartan after a single missed dose.

Topics: Adult; Amides; Antihypertensive Agents; Benzimidazoles; Benzoates; Double-Blind Method; Drug Administration Schedule; Female; Fumarates; Humans; Hypertension; Least-Squares Analysis; Male; Patient Compliance; Telmisartan; Treatment Outcome

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 2; Early Termination of Clinical Trials; Fumarates; Humans; Hypoglycemic Agents; Kidney Diseases; Renin; Renin-Angiotensin System

In this double-blind study, 1143 hypertensive participants with type 2 diabetes and stage 1 or 2 chronic kidney disease (CKD) were randomized to receive combination aliskiren/valsartan 150/160 mg or valsartan 160 mg monotherapy for 2 weeks, with force-titration to 300/320 mg and 320 mg, respectively, for another 6 weeks. Ambulatory blood pressure (ABP), the primary outcome, was available for 665 participants. Reductions from baseline to week 8 in 24-hour ABP were -14.1/-8.7 mm Hg with aliskiren/valsartan vs -10.2/-6.3 mm Hg with valsartan (P<.001). Adverse events were reported in 202 participants (35.2%) taking aliskiren/valsartan and 182 participants (32.2%) taking valsartan. No participant had blood urea nitrogen values>40 mg/dL or serum creatinine values>2.0 mg/dL. There were no confirmed cases of serum potassium values≥6.0 mEq/L. Combination aliskiren/valsartan has additive effects on blood pressure reduction and tolerability similar to valsartan in hypertensive/diabetic participants with early-stage (stages 1 and 2) CKD.

Topics: Aged; Amides; Antihypertensive Agents; Blood Pressure; Blood Urea Nitrogen; Comorbidity; Creatinine; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Severity of Illness Index; Tetrazoles; Treatment Outcome; Valine; Valsartan

Blockade of the renin-angiotensin-aldosterone system is a therapeutic mainstay in patients with chronic kidney disease (CKD). However, the renoprotective effect of the novel direct renin inhibitor aliskiren is unknown.. We performed a prospective study in 10 CKD patients. All 10 patients with persistent proteinuria (urinary protein-to-creatinin ratio 0.3-3.5 g/g), despite good blood pressure control (<130/80 mmHg) with olmesartan, were started on 150 mg/day aliskiren. Clinical parameters were examined before and after 4, 8, 12, and 16 weeks of treatment.. Urinary protein-to-creatinine ratio significantly decreased by about 40% at 16 weeks from baseline (P = 0.0002), although estimated glomerular filtration rate and blood pressure did not change throughout the study period. Plasma renin activity also decreased significantly from baseline (P = 0.019), although plasma aldosterone concentration did not change.. Aliskiren combined with olmesartan reduces proteinuria in CKD patients.

Topics: Adult; Aldosterone; Amides; Analysis of Variance; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Blood Pressure; Creatinine; Drug Therapy, Combination; Female; Fumarates; Glomerular Filtration Rate; Humans; Imidazoles; Male; Middle Aged; Olmesartan Medoxomil; Proteinuria; Renal Insufficiency, Chronic; Renin; Tetrazoles; Young Adult

Single-pill combinations (SPCs) of complementary antihypertensive agents provide patients with a simple and effective treatment regimen. To ensure that the efficacy and safety of an SPC is the same as that for the individual drugs administered together (free combination), SPC and free-combination formulations must be shown to be bioequivalent. Three open-label, randomized studies compared the pharmacokinetics of SPC tablets of the direct renin inhibitor aliskiren and hydrochlorothiazide (HCT), at doses of 150/25, 300/12.5, and 300/25 mg, with the corresponding free combinations in healthy volunteers. Data from 2 randomized, double-blinded studies of patients with hypertension were used to assess inhibition of plasma renin activity (PRA) by the aliskiren/HCT 300/25 mg SPC and the free combination. At all dose combinations, aliskiren and HCT systemic drug exposure was similar when administered as an SPC or free combination, indicating bioequivalence. Aliskiren/HCT 300/25 mg SPC inhibited PRA to the same extent as the free combination. HCT alone increased PRA through activation of the renin-angiotensin system; aliskiren prevented this diuretic-induced increase to the same extent when administered as the free combination or as the SPC. In conclusion, aliskiren/HCT SPCs are pharmacokinetically and pharmacodynamically bioequivalent to aliskiren and HCT in free combination.

Topics: Administration, Oral; Adolescent; Adult; Amides; Analysis of Variance; Antihypertensive Agents; Blood Pressure; Cross-Over Studies; Diuretics; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Least-Squares Analysis; Male; Middle Aged; Models, Biological; Renin; Tablets; Therapeutic Equivalency; Treatment Outcome; Young Adult

Aliskiren is a relatively new oral direct renin inhibitor (DRI) that has been increasingly used for the treatment of diabetic nephropathy and hypertension. Its potential efficacy in nondiabetic chronic kidney diseases that are driven by renin-angiotensin system activation remains to be explored.. From a teaching and regional hospital in Hong Kong between July 2009 and March 2010, patients with biopsy-proven immunoglobulin A nephropathy (IgAN) in whom the ratio of protein to creatinine, as measured in early morning urine samples, remained >113 mg/mmol (1000 mg/g), despite receiving the maximum recommended dose of losartan (100 mg daily) were recruited to receive additional DRI treatment. They were followed prospectively for 12 months with changes in proteinuria as the main outcome measure.. Twenty-five consecutive patients were enrolled. Treatment with aliskiren for 12 months reduced the mean urinary protein-to-creatinine ratio by 26.3% (95% confidence interval, 20.1-43.6; P = 0.001 versus baseline), with a reduction of ≥ 50% in 24% of patients. There were significant reductions in plasma renin activity (P < 0.0001) and serum interleukin-6 (P < 0.05) and transforming growth factor-β (P = 0.01) levels, compared with baseline. Two patients (8%) developed mild allergic reactions and six (24%) had transient hyperkalemia (K >5.5 mmol/L) during the study.. Aliskiren confers an antiproteinuric effect in IgAN patients with significant residual proteinuria, despite receiving the recommended renoprotective treatment. Further prospective randomized trials are warranted to examine its long-term renoprotective potential. This trial is registered with the ClinicalTrials.gov number NCT00922311.

Topics: Adult; Amides; Antihypertensive Agents; Confidence Intervals; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Fumarates; Glomerulonephritis, IGA; Hong Kong; Humans; Interleukin-6; Kidney Function Tests; Losartan; Male; Middle Aged; Odds Ratio; Pilot Projects; Prospective Studies; Proteinuria; Risk Assessment; Severity of Illness Index; Time Factors; Transforming Growth Factor beta; Treatment Outcome; Urinalysis

Aldosterone blockade reduces albuminuria in diabetic patients with chronic kidney disease (CKD), and improves prognosis in chronic heart failure. This study assessed the effects of direct renin inhibition with aliskiren in combination with losartan and optimal antihypertensive therapy on urinary aldosterone, plasma renin activity (PRA) and plasma renin concentration (PRC).. In the AVOID study, 599 patients with type 2 diabetes, hypertension and nephropathy received 6 months aliskiren (150 mg force titrated to 300 mg once daily after 3 months) or placebo added to losartan 100 mg and optimal antihypertensive therapy. Urinary aldosterone excretion, PRA and PRC were measured at baseline and after 24 weeks in a prespecified subset of 133 patients.. Aliskiren added to losartan provided reductions from baseline in urinary aldosterone compared with adding placebo (-24% vs. -4%, p = 0.017) at week 24. There was no significant difference between the aliskiren and placebo groups in the proportion of patients with aldosterone breakthrough (aliskiren 35%, placebo 46%, p = 0.199). Aliskiren treatment reduced PRA by 90% at 24 weeks and increased PRC by 328%.. Adding aliskiren to recommended renoprotective treatment with losartan and optimal antihypertensive therapy provided significant reductions in urinary aldosterone excretion which may attenuate decline in kidney function.

Topics: Aldosterone; Amides; Antihypertensive Agents; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Fumarates; Humans; Male; Middle Aged; Renin

This 8-week, randomized, double-blind, parallel-group study compared the efficacy and safety of aliskiren with ramipril in Asian patients with mild to moderate hypertension. Following a 2- to 3-week placebo run-in period, patients with mean sitting diastolic blood pressure (msDBP) ≥95 and <110 mm Hg were randomized to receive once daily dose of either aliskiren 75, 150, 300 mg or ramipril 5 mg for 8 weeks. Efficacy variables were the changes in msDBP and mean sitting systolic BP (msSBP) and BP control rates (<140/90 mm Hg). Safety was assessed by recording adverse events (AEs) and serious AEs (SAEs). Of 1316 randomized patients, 1160 (88.1%) completed the study. At the study endpoint, patients on aliskiren had greater mean BP reductions (14.39/11.63 mm Hg for 300 mg; 12.16/10.04 mm Hg for 150 mg; 12.24/10.66 mm Hg for 75 mg) than those on 5 mg ramipril (11.46/9.19 mm Hg). All aliskiren doses were statistically non-inferior (P<0.0001) to ramipril in reducing msDBP. The reduction in BP for aliskiren 300 mg was statistically superior vs. ramipril (P<0.002). Blood pressure control rates were higher for aliskiren (300 mg, 52.29%; 150 mg, 48.11%; 75 mg, 45.68%) than for ramipril (5 mg, 43.7%); the difference for aliskiren 300 mg vs. ramipril 5 mg was statistically significant (P<0.05). Aliskiren was well tolerated with a fourfold lower incidence of cough (0.6-1.2%) compared with ramipril (5.2%). SAEs were rare in this study (0.5%). Aliskiren produced greater BP reductions with a lower incidence of cough than ramipril in Asian patients with mild to moderate hypertension.

Topics: Adult; Aged; Aged, 80 and over; Amides; Antihypertensive Agents; Blood Pressure; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Ramipril; Severity of Illness Index; Treatment Outcome

Tubular injury is more important than glomerulopathy for renal prognosis in chronic kidney disease (CKD) patients. Numerous studies have demonstrated the active participation of the renin-angiotensin system (RAS) in CKD. However, whether addition of aliskiren, a direct renin inhibitor, to olmesartan improves renal tubular injury in CKD patients is unknown.. This study compared the effects of aliskiren (300 mg daily), olmesartan (40 mg daily), and its combination therapy on urinary L-fatty acid binding protein (L-FABP), a marker of tubular injury in stage I or II CKD patients. It also examined which clinical variables were independently correlated with tubular damage.. Olmesartan or aliskiren monotherapy for 6 months comparably decreased blood pressure (BP) and proteinuria. BP and proteinuria levels were reduced more by combination therapy than by either monotherapy. Olmesartan or aliskiren decreased urinary L-FABP level, and combination therapy produced more incremental reduction in L-FABP level relative to each monotherapy. Multiple stepwise regression analysis revealed that BMI, low-density lipoprotein (LDL)-cholesterol and proteinuria were independently related to urinary L-FABP level.. The present study demonstrated that addition of aliskiren to olmesartan decreased urinary L-FABP level partly via reduction of proteinuria in stage I or II CKD patients.

Topics: Adult; Amides; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Fatty Acid-Binding Proteins; Female; Fumarates; Humans; Imidazoles; Kidney Failure, Chronic; Kidney Tubules; Male; Proteinuria; Regression Analysis; Tetrazoles

We assessed the relationship between diabetes and cardiac structure and function following myocardial infarction (MI) and whether diabetes influences the effect of direct renin inhibition on change in left ventricular (LV) size.. The ASPIRE trial enrolled 820 patients 2-8 weeks after MI with ejection fraction ≤ 45% and randomized them to the direct renin inhibitor aliskiren (n= 423) or placebo (n = 397) added to standard medical therapy. Echocardiography was performed at baseline and after 36 weeks in 672 patients with evaluable paired studies. Compared with non-diabetic patients, diabetic patients (n = 214) were at higher risk for a composite of cardiovascular (CV) death, heart failure hospitalization, recurrent MI, stroke, or aborted sudden death (14 vs. 7%; adjusted hazard ratio 1.63, 95% confidence interval 1.01-2.64, P= 0.045), despite similar left ventricular ejection fraction (37.9 ± 5.3 vs. 37.6 ± 5.2%, P= 0.48) and end-systolic volume (ESV) (84 ± 25 vs. 82 ± 28 mL, P= 0.46). Diabetic patients demonstrated greater concentric remodelling (relative wall thickness 0.38 ± 0.07 vs. 0.36 ± 0.07, P= 0.0002) and evidence of higher LV filling pressure (E/E' 11.1 ± 5.3 vs. 9.1 ± 4.3, P= 0.0011). At 36 weeks, diabetic patients experienced similar per cent reduction in ESV overall (-4.9 ± 17.9 vs. -5.5 ± 16.9, P= 0.67) but tended to experience greater reduction in ESV than non-diabetic patients when treated with aliskiren (interaction P = 0.08).. Compared with non-diabetic patients, diabetic patients are at increased risk of CV events post-MI despite no greater LV enlargement or reduction in systolic function. Diabetic patients demonstrate greater concentric remodelling and evidence of higher LV filling pressure, suggesting diastolic dysfunction as a potential mechanism for the higher risk observed among these patients.

Topics: Aged; Amides; Cardiovascular Agents; Diabetic Cardiomyopathies; Diastole; Double-Blind Method; Female; Fumarates; Humans; Male; Middle Aged; Myocardial Infarction; Renin; Systole; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

The renin-angiotensin-aldosterone system (RAAS) has dual pathways to angiotensin II production; therefore, multiple blockages may be useful in heart failure. In this study, we evaluated the short-term haemodynamic effects of aliskiren, a direct renin inhibitor, in patients with decompensated severe heart failure who were also taking angiotensin-converting enzyme (ACE) inhibitors.. A total of 16 patients (14 men, two women, mean age: 60.3 years) were enrolled in the study. The inclusion criteria included hospitalisation due to decompensated heart failure, ACE inhibitor use, and an ejection fraction < 40% (mean: 21.9 ± 6.7%). The exclusion criteria were: creatinine > 2.0 mg/dl, cardiac pacemaker, serum K(+) > 5.5 mEq/l, and systolic blood pressure < 70 mmHg. Patients either received 150 mg/d aliskiren for 7 days (aliskiren group, n = 10) or did not receive aliskiren (control group, n = 6). Primary end points were systemic vascular resistance and cardiac index values. Repeated-measures analysis of variance (ANOVA) was used to assess variables before and after intervention. A two-sided p-value < 0.05 was considered statistically significant.. Compared to pre-intervention levels, systemic vascular resistance was reduced by 20.4% in aliskiren patients, but it increased by 2.9% in control patients (p = 0.038). The cardiac index was not significantly increased by 19.0% in aliskiren patients, but decreased by 8.4% in control patients (p = 0.127). No differences in the pulmonary capillary or systolic blood pressure values were observed between the groups.. Aliskiren use reduced systemic vascular resistance in patients with decompensated heart failure taking ACE inhibitors.

Topics: Amides; Antihypertensive Agents; Female; Fumarates; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Vascular Resistance

To evaluate the effect of aliskiren compared to amlodipine on QT duration and dispersion in hypertensive patients with type 2 diabetes.. A total of 170 outpatients aged 50-75 years with mild to moderate hypertension (SBP >130 and <180 mmHg and DBP >80 and <100 mmHg) and type 2 diabetes were randomly treated with aliskiren 300 mg or amlodipine 10 mg, both given once daily for 24 weeks, according to a prospective, open label, blinded-end point, parallel group design. At the end of the placebo run-in, and after 12, and 24 weeks of treatment blood pressure (BP) measurements (by mercury sphygmomanometer, Korotkoff I and V), plasma biochemistry and a standard 12-lead surface ECG were evaluated.. Both aliskiren and amlodipine significantly reduced systolic blood pressure (SBP)/diastolic blood pressure (DBP) values (-27.2/-14.3 mmHg, p < 0.001 vs. placebo and -27.8/-14.2 mmHg, p < 0.001 vs. placebo, respectively), with no statistical difference between the two drugs. Aliskiren, but not amlodipine, significantly reduced maximum QT interval (QTmax) (-14 ms at 12 weeks and -17 ms at 24 weeks, both p < 0.05 vs. placebo) and corrected QT max (QTc max) (-26 ms and -31 ms, p < 0.01) as well as the dispersion of both QT (-11 ms and -13 ms, p < 0.01) and QTc (-18 ms and -19 ms, p < 0.01).. Despite similar BP lowering effect, aliskiren, but not amlodipine, reduced QT duration and dispersion, which might be related to the ability of aliskiren to interfere with mechanisms underlying myocardial electrical instability in the heart of diabetic hypertensive patients.

Topics: Aged; Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Electrocardiography; Female; Fumarates; Heart Conduction System; Humans; Hypertension; Long QT Syndrome; Male; Middle Aged; Prospective Studies

We aimed to investigate whether the single pill combination (SPC) of aliskiren 300 mg and amlodipine 10 mg (ALIS 300/AMLO 10) improves blood pressure (BP) reduction in hypertensive patients not adequately controlled by the SPC olmesartan 40 mg and amlodipine 10 mg (OLM 40/AMLO 10).. Open-label, non-randomized single-arm study. Patients with stage 2 hypertension were titrated to the SPC OLM 40/AMLO 10 (4-week Phase 1). If hypertension was not controlled they were switched to the SPC ALIS 300/AMLO 10 (4-week Phase 2). In the optional 4-week study extension hydrochlorothiazide (HCT) 12.5 mg was added. EudraCT 2009-016693-33.. In the 342 patients treated, OLM 40/AMLO 10 reduced systolic BP (SBP)/diastolic BP (DBP) by 24.5/14.5 mmHg by end of Phase 1. Those 187 patients with uncontrolled hypertension at the end of Phase 1 switched to ALIS 300/AMLO 10 experienced a further SBP reduction of 5.1 mmHg (95% confidence interval [CI] 3.7 to 6.5, p < 0.0001) and a DBP reduction of 4.8 mmHg (95% CI 3.8 to 5.8; p < 0.0001) in Phase 2. DBP or SBP responder rates were achieved by 51.3% or 44.4%, respectively, SBP and DBP normalization by 36.4%. In 65 patients whose BP was not controlled in Phase 2, SPC ALIS 300/AMLO 10/HCT 12.5 mg decreased SBP/DBP by further 8.1/6.7 mmHg (p < 0.0001 each). No deaths or serious adverse events were noted. Significant adverse events leading to study discontinuation were reported in 2.6% (Phase 1), 2.7% (Phase 2), and 0% (extension). Limitations included the open-label, single-arm non-randomized design, and the relatively short duration.. In this switch study reflecting clinical practice, patients with moderate hypertension not controlled by the SPC OLM 40/AMLO 10 achieved a clinically and statistically significant reduction of blood pressure from the SPC ALIS 300/AMLO 10 and the optional addition of HCT. All drug combinations were well tolerated.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amides; Amlodipine; Antihypertensive Agents; Drug Combinations; Drug Resistance; Drug Substitution; Female; Fumarates; Humans; Hypertension; Imidazoles; Male; Middle Aged; Tablets; Tetrazoles; Treatment Failure; Treatment Outcome; Young Adult

To conduct a mechanistic investigation of the interaction between aliskiren and grapefruit juice in healthy subjects.. Twenty-eight subjects received an oral dose of aliskiren 300 mg (highest recommended clinical dose) with 300 mL of either water or grapefruit juice in a two-way crossover design. Safety and pharmacokinetic analyses were performed. In vitro studies were performed in HEK293 cells to investigate the role of organic anion transporting polypeptide (OATP) transporter-mediated uptake of aliskiren.. Co-administration of a single dose of aliskiren with grapefruit juice decreased the plasma concentration of aliskiren, with mean decreases in the AUC(inf), AUC(last), and C(max) of 38, 37, and 61%, respectively. The uptake of [¹⁴C]aliskiren into OATP2B1-expressing cells was essentially the same as that into control cells, and the inhibitor combination atorvastatin and rifamycin had no effect on [¹⁴C]aliskiren accumulation in either cell type. The uptake of [¹⁴C]aliskiren and [³H]fexofenadine was linear in OATP1A2-expressing cells and was reduced by naringin, with IC₅₀ values of 75.5 ± 11.6 and 24.2 ± 2.0 μM, respectively.. Grapefruit juice decreases exposure of aliskiren partially via inhibition of intestinal OATP1A2.

Topics: Adult; Amides; Antihypertensive Agents; Beverages; Biological Transport; Citrus paradisi; Cross-Over Studies; Flavanones; Food-Drug Interactions; Fruit; Fumarates; Half-Life; HEK293 Cells; Humans; Intestinal Mucosa; Male; Organic Anion Transporters; Recombinant Proteins; Renin; Terfenadine; Young Adult

This randomized, double-blind, placebo-controlled study assessed the efficacy, safety, and tolerability of aliskiren 75, 150, and 300 mg to clarify the dose-response relationship and characterize the optimum aliskiren dose when given with a light meal to elderly hypertensive patients. After washout, 754 patients aged ≥65 years with hypertension (mean sitting systolic blood pressure [msSBP] ≥150 and <180 mm Hg; mean sitting diastolic blood pressure [msDBP] <110 mm Hg) were randomized to aliskiren 75, 150, or 300 mg or placebo for 8 weeks; medication was taken each morning with a light meal. The primary efficacy variable was change in msSBP from baseline to week 8 end point. Change from baseline in msDBP and dose-response curves for aliskiren 75, 150, and 300 mg were also assessed. At week 8 end point, all 3 aliskiren doses provided significantly greater least squares mean reductions in msSBP/msDBP (75 mg, 13/5 mm Hg; 150 mg, 15/6 mm Hg; 300 mg, 14/7 mm Hg) compared with placebo (8/4 mm Hg; P < .05). Aliskiren was generally well tolerated at all doses. There was a significant dose-response relationship for aliskiren, with an estimated minimum effective dose of 81.9 mg. In conclusion, aliskiren 150 and 300 mg provided effective blood pressure control in elderly patients when given with a light meal.

Topics: Aged; Amides; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Male; Meals; Treatment Outcome

Topics: Aged; Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Carotid Intima-Media Thickness; Diabetic Nephropathies; Drug Therapy, Combination; Female; Fumarates; Humans; Kidney Tubules; Male; Middle Aged

In animals, the direct renin inhibitor aliskiren showed extensive tissue binding in the kidney and long-lasting renal effects. Aliskiren provides prolonged blood pressure-lowering effects following treatment discontinuation in patients. Therefore, we investigated whether aliskiren attains tissue concentrations sufficient to inhibit local renin-angiotensin system (RAS) activity in patients.. We included 10 hypertensive patients with abdominal adiposity in an open-label study. Following 1-2 weeks washout, patients received 2 weeks placebo, then 4 weeks aliskiren 300 mg once daily, followed by 4 weeks washout, and then 4 weeks amlodipine 5 mg once daily. Drug concentrations and RAS biomarkers were measured in interstitial fluid using microdialysis and in biopsies from abdominal subcutaneous adipose and skeletal muscle.. We detected aliskiren in all compartments. After 4 weeks of treatment, microdialysate aliskiren concentrations (ng/ml) were 2.4 ± 2.1 (adipose) and 7.1 ± 4.2 (skeletal muscle), similar to plasma concentrations (8.4 ± 4.4); tissue concentrations (ng/g) were 29.0 ± 16.7 (adipose) and 107.3 ± 68.6 (skeletal muscle). Eight weeks after discontinuation, aliskiren was measurable in tissue biopsies but not in plasma or in interstitial fluid. Pooled microdialysate samples from two sets of four patients suggested reduction in tissue angiotensin II with aliskiren but not with amlodipine.. In obese hypertensive patients, aliskiren penetrates adipose and skeletal muscle tissue at levels that are apparently sufficient to reduce tissue RAS activity. Furthermore, tissue binding may contribute to aliskiren's prolonged blood pressure-lowering effect following discontinuation.

Topics: Adipose Tissue; Adult; Amides; Amlodipine; Antihypertensive Agents; Calcium Channel Blockers; Extracellular Fluid; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Muscle, Skeletal; Obesity; Pilot Projects; Renin-Angiotensin System

Many patients with hypertension will require multiple antihypertensive drugs to achieve blood pressure (BP) control. This double-blind study evaluated the efficacy and safety of aliskiren/amlodipine single-pill combinations (SPCs) in patients with mild-to-moderate hypertension who were non-responsive to aliskiren monotherapy. After a 4-week run-in with aliskiren 300 mg, patients with mean sitting diastolic BP (msDBP) ≥ 90 and < 110 mmHg were randomized to oncedaily aliskiren/ amlodipine 300/10 mg or 300/5 mg, or aliskiren 300 mg for 8 weeks. Aliskiren/amlodipine SPCs provided significantly greater mean reductions in mean sitting systolic BP/msDBP (300/10 mg, 18.0/13.1 mmHg; 300/5 mg, 14.4/10.5 mmHg) than aliskiren 300 mg (6.4/5.8 mmHg) at week 8 endpoint. This represents additional mean reductions of 11.6/7.2 mmHg (300/10 mg) and 8.0/4.7 mmHg (300/5 mg) over aliskiren alone (both p < 0.0001). Significantly more patients achieved BP control ( < 140/90 mmHg) with aliskiren/amlodipine 300/10 mg (65.5%) and 300/5 mg (56.6%) than with aliskiren (31.5% both p < 0.0001). Aliskiren, alone and in combination with amlodipine, was well tolerated, with a slightly higher incidence of adverse events with SPCs (29.0-30.1%) than with monotherapy (22.7%). In conclusion, aliskiren/amlodipine SPCs offer an effective next step for patients who have an inadequate BP response to aliskiren alone.

Topics: Administration, Oral; Adult; Aged; Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Drug Resistance; Europe; Female; Fumarates; Humans; Hypertension; India; Least-Squares Analysis; Logistic Models; Male; Middle Aged; Republic of Korea; Tablets; Time Factors; Treatment Outcome; Vasodilator Agents; Venezuela

Most patients with hypertension will require treatment with at least two antihypertensive agents to achieve blood pressure (BP) control. This double-blind study evaluated the efficacy and safety of aliskiren/amlodipine single-pill combination (SPC) therapy in patients with mild-to-moderate hypertension who are inadequately responsive to amlodipine monotherapy. Patients with mean sitting diastolic BP (msDBP) ≥ 90 and < 110 mmHg 110 mmHg after 4 weeks' treatment with amlodipine 10 mg were randomized to once-daily aliskiren/amlodipine 300/10 mg (n = 279) or 150/10 mg (n = 285) or amlodipine 10 mg monotherapy (n = 283) for 8 weeks. Aliskiren/amlodipine 300/10 and 150/10 mg SPCs provided significantly greater reductions in mean sitting systolic BP/msDBP (14.4/11.0 and 11.0/9.0 mmHg, respectively) than amlodipine 10 mg (8.2/7.2 mmHg) at week 8 endpoint. This represents additional mean reductions of 6.2/3.8 mmHg (300/10 mg) and 2.8/1.7 mmHg (150/10 mg) over amlodipine alone (all P < 0.01). Significantly more patients achieved BP control (< 140/90 mmHg) with aliskiren/amlodipine 300/10 mg (58.8%) than amlodipine 10 mg (38.4%; P < 0.0001). Aliskiren/amlodipine SPCs were generally well tolerated. In conclusion, aliskiren/amlodipine SPCs offers an effective option for management of patients who have an inadequate BP response to amlodipine alone.

Topics: Administration, Oral; Adult; Aged; Amides; Amlodipine; Antihypertensive Agents; Argentina; Blood Pressure; Calcium Channel Blockers; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Drug Resistance; Europe; Female; Fumarates; Humans; Hypertension; Logistic Models; Male; Middle Aged; Tablets; Time Factors; Treatment Outcome; Turkey; Vasodilator Agents

The renin-angiotensin system (RAS) is a key target for blood pressure control and for cardiovascular and renal protection. Aliskiren is the first-in-class direct oral inhibitor of renin that controls the rate-limiting step in the RAS cascade. So far little is known about the use and efficacy of aliskiren in the treatment of essential hypertension under clinical practice conditions.. The 3A registry was an open, prospective cohort study (observational registry) of 14,988 patients in 899 offices throughout Germany. Consecutive patients were eligible for inclusion if their physician had decided to modify their antihypertensive therapy. This included treatment with aliskiren or an angiotensin converting enzyme inhibitor (ACE-I)/angiotensin receptor blocker (ARB) or agents not blocking the RAS, alone or on top of an existing drug regimen.. Mean age of patients was 65 years, their mean body mass index was 28.2 kg/m(2) 53.5% were men, 36% working, 90% in statutory health insurance and 26% in any disease management programme. Patients in the aliskiren and the RAS groups compared with the non-RAS group were older, more often men, had a longer history of hypertension, and had a higher prevalence of comorbidities (diabetes, chronic heart failure, ischaemic heart disease, renal disease). Mean systolic, but not diastolic blood pressure was substantially higher in the aliskiren group (158/91 mmHg vs. 154/89 mmHg in ACE-I/ARB vs. 152/89 mmHg in non-RAS). Mean number of antihypertensive drugs was higher in the aliskiren group compared with the other groups (3.0 drugs vs. 2.5 in ACE-I/ARB vs. 1.6 in non-RAS; p < 0.0001).. In this large cohort of outpatients with hypertension, aliskiren was used mainly in patients with more severe stages of hypertension and those with concomitant diseases such as diabetes mellitus and impaired renal function. The 3A registry will provide important information about the use and efficacy of aliskiren in a real-life setting.

Topics: Aged; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Drug Substitution; Drug Utilization Review; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Registries; Risk Factors

Patients with type 2 diabetes are at enhanced risk for macro- and microvascular complications. Albuminuria and/or reduced kidney function further enhances the vascular risk. We initiated the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE). Aliskiren, a novel direct renin inhibitor, which lowers plasma renin activity, may thereby provide greater cardio-renal protection compared with angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) alone.. ALTITUDE is a randomized, double-blind, placebo-controlled study in high risk type 2 diabetic patients receiving aliskiren 300 mg once daily or placebo added to recommended cardio-renal protective treatment including ACEi or ARB, but not both. The number of patients randomized was 8606.. Baseline characteristics (median, IQR) are: age 65 (58, 72) years, male 68%, BMI 29.1 (25.7, 32.2) kg/m(2), cardiovascular disease 47.9%, blood pressure 134.7 (126, 150)/74.3 (67, 81) mmHg, HbA(1c) 7.5 (6.6, 8.6)%, LDL-cholesterol 2.4 (1.9, 3.0) mmol/L, haemoglobin 130 (119, 143) g/L, serum creatinine 115 (91, 137) µmol/L, eGFR 51.7 (42, 65) ml/min per 1.73 m(2), geometric mean UACR 198.9 (52, 2886) mg/g and frequency of micro/macroalbuminuria 25.7% and 58.2%. ALTITUDE is an event-driven trial to continue until 1628 patients experience a primary cardiovascular-renal event.. ALTITUDE will determine the potential cardio-renal benefit and safety of aliskiren in combination with ACEi or ARB in high risk patients with type 2 diabetes.

Topics: Aged; Albuminuria; Amides; Antihypertensive Agents; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Endpoint Determination; Female; Fumarates; Humans; Kidney; Male; Middle Aged; Myocardium

Hyperglycaemia induces development and progression of microvascular complications in diabetes. A direct link between high glucose levels and intrarenal renin-angiotensin activation has been demonstrated. This post-hoc analysis assessed the influence of baseline glycaemic control on the reduction of albuminuria with aliskiren or placebo added to losartan in the Aliskiren in the EValuation of PrOteinuria In Diabetes (AVOID) study.. In AVOID, 599 patients with type 2 diabetes, hypertension and nephropathy received 6 months' aliskiren or placebo added to losartan 100 mg and optimal antihypertensive therapy. Changes in urinary albumin creatinine ratio at end of study were assessed by tertiles of baseline HbA(1c) levels.. Patients were divided into tertiles of HbA(1c) (<7.1%, 7.1 to <8.4% and ≥8.4%). There were no differences between tertiles, except patients in the highest tertile group more frequently used insulin. The antiproteinuric effect of aliskiren was consistent across tertiles, with the largest effect in the highest tertile (HbA(1c) ≥8.4%).. This post-hoc analysis of the AVOID study suggests that renin inhibition with aliskiren 300 mg once daily added to losartan 100 mg once daily plus optimal antihypertensive therapy provides reductions in urinary albumin creatinine ratio that are efficacious in all, but particularly in poorly controlled, diabetic patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amides; Body Mass Index; Diabetes Complications; Female; Fumarates; Glycated Hemoglobin; Health Surveys; Humans; Hyperglycemia; Hypoglycemic Agents; Male; Middle Aged; Placebos; Proteinuria; Renin; Young Adult

It is highly likely that the rise in plasma prorenin and plasma renin during renin inhibitor treatment is induced at least as much by the fall in blood pressure (BP) as it is by the negative feedback of angiotensin II. This could potentially be harmful because high levels of renin and prorenin may stimulate the (pro)renin receptor, thus inducing profibrotic effects. To further understand this relationship, the influence of aliskiren on the urinary excretion of transforming growth factor-β1 (TGF-β1) and procollagen III N-terminal propeptide (PIIINP) was evaluated in patients with nondiabetic kidney diseases.. Aliskiren 300 mg and perindopril 10 mg, were each individually administered for 12 weeks separated by a placebo period in a cross-over, randomized, double-blinded pilot study.. A 1,131% (P < 0.001) and 628% (P < 0.001) increase in plasma renin concentration was observed after the aliskiren and perindopril therapies, respectively, as compared to the placebo. Aliskiren and perindopril increased prorenin concentrations as compared to the placebo by 100% (P < 0.01) and 52.4% (P = 0.53), respectively. The TGF-β1 excretion was lower after tested therapies compared to the placebo (55.0 ± 7.56 vs. 56.21 ± 8.56 vs. 85.79 ± 14.11 pg/mg creatinine; P = 0.016); without differences between aliskiren and perindopril. PIIINP excretion did not differ between treatments.. The study shows that both aliskiren and perindopril suppress TGF-β1 in patients with chronic kidney diseases. This effect was observed despite significant increases in the renin and prorenin concentrations. Further studies involving histological assessments are required to elucidate the exact impact of these agents on renal fibrosis.

Topics: Adult; Amides; Antihypertensive Agents; Chronic Disease; Creatinine; Cross-Over Studies; Double-Blind Method; Female; Fibrosis; Fumarates; Humans; Kidney; Kidney Diseases; Male; Peptide Fragments; Perindopril; Pilot Projects; Procollagen; Renin; Transforming Growth Factor beta; Treatment Outcome

HYPOTHESIS/ INTRODUCTION: We investigated whether diabetes modified the effectiveness of renin-angiotensin-aldosterone system (RAAS) inhibition on left ventricular hypertrophy (LVH) regression in hypertensive patients in the Aliskiren in Left Ventricular Hypertrophy (ALLAY) trial.. Participants (n=465) with LVH and a BMI > 25 kg/m(2) were randomized to aliskiren 300mg, losartan 100mg or both daily for 36 weeks, and LVH regression was assessed by cardiac magnetic resonance imaging. Renin concentration, plasma renin activity and aldosterone were assessed in a subset of patients.. Patients with diabetes mellitus (DM) (n=111, 24%) were older (61±9 vs. 58±11 years, p=0.03), had higher BMI (32.2±4.2 vs. 30.7 ± 4 kg/m(2), p=0.004), higher systolic blood pressure (148±14 vs. 145±14mmHg, p=0.03) and lower eGFR (79±16 vs. 84±16ml/min, p=0.03) at baseline. Combination therapy with aliskiren plus losartan was associated with greater LVH reduction than losartan alone in patients with DM (p=0.01), but not in patients without DM (p=0.91; unadjusted interaction p=0.06; adjusted p = 0.038). In a subset of 138 participants, plasma aldosterone was reduced to a greater extent in patients with DM (p-interaction = 0.004).. Patients with DM and LVH may derive differential benefit with dual RAAS inhibition with a combination of aliskiren and losartan compared with losartan alone with respect to LVH reduction. Whether these findings will result in improved outcomes will be further explored in larger studies.

Topics: Aldosterone; Amides; Antihypertensive Agents; Biomarkers; Blood Pressure; Diabetes Complications; Female; Fumarates; Heart Ventricles; Humans; Hypertrophy, Left Ventricular; Losartan; Male; Middle Aged; Organ Size; Renin; Treatment Outcome

The AliSkiren Study of profound antihypERtensive efficacy in hyperTensIVE patients (ASSERTIVE) study was designed to assess the sustained blood pressure (BP)-lowering effect of aliskiren vs. telmisartan after a 7-day treatment withdrawal in patients with hypertension.. Patients were randomized to once-daily aliskiren 150  mg (N = 414) or telmisartan 40  mg (N = 408). After 2 weeks, all patients were uptitrated to double the initial dose for 10 weeks; subsequently, all patients were treated with placebo to simulate a 7-day treatment withdrawal.. At the end of active treatment (EoA), similar decreases in mean ambulatory BP were observed with aliskiren and telmisartan. From EoA to day 7 of treatment withdrawal (end of withdrawal, EoW), the least squares mean increase in 24-h mean ambulatory SBP was smaller for aliskiren (2.7 mmHg) vs. telmisartan (6.5  mmHg). Between-treatment difference was significant in favour of aliskiren (-3.8  mmHg; P < 0.0001). Similar effects were observed for the increase in 24-h mean ambulatory DBP after EoW (-2.1 mmHg; P < 0.0001). Mean sitting SBP and DBP were also significantly lower with aliskiren than telmisartan after EoW with SBP (2.0  mmHg) and DBP (1.1  mmHg) differences in favour of aliskiren, already evident on day 2 after a single 'missed dose'.. Aliskiren showed a greater and more sustained BP-lowering effect than telmisartan during a 7-day treatment withdrawal. Aliskiren may provide sustained BP lowering during 1 day or more missed dose.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Benzimidazoles; Benzoates; Biomarkers; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Diabetes Complications; Double-Blind Method; Female; Fumarates; Humans; Hypertension; International Cooperation; Male; Medication Adherence; Middle Aged; Placebos; Telmisartan; Time Factors; Treatment Outcome

Aliskiren is a new oral non-peptide renin inhibitor. Its effects on vascular function in human hypertension are unknown. We assessed whether aliskiren may improve peripheral endothelial function and arterial stiffness in essential hypertensive patients (EH), when compared with the angiotensin-converting enzyme-inhibitor ramipril.. Fifty EH received treatment with aliskiren (150-300 mg/daily) or ramipril (5-10 mg/daily) for 12 weeks, according to a randomized, open with blind endpoints, parallel group design. We studied the forearm blood flow (straingauge plethysmography) response to intrabrachial acetylcholine, repeated under the nitric oxide synthase inhibitor N(G)-monomethyl-l-arginine (l-NMMA) (4 μmol/min), or the antioxidant ascorbic acid (8 mg/100 mL/min). Carotid-to-femoral pulse wave velocity (PWV), central blood pressure and augmentation index (AIx) were obtained by applanation tonometry. Brachial blood pressure was similarly normalized by aliskiren (from 149/94 to 136/86 mmHg) and ramipril (from 148/92 to 135/85 mmHg), as well as central blood pressure. Aliskiren increased (P < 0.001) the vasodilation to acetylcholine and restored the inhibitory effect of l-NMMA on acetylcholine. Ascorbic acid, which at baseline potentiated the response to acetylcholine, no longer improved endothelium-dependent relaxation after aliskiren treatment. In contrast, ramipril failed to affect the response to acetylcholine, the lacking inhibitory effect of l-NMMA, or the potentiating effect of ascorbic acid. Pulse wave velocity was significantly (P < 0.05) and similarly reduced by both drugs. Aliskiren induced a significantly (P < 0.05) greater AIx reduction than ramipril.. Aliskiren increased nitric oxide availability in the forearm resistance arterioles of EH, an effect probably determined by an antioxidant activity, which can also contribute to improved peripheral wave reflection.

Topics: Adult; Amides; Antihypertensive Agents; Arterioles; Blood Flow Velocity; Double-Blind Method; Endothelium, Vascular; Enzyme Inhibitors; Female; Forearm; Fumarates; Humans; Hypertension; Male; Middle Aged; omega-N-Methylarginine; Ramipril; Vascular Resistance; Vascular Stiffness; Vasodilator Agents

This open-label, randomized, parallel-controlled study investigated the effects of the direct renin inhibitor aliskiren on 64 hypertensive type 2 diabetic patients with chronic kidney disease (CKD) and stable glycemic control who were already being treated with fixed doses of antihypertensive agents over a 24-week period. These agents were 80 mg of the angiotensin II receptor blocker (ARB) telmisartan and 5 mg of the calcium channel blocker (CCB) amlodipine. Patients were randomly assigned to two groups: the aliskiren group, receiving 150 mg per day aliskiren, which was increased to 300 mg per day (n=32), and the CCB group, which received an increased dose (7.5 mg per day) of amlodipine that was increased to 10 mg per day (n=32). Urinary albumin excretion and urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and liver-type fatty acid-binding protein (L-FABP) were investigated in each group. Mean systolic and diastolic blood pressure decreased significantly in both groups, but there was no significant difference between the two groups at the end of the study. Serum creatinine levels and estimated glomerular filtration rate did not differ significantly between the two groups, but percent changes of urinary albumin/creatinine ratios, 8-OHdG and L-FABP levels decreased significantly in the aliskiren group compared with the CCB group. Plasma aldosterone levels were significantly decreased in the aliskiren group, which correlated significantly with those of urinary 8-OHdG and L-FABP. Our results suggest that the addition of aliskiren to the maximal recommended dose of ARB and usual dose of amlodipine is more effective in reducing albuminuria and oxidant stress in hypertensive diabetic patients with CKD than increasing the dose of amlodipine.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Albuminuria; Aldosterone; Amides; Amlodipine; Angiotensin II Type 2 Receptor Blockers; Antihypertensive Agents; Benzimidazoles; Benzoates; Blood Pressure; Calcium Channel Blockers; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Fatty Acid-Binding Proteins; Female; Fumarates; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Male; Middle Aged; Renin; Telmisartan; Young Adult

To evaluate the clinic and ambulatory blood pressure (BP)-lowering efficacy and safety of an aliskiren/amlodipine/hydrochlorothiazide (HCT) triple combination compared with the component dual combinations, in patients with moderate-to-severe hypertension.. This 8-week, double-blind, randomized, active-controlled study, after 1-4 weeks single-blind placebo run-in period, randomized 1191 patients to receive once-daily aliskiren/amlodipine 150/5 mg (n = 287), aliskiren/HCT 150/12.5 mg (n = 298), amlodipine/HCT 5/12.5 mg (n = 296), or aliskiren/amlodipine/HCT 150/5/12.5 mg (up-titrated from aliskiren/HCT 150/12.5 mg after initial 3 days) (n = 310) for 4 weeks, followed by forced titration to double the initial dose for the next 4 weeks.. Baseline mean sitting SBP and DBP (msSBP/msDBP) was comparable among treatment groups. The aliskiren/amlodipine/HCT combination resulted in significant least squares mean reduction in msSBP/msDBP from baseline to endpoints (week 4, -30.7/-15.9  mmHg; week 8, -37.9/-20.6  mmHg), superior (P < 0.001) to each of the dual combinations. The triple combination was associated with -27.8  mmHg reduction in msSBP at week 2, significantly better than the dual combinations (P < 0.05). Significantly greater mean SBP/DBP-lowering effect for triple vs. dual combinations was also demonstrated through 24-h, daytime, and night-time ambulatory BP measurements. Significantly greater (P < 0.001) BP control (msSBP/msDBP < 140/90  mmHg) was achieved with triple combination in patients with moderate-to-severe (62.3%) and severe (57.5%) hypertension.. Aliskiren/amlodipine/HCT at 150/5/12.5 mg (week 4) and 300/10/25 mg (week 8) provided statistically superior reductions in msSBP/msDBP and greater BP control rates vs. the dual combinations, and was well tolerated. The improved efficacy of BP reduction was evident within 2 weeks of initiating triple therapy even at low dose.

Topics: Aged; Amides; Amlodipine; Antihypertensive Agents; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Placebos; Severity of Illness Index; Single-Blind Method

In a prespecified subgroup analysis of a 12-week multinational, randomized, double-blind, parallel-group trial, self-identified Hispanic/Latino adult men and women with systolic blood pressure 160 mm Hg to 179 mm Hg received combination aliskiren/hydrochlorothiazide (HCT) 150/12.5 mg or aliskiren 150 mg (force-titrated to 300/25 mg and 300 mg, respectively, at week 1). At week 12, combination aliskiren/HCT provided greater reduction in mean sitting systolic blood pressure from baseline, the primary efficacy variable, compared with aliskiren monotherapy (-32.6 mm Hg vs -19.6 mm Hg; P<.0001). Differences in mean sitting diastolic blood pressure reductions followed a similar pattern (-13.5 mm Hg vs -7.1 mm Hg; P<.0001). Notable blood pressure reductions were evident at week 1 in both treatment groups, with near-maximal effects reached by week 8. Results were consistent regardless of country of residence. Both treatments were well tolerated. Aliskiren alone or in combination with HCT is safe and effective in Hispanic/Latino patients with stage 2 hypertension. Combination aliskiren/HCT produced greater blood pressure reductions than aliskiren monotherapy.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure; Diastole; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Hispanic or Latino; Humans; Hydrochlorothiazide; Hypertension; International Cooperation; Male; Middle Aged; Severity of Illness Index; Systole; Treatment Outcome

Aliskiren is a direct renin inhibitor that exerts its effect at the rate-limiting step of the renin-angiotensin system. This study was performed to examine the beneficial effects of aliskiren-based antihypertensive therapy on the ambulatory blood pressure (BP) profile, central hemodybamics, and arterial stiffness in untreated Japanese patients with mild to moderate hypertension. Twenty-one Japanese nondiabetic patients with untreated mild to moderate essential hypertension were initially given aliskiren once daily at 150 mg, and the dose was titrated up to 300 mg as needed. After 12 weeks of aliskiren-based therapy, the clinic, ambulatory, and central BP values as well as brachial-ankle pulse wave velocity (baPWV) were all significantly decreased compared with baseline (clinic systolic BP, 151 ± 11 mm Hg vs 132 ± 11 mm Hg; clinic diastolic BP, 91 ± 13 mm Hg vs 82 ± 9 mm Hg; 24-hour systolic BP, 144 ± 12 mm Hg vs 133 ± 11 mm Hg; 24-hour diastolic BP, 88 ± 8 mm Hg vs 81 ± 9 mm Hg; central BP, 162 ± 16 mm Hg vs 148 ± 14 mm Hg; baPWV, 1625 ± 245 cm/s vs 1495 ± 199 cm/s; P<.05). These results show that aliskiren, as a first-line regimen, improves the ambulatory BP profile and may have protective vascular effects in Japanese nondiabetic patients with untreated mild to moderate essential hypertension.

Topics: Aged; Amides; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Dose-Response Relationship, Drug; Female; Fumarates; Hemodynamics; Humans; Hypertension; Japan; Male; Middle Aged; Prospective Studies; Renin-Angiotensin System; Retrospective Studies; Severity of Illness Index; Treatment Outcome; Vascular Stiffness

To assess the extent of reduction in blood pressure (BP) of aliskiren/amlodipine combination therapy compared with amlodipine monotherapy in moderate-to-severe hypertensive patients.. This was an 8-week multicentre, randomised, double-blind study. After a 1-to 4-week washout period, eligible patients [mean sitting systolic blood pressure (msSBP) ≥ 160 to < 200 mmHg] were randomised to receive a once-daily dose of aliskiren/amlodipine 150/5mg (n = 244) or amlodipine 5 mg (n = 241) for 1 week, followed by up-titration to aliskiren/amlodipine 300/10 mg or amlodipine 10 mg for 7 weeks. Efficacy outcome measures included change from baseline to week 8 endpoint in msSBP (primary endpoint), mean sitting diastolic blood pressure (msDBP), and BP control rate (< 140/90 mmHg). Safety was assessed by monitoring and recording all adverse events (AEs) and laboratory abnormalities.. Patients' demographic characteristics were balanced between the two groups, mean baseline BP being 171.0/94.3 mmHg for aliskiren/amlodipine and 171.8/95.6 mmHg for amlodipine. Of 485 randomised patients, 433 (89.3%) completed the study. At week 8 endpoint, combination therapy resulted in significantly greater msSBP/msDBP reductions and BP control rate, compared with monotherapy (all: p ≤ 0.0001). The overall incidence of AEs was similar between the two groups. The most commonly reported AE was peripheral oedema with the incidence lower for combination therapy (14.4%) than for monotherapy (18.3%).. In this population with considerably elevated BP, use of aliskiren/amlodipine combination showed significantly greater BP reductions and allowed more patients to achieve BP control compared with amlodipine monotherapy, with no additional safety concerns.

Topics: Aged; Amides; Amlodipine; Antihypertensive Agents; Double-Blind Method; Drug Combinations; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Treatment Outcome

Aliskiren represents a novel class of orally active renin inhibitors. This study analyses the pharmacokinetics, tolerability and safety of single-dose aliskiren inpatients with end-stage renal disease (ESRD) undergoing haemodialysis.. Six ESRD patients and six matched healthy volunteers were enrolled in an open-label, parallel-group, single-sequence study. The ESRD patients underwent two treatment periods where 300 mg of aliskiren was administered 48 or 1 h before a standardized haemodialysis session (4 h, 1.4 m(2) high-flux filter, blood flow 300 mL/min, dialysate flow 500 mL/min). Washout was >10 days between both periods. Blood and dialysis samples were taken for up to 96 h postdose to determine aliskiren concentrations.. Compared with the healthy subjects (1681 ± 1034 ng·h/mL), the area under the plasma concentration-time curve (AUC) from time zero to infinity was 61% (haemodialysis at 48 h) and 41% (haemodialysis at 1 h) higher in ESRD patients receiving single-dose aliskiren 300 mg. The maximum (peak) plasma drug concentration (481 ± 497 ng/mL in healthy subjects) was 17% higher (haemodialysis at 48 h) and 16% lower (haemodialysis at 1 h). In both treatment periods, dialysis clearance was below 2% of oral clearance and the mean fraction eliminated from circulation was 10 and 12% in period 1 and 2, respectively. Drug AUCs were similar in ESRD patients receiving aliskiren 1 or 48 h before dialysis. No severe adverse events occurred.. The exposure of aliskiren is moderately higher in ESRD patients. Only a minor portion is removed by a typical haemodialysis session. Aliskiren exposure is not significantly affected by intermittent haemodialysis, suggesting that no dose adjustment is necessary in this population.

Topics: Administration, Oral; Adult; Amides; Blood Pressure; Drug Administration Schedule; Fumarates; Humans; Hypertension; Hypoglycemic Agents; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Renin

This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both.. In a double-blind fashion, we randomly assigned 8561 patients to aliskiren (300 mg daily) or placebo as an adjunct to an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker. The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level.. The trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary end point had occurred in 783 patients (18.3%) assigned to aliskiren as compared with 732 (17.1%) assigned to placebo (hazard ratio, 1.08; 95% confidence interval [CI], 0.98 to 1.20; P=0.12). Effects on secondary renal end points were similar. Systolic and diastolic blood pressures were lower with aliskiren (between-group differences, 1.3 and 0.6 mm Hg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95% CI, 11 to 17). The proportion of patients with hyperkalemia (serum potassium level, ≥6 mmol per liter) was significantly higher in the aliskiren group than in the placebo group (11.2% vs. 7.2%), as was the proportion with reported hypotension (12.1% vs. 8.3%) (P<0.001 for both comparisons).. The addition of aliskiren to standard therapy with renin-angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful. (Funded by Novartis; ALTITUDE ClinicalTrials.gov number, NCT00549757.).

Topics: Aged; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Fumarates; Humans; Hyperkalemia; Hypokalemia; Kidney Diseases; Male; Middle Aged; Patient Dropouts; Renin; Treatment Failure

Combination antihypertensive therapies are recommended to attain blood pressure (BP) targets especially in high-risk patients in whom rapid and pronounced BP control is essential. This 28- to 54-week, open-label, multicenter study evaluated the safety and efficacy of a triple combination, aliskiren with amlodipine and hydrochlorothiazide (HCTZ), in patients with moderate to severe hypertension. Following a washout period of up to 4 weeks, patients received aliskiren/HCTZ 300/12.5 mg for 1 week, followed by add-on amlodipine 5 mg for 1 week. Thereafter, the doses of amlodipine and HCTZ were doubled. The first 206 of 564 patients who completed 28 weeks of study continued for an additional 26 weeks. Safety was assessed by recording all adverse events. Efficacy variables included changes in BP from baseline to endpoint and BP control rate. Of 564 patients, 493 completed the study. Peripheral edema (9.4%), headache (5.7%), nasopharyngitis (4.1%), and bronchitis (3.7%) were reported frequently. Clinically significant reductions in mean sitting systolic BP/mean sitting diastolic BP from baseline (-34.2/-20.3 mm Hg and -37.3/-21.8 mm Hg at weeks 28 and 54, respectively) were observed. Corresponding BP control rates were 69.1% and 77.1%. The aliskiren/amlodipine/HCTZ combination in patients with moderate to severe hypertension was well tolerated and provided clinically significant BP reductions and effective BP control.

Topics: Adult; Aged; Amides; Amlodipine; Antihypertensive Agents; Biological Availability; Blood Pressure; Drug Monitoring; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Middle Aged; Pharmacovigilance; Severity of Illness Index; Treatment Outcome

Pharmacological inhibition of renin-angiotensin-aldosteron system (RAAS) may reduce proteinuria and the rate of chronic kidney disease progression. The aim was to compare the effects on albuminuria of the therapy with either: (i) telmisartan 80 mg and aliskiren 300 mg, (ii) telmisartan 80 mg and eplerenone 50 mg, (iii) telmisartan 160 mg as monotherapy.. Randomized, double-center, double-blind, cross-over, three treatments-three periods of 8 weeks each study. 18 patients with non-diabetic proteinuric CKD stage 1-3 completed the protocol.. There was significant difference in albuminuria between studied therapies (ANOVA; p<0.01). The combination therapy with telmisartan plus aliskiren decreased albuminuria more effectively than the treatment with telmisartan plus eplerenone and monotherapy with telmisartan 160 mg OD [376 mg/g creatinine (286-686) vs. 707 (502-1204) vs. 525 (318-763); post-hoc p<0.01 and p<0.05, respectively].. The study demonstrated that the combination therapy with angiotensin receptor blocker (ARB) and renin inhibitor was more effective in albuminuria lowering than the concomitant usage of ARB and mineralocorticoid receptor antagonist as well as than ARB in doses two-fold higher than usually used in treatment of hypertension in patients with non-diabetic CKD and that this higher antiproteinuric efficacy was independent on changes in blood pressure.

Topics: Adult; Albuminuria; Amides; Angiotensin Receptor Antagonists; Benzimidazoles; Benzoates; Comorbidity; Cross-Over Studies; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Eplerenone; Female; Fumarates; Humans; Hypertension; Male; Mineralocorticoid Receptor Antagonists; Prospective Studies; Proteinuria; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Severity of Illness Index; Spironolactone; Telmisartan; Treatment Outcome

To evaluate the proteinuria-lowering effect of a renin inhibitor (aliskiren), compared to placebo and to an angiotensin-converting enzyme inhibitor (perindopril), in patients with non-diabetic chronic kidney disease.. A randomised, double-blind, crossover trial was performed in 14 patients with nondiabetic chronic kidney disease with 24-h mean proteinuria of 2.01 g (95% CI, 1.36–2.66) and estimated creatinine clearance of 93±6.8 ml/min. The study consisted of five treatment periods. The patients were randomly assigned to receive aliskiren (150 mg), aliskiren (300 mg), perindopril (5 mg), perindopril (10 mg) or placebo.. Aliskiren and perindopril reduced proteinuria. These effects were dose-dependent. Furthermore, 24-h proteinuria was reduced by 23% (mean 95% CI; 2–44) by treatment with aliskiren (150 mg), by 36% (95% CI, 17–55; P<0.001) with aliskiren (300 mg), by 7.1% (95% CI, 11–26) with perindopril (5 mg) and by 25% (95% CI, 11–39; P<0.05) with perindopril (10 mg), compared to placebo. No significant difference was found between the effects of aliskiren and perindopril.. Aliskiren significantly reduced proteinuria. The antiproteinuric effect is probably similar to that of perindopril, for equivalent hypotensive dosages. The renin inhibitor provides a promising alternative approach for the treatment of patients with chronic proteinuric non-diabetic kidney disease.

Topics: Adult; Amides; Blood Pressure; Cross-Over Studies; Double-Blind Method; Female; Fumarates; Humans; Male; Proteinuria; Renal Insufficiency, Chronic; Renin

Metabolic syndrome, a cluster of risk factors that increase the risk of cardiovascular morbidity and mortality, is common in patients with hypertension. Chronic renin-angiotensin-aldosterone system (RAAS) activation, shown by elevated plasma renin activity (PRA), is implicated in many of the features of metabolic syndrome. The direct renin inhibitor aliskiren may be of benefit in this patient group as aliskiren targets the RAAS at the rate-limiting step. In this double-blind study, 141 patients with hypertension (mean baseline BP 155/93 mm Hg) and metabolic syndrome (modified National Cholesterol Education Program ATP III criteria) were randomized to aliskiren 300 mg or irbesartan 300 mg once daily. Patients treated with aliskiren 300 mg had their mean sitting blood pressure (BP) lowered by 13.8/7.1 mm Hg after 12 weeks, significantly greater (P≤0.001) than the 5.8/2.8 mm Hg reduction observed in patients treated with irbesartan 300 mg. A significantly greater proportion of patients treated with aliskiren achieved BP control to <135/85 mm Hg (29.2 vs 16.7% with irbesartan; P=0.019). Aliskiren treatment led to a 60% decrease in PRA from baseline, whereas irbesartan increased PRA by 99% (both P<0.001). Aliskiren and irbesartan had similar effects on glucose and lipid profiles and on a panel of biomarkers of inflammation and cardiovascular risk. Both aliskiren and irbesartan were well tolerated. Collectively, these results suggest that aliskiren 300 mg may offer treatment benefits compared with irbesartan 300 mg for BP reduction in patients with hypertension and metabolic syndrome.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Biphenyl Compounds; Blood Glucose; Cardiovascular Diseases; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Inflammation; Irbesartan; Lipids; Male; Metabolic Syndrome; Middle Aged; Renin; Renin-Angiotensin System; Tetrazoles; Treatment Outcome

In a randomized crossover study, 11 healthy volunteers took 100 mg (first dose 200 mg) of the antifungal drug itraconazole, a P-glycoprotein and CYP3A4 inhibitor, or placebo twice daily for 5 days. On day 3, they ingested a single 150-mg dose of aliskiren, a renin inhibitor used in the treatment of hypertension. Itraconazole raised the peak plasma aliskiren concentration 5.8-fold (range, 1.1- to 24.3-fold; P < .001) and the area under the plasma aliskiren concentration-time curve 6.5-fold (range, 2.6- to 20.5-fold; P < .001) but had no significant effect on aliskiren elimination half-life. Itraconazole increased the amount of aliskiren excreted into the urine during 12 hours 8.0-fold (P < .001) and its renal clearance 1.2-fold (P = .042). Plasma renin activity 24 hours after aliskiren intake was 68% lower during the itraconazole phase than during the placebo phase (P = .011). In conclusion, itraconazole markedly raises the plasma concentrations and enhances the renin-inhibiting effect of aliskiren. The interaction is probably mainly explained by inhibition of the P-glycoprotein-mediated efflux of aliskiren in the small intestine, with a minor contribution from inhibition of CYP3A4. Concomitant use of aliskiren and itraconazole is best avoided.

Topics: Adult; Amides; Antifungal Agents; Antihypertensive Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biotransformation; Cross-Over Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Enzyme Inhibitors; Female; Fumarates; Half-Life; Humans; Itraconazole; Male; Metabolic Clearance Rate; Renin; Young Adult

The authors describe the drug-drug interaction between aliskiren and verapamil in healthy participants. Eighteen participants first received an oral dose of aliskiren 300 mg (highest recommended clinical dose) in period 1. After a 10-day washout period, the participants received verapamil 240 mg/d for 8 days (period 2). On day 8, the participants also received an oral dose of aliskiren 300 mg. Safety and pharmacokinetic analyses were performed during each treatment period. Concomitant administration of a single dose of aliskiren during steady-state verapamil resulted in an increase in plasma concentration of aliskiren. The mean increase in AUC(0-∞), AUC(last), and C(max) was about 2-fold. On day 8, in the presence of aliskiren, AUC(τ,ss) of R-norverapamil, R-verapamil, S-norverapamil, and S-verapamil was decreased by 10%, 16%, 10%, and 25%, respectively. Similarly, the C(max,ss) of R-norverapamil, R-verapamil, S-norverapamil, and S-verapamil was decreased by 13%, 18%, 12%, and 24%, respectively. Aliskiren did not affect the AUC(τ,ss) ratios of R-norverapamil/R-verapamil and S-norverapamil/S-verapamil. Aliskiren administered alone or in combination with verapamil was well tolerated in healthy participants. In conclusion, no dose adjustment is necessary when aliskiren is administered with moderate ABCB1 inhibitors such as verapamil (240 mg/d).

Topics: Administration, Oral; Adolescent; Adult; Amides; Antihypertensive Agents; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Calcium Channel Blockers; Drug Interactions; Fumarates; Humans; Male; Prospective Studies; Verapamil; Young Adult

The majority of patients with essential hypertension of moderate severity (WHO grade 2) require combination therapy. We aimed to investigate whether the single-pill combination of aliskiren 300  mg and hydrochlorothiazide (HCT) 25  mg (ALIS 300/HCT 25) improves the BP reduction in hypertensive patients not adequately controlled by the free combination of candesartan 32  mg and HCT 25  mg (CAN 32 + HCT 25).. In an open-label, single-arm study, patients with mean sitting diastolic blood pressure (DBP) between 100-109  mmHg at baseline received 4-week treatment with CAN 32 + HCT 25 (Phase 1), followed - in patients whose BP was not controlled - by 4-week treatment with ALIS 300/HCT 25 (Phase 2). The DBP change between weeks 4 and 8 was the primary endpoint. The ClinicalTrials.gov Identifier is NCT00867490.. In the 186 patients treated, CAN 32 + HCT 25 reduced systolic BP (SBP)/DBP by 18.9/12.2 mmHg. Those 123 patients with uncontrolled hypertension switched to ALIS 300/HCT 25 experienced a further SBP/DBP reduction of 2.8/3.1  mmHg between week 4 and week 8 (p = 0.0064 and p < 0.0001), and 33.3% achieved DBP normalisation. In 61 patients not controlled after week 8 (SBP ≥ 140  mmHg or DBP  ≥  90  mmHg), who participated in an optional study extension, amlodipine 5  mg was added. Triple therapy over 4 weeks decreased SBP/DBP by further 9.2/5.9  mmHg (p < 0.0001 each). Adverse events with suspected drug relationship were noted in 4.3% (Phase 1), 3.3% (Phase 2), and 1.6% (extension) of the patients. Limitations of the study include the open-label, non-randomised approach and short treatment duration across the individual phases.. In this open-label, single-arm switch study reflecting clinical practice, patients with moderate hypertension not controlled by the free combination of CAN 32 + HCT 25 achieved a clinically and statistically significant reduction of blood pressure from the single pill combination of ALIS 300/HCT 25, and the optional addition of amlodipine.

Topics: Adult; Aged; Algorithms; Amides; Amlodipine; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Dose-Response Relationship, Drug; Drug Combinations; Drug Resistance; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Tetrazoles; Treatment Failure; Treatment Outcome

Hospitalizations for acute heart failure syndromes (AHFS) are associated with high post-discharge mortality and readmission rates in spite of available therapies. Renin-angiotensin-aldosterone system (RAAS) antagonists improve outcomes in outpatients with heart failure (HF) and reduced ejection fraction, however these therapies have not been tested in AHFS. Aliskiren is a direct renin inhibitor (DRI) that is known to enhance RAAS inhibition, which may result in improved clinical outcomes in AHFS. The aim of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) study is to evaluate the effect of aliskiren on cardiovascular death and HF in AHFS patients.. ASTRONAUT will be an event-driven trial with an estimated enrolment of 1782 patients hospitalized with worsening chronic HF, a left ventricular ejection fraction ≤40%, and an estimated glomerular filtration rate ≥40 mL/min/1.73 m(2). Patients will be randomized 1:1 in a double-blind fashion to receive aliskiren or placebo, in addition to standard HF therapy. The primary endpoint will be a composite of time to either cardiovascular death or first occurrence of HF re-hospitalization.. Aliskiren is a DRI with a favourable neurohormonal and haemodynamic profile that may benefit patients hospitalized with worsening HF. Given the neurohormonal abnormalities that are present during and after hospitalization for AHFS, it is hypothesized that adding aliskiren to standard therapy will reduce post-discharge mortality and re-hospitalization. NCT00894387.

Topics: Amides; Antihypertensive Agents; Double-Blind Method; Europe; Fumarates; Glomerular Filtration Rate; Heart Failure; Hemodynamics; Hospitalization; Humans; Multivariate Analysis; Outpatients; Placebos; Proportional Hazards Models; Renin; Renin-Angiotensin System; Research Design; Stroke Volume; Syndrome; Time Factors; United States; Ventricular Function, Left

The renin-angiotensin-aldosterone system (RAAS) has pivotal roles in the pathogenesis of hypertension in hemodialysis-dependent chronic kidney disease (HDD-CKD) patients. Activated RAAS also increases inflammatory mediators by directly increasing proinflammatory gene expression and by putting oxidative stress on the vascular endothelium. Both hypertension and inflammation are major risk factors for cardiovascular disease (CVD) in HDD-CKD patients. In this study, we assessed the efficacy of a direct renin inhibitor, aliskiren, on blood pressure (BP) and CVD predictive biomarkers, such as brain natriuretic peptide (BNP), high-sensitivity C-reactive protein (hs-CRP) and diacron-reactive oxygen metabolite (d-ROM). A total of 30 hypertensive HDD-CKD patients were assigned to receive aliskiren (150 mg) orally once daily with their existing antihypertensives. After 8 weeks, aliskiren treatments reduced systolic blood pressure (SBP) from 169.0±20.1 to 153.7±19.6 mmHg (P<0.001) and diastolic blood pressure (DBP) from 78.1±12.0 to 73.0±13.6 mmHg (P=0.048). RAAS was suppressed by aliskiren treatment as follows: PRA (from 3.6±4.0 to 1.0±1.5 ngml(-1)h(-1) (P=0.004)), angiotensin I (from 1704.0±2580.9 to 233.7±181.0 pgml(-1) (P=0.009)), angiotensin II (from 70.2±121.5 to 12.4±11.5 pgml(-1) (P=0.022)) and aldosterone (from 107.9±148.0 to 73.1±34.6 pgml(-1) (NS)). The biomarkers for CVD were inhibited by aliskiren: BNP (from 362.5±262.1 to 300.0±232.0 pgml(-1) (P=0.043)), hS-CRP (from 6.2±8.1 to 3.5±3.7 mgl(-1) (P=0.022)) and d-ROM (from 367.0±89.8 to 328.3±70.9 U.CARR (P=0.022)). The inhibition levels of biomarkers for CVD by aliskiren did not correlate with the decreased levels of SBP and DBP. These results suggested that aliskiren was effective for BP control and may have cardiovascular protective effects in hypertensive HDD-CKD patients.

Topics: Aged; Amides; Antihypertensive Agents; Biomarkers; Blood Pressure; C-Reactive Protein; Cardiovascular Diseases; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Natriuretic Peptide, Brain; Renal Dialysis; Renin; Renin-Angiotensin System; Treatment Outcome

The 'DRIVER' study was designed to investigate the 'real-world' effectiveness of aliskiren-based treatment of hypertension. This article reports the 180-day blood pressure (BP) outcomes, and the multilevel (physician- and patient-level) determinants thereof.. DRIVER was a prospective, observational, open-label, multi-centre, pharmaco-epidemiologic study of hypertensive patients treated with aliskiren in whom prior treatment failed or was not tolerated. 2070 patients (enrolled by 426 physicians) were enrolled; 1695 patients (81.9%) completed the 180-day aliskiren treatment period. Mean patient age was 64.2 ± 12.1 years; 53.7% were men, 25.3% diabetic and 40.7% had a high or very high cardiovascular (CV) risk. At 180 days, the mean ± SD reductions in systolic and diastolic BP were -22.9 ± 16.7 mmHg and -10.5 ± 10.9 mmHg respectively (both p < .001). 2007 and 2009 guideline-defined BP control was achieved in 36.4% and 56.3% of patients, respectively (both p < .001). 64.2% of eligible patients had a reduction in CV risk (p < .001). A physician-level class effect was responsible for 22.8% and 28.1% of variability in systolic and diastolic BP, respectively, for 20.1% of variability in BP control, and for 16.1% of variability in the reduction of CV risk. Both patient- (e.g. adherence) and physician-related factors (e.g. age and knowledge) were significant in profiling best response to treatment with aliskiren. Adverse events reported in this article were consistent with the aliskiren scientific leaflet.. Aliskiren is safe and effective in reducing BP, improving BP control and reducing global CV risk in a 'real-world' setting and for patients in whom prior treatment failed or was not tolerated. Optimising treatment adherence and strategic medical education may be ways of improving BP outcomes in patients with hypertension.

Topics: Adult; Amides; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Risk Factors; Treatment Outcome

The aim of this study was to investigate the effects of orange juice and apple juice on the pharmacokinetics and pharmacodynamics of aliskiren.. In a randomized crossover study, 12 healthy volunteers ingested 200 ml of orange juice, apple juice or water three times daily for 5 days. On day 3, they ingested a single 150-mg dose of aliskiren. Plasma aliskiren concentrations were measured up to 72 h, its excretion into urine up to 12 h and plasma renin activity up to 24 h.. Orange and apple juice reduced aliskiren peak plasma concentrations by 80% (95% CI 63%, 89%, P < 0.001) and 84% (95% CI 72%, 91%, P < 0.001), and the area under the plasma aliskiren concentration-time curve (AUC) by 62% (95% CI 47%, 72%, P < 0.001) and 63% (95% CI 46%, 74%, P < 0.001), respectively, but had no significant effect on its elimination half-life or renal clearance. The decreases in aliskiren AUC by orange and apple juice correlated with aliskiren AUC during the water phase (r= 0.98, P < 0.001). Plasma renin activity was 87% and 67% higher at 24 h after aliskiren during the orange juice and apple juice phases, respectively, than during the water phase (P < 0.05).. Orange juice and apple juice greatly reduce the plasma concentrations and renin-inhibiting effect of aliskiren, probably by inhibiting its OATP2B1-mediated influx in the small intestine. Concomitant intake of aliskiren with orange or apple juice is best avoided.

Topics: Adult; Amides; Antihypertensive Agents; Beverages; Citrus sinensis; Female; Food-Drug Interactions; Fumarates; Humans; Male; Malus; Organic Anion Transporters; Renin; Young Adult

Most patients miss occasional doses of antihypertensives. The use of 'forgiving' drugs (i.e. drugs with duration of action longer than the 24-h dosing interval) may allow an adequate blood pressure (BP) reduction to be maintained despite missed doses.. To quantify the effects of adherence level and duration of action on estimated mean systolic BP (SBP) reduction and cardiovascular disease (CVD) risk.. For 1250 patients, we simulated 256-day dosing histories with realistically distributed drug holidays based on a study of electronically monitored dosing records. Adherence was set to the desired level by altering the proportion of doses missed. Mean office SBP-lowering effect (aliskiren 300 mg, -14.1 mmHg; irbesartan 300 mg, -13.3; ramipril 10 mg, -10.1 mmHg) and the rate of SBP increase after stopping treatment (off-rate; aliskiren, 1.0 mmHg/day; irbesartan, 3.6 mmHg/day; ramipril, 4.0 mmHg/day) were taken from the results of a randomised, double-blind trial. SBP was averaged over time and patient to estimate mean reductions in SBP and 10-year CVD risk (Framingham risk equation, baseline absolute 10-year CVD risk: 27%).. Predicted reductions in SBP and CVD risk with aliskiren were larger and less affected by imperfect adherence than the reductions with irbesartan or ramipril. For aliskiren, reducing adherence from 90% to 60% led to a predicted rise in SBP of 1.0 mmHg and three additional CVD events per 1000 treated patients; larger predicted differences were observed for irbesartan (2.5 mmHg; 7.5 events/1000 treated patients) and ramipril (2.2 mmHg; 6.7 events/1000 treated patients).. To offset the effects of imperfect adherence, a common challenge with antihypertensives, for better BP management it may be prudent to prescribe 'forgiving' drugs.

Topics: Aged; Amides; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Cardiovascular Diseases; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Irbesartan; Male; Medication Adherence; Ramipril; Risk Factors; Tetrazoles; Treatment Outcome

Short-term studies have suggested that the use of initial combination therapy for the control of blood pressure improves early effectiveness. We tested whether a combination of aliskiren and amlodipine is superior to each monotherapy in early control of blood pressure without excess of adverse events, and if initial control by monotherapy impairs subsequent control by combination therapy.. We did a double-blind, randomised, parallel-group, superiority trial at 146 primary and secondary care sites in ten countries, with enrolment from Nov 28, 2008, to July 15, 2009. Patients eligible for enrolment had essential hypertension, were aged 18 years or older, and had systolic blood pressure between 150 and 180 mm Hg. Patients were randomly assigned (1:1:2) to treatment with 150 mg aliskiren plus placebo, 5 mg amlodipine plus placebo, or 150 mg aliskiren plus 5 mg amlodipine. Random assignment was through a central interactive voice response system and treatment allocation was masked from the patients. From 16-32 weeks, all patients received combination therapy with 300 mg aliskiren plus 10 mg amlodipine. Our primary endpoints, assessed on an intention-to-treat basis (ie, in patients who received the allocated treatment), were the adjusted mean reduction in systolic blood pressure from baseline over 8 to 24 weeks, and then the final reduction at 24 weeks. This trial is registered with ClinicalTrials.gov, number NCT00797862.. 318 patients were randomly assigned to aliskiren, 316 to amlodipine, and 620 to aliskiren plus amlodipine. 315 patients initially allocated to aliskiren, 315 allocated to amlodipine, and 617 allocated to aliskiren plus amlodipine were available for analysis. Patients given initial combination therapy had a 6·5 mm Hg (95% CI 5·3 to 7·7) greater reduction in mean systolic blood pressure than the monotherapy groups (p<0·0001). At 24 weeks, when all patients were on combination treatment, the difference was 1·4 mm Hg (95% CI -0·05 to 2·9; p=0·059). Adverse events caused withdrawal of 85 patients (14%) from the initial aliskiren plus amlodipine group, 45 (14%) from the aliskiren group, and 58 (18%) from the amlodipine group. Adverse events were peripheral oedema, hypotension, or orthostatic hypotension.. We believe that routine initial reduction in blood pressure (>150 mm Hg) with a combination such as aliskiren plus amlodipine can be recommended.. Novartis Pharma AG.

Topics: Amides; Amlodipine; Antihypertensive Agents; Calcium Channel Blockers; Diastole; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Systole

Direct renin inhibitors provide an alternative approach to inhibiting the renin-angiotensin-aldosterone system (RAAS) at the most proximal, specific, and rate-limiting step. We tested the hypothesis that direct renin inhibition would attenuate left ventricular remodelling in patients following acute myocardial infarction receiving stable, individually optimized therapy, including another inhibitor of the RAAS.. We randomly assigned 820 patients between ∼2 and 8 weeks following acute myocardial infarction, with the left ventricular ejection fraction (LVEF) ≤45%, and regional wall motion abnormalities (≥20% akinetic area), to receive aliskiren (n = 423), titrated to 300 mg, or matched placebo (n = 397), added to the standard therapy. All patients were required to be on a stable dose of an ACE-inhibitor or ARB, and beta-blocker unless contraindicated or not tolerated. Echocardiograms were obtained at baseline, and following 26-36 weeks of treatment. The primary endpoint was change in left ventricular end-systolic volume from baseline to 36 weeks, and was evaluable in 329 patients in the placebo group and 343 patients in the aliskiren group. We observed no difference in the primary endpoint of end-systolic volume change between patients randomized to aliskiren (-4.4 ± 16.8 mL) or placebo (-3.5 ± 16.3 mL), or in secondary measures of end-diastolic volume, or LVEF. We also observed no differences in a composite endpoint of cardiovascular death, hospitalization for heart failure, or reduction in LVEF >6 points. There were more investigator reported adverse events in the aliskiren group, including hypotension, increases in creatinine and hyperkalaemia.. Adding the direct renin inhibitor aliskiren to the standard therapy, including an inhibitor of the RAAS, in high-risk post-MI patients did not result in further attenuation of left ventricular remodelling, and was associated with more adverse effects. These findings do not suggest that dual RAAS blockade with aliskiren would provide additional benefit in these high-risk post-MI patients.

Topics: Aged; Amides; Blood Pressure; Cardiotonic Agents; Death, Sudden, Cardiac; Female; Fumarates; Hospitalization; Humans; Male; Middle Aged; Myocardial Infarction; Recurrence; Renin; Systole; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Remodeling

Elevated BP contributes to development and progression of proteinuria and decline in renal function in patients with type 2 diabetes. Our post hoc analysis assessed the baseline BP influence on the antiproteinuric effect in the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study.. In the AVOID study, 599 hypertensive type 2 diabetic patients with nephropathy received 6 months of aliskiren (150 mg force titrated to 300 mg daily after 3 months) or placebo added to losartan (100 mg) daily and optimal antihypertensive therapy. Changes in early morning urinary albumin:creatinine ratio and eGFR at week 24 were assessed by subgroups of baseline BP: Group A (prespecified target), <130/80 mmHg (n=159); Group B, <140/90 mmHg but ≥130/80 mmHg (n=189); and Group C (insufficient BP control), ≥140/90 mmHg (n=251).. Mean baseline BP (mmHg) levels for Groups A, B, and C were 120/71, 133/78, and 145/81, respectively. BP during the trial was nearly identical to baseline levels in all groups. The antiproteinuric effects of aliskiren were consistent across subgroups of baseline BP (19 to 22% reduction versus placebo). In Group C, the decline in eGFR was significantly lower with aliskiren than with placebo (P=0.013).. Aliskiren (300 mg) added to losartan (100 mg) plus optimal antihypertensive therapy provides antiproteinuric effects independent of BP in patients with type 2 diabetes and nephropathy. Renal function was better preserved with aliskiren in patients with insufficient BP control.

Topics: Aged; Albuminuria; Amides; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension, Renal; Losartan; Male; Middle Aged; Placebos; Treatment Outcome

Patients with stage 2 systolic hypertension require sizable blood pressure (BP) reductions to achieve recommended targets. This randomized double-blind study compared a single-pill combination of the direct renin inhibitor aliskiren and hydrochlorothiazide (aliskiren/HCTZ) with HCTZ monotherapy in older patients (older than 55 years) with systolic BP ≥160 mm Hg and <200 mm Hg. After a 1- to 4-week washout, 451 patients were randomized to once-daily aliskiren/HCTZ 150/12.5 mg or HCTZ 12.5 mg for 1 week, and then double the doses for 7 weeks. Overall baseline BP was 168.8/91.4 mm Hg. At week 4 (primary) end point, aliskiren/HCTZ provided significantly greater BP reductions from baseline than HCTZ monotherapy (29.6/9.3 mm Hg vs 22.3/6.8 mm Hg) and resulted in a greater proportion of patients achieving BP goal of <140/90 mm Hg (51.1% vs 33.3%). Aliskiren/HCTZ therapy provides substantial BP reductions and may thus be a useful treatment option for older patients with stage 2 hypertension.

Topics: Age Factors; Aged; Amides; Analysis of Variance; Antihypertensive Agents; Blood Pressure; Body Mass Index; Disease Progression; Diuretics; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Health Status Indicators; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Systole; Treatment Outcome; United States

To explore the clinical relevance of inhibition of multidrug resistance transporter 1 and organic anion transporting polypeptide transporter, a drug-drug interaction study was conducted using aliskiren and cyclosporine. This was an open-label, single-sequence, parallel-group, single-dose study in healthy subjects. Subjects (n = 14) first received aliskiren 75 mg orally (period 1), followed by aliskiren 75 mg + cyclosporine 200 mg (period 2) after a 7-day washout period, and aliskiren 75 mg + cyclosporine 600 mg (period 3) after a 14-day washout period. Safety and pharmacokinetics were analyzed during each period. The primary objective was to characterize pharmacokinetics of aliskiren (single-dose and combination with cyclosporine). The increases in area under the time-concentration curve from time 0 to infinity and maximum concentration associated with cyclosporine 200 mg or 600 mg were 4- to 5-fold and 2.5-fold, respectively. Mean half-life increased from 25 to 45 hours. Based on comparison to literature, a single-dose of aliskiren 75 mg did not alter the pharmacokinetics of cyclosporine. Aliskiren 75 mg was well tolerated. Combination with cyclosporine increased the number of adverse events, mainly hot flush and gastrointestinal symptoms, with no serious adverse events. Two adverse events led to withdrawal (ligament rupture, not suspected to be study-drug related; and vomiting, suspected to be study-drug related). Laboratory parameters, vital signs, and electrocardiographs showed no time- or treatment-related changes. As cyclosporine significantly altered the pharmacokinetics of aliskiren in humans, its use with aliskiren is not recommended.

Topics: Administration, Oral; Adult; Amides; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cyclosporine; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Female; Fumarates; Half-Life; Humans; Male; Middle Aged; Organic Anion Transporters; Young Adult

To examine the relationships between baseline characteristics and urinary albumin excretion in the extensively phenotyped patients in the ALiskiren Observation of heart Failure Treatment (ALOFT) study.. Urinary albumin creatinine ratio (UACR) was available in 190 of 302 (63%) patients randomized in ALOFT. Of these, 107 (56%) had normal albumin excretion, 63 (33%) microalbuminuria, and 20 (11%) macroalbuminuria. Compared with patients with normoalbuminuria, those with microalbuminuria had a greater prevalence of diabetes (48 vs. 26%, P = 0.005) and a lower estimated glomerular filtration rate (eGFR) (60.7 vs. 68.3 mL/min/1.73 m(2), P = 0.01). Patients with macroalbuminuria had additional differences from those with a normal UACR, including younger age (63 vs. 69 years, P = 0.02), higher glycated haemoglobin (HbA1c; 7.9 vs. 6.2%, P < 0.001), and different echocardiographic findings. Of the non-diabetic patients, 28% had microalbuminuria and 7% had macroalbuminuria. Independent predictors of UACR in these patients included N-terminal pro B-type natriuretic peptide (NT-proBNP), HbA1c, and left ventricular diastolic dimension. Increased UACR was not associated with markers of inflammation or of renin angiotensin aldosterone system activation and was not reduced by aliskiren.. Increased UACR is common in patients with heart failure, including non-diabetics. Urinary albumin creatinine ratio is independently associated with HbA1c and NT-proBNP, even in non-diabetic patients.

Topics: Aged; Albumins; Albuminuria; Amides; Antihypertensive Agents; Confidence Intervals; Creatinine; Female; Fumarates; Glycated Hemoglobin; Heart Failure; Humans; Linear Models; Male; Middle Aged; Phenotype; Prognosis; Statistics as Topic; Stroke Volume; Surveys and Questionnaires; Ventricular Function, Left

We evaluated the influence of concomitant mineralocorticoid receptor antagonists (MRAs) on the safety and neurohumoral effects of a direct renin inhibitor in the ALiskiren Observation of Heart Failure Treatment (ALOFT) study.. Patients with stable New York Heart Association class II-IV heart failure (HF), plasma B-type natriuretic peptide (BNP) concentration >100 pg/mL, and treated with an angiotensin-converting enzyme inhibitor (or angiotensin receptor blocker) and β-blocker were randomized to once-daily, double-blind treatment with aliskiren 150 mg or placebo, added to optimal HF therapy, for 12 weeks. Safety, tolerability, and effects of aliskiren on neurohumoral biomarkers were assessed in patients who received (MRA+) and did not receive (MRA-) MRA treatment at baseline. Of the 302 randomized patients, 101 were receiving MRA treatment (aliskiren, n = 52; placebo, n = 49). Mineralocorticoid receptor antagonist status did not affect the ability of aliskiren 150 mg, added to standard HF therapy, to lower BNP, N-terminal proBNP, plasma renin activity, and urinary aldosterone. For example, the end-of-study to baseline ratio of geometric mean for BNP was: MRA+ group: aliskiren 0.68 [95% confidence interval (CI) 0.47, 0.98], placebo 0.85 (0.58, 1.24); MRA- group: aliskiren 0.62 (0.45, 0.84), placebo 0.85 (0.63, 1.15), interaction P= 0.720. The incidence of pre-specified adverse events (renal dysfunction, symptomatic hypotension, and hyperkalaemia) was low, and there were no significant differences between aliskiren and placebo in either MRA subgroup.. Aliskiren 150 mg added to standard HF therapy was well tolerated over 12 weeks and provided beneficial changes in neurohumoral biomarkers regardless of concomitant MRA treatment.

Topics: Adrenergic beta-Antagonists; Aged; Amides; Analysis of Variance; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Confidence Intervals; Female; Fumarates; Heart Failure; Humans; Male; Mineralocorticoid Receptor Antagonists; Natriuretic Peptide, Brain; Peptide Fragments; Statistics as Topic; Stroke Volume; Ventricular Function, Left

Recent guidelines for the management of hypertension recommend an individualised stepped-care treatment approach in mild-to-moderate hypertensive patients, to achieve blood pressure (BP) goals. This study evaluated the probability of patients achieving BP targets with an aliskiren-based stepped-care treatment regimen.. This was a 24-week, open-label, non-comparator study design that included six sequential 4-week treatment periods in patients with mild-to-moderate hypertension. Over the potential 24 weeks of active treatment, incremental therapy included the following add-on therapies at 4-week intervals: aliskiren 150-300 mg once daily, hydrochlorothiazide (HCTZ) 12.5-25 mg once daily, and finally amlodipine 5-10 mg once daily, as needed to achieve target BP. Subjects achieving BP targets following any given 4 weeks of therapy were considered study completers, while subjects not achieving their clinical BP target entered into the next step of incremental therapy. The primary efficacy end-point was the estimated cumulative probability of patients achieving BP target.. Of 256 patients treated, 232 (90.6%) completed the study. Baseline mean sitting BP was 155.7/91.7 mmHg. At study end-point, the estimated cumulative probability of reaching BP target was 86.12%. The stepped-care treatment regimen was well tolerated at the maximal recommended doses of all the individual complimentary therapies.. An aliskiren-based stepped-care treatment regimen that subsequently included both HCTZ and amlodipine is effective in achieving BP goals in approximately 90% of patients with mild-to-moderate hypertension.

Topics: Adult; Aged; Algorithms; Amides; Antihypertensive Agents; Biomarkers; Blood Pressure; Blood Pressure Determination; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Treatment Outcome

The aim of this study was to assess the effect of aliskiren and amlopidine on ankle-foot volume (AFV) and pretibial subcutaneous tissue pressure (PSTP).. After 4-week placebo, 120 outpatients with grade 1 - 2 hypertension were randomized to amlodipine 10 mg or aliskiren 300 mg or their combination for 8 weeks in three crossover periods. At the end of each treatment, blood pressure, AFV, PSTP, plasma renin activity (PRA) and norepinephrine were assessed.. Both monotherapies similarly reduced systolic blood pressure (SBP; p < 0.001) and diastolic blood pressure (DBP; p < 0.001), but the reduction was greater with amlodipine/aliskiren combination (SBP: - 24.6 mmHg, p < 0.001 vs monotherapy; DBP: -20.9 mmHg, p < 0.01 vs monotherapy). Amlodipine increased both AFV (+ 28.4%, p < 0.01) and PSTP (+ 80.4%, p < 0.01), while the combination produced a less marked increase in AFV (+ 6.6%, p < 0.01 vs amlodipine) and PSTP (+ 20.1%, p < 0.01 vs amlodipine). Plasma norepinephrine increased with amlodipine (+ 53.5%, p < 0.01) and this increase was not reduced by aliskiren addition. PRA was unaffected by amlodipine, while it was reduced by both aliskiren monotherapy (- 77.7%, p < 0.01) and aliskiren/amlodipine combination (- 75.7%, p < 0.01).. Direct renin inhibition by aliskiren partially counteracts the microcirculatory changes responsible for calcium-channel-induced edema formation, possibly through preferential vasodilation of venous capacitance vessels.

Topics: Amides; Amlodipine; Ankle; Ankle Joint; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cross-Over Studies; Drug Synergism; Drug Therapy, Combination; Edema; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Norepinephrine; Prospective Studies; Renin; Renin-Angiotensin System

Efficacy of antihypertensive agents on central blood pressure (BP) in African Americans is not well studied. The authors report on an 8-week double-blind, randomized study of African American patients with stage 2 hypertension that compared brachial and central BP responses (substudy of 53 patients) to combination aliskiren/hydrochlorthiazide (HCTZ) and amlodipine monotherapy. Following a 1- to 4-week washout, initial therapy was aliskiren/HCTZ 150/12.5 mg (n=166) or amlodipine 5 mg (n=166) for 1 week, forced-titrated to aliskiren/HCTZ 300/25 mg or amlodipine 10 mg for 7 weeks. Mean seated systolic BP reductions from baseline was similar with both treatments (-28.6 mm Hg with aliskiren/HCTZ vs -28.2 mm Hg with amlodipine). In the substudy, significantly greater reductions in central systolic BP was observed with aliskiren/HCTZ vs amlodipine (-30.1 mm Hg vs -21.2; P=.031), although 24-hour mean ambulatory BP reductions between the two groups were similar. Central pressure is considered an important risk factor in African Americans, and these findings may suggest a new treatment option for these patients.

Topics: Adult; Amides; Amlodipine; Antihypertensive Agents; Black or African American; Blood Pressure; Brachial Artery; Diarrhea; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Headache; Humans; Hydrochlorothiazide; Hypertension; Incidence; Male; Middle Aged; Prospective Studies; Severity of Illness Index; Treatment Outcome

High circulating aldosterone levels stimulate myocardial fibrosis and left ventricular hypertrophy (LVH). However, it is not clear whether suppression of aldosterone directly contributes to LVH regression in hypertensive patients.. The Aliskiren in Left Ventricular Hypertrophy (ALLAY) trial randomised 465 hypertensive overweight subjects with LVH to the direct renin inhibitor aliskiren 300 mg, losartan 100 mg or the combination and followed patients for 9 months. All patients were treated to standard blood pressure targets. Left ventricular (LV) mass index (LVMI) and LV wall thickness (LVWT) were assessed by cardiac magnetic resonance. A subset of 136 patients who had plasma aldosterone concentration (ALDO) measured at baseline and study end was analysed.. At baseline, plasma ALDO was modestly related to systolic blood pressure, LVMI, and wall thickness (all, p < 0.05). Aliskiren, either alone or in combination, was associated with a significantly greater reduction from baseline to 9 months in plasma aldosterone than losartan alone (p < 0.02). Reduction in ALDO was related to reduction in LVMI even after adjustment for baseline ALDO, BP reduction and treatment group (p for trend = 0.042).. In hypertensive patients with increased LVWT, aliskiren alone or in combination with the angiotensin receptor blocker losartan provides greater reduction in aldosterone compared to losartan alone. Moreover, suppression of aldosterone was associated with reduction of LVH, independently of the change in SBP, suggesting that suppression of aldosterone, a known mediator of LVH, may be particularly important for LVH regression and as a target for therapy.

Topics: Aldosterone; Amides; Antihypertensive Agents; Blood Pressure; Demography; Female; Fumarates; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Losartan; Male; Middle Aged; Organ Size; Systole

Initial multiple drug therapy for hypertension achieves greater and quicker reductions and higher blood pressure (BP) control rates than monotherapy. This 8-week, prospective, multicenter, randomized, double-blind study compared the efficacy and safety of the initial combination of aliskiren/amlodipine with amlodipine monotherapy in African Americans with stage 2 hypertension. After a 1- to 4-week washout, patients received aliskiren/amlodipine 150/5 mg or amlodipine 5 mg for 1 week and then were force-titrated to aliskiren/amlodipine 300/10 mg or amlodipine 10 mg for 7 weeks. At week 8, greater reductions in mean sitting systolic BP were obtained with aliskiren/amlodipine (n = 220) than with amlodipine (n = 223) (least squares mean change [standard error of the mean], -34.1 [1.14] mm Hg vs -28.9 [1.12] mm Hg; P<.001). Ambulatory and central BP measures were consistent with clinic BP findings, although these were conducted in a small subset of patients (n = 94 in ambulatory BP monitoring substudy and n = 136 for central BP). More patients achieved goal BP (<140/90 mm Hg) with aliskiren/amlodipine than with amlodipine at week 8 (57.3% vs 48.0%; P = .051). Both treatment groups had similar adverse event rates (35.0% and 32.7%, respectively). The most common adverse events were peripheral edema (7.7% with aliskiren/amlodipine and 9.0% with amlodipine), headache, fatigue, and nausea. The combination of aliskiren/amlodipine reduced peripheral, ambulatory, and central BP more than amlodipine alone with similar tolerability in African Americans with stage 2 hypertension.

Topics: Adult; Amides; Amlodipine; Black or African American; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Double-Blind Method; Drug Therapy, Combination; Edema; Fatigue; Female; Fumarates; Headache; Humans; Hypertension; Incidence; Male; Middle Aged; Prospective Studies; Severity of Illness Index; Treatment Outcome

Hypertension frequently coexists with diabetes mellitus, resulting in increased cardiovascular risk. Thus, BP control is crucial in decreasing morbidity and mortality in this difficult-to-treat patient population.. The objective of this study was to evaluate the efficacy and safety of aliskiren in hypertensive patients with diabetes not adequately responsive to the combination of valsartan and hydrochlorothiazide (HCT).. After a 1- to 4-week washout period, patients with a mean sitting diastolic BP (msDBP) ≥95 mmHg were treated with valsartan 160 mg for 2 weeks followed by valsartan/HCT 160 mg/25 mg for an additional 4 weeks (single-blind active run-in period). Patients whose msDBP remained ≥85 mmHg after the active run-in period were randomized (1 : 1) to receive aliskiren 150 mg (n = 184) or placebo (n = 179) as add-on therapy for 6 weeks. Aliskiren was then force-titrated to 300 mg once daily for another 6 weeks. Efficacy variables were: the change in msDBP and mean sitting systolic BP (msSBP) from baseline to week 12 endpoint, diastolic response (msDBP <80 mmHg or reduction of at least 10 mmHg), and BP control rate (<130/80 mmHg).. Of the 363 patients randomized, 328 (90.4%) completed the study (aliskiren and placebo groups: 89.7% and 91.1%, respectively). At week 12 endpoint, the least squares mean (LSM) changes in msDBP (aliskiren vs placebo: -5.8 vs -4.8 mmHg; p = 0.2767) and msSBP (aliskiren vs placebo: -7.3 vs -4.8 mmHg; p = 0.0725) were numerically greater in patients treated with aliskiren compared with those treated with placebo; however, this difference was not statistically significant. The proportion of diastolic responders (aliskiren and placebo: 68.5% and 72.9%, respectively; p = 0.8482) and patients achieving BP control (aliskiren and placebo: 16.0% and 16.4%, respectively; p = 0.7511) were similar for both groups. Overall, 63 (34%) and 59 (33%) patients in the aliskiren and placebo groups, respectively, experienced adverse events (AEs). The most commonly reported AEs were headache (placebo group: 6.1%) and dizziness (aliskiren group: 4.4%). Aliskiren was well tolerated.. The reductions in BP with aliskiren added to valsartan/HCT in this study were numerically greater compared with placebo added to valsartan/HCT, although not statistically significant.

Topics: Aged; Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Resistance; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Patient Dropouts; Potassium; Single-Blind Method

Activation of the renal renin-angiotensin system in patients with diabetes mellitus appears to contribute to the risk of nephropathy. Recently, it has been recognized than an elevation of prorenin in plasma also provides a strong indication of risk of nephropathy. This study was designed to examine renin-angiotensin system control mechanisms in the patient with diabetes mellitus.. We enrolled 43 individuals with type 2 diabetes mellitus. All individuals were on a high-salt diet to minimize the contribution of the systemic renin-angiotensin system. After an acute exposure to captopril (25 mg), they were randomized to treatment with either irbesartan (300 mg) or aliskiren (300 mg) for 2 weeks.. All agents acutely lowered blood pressure and plasma aldosterone, and increased renal plasma flow and glomerular filtration rate. Yet, only captopril and aliskiren acutely increased plasma renin and decreased plasma angiotensin II, whereas irbesartan acutely affected neither renin nor angiotensin II. Plasma renin and angiotensin II subsequently did increase upon chronic irbesartan treatment. When given on day 14, irbesartan and aliskiren again induced the above hemodynamic, renal and adrenal effects, yet without significantly changing plasma renin. Irbesartan at that time did not affect plasma angiotensin II, whereas aliskiren lowered it to almost zero.. The relative resistance of the renal renin response to acute (irbesartan) and chronic (irbesartan and aliskiren) renin-angiotensin system blockade supports the concept of an activated renal renin-angiotensin system in diabetes, particularly at the level of the juxtaglomerular cell, and implies that diabetic patients might require higher doses of renin-angiotensin system blockers to fully suppress the renal renin-angiotensin system.

Topics: Aldosterone; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Biphenyl Compounds; Blood Pressure; Captopril; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fumarates; Humans; Irbesartan; Kidney; Male; Middle Aged; Renin-Angiotensin System; Sodium Chloride, Dietary; Tetrazoles; Treatment Outcome

Most patients with hypertension will require combination therapy with at least two agents from different antihypertensive classes to achieve blood pressure (BP) control. Thiazide diuretics, such as hydrochlorothiazide (HCTZ), are widely used in combination therapy. The volume reduction with these agents stimulates the renin-angiotensin system (RAS), making RAS inhibitors such as the direct renin inhibitor aliskiren a logical choice for combination therapy with HCTZ.. The aim of this study was to investigate the long-term safety, tolerability and efficacy of the direct renin inhibitor aliskiren, with or without addition of the diuretic HCTZ.. In the 12-month core study, patients with hypertension (mean sitting diastolic BP ≥90 mmHg and <110 mmHg) were randomized in a 3 : 2 ratio to once-daily aliskiren 150 mg or 300 mg. At months 2, 3, 4, 6 and 9, treatment was adjusted in patients not achieving a BP goal of <140/90 mmHg. Patients not at goal on aliskiren 150 mg once daily were up-titrated to aliskiren 300 mg once daily. Patients not at goal with aliskiren 300 mg once daily received add-on HCTZ 12.5 mg once daily, which was up-titrated to 25 mg once daily if BP remained inadequately controlled. At month 12, patients who received aliskiren/HCTZ 300 mg/25 mg once daily for at least 8 months in the core study were eligible to enter a 4-month extension study.. Overall, 1625/1955 patients completed the core study, and 870/1955 patients received add-on HCTZ; 189/198 patients completed the 4-month extension. Aliskiren, with or without add-on HCTZ, was generally well tolerated; the incidence of adverse events (AEs) during the core study was similar among the four final treatment groups. The most frequently reported AEs in the core and extension studies were mild and transient cases of nasopharyngitis, headache and dizziness. Few patients exhibited laboratory abnormalities. Overall, aliskiren, with or without add-on HCTZ, reduced mean BP by 18.0/12.7 mmHg at core study endpoint, and 61.2% of patients achieved BP control. BP reductions with aliskiren/HCTZ 300 mg/25 mg combination therapy at the core study endpoint were maintained during the extension study.. In patients with hypertension, long-term treatment with aliskiren, with or without add-on HCTZ, is well tolerated and provides effective BP lowering that is sustained over 12 months.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure; Diuretics; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Renin-Angiotensin System; Time Factors; Young Adult

Patients with stage 2 hypertension and diabetes are at high cardiovascular risk and require large blood pressure (BP) reductions to reach treatment goals. This randomized double-blind study compared aliskiren/hydrochlorothiazide (HCTZ) combination therapy with amlodipine monotherapy in 860 patients with mean sitting systolic BP (msSBP) ≥160 mm Hg to <200 mm Hg and type 2 diabetes. Patients received either once-daily aliskiren/HCTZ 150/12.5 mg or amlodipine 5 mg for 1 week then force-titrated to double the doses for 7 weeks. Baseline BP was 167.7/91.4 mm Hg. At week 8 end point, aliskiren/HCTZ provided significantly greater reductions in msSBP than amlodipine (28.8 mm Hg vs 26.2 mm Hg; P<.05). Mean sitting diastolic BP reductions were similar with aliskiren/HCTZ (9.9 mm Hg) and amlodipine (9.0 mm Hg). Achievement of BP control (<130/80 mm Hg) was significantly greater with aliskiren/HCTZ (23.2%) than amlodipine (13.8%; P<.0001). Aliskiren/HCTZ provides substantial msSBP reductions and greater BP control rates than amlodipine, and offers an attractive treatment option for patients with hypertension and diabetes mellitus.

Topics: Amides; Amlodipine; Analysis of Variance; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Renin; Systole

Most patients inadvertently miss an occasional dose of antihypertensive therapy, and hence drugs that provide sustained blood-pressure (BP) reduction beyond the 24-h dosing interval are desirable. The primary objective of this study was to compare the 24-h mean ambulatory BP reductions from baseline after a simulated missed dose of the direct renin inhibitor aliskiren, irbesartan or ramipril. In this double-blind study, 654 hypertensive patients (24-h mean ambulatory diastolic BP (MADBP) >or=85 mm Hg) were randomized 1:1:1 to once-daily aliskiren 150 mg, irbesartan 150 mg or ramipril 5 mg. Doses were doubled after 2 weeks. At day 42, patients were again randomized equally within each group to receive 1 day of placebo ('missed dose') on either day 42 or day 49. Patients with a successful 24-h ambulatory BP measurement at baseline and on day 42/49 were included in the analyses. The 24-h mean ambulatory systolic BP (MASBP)/MADBP reductions from baseline after a missed dose of aliskiren 300 mg (9.3/7.0 mm Hg) were similar to irbesartan 300 mg (9.5/7.3 mm Hg) and significantly larger than ramipril 10 mg (7.1/5.0 mm Hg, P

Topics: Adult; Aged; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Brazil; Canada; Double-Blind Method; Drug Administration Schedule; Europe; Female; Fumarates; Humans; Hypertension; Irbesartan; Male; Medication Adherence; Middle Aged; Ramipril; Tetrazoles; Time Factors; Treatment Outcome

This 12-week, multicenter, open-label study assessed the efficacy, pharmacokinetics and safety of a once-daily aliskiren in Japanese hypertensive patients with renal dysfunction. Patients (n=40, aged 20-80 years) with mean sitting diastolic blood pressure (msDBP) >or=95 and <110 mm Hg and serum creatinine between >or=1.3 and <3.0 mg per 100 ml in males or between >or=1.2 and <3.0 mg per 100 ml in females were eligible. Patients began therapy with a once-daily morning oral dose of 75 mg of aliskiren. In patients with inadequate blood pressure control (msDBP >or=90 or mean sitting systolic blood pressure [msSBP] >or=140 mm Hg) and without safety concerns (serum potassium >5.5 mEq l(-1) or an increase in serum creatinine >or=20%), the aliskiren dose was increased to 150 mg and then to 300 mg in sequential steps starting from Week 2. Efficacy was assessed as change in msSBP/msDBP from baseline to the Week 8 endpoint (with the last observation carried forward). The mean reduction from baseline to Week 8 endpoint was 13.9+/-16.6 and 11.6+/-9.7 mm Hg for msSBP and msDBP, respectively. At the Week 8 endpoint, 65% patients had achieved blood pressure response (msDBP <90 or a 10 mm Hg decrease or msSBP <140 or a 20 mm Hg decrease) and 30% had achieved blood pressure control (msSBP <140 mm Hg and msDBP <90 mm Hg). Aliskiren was well tolerated with no new safety concerns in Japanese hypertensive patients with renal dysfunction.

Topics: Adult; Aged; Aged, 80 and over; Amides; Antihypertensive Agents; Blood Chemical Analysis; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Japan; Kidney Diseases; Male; Middle Aged; Renin; Renin-Angiotensin System; Risk Assessment; Young Adult

Efficacy and safety of the direct renin inhibitor aliskiren was compared with ramipril for treatment of essential systolic hypertension in elderly patients. A 36-week, randomized, double-blind, parallel-group, active-controlled, optional-titration study was performed in 901 patients (aliskiren, n=457; ramipril, n=444) > or =65 years of age with systolic blood pressure (SBP) > or =140 mm Hg. Aliskiren 150-300 mg per day or ramipril 5-10 mg per day for was administered for 12 weeks with optional add-on therapy of hydrochlorothiazide (12.5-25 mg per day) at week 12 and amlodipine (5-10 mg per day) at week 22. The primary end point was non-inferiority of aliskiren vs ramipril monotherapy for change from baseline in mean sitting SBP (msSBP) at week 12. Decreases from baseline msSBP and mean sitting diastolic BP with aliskiren monotherapy (-14.0 and -5.1 mm Hg, respectively) were non-inferior (P<0.001 for both values) and superior to ramipril monotherapy (-11.6, -3.6 mm Hg; P=0.02, P<0.01, respectively). More patients achieved BP control with aliskiren (42%) than ramipril (33%; P<0.01). At week 36, fewer patients receiving aliskiren-based therapy required add-on treatment with hydrochlorothiazide or amlodipine (P=0.01 and 0.048, respectively). Tolerability was similar, but more patients receiving ramipril reported cough (P<0.001). In elderly patients with systolic hypertension, aliskiren proved to be more effective and better overall anti-hypertensive therapy compared to ramipril.

Topics: Aged; Amides; Antihypertensive Agents; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Male; Ramipril; Renin; Treatment Outcome

This study aimed to investigate the effect of rifampicin, an inducer of CYP3A4 and P-glycoprotein, on the pharmacokinetics and pharmacodynamics of aliskiren, a renin inhibitor used in the treatment of hypertension.. In a randomized crossover study, 12 healthy volunteers took 600 mg rifampicin or placebo once daily for 5 days. On day 6, they ingested a single 150-mg dose of aliskiren. Plasma aliskiren concentrations were measured up to 72 h and urine concentrations up to 12 h; pharmacodynamic variables were measured up to 24 h.. Rifampicin reduced the peak plasma aliskiren concentration (C(max)) by 39% (95% confidence interval 0.41, 0.90; P = 0.017) and the area under the plasma aliskiren concentration-time curve AUC(0-infinity) by 56% (95% confidence interval 0.35, 0.56; P < 0.001). Rifampicin had no significant effect on aliskiren elimination half-life (t(1/2)) or its renal clearance (Cl(renal)). Plasma renin activity 24 h after aliskiren intake was 61% higher during the rifampicin phase than during the placebo phase (P = 0.008).. Rifampicin considerably reduces the plasma concentrations and the renin-inhibiting effect of aliskiren by decreasing its oral bioavailability.

Topics: Adult; Amides; Antihypertensive Agents; Blood Pressure; Cross-Over Studies; Drug Interactions; Enzyme Inhibitors; Female; Fumarates; Heart Rate; Humans; Male; Renin; Rifampin

Aliskiren is the first oral direct renin inhibitor to be approved for the treatment of hypertension. The pharmacokinetic and pharmacodynamic profile of aliskiren has been extensively characterized in Caucasian individuals; however, drug disposition, treatment response and tolerability can vary among ethnic groups, and these variations are difficult to predict.. To evaluate the single- and multiple-dose pharmacokinetics of aliskiren in healthy Chinese subjects.. This was a randomized, single-blind, parallel-group, placebo-controlled study. On day -1, subjects were randomized to one of four cohorts (aliskiren 75, 150, 300 or 600 mg). On day 1, eight individuals in each cohort received a single dose of active treatment and two received placebo. Subjects randomized to aliskiren 300 mg received additional once-daily doses on days 5-11 to establish steady-state pharmacokinetics. Subjects receiving aliskiren 75, 150 or 600 mg (cohorts 1, 2 and 4) completed the study at the end of the 96-hour pharmacokinetic assessment period. Subjects receiving aliskiren 300 mg (cohort 3) had additional pharmacokinetic assessments on days 5-15. The study was carried out at the Peking Union Medical College Hospital, Beijing, China, and included 40 healthy Chinese subjects. The main outcome measures were the pharmacokinetic parameters for aliskiren, including area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) and maximum plasma concentration (C(max)).. Aliskiren AUC(infinity) and C(max) increased greater than proportionally across the 8-fold dose range (75-600 mg; mean AUC(infinity) 291-4726 ng x h/mL, mean C(max) 62-699 ng/mL), but a dose-proportional 2-fold increase was observed within the clinically approved dose range (150-300 mg; mean AUC(infinity) 876-1507 ng x h/mL, mean C(max) 137-271 ng/mL).. At steady state, the mean AUC during the dosage interval (AUC(tau)) for aliskiren 300 mg (1532 +/- 592 ng x h/mL) was similar to the AUC(infinity) observed following a single dose. Aliskiren exhibits similar single-dose and steady-state pharmacokinetics in Chinese subjects compared with those observed in Caucasian individuals in previous studies.

Topics: Administration, Oral; Adult; Amides; Antihypertensive Agents; Area Under Curve; Asian People; China; Cohort Studies; Dose-Response Relationship, Drug; Female; Fumarates; Humans; Male; Renin; Single-Blind Method; Young Adult

Aliskiren is the first direct renin inhibitor approved for the treatment of hypertension. Blood pressure (BP) control in stage 2 hypertension with aliskiren monotherapy has not been reported. This was a post hoc analysis of the subgroup of patients with stage 2 systolic hypertension (baseline mean sitting systolic BP [msSBP]≥160 mmHg) who completed the 12-week monotherapy phase of a 6-month, double-blind, randomized study. A total of 175 patients were randomized to aliskiren 150 mg (n = 88) or ramipril 5 mg (n = 87) with optional up-titration to aliskiren 300 mg or ramipril 10 mg, respectively, at weeks 6 and 12. In the subgroup of patients with stage 2 systolic hypertension, aliskiren lowered msSBP and mean sitting diastolic BP (msDBP) by 22.3/12.7 mmHg from baseline to week 12; compared with a reduction of 18.1/10.2 mmHg with ramipril. The maximum BP reductions achieved with aliskiren were 60.0/34.0 mmHg (from a baseline of 172.7/107.3 mmHg). Aliskiren was noninferior (P < 0.0001) to ramipril for SBP reduction with nonsignificant superiority (P = 0.052), and superior (P = 0.043) to ramipril for DBP reduction. The proportion of patients who achieved BP control (<140/90 mmHg) after 12 weeks of monotherapy was larger with aliskiren (34/88, 38.6%) than with ramipril (22/87, 25.3%; P = 0.038). In this post hoc analysis, 12 weeks of monotherapy with aliskiren 150-300 mg provided effective mean BP reductions (22/13 mmHg) and was superior to ramipril 5-10 mg in controlling BP in patients with stage 2 systolic hypertension.

Topics: Adult; Aged; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Ramipril; Renin; Time Factors; Treatment Outcome

The optimal antiproteinuric dose of aliskiren is unknown. This study compared the effect of placebo and increasing doses of aliskiren on urinary albumin excretion rate (UAER).. The trial was a double-blind crossover design. Twenty-six patients with type 2 diabetes mellitus, hypertension and albuminuria were randomised to 2-month treatments with placebo or aliskiren 150 mg, 300 mg or 600 mg once daily, in random order. Primary endpoint was change in UAER; secondary endpoints included changes in 24-h BP, GFR, biomarkers and components of the renin-angiotensin-aldosterone system.. Placebo geometric mean UAER was 350 mg/day, mean 24-h BP was 137/81 (SD 12/9) mmHg, GFR was 85 (SD 26) ml min(-1) 1.73 m(-2). Aliskiren 150, 300 and 600 mg daily reduced UAER significantly by 36% (95% CI 17-51), 48% (33-60) and 52% (38-63) respectively (p < 0.001) compared with placebo. UAER reduction during the 600 mg dose was not significantly different from the 300 mg dose. Twenty-four-hour systolic BP was reduced by 4.5, 8.0 and 9.2 mmHg versus placebo, significant for 300 and 600 mg (p < or = 0.001). Twenty-four-hour diastolic BP was reduced by 3.0, 4.1 and 4.4 mmHg, significant versus placebo (p = 0.019, p = 0.001 and p < 0.001). GFR was reduced by 3.0, 5.1 and 6.5 ml min(-1) 1.73 m(-2). hsPRA was reduced by 63%, 70%, and 82% (p < 0.001 for all). Adverse events, most frequently dizziness and fatigue, occurred during all doses.. In patients with type 2 diabetes mellitus, hypertension and albuminuria there is no improved antiproteinuric effect when using 600 mg aliskiren daily compared with the maximal recommended antihypertensive dose of 300 mg.. Clinicaltrials.gov NCT00464776. Novartis Pharma AG.

Topics: Adult; Albuminuria; Amides; Antihypertensive Agents; Blood Pressure; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Fumarates; Humans; Hypertension; Renin

Elevated natriuretic peptides (NPs) are associated with an increased cardiovascular risk following acute coronary syndromes (ACSs). However, the therapeutic implications are still undefined. We hypothesized that early inhibition of renin-angiotensin-aldosterone system (RAAS) in patients with preserved left ventricular function but elevated NPs but following ACS would reduce haemodynamic stress as reflected by a greater reduction NP compared with placebo.. AVANT GARDE-TIMI 43 trial, a multinational, double-blind trial, randomized 1101 patients stabilized after ACS without clinical evidence of heart failure or left ventricular function

Topics: Acute Coronary Syndrome; Aged; Amides; Analysis of Variance; Angiotensin II Type 1 Receptor Blockers; Blood Pressure; Death, Sudden, Cardiac; Double-Blind Method; Female; Fumarates; Hospitalization; Humans; Male; Middle Aged; Myocardial Infarction; Natriuretic Peptide, Brain; Peptide Fragments; Renin; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan

In a randomized crossover study, 11 healthy volunteers ingested 200 ml of grapefruit juice or water three times a day for 5 days. On day 3, they ingested a single 150-mg dose of aliskiren. Grapefruit juice reduced aliskiren peak plasma concentration (C(max)) by 81% (range, 42-91%, P < 0.001), area under the plasma aliskiren concentration-time curve (AUC)(0-infinity) by 61% (range, 15-72%, P < 0.001), and elimination half-life (t(1/2)) from 26.1 to 23.6 h (P = 0.020). Therefore, concomitant use of aliskiren and grapefruit juice is best avoided.

Topics: Adult; Amides; Antihypertensive Agents; Area Under Curve; Beverages; Citrus paradisi; Cross-Over Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Female; Food-Drug Interactions; Fumarates; Half-Life; Humans; Male; Organic Anion Transporters; Renin; Young Adult

Proteinuric diabetic patients with reduced glomerular filtration rate (GFR) are at high risk of renal and cardiovascular disease progression and treatment-related adverse events. This post hoc analysis assessed the efficacy and safety of aliskiren added to the maximal recommended dose of losartan according to baseline estimated GFR (eGFR) (stage 1-3 chronic kidney disease [CKD]).. In the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study, 599 hypertensive patients with type 2 diabetes and nephropathy received 6 months of aliskiren (150 mg daily titrated to 300 mg daily after 3 months) or placebo added to 100 mg losartan and optimal antihypertensive therapy. Exclusion criteria included eGFR<30 ml/min per 1.73 m2 and serum potassium>5.1 mmol/l.. Baseline characteristics were similar between treatment groups in all CKD stages. The antiproteinuric effects of aliskiren were consistent across CKD stages (19, 22, and 18% reduction). In the stage 3 CKD group, baseline serum creatinine levels were equal, but renal dysfunction, prespecified as a postrandomization serum creatinine elevation>176.8 μmol/l (2.0 mg/dl) occurred more frequently in the placebo group (29.2 vs. 13.6%, P=0.032). Serum potassium elevations>5.5 mmol/l (based on a single measurement) were more frequent with aliskiren (22.5 vs. 13.6%) in stage 3 CKD. Adverse event rates were similar between treatments, irrespective of CKD stage.. Aliskiren added to losartan reduced albuminuria and renal dysfunction and was well tolerated, except for hyperkalemia (stage 3), independent of baseline CKD stage in patients with type 2 diabetes, hypertension, and nephropathy.

Topics: Aged; Albuminuria; Amides; Antihypertensive Agents; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Fumarates; Humans; Kidney Diseases; Kidney Function Tests; Losartan; Male; Middle Aged

The aim of this study was to compare the effect of aliskiren and losartan on fibrinolysis and insulin sensitivity (IS) in hypertensive patients with metabolic syndrome. After 2-week placebo period, 76 outpatients with mild to moderate hypertension and metabolic syndrome were randomized to aliskiren 300 mg od or losartan 100 mg od for 12 weeks. Clinic blood pressure (BP), plasma PAI-1 antigen, and tPA activity were evaluated after 2, 4, 8, and 12 weeks of treatment. At the end of each treatment period patients performed an euglycemic hyperinsulinemic clamp and IS was assessed by glucose infusion rate (GIR). Both aliskiren and losartan induced a significant and similar SBP/DBP reduction (-15.6/10.7 mmHg and -15.5/10.5 mmHg, p<0.001 vs. baseline, respectively). Both drugs decreased PAI-1 antigen and activity after 2 weeks of treatment; subsequently, only the decreasing effect of aliskiren was sustained throughout the 12 weeks [-7.5 ng/ml (-31%) p<0.05 vs. baseline], while with losartan PAI-1 increased at week 12 [+3.6 ng/ml (+15%), p<0.05 vs. baseline and p<0.01 vs. aliskiren)]. The tPA activity showed no significant change with aliskiren and a decrease with losartan [-0.04 IU/ml (-8%), p<0.05 vs. baseline and p<0.01 vs. aliskiren]. Aliskiren significantly increased GIR [+1.4 mg/min/kg (+28%), p<0.01 vs. baseline] while losartan did not change it [+0.2 mg/min/kg (+4%), NS vs. baseline, p<0.05 vs. aliskiren)]. These results indicated that in this type of patients, despite similar BP reduction, aliskiren improved the fibrinolytic balance as well as IS, while losartan worsened the fibrinolytic balance and did not affect IS. The clinical relevance of these different effects remains to be clarified.

Topics: Adolescent; Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure; Female; Fibrinolysis; Fumarates; Humans; Hypertension; Insulin; Losartan; Male; Metabolic Syndrome; Middle Aged; Young Adult

Dietary sodium reduction and, as necessary, pharmacologic treatment are recommended for hypertension management. This prospective, randomized, open-label, blinded-end point, multicenter, crossover study investigated the effect of dietary sodium intake on mean ambulatory systolic blood pressure (maSBP) in patients with hypertension receiving aliskiren 300 mg once daily. Following a 2- to 4-week washout period, patients were randomized to a high- (≥ 200 mmol/d) or low- (≤ 100 mmol/d) sodium diet and were started on aliskiren, 300 mg/d. After 4 weeks, patients were crossed over to the alternate diet for an additional 4 weeks. The primary efficacy variable was change in maSBP between diets. During treatment with aliskiren, maSBP was significantly lower with the low-sodium diet compared with the high-sodium diet (least squares mean difference, 9.4 mm Hg; 95% CI, 7.5-11.4; P < .0001). The percentage of patients achieving a maSBP response to aliskiren (<130 mm Hg or a ≥ 20-mm Hg reduction from baseline) was greater with the low- (76.5%) versus the high-sodium diet (42.6%; P < .0001). Overall, 40.9% patients had ≥ 1 adverse event and the rates were similar between groups. In this study, aliskiren was well tolerated and a low-sodium diet accentuated its antihypertensive effect.

Topics: Adult; Amides; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Cross-Over Studies; Diet, Sodium-Restricted; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Systole; Young Adult

To assess the long-term safety and antihypertensive efficacy of aliskiren/valsartan 300/320 mg combination.. This was a 54-week, multicenter, open-label study (core phase), followed by a 26-week extension phase. Efficacy variables were change in msDBP and msSBP from baseline to endpoint (54-week and 80-week). Safety was assessed by monitoring and recording adverse events (AEs). ClinicalTrials.gov Identifier: NCT00386607 RESULTS: A total of 601 patients (msDBP ≥ 90 and <110 mmHg) entered the 54-week core study. Optional add-on HCT was allowed at week 10 onwards if BP was ≥ 140/90 mmHg at two consecutive visits. Of the 486 patients completed the core study, 180 patients entered the extension phase and received aliskiren/valsartan and add-on HCT (12.5 or 25 mg). Overall the combination of aliskiren/valsartan was well-tolerated and the majority of AEs were mild-to-moderate in severity. The incidence of SAEs was low (core phase: n = 22 [3.7%]; extension phase: n = 4 [2.2%]). Elevated serum potassium (>5.5 mmol/L at any time during the study) was observed in 21 (3.6%) patients. The majority of these elevations were transient and returned to normal in subsequent visits, and the discontinuation rate due to elevated serum potassium was low (0.3% [n = 2]). Decreased serum potassium levels (<3.5 mmol/L at any time during the study) was observed in 26 (4.4%) patients, mainly in patients receiving aliskiren/valsartan/HCT (n = 22; 7.1%). At the 54-week endpoint, a mean BP reduction of 20.5/13.4 mmHg from baseline (baseline BP: 152.9/97.0 mmHg) was observed and 66.9% (n = 398/595) of patients achieved BP control with aliskiren/valsartan with or without HCT. At the end of the extension phase (80-week endpoint), additional reduction in BP was obtained (overall, 28.8/18.3 mmHg) and 86.6% (n = 155/179) of patients achieved BP control with aliskiren/valsartan/HCT. A limitation is the absence of an active comparator group.. Long-term treatment with the combination of aliskiren/valsartan with or without HCT provided clinically meaningful BP reductions and high rates of BP control and was well-tolerated.

Topics: Adult; Aged; Aged, 80 and over; Algorithms; Amides; Antihypertensive Agents; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Incidence; Male; Middle Aged; Tetrazoles; Time Factors; Treatment Outcome; Valine; Valsartan; Young Adult

Patients with stage 2 hypertension (systolic blood pressure [SBP] ≥160mm Hg and/or diastolic blood pressure [DBP] ≥100mm Hg) are at high cardiovascular risk and require intensive blood pressure (BP)-lowering therapy. This randomized double-blind study is the first prospective trial specifically designed to evaluate the direct renin inhibitor aliskiren in patients with a mean sitting SBP ≥160 mm Hg and <180mm Hg (the lower ranges of stage 2 systolic hypertension). After a 2- to 4-week washout period, 688 patients were randomized to once-daily aliskiren/hydrochlorothiazide (HCT) 150/12.5mg or aliskiren 150mg for 1 week and then double the doses for 11 weeks. Baseline BP was 167.1/95.0mm Hg. At week 12, both aliskiren/HCT and aliskiren provided substantial BP reductions from baseline (30.0/12.6 mm Hg and 20.3/8.2 mm Hg, respectively). Aliskiren/HCT lowered BP significantly more than aliskiren (least-squares mean between-treatment differences [95% confidence interval] were -9.7 [-12.0 to -7.4] for SBP and -4.5 [-5.8 to -3.2] for DBP; both P<.0001). Similar BP reductions were seen in the subgroups of patients with isolated systolic hypertension and obesity. Aliskiren, with or without HCT, provides clinically significant BP reductions and may therefore be an effective treatment option in patients with stage 2 hypertension.

Topics: Aged; Amides; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Severity of Illness Index; Treatment Outcome

Diuretics are recommended as first-line agents for the treatment of hypertension. This randomized, double-blind, multicenter study assessed the long-term efficacy and safety of the direct renin inhibitor aliskiren in comparison with the diuretic hydrochlorothiazide in patients with essential hypertension.. After a 2- to 4-week placebo run-in, 1124 patients (mean sitting diastolic blood pressure [BP] 95 to 109 mm Hg) were randomized to aliskiren 150 mg (n=459), hydrochlorothiazide 12.5 mg (n=444), or placebo (n=221) once daily. Forced titration (to aliskiren 300 mg or hydrochlorothiazide 25 mg) occurred at week 3; at week 6, patients receiving placebo were reassigned (1:1 ratio) to aliskiren 300 mg or hydrochlorothiazide 25 mg. From week 12, amlodipine 5 mg was added and titrated to 10 mg from week 18 for patients whose BP remained uncontrolled. Efficacy variables were analyzed for the intent-to-treat population with the use of the last observation carried forward method. BP reductions (mean sitting systolic BP/mean sitting diastolic BP) were significantly greater with aliskiren- versus hydrochlorothiazide-based treatment at week 26 (-20.3/-14.2 versus -18.6/-13.0 mm Hg; P<0.05) and were also greater at week 52 (-22.1/-16.0 versus -21.2/-15.0 mm Hg; P<0.05 for mean sitting diastolic BP). At the end of the monotherapy period (week 12), aliskiren 300 mg was superior to hydrochlorothiazide 25 mg in reducing BP (-17.4/-12.2 versus -14.7/-10.3 mm H; P<0.001). Adverse event rates were similar with aliskiren- (65.2%) and hydrochlorothiazide-based therapy (61.5%). Hypokalemia was more frequent with hydrochlorothiazide-based therapy than aliskiren-based therapy (17.9% versus 0.9%; P<0.0001).. Aliskiren treatment, both as monotherapy and with optional addition of amlodipine, provided significantly greater BP reductions than the respective hydrochlorothiazide regimens. Aliskiren-based therapy was well tolerated. Direct renin inhibition with aliskiren therefore represents an effective option for the long-term treatment of essential hypertension.

Topics: Administration, Oral; Adult; Aged; Amides; Antihypertensive Agents; Double-Blind Method; Dyspepsia; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Renin; Single-Blind Method; Time

Patients with type 2 diabetes are at increased risk of macro- and microvascular disease, and the presence of albuminuria and/or reduced kidney function further enhances macrovascular risk. Angiotensin-converting-enzyme inhibitors reduce both macro- and microvascular events, yet the residual renal and cardiovascular risk still remains high. Aliskiren a novel oral direct renin inhibitor that unlike ACEi and ARBs, lowers plasma renin activity, angiotensin I and angiotensin II levels, may thereby provide greater benefit compared to ACEi or ARB alone.. The primary objective of the ALTITUDE trial is to determine whether aliskiren 300 mg once daily, reduces cardiovascular and renal morbidity and mortality compared with placebo when added to conventional treatment (including ACEi or ARB). ALTITUDE is an international, randomized, double-blind, placebo-controlled, parallel-group study, which will include three categories of high-risk patients with type 2 diabetes (aged > or =35 years): those with either urinary albumin/creatinine ratio (UACR) > or =200 mg/g; microalbuminuria (UACR) > or =20 <200 mg/g and eGFR > or =30 <60 mL/min/1.73 m2; and thirdly, those with a history of cardiovascular disease and eGFR > or =30 <60 mL/min/1.73 m2 with or without microalbuminuria. ALTITUDE is an event driven trial that aims to randomize 8600 patients with a planned follow-up time of 48 months. The primary outcome measure is time to first event for the composite endpoint of cardiovascular death, resuscitated death, myocardial infarction, stroke, unplanned hospitalization for heart failure, onset of end-stage renal disease or doubling of baseline serum creatinine concentration. Secondary endpoints include a composite CV endpoint and a composite renal endpoint.. ALTITUDE will determine whether dual RAAS blockade with the direct renin inhibitor aliskiren in combination with an ACEi or ARB will reduce major morbidity and mortality in a broad range of high-risk patients with type 2 diabetes.

Topics: Adult; Aged; Aged, 80 and over; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Endpoint Determination; Female; Fumarates; Glomerular Filtration Rate; Humans; Kidney Diseases; Male; Middle Aged; Outcome Assessment, Health Care; Renin-Angiotensin System; Treatment Outcome

Left ventricular (LV) hypertrophy, a marker of cardiac end-organ damage, is associated with an increased risk of cardiovascular morbidity and mortality. Inhibitors of the renin-angiotensin-aldosterone system may reduce LV mass to a greater extent than other antihypertensive agents. We compared the effect of aliskiren, the first orally active direct renin inhibitor, the angiotensin-receptor blocker losartan, and their combination on the reduction of LV mass in hypertensive patients.. We randomized 465 patients with hypertension, increased ventricular wall thickness, and body mass index >25 kg/m(2) to receive aliskiren 300 mg, losartan 100 mg, or their combination daily for 9 months. Patients were treated to standard blood pressure targets with add-on therapy, excluding other inhibitors of the renin-angiotensin-aldosterone system and beta-blockers. Patients underwent cardiovascular magnetic resonance imaging for assessment of LV mass at baseline and at study completion. The primary objective was to compare change in LV mass index from baseline to follow-up in the combination and losartan arms; the secondary objective was to determine whether aliskiren was noninferior to losartan in reducing LV mass index from baseline to follow-up. Systolic and diastolic blood pressures were reduced similarly in all treatment groups (6.5+/-14.9/3.8+/-10.1 mm Hg in the aliskiren group; 5.5+/-15.6/3.7+/-10.7 mm Hg in the losartan group; 6.6+/-16.6/4.6+/-10.5 mm Hg in the combination arm; P<0.0001 within groups, P=0.81 between groups). LV mass index was reduced significantly from baseline in all treatment groups (4.9-, 4.8-, and 5.8 g/m(2) reductions in the aliskiren, losartan, and combination arms, respectively; P<0.0001 for all treatment groups). The reduction in LV mass index in the combination group was not significantly different from that with losartan alone (P=0.52). Aliskiren was as effective as losartan in reducing LV mass index (P<0.0001 for noninferiority). Safety and tolerability were similar across all treatment groups.. Aliskiren was as effective as losartan in promoting LV mass regression. Reduction in LV mass with the combination of aliskiren plus losartan was not significantly different from that with losartan monotherapy, independent of blood pressure lowering. These findings suggest that aliskiren was as effective as an angiotensin receptor blocker in attenuating this measure of myocardial end-organ damage in hypertensive patients with LV hypertrophy.

Topics: Aged; Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Echocardiography; Female; Fumarates; Humans; Hypertension; Hypertrophy, Left Ventricular; Losartan; Magnetic Resonance Imaging; Male; Middle Aged; Treatment Outcome

Thiazide diuretics such as hydrochlorothiazide (HCT) are a widely used first-line treatment for hypertension, but most patients will not achieve blood pressure (BP) control with HCT alone and so will require combination therapy. In this study the efficacy, safety and tolerability of a single-pill combination (SPC) of the direct renin inhibitor aliskiren with HCT were investigated in patients non-responsive to HCT 25 mg therapy.. In this study, 722 patients with hypertension and an inadequate response to 4 weeks of HCT 25 mg (mean sitting diastolic BP > or =90 and <110 mmHg) were randomized to once-daily, double-blind treatment for 8 weeks with an SPC of aliskiren/HCT 300/25 mg or 150/25 mg, or continued HCT 25 mg monotherapy. Least-squares mean changes in mean sitting systolic/diastolic BP (msSBP/DBP) from double-blind baseline were analyzed for the ITT population at week 8 endpoint.. Aliskiren/HCT 300/25 mg and 150/25 mg SPCs lowered msSBP/DBP from baseline by 16.7/10.7 and 12.9/8.5 mmHg, respectively, both significantly greater reductions than HCT 25 mg alone (7.1/4.8 mmHg; both p < 0.001). Rates of BP control (<140/90 mmHg) were also significantly higher with aliskiren/HCT 300/25 mg (58%) and 150/25 mg (49%) than with HCT (26%; both p < 0.001). Aliskiren/HCT 300/25 mg provided significantly greater msSBP/DBP reductions and rates of BP control than the 150/25 mg SPC dose (all p < 0.05). Aliskiren/HCT SPC treatment showed similar tolerability to HCT alone and a numerically lower incidence of hypokalemia (serum potassium <3.5 mmol/L; aliskiren/HCT, 1.3-2.2%: HCT alone, 3.4%).. Aliskiren/HCT SPCs provide clinically significant BP reductions and improved BP control rates in patients who are non-responsive to HCT 25 mg monotherapy. Limitations of the study were the mainly Caucasian patient population and the non-responder design.

Topics: Adult; Amides; Antihypertensive Agents; Blood Pressure; Double-Blind Method; Drug Therapy, Combination; Drug Tolerance; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Young Adult

Inhibition of renin, the first rate-limiting enzyme in the renin-angiotensin system, has long been a therapeutic goal for treatment of hypertension. Aliskiren, the first in a new class of oral direct renin inhibitors, has been shown to reduce blood pressure (BP) in several short-term studies. In this 52-week, open-label, multicenter, parallel-group study, the long-term safety, tolerability, and efficacy of aliskiren-based therapy were assessed in Japanese patients (N=345) with mild-to-moderate essential hypertension. The study had two periods: (i) an 8-week, dose-titration period and (ii) a 44-week, fixed-dose period with an optional addition of a diuretic or a calcium channel blocker (CCB). Safety was assessed by monitoring all adverse events (AEs), serious AEs (SAEs), vital signs, laboratory parameters, ECGs, and physical examinations. Efficacy was assessed by trough mean sitting BP and responder rate. Aliskiren alone or in combination with a diuretic or a CCB was well tolerated. No deaths were reported during this study. Nine SAEs were reported, and for three of these, a possible relation to the study drug could not be excluded. The overall incidence of AEs was 85.2%, and most of these were mild-to-moderate events such as nasopharyngitis. The incidence of suspected study drug-related AEs was 25.3%. A clinically meaningful reduction of 17.6/12.8 mm Hg from baseline was achieved in the mean sitting BP at the end point with aliskiren, irrespective of the dose and additional treatments. The overall responder rate was 73.3% at the end point. In conclusion, this first long-term study in Japanese patients showed the safety and efficacy of aliskiren-based therapy in mild-to-moderate essential hypertension.

Topics: Adult; Aged; Aged, 80 and over; Amides; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diuretics; Drug Therapy, Combination; Female; Fumarates; Heart Rate; Humans; Hypertension; Japan; Long-Term Care; Male; Middle Aged; Renin; Young Adult

To compare the long-term efficacy, safety and tolerability of the direct renin inhibitor aliskiren against the diuretic hydrochlorothiazide (HCTZ) in obese patients with hypertension.. A post hoc analysis of 396 obese patients (body mass index > or = 30 kg/m2) in a 52-week study in 1124 patients with hypertension was performed. Patients were randomized to receive aliskiren 150 mg or HCTZ 12.5 mg for 3 weeks, or placebo for 6 weeks. At week 3, active treatment doses were doubled. Patients receiving placebo were randomized to aliskiren 300 mg or HCTZ 25 mg at week 6. Add-on amlodipine 5-10 mg was permitted from week 12 to achieve blood pressure (BP) control (<140/90 mmHg).. In the subgroup of obese patients, aliskiren monotherapy provided significantly greater BP reductions than HCTZ at week 12 endpoint (-16.7/-12.3 vs. -12.2/-9.1 mmHg, P < or = 0.001). Reductions were also greater with aliskiren-based therapy than HCTZ-based therapy at week 52 endpoint (-19.9/-15.5 vs. -17.5/-13.3 mmHg; P = 0.138 for systolic BP and P = 0.007 for diastolic BP). Mean BP reductions from baseline with aliskiren-based therapy were similar in obese and nonobese patients. By contrast, HCTZ-based therapy provided significantly smaller mean reductions in BP from baseline in obese patients vs. nonobese patients (P < 0.05). Aliskiren-based therapy was generally well tolerated in obese patients, and was associated with a significantly lower incidence of hypokalemia (1.0 vs. 14.0%, P < 0.0001) than HCTZ-based therapy.. Aliskiren-based therapy provided superior BP reductions to HCTZ-based therapy with good tolerability in obese patients with hypertension.

Topics: Amides; Antihypertensive Agents; Double-Blind Method; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Obesity; Placebos

This study investigated the efficacy and safety of several different multi-drug regimens including aliskiren, valsartan, and hydrochlorothiazide (HCTZ) in patients not adequately responsive to HCTZ as monotherapy. After 4 weeks of HCTZ treatment, patients (N=641) whose diastolic blood pressure (DBP) was > or =95 mm Hg were treated for 8 weeks with either aliskiren/valsartan/HCTZ, aliskiren/HCTZ, valsartan/HCTZ, or HCTZ alone. The primary efficacy variable was change in DBP from baseline to week 8 end point. The aliskiren/valsartan/HCTZ combination produced statistically significant additional reductions in systolic blood pressure (SBP)/DBP when compared with other groups. At week 8 end point, reductions in SBP/DBP in the respective treatment groups were 22/16, 15/11, 18/14, or 6/6 mm Hg. Aliskiren/valsartan/HCTZ produced significantly better blood pressure control (SBP/DBP <140/90 mm Hg; 66.7%) compared with other treatment groups (20.5%-48.7%). The safety profile of aliskiren/valsartan/HCTZ was similar to the 2-drug combinations, with a greater blood pressure-lowering effect in patients who had not responded to HCTZ monotherapy.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan

Hypertensive patients with low-baseline plasma renin activity (PRA) are known to respond best to natriuretic drugs, and those with high PRA respond best to renin-angiotensin system (RAS) blockade. However, there has been recent speculation that blood pressure (BP)-lowering responses to the renin inhibitor, aliskiren, might also be blunted in some patients with medium-to-high baseline PRA. It has been suggested that treatment resistance in these patients may result from excessive reactive increases in renin secretion, such that aliskiren's blockade of PRA is overwhelmed. In order to test for evidence in support of this hypothesis, we conducted a reanalysis of original data from three published clinical trials of aliskiren. When aliskiren was administered as a monotherapy, or in combination with other blockers of the RAS, changes in PRA were closely correlated with baseline PRA. Patients with low-baseline PRA demonstrated small reductions or rises in PRA, rather than patients with medium-to-high baseline PRA. We confirmed that ambulatory BP-lowering responses to full dose aliskiren monotherapy were greatest and least among patients with high- and low-baseline PRA, respectively. However no such association was demonstrated during aliskiren combination therapy. With either monotherapy or combination therapy, no patient with a baseline PRA >0.65 ng/ml/h was observed to have a rise in both PRA and BP. We conclude, therefore, that there is only evidence for one type of resistance to aliskiren--as with all blockers of the RAS, lesser BP-lowering responses to aliskiren occur in those with the least renin to block.

Topics: Amides; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Irbesartan; Ramipril; Renin; Renin-Angiotensin System; Tetrazoles; Treatment Outcome

We investigated whether the antiproteinuric effect of the direct renin inhibitor aliskiren is comparable to that of irbesartan and the effect of the combination.. This was a double-blind, randomized, crossover trial. After a 1-month washout period, 26 patients with type 2 diabetes, hypertension, and albuminuria (>100 mg/day) were randomly assigned to four 2-month treatment periods in random order with placebo, 300 mg aliskiren once daily, 300 mg irbesartan once daily, or the combination using identical doses. Patients received furosemide in a stable dose throughout the study. The primary end point was a change in albuminuria. Secondary measures included change in 24-h blood pressure and glomerular filtration rate (GFR).. Placebo geometric mean albuminuria was 258 mg/day (range 84-2,361), mean +/- SD 24-h blood pressure was 140/73 +/- 15/8 mmHg, and GFR was 89 +/- 27 ml/min per 1.73 m(2). Aliskiren treatment reduced albuminuria by 48% (95% CI 27-62) compared with placebo (P < 0.001), not significantly different from the 58% (42-79) reduction with irbesartan treatment (P < 0.001 vs. placebo). Combination treatment reduced albuminuria by 71% (59-79), more than either monotherapy (P < 0.001 and P = 0.028). Fractional clearances of albumin were significantly reduced (46, 56, and 67% reduction vs. placebo). Twenty-four-hour blood pressure was reduced 3/4 mmHg by aliskiren (NS/P = 0.009), 12/5 mmHg by irbesartan (P < 0.001/P = 0.002), and 10/6 mmHg by the combination (P = 0.001/P < 0.001). GFR was significantly reduced 4.6 (95% CI 0.3-8.8) ml/min per 1.73 m(2) by aliskiren, 8.0 (3.6-12.3) ml/min per 1.73 m(2) by irbesartan, and 11.7 (7.4-15.9) ml/min per 1.73 m(2) by the combination.. The combination of aliskiren and irbesartan is more antiproteinuric in type 2 diabetic patients with albuminuria than monotherapy.

Topics: Aged; Albuminuria; Amides; Antihypertensive Agents; Biphenyl Compounds; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Irbesartan; Kidney; Male; Middle Aged; Tetrazoles; Treatment Outcome

This subgroup analysis assessed the effects of treatment based on the direct renin inhibitor, aliskiren, or the angiotensin-converting enzyme inhibitor, ramipril, on plasma renin activity (PRA), plasma renin concentration (PRC) and other biomarkers in a 26-week randomised, double-blind trial. Changes in PRA and PRC after stopping treatment were also assessed.. After placebo run-in, 842 patients (mean sitting diastolic blood pressure (BP) 95-109 mmHg) were randomised to aliskiren 150 mg or ramipril 5 mg. Dose titration and hydrochlorothiazide addition were allowed after Week 6 and 12, respectively, for inadequate BP control. Patients completing active treatment were re-randomised to current regimen or placebo during a 4-week posttreatment phase.. BP reductions were independent of baseline PRA at Week 12, were greater with aliskiren- than ramipril-based therapy at Week 26 (17.9/13.3 vs. 15.2/12.0 mmHg, p<0.05) and persisted for longer after stopping aliskiren. Aliskiren-based therapy reduced geometric mean PRA (-63%, p<0.05; n=103), while ramipril-based therapy increased PRA (+143%, p<0.05; n=100) at Week 26; PRC increased in both groups (aliskiren: +224% [n=33], ramipril: +145% [n=39], both p<0.05). Four weeks after stopping aliskiren-based therapy, PRA remained 52% below pre-treatment baseline; PRA returned to baseline 2 weeks after stopping ramipril-based therapy.. Aliskiren-based therapy produced sustained BP and PRA reductions over 26 weeks; ramipril-based therapy lowered BP and increased PRA. PRA reductions persisted 4 weeks after stopping aliskiren, suggesting an inhibitory effect beyond the elimination half-life of the drug.

Topics: Albuminuria; Amides; Antihypertensive Agents; Biomarkers; Blood Pressure; Creatinine; Demography; Diastole; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Ramipril; Renin; Renin-Angiotensin System; Systole; Time Factors

Aliskiren is approved for the treatment of hypertension at once-daily doses of 150 or 300 mg by the US Food and Drug Administration and the European Commission. It is generally well tolerated and provides 24-hour, dose-dependent blood pressure (BP) reduction; however, the effect of the 75-mg dose has been inconsistent in previous trials.. This study was designed to assess the efficacy and tolerability of once-daily administration of aliskiren 75 mg and to evaluate the dose-response relationship across all 3 doses of aliskiren (75, 150, and 300 mg).. In this 8-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled study, patients aged > or =18 years with stage 1 or 2 essential hypertension entered a 3- to 4-week, single-blind, placebo run-in period. Eligible patients were randomized (1:1:1:1) to receive oral, once-daily doses of aliskiren 75, 150, or 300 mg or placebo. The primary efficacy variable was the change from baseline in mean sitting diastolic BP (msDBP) at the week-8 end point. Tolerability was assessed by monitoring and recording all adverse events (AEs).. A total of 642 patients (mean [SD] age, 52.0 [10.73] years; 60.0% male; 80.8% white; mean body weight, 89.2 [18.4] kg [range, 50-160 kg]) were included in the study. Overall, 576 patients (89.7%) completed the double-blind treatment period. The most frequent reasons for discontinuation were unsatisfactory therapeutic effect (27/642 randomized patients [4.2%]) and AEs (17/642 [2.6%]). At end point, aliskiren 150 and 300 mg significantly reduced msDBP (both, P < 0.001) and mean sitting systolic. This study found a positive linear dose-response relationship in BP reduction with aliskiren 75, 150, and 300 mg dosed once daily, but only aliskiren 150 and 300 mg provided statistically significant reductions from baseline compared with placebo. All 3 doses of aliskiren were generally well tolerated.

Topics: Administration, Oral; Adult; Amides; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Europe; Female; Fumarates; Humans; Hypertension; Logistic Models; Male; Middle Aged; Placebo Effect; Renin; Severity of Illness Index; Time Factors; Treatment Outcome; United States

Diabetic nephropathy is the leading cause of end-stage renal disease in developed countries. We evaluated the renoprotective effects of dual blockade of the renin-angiotensin-aldosterone system by adding treatment with aliskiren, an oral direct renin inhibitor, to treatment with the maximal recommended dose of losartan (100 mg daily) and optimal antihypertensive therapy in patients who had hypertension and type 2 diabetes with nephropathy.. We enrolled 599 patients in this multinational, randomized, double-blind study. After a 3-month, open-label, run-in period during which patients received 100 mg of losartan daily, patients were randomly assigned to receive 6 months of treatment with aliskiren (150 mg daily for 3 months, followed by an increase in dosage to 300 mg daily for another 3 months) or placebo, in addition to losartan. The primary outcome was a reduction in the ratio of albumin to creatinine, as measured in an early-morning urine sample, at 6 months.. The baseline characteristics of the two groups were similar. Treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-to-creatinine ratio by 20% (95% confidence interval, 9 to 30; P<0.001), with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo (P<0.001). A small difference in blood pressure was seen between the treatment groups by the end of the study period (systolic, 2 mm Hg lower [P=0.07] and diastolic, 1 mm Hg lower [P=0.08] in the aliskiren group). The total numbers of adverse and serious adverse events were similar in the groups.. Aliskiren may have renoprotective effects that are independent of its blood-pressure-lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who are receiving the recommended renoprotective treatment. (ClinicalTrials.gov number, NCT00097955 [ClinicalTrials.gov].).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Albuminuria; Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Losartan; Male; Middle Aged; Multivariate Analysis; Proteinuria; Renin

To evaluate the dose-proportionality of the pharmacokinetics of aliskiren, the first in a new class of orally active direct renin inhibitors approved for the treatment of hypertension.. This was an open-label, single-center, single-dose, randomized, 4-period crossover study. Following a 21-day screening period, 32 healthy male or female subjects (ages 18 - 45 years) were randomized to 1 of 4 aliskiren dosing sequence groups (8 subjects per group): 75, 150, 300 and 600 mg. Blood samples were obtained for determination of plasma aliskiren concentrations (HPLC/MS/MS) for 96 h post dose. Log-transformed pharmacokinetic parameters AUC and C(max) were analyzed to determine dose-proportionality using the power model, parameter = A*(Dose)(beta), where A = intercept and beta = dose-proportionality coefficient. The predefined dose-proportionality criteria over the dose range 75 â 600 mg were 90% confidence intervals (CI) for beta contained within the range 0.89 - 1.11.. AUC and Cmax values increased with increasing doses of aliskiren. Both AUC and C(max) were associated with high variability (coefficient of variation 55 - 64% for AUC and 59 - 117% for C(max)). The estimated proportionality coefficients (beta) for AUC(0-infiniti), AUC(0-t) and C(max) were 1.18 (90% CI 1.10, 1.25), 1.29 (90% CI 1.22, 1.36) and 1.42 (90% CI 1.31, 1.52), respectively. Dose-proportionality was, therefore, not demonstrated across the entire 8-fold dose range. For the clinical dose range of 150 â 300 mg, increases of 2.3- and 2.6-fold were observed for AUC and C(max), respectively. All doses of aliskiren were well tolerated.. Exposure to aliskiren was greater than proportional over the dose range of 75 - 600 mg. Over the therapeutic dose range of 150 â 300 mg approved for the treatment of hypertension, AUC and Cmax increased by 2.3- and 2.6-fold, respectively. The pharmacokinetics of aliskiren show relatively high intersubject variability.

Topics: Administration, Oral; Adolescent; Adult; Amides; Antihypertensive Agents; Area Under Curve; Chromatography, High Pressure Liquid; Cross-Over Studies; Dose-Response Relationship, Drug; Female; Fumarates; Humans; Male; Mass Spectrometry; Middle Aged; Renin

Pharmacological interruption of the renin-angiotensin system focuses on optimization of blockade. As a measure of intrarenal renin activity, we have examined renal plasma flow (RPF) responses in a standardized protocol. Compared with responses with angiotensin-converting enzyme inhibition (rise in RPF approximately 95 mL x min(-1) x 1.73 m(-2)), greater renal vasodilation with angiotensin receptor blockers (approximately 145 mL x min(-1) x 1.73 m(-2)) suggested more effective blockade. We predicted that blockade with the direct oral renin inhibitor aliskiren would produce renal vascular responses exceeding those induced by angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.. Twenty healthy normotensive subjects were studied on a low-sodium (10 mmol/d) diet, receiving separate escalating doses of aliskiren. Six additional subjects received captopril 25 mg as a low-sodium comparison and also received aliskiren on a high-sodium (200 mmol/d) diet. RPF was measured by clearance of para-aminohippurate. Aliskiren induced a remarkable dose-related renal vasodilation in low-sodium balance. The RPF response was maximal at the 600-mg dose (197+/-27 mL x min(-1) x 1.73 m(-2)) and exceeded responses to captopril (92+/-20 mL x min(-1) x 1.73 m(-2); P<0.01). Furthermore, significant residual vasodilation was observed 48 hours after each dose (P<0.01). The RPF response on a high-sodium diet was also higher than expected (47+/-17 mL x min(-1) x 1.73 m(-2)). Plasma renin activity and angiotensin levels were reduced in a dose-related manner. As another functional index of the effect of aliskiren, we found significant natriuresis on both diets.. Renal vasodilation in healthy people with the potent renin inhibitor aliskiren exceeded responses seen previously with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. The effects were longer lasting and were associated with significant natriuresis. These results indicate that aliskiren may provide more complete and thus more effective blockade of the renin-angiotensin system.

Topics: Administration, Oral; Adult; Amides; Angiotensin I; Angiotensin II; Antihypertensive Agents; Blood Pressure; Captopril; Diet; Dose-Response Relationship, Drug; Female; Fumarates; Glomerular Filtration Rate; Humans; Male; Middle Aged; Natriuresis; Predictive Value of Tests; Reference Values; Renal Circulation; Renal Plasma Flow; Renin; Sodium; Sodium, Dietary; Vasodilation

Aliskiren is a direct renin inhibitor approved for the treatment of hypertension. This study investigated the effects of aliskiren on the pharmacokinetics and pharmacodynamics of a single dose of acenocoumarol in healthy volunteers.. This two-sequence, two-period, randomized, double-blind crossover study recruited 18 healthy subjects (ages 18-45) to receive either aliskiren 300 mg or placebo once daily on days 1-10 of each treatment period and a single dose of acenocoumarol 10 mg on day 8. Treatment periods were separated by a 10-day washout. Blood samples were taken frequently for determination of steady-state plasma concentrations of aliskiren (LC-MS/MS) and of R(+)- and S(-)-acenocoumarol (HPLC-UV), prothrombin time (PT) and international normalized ratio (INR).. Co-administration with aliskiren had no effect on exposure to R(+)-acenocoumarol. Geometric mean ratios (GMR; aliskiren:placebo co-administration) for R(+)-acenocoumarol AUC(0-t) and C(max) were 1.08 and 1.04, respectively, with 90% CI within the range 0.80-1.25. Co-administration of aliskiren resulted in a 19% increase in S(-)-acenocoumarol AUC(0-t) (GMR 1.19; 90% CI 0.92, 1.54) and a 9% increase in C(max) (GMR 1.09; 90% CI 0.88, 1.34). The anticoagulant effect of acenocoumarol was not affected by co-administration of aliskiren. Geometric mean ratios were 1.01 for all pharmacodynamic parameters (AUC(PT), PT(max), AUC(INR) and INR(max)), with 90% CI within the range 0.97-1.05.. Aliskiren has no clinically relevant effect on the pharmacokinetics or pharmacodynamic effects of a single dose of acenocoumarol in healthy volunteers, hence no dosage adjustment of acenocoumarol is likely to be required during co-administration with aliskiren.

Topics: Acenocoumarol; Administration, Oral; Amides; Anticoagulants; Area Under Curve; Chromatography, High Pressure Liquid; Cross-Over Studies; Double-Blind Method; Female; Fumarates; History, 16th Century; Humans; Male; Renin; Spectrophotometry, Ultraviolet

This study investigated the potential pharmacokinetic interaction between the direct renin inhibitor aliskiren and modulators of P-glycoprotein and cytochrome P450 3A4 (CYP3A4). Aliskiren stimulated in vitro P-glycoprotein ATPase activity in recombinant baculovirus-infected Sf9 cells with high affinity (K(m) 2.1 micromol/L) and was transported by organic anion-transporting peptide OATP2B1-expressing HEK293 cells with moderate affinity (K(m) 72 micromol/L). Three open-label, multiple-dose studies in healthy subjects investigated the pharmacokinetic interactions between aliskiren 300 mg and digoxin 0.25 mg (n = 22), atorvastatin 80 mg (n = 21), or ketoconazole 200 mg bid (n = 21). Coadministration with aliskiren resulted in changes of <30% in AUC(tau) and C(max,ss) of digoxin, atorvastatin, o-hydroxy-atorvastatin, and rho-hydroxy-atorvastatin, indicating no clinically significant interaction with P-glycoprotein or CYP3A4 substrates. Aliskiren AUC(tau) was significantly increased by coadministration with atorvastatin (by 47%, P < .001) or ketoconazole (by 76%, P < .001) through mechanisms most likely involving transporters such as P-glycoprotein and organic anion-transporting peptide and possibly through metabolic pathways such as CYP3A4 in the gut wall. These results indicate that aliskiren is a substrate for but not an inhibitor of P-glycoprotein. On the basis of the small changes in exposure to digoxin and atorvastatin and the <2-fold increase in exposure to aliskiren during coadministration with atorvastatin and ketoconazole, the authors conclude that the potential for clinically relevant drug interactions between aliskiren and these substrates and/or inhibitors of P-glycoprotein/CPY3A4/OATP is low.

Topics: Adult; Amides; Animals; Antifungal Agents; Atorvastatin; ATP Binding Cassette Transporter, Subfamily B, Member 1; Caco-2 Cells; Cell Line; Cytochrome P-450 CYP3A; Digoxin; Drug Interactions; Female; Fumarates; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ketoconazole; Male; Organic Anion Transporters; Pyrroles; Renin; Tissue Distribution; Young Adult

Aliskiren is the first in a new class of direct renin inhibitors to be approved for the treatment of hypertension.. In this double-blind, multicentre trial, 694 patients with hypertension (mean sitting diastolic blood pressure [BP] > or = 95 and < 110 mmHg) were randomised to once-daily aliskiren 150 mg (n=231), atenolol 50 mg (n=231) or the combination (150/50 mg; n=232) for six weeks, followed by a further six weeks on double the initial doses of aliskiren and atenolol. Efficacy (reduction from baseline in mean sitting systolic and diastolic BP) and tolerability of study treatments were assessed; plasma renin activity (PRA) was measured in a subset of patients.. At Week 12 endpoint, aliskiren, atenolol and aliskiren/atenolol lowered systolic and diastolic BP from baseline by 14.3/11.3, 14.3/13.7 and 17.3/14.1 mmHg, respectively. Systolic BP reductions with aliskiren/atenolol were significantly greater than those with aliskiren (p=0.039) or atenolol (p=0.034) alone, and diastolic BP reductions were greater than with aliskiren alone (p<0.001). Diastolic BP changes were larger with atenolol than with aliskiren (p=0.003, correlating with the large reductions in pulse rate (> 10 bpm) observed with atenolol. Aliskiren, atenolol and aliskiren/atenolol reduced geometric mean PRA from baseline by 65%, 52% and 61%, respectively. In patients with moderate or high baseline PRA (> or = 0.65 ng/ml/hour), PRA was reduced to low levels (< 0.65 ng/ml/hour) at Week 12 endpoint in a greater proportion of patients receiving aliskiren (11/15 patients, 73.3%) or aliskiren/atenolol (18/23, 78.3%) than with atenolol (10/21, 47.6%). Aliskiren treatment was associated with numerically lower rates of adverse events and discontinuations due to adverse events compared with atenolol or combination treatment, and unlike atenolol was not associated with bradycardia.. Direct renin inhibition with aliskiren may be an appropriate substitute for beta-blocker treatment in patients with uncomplicated hypertension. Aliskiren also represents an attractive option for dual therapy with atenolol to improve systolic BP/pulse pressure reductions and BP control with maintained tolerability compared with atenolol alone.

Topics: Aged; Aged, 80 and over; Amides; Antihypertensive Agents; Atenolol; Blood Pressure; Demography; Diastole; Drug Therapy, Combination; Endpoint Determination; Female; Fumarates; Heart Rate; Humans; Hypertension; Male; Renin; Renin-Angiotensin System; Systole

The vascular effects of aliskiren last longer than expected based on its half life, and this renin inhibitor has been reported to cause a greater renin rise than other renin-angiotensin system blockers. To investigate whether aliskiren accumulation in secretory granules contributes to these phenomena, renin-synthesizing mast cells were incubated with aliskiren, washed, and exposed to forskolin in medium without aliskiren (0.1 to 1000 nmol/L). (Pro)renin concentrations were measured by renin- and prorenin-specific immunoradiometric assays, and renin activity was measured by enzyme-kinetic assay. Without aliskiren, the culture medium predominantly contained prorenin, the cells exclusively stored renin, and forskolin doubled renin release. Aliskiren dose-dependently bound to (pro)renin in the medium and cell lysates and did not alter the effect of forskolin. The aliskiren concentrations required to bind prorenin were 1 to 2 orders of magnitude higher than those needed to bind renin. Blockade of cell lysate renin activity ranged from 27+/-15% to 79+/-5%, and these percentages were identical for the renin that was released by forskolin, indicating that they represented the same renin pool, ie, the renin storage granules. Comparison of renin and prorenin measurements in blood samples obtained from human volunteers treated with aliskiren, both before and after prorenin activation, revealed that

Topics: Amides; Angiotensin I; Antihypertensive Agents; Cell Line, Tumor; Colforsin; Culture Media; Dose-Response Relationship, Drug; Fumarates; Humans; Leukemia, Mast-Cell; Mast Cells; Renin; Secretory Vesicles

This study investigated the pharmacokinetics, safety, and tolerability of aliskiren administered alone or in combination with either the loop diuretic furosemide or an oral extended-release formulation of isosorbide-5-mononitrate (ISMN). In separate studies, 22 healthy subjects (ages 18-45 years) received either ISMN 40 mg or furosemide 20 mg once-daily for 3 days followed by a 3-day washout. Subjects then received aliskiren 300 mg once-daily for 7 days followed by combination therapy for 3 days. Pharmacokinetic assessments were taken at regular intervals over 24 h after dosing on the last day of each treatment period. At steady state, aliskiren AUC(tau) was decreased by 7% (geometric mean ratio [90% CI], 0.93 [0.84, 1.04]), and C(max) by 20% (0.80 [0.65, 0.97]) with furosemide coadministration compared with aliskiren administration alone. Aliskiren coadministration reduced furosemide AUC(tau) by 28% (0.72 [0.64, 0.81]) and C(max) by 49% (0.51 [0.39, 0.66]) compared with furosemide alone. Coadministration of aliskiren and ISMN was associated with only minor changes in the pharmacokinetic parameters of aliskiren (AUC(tau) 1.03 [0.90, 1.18]; C(max) 0.94 [0.69, 1.29]) and ISMN (AUC(tau) 0.88 [0.71, 1.10]; C(max) 0.94 [0.79, 1.13]). Headache and dizziness were the most common adverse events in both studies; dizziness and BP values below normal (SBP < 90 and/or DBP < 50 mmHg) were more frequent with aliskiren and ISMN coadministration than with either agent alone. Coadministration of aliskiren and ISMN had no clinically relevant effect on either aliskiren or ISMN pharmacokinetics. In conclusion, coadministration of aliskiren and furosemide reduced furosemide exposure and had a minor effect on aliskiren pharmacokinetics. The clinical significance of reduced systemic exposure to furosemide during coadministration of aliskiren is uncertain.

Topics: Adolescent; Adult; Amides; Area Under Curve; Blood Pressure; Cross-Over Studies; Delayed-Action Preparations; Diuretics; Drug Interactions; Female; Fumarates; Furosemide; Humans; Isosorbide Dinitrate; Male; Middle Aged; Renin; Vasodilator Agents; Young Adult

Patients with stage 2 hypertension require large absolute reductions in blood pressure (BP) to achieve recommended BP goals. Combination therapy with the direct renin inhibitor, aliskiren, and the angiotensin receptor blocker, valsartan, has been shown to produce greater BP reductions than either agent alone in a double-blind study in 1797 hypertensive patients.. This post-hoc analysis evaluated the BP-lowering efficacy of aliskiren in combination with valsartan in a subset of patients (n=581) with stage 2 hypertension (baseline mean sitting systolic BP [msSBP] > or =160 mmHg). Patients were randomized to receive aliskiren/valsartan 150/160 mg, aliskiren 150 mg, valsartan 160 mg, or placebo once daily for 4 weeks followed by 4 weeks at double the initial dose. Mean changes from baseline in msSBP and mean sitting diastolic BP were assessed at week-8 endpoint (intent-to-treat population).. Aliskiren/valsartan 300/320 mg reduced BP from baseline by 22.5/11.4 mmHg at week-8 endpoint. BP reductions with combination therapy were significantly greater than with aliskiren 300 mg (17.3/8.9 mmHg, P<0.05), valsartan 320 mg (15.5/8.3 mmHg, P<0.01), or with placebo (7.9/3.7 mmHg, P<0.0001). BP control rates (<140/90 mmHg) were also significantly higher (P<0.05) with aliskiren/valsartan 300/320 mg (29.8%) compared with either aliskiren 300 mg (19.0%) or valsartan 320 mg (13.8%) monotherapy, or placebo (8.9%). All treatments were generally well tolerated.. Combination therapy with aliskiren and valsartan provided significantly greater BP reductions over aliskiren or valsartan monotherapy and is an appropriate option for management of BP in patients with stage 2 hypertension.

Topics: Aged; Amides; Antihypertensive Agents; Blood Pressure; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Tetrazoles; Valine; Valsartan

To evaluate the efficacy, safety and tolerability of a single-pill combination of the direct renin inhibitor aliskiren and hydrochlorothiazide (HCT) in patients with hypertension and an inadequate BP response to aliskiren monotherapy (mean sitting diastolic BP [msDBP] > 90 and < or = 110 mmHg following 4 weeks of aliskiren 300 mg).. In this study, 880 patients with hypertension and an inadequate BP response to aliskiren monotherapy were randomized to once-daily, double-blind treatment with a single-pill combination of aliskiren/HCT 300/25 mg or 300/12.5 mg, or aliskiren 300 mg monotherapy. At the week 8 endpoint, least-squares mean changes in mean sitting systolic/diastolic BP (msSBP/DBP) from baseline were analyzed for the intent-to-treat population.. Aliskiren/HCT 300/25 mg and 300/12.5 mg provided significantly greater msSBP/DBP reductions from baseline (15.9/11.0 mmHg and 13.5/10.5 mmHg, respectively) than aliskiren 300 mg alone (8.0/7.4 mmHg; both p<0.001). Rates of BP control (<140/90 mmHg) were significantly higher with aliskiren/HCT 300/25 mg (60.2%) and 300/12.5 mg (57.9%) than with aliskiren 300 mg alone (40.9%; both p<0.001). Aliskiren/HCT single-pill combination treatment showed similar tolerability to aliskiren monotherapy.. Aliskiren/HCT single-pill combinations provide clinically significant additional BP reductions and improved BP control rates over aliskiren alone in patients who are non-responsive to aliskiren 300 mg monotherapy.

Topics: Adolescent; Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure; Diuretics; Double-Blind Method; Drug Combinations; Drug Resistance; Endpoint Determination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Treatment Outcome; Young Adult

Loss of negative feedback inhibition of renin release during chronic treatment with an angiotensin-converting enzyme (ACE) inhibitor leads to a compensatory rise in renin secretion and downstream components of the renin-angiotensin-aldosterone (RAAS) cascade. This may overcome ACE inhibition but should be blocked by a direct renin inhibitor. We studied the effects of adding the direct renin inhibitor aliskiren to an ACE inhibitor in patients with heart failure.. Patients with New York Heart Association class II to IV heart failure, current or past history of hypertension, and plasma brain natriuretic peptide (BNP) concentration >100 pg/mL who had been treated with an ACE inhibitor (or angiotensin receptor blocker) and beta-blocker were randomized to 3 months of treatment with placebo (n=146) or aliskiren 150 mg/d (n=156). The primary efficacy outcome was the between-treatment difference in N-terminal pro-BNP (NT-proBNP). Patients' mean age was 68 years, mean ejection fraction was 31%, and mean+/-SD systolic blood pressure was 129+/-17.4 mm Hg. Sixty-two percent of the patients were in New York Heart Association functional class II, and 33% were taking an aldosterone antagonist. Plasma NT-proBNP rose by 762+/-6123 pg/mL with placebo and fell by 244+/-2025 pg/mL with aliskiren (P=0.0106). BNP and urinary (but not plasma) aldosterone were also reduced by aliskiren. Clinically important differences in blood pressure and biochemistry were not seen between aliskiren and placebo.. Addition of aliskiren to an ACE inhibitor (or angiotensin receptor blocker) and beta-blocker had favorable neurohumoral effects in heart failure and appeared to be well tolerated.

Topics: Administration, Oral; Adrenergic beta-Antagonists; Aged; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Drug Therapy, Combination; Female; Fumarates; Heart Failure; Humans; Hypertension; Male; Natriuretic Peptide, Brain; Severity of Illness Index; Treatment Outcome

Aliskiren is the first in a new class of orally effective direct renin inhibitors approved for the treatment of hypertension. This multiple-dose study investigated the potential for pharmacokinetic interactions between aliskiren and three drugs, each predominantly eliminated by a different clearance/metabolic pathway: allopurinol (glomerular filtration), celecoxib (cytochrome P450 metabolism) and cimetidine (P-glycoprotein and organic anion/cation transporters).. Three open-label, multiple-dose studies in healthy subjects investigated possible pharmacokinetic interactions between aliskiren 300 mg od and allopurinol 300 mg od (n = 20), celecoxib 200 mg bid (n = 22), or cimetidine 800 mg od (n = 22). Subjects received aliskiren alone or co-administered with allopurinol, celecoxib or cimetidine. Allopurinol and celecoxib were also administered alone and in combination with aliskiren. Plasma drug concentrations were determined by LC/MS/MS.. Co-administration of aliskiren with allopurinol had no effect on allopurinol AUC(tau) (ratio of geometric means 0.93 [90% CI, 0.88, 0.98]) or oxypurinol AUC(tau) (mean ratio 1.12 [90% CI, 1.08, 1.16]) and C(max) (mean ratio 1.08 [90% CI, 1.04, 1.13]), with 90% CI within the bioequivalence range 0.80-1.25, and a minor effect on allopurinol C(max) (mean ratio 0.88 [90% CI, 0.78, 1.00]). Aliskiren co-administration had no effect on AUC(tau) or C(max) of celecoxib (mean ratios and 90% CI within range 0.80-1.25). Neither allopurinol nor celecoxib significantly altered aliskiren AUC(tau) or C(max) (geometric mean ratios 0.88-1.02 with 90% CI including 1.00, but with some 90% CI outside the 0.80-1.25 range due to high variability). Co-administration of aliskiren with cimetidine increased aliskiren AUC(tau) by 20% (mean ratio 1.20 [90% CI, 1.07, 1.34]) and C(max) by 25% (mean ratio 1.25 [90% CI, 0.98, 1.59]).. In this multiple-dose study, aliskiren showed no clinically relevant pharmacokinetic interactions when co-administered with allopurinol, celecoxib or cimetidine in healthy subjects.

Topics: Adolescent; Adult; Allopurinol; Amides; Antihypertensive Agents; Celecoxib; Cimetidine; Cyclooxygenase Inhibitors; Drug Interactions; Female; Fumarates; Gout Suppressants; Histamine H2 Antagonists; Humans; Hypertension; Male; Middle Aged; Pyrazoles; Reference Values; Renin; Sulfonamides

This double-blind study compared long-term efficacy, safety and tolerability of the oral direct renin inhibitor aliskiren and the angiotensin-converting enzyme inhibitor ramipril alone and combined with hydrochlorothiazide in patients with hypertension.. After a 2-4-week placebo run-in, 842 patients [mean sitting diastolic blood pressure (msDBP) 95-109 mmHg] were randomized to aliskiren 150 mg (n = 420) or ramipril 5 mg (n = 422). Dose titration (to aliskiren 300 mg/ramipril 10 mg) and subsequent hydrochlorothiazide addition (12.5 mg, titrated to 25 mg if required) were permitted at weeks 6, 12, 18 and 21 for inadequate blood pressure control. Patients completing the 26-week active-controlled treatment period were re-randomized to their existing regimen or placebo for a 4-week double-blind withdrawal phase.. Six hundred and eighty-seven patients (81.6%) completed the active treatment period. At week 26, aliskiren-based therapy produced greater mean reductions in mean sitting systolic blood pressure (17.9 versus 15.2 mmHg, P = 0.0036) and msDBP (13.2 versus 12.0 mmHg, P = 0.025), and higher rates of systolic blood pressure control (< 140 mmHg; 72.5 versus 64.1%, P = 0.0075) compared with ramipril-based therapy. During withdrawal, blood pressure increased more rapidly after stopping ramipril than aliskiren-based therapy; median blood pressure reached 140/90 mmHg after 1 and 4 weeks, respectively. Blood pressure reductions were maintained with continued active treatment. Aliskiren therapy was well tolerated. Overall adverse event rates were similar with aliskiren (61.3%) and ramipril (60.4%); cough was more frequent with ramipril (9.5%) than aliskiren (4.1%).. Aliskiren-based therapy was well tolerated and produced sustained blood pressure reductions in patients with hypertension over 6 months, greater than those with ramipril-based therapy.

Topics: Administration, Oral; Adult; Amides; Antihypertensive Agents; Blood Pressure; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Ramipril; Renin; Time Factors; Treatment Outcome

Inhibition of renin with an active site inhibitor, aliskiren, lowers blood pressure (BP) in diabetic patients. Here, we studied the time course of the antihypertensive and antiproteinuric effect of renin inhibition in 15 patients with type 2 diabetes and elevated urinary albumin/creatinine ratios (UACRs) to check whether aliskiren can decrease proteinuria. After a 4-week washout of previous medications, patients received aliskiren and furosemide daily for 28 days followed by a 4-week withdrawal period. Twenty-four-hour BPs were measured at baseline throughout treatment and withdrawal periods. The UACR was significantly reduced after 2-4 days of treatment with another significant reduction after 28 days. Systolic blood pressure (SBP) was significantly lower after 7 days with no further reduction after 28 days. The BP returned toward baseline 3 days after withdrawal, whereas the UACR was still significantly reduced compared with baseline 12 days after withdrawal. Our study shows that aliskiren reduced 24 h SBP, and this was associated with a reduction in albuminuria in type 2 diabetic patients.

Topics: Aged; Albuminuria; Amides; Antihypertensive Agents; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Female; Fumarates; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Renin; Treatment Outcome

This multicenter, double-blind study evaluated the effects of aliskiren, a direct renin inhibitor approved for hypertension, on cardiac repolarization and conduction. Healthy volunteers (n = 298) were randomized to aliskiren 300 mg, aliskiren 1200 mg, moxifloxacin 400 mg (positive control), or placebo once daily for 7 days. Digitized electrocardiograms were obtained at baseline and day 7 of treatment over 23 hours postdose. Placebo-adjusted mean changes from baseline in QTcF (Fridericia corrected), QTcI (individualized correction), PR, and QRS intervals were compared at each time point (time-matched analysis) and for values averaged across the dosing period (baseline-averaged analysis). In time-matched analysis, mean changes in QTcF with aliskiren were below predefined limits for QTc prolongation (mean increase <5 milliseconds; upper 90% confidence interval [CI] <10 milliseconds) except aliskiren 1200 mg at 23 hours (5.2 milliseconds; 90% CI 2.2, 8.1). With moxifloxacin, significant QTcF prolongation occurred at most time points, confirming the sensitivity of the assay. Baseline-averaged analysis was consistent with time-matched analysis. Instances of QTcF interval >450 milliseconds or a >30-millisecond increase from baseline with aliskiren (< or = 1%) were similar or lower than placebo (< or = 4%). Results were similar for QTcI. Aliskiren had no effect on PR or QRS duration. In conclusion, aliskiren at the highest approved dose (300 mg) and a 4-fold higher dose had no effect on cardiac repolarization or conduction in healthy volunteers.

Topics: Adult; Amides; Antihypertensive Agents; Aza Compounds; Double-Blind Method; Electrocardiography; Female; Fluoroquinolones; Fumarates; Humans; Male; Middle Aged; Moxifloxacin; Quinolines; Renin

Aliskiren is a novel, orally active renin inhibitor. Its antihypertensive efficacy and safety, alone and in combination with hydrochlorothiazide (HCTZ), were investigated in an 8-week, double-blind, placebo-controlled trial in hypertensive patients. The effects of these treatments on plasma renin activity (PRA) were also assessed.. A total of 2776 patients aged >or=18 years with mean sitting diastolic blood pressure (MSDBP) 95-109 mmHg were randomized to receive once-daily treatment with aliskiren (75, 150 or 300 mg), HCTZ (6.25, 12.5 or 25 mg), the combination of aliskiren and HCTZ, or placebo, in a factorial design. The primary endpoint was the change in MSDBP from baseline to week 8. PRA was assessed at these timepoints at selected study centers.. Aliskiren monotherapy was superior to placebo (P < 0.001; overall Dunnett's test) in reducing MSDBP and mean sitting systolic blood pressure (MSSBP). Combination treatment was superior to both component monotherapies in reducing BP (maximum MSSBP/MSDBP reduction of 21.2/14.3 mmHg from baseline with aliskiren/HCTZ 300/25 mg), and resulted in more responders (patients with MSDBP < 90 mmHg and/or >or=10 mmHg reduction) and better control rates (patients achieving MSSBP/MSDBP < 140/90 mmHg) than either monotherapy. Aliskiren monotherapy reduced PRA by up to 65% from baseline. Although HCTZ monotherapy increased PRA by up to 72%, PRA decreased in all of the combination therapy groups. All active treatments were well tolerated.. Aliskiren monotherapy demonstrated significant BP lowering, and its effect was considerably greater when combined with HCTZ. Renin inhibition with aliskiren neutralized the compensatory rise in PRA induced by HCTZ.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Least-Squares Analysis; Male; Middle Aged; Renin; Time Factors; Treatment Outcome

Thiazide diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers all cause reactive rises in plasma renin activity. We hypothesized that renin inhibition with aliskiren would prevent this reactive rise and also enhance blood pressure lowering. In 3 open-label studies in which blood pressure was assessed with ambulatory measurement, aliskiren was administered to patients with mild-to-moderate hypertension in combination with hydrochlorothiazide (n=23), ramipril (n=21), or irbesartan (n=23). In the diuretic combination study, the addition of 25 mg of hydrochlorothiazide to 150 mg of aliskiren daily for 3 weeks significantly lowered daytime pressure, compared with aliskiren monotherapy (systolic/diastolic mean change from baseline [SEM]: daytime: -18.4 [2.1]/ -10.6 [1.7] versus -10.4 [1.8]/-5.8 [1.4]; nighttime: -15.6 [2.7]/-8.1 [1.8] versus -8.8 [2.9]/-5.0 [2.2]). In the angiotensin-converting enzyme inhibitor combination study, the addition of 75 or 150 mg of aliskiren to 5 mg of ramipril alone for 3 weeks further lowered both daytime and nighttime pressures compared with ramipril monotherapy (daytime: -10.5 [2.9]/-8.1 [2.1] and -14 [3.7]/-8.7 [2.3] versus -6.1 [2.4]/-5.9 [1.5]; nighttime: -8.1 [2.6]/-5.3 [2.4] and -9.6 [3.4]/-5.3 [2.4] versus -2 [2.3]/-0.7 [2.2]). In the angiotensin receptor blocker combination study, the addition of 75 or 150 mg of aliskiren to 150 mg of irbesartan alone, for 3 weeks, resulted in significantly lower nighttime pressures compared with irbesartan monotherapy (daytime: -14.8 [2]/-8.2 [1.3] and -13.3 [1.6]/-6.8 [0.9] versus -11.4 [1.6]/-6.5 [1.1]; nighttime: -16.1 [2.4]/-8.6 [1.7] and -13.2 [2.7]/-7.2 [1.9] versus -9.0 [2.5]/-4.7 [1.9]). Aliskiren (150 mg) alone significantly inhibited plasma renin activity by 65% (P<0.0001). Ramipril and irbesartan monotherapy caused 90% and 175% increases in plasma renin activity, respectively. By contrast, when aliskiren was coadministered with hydrochlorothiazide, ramipril, or irbesartan, plasma renin activity did not increase but remained similar to baseline levels or was decreased (combination therapy versus untreated; median [interquartile range]; aliskiren and hydrochlorothiazide: 0.4 [0.2 to 1.1] versus 0.7 [0.5 to 1.3]; ramipril and aliskiren: 0.5 [0.3 to 0.9] versus 0.6 [0.5 to 0.8]; irbesartan and aliskiren: 0.4 [0.2 to 0.9] versus 0.6 [0.4 to 0.9]). These results suggest that renin inhibition with aliskiren in these combinations increases renin-angi

Topics: Adult; Aged; Aged, 80 and over; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Irbesartan; Male; Middle Aged; Patient Compliance; Ramipril; Renin; Sodium Chloride Symporter Inhibitors; Tetrazoles

By blocking the renin-angiotensin-aldosterone system (RAAS) at its rate-limiting step, renin inhibition may provide improved RAAS suppression. We investigated the blood pressure (BP)-lowering effects of the oral direct renin inhibitor aliskiren, alone or in combination with the angiotensin receptor blocker valsartan.. In this multicenter, randomized, placebo-controlled, 8-week trial, 1123 patients with mild-to-moderate hypertension underwent a 3 to 4 week single-blind placebo run-in and were then randomized in a modified factorial study design to receive once-daily, double-blind oral treatment with placebo, aliskiren monotherapy (75, 150, or 300 mg), valsartan monotherapy (80, 160, or 320 mg), aliskiren and valsartan in combination, or valsartan/hydrochlorothiazide (160/12.5 mg). The primary efficacy variable was the change from baseline in mean sitting diastolic BP (DBP) at endpoint.. Once-daily oral treatment with aliskiren 300 mg significantly (P < .0001) lowered mean sitting DBP and systolic BP (SBP) compared with placebo; aliskiren monotherapy demonstrated a safety and tolerability profile comparable to placebo. Changes in DBP and SBP were fitted to a first-order dose-response surface (lack-of-fit test, P = .65), which showed that aliskiren and valsartan alone and in combination produced dose-related reductions in DBP and SBP. Coadministration of aliskiren and valsartan produced a greater antihypertensive effect than either drug alone, comparable in magnitude to the effect of valsartan/hydrochlorothiazide, with similar tolerability to the component monotherapies and to placebo.. Aliskiren monotherapy provides antihypertensive efficacy and placebo-like tolerability in patients with hypertension. Aliskiren and valsartan in combination may provide additive BP-lowering effects with maintained tolerability.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Tetrazoles; Valine; Valsartan

Aliskiren is the first in a new class of orally active, direct renin inhibitors for the treatment of hypertension. This open-label, nonrandomized, single-center, parallel-group study compared the pharmacokinetics and safety of a single 300-mg oral dose of aliskiren in patients with mild, moderate, or severe hepatic impairment to that in healthy subjects. When pooled across subgroups, there were no significant differences between patients with hepatic impairment and healthy subjects in aliskiren AUC(0-infinity) (ratio of geometric means, 1.12; 90% confidence interval, 0.85, 1.48) or Cmax (mean ratio, 1.19; 90% confidence interval, 0.84, 1.68), and there was no correlation between severity of hepatic impairment and either AUC(0-infinity) or Cmax. Aliskiren was well tolerated by healthy subjects and patients with hepatic impairment. In conclusion, hepatic impairment has no significant effect on the pharmacokinetics of aliskiren following single-dose administration, and dosage adjustment is unlikely to be needed in patients with liver disease.

Topics: Amides; Antihypertensive Agents; Fumarates; Humans; Liver Diseases; Renin

Current guidelines from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommend first-line treatment with a thiazide diuretic but do not provide specific guidance for obese patients. The renin system is activated in obesity-associated arterial hypertension. Therefore, we tested the hypothesis that the oral direct renin inhibitor aliskiren could provide additive blood pressure lowering in obese patients with hypertension (body mass index >or=30 kg/m(2); mean sitting diastolic blood pressure: 95 to 109 mm Hg) who had not responded to 4 weeks of treatment with hydrochlorothiazide (HCTZ) 25 mg. After a 2- to 4-week washout, 560 patients received single-blind HCTZ (25 mg) for 4 weeks; 489 nonresponders were randomly assigned to double-blind aliskiren (150 mg), irbesartan (150 mg), amlodipine (5 mg), or placebo for 4 weeks added to HCTZ (25 mg), followed by 8 weeks on double the initial doses of aliskiren, irbesartan, or amlodipine. After 8 weeks of double-blind treatment (4 weeks on the higher dose), aliskiren/HCTZ lowered blood pressure by 15.8/11.9 mm Hg, significantly more (P<0.0001) than placebo/HCTZ (8.6/7.9 mm Hg). Aliskiren/HCTZ provided blood pressure reductions similar to those with irbesartan/HCTZ and amlodipine/HCTZ (15.4/11.3 and 13.6/10.3 mm Hg, respectively), with similar tolerability to placebo/HCTZ. Adverse event rates were highest with amlodipine/HCTZ because of a higher incidence of peripheral edema (11.1% versus 0.8% to 1.6% in other groups). In conclusion, combination treatment with aliskiren is a highly effective and well-tolerated therapeutic option for obese patients with hypertension who fail to achieve blood pressure control with first-line thiazide diuretic treatment.

Topics: Administration, Oral; Adult; Aged; Amides; Amlodipine; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Diastole; Double-Blind Method; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Irbesartan; Male; Middle Aged; Obesity; Renin; Systole; Tetrazoles; Treatment Outcome

This dose-ranging study evaluated the antihypertensive efficacy and tolerability of aliskiren in patients with mild-to-moderate hypertension.. Low blood pressure (BP) control rates among patients with hypertension indicate a need for improved treatment options. This study investigates aliskiren, the first in a new antihypertensive class called renin inhibitors.. Patients with mean sitting diastolic BP 95 to 109 mm Hg were randomized to aliskiren 150, 300, or 600 mg or placebo once daily for 8 weeks. Patients completing this treatment phase entered a 2-week treatment-free withdrawal period. Office BP was recorded at baseline, weeks 2, 4, 6, and 8 of treatment, and 4 days and 2 weeks after cessation of treatment. A subgroup of patients underwent ambulatory BP monitoring.. In total, 672 patients were randomized to treatment. After 8 weeks, aliskiren 150, 300, and 600 mg significantly reduced mean sitting BP (systolic/diastolic) by 13.0/10.3, 14.7/11.1, and 15.8/12.5 mm Hg, respectively, versus 3.8/4.9 mm Hg with placebo (all p < 0.0001 for systolic and diastolic BP). The BP-lowering effect of aliskiren persisted for up to 2 weeks after treatment withdrawal. Aliskiren significantly reduced mean 24-h ambulatory BP (p < 0.0001 vs. placebo with all doses) exhibiting smooth, sustained effects and high trough-to-peak ratios. Aliskiren was well tolerated; overall adverse event rates were 40.1%, 46.7%, and 52.4% with aliskiren 150, 300, and 600 mg, respectively, and 43.0% with placebo. Few patients discontinued treatment due to adverse events.. Aliskiren provides significant antihypertensive efficacy in patients with hypertension, with no rebound effects on blood pressure after treatment withdrawal.

Topics: Administration, Oral; Aged; Amides; Blood Pressure Determination; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Fumarates; Humans; Hypertension; Male; Maximum Tolerated Dose; Middle Aged; Multivariate Analysis; Probability; Reference Values; Renin; Risk Assessment; Severity of Illness Index; Treatment Outcome

This open-label, multicenter study compared the pharmacokinetics and safety of the oral direct renin inhibitor aliskiren in 29 elderly (>or=65 years) and 28 young (18-45 years) healthy subjects. Plasma drug concentrations were determined for up to 168 hours following a single 300-mg oral dose of aliskiren. In elderly compared with young subjects, AUC(0-infinity) was 57% higher (ratio of geometric means 1.57, 90% confidence interval: 1.19, 2.06; P = .008) and C(max) was 28% higher (1.28, 90% confidence interval: 0.91, 1.79; P=.233). Other parameters, including t(max) and Vd/F, were similar between age groups. No differences in aliskiren exposure were observed between subjects ages 65 to 74 years (n=16) and >or=75 years (n=13). Aliskiren was well tolerated by all age groups, including the very elderly. In conclusion, aliskiren exposure is modestly increased in elderly subjects. Based on its wide therapeutic index and shallow dose response for blood pressure lowering, no initial dose adjustment should be needed for elderly patients.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Amides; Area Under Curve; Female; Fumarates; Glomerular Filtration Rate; Half-Life; Humans; Male; Metabolic Clearance Rate; Middle Aged; Renin

Aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamid hemifumarate) is the first in a new class of orally active, nonpeptide direct renin inhibitors developed for the treatment of hypertension. The absorption, distribution, metabolism, and excretion of [(14)C]aliskiren were investigated in four healthy male subjects after administration of a single 300-mg oral dose in an aqueous solution. Plasma radioactivity and aliskiren concentration measurements and complete urine and feces collections were made for 168 h postdose. Peak plasma levels of aliskiren (C(max)) were achieved between 2 and 5 h postdose. Unchanged aliskiren represented the principal circulating species in plasma, accounting for 81% of total plasma radioactivity (AUC(0-infinity)), and indicating very low exposure to metabolites. Terminal half-lives for radioactivity and aliskiren in plasma were 49 h and 44 h, respectively. Dose recovery over 168 h was nearly complete (91.5% of dose); excretion occurred almost completely via the fecal route (90.9%), with only 0.6% recovered in the urine. Unabsorbed drug accounted for a large dose proportion recovered in feces in unchanged form. Based on results from this and from previous studies, the absorbed fraction of aliskiren can be estimated to approximately 5% of dose. The absorbed dose was partly eliminated unchanged via the hepatobiliary route. Oxidized metabolites in excreta accounted for at least 1.3% of the radioactive dose. The major metabolic pathways for aliskiren were O-demethylation at the phenyl-propoxy side chain or 3-methoxy-propoxy group, with further oxidation to the carboxylic acid derivative.

Topics: Adult; Amides; Antihypertensive Agents; Area Under Curve; Biotransformation; Feces; Fumarates; Humans; Intestinal Absorption; Male; Middle Aged; Molecular Structure; Renin; Spectrometry, Mass, Electrospray Ionization; Tissue Distribution; Urine

Patients with severe hypertension (>180/110 mm Hg) require large blood pressure (BP) reductions to reach recommended treatment goals (<140/90 mm Hg) and usually require combination therapy to do so. This 8-week, multicenter, randomized, double-blind, parallel-group study compared the tolerability and antihypertensive efficacy of the novel direct renin inhibitor aliskiren with the angiotensin converting enzyme inhibitor lisinopril in patients with severe hypertension (mean sitting diastolic blood pressure (msDBP)>or=105 mm Hg and <120 mm Hg). In all, 183 patients were randomized (2:1) to aliskiren 150 mg (n=125) or lisinopril 20 mg (n=58) with dose titration (to aliskiren 300 mg or lisinopril 40 mg) and subsequent addition of hydrochlorothiazide (HCTZ) if additional BP control was required. Aliskiren-based treatment (ALI) was similar to lisinopril-based treatment (LIS) with respect to the proportion of patients reporting an adverse event (AE; ALI 32.8%; LIS 29.3%) or discontinuing treatment due to AEs (ALI 3.2%; LIS 3.4%). The most frequently reported AEs in both groups were headache, nasopharyngitis and dizziness. At end point, ALI showed similar mean reductions from baseline to LIS in msDBP (ALI -18.5 mm Hg vs LIS -20.1 mm Hg; mean treatment difference 1.7 mm Hg (95% confidence interval (CI) -1.0, 4.4)) and mean sitting systolic blood pressure (ALI -20.0 mm Hg vs LIS -22.3 mm Hg; mean treatment difference 2.8 mm Hg (95% CI -1.7, 7.4)). Responder rates (msDBP<90 mm Hg and/or reduction from baseline>or=10 mm Hg) were 81.5% with ALI and 87.9% with LIS. Approximately half of patients required the addition of HCTZ to achieve BP control (ALI 53.6%; LIS 44.8%). In conclusion, ALI alone, or in combination with HCTZ, exhibits similar tolerability and antihypertensive efficacy to LIS alone, or in combination with HCTZ, in patients with severe hypertension.

Topics: Aged; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Lisinopril; Male; Middle Aged; Renin; Renin-Angiotensin System; Treatment Outcome

Aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension.. In 569 patients with mild-to-moderate hypertension, blood pressure (BP), plasma renin activity (PRA) and plasma renin concentration (PRC) were measured before and after 8 weeks of double-blind treatment with once-daily oral doses of aliskiren (150, 300 or 600 mg), irbesartan 150 mg or placebo.. Aliskiren 150, 300 and 600 mg and irbesartan 150 mg significantly reduced mean cuff sitting systolic BP (SBP) from baseline (p < 0.001 vs. placebo). Aliskiren 150, 300 and 600 mg significantly reduced geometric mean PRA by 69%, 71% and 75% from baseline respectively (p < 0.05 vs. placebo). Irbesartan 150 mg significantly increased PRA by 109% (p < 0.05 vs. placebo). Aliskiren dose-dependently increased PRC from baseline by 157%, 246% and 497%, at 150, 300 and 600 mg respectively, compared with a 9% decrease with placebo (p < 0.05). PRC increased significantly more with aliskiren 300 and 600 mg compared with irbesartan 150 mg (105%; p < 0.05). Regression analysis showed no significant correlations between baseline PRA and changes in SBP in any of the treatment groups, but interestingly, the slopes of the regression lines between changes in SBP and log-transformed baseline PRA were +2.0 for placebo and -1.5, -1.8 and -2.3 for aliskiren 150, 300 and 600 mg respectively. The slope for irbesartan 150 mg (-1.4) was similar to that for aliskiren 150 mg.. Aliskiren reduces SBP and PRA and increases PRC dose-dependently. In contrast, irbesartan reduces SBP but increases both PRC and PRA. As PRA is a measurement of angiotensin I-generating capacity, PRA can be used for measuring the ability of an antihypertensive agent to prevent the generation or action of Ang II, either directly (renin inhibitors, beta-blockers, central alpha(2)-agonists) or indirectly (AT(1)-receptor blockers, ACE inhibitors).

Topics: Administration, Oral; Adult; Amides; Antihypertensive Agents; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Renin

The aim of this study was to assess dual renin system intervention with the maximum recommended doses of aliskiren and valsartan, compared with each drug alone in patients with hypertension.. In this double-blind study, 1797 patients with hypertension (mean sitting diastolic blood pressure 95-109 mm Hg and 8-h daytime ambulatory diastolic blood pressure > or =90 mm Hg) were randomly assigned to receive once-daily aliskiren 150 mg (n=437), valsartan 160 mg (455), a combination of aliskiren 150 mg and valsartan 160 mg (446), or placebo (459) for 4 weeks, followed by forced titration to double the dose to the maximum recommended dose for another 4 weeks. The primary endpoint was change in mean sitting diastolic blood pressure from baseline to week 8 endpoint. Analyses were done by intention to treat. This trial is registered at ClinicalTrials.gov with the number NCT00219180.. 196 (11%) patients discontinued study treatment before the end of the trial (63 in the placebo group, 53 in the aliskiren group, 43 in the valsartan group, and 37 in the aliskiren/valsartan group), mainly due to lack of therapeutic effect. At week 8 endpoint, the combination of aliskiren 300 mg and valsartan 320 mg lowered mean sitting diastolic blood pressure from baseline by 12.2 mm Hg, significantly more than either monotherapy (aliskiren 300 mg 9.0 mm Hg decrease, p<0.0001; valsartan 320 mg, 9.7 mm Hg decrease, p<0.0001), or with placebo (4.1 mm Hg decrease, p<0.0001). Rates of adverse events and laboratory abnormalities were similar in all groups.. The combination of aliskiren and valsartan at maximum recommended doses provides significantly greater reductions in blood pressure than does monotherapy with either agent in patients with hypertension, with a tolerability profile similar to that with aliskiren and valsartan alone.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Double-Blind Method; Drug Therapy, Combination; Endpoint Determination; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Renin; Tetrazoles; Valine; Valsartan

An AT1 receptor antagonist induces a counterregulatory renin release whose intensity and duration reflect the magnitude of the renin-angiotensin blockade. We investigated whether a renin inhibitor may neutralize this counterregulation and amplify the effects of AT1 receptor antagonists.. In 12 normotensive male individuals who were on a high-sodium diet, a double-blind, placebo-controlled, randomized, crossover design was used to study the hormonal and BP effects of single oral administrations of 300 mg of the renin inhibitor aliskiren, 320 mg of valsartan, and a combination of these two drugs, each at half dosage (150 mg of aliskiren and 160 mg of valsartan).. Valsartan (320 mg) increased plasma renin activity and angiotensin I and angiotensin II levels, but 300 mg of aliskiren decreased them for 48 h. Aliskiren (300 mg) stimulated immunoreactive renin release more strongly than 320 mg of valsartan, decreased urinary aldosterone excretion for longer than 320 mg of valsartan, and had a similar BP-lowering effect as 320 mg of valsartan. In combination, 150 mg of aliskiren neutralized the valsartan (160 mg)-induced increase in plasma angiotensins for 48 h. The renin and aldosterone effects of the combination of 150 mg of aliskiren and 160 mg of valsartan were similar to those of 300 mg of aliskiren and greater than those of 320 mg of valsartan. When plasma drug concentrations were taken into account, the combination of 150 mg of aliskiren and 160 mg of valsartan had a synergistic effect on renin release. The BP-lowering effect of 150 mg of aliskiren and 160 mg of valsartan was similar to that of 300 mg of aliskiren and 320 mg of valsartan at peak but was more prolonged.. The stronger and longer lasting effects on plasma active renin and urinary aldosterone of aliskiren, alone or in combination, demonstrate a more effective blockade of the renin-angiotensin system than that obtained with 320 mg of valsartan alone.

Topics: Adult; Amides; Angiotensin II Type 1 Receptor Blockers; Blood Pressure; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Fumarates; Humans; Male; Renin; Sodium; Tetrazoles; Valine; Valsartan

This study investigated the addition of the direct renin inhibitor aliskiren to amlodipine in patients with mild to moderate hypertension that was inadequately controlled with amlodipine alone. Following once-daily treatment with amlodipine 5 mg for 4 weeks, patients whose hypertension responded inadequately to therapy (mean sitting diastolic blood pressure [DBP] 90-109 mm Hg) (n=545) were randomized to 6 weeks of double-blind treatment with amlodipine 5 mg plus aliskiren 150 mg, amlodipine 5 mg, or amlodipine 10 mg. At the study's end, mean systolic blood pressure and DBP reductions with the combination of aliskiren 150 mg and amlodipine 5 mg (11.0/8.5 mm Hg) were significantly greater (P<.0001) than with amlodipine 5 mg (5.0/4.8 mm Hg)--the comparator group--but similar to amlodipine 10 mg (9.6/8.0 mm Hg). All treatments were well tolerated. Edema occurred more frequently with amlodipine 10 mg (11.2%) than with combination therapy (2.1%) or amlodipine 5 mg (3.4%). In conclusion, aliskiren 150 mg plus amlodipine 5 mg shows similar but not better blood pressure-lowering efficacy when compared with amlodipine 10 mg in patients not completely responsive to amlodipine 5 mg; less edema was noted with combination therapy.

Topics: Aged; Amides; Amlodipine; Antihypertensive Agents; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Male; Middle Aged; Renin

Suppression of the renin-angiotensin-aldosterone system (RAAS) is therapeutically valuable in chronic heart failure (CHF). RAAS inhibition can be achieved in a number of ways though an orally active renin inhibitor (RI) has never been studied before. We describe the neurohumoral effects of an RI.. 27 patients with NYHA class II or III CHF and an ejection fraction

Topics: Aged; Aldosterone; Amides; Analysis of Variance; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Female; Fumarates; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Ramipril; Renin; Statistics, Nonparametric; Treatment Outcome

To evaluate the efficacy, safety and tolerability of aliskiren in elderly patients (> or =65 years old) with essential hypertension.. In this double-blind, multicenter study, 355 elderly patients with hypertension [office mean sitting systolic blood pressure (msSBP) > or =145-<180 mmHg and mean 24-h ambulatory systolic BP (ASBP) > or =135 mmHg] were randomized to once-daily treatment for 8 weeks with aliskiren 75 mg (n = 91), 150 mg (n = 84), 300 mg (n = 94) or the comparator lisinopril 10 mg (n = 86). The primary efficacy variable was change in mean 24-h ASBP.. At endpoint, aliskiren 75 mg, 150 mg, 300 mg and lisinopril 10 mg lowered mean 24-h ASBP (least-squares mean+/-SEM) by 8.4+/-0.8, 7.1+/-0.8, 8.7+/-0.8 and 10.2+/-0.9 mmHg, and mean 24-h ambulatory diastolic BP by 4.5+/-0.5, 3.6+/-0.5, 3.9+/-0.5 and 6.3+/-0.5 mmHg, respectively, with no significant difference between aliskiren doses. The trough-to-peak ratio for ASBP reduction with aliskiren 75 mg, 150 mg, 300 mg and lisinopril 10 mg was 0.77, 0.64, 0.79 and 0.87, respectively. All treatments lowered office msSBP and mean sitting diastolic BP (msDBP) compared with baseline. A significantly greater proportion of patients receiving aliskiren 300 mg achieved BP control (msSBP/msDBP <140/90 mmHg) compared with those receiving aliskiren 75 mg (36.2% vs 24.2%, p = 0.033). There was no evidence of dose-related increases in the rate of adverse events with aliskiren treatment.. Aliskiren, a novel direct renin inhibitor, provides effective 24-h BP lowering with no evidence of dose-related increases in the incidence of adverse events in elderly patients with hypertension.

Topics: Administration, Oral; Aged; Aged, 80 and over; Amides; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Fumarates; Humans; Hypertension; Lisinopril; Male; Renin

To assess the antihypertensive efficacy and safety of the combination of the direct renin inhibitor aliskiren and ramipril in patients with diabetes and hypertension.. In this double-blind, multicentre trial, 837 patients with diabetes mellitus and hypertension (mean sitting diastolic blood pressure [BP] > 95 and < 110 mmHg) were randomised to once-daily aliskiren (150 mg titrated to 300 mg after four weeks; n=282), ramipril (5 mg titrated to 10 mg; n=278) or the combination (n=277) for eight weeks. Efficacy variables were cuff mean sitting diastolic BP (msDBP) and mean sitting systolic BP (msSBP); 24-hour ambulatory BP, plasma renin activity (PRA) and plasma renin concentration (PRC) were also assessed.. At week 8, aliskiren, ramipril and aliskiren/ramipril lowered msDBP (mean+/-SEM) by 11.3+/-0.5, 10.7+/-0.5 and 12.8+/-0.5 mmHg, and msSBP by 14.7+/-0.9, 12.0+/-0.9 and 16.6+/-0.9 mmHg, respectively. Aliskiren/ramipril provided superior msDBP reductions to ramipril (p=0.004) or aliskiren (p=0.043) monotherapy; adding aliskiren to ramipril provided an additional mean BP reduction of 4.6/2.1 mmHg. Aliskiren monotherapy was non-inferior to ramipril for msDBP reduction (p=0.0002) and superior for msSBP reduction (p=0.021). All treatments significantly lowered mean 24-hour ambulatory BP. Aliskiren significantly reduced PRA from baseline as monotherapy (by 66%, p<0.0001) or in combination with ramipril (by 48%, p<0.0001), despite large increases in PRC in all treatment groups. Aliskiren was well tolerated as monotherapy or in combination with ramipril.. Combining aliskiren with ramipril provided a greater reduction in msDBP than either drug alone in patients with diabetes and hypertension.

Topics: Amides; Antihypertensive Agents; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Diabetes Complications; Diastole; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Ramipril; Renin; Systole; Treatment Outcome

Some renin inhibitors induce changes in the conformation of prorenin in vitro and influence the quantification of active renin by immunoradiometric assays. Whether such changes in renin recognition by monoclonal antibodies exist after oral administration of aliskiren, the first orally available renin inhibitor, is not known.. Two commercially available immunoradiometric assays (Cisbio and Nichols) were compared to determine immunoreactive active renin concentrations in plasma samples collected in a single oral dose crossover study comparing the renin inhibitor, aliskiren (300 mg), with the angiotensin II antagonist, valsartan (160 mg), in healthy male subjects.. The addition of aliskiren to plasma samples in vitro, at concentrations of 1-100 micromol/l, increased active renin immunoreactivity in both the Cisbio and Nichols assays. In the crossover study, the two assays gave similar values for the plasma immunoreactive active renin concentration before treatment and following valsartan administration (intraclass coefficient for agreement between the two assays = 0.92). However, a Bland-Altman plot showed a systematic bias towards higher values (1.75-fold higher; 95% confidence interval = 1.02-3.01) in the Nichols than in the Cisbio assay following aliskiren administration. The difference between the results obtained with the two assays depended on incubation time.. Depending on incubation conditions, circulating renin inhibitors interfere with the recognition of active renin molecules by the monoclonal antibodies used in commercially available assays. Careful consideration must therefore be given to the methodology used for quantifying immunoreactive plasma active renin when patients are treated with renin inhibitors, to avoid an overestimation of the magnitude of active renin release attributable to conformational changes in plasma prorenin.

Topics: Adolescent; Adult; Amides; Antihypertensive Agents; Cross-Over Studies; Double-Blind Method; Fumarates; Humans; Immunoradiometric Assay; Male; Protein Conformation; Renin; Sodium; Tetrazoles; Valine; Valsartan

The renin system is an attractive target for antihypertensive therapy in patients with diabetes mellitus. However, diabetes is associated with changes in gastrointestinal, renal and hepatic function that may affect the absorption and disposition of oral drugs. This study compared the pharmacokinetics and pharmacodynamics of the orally active direct renin inhibitor, aliskiren, in healthy volunteers and patients with type 2 diabetes.. This was an open-label study conducted in 30 patients with type 2 diabetes and 30 healthy volunteers matched for age, bodyweight and race. Following a 10-hour fast, all participants received a single oral dose of aliskiren 300mg. Blood samples were taken at frequent intervals for 96 hours post-dose for determination of plasma concentrations of aliskiren (using a high-performance liquid chromatography-tandem mass spectroscopy method). Plasma renin activity (PRA) and renin concentration (RC) were also measured for 24 hours after dosing.. Aliskiren exhibited similar pharmacokinetics in patients with type 2 diabetes and healthy volunteers. Exposure to aliskiren was slightly higher in patients with type 2 diabetes compared with healthy volunteers (mean area under the plasma concentration-time curve from 0 to 24 hours 1859 vs 1642 ng . h/mL; maximum observed plasma drug concentration 394 vs 348 ng/mL), while apparent clearance corrected for bioavailability was slightly lower (205 vs 234 L/h) and elimination half-life slightly longer (44 vs 39.9 hours), but there were no statistically significant differences for any pharmacokinetic parameters. There was no significant correlation between glycaemic control (% glycosylated haemoglobin) and any of the measured pharmacokinetic parameters in patients with type 2 diabetes. Aliskiren caused sustained suppression of PRA for at least 24 hours after dosing despite increasing RC; there were no major differences in the pharmacodynamic effects of aliskiren between patients with type 2 diabetes and healthy volunteers. Aliskiren was well tolerated in both patient groups, with no clinically significant changes in laboratory values and a low risk of adverse events.. Aliskiren showed a similar pharmacokinetic profile in healthy volunteers and patients with type 2 diabetes, and administration of a single oral 300 mg dose of aliskiren was well tolerated by both patients and healthy volunteers. The pharmacodynamic effects of aliskiren were also similar in healthy volunteers and diabetic patients, with sustained inhibition of renin system activity observed for at least 24 hours after dosing.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure; Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 2; Female; Fumarates; Humans; Male; Mass Spectrometry; Middle Aged; Reference Values; Renin; Renin-Angiotensin System

Aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension. This study compared the pharmacokinetic and pharmacodynamic properties of aliskiren in Japanese and Caucasian subjects.. In this open-label, single-centre, parallel-group, single- and multiple-dose study, 19 Japanese and 19 Caucasian healthy young male subjects received a single 300-mg oral dose of aliskiren on day 1 and then aliskiren 300 mg once daily on days 4-10. Blood samples were collected for the measurement of plasma aliskiren concentration, plasma renin concentration (PRC) and plasma renin activity (PRA).. Pharmacokinetic parameters were comparable in Japanese and Caucasian subjects following administration of a single dose of aliskiren {ratio of geometric means: C(max) 1.12 [90% confidence interval (CI) 0.88, 1.43]; AUC(0-72 h) 1.19 [90% CI 1.02, 1.39]} and at steady state [mean ratio: C(max) 1.30 (90% CI 1.00, 1.70); AUC(0-tau) 1.16 (90% CI 0.95, 1.41)]. There was no notable difference in the plasma half-life of aliskiren between Japanese and Caucasian groups (29.7 +/- 10.2 h and 32.0 +/- 6.6 h, respectively). At steady state, peak PRC level and AUC for the concentration-time plot were not significantly different between Japanese and Caucasian subjects (P = 0.64 and P = 0.80, respectively). A single oral dose of aliskiren significantly reduced PRA to a similar extent in Japanese and Caucasian subjects (by 87.5% and 85.7%, respectively, compared with baseline; P < 0.01). Aliskiren was well tolerated by both ethnic groups.. The oral renin inhibitor aliskiren demonstrated similar pharmacokinetic and pharmacodynamic properties in Japanese and Caucasian subjects.

Topics: Adult; Amides; Antihypertensive Agents; Asian People; Blood Pressure; Fumarates; Humans; Hypertension; Male; Middle Aged; Renin; Renin-Angiotensin System; White People

Aliskiren is a novel orally active renin inhibitor for the treatment of hypertension. This study evaluated the antihypertensive efficacy, safety and tolerability of aliskiren in Japanese patients with hypertension. Forty hundred and fifty-five Japanese men and women with a mean sitting diastolic blood pressure of 95-110 mmHg were randomized to receive once-daily double-blind treatment for 8 weeks with aliskiren 75, 150 or 300 mg or placebo. Aliskiren produced significant, dose-dependent reductions in mean sitting diastolic blood pressure (p<0.0005 vs. placebo for each dose) and mean sitting systolic blood pressure (p<0.001 vs. placebo for each dose). The placebo-corrected reductions in mean sitting systolic/diastolic blood pressure were 5.7/4.0, 5.9/4.5 and 11.2/7.5 mmHg in the aliskiren 75, 150 and 300 mg groups, respectively. After 8 weeks' treatment, 27.8%, 47.8%, 48.2% and 63.7% of patients in the placebo and aliskiren 75, 150 and 300 mg groups, respectively, achieved a successful treatment response (diastolic blood pressure <90 mmHg and/or reduced by > or =10 mmHg from baseline; p<0.005 vs. placebo for each dose). Aliskiren treatment was well tolerated, with the incidence of adverse events reported in the active treatment groups (53-55%) being similar to that in the placebo group (50%). This study, which is the first to assess the antihypertensive efficacy and safety of aliskiren in Japanese patients with hypertension, demonstrates that the once-daily oral renin inhibitor aliskiren provides significant, dose-dependent reductions in blood pressure with placebo-like tolerability.

Topics: Adult; Aged; Aged, 80 and over; Amides; Antihypertensive Agents; Asian People; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Placebos; Renin; Treatment Outcome

Stopping the detrimental effects of the renin-angiotensin system at the most upstream point of the cascade offers theoretical advantages for cardiovascular protection. This study compares the antihypertensive efficacy and safety of the novel oral renin inhibitor aliskiren with placebo and an active comparator.. The study was a randomized, multicenter, double-blind, placebo-controlled, active-comparator 8-week trial in patients with mild-to-moderate hypertension (mean sitting diastolic blood pressure [DBP] > or =95 and <110 mm Hg). After a 2-week, single-blind placebo run-in, 652 patients were randomized to receive double-blind treatment with once-daily oral doses of aliskiren (150, 300, or 600 mg), irbesartan 150 mg, or placebo. Aliskiren 150, 300, and 600 mg effectively lowered both trough mean sitting DBP and systolic blood pressure (SBP) (P<0.001 versus placebo for both variables). The least-squares mean reductions in trough DBP were 9.3+/-0.8, 11.8+/-0.8, and 11.5+/-0.8 mm Hg, respectively, versus 6.3+/-0.8 mm Hg for placebo, and the least-squares mean reductions in trough SBP were 11.4+/-1.3, 15.8+/-1.2, and 15.7+/-1.2 mm Hg, respectively, versus 5.3+/-1.2 mm Hg for placebo. The antihypertensive effect of aliskiren 150 mg was comparable to that of irbesartan 150 mg (8.9+/-0.7 and 12.5+/-1.2 mm Hg, least-squares reduction in mean sitting DBP and SBP, respectively, for irbesartan). Aliskiren 300 and 600 mg lowered mean sitting DBP significantly more than irbesartan 150 mg (P<0.05). Aliskiren showed safety and tolerability comparable to those of placebo and irbesartan; the incidence of adverse events and number of patients discontinuing therapy were similar in all groups.. Once-daily oral treatment with aliskiren lowers blood pressure effectively, with a safety and tolerability profile comparable to that of irbesartan and placebo, in patients with mild-to-moderate hypertension. Aliskiren 150 mg is as effective as irbesartan 150 mg in lowering blood pressure.

Topics: Administration, Oral; Amides; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Diastole; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Irbesartan; Male; Middle Aged; Placebos; Renin; Substance Withdrawal Syndrome; Systole; Tetrazoles; Treatment Outcome

Aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension. This study investigated the interaction profile of aliskiren, which is of clinical importance because hypertensive patients often require concomitant drug therapy for associated comorbidities.. Four separate studies investigated the pharmacokinetic interaction between single oral doses of aliskiren and lovastatin, atenolol, celecoxib or cimetidine, respectively. All studies involved healthy male volunteers aged 18-45 years. In 3 studies, subjects (n = 15 in each study) received single doses of aliskiren 150 mg alone, the test drug alone (lovastatin 40 mg, atenolol 100 mg or celecoxib 200 mg), or both drugs in combination, according to a 3-period crossover design. In the cimetidine study (n = 12), aliskiren 150 mg was administered alone or concomitantly with cimetidine 800 mg according to a two-period crossover design. Plasma concentrations of aliskiren and test drugs were determined by liquid chromatography and mass spectrometry methods. Pharmacokinetic parameters were derived from these data.. Mean AUC and t1/2 for aliskiren were not significantly changed by lovastatin, atenolol or celecoxib (< 10% difference between treatments). Aliskiren mean Cmax was not affected by either lovastatin or atenolol, although a non-significant 36% increase was observed with celecoxib. Modest, non-significant increases in aliskiren systemic availability followed coadministration with cimetidine (aliskiren mean AUC, Cmax and t1/2 increased by 17%, 19% and 15%, respectively). Aliskiren coadministration had no significant effect on the disposition of lovastatin, atenolol or celecoxib.. Overall, single doses of aliskiren showed no evidence of clinically important pharmacokinetic interactions with lovastatin, atenolol, celecoxib or cimetidine.

Topics: Adolescent; Adrenergic beta-Antagonists; Adult; Amides; Atenolol; Celecoxib; Cimetidine; Cross-Over Studies; Cyclooxygenase 2 Inhibitors; Drug Interactions; Enzyme Inhibitors; Fumarates; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Lovastatin; Male; Middle Aged; Pyrazoles; Renin; Sulfonamides

To investigate the effects of aliskiren, an oral renin inhibitor, on the pharmacokinetics and pharmacodynamics of warfarin.. In a single-blind, placebo-controlled, randomized, two-period crossover study, 15 healthy male and female subjects received a single oral dose of 25 mg racemic warfarin twice, once in the morning of the 8th day of treatment with 150 mg aliskiren and once at the same time point during treatment with placebo. Blood samples were collected for the measurement of prothrombin time (PT) and activated thromboplastin time (aPTT) and for determination of plasma concentrations of (R)- and (S)-warfarin.. Aliskiren treatment had no effect on the blood coagulation parameters (PT, INR and aPTT). The ratios of least square means (90% CI) of pharmacokinetic parameters in the presence and absence of aliskiren for (R)- and (S)-warfarin were Cmax 0.89 (0.82, 0.96) and 0.88 (0.80, 0.97), AUC(0, infinity) 1.00 (0.94, 1.07) and 1.06 (0.96, 1.16) and t(1/2) 0.99 (0.92, 1.07) and 1.05 (0.96, 1.14).. Multiple doses of aliskiren had no detectable effect on the pharmacokinetics or pharmacodynamics of a single dose of warfarin in healthy subjects.

Topics: Adult; Amides; Anticoagulants; Cross-Over Studies; Female; Fumarates; Humans; Male; Partial Thromboplastin Time; Prothrombin Time; Renin; Single-Blind Method; Warfarin

Interrupting the renin-angiotensin system (RAS) with a usual daily dose of a single-site RAS inhibitor does not achieve complete and long-lasting pharmacologic blockade. Hormonal and BP effects were compared for 48 h after administration of single oral doses of 300 mg (high dose) of the renin inhibitor aliskiren (A300) and 160 mg (standard antihypertensive dose) of the AT1 receptor antagonist valsartan (V160) and their combination each at half dose (A150+V80) in 12 mildly sodium-depleted normotensive individuals. In this double-blind, placebo-controlled, randomized, four-period crossover study, A300 decreased plasma renin activity and angiotensin I and II levels for 48 h, stimulated immunoreactive active renin release more strongly than V160, and decreased urinary aldosterone excretion for a longer duration than V160. In contrast to V160, the A150+V80 combination did not increase plasma angiotensins. The renin and aldosterone effects of the A150+V80 combination were similar to those of A300 and greater than those of V160. When plasma drug concentrations were taken into account, the A150 +V80 combination had a synergistic effect on renin release. The A150+V80 combination lowered BP at least as effectively as either higher dose monotherapy. In conclusion, in mildly sodium-depleted normotensive individuals, the long-lasting effects of aliskiren alone or in combination with valsartan on plasma immunoreactive active renin and urinary aldosterone effects demonstrate strong and prolonged blockade of angiotensin II at the kidney and the adrenal level. Moreover, a renin inhibitor and AT1R antagonist combination may provide synergistic effects on RAS hormone levels.

Topics: Administration, Oral; Adolescent; Adult; Aldosterone; Amides; Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Blood Pressure; Cross-Over Studies; Drug Synergism; Feedback, Physiological; Fumarates; Humans; Male; Renin; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan

Inhibition of the first and rate-limiting step of the renin-angiotensin system has long been an elusive therapeutic goal. Aliskiren, the first known representative of a new class of completely nonpeptide, orally active, renin inhibitors, has been shown to inhibit the production of angiotensin I and II in healthy volunteers and to reduce blood pressure (BP) in sodium-depleted marmosets. The aim of this randomized, double-blind, active comparator trial study was to assess the BP-lowering efficacy and safety of aliskiren. Two hundred twenty-six patients, 21 to 70 years of age, with mild to moderate hypertension, were randomly assigned to receive 37.5 mg, 75 mg, 150 mg, or 300 mg aliskiren or 100 mg losartan daily for 4 weeks. Dose-dependent reductions in daytime ambulatory systolic pressure (mean change, mm Hg [SD of change]; -0.4 [11.7], -5.3 [11.3], -8.0 [11.0], and -11.0 [11.0], P=0.0002) and in plasma renin activity (median change % [interquartile range]; -55 [-64, -11], -60 [-82, -46], -77 [-86, -72], and -83 [-92, -71], P=0.0008) were observed with 37.5, 75, 150, and 300 mg aliskiren. The change in daytime systolic pressure with 100 mg losartan (-10.9 [13.8]) was not significantly different from the changes seen with 75, 150, and 300 mg aliskiren. Aliskiren was well tolerated at all doses studied. This study demonstrates that aliskiren, through inhibition of renin, is an effective and safe orally active BP-lowering agent. Whether renin inhibition results in protection from heart attack, stroke, and nephropathy, similar to angiotensin-converting enzyme inhibition and angiotensin receptor blockade, needs to be researched.

Topics: Administration, Oral; Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Losartan; Male; Middle Aged; Patient Compliance; Renin

Topics: Administration, Oral; Amides; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Cross-Over Studies; Enalapril; Fumarates; Humans; Renin

Renin is the main determinant of angiotensin (Ang) II levels. It, therefore, always appeared desirable to reduce Ang II levels by direct inhibition of renin. So far, specific renin inhibitors lacked potency and/or oral availability. We tested the new orally active nonpeptidic renin inhibitor SPP100 (Aliskiren, an octanamide with a 50% inhibitory concentration [IC50] in the low nanomolar range) in 18 healthy volunteers on a constant 100 mmol/d sodium diet using a double-blind, 3-way crossover protocol. In 3 periods of 8 days, separated by wash-outs of 6 days, each volunteer received 2 dosage levels of Aliskiren (low before high; 40 and 80 or 160 and 640 mg/d) and randomized placebo or 20 mg enalapril. Aliskiren was well tolerated. Not surprisingly, blood pressure and heart rate remained unchanged in these normotensive subjects. There was a dose-dependent decrease in plasma renin activity, Ang I, and Ang II following single doses of Aliskiren starting with 40 mg. Inhibition was still marked and significant after repeated dosing with maximal decreases in Ang II levels by 89% and 75% on Days 1 and 8, respectively, when the highest dose of Aliskiren was compared with placebo. At the same time, mean plasma active renin was increased 16- and 34-fold at the highest dose of Aliskiren. Plasma drug levels of Aliskiren were dose-dependent with maximal concentrations reached between 3 to 6 hours after administration; steady state was reached between 5 and 8 days after multiple dosing. Less than 1% of dose was excreted in the urine. Plasma and urinary aldosterone levels were decreased after doses of Aliskiren > or =80 mg and after enalapril. Aliskiren at 160 and 640 mg enhanced natriuresis on Day 1 by +45% and +62%, respectively, compared with placebo (100%, ie, 87+/-11 mmol/24h) and enalapril (+54%); kaliuresis remained unchanged. In conclusion, the renin inhibitor Aliskiren dose-dependently decreases Ang II levels in humans following oral administration. The effect is long-lasting and, at a dose of 160 mg, is equivalent to that of 20 mg enalapril. Aliskiren has the potential to become the first orally active renin inhibitor that provides a true alternative to ACE-inhibitors and Ang II receptor antagonists in therapy for hypertension and other cardiovascular and renal diseases.

Topics: Administration, Oral; Adult; Aldosterone; Amides; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Enalapril; Fumarates; Heart Rate; Humans; Male; Potassium; Renin; Renin-Angiotensin System; Sodium

The long-term clinical outcomes in biopsy proven IgAN patients treated with aliskiren on top of a maximally tolerated dose of ACEi/ARB remain unknown.. Patients with IgAN treated with a direct renin inhibitor and ACEi/ARB for at least 6 months were compared with a 1:1 propensityscore-matched cohort (including MEST-C score and the 12-months pre-exposure slope of eGFR matching) who received ACEi/ARB without aliskiren exposure to compute the hazard ratio of reaching the primary endpoint of a composite of 40% reduction in eGFR, initiation of KRT and all-cause mortality. Secondary outcome measures included changes in mean UPCR, blood pressure, eGFR, incidence of hyperkalemia and other adverse events during follow-up.. Among patients with IgAN, add-on aliskiren was associated with less favorable long-term kidney outcomes despite an initial anti-proteinuric effect.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cohort Studies; Fumarates; Glomerulonephritis, IGA; Humans; Hyperkalemia; Propensity Score; Renin

Lung cancer has risen to the top of the list of cancer-related deaths worldwide. Aliskiren is a direct renin inhibitor.. This study aims to investigate the impact of cell signaling of Renin-Angiotensin system (RAS)/NF-κB on lung cancer by investigating the potential therapeutic effects of aliskiren for lung cancer treatment in urethane-induced lung cancer in mice.. Male BALB/c mice were randomly assigned to one of five treatment groups for 150 days, including (1) normal control; (2) aliskiren (25 mg/kg/i.p) daily, (3) urethane at a dose of 1.5 g/kg (i.p) at Day 1 and 60 (nonsmall cell lung cancer[NSCLC] group) (4) NSCLC mice received carboplatin (15 mg/kg/i.p) every other day for the last 4 successive weeks and (5) NSCLC mice treated with aliskiren daily. Tumor size was determined based on blood sampling, and lungs were isolated for biochemical analysis, western blot analysis assay, and histopathological examination.. Urethane demonstrated significant changes in all biochemical and molecular parameters and histological patterns. Aliskiren-treated mice had significantly lower levels of NF-κB p65, Bcl-2, cyclin D1, ICAM-1, MMP-2, and Nrf2, with an increase in the catalytic activity of caspase-3 due to its RAS inhibitory mechanism. The combined urethane administration with aliskiren demonstrated a significant improvement in the histopathological examination.. RAS/NF-B cell signaling is a potential therapeutic target for preventing and treating lung adenocarcinoma, evidenced by the fundamental cytotoxic mechanism and attenuation of metastasis and angiogenesis induced by the treatment of NSCLC mice with aliskiren.

Topics: Amides; Animals; Apoptosis; Carboplatin; Carcinoma, Non-Small-Cell Lung; Caspase 3; Cell Cycle Checkpoints; Cyclin D1; Fumarates; Intercellular Adhesion Molecule-1; Lung Neoplasms; Male; Matrix Metalloproteinase 2; Mice; Mice, Inbred BALB C; NF-E2-Related Factor 2; NF-kappa B; Proto-Oncogene Proteins c-bcl-2; Renin; Renin-Angiotensin System; Signal Transduction; Urethane

The neurotoxicity of amyloid-β (Aβ) and its deposition in neurons plays a critical role in the occurrence and development of Alzheimer's disease (AD). Several preclinical experiments have found that the renin inhibitor aliskiren has a wide range of physiological effects, including hindering the progression of atherosclerosis and anti-inflammatory. This study is aimed to explore the effect of aliskiren on neuronal toxic damage and the underlying mechanism. This study established an

Topics: Alzheimer Disease; Amides; Amyloid beta-Peptides; Apoptosis; Cell Line, Tumor; Fumarates; Humans; Molecular Docking Simulation; Neurons; Peptide Fragments; Renin

Among cases of SARS-CoV-2 infections that result in serious conditions or death, many have pre-existing conditions such as hypertension and are on renin-angiotensin-aldosterone system (RAAS) inhibitors. The angiotensin-converting-enzyme-2 (ACE2), a key protein of the RAAS pathway, also mediates cellular entry of SARS-CoV-2. RAAS inhibitors might affect the expression levels of ace2, which could impact patient susceptibility to SARS-CoV-2. However, multi-organ-specific information is currently lacking and no species other than rodents have been examined. To address this knowledge gap, we treated adult zebrafish with the RAAS inhibitors aliskiren, olmesartan, and captopril for 7 consecutive days and performed qRT-PCR analysis of major RAAS pathway genes in the brain, gill, heart, intestine, kidney, and liver. Both olmesartan and captopril significantly increased ace2 expression in the heart, gill, and kidney. Olmesartan also increased ace2 expression in the intestine. Conversely, aliskiren significantly decreased ace2 expression in the heart. Discontinuation of compound treatments for 7 days did not return ace2 expression to baseline levels. While potential risks or benefits of antihypertensive RAAS inhibitors to SARS-CoV-2 infections in humans remain uncertain, this study provides new insights regarding the impact of RAAS inhibitors on organ-specific ace2 expression in another vertebrate model, thereby providing comparative data and laying scientific groundwork for future clinical decisions of RAAS inhibitor use in the context of COVID-19.

Topics: Amides; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Brain; COVID-19; Down-Regulation; Fumarates; Gills; Humans; Imidazoles; Liver; Models, Animal; SARS-CoV-2; Tetrazoles; Up-Regulation; Zebrafish

Atrial fibrillation (AF) is the most common type of arrhythmia. Atrial remodeling is a major factor to the AF substrate. The purpose of the study is to explore whether aliskiren (ALS) has a cardioprotective effect and its potential molecular mechanisms on atrial remodeling.. The electrophysiological changes were observed after 2-h pacing. The AERP shortened with increased AFi and ADT, which was attenuated by ALS (P < 0.05). After pacing for 2 weeks, oxidative stress and inflammation markers in the Paced group were significantly higher than those in the Sham group (P < 0.01) and were reduced by ALS treatment (P < 0.01). The reduced level of antioxidant enzymes caused by RAP was also found to be elevated in ALS-treated group (P < 0.01). The results of pathology and echocardiography showed that RAP can cause atrial enlargement, fibrosis (P < 0.01), and were attenuated in ALS treatment group. The PI3K/Akt signaling pathway were downregulated induced by RAP. ALS could upregulate the PI3K/Akt pathway expression (P < 0.05). Furthermore, the cardioprotective effects in structural remodeling of ALS were suppressed by WM.. ALS may offer cardioprotection in RAP-induced atrial remodeling, which may partly be ascribed to its anti-inflammatory and anti-oxidative stress action and the regulation of PI3K/Akt signaling pathway.

Topics: Amides; Animals; Atrial Remodeling; Dogs; Echocardiography; Female; Fumarates; Inflammation Mediators; Male; Oxidative Stress; Phosphatidylinositol 3-Kinases; Random Allocation; Signal Transduction; Wortmannin

To study the effect of direct renin inhibitor (aliskiren) on the renal function during acute and chronic partial ureteral obstruction (PUO) in rat solitary kidney.. Sixty male Sprague-Dawley rats were randomly allocated into three groups (20 rats each); sham, PUO and aliskiren groups. Right nephrectomy was performed in all groups. Rats in PUO and aliskiren groups were subjected to left PUO and received no treatment and aliskiren (10 mg/kg, orally, once per day till sacrification), respectively. Blood samples were then collected for biochemical measurements. Ten rats from each group were sacrificed after two weeks, while the remaining rats were sacrificed after four weeks. Left kidneys were harvested for histopathological examination, BCL-2, interleukin (IL)-6, transforming growth factor (TGF)-β1, collagen I and fibronectin relative gene expression and assessment of glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) activity.. After two and four weeks of PUO, aliskiren significantly recompensed the rise of serum creatinine (Scr) and blood urea nitrogen (BUN). Aliskiren also revealed significantly better histopathological results regarding cortical and medullary necrosis, regeneration and inflammatory cell infiltration. Aliskiren group showed statistically significant up-regulation of BCL-2 and down-regulation of IL-6, TGF-β1, collagen I and fibronectin relative gene expression. Aliskiren significantly increased GSH and SOD activity and reduced MDA and NO activity. Moreover, aliskiren administration for four weeks after PUO significantly yielded more renoprotective effect compared to its administration for two weeks.. Aliskiren ameliorates the deterioration of the renal function during acute and chronic PUO in a solitary kidney.

Topics: Amides; Animals; Creatinine; Disease Models, Animal; Fumarates; Gene Expression Regulation; Kidney Function Tests; Male; Rats; Rats, Sprague-Dawley; Renin; Solitary Kidney; Time Factors; Ureteral Obstruction

Cyr61 is a member of the CCN family of proteins that is expressed in atherosclerotic lesions and regulated by angiotensin II. It is unknown whether renal artery stenosis (RAS) increases Cyr61 expression. Male ApoE

Topics: Amides; Amlodipine; Angiotensin II; Animals; Antihypertensive Agents; Apolipoproteins E; Blood Pressure; Cysteine-Rich Protein 61; Fumarates; Gene Expression Regulation; Humans; Hypertension; Irbesartan; Mice; Mice, Knockout; Renal Artery; Renal Artery Obstruction

Efficacy of aliskiren combination therapy with other antihypertensive has been evaluated in the treatment of patients with hypertension in recent systematic reviews. However, most previous reviews only focused on one single health outcome or one setting, none of them made a full summary that assessed the impact of aliskiren combination treatment comprehensively. As such, this umbrella review based on systematic reviews and meta-analyses is aimed to synthesise the evidences on efficacy, safety and tolerability of aliskiren-based therapy for hypertension and related comorbid patients.. A comprehensive search of PubMed, EMBASE, Cochrane Library, CNKI published from inception to August 2020 will be conducted. The selected articles are systematic reviews which evaluated efficacy, safety and tolerability of aliskiren combination therapy. Two reviewers will screen eligible articles, extract data and evaluate quality independently. Any disputes will be resolved by discussion or the arbitration of a third person. The quality of reporting evidence will be assessed using the Assessment of Multiple Systematic Reviews V.2 tool tool. We will take a mixed-methods approach to synthesising the review literatures, reporting summary of findings tables and iteratively mapping the results.. Ethical approval is not required for the study, as we would only collect data from available published materials. This umbrella review will be also submitted to a peer-reviewed journal for publication after completion.. CRD42020192131.

Topics: Amides; Antihypertensive Agents; Fumarates; Humans; Research Design; Review Literature as Topic; Systematic Reviews as Topic

Worldwide, diabetic neuropathy (DN) is a major complication of diabetes mellitus. The direct renin inhibitor aliskiren is recognized as a treatment for cardiovascular disease in diabetic patients, but little is known about its potential benefits in cases of diabetic neuropathy. Accordingly, we investigated the effects of aliskiren (ALIS) and gliclazide (GLZ) and their combination therapy on peripheral neuropathy in streptozotocin-induced diabetic rats.. In total, 112 adult Sprague-Dawley rats were used for this study. Diabetes was induced using streptozotocin (STZ), whereas the control group was treated with an equal volume of citrate buffer. The diabetic rats were divided randomly into six groups according to the proposed treatment regime: diabetic control (DC), gliclazide (GLZ), aliskiren (ALIS), ramipril (RAM), (GLZ + ALIS) and (GLZ + RAM). Behavioural responses to thermal (hot-plate) and mechanical (tail-pinch) pain were evaluated. After eight weeks of daily treatments, the animals were fasted and sacrificed. The blood samples were collected, with the serum separated and subjected to various biochemical and enzyme analyses so as to assess the effect of the treatments on diabetic peripheral neuropathy.. After 8 weeks, aliskiren alone and in combination with gliclazide therapy had a significant effect (. These data suggest that either aliskerin alone or in combination with gliclazide can protect against the development and progression of diabetic neuropathy.

Topics: Amides; Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Disease Progression; Drug Therapy, Combination; Fumarates; Gliclazide; Male; Neuralgia; Ramipril; Rats, Sprague-Dawley; Streptozocin; Treatment Outcome

Aliskiren was selected as a compound of potential concern among a suspect screening list of more than 40,000 substances on a basis of high occurrence, potential risk and the absence of information about its environmental fate. This study investigated the photoinduced degradation of aliskiren in river water samples spiked at trace levels exposed to simulated sunlight. A half-life time of 24 h was observed with both direct and indirect photolysis playing a role on pollutant degradation. Its photo-induced transformation involved the formation of six transformation products (TPs), elucidated by LC-HRMS - resulted from the drug hydroxylation, oxidation and moieties loss with subsequent cyclization structurally. The retrospective suspected analysis performed on a total of 754 environmental matrices evidenced the environmental occurrence of aliskiren and two TPs in surface waters (river and seawater), fresh water, sediments and biota. In silico bioassays suggested that aliskiren degradation undergoes thought the formation of TPs with distinct toxicity comparing with the parent compound.

Topics: Amides; Chromatography, Liquid; Fresh Water; Fumarates; Mass Spectrometry; Photolysis; Retrospective Studies; Rivers; Water; Water Pollutants, Chemical

Hypertension is characterized by persistent elevated blood pressure levels, one of the leading causes of death in the world. Renovascular hypertension represents the most common cause of secondary hypertension, and its progress is associated with overactivation of the renin angiotensin aldosterone system (RAAS), causing systemic and local changes. Aliskiren is a renin-inhibiting drug that optimizes RAAS suppression. In this sense, the objective of the present study was to analyze the morphophysiology of the left kidney in Wistar rats with renovascular hypertension after treatment with Aliskiren. Parameters such as systolic blood pressure, urinary creatinine and protein excretion, renal cortex structure and ultrastructure, fibrosis and tissue inflammation were analyzed. Our results showed that the hypertensive animals treated with Aliskiren presented a reestablishment of blood pressure, expression of renin, and renal function, as well as a remodeling of morphological alterations through the reduction of fibrosis. The treatment regulated the laminin expression and decreased pro-inflammatory cytokines, restoring the integrity of the glomerular filtration barrier. Therefore, our findings suggest that Aliskiren has a renoprotective effect acting on the improvement of the morphology, physiology and pathology of the renal cortex of animals with renovascular hypertension.

Topics: Amides; Animals; Antihypertensive Agents; Disease Models, Animal; Fibrosis; Fumarates; Hypertension, Renovascular; Inflammation; Kidney; Rats; Renin-Angiotensin System

Aliskiren (ALS) is well known for its antihypertensive properties. However, the potential underlying the molecular mechanism and the anti-hypertrophic effect of ALS have not yet been fully elucidated. The aim of the present study was to investigate the role of ALS in mammalian target of rapamycin (mTOR) and apoptosis signaling using in vivo and in vitro models of cardiac hypertrophy. A rat model of cardiac hypertrophy was induced by isoproterenol treatment (5 mg·kg-1·day-1) for 4 weeks, with or without ALS treatment at 20 mg·kg-1·day-1. The expression of hypertrophic, fibrotic, and apoptotic markers was determined by RT-qPCR. The protein expression of apoptotic markers mTOR and p-mTOR was assessed by western blot analysis. The proliferation of H9C2 cells was monitored using the MTS assay. Cell apoptosis was analyzed using flow cytometry. In vivo, isoproterenol-treated rats exhibited worse cardiac function, whereas ALS treatment reversed these dysfunctions, which were associated with changes in p-mTOR, Bcl-2, Bax, and cleaved caspase-3 expression, as well as the number of apoptotic cells. In vitro, H9C2 cardiomyocyte viability was significantly inhibited and cardiac hypertrophy was induced by Ang II administration, but ALS reversed Ang II-induced H9C2 cardiomyocyte hypertrophy and death. Furthermore, Ang II triggered the activation of the mTOR and apoptosis pathways in hypertrophic cardiomyocytes that were inhibited by ALS treatment. These results indicated that ALS alleviated cardiac hypertrophy through inhibition of the mTOR and apoptosis pathways in cardiomyocytes.

Topics: Amides; Angiotensin II; Animals; Apoptosis; Blotting, Western; Cardiomegaly; Disease Models, Animal; Fibrosis; Flow Cytometry; Fumarates; Isoproterenol; Male; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; TOR Serine-Threonine Kinases

Learning and memory deficits are obvious symptoms that develop over time in patients with poorly controlled diabetes. Hyperactivity of the renin-angiotensin system (RAS) is directly associated with β-cell dysfunction and diabetic complications, including cognitive impairment. Here, we investigated the protective and molecular effects of two RAS modifiers, aliskiren; renin inhibitor and captopril; angiotensin converting enzyme inhibitor, on cognitive deficits in the rat hippocampus. Injection of low dose streptozotocin for 4 days resulted in type 1 diabetes. Then, poorly controlled diabetes was mimicked with ineffective daily doses of insulin for 4 weeks. The hyperglycaemia and pancreatic atrophy caused memory disturbance that were identifiable in behavioural tests, hippocampal neurodegeneration, and the following significant changes in the hippocampus, increases in the inflammatory marker interleukin 1β, cholinesterase, the oxidative stress marker malondialdehyde and protein expression of phosphorylated extracellular-signal-regulated kinase and glycogen synthase kinase-3 beta versus decrease in the antioxidant reduced glutathione and protein expression of phosphorylated glycogen synthase kinase-3 beta. Blocking RAS with either drugs along with insulin amended all previously mentioned parameters. Aliskiren stabilized the blood glucose level and restored normal pancreatic integrity and hippocampal malondialdehyde level. Aliskiren showed superior protection against the hippocampal degeneration displayed in the earlier behavioural modification in the passive avoidance test, and the aliskiren group outperformed the control group in the novel object recognition test. We therefore conclude that aliskiren and captopril reversed the diabetic state and cognitive deficits in rats with poorly controlled STZ-induced diabetes through reducing oxidative stress and inflammation and modulating protein expression.

Topics: Amides; Animals; Avoidance Learning; Brain; Captopril; Cholinesterases; Cognitive Dysfunction; Diabetes Mellitus, Experimental; Fumarates; Glycogen Synthase Kinase 3; Hippocampus; Interleukin-1beta; Male; MAP Kinase Signaling System; Maze Learning; Pancreas; Rats; Rats, Sprague-Dawley; Recognition, Psychology

Megalin is an endocytic receptor contributing to protein reabsorption. Impaired expression or trafficking of megalin increases urinary renin and allowed the detection of prorenin, which normally is absent in urine. Here, we investigated (pro)renin uptake by megalin, using both conditionally immortalized proximal tubule epithelial cells and Brown Norway Rat yolk sac cells (BN16). To distinguish binding and internalization, cells were incubated with recombinant human (pro)renin at 4°C and 37°C, respectively. (Pro)renin levels were assessed by immunoradiometric assay. At 4°C, BN16 cells bound 3× more prorenin than renin, suggestive for a higher affinity of prorenin. Similarly, at 37°C, prorenin accumulated at 3- to 4-fold higher levels than renin in BN16 cells. Consequently, depletion of medium prorenin (but not renin) content occurred after 24 hours. No such differences were observed in conditionally immortalized proximal tubule epithelial cells, and M6P (mannose-6-phosphate) greatly reduced conditionally immortalized proximal tubule epithelial cells (pro)renin uptake, suggesting that these cells accumulate (pro)renin largely via M6P receptors. M6P did not affect (pro)renin uptake in BN16 cells. Yet, inhibiting megalin expression with siRNA greatly reduced (pro)renin binding and internalization by BN16 cells. Furthermore, treating BN16 cells with albumin, an endogenous ligand of megalin, also decreased binding and internalization of (pro)renin, while deleting the (pro)renin receptor affected the latter only. Exposing prorenin's prosegment with the renin inhibitor aliskiren dramatically increased prorenin binding, while after prosegment cleavage with trypsin prorenin binding was identical to that of renin. In conclusion, megalin might function as an endocytic receptor for (pro)renin and displays a preference for prorenin. Megalin-mediated endocytosis requires the (pro)renin receptor.

Topics: Amides; Animals; Cell Line, Transformed; Endocytosis; Enzyme Precursors; Epithelial Cells; Fumarates; Humans; Kidney Tubules, Proximal; Low Density Lipoprotein Receptor-Related Protein-2; Peptide Fragments; Prorenin Receptor; Protein Binding; Rats; Rats, Inbred BN; Rats, Sprague-Dawley; Receptor, IGF Type 2; Receptors, Cell Surface; Recombinant Proteins; Renin; RNA Interference; RNA, Small Interfering; Serum Albumin, Bovine; Substrate Specificity; Temperature; Trypsin; Yolk Sac

Angioedema is a subcutaneous swelling typically affecting the face, larynx or pharynx. It is a known adverse drug reaction (ADR) of ACE inhibitors (ACEi), angiotensin-II-receptor blockers (ARBs) and aliskiren (renin inhibitor). Several studies have reported pathophysiological mechanisms and risk factors of ACEi-associated angioedemas, whereas little is known for ARBs and aliskiren. The aim of the study was to analyze comparatively ACEi versus ARBs and aliskiren angioedema reports contained in the European ADR database EudraVigilance with regard to reported risk factors and clinical phenotypes.. All spontaneous angioedema reports received between 01/2010-06/2017 reporting either an ACEi, ARB, or aliskiren as "suspected/interacting" drug were identified using the Standardized MedDRA Query "angioedema (narrow)". In order to perform a comparative analysis, odds ratios (ORs) were calculated for angioedema reports of ACEi (n = 3.194) versus ARBs (n = 687) and aliskiren (n = 162).. More patients with a history of allergy were included in angioedema reports of ARBs (6.8%) and aliskiren (13.6%) versus ACEi (4.3%). "Urticaria" as an ADR was reported more frequently in angioedema reports of ARBs (18.5%) and aliskiren (9.0%) versus ACEi (5.0%). ACEi-associated angioedemas were more often designated as "life-threatening" compared to ARBs (OR 2.2 [1.6-2.9]) and aliskiren-associated angioedemas (OR 14.2 (3.5-57.4). Concomitant therapy with mTOR inhibitors (OR 4.3 [1.0-17.9]) and fibrinolytics (OR 7.8 [1.1-57.2]) was reported more often in ACEi versus ARBs angioedema reports.. The reported clinical phenotypes differed between ACEi versus ARBs and aliskiren angioedema reports. Differences between the patient populations as observed in our study or differences with regard to underlying pathomechanisms could account for this finding. Due to the methodological limitations of spontaneous reporting systems, we cannot draw a firm conclusion in this regard. Hence, further research is necessary to confirm our observation and elucidate the underyling causes.

Topics: Aged; Amides; Angioedema; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Databases, Factual; Drug Prescriptions; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Odds Ratio; Renin-Angiotensin System; Smoking

Topics: Aged; Aged, 80 and over; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; COVID-19; Female; Fumarates; Humans; Hypertension; Male; Renin; Retrospective Studies

It has been suggested that aldosterone breakthrough during treatment with a type 1 angiotensin II receptor (AT1R) blocker (ARB) may be an important risk factor for the progression of renal and cardiovascular disease. We examined whether the direct renin inhibitor, aliskiren caused aldosterone breakthrough in angiotensin II (Ang II)-dependent hypertensive mice. The effect of combination therapy with aliskiren and eplerenone was compared with that of therapy using renin-angiotensin system (RAS) blockade. Tsukuba hypertensive mice were treated for 12 weeks with aliskiren (30 mg/kg/day, i.p), candesartan (5 mg/kg/day, p.o), eplerenone (100 mg/kg/day, p.o) aliskiren and candesartan, aliskiren and eplerenone or candesartan and eplerenone. Blood pressure, urinary aldosterone and angiotensinogen (AGTN) excretion; plasma endothelin-1 concentration; kidney weight; urinary albumin excretion (UAE); glomerular injury; and renal messenger RNA (mRNA) levels for transforming growth factor (TGF)-β1, plasminogen activator inhibitor (PAI)-1, angiotensin-converting enzyme (ACE) and AT1R were measured. Combination therapy with aliskiren and candesartan caused a further decrease in blood pressure (p < 0.05) compared with either agent alone. Urinary aldosterone excretion was decreased significantly by 4 weeks of treatment with aliskiren or candesartan (p < 0.05). However, it was increased again by treatment with candesartan or aliskiren for 12 weeks. Combination therapy with aliskiren and eplerenone significantly decreased UAE, the glomerulosclerosis index, and PAI-1 and TGF-β1 mRNA levels compared with all other therapies (p < 0.05). Treatment with aliskiren decreased urinary aldosterone excretion at 4 weeks and increased it at 12 weeks. Combination therapy with a direct renin inhibitor and a mineralocorticoid receptor blocker may be effective for the prevention of renal injury in Ang II-dependent hypertension.

Topics: Aldosterone; Amides; Animals; Antihypertensive Agents; Drug Evaluation, Preclinical; Drug Therapy, Combination; Eplerenone; Fumarates; Hypertension; Male; Mice; Mineralocorticoid Receptor Antagonists

The present study was designed to evaluate the anti-inflammatory effects of different doses of aliskiren in two animal models of inflammation.. Sixty-six Wistar rats were allocated into five groups: the first group (six rats) was treated with the vehicle only, without induction of paw edema and granulomatous inflammation, and served as a negative control; the second group (12 rats) was allocated into two subgroups and treated with the vehicle only, with induction of paw edema and granulomatous inflammation, and served as a positive control; the third group (36 rats) was allocated into six subgroups and treated with different doses of aliskiren (15, 30, and 60 mg/kg) in both models; the fourth group (12 rats) was treated with dexamethasone (1 mg/kg) in both models of inflammation. Serum concentrations of tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), vascular cell adhesion molecule-1 (VCAM-1), and high sensitivity C-reactive protein (hs-CRP) were measured. Skin samples were also sent for histopathological examination.. Aliskiren, in a dose-dependent pattern, significantly decreased inflammation in rat models of inflammation, by attenuating the percentage of exudate, granuloma, and paw edema. Furthermore, it significantly reduced serum concentrations of TNF-α, VCAM-1, and hs-CRP and restored the serum concentration of IL-10. Additionally, significant improvement was seen in the histopathological findings.. In the current study, aliskiren was successful in decreasing inflammation in both models. These findings suggest that aliskiren is a good candidate for the treatment of inflammatory diseases.

Topics: Amides; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Female; Formaldehyde; Fumarates; Inflammation; Male; Rats; Rats, Wistar; Skin

Topics: Amides; Animals; Anticonvulsants; Avoidance Learning; Brain; Carbamazepine; Disease Models, Animal; Drug Interactions; Epilepsy, Temporal Lobe; Fumarates; Mice; Pentylenetetrazole; Phenobarbital; Seizures

(Pro)renin receptor [(P)RR] has multiple functions, but its regulation and role in the pathogenesis in glomerulonephritis (GN) are poorly defined. The aims of the present study were to determine the effects of direct renin inhibition (DRI) and demonstrate the role of (P)RR on the progression of crescentic GN. The anti-glomerular basement membrane nephritis rat model developed progressive proteinuria (83.64 ± 10.49 mg/day) and glomerular crescent formation (percent glomerular crescent: 62.1 ± 2.3%) accompanied by increased macrophage infiltration and glomerular expression of monocyte chemoattractant protein (MCP)-1, (P)RR, phospho-extracellular signal-regulated kinase (ERK)1/2, Wnt4, and active β-catenin. Treatment with DRI ameliorated proteinuria (20.33 ± 5.88 mg/day) and markedly reduced glomerular crescent formation (20.9 ± 2.6%), induction of macrophage infiltration, (P)RR, phospho-ERK1/2, Wnt4, and active β-catenin. Furthermore, primary cultured parietal epithelial cells stimulated by recombinant prorenin showed significant increases in cell proliferation. Notably, while the ERK1/2 inhibitor PD98059 or (P)RR-specific siRNA treatment abolished the elevation in cell proliferation, DRI treatment did not abrogate this elevation. Moreover, cultured mesangial cells showed an increase in prorenin-induced MCP-1 expression. Interestingly, (P)RR or Wnt4-specific siRNA treatment or the β-catenin antagonist XAV939 inhibited the elevation of MCP-1 expression, whereas DRI did not. These results suggest that (P)RR regulates glomerular crescent formation via the ERK1/2 signaling and Wnt/β-catenin pathways during the course of anti-glomerular basement membrane nephritis and that DRI mitigates the progression of crescentic GN through the reduction of (P)RR expression but not inhibition of prorenin binding to (P)RR.

Topics: Amides; Animals; beta Catenin; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Fumarates; Glomerulonephritis; Male; Mesangial Cells; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphorylation; Rats, Inbred WKY; Receptors, Cell Surface; Vacuolar Proton-Translocating ATPases; Wnt Signaling Pathway; Wnt4 Protein

Topics: Amides; Angiotensin-Converting Enzyme 2; Antihypertensive Agents; Betacoronavirus; Coronavirus Infections; COVID-19; Fumarates; Humans; Pandemics; Peptidyl-Dipeptidase A; Pneumonia, Viral; Renin-Angiotensin System; SARS-CoV-2

Topics: Amides; Calcium Channel Blockers; Female; Fumarates; Humans; Hypertension; Hyponatremia; Middle Aged; Nifedipine; Renal Artery Obstruction; Renin; Syndrome; Thirst

The early suspension of Altitude trial in recent years has induced most nephrologists and cardiologists to abandon Aliskiren use. Consequently, the potential usefulness of the direct renin inhibition in IgA glomerulonephritis remained an under-investigated therapeutic option.. We report the case of a 53 years old IgA GMN patient unresponsive to all conventional anti-angiotensin-2 agents, steroids and immunosuppressants, in which the administration of Aliskiren permitted to achieve and maintain a complete proteinuria remission in the absence of any adverse event.. Aliskiren might represent a valid and safe therapeutic option in IgA GMN, although further investigations would be needed to confirm this conclusion.

Topics: Amides; Biopsy, Needle; Drug Administration Schedule; Drug Resistance, Multiple; Drug Therapy, Combination; Follow-Up Studies; Fumarates; Glomerulonephritis, IGA; Humans; Immunohistochemistry; Immunosuppressive Agents; Irbesartan; Male; Middle Aged; Prednisone; Ramipril; Retreatment; Time Factors; Treatment Outcome

Topics: Amides; Animals; Anticonvulsants; Avoidance Learning; Behavior, Animal; Brain; Disease Models, Animal; Drug Interactions; Fumarates; Male; Memory, Long-Term; Mice; Motor Activity; Pentylenetetrazole; Reaction Time; Renin; Seizures; Time Factors

Despite emergence of new systemic therapies, metastatic melanoma remains a challenging and often fatal form of skin cancer. The renin-angiotensin system (RAS) is a major physiological regulatory pathway controlling salt-water equilibrium, intravascular volume and blood pressure. Biological effects of the RAS are mediated by the vasoactive hormone angiotensin II (AngII) via two receptor subtypes, AT1R (encoded by AGTR1) and AT2R (encoded by AGTR2). We report decreasing expression and increasing CpG island methylation of AGTR1 in metastatic versus primary melanoma and detection in serum of methylated genomic DNA from the AGTR1 CpG island in metastatic melanoma implying that AGTR1 encodes a tumour suppressor function in melanoma. Consistent with this hypothesis, antagonism of AT1R using losartan or shRNA-mediated knockdown in melanoma cell lines expressing AGTR1 resulted in acquisition of the ability to proliferate in serum-free conditions. Conversely, ectopic expression of AGTR1 in cell lines lacking endogenous expression inhibits proliferation irrespective of the presence of AngII implying a ligand-independent suppressor function for AT1R. Treatment of melanoma cell lines expressing endogenous AT2R with either AngII or the AT2R-selective agonist Y6AII induces proliferation in serum-free conditions whereas the AT2R-specific antagonists PD123319 and EMA401 inhibit melanoma growth and angiogenesis and potentiate inhibitors of BRAF and MEK in cells with BRAF V600 mutations. Our results demonstrate that the RAS has both oncogenic and tumour suppressor functions in melanoma. Pharmacological inhibition of AT2R may provide therapeutic opportunities in melanomas expressing this receptor and AGTR1 CpG island methylation in serum may serve as a novel biomarker of metastatic melanoma.

Topics: Amides; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; DNA Methylation; Embryo, Nonmammalian; Fumarates; Humans; Imidazoles; Melanoma; Molecular Targeted Therapy; Neoplasm Metastasis; Pyridines; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; Xenograft Model Antitumor Assays; Zebrafish

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Antineoplastic Agents; Bevacizumab; Cardiotoxicity; Fumarates; Hydralazine; Male; Mice; Mice, Inbred C57BL; Perindopril; Renin-Angiotensin System; Sunitinib; Valsartan; Ventricular Dysfunction

Our aim is to investigate the potentially preventive effects of Aliskiren in a carrageenan-induced lung pleurisy model and to compare the standard anti-inflammatory agents, indomethacin and dexamethasone. The pleurisy model was induced through the injection of carrageenan (0.2 ml-%2) into the pleural cavity. After the experiment, serum and lung tissues were collected and biochemical, molecular and pathological examinations were performed. In our study, pleural inflammation decreased superoxide dismutase activity and the glutathione level and increased the malondialdehyde level in the lung of rats, while Aliskiren increased the superoxide dismutase activity and glutathione level and decreased the malondialdehyde level. In addition, carrageenan-induced pleurisy caused a significant increase in pro-inflammatory cytokines mRNA expressions (TNF-α, IL-1β, and NF-KB), while Aliskiren administration decreased their expressions as well as the standard treatments, indomethacin and dexamethasone, did. Aliskiren administration at the 200 mg/kg dose protected the lungs in the pathological evaluation, especially against inflammatory cell infiltration and edematous lesions. It appears that Aliskiren protects the lung from carrageenan-induced pleurisy damage by regulating inflammation and antioxidant-oxidant balance via Renin Angiotensin Aldosterone System inhibition.

Topics: Amides; Animals; Anti-Inflammatory Agents; Carrageenan; Disease Models, Animal; Fumarates; Glutathione; Interleukin-1beta; Lung; Male; Malondialdehyde; NF-kappa B; Oxidative Stress; Pleurisy; Rats, Wistar; Real-Time Polymerase Chain Reaction; Renin-Angiotensin System; Tumor Necrosis Factor-alpha

Vitamin D plays an important role in water and salt homeostasis. The aim of our study was to investigate the underlying relationship of Vitamin D and Aquaporins (AQP).. The behaviors of 1. Diuresis and polydipsia were observed in 1. Overall, Vitamin D and renin inhibitors have synergistic effects in regulating water channels in mice kidneys.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Animals; Aquaporin 1; Aquaporin 4; Fumarates; Gene Expression Regulation; Humans; Kidney; Kidney Tubules, Proximal; Mice; Mice, Knockout; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Telmisartan; Vitamin D; Water

Topics: Amides; Complement Activation; Fumarates; Humans; Hypertension; Kidney Diseases; Renin

The activation of neurohumoral compensatory mechanisms is a common physiological phenomenon in heart failure in order to make up for a failing heart, which will usually have a deteriorating effect on overall health condition. Many medications, such as neprilysin and angiotensin inhibitors, have recently been introduced to remediate neurohumoral changes. This study was conducted to evaluate the efficacy of the sacubitril-aliskiren combination versus the sacubitril-ramipril combination in the treatment of neurohumoral changes in rats with experimentally induced heart failure.. Thirty Wister rats were randomly assigned into five groups each of six rats, the first group was the control group. Intraperitoneal isoprenaline injections of 5 mg/kg/day for 1 week were used to induce experimental models of heart failure in rats of the rest of experimental groups. The second group served as a positive control. Rats in the third, fourth, and fifth groups received oral daily dose of sacubitril 30 mg/kg/day, sacubitril-aliskiren 30,10 mg/kg/day, and sacubitril-ramipril 30/10 mg/kg/day respectively, for 2 weeks.. Induction of heart failure in rats has significantly increased circulating NT-proBNP (980 ± 116.71 pg/ml), MMP9 (15.85 ± 0.57 ng/ml), troponin-I (3.09 ± 0.147 ng/ml), CK-MB (31.55 ± 1.69 ng/ml), renin (736 ± 45.8 pg/ml), urea (52.1 ± 1.57 mg/dl), and creatinine (0.92 ± 0.04 mg/dl). Significant decreases in glomerular filtration rate (7.031 ± 1.6 ml/hr./kg), urine flow (0.2761 ± 0.06 ml/h/kg), total solute excretion (0.11 ± 0.03 meq/m), and mean blood pressure (83.5 ± 2.6 mm hg) were seen in rats with heart failure. Rats treated with sacubitril combined with aliskiren or ramipril showed a statistically significant reduction of NT-proBNP, MMP9, troponin serum urea, and serum creatinine. Sacubitril-aliskiren or sacubitril-ramipril administration produced a significant increase in renin plasma level, total solute excretion, urine flow, and glomerular filtration rate.. Sacubitril in combination with aliskiren or with ramipril effectively reduced plasma cardiac biomarkers, such as CK-MB, MMP9, and NT-proBNP, in rats with heart failure. Both combinations showed significant remediation of renal function through increasing GFR, urine flow, and total solute excretion, as well as reducing plasma level of renin. Net results revealed that the sacubitril-aliskiren combination has similar remediating effects on neurohumoral changes compared to the sacubitril-ramipril combination.

Topics: Amides; Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensins; Animals; Biomarkers; Biphenyl Compounds; Blood Pressure; Creatine Kinase, MB Form; Drug Combinations; Female; Fumarates; Heart Failure; Heart Rate; Kidney; Matrix Metalloproteinase 9; Natriuretic Peptide, Brain; Neprilysin; Peptide Fragments; Ramipril; Rats, Wistar; Renin; Tetrazoles; Troponin I; Valsartan

Aliskiren, a renin inhibitor, has been shown to have cardioprotective and blood pressure (BP) lowering effects. We aimed to determine the effects of nanoparticle-loaded aliskiren on BP, nitric oxide synthase activity (NOS) and structural alterations of the heart and aorta developed due to spontaneous hypertension in rats. Twelve week-old male spontaneously hypertensive rats (SHR) were divided into the untreated group, group treated with powdered or nanoparticle-loaded aliskiren (25 mg/kg/day) and group treated with nanoparticles only for 3 weeks by gavage. BP was measured by tail-cuff plethysmography. NOS activity, eNOS and nNOS protein expressions, and collagen content were determined in both the heart and aorta. Vasoactivity of the mesenteric artery and wall thickness, inner diameter, and cross-sectional area (CSA) of the aorta were analyzed. After 3 weeks, BP was lower in both powdered and nanoparticle-loaded aliskiren groups with a more pronounced effect in the latter case. Only nanoparticle-loaded aliskiren increased the expression of nNOS along with increased NOS activity in the heart (by 30%). Moreover, nanoparticle-loaded aliskiren decreased vasoconstriction of the mesenteric artery and collagen content (by 11%), and CSA (by 25%) in the aorta compared to the powdered aliskiren group. In conclusion, nanoparticle-loaded aliskiren represents a promising drug with antihypertensive and cardioprotective effects.

Topics: Amides; Animals; Antihypertensive Agents; Biomarkers; Blood Pressure; Cardiovascular System; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Carriers; Fumarates; Heart; Hypertension; Nanoparticles; Nitric Oxide; Polyesters; Rats; Rats, Inbred SHR

Estimating the solubility and solution thermodynamics parameters of aliskiren hemifumarate (AHF) in three different room temperature ionic liquids (RTILs), Transcutol-HP (THP) and water are interesting as there is no solubility data available in the literature. In the current study, the solubility and solution thermodynamics of AHF in three different RTILs, THP and water at the temperature range from 298.2 to 318.2 K under air pressure 0.1 MP were evaluated. The solid phase evaluation by Differential Scanning Calorimetry (DSC) and Powder X-ray Diffraction (PXRD) indicated no conversion of AHF into polymorph. The mole fraction solubility of AHF was found to be highest in 1-hexyl-3-methylimidazolium hexafluorophosphate (HMMHFP) ionic liquid (7.46 × 10

Topics: Amides; Ethylene Glycols; Fumarates; Ionic Liquids; Solubility; Solvents; Temperature; Thermodynamics; Water; X-Ray Diffraction

Topics: Aged; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Drug Therapy, Combination; Female; Fumarates; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System

Cardioprotective potential of aliskiren against isoproterenol-induced myocardial infarction was evaluated in this study.. Isoproterenol treatment caused a significant increase in cardiac markers, malondialdehyde, and caspase-3 levels with a considerable decrease in reduced glutathione, superoxide dismutase and catalase enzyme levels. Aliskiren at 50 and 100 mg/kg doses significantly alleviated the increase of caspase-3 and cardiac marker enzymes as well as the changes in antioxidant enzymes, which was confirmed by histopathological analysis. Aliskiren (100 mg/kg) produced more pronounced protective effects than its other two doses. Moreover, the changes in per se group were insignificant as compared to normal control group.. The present study thus provides an evidence for the protective effects of aliskiren in isoproterenol-induced myocardial infarction.

Topics: Amides; Animals; Biomarkers; Cardiotonic Agents; Catalase; Creatine Kinase, MB Form; Dose-Response Relationship, Drug; Fumarates; Glutathione; Isoproterenol; Male; Malondialdehyde; Myocardial Infarction; Myocardium; Rats; Renin; Superoxide Dismutase

The intrarenal renin angiotensin system (RAS) is activated in polycystic kidney disease. We have recently shown in the Pkd1 mouse that Gen 2 antisense oligonucleotide (ASO), which suppresses angiotensinogen (Agt) synthesis, is efficacious in slowing kidney cyst formation compared with lisinopril. The aim of this current study was to determine 1) if unilateral nephrectomy accelerates cystogenesis in Pkd1 mice (as previously shown in cilia knockout mice) and 2) whether Agt ASO can slow the progression in this accelerated cystic mouse model. Adult Pkd1 conditional floxed allele mice expressing cre were administered tamoxifen, resulting in global knockout of Pkd1. Three weeks after tamoxifen injection, mice underwent left unilateral nephrectomy. Mice were then treated with Agt ASO (75 mg/kg per week) or aliskiren (20 mg/kg per day)+Agt ASO or control for 8 wk. Unilateral nephrectomy accelerated kidney cyst formation compared with nonnephrectomized mice. Both Agt ASO and Aliskiren+Agt ASO treatments significantly reduced plasma and urinary Agt levels. Blood pressure was lowest in Aliskiren+Agt ASO mice among all treatment groups, and the control group had the highest blood pressure. All mice developed significant kidney cysts at 8 wk after nephrectomy, but Agt ASO and Aliskiren+Agt ASO groups had fewer kidney cysts than controls. Renal pAkt, pS6 levels, and apoptosis were significantly suppressed in those receiving Agt ASO compared with controls. These results indicate that suppressing Agt using an ASO slowed the progression of accelerated cystic kidney disease induced by unilateral nephrectomy in Pkd1 mice by suppressing intrarenal RAS, mammalian target of rapamycin pathway, and cell proliferation.

Topics: Amides; Angiotensinogen; Animals; Apoptosis; Cell Proliferation; Disease Models, Animal; Disease Progression; ErbB Receptors; Female; Fumarates; Genetic Predisposition to Disease; Kidney; Male; Mice, Knockout; Nephrectomy; Oligonucleotides, Antisense; Phenotype; Polycystic Kidney, Autosomal Dominant; Renin; Renin-Angiotensin System; Time Factors; TOR Serine-Threonine Kinases; TRPP Cation Channels

Neither ACEI nor ARBs completely repress the RAAS. Aliskiren is a newer agent that inhibits renin. However, it increases the biosynthesis and secretion of renin and prorenin, that might induce renal tissue damage. This study was conducted to investigate the renoprotective effects of aliskiren and valsartan the ARB, either alone or in combination, on hypertensive nephropathy induced by L-NAME. Aliskiren (50 mg/kg/daily i.p.), valsartan (10 mg/kg daily i.p.) alone or in half dose combination were administered with L-NAME (30-40 mg daily in drinking water) for 8 weeks. Aliskiren and valsartan significantly reduced systolic blood pressure, proteinuria, serum creatinine, blood urea nitrogen, oxidative stress, and structural renal injury although not to the same extent. Valsartan reduced systolic blood pressure and proteinuria in L-NAME treated rats more significantly than aliskiren. However, glomerular collapse index and the expansion of interstitial tissue were significantly attenuated by aliskiren than by valsartan. Cotreatment with aliskiren and valsartan markedly reduced the oxidative stress and further reduced the glomerular collapse and the expansion of interstitial tissue compared with aliskiren monotherapy.. These results suggest that therapies aimed at different targets within the RAAS may have additional effects in attenuating structural injury in experimental hypertensive nephropathy.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Blood Urea Nitrogen; Creatinine; Drug Therapy, Combination; Enzyme Inhibitors; Fumarates; Hypertension; Kidney; Kidney Diseases; Male; NG-Nitroarginine Methyl Ester; Oxidative Stress; Proteinuria; Rats; Rats, Wistar; Valsartan

Topics: Amides; Animals; Anticonvulsants; Drug Interactions; Electroshock; Fumarates; Male; Mice; Protease Inhibitors; Renin

Arterial hypertrophy and interstitial fibrosis are important characteristics in kidneys of angiotensinogen-knockout (Atg. We performed renal denervation and administered the α2-adrenergic receptor (AR) antagonist, atipamezole, to Atg. Norepinephrine content in kidneys of Atg. Alpha2-AR signaling is one of the causes of persistent renal arterial hypertrophy in Atg

Topics: Adrenergic alpha-2 Receptor Antagonists; Amides; Angiotensinogen; Animals; Fibrosis; Fumarates; Hypertrophy; Japan; Kidney; Mice; Mice, Inbred ICR; Mice, Knockout; Renal Artery; Renin; Tokyo; Transforming Growth Factor beta1

Renin-angiotensin system activation promotes oxidative stress and endothelial dysfunction. However, no previous study has examined the effects of the renin inhibitor aliskiren, either alone or combined with angiotensin II type 1 antagonists on alterations induced by two-kidney, one-clip (2K1C) hypertension. We compared the vascular effects of aliskiren (50mg/kg/day), losartan (10mg/kg/day), or both by gavage for 4 weeks in 2K1C and control rats. Treatment with losartan, aliskiren, or both exerted similar antihypertensive effects. Aliskiren lowered plasma Ang I concentrations in sham rats and in hypertensive rats treated with aliskiren or with both drugs. Aliskiren alone or combined with losartan decreased plasma angiotensin II concentrations measured by high performance liquid chromatography, whereas losartan alone had no effects. In contrast, losartan alone or combined with aliskiren abolished hypertension-induced increases in aortic angiotensin II concentrations, whereas aliskiren alone exerted no such effects. While hypertension enhanced aortic oxidative stress assessed by dihydroethidium fluorescence and by lucigenin chemiluminescence, losartan alone or combined with aliskiren, but not aliskiren alone, abolished this alteration. Hypertension impaired aortic relaxation induced by acetylcholine, and losartan alone or combined with aliskiren, but not aliskiren alone, reversed this alteration. Losartan alone or combined with aliskiren, but not aliskiren alone, increased plasma nitrite concentrations in 2K1C rats. These findings show that antihypertensive effects of aliskiren do not prevent hypertension-induced vascular oxidative stress and endothelial dysfunction. These findings contrast those found with losartan and suggest that renin inhibition is not enough to prevent hypertension-induced impaired redox biology and vascular dysfunction.

Topics: Amides; Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Aorta; Drug Synergism; Fumarates; Hypertension, Renovascular; Losartan; Male; Nitrites; Oxidative Stress; Rats; Reactive Oxygen Species; Relaxation; Renin

Psoriasis is a complex inflammatory and hyperproliferative skin disease. The pathogenesis and mechanisms involved are not completely understood, which makes treatment a difficult issue. Angiotensin II, the most active peptide of the renin-angiotensin system, seems to be involved in processes related to psoriasis pathogenesis, such as inflammation and cell proliferation. The aim of this study was to investigate the influence of renin inhibition on inflammation parameters and keratinocyte proliferation in a mouse model of chronic skin inflammation induced by croton oil. Aliskiren had anti-inflammatory effects by reducing levels of tumor necrosis factor-α and interleukin -6, and by inhibiting myeloperoxidase activity. Aliskiren also showed antiproliferative activity by reducing epidermal hyperplasia and proliferating cell nuclear antigen levels. Aliskiren treatment did not induce alterations in the cardiovascular system, normal skin thickness, and organ weight. These results suggest that aliskiren could be a valuable tool to be incorporated in the treatment of hyperproliferative and inflammatory skin disorders such as psoriasis.

Topics: Amides; Angiotensin II; Animals; Anti-Inflammatory Agents; Antihypertensive Agents; Cardiovascular System; Disease Models, Animal; Female; Fumarates; Inflammation; Keratinocytes; Mice; Psoriasis; Renin; Renin-Angiotensin System; Skin Diseases

In 2012, the European Medicines Agency reviewed the safety of dual renin-angiotensin system (RAS) blockade because of potentially increased risks for inter alia acute kidney injury (AKI). Since residents of nursing homes are particularly vulnerable to adverse drug outcomes, the aims of our study were to describe RAS-inhibiting drug use in German nursing home residents and examine the risk of AKI associated with dual RAS blockade.. Based on claims data, a nested case-control study within a cohort of RAS-inhibiting drug users was conducted. Using conditional logistic regression, confounder-adjusted odds ratios (aORs) and 95% confidence intervals (CI) were obtained for the risk of AKI associated with dual RAS blockade. Subgroup analyses were performed in patients with diabetes or chronic kidney disease and both comorbidities.. Of all 127,227 nursing home residents, the study cohort included 64,567 (50.7%) who were treated with at least one RAS-inhibiting drug. More than three quarters of the study population were female (77.1%). Mean age was 86.0 ± 6.8 years. Most residents were treated with angiotensin-converting enzyme inhibitors (77.8%), followed by angiotensin II receptor blockers (21.6%) and aliskiren (0.2%). Annual prevalence of dual RAS blockade declined from 9.6 (95% CI 7.8-11.8) in 2010 to 4.7 (95% CI 4.0-5.4) per 1,000 users in 2014. In the overall cohort, AKI was not significantly associated with dual RAS blockade (aOR 1.99; 0.77-5.17). However, significantly increased aORs were observed when considering patients with diabetes (3.47; 1.27-9.47), chronic kidney disease (4.74; 1.24-18.13) or both (11.17; 2.65-47.15).. Prescribing of drugs inhibiting the RAS is common in German nursing homes. Though the prevalence of dual RAS blockade declined, our study showed an increased risk of AKI in patients with diabetes and/or chronic kidney disease. Therefore, cautious use is warranted in these vulnerable patients.

Topics: Acute Kidney Injury; Aged; Aged, 80 and over; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Case-Control Studies; Cohort Studies; Diabetes Mellitus; Drug Prescriptions; Drug Therapy, Combination; Female; Fumarates; Germany; Humans; Male; Nursing Homes; Renal Insufficiency, Chronic; Renin-Angiotensin System; Risk Factors

Certain kidney diseases are associated with complement activation although a renal triggering factor has not been identified. Here we demonstrated that renin, a kidney-specific enzyme, cleaves C3 into C3b and C3a, in a manner identical to the C3 convertase. Cleavage was specifically blocked by the renin inhibitor aliskiren. Renin-mediated C3 cleavage and its inhibition by aliskiren also occurred in serum. Generation of C3 cleavage products was demonstrated by immunoblotting, detecting the cleavage product C3b, by N-terminal sequencing of the cleavage product, and by ELISA for C3a release. Functional assays showed mast cell chemotaxis towards the cleavage product C3a and release of factor Ba when the cleavage product C3b was combined with factor B and factor D. The renin-mediated C3 cleavage product bound to factor B. In the presence of aliskiren this did not occur, and less C3 deposited on renin-producing cells. The effect of aliskiren was studied in three patients with dense deposit disease and this demonstrated decreased systemic and renal complement activation (increased C3, decreased C3a and C5a, decreased renal C3 and C5b-9 deposition and/or decreased glomerular basement membrane thickness) over a follow-up period of four to seven years. Thus, renin can trigger complement activation, an effect inhibited by aliskiren. Since renin concentrations are higher in renal tissue than systemically, this may explain the renal propensity of complement-mediated disease in the presence of complement mutations or auto-antibodies.

Topics: Amides; Chemotaxis; Child; Complement Activation; Complement C3; Complement C3a; Complement C3b; Complement C4; Complement C5a; Complement C5b; Complement Factor B; Complement Factor D; Female; Fumarates; Glomerular Basement Membrane; Glomerulonephritis, Membranoproliferative; Humans; Mast Cells; Renin

Schistosomiasis mansoni is involved in hepatic fibrogenesis and portal hypertension. Previous studies proved that blockade of some components of the renin-angiotensin system (RAS) reduce liver fibrogenesis. However, the effects of inhibition of early stages of RAS pathway in schistosomal fibrosis have not been studied yet. Thus, the aim of this study was to compare the role of different antihypertensive drugs on hepatic fibrosis in murine schistosomiasis. BALB/c mice (n = 50) weighing 20g were subjected to inoculation of 50 cercariae and submitted to different treatments: aliskiren, 50 mg/kg (n = 10); bradykinin, 2 μg/kg (n = 5); losartan, 10 mg/kg (n = 10); lisinopril 10 mg/kg (n = 5) and control, proportional volume vehicle (n = 5); daily for 14 weeks. Six animals were not subjected to cercariae inoculation or any type of treatment. Ultrasound, histological, immunohistochemical and proteomic analyzes were performed to evaluate markers associated with hepatic fibrogenesis. The hepatic areas stained with Sirius red and thenumber of cells marked by α-SMA in animals treated with aliskiren, bradykinin, lisinopril and losartan were diminished when compared to control group, demonstrating reduced hepatic fibrosis after RAS blockade. These results were reinforced by ultrasonography analysis and protein expression of TGFβ. These findings demonstrated the effect of RAS inhibition on hepatic fibrosis in murine schistosomiasis, with the most evident results being observed in the losartan and aliskiren treated groups. The main mechanisms underlying this process appear to involve anti-fibrogenic activity through the inhibition of collagen and TGFβ synthesis.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Bradykinin; Fumarates; Lisinopril; Liver; Liver Cirrhosis; Losartan; Male; Mice; Mice, Inbred BALB C; Nitric Oxide Synthase Type III; p38 Mitogen-Activated Protein Kinases; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Renin; Renin-Angiotensin System; Schistosomiasis mansoni; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta1; Vasodilator Agents

Topics: Aged; Amides; Antihypertensive Agents; Blood Pressure; Double-Blind Method; Exercise Tolerance; Female; Fumarates; Heart Failure; Humans; Male; Randomized Controlled Trials as Topic; Stroke Volume

This study examined the effects of aliskiren (Ali) (direct renin inhibitor) on serum cardiac enzymes (LDH and CK-MB), electrocardiography (ECG) changes, myocardial oxidative stress markers (MDA, CAT, and GSH) and the expression of Bcl2, HO-1, and Nrf2 genes in isoproterenol (ISO)-induced myocardial infarction (MI). A total of 40 male albino rats were allocated into four groups, (1) normal control (NC) group, (2) Ali group (rats received Ali at 10 mg/kg/day p.o. for 5 days), (3) ISO group (rats received ISO 150 mg/kg i.p. for two consecutive days at 24 h intervals), and (4) Ali + ISO group (rats received ISO + Ali at 10 mg/kg/day p.o. for 5 days from the 2

Topics: Amides; Animals; Apoptosis; Cardiotonic Agents; Fumarates; Isoproterenol; Male; Myocardial Infarction; Oxidative Stress; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System

Lipotoxicity plays an important role in the pathogenesis of kidney injury. Our previous study demonstrated that activation of local renin-angiotensin system (RAS) was involved in saturated free fatty acids palmitic acid (PA)-induced tubular cell injuries. The current study aims to investigate whether suppression of RAS by combination of direct renin inhibitor aliskiren and noncanonical RAS pathway chymase inhibitor chymostatin attenuates PA or cholesterol induced-endoplasmic reticulum stress (ER stress) and apopotosis in cultured human proximal tubular HK2 cells.. HK2 cells were treated with saturated fatty acid PA (0.6 mM) for 24 h or cholesterol (10 μg/ml) for 6d with or without chymostatin and/or aliskiren. Expressions of the ER stress associated proteins and apoptosis markers were detected by western blotting. The mRNA levels of RAS components were measured by real-time qPCR.. Combination treatment of chymostatin and aliskiren markedly suppressed PA or cholesterol-induced ER stress, as reflected by increased BiP, IRE1α, phosphorylated-eIF2α and ATF4 as well as proapoptotic transcription factor CHOP. The ratio of Bax/Bcl-2 and cleaved caspase-3, two markers of apoptosis were upregulated by PA or cholesterol treatment. PA treatment was also associated with increased levels of angiotensinogen and angiotensin type 1 receptor (AT1R) mRNA expression. Combination treatment of chymostatin and aliskiren markedly suppressed PA or cholesterol-induced ER stress and apoptosis. The protective effect of two inhibitors was also observed in primary cultured cortical tubular cells treated with PA. In contrast, chymostatin and/or aliskiren failed to prevent ER stress induced by tunicamycin.. These results suggested that combination treatment of chymostatin and aliskiren attenuates lipid-induced renal tubular cell injury, likely through suppressing activation of intracellular RAS.

Topics: Activating Transcription Factor 4; Amides; Antihypertensive Agents; bcl-2-Associated X Protein; Caspase 3; Cell Line, Transformed; Cholesterol; Drug Combinations; Drug Synergism; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Endoribonucleases; Epithelial Cells; Eukaryotic Initiation Factor-2; Fumarates; Gene Expression Regulation; Heat-Shock Proteins; Humans; Kidney Tubules, Proximal; Oligopeptides; Palmitic Acid; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-bcl-2; Receptor, Angiotensin, Type 1; Serine Proteinase Inhibitors; Signal Transduction; Transcription Factor CHOP

The renin-angiotensin system (RAS), which plays an important role in the progression of heart failure, is efficiently blocked by the inhibition of renin, the rate-limiting enzyme in the RAS cascade. In the present study, we investigated the cardioprotective effects of TAK-272 (SCO-272, imarikiren), a novel, orally effective direct renin inhibitor (DRI), and compared its efficacy with that of aliskiren, a DRI that is already available in the market. TAK-272 was administered to calsequestrin transgenic (CSQ-tg) heart failure mouse model that show severe symptoms and high mortality. The CSQ-tg mice treated with 300 mg/kg, the highest dose tested, of TAK-272 showed significantly reduced plasma renin activity (PRA), cardiac hypertrophy, and lung congestion. Further, TAK-272 reduced cardiomyocyte injury accompanied by an attenuation of the increase in NADPH oxidase 4 and nitric oxide synthase 3 expressions. TAK-272 also prolonged the survival of CSQ-tg mice in a dose-dependent manner (30 mg/kg: P = 0.42, 100 mg/kg: P = 0.12, 300 mg/kg: P < 0.01). Additionally, when compared at the same dose level (300 mg/kg), TAK-272 showed strong and sustained PRA inhibition and reduced the heart weight and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration, a heart failure biomarker, while aliskiren showed a significant weaker PRA inhibition and failed to demonstrate any cardioprotective effects. Our results showed that TAK-272 is an orally active and persistent renin inhibitor, which reduced the mortality of CSQ-tg mice and conferred protection against cardiac hypertrophy and injury. Thus, TAK-272 treatment could provide a new therapeutic approach for heart failure.

Topics: Amides; Animals; Benzimidazoles; Cardiovascular Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fumarates; Heart; Heart Failure; Hypertrophy; Lung Diseases; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Morpholines; Piperidines; Protective Agents; Random Allocation; Renin

Aberrant regulation of an alternative pathway of the complement system could be a therapeutic target of C3 glomerulopathy, including dense deposit disease. In the current issue, Békássy and colleagues provide data on enzymatic conversion of C3 by renin in vitro and on the efficacy of a direct renin inhibitor, aliskiren, on systemic and renal complement activation in patients with dense deposit disease.

Topics: Amides; Complement Activation; Complement C3; Complement Pathway, Alternative; Fumarates; Glomerulonephritis, Membranoproliferative; Humans; Renin

Considering the importance of the renin-angiotensin system (RAS) in diabetic nephropathy (DN) and the link between mast cells (MC) and the RAS, this study evaluated the effects of RAS blockade on the MC cell population in the kidneys from rats with experimental diabetes. Wistar rats were divided into six groups: control non-diabetic (C); sham (S); diabetic (D); and D treated with enalapril (EN), losartan (LO), or aliskiren (AL). Ninety days after diabetes induction, glomerular filtration rate (GFR) and urinary albumin excretion (UAE) were determined. Kidneys were collected for MC counting. RAS blockers minimized changes in morphometrical parameters (EN), cortical collagen (LO, AL), GFR (AL) and UAE (EN, LO). An increased number of MC was observed in the kidneys from D animals. Only AL treatment prevented this increase. MC may be involved in some aspects of DN pathogenesis and the possible protective effects of AL on the kidneys might involve MC modulation.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enalapril; Fumarates; Glomerular Filtration Rate; Losartan; Male; Mast Cells; Rats; Rats, Wistar; Renin-Angiotensin System

Although physicians learn about new medical technologies from their peers, the magnitude and source of peer influence is unknown. We estimate the effect of peer adoption of three first-in-class medications (dabigatran, sitigliptin, and aliskiren) on physicians' own adoption of those medications. We included 11,958 physicians in Pennsylvania prescribing anticoagulant, antidiabetic, and antihypertensive medications. We constructed 4 types of peer networks based on shared Medicare and Medicaid patients, medical group affiliation, hospital affiliation, and medical school/residency training. Instrumental variables analysis was used to estimate the causal effect of peer adoption (fraction of peers in each network adopting the new drug) on physician adoption (prescribing at least the median number prescriptions within 15 months of the new drug's introduction). We illustrate how physician network position can inform targeting of interventions to physicians by computing a social multiplier. Dabigatran was adopted by 25.2%, sitagliptin by 24.5% and aliskiren by 8.3% of physicians. A 10-percentage point increase in peer adoption in the patient-sharing network led to a 5.90% (SE = 1.50%, p<0.001) increase in physician adoption of dabigatran, 8.32% (SE = 1.51%, p<0.001) increase in sitagliptin, and 7.84% increase in aliskiren adoption (SE = 2.93%, p<0.001). Peer effects through shared hospital affiliation were positive but not significant, and medical group and training network effects were not reliably estimated. Physicians in the top decile of patient-sharing network peers were estimated to have nearly 2-fold stronger influence on their peers' adoption compared to physicians in the top decile of prescribing volume. Limitations include lack of detailed clinical information and pharmaceutical promotion, variables which may influence physician adoption but which are unlikely to bias our peer effect estimates. Peer adoption, especially by those with whom physicians share patients, strongly influenced physician adoption of new drugs. Our study shows the potential for using information on physician peer networks to improve technology diffusion.

Topics: Amides; Dabigatran; Drug Prescriptions; Drug Utilization; Female; Fumarates; Humans; Male; Medicaid; Medicare; Peer Group; Pennsylvania; Practice Patterns, Physicians'; Sitagliptin Phosphate; United States

Topics: Acute Disease; Amides; Fumarates; Heart Failure; Hospitalization; Humans; Inpatients; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Treatment Outcome

Objective To investigate the role of aliskiren (AL) in the angiotensinII/ angiotensin 1-7 (AngII/Ang1-7) signal pathway in renal tissue of diabetic nephropathy (DN) rats. Methods 40 male SD rats were randomly divided into 4 groups including normal group, diabetes group, AL group and valsartan (Val) group. Animal models of diabetes were induced by high fat diet combined with small dose of streptozotocin injection. Rats in AL group were administered 50 mg/(kg.d) AL by gavage, and rats in Val group were administered 30 mg/(kg.d)Val by gavage. 24-hour urine protein (24 h-UP) were observed by Coomassie blue colorimetry at 2, 4 and 6 weeks after modeling, serum creatinine was detected by automatic biochemical analyser, kidney index [kidneys mass(g)/body mass (kg)] was measured. HE and PAS staining were used to observe renal pathological changes. Immunohistochemistry was used to detect the expression of ACE2, MAS receptor, AT1R and AT2R in the kidney. Results After 6 weeks of modeling, there was no significant difference in creatinine level among groups. The levels of glucose, 24 h-UP and kidney index in diabetes group, AL group and Val group significantly increased. Compared with diabetes group, the levels of 24 h-UP and kidney index were lower in AL group and Val group. Immunohistochemistry showed that the expression of AT2R and ACE2 was lower and the expression of MAS receptor was higher in AL group than diabetes group and Val group. Compared to normal group and Val group, AT1R expression was significantly up-regulated in AL group, without significant difference between diabetes group and AL group. Conclusion AL down-regulates the expression of AT2R and ACE2, thus inhibits the AngII/ Ang1-7 signal axis and improves/alleviates the symptoms in diabetic rats.

Topics: Amides; Angiotensin I; Angiotensin II; Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Fumarates; Male; Peptide Fragments; Random Allocation; Rats; Rats, Sprague-Dawley; Signal Transduction

Microcystins (MCs) are a group of monocyclic heptapeptide toxins that have been shown to act as potent hepatotoxins. However, the observed symptoms of water metabolism disruption induced by microcystin-RR (MC-RR) or MCs have rarely been reported, and a relatively clear mechanism has not been identified. In the present study, male mice were divided into 4 groups (A: 140μg/kg, B: 70μg/kg,C: 35μg/kg, and D: 0μg/kg) and administered MC-RR daily for a month. On day 8 of treatment, an increase in water intake and urine output was observed in the high-dose group compared with the control, and the symptoms worsened with the repeated administration of the toxin until day 30. In addition, the urine specific gravity decreased and serum enzymes that can reflect hepatic damage increased in the high-dose group compared with the control (P<0.05). The mRNA level of angiotensinogen (AGT) in hepatocytes was upregulated to approximately 150% of the control (P<0.05), and the serum renin-angiotensin system (RAS) was activated in the high-dose group; however, signs of renal injury were not observed throughout the experiment. After the toxin treatment was completed, the high levels of the RAS and vasopressin in group A returned to normal levels within 1 week. As expected, the symptoms of polyuria and polydipsia also disappeared. Therefore, we propose that water metabolism dysfunction occurs via RAS activation caused by liver damage because the increased serum RAS levels in the experiment were consistent with the increased urine output and water intake in the mice during the observation period. In addition, we found for the first time that a RAS blocker could alleviate the observed polyuria and polydipsia and inactivate the high level of the RAS induced by MC-RR in a dose-dependent manner, which further supported our hypothesis.

Topics: Amides; Animals; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Fumarates; Male; Marine Toxins; Mice, Inbred Strains; Microcystins; Polydipsia; Polyuria; Renin-Angiotensin System; Water; Water Pollutants, Chemical

Because of the presence of the blood-brain barrier, brain renin-angiotensin system activity should depend on local (pro)renin synthesis. Indeed, an intracellular form of renin has been described in the brain, but whether it displays angiotensin (Ang) I-generating activity (AGA) is unknown. Here, we quantified brain (pro)renin, before and after buffer perfusion of the brain, in wild-type mice, renin knockout mice, deoxycorticosterone acetate salt-treated mice, and Ang II-infused mice. Brain regions were homogenized and incubated with excess angiotensinogen to detect AGA, before and after prorenin activation, using a renin inhibitor to correct for nonrenin-mediated AGA. Renin-dependent AGA was readily detectable in brain regions, the highest AGA being present in brain stem (>thalamus=cerebellum=striatum=midbrain>hippocampus=cortex). Brain AGA increased marginally after prorenin activation, suggesting that brain prorenin is low. Buffer perfusion reduced AGA in all brain areas by >60%. Plasma renin (per mL) was 40× to 800× higher than brain renin (per gram). Renin was undetectable in plasma and brain of renin knockout mice. Deoxycorticosterone acetate salt and Ang II suppressed plasma renin and brain renin in parallel, without upregulating brain prorenin. Finally, Ang I was undetectable in brains of spontaneously hypertensive rats, while their brain/plasma Ang II concentration ratio decreased by 80% after Ang II type 1 receptor blockade. In conclusion, brain renin levels (per gram) correspond with the amount of renin present in 1 to 20 μL of plasma. Brain renin disappears after buffer perfusion and varies in association with plasma renin. This indicates that brain renin represents trapped plasma renin. Brain Ang II represents Ang II taken up from blood rather than locally synthesized Ang II.

Topics: Amides; Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Blood-Brain Barrier; Brain; Desoxycorticosterone Acetate; Disease Models, Animal; Fumarates; Hypertension; Mice; Mice, Knockout; Random Allocation; Rats; Rats, Inbred SHR; Reference Values; Renin-Angiotensin System

The renoprotective effects of the direct renin inhibitor, aliskiren, in renal transplant recipients have been supposed, but not finally proven. We performed an exploratory double-blind, losartan controlled, cross-over study to evaluate the influence of aliskiren, direct renin inhibitor, on albuminuria and other surrogate markers of kidney injury in patients after renal transplantation. The safety of this therapy was also evaluated.. 16 of 18 patients (12 M, 4 F), 48.3 ± 9.0 years, 57.7 ± 9.1 months after kidney transplantation, with hypertension and stable serum creatinine 1.4 ± 0.08 mg/dl without proteinuria, completed the protocol. Each patient underwent two 8-week treatment periods (one with 150 mg of aliskiren, and one with 50 mg of losartan) in random order, allowing an 8-week placebo washout between them.. There were no differences in albuminuria, transforming growth factor β-1 and 15-F2t-isoprostanes urine excretion between aliskiren and losartan. Creatinine serum level, eGFR, 24 h systolic and 24 h diastolic blood pressure were stable through the study. There were no differences in haemoglobin and potassium serum concentration between studied drugs.. Aliskiren decreases albuminuria in renal transplant recipients with clinically minimal side effects. The effect does not differ from that of losartan.

Topics: Adult; Aged; Albuminuria; Amides; Blood Pressure; Creatinine; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Kidney Transplantation; Losartan; Male; Middle Aged

The accelerated generation of endothelial microparticles (EMPs) and impaired angiogenesis are the markers of vascular pathology during various cardiovascular and inflammatory conditions including hypertension. Because studies comparing the effects of antihypertensive agents on these 2 parameters are limited, this study was designed to compare the effects of 3 antihypertensive agents: aliskiren, nebivolol, and olmesartan, on the EMP generation and angiogenesis. Changes in the hemodynamic parameters and serum EMP count were determined after 3 weeks of the drug treatments [aliskiren (30 mg/kg), nebivolol (10 mg/kg), or olmesartan (5 mg/kg) per orally] in L-NAME-induced rat model of hypertension. The 3 drugs prevented the rise in blood pressure and EMP count to a similar extent. Furthermore, nebivolol was found to possess more potent and concentration-dependent antiangiogenic activity compared with aliskiren, whereas olmesartan was devoid of such an effect. The EMPs generated by virtue of the respective drug treatments were found to be involved in mediating the antiangiogenic effect of nebivolol and aliskiren. In addition, olmesartan treatment also resulted in the increased eNOS expression. The results of this study show that the antihypertensive drugs, viz. aliskiren, nebivolol, and olmesartan, regulate the vascular health by their differential effects on the EMP generation and angiogenesis.

Topics: Amides; Animals; Antihypertensive Agents; Cell-Derived Microparticles; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Imidazoles; Male; Nebivolol; Neovascularization, Pathologic; Random Allocation; Rats; Rats, Sprague-Dawley; Tetrazoles

Pulmonary fibrosis, which influences lung function and exacerbates a patient's condition, is the ultimate stage of many lung diseases. Vitamin D deficiency is associated with pulmonary fibrosis and impaired lung function, but the underlying mechanism has not yet been fully elucidated. Moreover, vitamin D deficiency may cause over-activation of the renin-angiotensin system (RAS), which aggravates extracellular matrix (ECM) deposition and lung fibrosis. This study aims to investigate the effect of chronic vitamin D deficiency on lung fibrosis in otherwise healthy mice and to explore the role of RAS in this process. Mice were depleted of vitamin D through diet control and were compared with healthy subjects. Chronic vitamin D deficiency destructs lung structures, impairs lung development and stimulates ECM deposition. RAS components are also found to increase. These effects seem to worsen with prolonged vitamin D deficiency. By giving RAS blockers, these changes can be largely rescued. However, a smooth muscle relaxant whose regulatory effect on blood pressure is independent of RAS does not show similar effects. This study demonstrated that chronic vitamin D deficiency may induce RAS activation, which subsequently stimulates the expression of profibrotic factors and activates the fibrotic cascade. This profibrotic effect of RAS is independent of elevated blood pressure.

Topics: Amides; Animals; Blood Pressure; Chronic Disease; Extracellular Matrix; Female; Fumarates; Losartan; Lung; Mice; Pulmonary Fibrosis; Renin-Angiotensin System; Vitamin D Deficiency

Renin-angiotensin system in visceral fat plays a crucial role in the pathogenesis of metabolic syndrome in fructose-fed rats. However, the effects of renin inhibition on visceral adiposity in metabolic syndrome are not fully investigated. We investigated the effects of renin inhibition on visceral adiposity in fructose-fed rats. Male Wistar-Kyoto rats were divided into 4 groups for 8-week experiments: Group Con (standard chow diet), Group Fru (high-fructose diet; 60% fructose), Group FruA (high-fructose diet and concurrent aliskiren treatment; 100 mg/kg body weight [BW] per day), and Group FruB (high-fructose diet and subsequent, i.e. 4 weeks after initiating high-fructose feeding, aliskiren treatment; 100 mg/kg BW per day). The high-fructose diet induced metabolic syndrome, increased visceral fat weights and adipocyte sizes, and augmented angiotensin II (Ang II), NADPH oxidase (NOX) isoforms expressions, oxidative stress, and dysregulated production of adipocytokines from visceral adipose tissues. Concurrent and subsequent aliskiren administration ameliorated metabolic syndrome, dysregulated adipocytokines, and visceral adiposity in high fructose-fed hypertensive rats, and was associated with reducing Ang II levels, NOX isoforms expressions and oxidative stress in visceral fat tissues. Therefore, this study demonstrates renin inhibition could improve metabolic syndrome, and reduce Ang II levels and oxidative stress in visceral fat tissue in fructose-fed rats, and suggests that visceral adipose Ang II plays a crucial role in the pathogenesis of metabolic syndrome in fructose-fed rats.

Topics: Adipocytes; Adipokines; Amides; Angiotensin II; Animals; Blood Glucose; Blood Pressure; Cell Size; Cholesterol; Feeding Behavior; Fructose; Fumarates; Insulin; Intra-Abdominal Fat; Male; Metabolic Syndrome; Oxidative Stress; Rats, Inbred WKY; Renin; Superoxide Dismutase; Systole; Thiobarbituric Acid Reactive Substances; Triglycerides

The aim of this study was to assess any potential additive effects of a treatment combining aliskiren with paricalcitol on reducing renal fibrosis. C57BL/6J mice were treated individually with aliskiren and/or paricalcitol until 7 days after initiation of unilateral ureteral obstruction (UUO).In obstructed kidneys of UUO mice, monotherapy with aliskiren or paricalcitol significantly attenuated interstitial fibrosis, collagen IV accumulation, and α-smooth muscle actin- and terminal deoxynucleotidyl transferase-mediated biotin nick end-labeling-positive cells. The combination treatment showed additive efficacy in inhibition of these parameters. Renal NADPH oxidase (Nox)1 and Nox2 were significantly decreased by aliskiren or paricalcitol alone or in combination, while renal Nox4 expression was significantly reduced by paricalcitol mono- or combination treatment. Increased levels of p-Erk and p-p38 MAPK, and NF-κB in UUO kidneys were also significantly reduced by either aliskiren or paricalcitol treatment alone or in combination. Aliskiren or paricalcitol monotherapy significantly reduced the expression of (pro)renin receptor in UUO kidneys. In addition, aliskiren tended to augment renin expression in UUO kidneys, but paricalcitol reduced its expression level. The combination treatment effectively blocked both (pro)renin receptor and renin expression induced by aliskiren, and resulted in a further reduction of the renal expression of angiotensin II AT1 receptor. Aliskiren failed to increase the expression of vitamin D receptor in UUO kidneys, but the combination treatment restored its expression level. Taken together, a treatment combining aliskiren with paricalcitol better inhibits UUO-induced renal injury. The mechanism of this synergy may involve more profound inhibition of the intrarenal renin-angiotensin system.

Topics: Amides; Animals; Apoptosis; Collagen Type IV; Disease Progression; Drug Therapy, Combination; Ergocalciferols; Fibrosis; Fumarates; Inflammation Mediators; Kidney; Kidney Diseases; Male; Mice, Inbred C57BL; Myofibroblasts; Oxidative Stress; Receptors, Calcitriol; Renin; Renin-Angiotensin System; Treatment Outcome; Ureteral Obstruction

The local renin-angiotensin system (RAS) has been reported to have an important role in the pathogenesis and progression of metabolic bone diseases, including osteoarthritis (OA). Aliskiren is the first in a new class of orally effective direct renin inhibitors and is approved for the treatment of hypertension in humans. However, its efficacy in patients with OA is unknown. A rat model of OA was induced to investigate the potential efficacy of aliskiren. Effects of aliskiren on the cartilage structure were detected by safranin O staining and its effects on the widths of the proliferation zone and hypertrophic zone (HZ) of chondrocytes were analyzed by Masson's staining. Tartate‑resistant acid phosphatase staining was used to evaluate the effects of aliskiren on osteoclasts in the chondrocytes. Relative histological analyses were performed. Additionally, the expression levels of factors associated with osteoclast differentiation (receptor activator of nuclear factor κB ligand and osteoprotegerin), articular cartilage destruction [tumor necrosis factor‑α (TNF‑α) and matrix metalloproteinase 9] and osteoblast differentiation [runt related transcription factor 2 (Runx2)], along with RAS components (renin, renin‑receptor, angiotensin type 1 receptor (AT1R), AT2R, angiotensin converting enzyme (ACE) and angiotensin II (Ang II)] were detected in samples from the proximal tibias. Aliskiren did not fully suppress the inflammatory reaction in OA model animals and had marginal regulatory effects on biochemical bone markers induced by OA. However, aliskiren attenuated cartilage destruction, abnormal cartilage cellularity and the expansion of the HZ of chondrocytes, and significantly attenuated the expression of interleukin‑1, TNF‑α, Runx2 and procollagen type I N‑terminal propeptide. These chondroprotective properties were accompanied by reductions in the levels of RAS components (renin, Ang II, ACE and AT1R), indicating that aliskiren exerts multiple effects of on bone formation, osteoblast differentiation and articular cartilage protection via the RAS. OA activates the local bone RAS, inhibits bone formation and stimulates bone resorption. Aliskiren, a renin inhibitor, demonstrated chondroprotective efficacy in a rat model of OA through suppression of the local RAS.

Topics: Amides; Animals; Biomarkers; Cartilage, Articular; Chondrocytes; Core Binding Factor Alpha 1 Subunit; Disease Models, Animal; Fumarates; Immunohistochemistry; Matrix Metalloproteinase 9; Osteoarthritis; Osteoclasts; Protective Agents; ras Proteins; Rats; Renin-Angiotensin System; Tumor Necrosis Factor-alpha

A non-interventional study suggested that use of angiotensin-converting enzyme inhibitors (ACEIs) or aliskiren was associated with an angioedema risk three times that of beta-blockers (BBs).. The aim was to assess angioedema incidence rates (IRs) and the relative angioedema risk of aliskiren compared to other antihypertensive drugs (AHDs).. A cohort study in hypertensive patients with an AHD prescription between 2007 and 2012 was conducted using data from the US PharMetrics Plus™ claims database. Angioedema was identified using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9CM) code 995.1. Additionally, a nested case-control analysis was conducted to assess the relative angioedema risk of aliskiren or other AHDs versus BBs.. A total of 3,090,114 patients were included (aliskiren n = 30,720). There were 15,744 angioedema events (IR 2.28/1000 person-years; 95% confidence interval (CI) 2.24-2.32). Aliskiren IRs were: any aliskiren 2.58 (2.08-3.17), aliskiren monotherapy 1.71 (0.74-3.37), aliskiren fixed-dose combination (FDC) 1.27 (0.41-2.96), and aliskiren free-standing combination (FSC) 2.93 (2.31-3.66). The case-control analysis included 15,100 angioedema cases and 60,400 controls; the angioedema risk for both aliskiren monotherapy and FDC was not significantly different from BBs [adjusted odds ratio (adjOR) 0.99 (95% CI 0.45-2.20) and 1.06 (0.40-2.76)]; aliskiren FSC was associated with an increased angioedema risk [adjOR 3.29 (2.42-4.48)], mainly driven by concomitant ACEI use [adjOR 7.03 (4.10-12.05)].. The IR and risk of angioedema in patients with aliskiren monotherapy or FDC are comparable to BBs. The higher IR and risk of angioedema identified in the aliskiren FSC group may largely be driven by the concomitant use of ACEIs.

Topics: Adolescent; Adrenergic beta-Antagonists; Adult; Aged; Amides; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Case-Control Studies; Cohort Studies; Databases, Factual; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Incidence; Male; Middle Aged; United States; Young Adult

In addition to its role in regulation of blood pressure, fluid and electrolyte homeostasis, the renin-angiotensin system (RAS) components were expressed in many other tissues suggesting potential roles in their functions.. The present study aims to evaluate the protective effect aliskiren, when used alone or in combination with azilsartan against high fat diet-induced liver disease in rats.. Thirty-two Wistar male rats, weighing 150-200 gm were allocated evenly into four groups and treated as follow: group I, rats were fed a specially formulated high-fat diet for 8 weeks to induce non-alcoholic liver disease and considered as control group; groups II, III and IV, the rats were administered azilsartan (0.5 mg/kg), aliskiren (25 mg/kg) or their combination orally via gavage tube once daily, and maintained on high fat diet for 8 weeks. The possible treatment outcome was evaluated through measuring serum levels of glucose, insulin, lipid profile, TNF-α, IL-1β and liver enzymes. Additionally, the liver tissue contents of glycogen and lipids and histological changes were also evaluated.. The results showed that azilsartan significantly improves the studied markers greater than aliskiren, and their combination o has no additive or synergistic effects on the activity of each one of them.. Both azilsartan and aliskiren protects the rats against high-fat diet induced NAFLD with predominant effects for the former, and their combination showed no beneficial synergistic or additive effects.

Topics: Amides; Animals; Benzimidazoles; Diet, High-Fat; Disease Models, Animal; Drug Therapy, Combination; Fumarates; Liver; Male; Non-alcoholic Fatty Liver Disease; Oxadiazoles; Rats; Rats, Wistar

Angiotensin II is thought to participate in aneurysm formation, because of its ability to induce and perpetuate inflammation in the aortic wall. Because activation of renin is the first step of the renin-angiotensin system, renin inhibition could inhibit all components of this system effectively. Therefore, we examined the hypothesis that direct inhibition of renin activity could decrease the expansion of aortic aneurysm using a rabbit model. Aortic dilatation was induced by incubation with elastase around the rabbit abdominal aorta. Continuous administration of a direct renin inhibitor, aliskiren, was started at 1 week before incubation with elastase and continued for 5 weeks. Treatment with aliskiren markedly inhibited tissue renin activation and resulted in a significant reduction in angiotensin I and II production in the aneurysm wall. Consequently, the inhibition of renin activity prevented the expansion of experimental aortic aneurysm associated with preservation of the medial layer, independent of its blood pressure-lowering effect. Administration of aliskiren led to the inhibition of activation of NF-κB (nuclear factor-κB), AP-1 (activator protein-1), and CREB (cAMP response element-binding protein), which are thought to cooperatively regulate the inflammatory gene expression profile associated with aneurysm formation. As a result, treatment with aliskiren inhibited macrophage accumulation through suppression of MCP-1 (monocyte chemoattractant protein-1) and CCL4 (C-C motif chemokine ligand 4) expression, and TNF-α (tumor necrosis factor-α) production and activation of MMP-2 (matrix metalloproteinase-2) and MMP-9 (matrix metalloproteinase-9) were also suppressed in the aneurysm wall. In addition, inhibition of (pro)renin receptor elevation was also observed after treatment with aliskiren. Direct inhibition of renin activity using aliskiren prevented the progression of aortic aneurysm, suggesting it as a therapeutic option to treat abdominal aortic aneurysm.

Topics: Amides; Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Blotting, Western; Disease Models, Animal; Disease Progression; Fumarates; Gene Expression Regulation; Immunoenzyme Techniques; Immunohistochemistry; Rabbits; Real-Time Polymerase Chain Reaction; Renin; Renin-Angiotensin System; RNA; Ultrasonography

Chagas' disease is an important cause of cardiomyopathy in Latin America. We aimed to compare clinical characteristics and outcomes in patients with heart failure (HF) with reduced ejection fraction caused by Chagas' disease, with other etiologies, in the era of modern HF therapies.. This study included 2552 Latin American patients randomized in the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and ATMOSPHERE (Aliskiren Trial to Minimize Outcomes in Patients With Heart Failure) trials. The investigator-reported etiology was categorized as Chagasic, other nonischemic, or ischemic cardiomyopathy. The outcomes of interest included the composite of cardiovascular death or HF hospitalization and its components and death from any cause. Unadjusted and adjusted Cox proportional hazards models were performed to compare outcomes by pathogenesis. There were 195 patients with Chagasic HF with reduced ejection fraction, 1300 with other nonischemic cardiomyopathy, and 1057 with ischemic cardiomyopathy. Compared with other etiologies, Chagasic patients were more often female, younger, and had lower prevalence of hypertension, diabetes mellitus, and renal impairment (but had higher prevalence of stroke and pacemaker implantation) and had worse health-related quality of life. The rates of the composite outcome were 17.2, 12.5, and 11.4 per 100 person-years for Chagasic, other nonischemic, and ischemic patients, respectively-adjusted hazard ratio for Chagasic versus other nonischemic: 1.49 (95% confidence interval, 1.15-1.94;. Despite younger age, less comorbidity, and comprehensive use of conventional HF therapies, patients with Chagasic HF with reduced ejection fraction continue to have worse quality of life and higher hospitalization and mortality rates compared with other etiologies.. PARADIGM-HF: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255; ATMOSPHERE: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00853658.

Topics: Aged; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Chagas Cardiomyopathy; Female; Fumarates; Heart Failure; Hospitalization; Humans; Kaplan-Meier Estimate; Latin America; Male; Middle Aged; Multicenter Studies as Topic; Quality of Life; Randomized Controlled Trials as Topic; Risk Factors; Stroke Volume; Time Factors; Treatment Outcome; Ventricular Function, Left

A series of new seven potential renin inhibitors containing pseudodipeptides were synthesized. Stability for all compounds (1-7) in homogenates of liver, kidney, lung and in serum, gastric, intestinal juice and in the presence of α-chymotrypsin was determined. Compound 1 was unstable in all determined mediums. Compounds 2, 4, 5 and 7 were unstable, compound 3 was stable, compound 6 was unstable only in α-chy-motrypsin solution. Inhibitory activity of the compounds was measured in vitro by HPLC determination of low-ering concentration of substrate (angiotensinogen) in the presence of renin and the potential renin inhibitor (compounds 1-7). Compounds 1, 2, 4, 5, 6 and 7 showed inhibitory activity (1.12 x 10⁻⁷, 0.96 x 10⁻⁶, 1.58 x10⁻⁷,1.68 x 10⁻⁶, 1.30 x 10⁻⁶, 0.96 x 10⁻⁷M, respectively).

Topics: Amides; Angiotensinogen; Antihypertensive Agents; Drug Discovery; Drug Stability; Fumarates; Gastric Juice; Humans; Intestinal Secretions; Kidney; Liver; Lung; Molecular Structure; Protease Inhibitors; Renin; Structure-Activity Relationship

Aliskiren, a direct renin inhibitor is expected to achieve sufficient suppression of renin-angiotensin system. We evaluated the effect of aliskiren on the electrical and structural remodeling in a canine atrial fibrillation (AF) model. Twenty-eight dogs were divided into three groups: (1) pacing control group (n = 12), with continuous atrial rapid pacing for 3 or 6 weeks, (2) pacing + aliskiren group (n = 12), with oral aliskiren (30 mg/kg/day), and (3) sham group (n = 4), no pacing nor drug administration. Electrophysiological properties and AF inducibility were evaluated every week. After the protocol, the left atrial tissue was sampled for the further histological and mRNA analysis. The electrical remodeling, AF inducibility, the left atrial enlargement and interstitial fibrosis were observed in pacing control group and were more prominent in the 6-week protocol (vs. 3 week, p < 0.05). The mRNA expressions of matricellular proteins exhibited upregulation in 3-week pacing control, but these upregulations became insignificant in 6 weeks. In contrast, collagen type 3 exhibited significant upregulation in 6 week but not in 3-week protocol. These changes were suppressed in the pacing + aliskiren group. Aliskiren suppressed the atrial remodeling in a canine AF model. This effect was accompanied by the suppression of tissue fibrosis.

Topics: Amides; Animals; Atrial Fibrillation; Cardiac Pacing, Artificial; Disease Models, Animal; Dogs; Echocardiography; Female; Fibrosis; Fumarates; Gene Expression; Heart Atria; Hemodynamics; Renin; Renin-Angiotensin System

There is growing evidence on the role of ocular renin-angiotensin system (RAS) in the development of diabetic retinopathy (DR), particularly due to the trigger of oxidative stress and angiogenesis. Despite this there is no effective RAS-based therapy in DR capable of preventing retinal damage induced by RAS activation. We recently described that retinal pigment epithelium (RPE) cells express the main components of the RAS. We here propose to investigate the role of glucose upon the retinal RAS and whether aliskiren, a direct renin inhibitor, protects RPE cells from angiogenesis and oxidative stress. RPE cells were chosen as target since one of the first events in DR is the dysfunction of the RPE retinal layer, which as a key function in maintaining the integrity of the retina. We found that the RAS present in the RPE cells was deregulated by hyperglycemic glucose concentrations. Exposure of RPE cells to angiotensin II increased the levels of the main pro-angiogenic factor, vascular endothelial growth factor (VEGF) in a concentration-dependent manner. Additionally, angiotensin II also stimulated the production of reactive oxygen species in RPE cells. Treatment of RPE cells with aliskiren decreased the levels of oxidative stress and promoted the expression of anti-angiogenic factors such as the pigment epithelium-derived factor and the VEGF

Topics: Amides; Biomarkers; Cell Line; Fumarates; Glucose; Humans; Neovascularization, Physiologic; Oxidative Stress; Prorenin Receptor; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Retinal Pigment Epithelium

Change in NT-proBNP level is a common surrogate endpoint in early phase heart failure (HF) trials, but whether this endpoint is influenced by atrial fibrillation/flutter (AFF) is unclear.. This analysis included 1358 patients from the ASTRONAUT trial, which randomized patients hospitalized for HF with EF ≤40% to aliskiren or placebo in addition to standard care. Patients were stratified by presence of AFF on baseline ECG. NT-proBNP was measured longitudinally by a core laboratory at baseline, 1 month, 6 months, and 12 months. Compared with non-AFF patients, AFF patients experienced greater reduction from baseline in log-transformed NT-proBNP (interaction P < 0.001), but this difference was not significant after adjustment (interaction P = 0.726). The ability of aliskiren to lower NT-proBNP during follow-up differed by AFF status (interaction P = 0.001), with aliskiren lowering NT-proBNP more than placebo among non-AFF patients only. After adjustment, baseline AFF was not associated with mortality or HF hospitalization at 12 months (all P ≥ 0.152).. In this hospitalized HF cohort, AFF status did not influence post-discharge NT-proBNP trajectory or clinical outcomes after adjustment for patient characteristics. Aliskiren lowered follow-up NT-proBNP levels in patients without AFF, but had no influence among patients with AFF. This study generates the hypothesis that the ability of a HF trial to meet an NT-proBNP defined endpoint may be influenced by the prevalence of AFF in the population. Because aliskiren did not improve outcomes in patients without AFF, this analysis suggests changes in NT-proBNP induced by investigational therapies may be dissociated from clinical effects.

Topics: Aged; Amides; Antihypertensive Agents; Atrial Fibrillation; Atrial Flutter; Disease Progression; Female; Fumarates; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Randomized Controlled Trials as Topic

The purpose of the study is to analyze the impact of an intervention to disseminate safety alerts on the utilization of Aliskiren added to angiotensin converting enzyme inhibitor (ACEI) or an angiotensin-receptor blocker (ARB).. Quasi-experimental design (non-randomized intervention) comparing the utilization of Aliskiren + ACEI or ARB in a primary care area-intervention (PCA-I) with a primary care area-control (PCA-C) following a safety alert. All physicians were provided with a list of diabetic patients (DM) on Aliskiren + ACEI or ARB. Physicians in the PCA-I received also a non-DM patients list, a report with recommendations and information on the utilization of Aliskiren + ACEI or ARB in their area. Information was obtained from electronic medical records, period from May 2010 to December 2012. Interrupted time series analysis were used to assess the effect of the intervention on the number of patients on Aliskiren + ACEI or ARB.. The number of DM receiving Aliskiren + ACEI or ARB at the time of the alert (23 December 2011) was 106 in the PCA-I (91 non-DM) and 45 in the PCA-C (25 non-DM). After the alert, a decreased in the number of patients on Aliskiren + ACEI or ARB was noted at both PCAs, although the average of daily treatments ended was significantly higher in the PCA-I, both in the DM group (slope after alert: -0.81, 95%CI -0.91 to -0.71 vs. -0.30, 95%CI -0.37 to -0.22) as well as in the non-DM group (-0.56, 95%CI -0.67 to -0.45 vs. -0.10 95%CI -0.17 to -0.04).. The prescription of Aliskiren + ACEI or ARB decreased at both PCAs, albeit such decreased was more significant at the PCA-I. The intervention led to a more expeditious implementation of the safety alert recommendations. Copyright © 2016 John Wiley & Sons, Ltd.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diabetes Mellitus; Electronic Health Records; Fumarates; Humans; Interrupted Time Series Analysis; Practice Patterns, Physicians'; Primary Health Care

Fat embolism (FE) and the consequent FE syndrome occurring after trauma or surgery can lead to serious pulmonary injury, including ARDS and death. Current treatment of FE syndrome is limited to supportive therapy. We have shown in a rat model that the renin angiotensin system plays a significant role in the pathophysiology of FE because drugs interfering with the renin angiotensin system, captopril and losartan reduce the histopathologic pulmonary damage. The purpose of the current study was to determine if inhibition of renin by aliskiren, an FDA-approved drug for treating hypertension, would produce effective protection in the same model.. The FE model used intravenous injection of the neutral fat triolein in unanesthetized rats. Intraperitoneal injections of saline or aliskiren at either 50 or 100 mg/kg were performed 1 hour after FE induction via triolein. Rats were euthanized at 48 hours, and various histologic stains were used to examine the lungs.. (1) Fibrosis: rats treated with triolein showed significant fibrotic changes with increased collagen and myofibroblast activation (p < 0.0001 for both trichrome and α-smooth muscle actin staining). Aliskiren blocked this inflammatory and profibrotic process to a level indistinguishable from the controls (p < 0.0001 for both trichrome and α-smooth muscle actin staining). (2) Fat: rats treated with triolein showed a statistically significant increase in fat (p = 0.0006). Subsequent aliskiren administration at both doses reduced the size, distribution, and amount of fat droplets (low dose, p = 0.0095; high dose, p = 0.0028). (3) Vessel patency: the low dose of aliskiren blocked the reduction of lumen patency observed after triolein administration (p = 0.0058).. Aliskiren protected the lungs of rats from gross and histopathologic FE-induced pulmonary damage at 48 hours. Clinical implications include the use of aliskiren both prophylactically (before certain orthopedic procedures) and therapeutically (after severe trauma) to prevent the consequent severe pulmonary pathologic sequelae.

Topics: Amides; Animals; Disease Models, Animal; Embolism, Fat; Fumarates; Male; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Triolein

The direct renin inhibitor aliskiren has been shown to be retained and persist in medullary collecting ducts even after treatment is discontinued, suggesting a new mechanism of action for this drug. The purpose of the present study was to investigate whether aliskiren regulates renal aquaporin expression in the collecting ducts and improves urinary concentrating defect induced by lithium in mice. The mice were fed with either normal chow or LiCl diet (40 mmol·kg dry food

Topics: Amides; Angiotensin II; Animals; Antihypertensive Agents; Aquaporin 2; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Diabetes Insipidus, Nephrogenic; Drug Evaluation, Preclinical; Fumarates; Kidney Medulla; Kidney Tubules, Collecting; Lithium; Male; Mice, Inbred C57BL; Polyuria; Prorenin Receptor; Receptors, Cell Surface

Paracetamol is one of the most popular and widely used analgesic and antipyretic agents, but an overdose can cause hepatotoxicity and lead to acute liver failure. Aliskiren directly inhibits renin which downregulates the renin-angiotensin-aldosterone system (RAAS). Recent findings suggest that RAAS system takes part in the pathogenesis of liver fibrosis. We aimed to reveal the relationship between hepatotoxicity and the RAAS by examining paracetamol induced hepatotoxicity. Rats were separated into five groups as follows: control, 100 mg/kg aliskiren (p.o.), 2 g/kg paracetamol (per os (p.o.)), 2 g/kg paracetamol + 50mg/kg aliskiren (p.o.), and 2 g/kg paracetamol + 100 mg/kg aliskiren(p.o.). Samples were analyzed at the biochemical, molecular, and histopathological levels. Paracetamol toxicity increased alanine aminotransferases (ALT), aspartate aminotransferases (AST), renin, and angiotensin II levels in the serum samples. In addition, the SOD activity and glutathione (GSH) levels decreased while Lipid Peroxidation (MDA) levels increased in the livers of the rats treated with paracetamol. Paracetamol toxicity caused a significant increase in TNF-α and TGF-β. Both aliskiren doses showed an improvement in ALT, AST, oxidative parameters, angiotensin II, and inflammatory cytokines. Only renin levels increased in aliskiren treatment groups due to its pharmacological effect. A histopathological examination of the liver showed that aliskiren administration ameliorated the paracetamol-induced liver damage. In immunohistochemical staining, the expression of TNF-α in the cytoplasm of the hepatocytes was increased in the paracetamol group but not in other treatment groups when compared to the control group. In light of these observations, we suggest that the therapeutic administration of aliskiren prevented oxidative stress and cytokine changes and also protected liver tissues during paracetamol toxicity by inhibiting the RAAS.

Topics: Acetaminophen; Alanine Transaminase; Amides; Angiotensin II; Animals; Antioxidants; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Fumarates; Liver; Male; Oxidants; Rats, Wistar; Renin; Renin-Angiotensin System

A novel spectrophotometric method was developed for determination of ternary mixtures without previous separation, showing significant advantages over conventional methods. The new method is based on mean centering of double divisor ratio spectra. The mathematical explanation of the procedure is illustrated. The method was evaluated by determination of model ternary mixture and by the determination of Amlodipine (AML), Aliskiren (ALI) and Hydrochlorothiazide (HCT) in laboratory prepared mixtures and in a commercial pharmaceutical preparation. For proper presentation of the advantages and applicability of the new method, a comparative study was established between the new mean centering of double divisor ratio spectra (MCDD) and two similar methods used for analysis of ternary mixtures, namely mean centering (MC) and double divisor of ratio spectra-derivative spectrophotometry (DDRS-DS). The method was also compared with a reported one for analysis of the pharmaceutical preparation. The method was validated according to the ICH guidelines and accuracy, precision, repeatability and robustness were found to be within the acceptable limits.

Topics: Amides; Amlodipine; Analysis of Variance; Chromatography, High Pressure Liquid; Fumarates; Hydrochlorothiazide; Methanol; Models, Molecular; Reference Standards; Reproducibility of Results; Spectrophotometry; Tablets

The skeletal renin-angiotensin system contributes to the development of osteoporosis. The renin inhibitor aliskiren exhibited beneficial effects on trabecular bone of osteoporotic mice, and this action might be mediated through angiotensin and bradykinin receptor pathways. This study implies the potential application of renin inhibitor in the management for postmenopausal osteoporosis.. The skeletal renin-angiotensin system plays key role in the pathological process of osteoporosis. The present study is designed to elucidate the effect of renin inhibitor aliskiren on trabecular bone and its potential action mechanism in ovariectomized (OVX) mice.. The OVX mice were treated with low dose (5 mg/kg) or high dose (25 mg/kg) of aliskiren or its vehicle for 8 weeks. The bone turnover markers were measured by ELISA. The structural parameters of trabecular bone at lumbar vertebra (LV) and distal femoral metaphysis were measured by micro-CT. The expression of messenger RNA (mRNA) and protein was studied by RT-PCR and immunoblotting, respectively.. Aliskiren treatment reduced urinary excretion of calcium and serum level of tartrate-resistant acid phosphatase in OVX mice. The treatment with aliskiren significantly increased bone volume (BV/TV) and connectivity density (Conn.D) of trabecular bone at LV-2 and LV-5 as well as dramatically enhanced BV/TV, Conn.D, bone mineral density (BMD/BV) and decreased bone surface (BS/BV) at the distal femoral end. Aliskiren significantly down-regulated the expression of angiotensinogen, angiotensin II (Ang II), Ang II type 1 receptor, bradykinin receptor (BR)-1, and osteocytic-specific gene sclerostin as well as the osteoclast-specific genes, including carbonic anhydrase II, matrix metalloproteinase-9, and cathepsin K.. This study revealed that renin inhibitor aliskiren exhibited the beneficial effects on trabecular bone of ovariectomy-induced osteoporotic mice, and the underlying mechanism for this action might be mediated through Ang II and BR signaling pathways in bone.

Topics: Amides; Animals; Biomarkers; Blood Pressure; Bone Density; Bone Density Conservation Agents; Cancellous Bone; Drug Evaluation, Preclinical; Female; Femur; Fumarates; Gene Expression Regulation; Humans; Kallikrein-Kinin System; Lumbar Vertebrae; Mice, Inbred C57BL; Osteoclasts; Osteoporosis; Ovariectomy; Proteins; Renin; Renin-Angiotensin System; RNA, Messenger; X-Ray Microtomography

The renin angiotensin system (RAS) plays an important role in the pathogenesis of cardiovascular diseases and inflammation. Myocarditis is an inflammatory disease of the heart, and the role of the RAS in its pathophysiology is unknown. Because the direct renin inhibitor, aliskiren, is thought to block RAS completely, we investigated the cardioprotective effect of aliskiren in mice with experimental autoimmune myocarditis (EAM).. A cardiac α-myosin heavy chain peptide was injected in mice on days 0 and 7. Aliskiren 25mg/kg per day (n=10) or vehicle (n=10) was administered to EAM mice starting on day 0 and the animals were killed on day 21.. Aliskiren significantly prevented the progression of left ventricular wall thickening in EAM hearts compared to the vehicle-treated group. Histologically, the inflammatory cell infiltration and fibrosis area ratios in the aliskiren-treated group were lower than that in the vehicle-treated group. Immunohistochemistry revealed that aliskiren suppressed CD4 positive cell infiltration in EAM hearts compared to vehicle. Moreover, aliskiren decreased mRNA levels of interleukin (IL)-2, interferon-γ, tumor necrosis factor-α, and collagen 1. In vitro study showed that aliskiren inhibited T cell proliferation and IL-2 production induced by myosin stimulation.. Our results suggest that aliskiren ameliorates EAM by suppressing T-cell activation and inflammatory cytokines, and has potential as a treatment for myocarditis.

Topics: Amides; Animals; Antihypertensive Agents; Cytokines; Fumarates; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Nervous System Autoimmune Disease, Experimental; Renin; RNA, Messenger

Tacrolimus (Tac) and Cyclosporine A (CyA) calcineurin inhibitors (CNIs) are 2 effective immunosuppressants which are essential to prevent allograft rejection. Calcineurin inhibitors are known to be nephrotoxic. However, the precise mechanism of nephrotoxicity is not fully understood. In this study, we investigated the in vivo effects of CNIs on the local renal renin-angiotensin system in the collecting duct (CD).. Three-week-old mice were treated with either vehicle, CyA (2 mg/kg per day), Tac (0.075 mg/kg per day), CyA + Aliskiren (25 mg/kg per day), or Tac + Aliskiren for 3 weeks. Serum creatinine was measured. Renin and vascular endothelial growth factor (VEGF) contents in CD were evaluated with flow cytometry and multiphoton microscopy. The diameter of vessels was assessed with multiphoton microscopy, and the amount of renal collagen was determined by real-time polymerase chain reaction and Masson staining.. The elevated level of serum creatinine in CNI groups was abolished by Aliskiren. Flow cytometric analysis found elevated renin content in principal cells, which was prevented by Aliskiren. This result was further confirmed with multiphoton microscopy. The VEGF content in CD correlated with reduced capillary diameter and with the formation of fibrotic islands.. Calcineurin inhibitors induce production of renin in the CD that may contribute to decreased renal blood flow. In turn, CD responds with increased VEGF production, resulting in disproportional vessel growth, further worsening the local hypoxia and striped fibrosis surrounding the CDs. Aliskiren, a direct renin inhibitor blocks these effects and improves CNI-induced nephropathy by decreasing renin production in the CDs. Our data suggest that Aliskiren may be used for the prevention of CNI nephrotoxicity.

Topics: Amides; Animals; Biomarkers; Calcineurin Inhibitors; Capillaries; Collagen Type I; Creatinine; Cyclosporine; Cytoprotection; Disease Models, Animal; Fibrosis; Flow Cytometry; Fumarates; Immunosuppressive Agents; Kidney Diseases; Kidney Tubules, Collecting; Male; Mice, Inbred C57BL; Microscopy, Fluorescence, Multiphoton; Real-Time Polymerase Chain Reaction; Renal Circulation; Renin; Renin-Angiotensin System; Tacrolimus; Time Factors; Up-Regulation; Vascular Endothelial Growth Factor A

Obesity-related kidney disease is related to caloric excess promoting deleterious cellular responses. Accumulation of saturated free fatty acids in tubular cells produces lipotoxicity involving significant cellular dysfunction and injury. The objectives of this study were to elucidate the role of renin-angiotensin system (RAS) activation in saturated fatty acid-induced endoplasmic reticulum (ER) stress in cultured human proximal tubule epithelial cells (HK2) and in mice fed with a high-fat diet. Treatment with saturated fatty acid palmitic acid (PA; 0.8 mM) for 24 h induced ER stress in HK2, leading to an unfolded protein response as reflected by increased expressions of the ER chaperone binding immunoglobulin protein (BiP) and proapoptotic transcription factor C/EBP homologous protein (CHOP) protein as evaluated by immunoblotting. PA treatment also induced increased protein expression of inositol requiring protein 1α (IRE1α), phosphorylated eukaryotic initiation factor-α (eIF2α), and activating transcription factor 4 (ATF4) as well as activation of caspase-3. PA treatment was associated with increased angiotensin II levels in cultured medium. The angiotensin II type 1 receptor (AT1R) blocker valsartan or renin inhibitor aliskiren dramatically suppressed PA-induced upregulation of BiP, CHOP, IRE1α, p-eIF2α, and ATF4 in HK2 cells. In contrast, valsartan or aliskiren did not prevent ER stress induced by tunicamycin. C57BL/6 mice fed with a high-fat diet for 14 wk exhibited increased protein expressions of BiP and CHOP compared with control mice, which were significantly attenuated by the valsartan treatment. Increased angiotensin II levels in serum and urine were observed in mice fed with a high-fat diet when compared with controls. It is suggested that the intrarenal RAS activation may play an important role in diabetic kidney injury via mediating ER stress induced by saturated fatty acid.

Topics: Amides; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Apoptosis; Blood Glucose; Cell Line; Cell Survival; Diet, High-Fat; Disease Models, Animal; Dose-Response Relationship, Drug; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Fumarates; Gene Expression Regulation; Heat-Shock Proteins; Humans; Kidney Diseases; Kidney Tubules, Proximal; Male; Mice, Inbred C57BL; Palmitic Acid; Renin-Angiotensin System; RNA, Messenger; Signal Transduction; Transcription Factor CHOP; Tunicamycin; Unfolded Protein Response; Valsartan

This study determined whether angiotensinogen (AGT) has angiotensin II-independent effects using multiple genetic and pharmacological manipulations.. All study mice were in low-density lipoprotein receptor -/- background and fed a saturated fat-enriched diet. In mice with floxed alleles and a neomycin cassette in intron 2 of the AGT gene (hypoAGT mice), plasma AGT concentrations were >90% lower compared with their wild-type littermates. HypoAGT mice had lower systolic blood pressure, less atherosclerosis, and diminished body weight gain and liver steatosis. Low plasma AGT concentrations and all phenotypes were recapitulated in mice with hepatocyte-specific deficiency of AGT or pharmacological inhibition of AGT by antisense oligonucleotide administration. In contrast, inhibition of AGT cleavage by a renin inhibitor, aliskiren, failed to alter body weight gain and liver steatosis in low-density lipoprotein receptor -/- mice. In mice with established adiposity, administration of AGT antisense oligonucleotide versus aliskiren led to equivalent reductions of systolic blood pressure and atherosclerosis. AGT antisense oligonucleotide administration ceased body weight gain and further reduced body weight, whereas aliskiren did not affect body weight gain during continuous saturated fat-enriched diet feeding. Structural comparisons of AGT proteins in zebrafish, mouse, rat, and human revealed 4 highly conserved sequences within the des(angiotensin I)AGT domain. des(angiotensin I)AGT, through adeno-associated viral infection in hepatocyte-specific AGT-deficient mice, increased body weight gain and liver steatosis, but did not affect atherosclerosis.. AGT contributes to body weight gain and liver steatosis through functions of the des(angiotensin I)AGT domain, which are independent of angiotensin II production.

Topics: Amides; Amino Acid Sequence; Angiotensin II; Angiotensinogen; Animals; Atherosclerosis; Blood Pressure; Conserved Sequence; Dependovirus; Diet, High-Fat; Disease Models, Animal; Fatty Liver; Fumarates; Genetic Vectors; Genotype; Hepatocytes; Hypertension; Liver; Male; Mice, Inbred C57BL; Mice, Knockout; Models, Molecular; Oligonucleotides, Antisense; Phenotype; Protein Binding; Protein Interaction Domains and Motifs; Receptors, LDL; Renin; Signal Transduction; Time Factors; Transduction, Genetic; Weight Gain

Aliskiren has been found to reduce chronic injury and steatosis in the liver of methionine-choline-deficient (MCD) diet-fed mice. This study investigated whether aliskiren has an anti-steatotic effect in HFD-fed mice, which are more relevant to human patients with non-alcoholic fatty liver disease than MCD mice. Mice fed with 4-week normal chow or HFD randomly received aliskiren (50 mg/kg/day) or vehicle via osmotic minipumps for further 4 weeks. Aliskiren reduced systemic insulin resistance, hepatic steatosis, epididymal fat mass and increased gastrocnemius muscle glucose transporter type 4 levels with lower tissue angiotensin II levels in the HFD-fed mice. In addition, aliskiren lowered nuclear peroxisome proliferator-activated receptor gamma and its down-signaling molecules and increased cytochrome P450 4A14 and carnitine palmitoyltransferase 1A (CPT1a) in liver. In epididymal fat, aliskiren inhibited expressions of lipogenic genes, leading to decrease in fat mass, body weight, and serum levels of leptin and free fatty acid. Notably, in the gastrocnemius muscle, aliskiren increased phosphorylation of insulin receptor substrate 1 and Akt. Based on these beneficial effects on liver, peripheral fat and skeletal muscle, aliskiren is a promising therapeutic agent for patients with NAFLD.

Topics: Adipose Tissue; Amides; AMP-Activated Protein Kinases; Animals; Carnitine O-Palmitoyltransferase; Cytochrome P450 Family 4; Diet, High-Fat; Disease Models, Animal; Epididymis; Fumarates; Insulin; Insulin Resistance; Lipid Metabolism; Liver; Male; Mice; Muscle, Skeletal; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Phosphorylation; PPAR gamma; Proto-Oncogene Proteins c-akt; Signal Transduction

Aliskiren, a direct renin blocker, has been approved for the treatment of hypertension. However, the potential role of aliskiren on vascular endothelial function in spontaneously hypertensive rats (SHR) remains unclear. In the present study, male SHRs at 12 weeks of age were orally administrated 30 mg/kg per day or 60 mg/kg per day aliskiren. After a 4-week treatment, aliskiren showed a significant effect on the reduction of blood pressure at a dosage of 60 mg/kg per day, but not of 30 mg/kg per day. Moreover, both dosages of aliskiren improved endothelium-dependent relaxation, reduced dihydroethidium fluorescence intensity, decreased level of malondialdehyde but heightened total antioxidant capacity and superoxide dismutase activity in thoracic aorta in SHR. Aliskiren also markedly increased expression of p85α, an important subunit of phosphatidylinositol 3 kinase (PI3K), enhancing phosphorylation of protein kinase B (Akt) at Ser473 and endothelial nitric oxide synthase (eNOS) at Ser1177, as well as cyclic guanosine-3'5'-monophosphate (cGMP, a sensitive index of biological activity of nitric oxide) concentration. Furthermore, both anti-oxidative and endothelium protective effects of aliskiren were diminished when PI3K was inhibited in vivo. The data presented here indicates that, aliskiren improves endothelium-dependent relaxation of thoracic aorta in SHR, predominantly through attenuating oxidative stress and activation of the PI3K/Akt/eNOS pathway. These data might propose novel strategies to prevent and improve vascular endothelial dysfunction.

Topics: Acetylcholine; Amides; Animals; Aorta, Thoracic; Blood Pressure; Endothelium, Vascular; Enzyme Inhibitors; Fumarates; Male; Nitric Oxide Synthase Type III; Oxidative Stress; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Rats; Rats, Inbred SHR; Signal Transduction; Vasodilation

The current investigation, designed to investigate the role of rutin in two-kidney one-clip (2K1C) induced renovascular dysfunction associated with hypertension in rat.. The renovascular hypertension was developed by the application of vascular clip on left renal artery in rats; the right kidney was kept as such throughout the experimental protocol. The rutin (200 and 300 mg/kg; p.o.) and aliskiren (50mg/kg; p.o.) were administered for 9 consecutive days. The battery of pathophysiological tests i.e., systolic pressure, diastolic pressure and heart rate were performed to assess the anti-hypertensive effect of rutin. In addition, changes of kidney weight/body weight (KW/BW) ratio along with plasma renin content and renal tissue biomarkers i.e., thiobarbituric acid reactive substance (TBAR) and reduced glutathione (GSH) levels were estimated.. The administration of rutin significantly (P<0.05) attenuated the 2K1C of left kidney induced elevated systolic and diastolic pressure in a dose dependent manner. In addition, it also reduces the ratio of KW/BW along with a decrease in plasma renin content, tissue TBARS and increase the GSH levels. There were no significant changes observed in heart rate. Similar results were observed in aliskiren treated group.. The anti-hypertensive effect of rutin may be a useful herbal medicine for the management of hypertension due to its potential free radical scavenging, inhibition of lipid peroxidation and plasma renin inhibitory action.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Dose-Response Relationship, Drug; Fumarates; Glutathione; Heart Rate; Hypertension, Renovascular; Male; Organ Size; Rats; Rats, Sprague-Dawley; Renin; Rutin; Thiobarbituric Acid Reactive Substances

There has been controversy about the role of Toll-like receptor 2 (TLR2) in renal injury following ureteric obstruction. Although inhibition of the renin angiotensin system (RAS) reduces TLR2 expression in mice, the exact relationship between TLR2 and RAS is not known. The aim of this study was to determine whether the RAS modulates TLR2.. We used 8-week-old male wild type (WT) and TLR2-knockout (KO) mice on a C57Bl/6 background. Unilateral ureteral obstruction (UUO) was induced by complete ligation of the left ureter. Angiotensin (Ang) II (1,000 ng/kg/min) and the direct renin inhibitor aliskiren (25 mg/kg/day) were administrated to mice using an osmotic minipump. Molecular and histologic evaluations were performed.. Ang II infusion increased mRNA expression of TLR2 in WT mouse kidneys (p < 0.05). The expression of renin mRNA in TLR2-KO UUO kidneys was significantly higher than that in WT UUO kidneys (p < 0.05). There were no differences in tissue injury score or mRNA expression of monocyte chemotactic protein 1 (MCP-1), osteopontin (OPN), or transforming growth factor β (TGF-β) between TLR2-KO UUO and WT UUO kidneys. However, aliskiren decreased the tissue injury score and mRNA expression of TLR2, MCP-1, OPN, and TGF-β in WT UUO kidneys (p < 0.05). Aliskiren-treated TLR2-KO UUO kidneys showed less kidney injury than aliskiren-treated WT UUO kidneys.. TLR2 deletion induced activation of the RAS in UUO kidneys. Moreover, inhibition of both RAS and TLR2 had an additive ameliorative effect on UUO injury of the kidney.

Topics: Amides; Angiotensin II; Animals; Disease Models, Animal; Fibrosis; Fumarates; Kidney; Male; Mice, Inbred C57BL; Mice, Knockout; Nephritis, Interstitial; Renin; Renin-Angiotensin System; RNA, Messenger; Toll-Like Receptor 2; Ureteral Obstruction

A direct renin inhibitor, aliskiren, has a longer stable antihypertensive effect compared with other renin-angiotensin-aldosterone system (RAAS) inhibitors.. This study was a 6-month, single-center, open trial conducted between December 2010 and November 2011 to assess the antihypertensive effect of adding aliskiren (300 mg) to the treatment of essential hypertension patients whose target blood pressure (BP) had not been achieved and to assess whether it was possible to reduce the amount of antihypertensive drugs used.. The results showed an overall improvement in the target BP achievement rate of 60% for clinic BP and 52% for home BP measurements (75 cases total). The mean number of drugs before treatment with aliskiren was 3.28±1.52, whereas at the end of the six months the mean number of drugs prescribed other than aliskiren was 2.85±1.72 (p<0.0001). Moreover, no worsening of the renal function was observed in patients with diabetes or chronic kidney disease (CKD) who were being treated with other RAAS inhibitors in combination to aliskiren.. These results showed that when aliskiren was added to the treatment of poorly controlled hypertension, the BP achievement rate increased, and it was possible to reduce the amount of antihypertensive drugs used in combination with aliskiren. Moreover, as a result of careful monitoring of the renal function or decreasing the amounts of drugs used in combination, no worsening of the renal function was observed even in the cases complicated by diabetes or CKD being treated with other RAAS inhibitors.

Topics: Aged; Amides; Antihypertensive Agents; Blood Pressure; Drug Administration Schedule; Female; Fumarates; Humans; Hypertension; Japan; Male; Renin; Renin-Angiotensin System; Treatment Outcome

The aim of this study was to evaluate the effects of aliskiren, direct renin inhibitor, as an antioxidant and tissue protective agent and evaluate the molecular, biochemical, and histopathological changes in experimental ischemia and ischemia/reperfusion injury in rat ovaries. Forty-eight female rats were randomly divided into eight groups: in Group 1, only sham operation was performed. Group 2 received 100 mg/kg aliskiren and sham operated. In Group 3, 3 h-period of bilateral ovarian ischemia was applied. Group 4 received a 3-h period of ischemia followed by 3 h of reperfusion. Groups 5 and 6 received 50 and 100 mg/kg, respectively, of aliskiren and bilateral ovarian ischemia was applied (after a 3-h period of ischemia, both ovaries were surgically removed). To Groups 7 and 8, 50 and 100 mg/kg of aliskiren were administered, respectively, and the induction of ischemia was performed. At the end of a 3-h period of ischemia, bilateral vascular clips were removed, and 3 h of reperfusion continued. After the experiments, IL-1β, IL-6, TNF-α, and iNOS mRNA expressions and SOD, GSH, MDA, renin, and angiotensin-II levels were determined and histopathological changes were examined in rat ovaries. Aliskiren treatment normalized excessive changes in cytokine and oxidative stress markers in both ischemia and ischemia/reperfusion injury. Histopathologically, treatment with aliskiren ameliorated the development of ischemia and/or ischemia/reperfusion tissue injury. This study concluded that aliskiren treatment is effective in reversing ischemia and/or ischemia/reperfusion induced ovary damage via the improvement of oxidative stress, reduction of inflammation, and suppression of the renin-angiotensin aldosterone system.

Topics: Amides; Animals; Disease Models, Animal; Female; Fumarates; Ischemia; Ovarian Diseases; Protective Agents; Random Allocation; Rats; Rats, Wistar; Renin-Angiotensin System; Reperfusion Injury

The critical role of CaMKIIδ isoforms in cardiac hypertrophy is well documented.. This study was aimed to investigate the possible inhibitory effects of aliskiren (ALS) and/or carvedilol (CAV) on CaMKIIδ isoforms expression in experimental cardiac hypertrophy.. Male Wistar albino rats were subcutaneously injected with isoproterenol (ISO) (5 mg/kg/day) for 4 weeks to induce cardiac hypertrophy. Hypertrophied rats were daily treated with either ALS (10 mg/kg) and/or CAV (10 mg/kg). At the end of the treatment, rats were killed; blood and hearts were collected for assessing different biochemical parameters.. ISO treatment significantly increased heart weight to body weight (HW/BW) ratio, serum creatine kinase MB (CK-MB) and troponin T (Tn-T) levels, and plasma renin activity (PRA) as compared to control rats. Additionally, ISO treatment produced a significant increase in the expression of myocardial CaMKIIδ2 and CaMKIIδ3 that were associated with significant elevation in myocardial caspase-3 protein expression. Histopathological examination of rats exposed to ISO treatment showed severe myocardial cell degeneration. ALS and/or CAV treatment significantly reduced the altered HW/BW ratio, serum CK-MB and Tn-T levels, PRA, and caspase-3 protein expression in hypertrophied rats, with maximal improvement in the combination group. These biochemical findings were supported by the histopathological examination of the heart tissue. Additionally, treatment with ALS and CAV significantly inhibited ISO-induced increase in CaMKIIδ2 and CaMKIIδ3 expression levels.. The present study indicated that ALS and CAV treatment ameliorated ISO-induced hypertrophy via inhibiting the expression and the activity of CaMKIIδ isoforms and the associated myocardial apoptosis.

Topics: Amides; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Carbazoles; Cardiomegaly; Carvedilol; Creatine Kinase, MB Form; Disease Models, Animal; Drug Therapy, Combination; Fumarates; Heart; Isoproterenol; Male; Myocardium; Organ Size; Propanolamines; Protein Isoforms; Rats, Wistar; Real-Time Polymerase Chain Reaction; Renin; Renin-Angiotensin System; Troponin T

Insulin resistance can occur as a consequence of heart failure (HF). Activation of the renin-angiotensin system (RAS) may play a crucial role in this phenomenon. We thus investigated the effect of a direct renin inhibitor, aliskiren, on insulin resistance in HF after myocardial infarction (MI). MI and sham operation were performed in male C57BL/6J mice. The mice were divided into 4 groups and treated with sham-operation (Sham, n=10), sham-operation and aliskiren (Sham+Aliskiren; 10mg/kg/day, n=10), MI (n=11), or MI and aliskiren (MI+Aliskiren, n=11). After 4 weeks, MI mice showed left ventricular dilation and dysfunction, which were not affected by aliskiren. The percent decrease of blood glucose after insulin load was significantly smaller in MI than in Sham (14±5% vs. 36±2%), and was ameliorated in MI+Aliskiren (34±5%) mice. Insulin-stimulated serine-phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle of MI compared to Sham by 57% and 69%, and both changes were ameliorated in the MI+Aliskiren group (91% and 94%). Aliskiren administration in MI mice significantly inhibited plasma renin activity and angiotensin II (Ang II) levels. Moreover, (pro)renin receptor expression and local Ang II production were upregulated in skeletal muscle from MI and were attenuated in MI+Aliskiren mice, in tandem with a decrease in superoxide production and NAD(P)H oxidase activities. In conclusion, aliskiren ameliorated insulin resistance in HF by improving insulin signaling in the skeletal muscle, at least partly by inhibiting systemic and (pro)renin receptor-mediated local RAS activation, and subsequent NAD(P)H oxidase-induced oxidative stress.

Topics: Amides; Animals; Fumarates; Heart; Heart Failure; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Myocardial Infarction; Oxidative Stress; Prorenin Receptor; Protease Inhibitors; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Signal Transduction

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Clinical Trials Data Monitoring Committees; Diabetes Mellitus, Type 2; Fumarates; Government Regulation; Heart Failure; Humans; Randomized Controlled Trials as Topic; Renin

The discovery of a receptor that binds prorenin and renin in human endothelial and mesangial cells highlights the possible effect of renin-independent prorenin in the resumption of meiosis in oocytes that was postulated in the 1980s.This study aimed to identify the (pro)renin receptor in the ovary and to assess the effect of prorenin on meiotic resumption. The (pro)renin receptor protein was detected in bovine cumulus-oocyte complexes, theca cells, granulosa cells, and in the corpus luteum. Abundant (pro)renin receptor messenger ribonucleic acid (mRNA) was detected in the oocytes and cumulus cells, while prorenin mRNA was identified in the cumulus cells only. Prorenin at concentrations of 10(-10), 10(-9), and 10(-8)M incubated with oocytes co-cultured with follicular hemisections for 15h caused the resumption of oocyte meiosis. Aliskiren, which inhibits free renin and receptor-bound renin/prorenin, at concentrations of 10(-7), 10(-5), and 10(-3)M blocked this effect (P<0.05). To determine the involvement of angiotensin II in prorenin-induced meiosis resumption, cumulus-oocyte complexes and follicular hemisections were treated with prorenin and with angiotensin II or saralasin (angiotensin II antagonist). Prorenin induced the resumption of meiosis independently of angiotensin II. Furthermore, cumulus-oocyte complexes cultured with forskolin (200μM) and treated with prorenin and aliskiren did not exhibit a prorenin-induced resumption of meiosis (P<0.05). Only the oocytes' cyclic adenosine monophosphate levels seemed to be regulated by prorenin and/or forskolin treatment after incubation for 6h. To the best of our knowledge, this is the first study to identify the (pro)renin receptor in ovarian cells and to demonstrate the independent role of prorenin in the resumption of oocyte meiosis in cattle.

Topics: Amides; Angiotensin II; Animals; Cattle; Cells, Cultured; Colforsin; Corpus Luteum; Cumulus Cells; Female; Fumarates; Granulosa Cells; Humans; Meiosis; Nucleotides, Cyclic; Oocytes; Ovarian Follicle; Ovary; Prorenin Receptor; Receptors, Cell Surface; Renin; Reproduction; RNA, Messenger; Saralasin; Theca Cells

Endothelial progenitor cell (EPC) functions are impaired in the presence of diabetes mellitus. Aliskiren is a direct renin inhibitor, which is expected to modify proangiogenic cells. This study aimed to investigate whether and how aliskiren could improve the function of EPCs from patients with type II diabetes (T2DM).. Endothelial progenitor cells fibronectin adhesion assay, chamber assay and in vitro tube formation assay were used to estimate the degree of EPC adhesion, migration and tube formation abilities. EPC protein and mRNA expressions were evaluated by Western blot and quantitative RT-PCR, respectively. EPC vascular endothelial growth factor (VEGF) and (pro)renin receptor ((P)RR) expression was knocked down by VEGF and (P)RR siRNA.. Aliskiren (0·1 or 10 μM) dose-dependently improved functions and increased both VEGF and stromal cell-derived factor-1α (SDF-1α) expression of EPCs from patients with T2DM or EPCs from healthy volunteers and treated with high glucose. Transfection with VEGF siRNA significantly reduced the aliskiren-induced SDF-1α expression. Furthermore, (P)RR siRNA transfection impaired the aliskiren-induced VEGF and SDF-1 expression.. The results show that aliskiren improved EPC function from patients with T2DM in a dose-dependent manner probably via the (P)RR and VEGF/SDF-1α-related mechanisms.

Topics: Amides; Antihypertensive Agents; Blotting, Western; Cell Adhesion; Cell Movement; Cell Proliferation; Cells, Cultured; Chemokine CXCL12; Diabetes Mellitus, Type 2; Endothelial Progenitor Cells; Fumarates; Humans; Hydralazine; Imidazoles; In Vitro Techniques; Nitric Oxide Synthase Type III; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Tetrazoles; Vascular Endothelial Growth Factor A

The authors sought to retrospectively analyze the real-world evidence on aliskiren in diabetic patients with or without concomitant renin-angiotensin system (RAS) blocker use based on the Registry for Ambulant Therapy With RAS Inhibitors in Hypertension Patients in Germany (3A). Of 14,986 patients included, 3772 patients had diabetes and 28.5% received aliskiren, 14.3% received angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), 35.4% received aliskiren plus an ACE inhibitor/ARB, and 10.5% received other drugs. Ambulatory blood pressure (BP) monitoring (baseline BP 148±15.8/84.0±10.9 mm Hg) revealed stronger diastolic BP reduction for aliskiren plus ACE inhibitor/ARB than aliskiren alone in the low (2.8±0.5 vs 0.6±0.6; P=.004) and intermediate (5.9±0.5 vs 4.5±0.5; P=.04) baseline BP groups. There was a lesser ambulatory BP reduction observed for patients receiving non-RAS in the high baseline category for both systolic (12.5±1.8 vs 17.1±1.0; P=.02) and diastolic (6.9±1.0 vs 9.8±0.6; P=.01) BP. In patients with hypertension and type 2 diabetes, aliskiren was beneficial in lowering BP, with no observed increases in major adverse effects compared with RAS-blocking therapy alone.

Topics: Aged; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Fumarates; Germany; Humans; Hypertension; Male; Middle Aged; Registries; Retrospective Studies; Treatment Outcome

Atrial fibrillation (AF) contributing to the increasing mortality risk is the most common disease in clinical practice. Owing to the side effects and relative inefficacy of current antiarrhythmic drugs, some research focuses on renin-angiotensin-aldosterone system (RAS) for finding out the new treatment of AF. The purpose of this study is to confirm whether aliskiren as a proximal inhibitor of renin, which completely inhibits RAS, has beneficial effects on atrial structural remodeling in AF. In this study, rapid atrial pacing was induced at 500 beats per minute for 2 weeks in a canine model. A different dose of aliskiren was given orally for 2 weeks before rapid atrial pacing. HE staining and Masson's staining were used for analysis of myocardial fibrosis. TGF-β1, signal pathways, and pro-inflammatory cytokines were shown for the mechanism of structural remodeling after the treatment of aliskiren. Serious atrial fibrosis was induced by rapid atrial pacing, followed by the elevated TGF-β1, upregulated MEK and ERK1/2, and increased inflammatory factors. Aliskiren could apparently improve myocardial fibrosis by reducing the expression of TGF-β1, inhibiting MEK and ERK1/2 signal pathways, and decreasing IL-18 and TLR4 in both serum and atrial tissue. In conclusion, aliskiren could prevent atrial structural remodeling from rapid atrial pacing for 2 weeks. Aliskiren may play a potential beneficial role in the treatment of AF induced by rapid atrial pacing.

Topics: Action Potentials; Amides; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Remodeling; Cardiac Pacing, Artificial; Cytokines; Disease Models, Animal; Dogs; Extracellular Signal-Regulated MAP Kinases; Female; Fibrosis; Fumarates; Heart Atria; Heart Rate; Inflammation Mediators; Male; MAP Kinase Kinase 1; Renin; Signal Transduction; Transforming Growth Factor beta1

Four new spectrophotometric methods were developed, applied to resolve the overlapped spectra of a ternary mixture of [aliskiren hemifumarate (ALS)-amlodipine besylate (AM)-hydrochlorothiazide (HCT)] and to determine the three drugs in pure form and in combined dosage form. Method A depends on simultaneous determination of ALS, AM and HCT using principal component regression and partial least squares chemometric methods. In Method B, a modified isosbestic spectrophotometric method was applied for the determination of the total concentration of ALS and HCT by measuring the absorbance at 274.5nm (isosbestic point, Aiso). On the other hand, the concentration of HCT in ternary mixture with ALS and AM could be calculated without interference using first derivative spectrophotometric method by measuring the amplitude at 279nm (zero crossing of ALS and zero value of AM). Thus, the content of ALS was calculated by subtraction. Method C, double divisor first derivative ratio spectrophotometry (double divisor (1)DD method), was based on that for the determination of one drug, the ratio spectra were obtained by dividing the absorption spectra of its different concentrations by the sum of the absorption spectra of the other two drugs as a double divisor. The first derivative of the obtained ratio spectra were then recorded using the appropriate smoothing factor. The amplitudes at 291nm, 380nm and 274.5nm were selected for the determination of ALS, AM and HCT in their ternary mixture, respectively. Method D was based on mean centering of ratio spectra. The mean centered values at 287, 295.5 and 269nm were recorded and used for the determination of ALS, AM and HCT, respectively. The developed methods were validated according to ICH guidelines and proved to be accurate, precise and selective. Satisfactory results were obtained by applying the proposed methods to the analysis of pharmaceutical dosage form.

Topics: Amides; Amlodipine; Antihypertensive Agents; Drug Combinations; Fumarates; Hydrochlorothiazide; Spectrophotometry, Ultraviolet; Tablets

Pulmonary fibrosis is a progressive lung disorder with high mortality rate and limited successful treatment. This study was designed to assess the potential anti-oxidant and anti-fibrotic effects of aliskiren (Alsk) during bleomycin (BLM)-induced pulmonary fibrosis. Male Wistar rats were used as control untreated or treated with the following: a single dose of 2.5 mg/kg of BLM endotracheally and BLM and Alsk (either low dose 30 mg/kg/day or high dose 60 mg/kg/day), and another group was given Alsk 60 mg/kg/day alone. Alsk was given by gavage. Alsk anti-oxidant and anti-fibrotic effects were assessed. BLM significantly increased relative lung weight and the levels of lactate dehydrogenase and total and differential leucocytic count in bronchoalveolar lavage that was significantly ameliorated by high-dose Alsk treatment. As markers of oxidative stress, BLM caused a significant increase in the levels of lipid peroxides and nitric oxide accompanied with a significant decrease of superoxide dismutase and glutathione transferase enzymes. High-dose Alsk treatment restored these markers toward normal values. Alsk counteracted the overexpression of advanced glycation end products, matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinases-1 in lung tissue induced by BLM. Fibrosis assessed by measuring hydroxyproline content, which markedly increased in the BLM group, was also significantly reduced by Alsk. These were confirmed by histopathological and immunohistochemical examination which revealed that Alsk attenuates signs of pulmonary fibrosis and decreased the overexpressed MMP-9 and transforming growth factor β1. Collectively, these findings indicate that Alsk has a potential anti-fibrotic effect beside its anti-oxidant activity.

Topics: Amides; Animals; Antioxidants; Biomarkers; Bleomycin; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Fumarates; Glycation End Products, Advanced; Hydroxyproline; Lipid Peroxidation; Lung; Male; Matrix Metalloproteinase 9; Oxidative Stress; Pulmonary Fibrosis; Rats, Wistar; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta1

Aliskiren (ALK), a pharmacological renin inhibitor, is an effective antihypertensive drug and has potent anti-apoptotic activity, but it is currently unknown whether ALK is able to attenuate brain damage caused by acute cerebral ischemia independent of its blood pressure-lowering effects. This study aimed to investigate the role of ALK and its potential mechanism in cerebral ischemia. C57/BL6 mice were subjected to transient middle cerebral artery occlusion (tMCAO) and treated for 5 days with Vehicle or ALK (10 or 25 mg/kg per day via intragastric administration), whereas Sham-operated animals served as controls. Treatment with ALK significantly improved neurological deficits, infarct volume, brain water content and Nissl bodies after stroke (P < 0.05), which did not affect systemic blood pressure. Furthermore, the protection of ALK was also related to decreased levels of apoptosis in mice by enhanced activation of phosphatidylinositol 3-kinase (PI3K)/AKT pathway, increased level of Bcl-2 and reduced Bax expression (P < 0.05). In addition, ALK's effects were reversed by PI3K inhibitors LY294002 (P < 0.05). Our data indicated that ALK protected the brain from reperfusion injuries without affecting blood pressure, and this effect may be through PI3K/AKT signaling pathway.

Topics: Amides; Animals; Apoptosis; bcl-2-Associated X Protein; Brain Ischemia; Fumarates; Male; Mice, Inbred C57BL; Neuroprotective Agents; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Stroke; Up-Regulation

Aliskiren (Rasilez), a direct renin inhibitor, is indicated for the treatment of essential hypertension. A postmarketing prescription-event monitoring (PEM) study was conducted in England to monitor the safety and utilization of aliskiren. Summary statistics and event incidence densities were calculated. The cohort consisted of 6385 individuals with a median age of 68 years (interquartile range, 59-76). Aliskiren was largely prescribed for its licensed indication of hypertension (93.3%) and was reported as "effective" by the prescriber in 77.4% of individuals. Frequently reported clinical events during treatment were diarrhea (3.1% of on-treatment events), malaise/lassitude (3.0%), and nausea/vomiting (1.2%), which were also common reasons for treatment cessation. Renal events were rare, with 24 cases probably or possibly related to aliskiren use, and four of which were classified as acute renal failure using RIFLE (Risk Injury Failure Loss End-Stage Kidney Disease) criteria. These results should be used in conjunction with other clinical and pharmacoepidemiologic studies to optimize the safe prescribing of aliskiren.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Amides; Child; Child, Preschool; Cohort Studies; England; Essential Hypertension; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Product Surveillance, Postmarketing; Young Adult

The renin-angiotensin system (RAS) plays pathogenic roles in renal and cardiovascular disorders, but whether it is involved in colitis is unclear. Here we show that RenTgMK mice that overexpress active renin from the liver developed more severe colitis than wild-type controls. More than 50% RenTgMK mice died whereas all wild-type mice recovered. RenTgMK mice exhibited more robust mucosal TH17 and TH1/TH17 responses and more profound colonic epithelial cell apoptosis compared to wild-type controls. Treatment with aliskiren (a renin inhibitor), but not hydralazine (a smooth muscle relaxant), ameliorated colitis in RenTgMK mice, although both drugs normalized blood pressure. Chronic infusion of angiotensin II into wild-type mice mimicked the severe colitic phenotype of RenTgMK mice, and treatment with losartan [an angiotensin type 1 receptor blocker (ARB)] ameliorated colitis in wild-type mice, confirming a colitogenic role for the endogenous RAS. In human biopsies, pro-inflammatory cytokines were suppressed in patients with inflammatory bowel disease who were on ARB therapy compared to patients not receiving ARB therapy. These observations demonstrate that activation of the RAS promotes colitis in a blood pressure independent manner. Angiotensin II appears to drive colonic mucosal inflammation by promoting intestinal epithelial cell apoptosis and mucosal TH17 responses in colitis development.

Topics: Amides; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Apoptosis; Colitis; Colon; Epithelial Cells; Fumarates; Humans; Hydralazine; Inflammatory Bowel Diseases; Losartan; Mice; Mice, Transgenic; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Th17 Cells

The present study investigated the possible renoprotective effect of direct renin inhibitor (aliskiren) on renal dysfunctions, as well as its underlying mechanisms in rat model of adenine-induced tubulointerstitial nephropathy. Forty male Sprague-Dawley rats were randomized into 4 groups; normal group, aliskiren group (normal rats received 10 mg/kg aliskiren), adenine group (animals received high-adenine diet for 4 weeks and saline for 12 weeks), and adenine + aliskiren group (animals received adenine for 4 weeks and aliskiren 10 mg/kg for 12 weeks). It was found that adenine caused significant decrease in body mass, Hb, HR, serum Ca(2+), eNOS and nrf2 expression, GSH, and catalase in kidney tissues with significant increase in arterial blood pressure (ABP), serum creatinine, BUN, plasma renin activity (PRA), K(+) and P, urinary albumin excretion (UAE), caspase-3, and MDA (lipid peroxidation marker) in kidney tissues compared to normal group (p < 0.05). Administration of aliskiren caused significant improvement in all studied parameters compared to adenine group (p < 0.05). We concluded that aliskiren has renoprotective effect against adenine-induced nephropathy. This might be due to inhibition of PRA, attenuation of oxidative stress, activation of Nrf2 and eNOS genes, and suppression of caspase-3.

Topics: Adenine; Amides; Animals; Apoptosis; Fumarates; Male; Nephritis, Interstitial; Protective Agents; Random Allocation; Rats; Rats, Sprague-Dawley; Renin

Observations of increased angiotensin II levels and activation of the (pro)renin receptor in retinopathies support the role of ocular renin-angiotensin system (RAS) in the development of retinal diseases. While targeting RAS presents significant therapeutic potential, current RAS-based therapies are ineffective halting the progression of these diseases. A new class of drugs, the direct renin inhibitors such as aliskiren, is a potential therapeutic alternative. However, it is unclear how aliskiren acts in the retina, in particular in the retinal pigment epithelium (RPE), the structure responsible for the maintenance of retinal homeostasis whose role is deeply compromised in retinal diseases. We firstly analyzed the expression and activity of the main RAS components in RPE cells. Time- and concentration-dependent treatments with aliskiren were performed to modulate different pathways of the RAS in RPE cells. Our data demonstrate that RPE cells express the main RAS constituents. Exposure of RPE cells to aliskiren inhibited the activity of renin and consequently decreased the levels of angiotensin II. Additionally, aliskiren reduced the translocation of the (pro)renin receptor to the cellular membrane of RPE cells preventing the activation of ERK1/2. Our findings of the RPE well-defined RAS, together with the demonstration that aliskiren effectively blocks this system at different steps of the cascade, suggest that aliskiren might be an alternative and successful drug in preventing the deleterious effects derived from the overactivation of the RAS, known to contribute to the pathogenesis of different retinal diseases.

Topics: Amides; Angiotensin II; Antihypertensive Agents; Cell Line; Fumarates; Humans; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Retinal Pigment Epithelium; Vacuolar Proton-Translocating ATPases

Renovascular hypertension is characterized by increased angiotensin II and oxidative stress, and by endothelial dysfunction. The purpose of this study was to test whether the administration of aliskiren (ALSK) and l-arginine (l-ARG) would restore impaired baroreflex sensitivity and reduce oxidative stress in a rat renovascular hypertension model. Hypertension was induced by clipping the left renal artery, and the following five groups were created: SHAM; two-kidney, 1-clip (2K1C); 2K1C plus ALSK (ALSK); 2K1C plus l-ARG (l-ARG); and 2K1C plus ALSK+l-ARG (ALSK+l-ARG). After 21 days of treatment, only the ALSK+l-ARG group was effective in normalizing the arterial pressure (108.8±2.8 mm Hg). The l-ARG and ALSK+l-ARG groups did not show hypertrophy of the left ventricle. All the treatments restored the depressed baroreflex sensitivity to values found in the SHAM group. Acute administration of TEMPOL restored the depressed baroreflex sensitivity in the 2K1C group to values that resembled those presented by the other groups. All treatments were effective for an increase in the antioxidant pathway and reduction in the oxidative pathway. In conclusion, the treatment with ALSK or l-ARG reduced oxidative stress and restored reduced baroreflex sensitivity in renovascular hypertension. In addition, the treatments were able to normalize blood pressure and reverse left ventricular hypertrophy when used in combination.

Topics: Amides; Animals; Arginine; Baroreflex; Blood Pressure; Catalase; Fumarates; Heart Rate; Hypertension, Renovascular; Kidney; Male; Oxidative Stress; Rats; Rats, Wistar; Superoxide Dismutase; Sympathetic Nervous System

Aging impairs endothelium-dependent NO-mediated dilatation, which results from increased production of reactive oxygen species (ROS). The local generation of angiotensin II (ANG II) is increased in aging arteries and contributes to inflammatory and fibrotic activity of smooth muscle cells and arterial wall remodeling. Although prolonged in vivo ANG II inhibition improves the impaired endothelial dilatation of aging arteries, it is unclear whether this reflects inhibition of intravascular or systemic ANG II systems. Experiments were therefore performed on isolated tail arteries from young (3-4 mo) and old (22-24 mo) F344 rats to determine if a local renin-angiotensin system contributes to the endothelial dilator dysfunction of aging. Aging impaired dilatation to the endothelial agonist acetylcholine but did not influence responses to a nitric oxide (NO) donor (DEA NONOate). Dilatation to acetylcholine was greatly reduced by NO synthase inhibition [nitro-l-arginine methyl ester (l-NAME)] in young and old arteries. In isolated arteries, acute inhibition of angiotensin-converting enzyme (ACE) (perindoprilat), renin (aliskiren), or AT1 receptors (valsartan, losartan) did not influence dilatation to acetylcholine in young arteries but increased responses in old arteries. After ANG II inhibition, the dilator response to acetylcholine was similar in young and old arteries. ROS activity, which was increased in endothelium of aging arteries, was also reduced by inhibiting ANG II (perindoprilat, losartan). Renin expression was increased by 5.6 fold and immunofluorescent levels of ANG II were confirmed to be increased in aging compared with young arteries. Exogenous ANG II inhibited acetylcholine-induced dilatation. Therefore, aging-induced impairment of endothelium-dependent dilatation in aging is caused by a local intravascular renin-angiotensin system.

Topics: Adrenergic alpha-1 Receptor Agonists; Aging; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Arteries; Endothelium, Vascular; Enzyme Inhibitors; Fumarates; Indoles; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Phenylephrine; Rats; Rats, Inbred F344; Renin; Renin-Angiotensin System; Valsartan; Vasodilation

Propranolol injection (0.5 mg/kg, s.c.) in anesthetized rats increases diuresis 1.60 times (p < 0.05) with simultaneous 1.54- and 1.62-fold increase (p < 0.05) in sodium and potassium excretion, respectively. Preliminary inhibition of renin-angiotensin system (RAS) activity using ACE inhibitor enalapril (1 mg/kg, orally, 7 days) increases the sensitivity of rat kidney to drug, increasing its diuretic effect 2.33 times, natriuresis 2.49 times, and urine potassium excretion 1.80 times (p < 0.05). After the preliminary insertion of AT1 angiotensin receptor antagonist losartan (1 mg/kg, orally, 7 days), propranolol causes 1.8-fold increase in diuresis, 2.48-fold decrease in urine sodium, and 1.71-fold decrease in kaliuresis (p < 0.05). Preliminary administration of direct renin inhibitor aliskiren (4 mg/kg, orally, 7 days) is accompanied by 2.30-fold increase in the diuretic effect of propranolol, 2.56-fold increase in natriuresis, and 2.27-fold increase in urine potassium excretion (p < 0.05). It is concluded that the renal tissue RAS is involved in the mechanism of propranolol action in the kidney, acting as modulator preventing excessive loss of water and electrolytes with urine.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Diuresis; Diuretics; Drug Synergism; Enalapril; Fumarates; Kidney; Losartan; Male; Natriuresis; Potassium; Propranolol; Rats; Renin-Angiotensin System; Sodium

Due to the presence of the renin-angiotensin system (RAS) in tissues and its specific influence on white adipose tissue, fat cells are possible targets of pharmacological RAS blockers commonly used as anti-hypertensive drugs. In the present study, we investigated the effects of different RAS blockers on fat cell metabolism, more specifically on lipolysis, lipogenesis and oxidation of energy substrates. Isolated primary adipocytes were incubated with different RAS blockers (aliskiren, captopril and losartan) in vitro for 24 h and lipolysis, lipogenesis and glucose oxidation capacities were determined in dose-response assays to a β-adrenergic agonist and to insulin. Although no change was found in lipolytic capacity, the RAS blockers modulated lipogenesis and glucose oxidation in a different way. While captopril decreased insulin-stimulated lipogenesis (-19% of maximal response and -60% of insulin responsiveness) due to reduced glucose derived glycerol synthesis (-19% of maximal response and 64% of insulin responsiveness), aliskiren increased insulin-stimulated glucose oxidation (+49% of maximal response and +292% of insulin responsiveness) in fat cells. Our experiments demonstrate that RAS blockers can differentially induce metabolic alterations in adipocyte metabolism, characterized by a reduction in lipogenic responsiveness or an increase in glucose oxidation. The impact of RAS blockers on adipocyte metabolism may have beneficial implications on metabolic disorders during their therapeutic use in hypertensive patients.

Topics: Adipocytes; Amides; Animals; Antihypertensive Agents; Captopril; Fumarates; Glucose; Glycerol; Lipogenesis; Lipolysis; Losartan; Male; Rats, Wistar; Renin-Angiotensin System

The influence of intracellular renin on the inward calcium current in isolated smooth muscle cells from SHR mesenteric arteries was investigated. Measurements of calcium current were performed using the whole cell configuration of pCLAMP. The results indicated that: 1) renin (100nM) dialyzed into smooth muscle cells, increased the inward calcium current; 2) verapamil (10-9M) administered to the bath inhibited the effect of renin on the inward calcium current; 3) concurrently with the increase of calcium current a depolarization of 6.8+/-2.1mV (n=16)(P<0.05) was found in cells dialyzed with renin; 4) intracellular dialysis of renin (100nM) into smooth muscle cells isolated from mesenteric arteries of normal Wystar Kyoto rats showed no significant change on calcium current; 5) aliskiren (10-9M) dialyzed into the cell together with renin (100nM) abolished the effect of the enzyme on the calcium current in SHR; 6) Ang II (100nM) dialyzed into the smooth muscle cell from mesenteric artery of SHR in absence of renin, decreased the calcium current-an effect greatly reduced by valsartan (10-9M) added to the cytosol; 7) administration of renin (100nM) plus angiotensinogen (100nM) into the cytosol of muscles cells from SHR rats reduced the inward calcium current; 8) extracellular administration of Ang II (100nM) increased the inward calcium current in mesenteric arteries of SHR.. intracellular renin in vascular resistance vessels from SHR due to internalization or expression, contributes to the regulation of vascular tone and control of peripheral resistance-an effect independently of Ang II. Implications for hypertension and vascular remodeling are discussed.

Topics: Amides; Angiotensin II; Animals; Calcium; Calcium Signaling; Disease Models, Animal; Fumarates; Humans; Hypertension; Mesenteric Arteries; Myocytes, Smooth Muscle; Rats; Renin; Vascular Remodeling; Verapamil

Renin, in addition to its activation of the renin-angiotensin system, binds to the (pro)renin receptor (PRR) and triggers inflammatory and fibrogenic signaling in tissue. In addition, aliskiren, a direct renin inhibitor, has been shown to affect IgG metabolism by altering PRR and neonatal Fc receptors (FcRns).. We investigated the effect of aliskiren on proteinuria, glomerular extracellular matrix, expressions of fibronectin, transforming growth factor β1 (TGF-β1), PRR, FcRn and renal metabolism of IgG in a mice model of anti-glomerular basement membrane glomerulonephritis (anti-GBM GN).. IgG deposition and expressions of FcRn and PRR were enhanced at glomeruli and urinary IgG levels increased in anti-GBM GN. Aliskiren attenuated anti-GBM GN with reduction of proteinuria and cortical expressions of fibronectin and TGF-β1. In addition, aliskiren suppressed the renal cortical expressions of FcRn and PRR. Aliskiren also reduced the glomerular IgG depositions and the urinary IgG levels albeit with increased circulating serum IgG levels.. These results suggest that suppression of FcRn and PRR and regulation of IgG metabolism may be related to the attenuation of anti-GBM GN by aliskiren.

Topics: Amides; Animals; Anti-Glomerular Basement Membrane Disease; Fumarates; Histocompatibility Antigens Class I; Immunoglobulin G; Kidney Cortex; Male; Mice; Mice, Inbred BALB C; Prorenin Receptor; Rabbits; Receptors, Cell Surface; Receptors, Fc; Renin; Renin-Angiotensin System; Transforming Growth Factor beta1

Since chronic kidney disease due to diabetic nephropathy (DN) is becoming an ever larger health burden worldwide, more effective therapies are desperately needed. In the present study, the anti-diabetic and renoprotective effects of aliskiren have been evaluated in streptozotocin (STZ)-induced DN in rats. DN was induced by a single intraperitoneal injection of STZ (65 mg/kg). Three weeks after STZ, rats were divided into four groups; normal, diabetic, diabetic treated with gliclazide (10 mg/kg/day) for 1 month, and diabetic treated with aliskiren (50 mg/kg/day) for 1 month. At the end of the experiment, mean arterial blood pressure and heart rate were recorded. Rats were then euthanized and serum was separated for determination of glucose, insulin, kidney function tests, superoxide dismutase activity (SOD), adiponectin, and tumor necrosis factor-alpha (TNF-α). One kidney was used for estimation of malondialdehyde (MDA), reduced glutathione (GSH), and nitric oxide (NO) contents. Other kidney was used for histopathological study and immunohistochemical measurement of caspase-3 and transforming growth factor beta (TGF-β). In addition, islets of Langerhans were isolated from normal rats by collagenase digestion technique for in vitro study. Aliskiren normalized STZ-induced hyperglycemia, increased insulin level both in vivo and in vitro, normalized kidney function tests and blood pressure, and alleviated STZ-induced kidney histopathological changes. This could be related to the ability of aliskiren toward preserving hemodynamic changes and alleviating oxidative stress and inflammatory and apoptotic markers induced by STZ in rats. However, aliskiren was more effective than gliclazide in relieving STZ-induced DN. These findings support the beneficial effect of aliskiren treatment in DN which could be attributed to its anti-diabetic, renoprotective, antioxidant, anti-inflammatory, and anti-apoptotic effects. Moreover, clinical studies are required to establish the effectiveness of aliskiren treatment in patients suffering from hypertension and diabetes.

Topics: Amides; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Apoptosis Regulatory Proteins; Biomarkers; Blood Glucose; Blood Pressure; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Fumarates; Gliclazide; Heart Rate; Hypoglycemic Agents; Inflammation Mediators; Insulin; Insulin-Secreting Cells; Kidney; Oxidative Stress; Rats, Wistar; Streptozocin; Urological Agents

Previously blocking the renin angiotensin system (RAAS) has been effective in the prevention of gastric damage. Therefore, the aim of this study was to investigate the effects of aliskiren, and thus, direct renin blockage, in indomethacin-induced gastric damage model.. Effects of aliskiren were evaluated in indomethacin-induced gastric damage model on Albino Wistar rats. Effects of famotidine has been investigated as standard antiulcer agent. Stereological analyses for ulcer area determination, biochemical analyses for oxidative status determination and molecular analyses for tissue cytokine and cyclooxygenase determination were performed on stomach tissues. In addition, to clarify antiulcer effect mechanism of aliskiren pylorus ligation-induced gastric acid secretion model was applied on rats.. Aliskiren was able to inhibit indomethacin-induced ulcer formation. It also inhibited renin, and thus, decreased over-produced Angiotensin-II during ulcer formation. Aliskiren improved the oxidative status and cytokine profile of the stomach, which was most probably impaired by increased Angiotensin II concentration. Aliskiren also increased gastroprotective prostaglandin E2 concentration. Finally, aliskiren did not change the gastric acidity in pylorus ligation model.. Aliskiren exerted its protective effects on stomach tissue by decreasing inflammatory cytokines and oxidative stress as a result of inhibiting the RAAS, at a rate-limiting step, as well as its end product, angiotensin II. Aliskiren also significantly increased protective factors such as PGE2, but not affect aggressive factors such as gastric acidity.

Topics: Amides; Animals; Cyclooxygenase 1; Cyclooxygenase 2; Cytokines; Dinoprostone; Fumarates; Glutathione; Hydrogen-Ion Concentration; Indomethacin; Kinetics; Male; Malondialdehyde; Models, Biological; Oxidative Stress; Rats, Wistar; Renin-Angiotensin System; RNA, Messenger; Stomach; Stomach Ulcer; Superoxide Dismutase

To examine the effects of aliskiren, a small-molecule renin inhibitor, on cancer cachexia and to explore the underlying mechanisms. A cancer cachexia model was established by subcutaneously injecting C26 mouse colon carcinoma cells into isogenic BALB/c mice. Aliskiren was administered intragastrically [10 mg/kg body weight (BW)] on day 5 (as a preventive strategy, AP group) or on day 12 (as a therapeutic strategy, AT group) after C26 injection. Mice that received no C26 injection (healthy controls, HC group) or only C26 injection but not aliskiren (cancer, CA group) were used as controls. BW, tumor growth, whole body functions, and survival were monitored daily in half of the mice in each group, whereas serum, tumors, and gastrocnemius muscles were harvested from the other mice after sacrifice on day 20 for further analysis. Aliskiren significantly alleviated multiple cachexia‑associated symptoms, including BW loss, tumor burden, muscle wasting, muscular dysfunction, and shortened survival. On the molecular level, aliskiren antagonized cachexia‑induced activation of the renin‑angiotensin system (RAS), systematic and muscular inflammation, oxidative stress, and autophagy‑lysosome as well as ubiquitin‑proteasome stimulation. In addition, early administration of aliskiren before cachexia development (AP group) resulted in more robust effects in alleviating cachexia or targeting underlying mechanisms than administration after cachexia development (AT group). Aliskiren exhibited potent anti‑cachexia activities. These activities were achieved through the targeting of at least four mechanisms underlying cachexia development: RAS activation, increase in systematic inflammation, upregulation of oxidative stress, and stimulation of autophagy-lysosome pathway (ALP) and ubiquitin-proteasome pathway (UPP).

Topics: Amides; Animals; Autophagy; Cachexia; Cell Line, Tumor; Colonic Neoplasms; Disease Models, Animal; Fumarates; Humans; Mice; Muscle, Skeletal; Muscular Atrophy; Oxidative Stress; Renin; Renin-Angiotensin System

Renin inhibitors enhance endothelial nitric oxide synthase (eNOS) bioavailability and have protective effects on endothelial function and atherosclerotic changes. This study was designed to investigate whether aliskiren attenuates the effects of interleukin-6 (IL-6) on eNOS and the eNOS-caveolin-1 interaction in human aortic endothelial cells (HAECs). In this study, we examined the effects of pretreatment with aliskiren on the changes of IL-6-induced expression and activation of eNOS and caveolin-1 in cultured HAECs. IL-6 inhibited and aliskiren increased the phosphorylation of eNOS at Ser1177; however, eNOS protein and mRNA expression were not changed. Pretreatment with aliskiren attenuated the inhibitory effects of IL-6 on eNOS phosphorylation and nitric oxide production. IL-6 increased the phosphorylation of caveolin-1 at Tyr14 without affecting the caveolin-1 protein and mRNA expression. Pretreatment with aliskiren attenuated the effects of IL-6 on caveolin-1 phosphorylation. The binding of eNOS and caveolin-1, as determined by a co-immunoprecipitation assay, was increased by IL-6 treatment and decreased by aliskiren pretreatment. Furthermore, treatment with short interfering RNA of the extracellular signal-regulated kinase gene reversed the effects of IL-6 and aliskiren on eNOS and caveolin-1. In conclusion, aliskiren attenuates the inhibitory effects of IL-6 on eNOS phosphorylation and nitric oxide production and IL-6 induced caveolin-1 phosphorylation. In addition, aliskiren reverses the effects of IL-6 on the eNOS-caveolin-1 interaction.

Topics: Amides; Aorta; Caveolin 1; Cells, Cultured; Endothelial Cells; Fumarates; Humans; Nitric Oxide Synthase Type III; Signal Transduction

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Brazil; Calcium Channel Blockers; Diuretics; Evidence-Based Medicine; Fumarates; Humans; Hypertension; Renin; Vasodilator Agents

BACKGROUND Myocardial ischemia and reperfusion lead to impairment of electrolyte balance and, eventually, lethal arrhythmias. The aim of this study was to investigate the effects of pharmacological inhibition of angiotensin-II (Ang-II) production on heart tissue with ischemia-reperfusion damage, arrhythmia, and oxidative stress. MATERIAL AND METHODS Rats were divided into 4 groups: only ischemia/reperfusion (MI/R), captopril (CAP), aliskiren (AL), and CAP+AL. The drugs were given by gavage 30 min before anesthesia. Blood pressure and electrocardiography (ECG) were recorded during MI/R procedures. The heart tissue and plasma was kept so as to evaluate the total oxidant (TOS), antioxidant status (TAS), and creatine kinase-MB (CK-MB). RESULTS Creatine kinase-MB was not different among the groups. Although TAS was not affected by inhibition of Ang-II production, TOS was significantly lower in the CAP and/or AL groups than in the MI/R group. Furthermore, oxidative stress index was significantly attenuated in the CAP and/or AL groups. Captopril significantly increased the duration of VT during ischemia; however, it did not have any effect on the incidence of arrhythmias. During reperfusion periods, aliskiren and its combinations with captopril significantly reduced the incidence of other types of arrhythmias. Captopril alone had no effect on the incidence of arrhythmias, but significantly increased arrhythmias score and durations of arrhythmias during reperfusion. MAP and heart rate did not show changes in any groups during ischemic and reperfusion periods. CONCLUSIONS Angiotensin-II production appears to be associated with elevated levels of reactive oxygen species, but Ang-II inhibitions increases arrhythmia, mainly by initiating ventricular ectopic beats.

Topics: Amides; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Arrhythmias, Cardiac; Blood Pressure; Captopril; Creatine Kinase, MB Form; Fumarates; Heart; Heart Rate; Male; Myocardial Reperfusion Injury; Oxidative Stress; Rats

Angiotensin-converting enzyme (ACE) inhibitors cause angioedema due to diminished degradation of bradykinin. Angiotensin receptor blockers may occasionally cause angioedema but the mechanism is unknown, and are generally considered safe, even in those who have reacted to ACE inhibitors. We determined whether aliskiren, a renin inhibitor, has an effect on the rate of bradykinin degradation.. The ability of renin to metabolize bradykinin was studied and the rate of bradykinin degradation compared in the presence or absence of aliskiren. Enalapril, a known ACE inhibitor that causes angioedema served as positive control.. Renin was unable to digest bradykinin, indicating that a renin inhibitor is unlikely to affect the rate of bradykinin degradation. In a plasma system, aliskiren had no effect on the rate of bradykinin degradation while enalapril inhibited it appreciably. An inhibitory effect of aliskiren on the rate of bradykinin degradation by human pulmonary endothelial cells was observed, estimated to be about 5% of that of enalapril.. Aliskiren has no effect upon the rate of bradykinin degradation in plasma and a minimal effect employing vascular endothelial cells. The latter suggests inhibition of a non-renin enzyme that is a minor contributor to bradykinin degradation.

Topics: 3-Mercaptopropionic Acid; Amides; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Endothelial Cells; Fumarates; Humans; Peptidyl-Dipeptidase A; Pulmonary Artery; Renin

To investigate the influence of simultaneous administration of spironolactone (20 mg/kg per day, intraperitoneal (i.p.)) and aliskiren (50 mg/kg per day, i.p.) for a period of eight weeks on cardiac remodeling in TGR(mRen2)27 rats.. Echocardiographic and electrophysiological and histological methods were used to determine the influence of spironolactone and aliskiren on cardiac remodeling.. 1) the beneficial effect of aliskiren on SBP was enhanced by simultaneous administration of spironolactone; 2) echocardiographic studies showed that the left ventricle diameter (LVD), the left ventricle end diastolic volume (LVEDV) and the left ventricle posterior wall thickness (LVPW) were significantly reduced by the combination of both drugs when compared with aliskiren alone; 3) the ejection fraction was also increased; 4) histological studies indicated a greater decline in perivascular and interstitial fibrosis when both drugs were used; 5) the decrease of electrical remodeling of the left ventricle caused by aliskiren was further reduced by simultaneous administration of spironolactone; 6) the cardiac refractoriness increased by aliskiren was further incremented by spironolactone. Spironolactone (20 mg/kg per day) alone increased the ejection fraction and reduced LVD, LVEDV and LVPW but its effect was smaller than that achieved with the combination spironolactone plus aliskiren.. The combination of an aldosterone inhibitor with a direct renin inhibitor proved to be of greater benefit for cardiac structural and electrical remodeling in this experimental model of hypertension than aliskiren alone.

Topics: Amides; Animals; Blood Pressure; Coronary Vessels; Echocardiography; Fibrosis; Fumarates; Heart; Heart Conduction System; Injections, Intraperitoneal; Male; Rats, Transgenic; Renin; Rest; Spironolactone; Systole; Ventricular Remodeling

Various stress hormones are responsible for bringing out stress-related changes and are implicated in learning and memory processes. The extensive clinical experience of angiotensin receptor blockers (ARBs) and direct renin inhibitor as antihypertensive agents provides anecdotal evidence of improvements in cognition. The neurochemical basis underlying the anti-stress and nootropic effects are unclear. This study was aimed to determine the effects of aliskiren, valsartan and their combination on the neuromediators of the central nervous system (CNS) and periphery as well as on cognitive function.. Groups of rats were subjected to a forced swim stress for one hour after daily treatment with aliskiren, valsartan and their combination. The 24 h urinary excretion of vanillylmandellic acid (VMA), 5-hydroxyindoleacetic acid (5-HIAA), 6-β-hydroxycortisol (6-β-OH) cortisol and homovanillic acid (HVA) was determined in all groups under normal and stressed conditions. Nootropic activity was studied using cook's pole climbing apparatus and acetylcholinesterase (AChE) inhibitory activity by Ellman's method.. Administration of aliskiren (10 mg/kg), valsartan (20 mg/kg) and their combination at a dose of 5 and 10 mg/kg respectively reduced the urinary metabolite levels. Further, all drugs showed significant improvement in scopolamine-impaired performance and produced inhibition of the AChE enzyme.. The present study provides scientific support for the anti-stress and nootropic activities of aliskiren, valsartan and their combination.

Topics: Acetylcholinesterase; Amides; Animals; Avoidance Learning; Brain; Female; Fumarates; Homovanillic Acid; Hydrocortisone; Hydroxyindoleacetic Acid; Metabolome; Nootropic Agents; Rats, Wistar; Renin-Angiotensin System; Stress, Physiological; Valsartan; Vanilmandelic Acid

Tacrolimus is frequently used as immunosuppressive agent in organ transplantation but its clinical use is limited due to its marked nephrotoxicity.. Male Wistar albino rats weighing 150-200 g (10-12 weeks old) were used. Animals were divided into four groups. Group 1 served as control group and received normal saline, group 2 served as toxic group and received 2 mg/kg tacrolimus i.p., group 3 served as treatment group and received 2 mg/kg tacrolimus i.p. followed by 2 mg/kg aliskiren orally and group 4 served as drug per se group and received 2 mg/kg aliskiren orally. Tacrolimus-induced nephrotoxicity was assessed biochemically and histopathologically.. Treatment with aliskiren decreased the tacrolimus-induced changes in biochemical markers of nephrotoxicity such as blood urea nitrogen and creatinine. Aliskiren also attenuated the effects of tacrolimus on oxidative stress parameters such as malondialdehyde, reduced glutathione and catalase. Histopathological and ultrastructural studies showed that aliskiren attenuated tacrolimus-induced renal damage.. These results suggest that aliskiren has protective effects against tacrolimus-induced nephrotoxicity; implying that renin inhibitor may counteract nephrotic syndrome associated with immunosuppressant use.

Topics: Amides; Animals; Catalase; Fumarates; Glutathione; Kidney; Kidney Diseases; Lipid Peroxidation; Male; Oxidative Stress; Rats, Wistar; Tacrolimus

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is involved in hypertension. We tested whether aliskiren treatment in early postnatal life can reduce ADMA and regulate the renin-angiotensin system to prevent hypertension in rat offspring exposed to maternal caloric restriction (CR).. Four groups of 12-week-old male offspring were sacrificed: control, CR, CR+aliskiren, and CR+losartan group. The CR group included offspring from 50% food-restricted maternal rats. The CR+aliskiren and CR+losartan groups were produced by treating CR offspring with oral aliskiren 10 mg/kg/day or losartan 20 mg/kg/day between 2-4 weeks of age, respectively.. Blood pressure increased in CR rats, which was prevented by aliskiren or losartan. CR increased plasma ADMA levels, which aliskiren prevented. Renal renin and prorenin receptor (PRR) expression increased in CR rats treated with aliskiren, whereas both were reduced by losartan. Both aliskiren and losartan decreased renal mRNA expression of angiotensinogen, angiotensin II type 2 receptor, and Mas in CR rats. However, aliskiren increased angiotensin II type 2 receptor and Mas protein levels in CR kidneys.. Early aliskiren therapy prevents CR-induced hypertension via ADMA reduction, decreases angiotensinogen expression, and increases renal angiotensin II type 2 receptor and Mas protein.

Topics: Amides; Angiotensin-Converting Enzyme 2; Animals; Animals, Newborn; Arginine; Blood Pressure; Blotting, Western; Body Weight; Caloric Restriction; Female; Fumarates; Gene Expression Regulation; Histone Deacetylases; Hypertension; Losartan; Male; Peptidyl-Dipeptidase A; Rats, Sprague-Dawley

A simple, unique and selective HPLC-PDA method was developed and validated for the simultaneous estimation of aliskiren (ALS) and amlodipine (AML) in human plasma. Extraction of the sample was accomplished by protein precipitation. Plasma proteins were precipitated by employing acetonitrile containing hydrochlorothiazide as internal standard. The compounds were analyzed by HPLC by using PDA detector on a Hibar C18 (250 × 4.6 mm) column with a mobile phase comprising acetonitrile and phosphate buffer (pH 4.2 and 25 mm; 60:40 v/v) with a flow rate of 0.8 mL/min. Different sample pretreatment techniques were evaluated but protein precipitation was found to be satisfactory, offering good recovery values of 97.11-98.45% for ALS and 97.5-99.12% for AML. The within-day precisions for ALS were 96.66, 99.16 and 99.41% at 90, 240 and 480 ng/mL, respectively, and for AML they were 97.27, 99.54 and 99.31% at 3.3, 8.8 and 17.6 ng/mL, respectively. The between-day precisions for ALS were 96.66, 99.16 and 99.41% at 90, 240 and 480 ng/mL, respectively and the between-day precisions for AML were 98.18, 99.20 and 99.40% at 3.3, 8.8 and 17.6 ng/mL, respectively. The limit of quantitation was 30 and 1.0 ng/mL for ALS and AML respectively. Different constituents of plasma proteins did not interfere with the absolute recovery of ALS and AML.

Topics: Acetonitriles; Amides; Amlodipine; Chemical Precipitation; Chromatography, High Pressure Liquid; Drug Stability; Fumarates; Humans; Hydrochlorothiazide; Limit of Detection; Sensitivity and Specificity

The aim of this study was to investigate the effects of aliskiren on vascular function and endothelial progenitor cells (EPCs) in patients with type 2 diabetes and essential hypertension.. The study enrolled type 2 diabetic patients aged >50 years under stable glycemic control and first diagnosed mild essential hypertension. In phase A (n = 20), patients received aliskiren 150-300 mg daily for 3 months. In phase B (n = 12), hydrochlorothiazide (HCTZ) 12.5-25mg daily substituted for aliskiren for 3 more months. At baseline and at the end of each phase, we assessed (i) brachial blood pressure (BBP); (ii) central aortic systolic pressure (CSP), aortic augmentation index (Aix), and pulse wave velocity (PWV) as markers of arterial stiffness; (iii) brachial artery flow-mediated dilatation (FMD) as a marker of endothelial function; (iv) left ventricular (LV) twisting and untwisting as markers of LV function and (v) EPC numbers in culture of peripheral blood mononuclear cells.. Aliskiren similarly reduced BBP and CSP, increased FMD (P < 0.001) and EPC numbers (P < 0.001), decreased PWV and Aix (P < 0.05), and improved LV twisting and untwisting (P < 0.05). Although substitution of HCTZ sustained BBP at similar levels, CSP and echocardiographic indices nearly returned at baseline levels, and the improvement of FMD, PWV, Aix, and EPC numbers was abolished.. Aliskiren had a favorable effect on endothelial function and EPCs, reduced arterial stiffness, and improved LV twisting and untwisting. These effects were independent of BBP lowering, as they were not observed after the achievement of similar values of BBP with HCTZ.

Topics: Aged; Amides; Antihypertensive Agents; Arterial Pressure; Biomarkers; Cells, Cultured; Diabetes Mellitus, Type 2; Diuretics; Drug Substitution; Endothelial Progenitor Cells; Endothelium, Vascular; Female; Fumarates; Hemodynamics; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Pilot Projects; Time Factors; Treatment Outcome; Vascular Stiffness; Vasodilation; Ventricular Function, Left

In the present study, we investigated the potential effect of aliskiren on smooth muscle cell (SMC) migration in response to prorenin.. Cultured human SMCs were incubated with angiotensinogen (ANG) (1.5 × 10(-7)M) and increasing concentrations of aliskiren (10(-6)-10(-5)M). After 24 h, SMC migration was assessed by Boyden's chamber chemotactic assay using prorenin as chemotactic factor (10(-8)M). The effect of aliskiren on RhoA and Rac activity was also determined by G-LISA assay and the lamellipodia formation by rhodamine-phalloidin staining. Changes in cell morphology were recorded in real-time using the iCelligence system.. Aliskiren determined, at 10(-5)M, a significant inhibition of SMC migration induced by prorenin (-66.4 ± 18.1%; p < 0.05), while no significant effect was observed when PDGF-BB was utilized as chemotactic agent. Aliskiren also reduced Rac-GTP levels in response to prorenin (-54.2 ± 5.4%) without affecting the RhoA-GTP levels. Finally, aliskiren inhibited both the lamellipodia formation and morphological changes induced by prorenin with no significant effect on PDGF-BB activity.. Taken together, we provide the first evidence of the inhibitory action of aliskiren on SMC migration induced by prorenin.

Topics: Amides; Aorta; Becaplermin; Cell Movement; Cell Shape; Fumarates; Humans; Myocytes, Smooth Muscle; Proto-Oncogene Proteins c-sis; Pseudopodia; rac GTP-Binding Proteins; Renin; Time Factors

Aliskiren is a substrate for P-glycoprotein (P-gp) and is metabolized via cytochrome P450 3A4 (CYP3A4). The aim of the present study was to assess whether P-gp influenced the pharmacokinetics of aliskiren and also if drug-drug interactions (DDIs) mediated through P-gp could be reproduced in cynomolgus monkeys. The study investigated the pharmacokinetics of aliskiren in mdr1a/1b gene-deficient (P-gp KO) and wild-type (WT) mice. The area under the plasma concentration-time curve (AUC) following the oral administration of aliskiren was 6.9-fold higher in P-gp KO mice than in WT mice, while no significant differences were observed in the AUC or total plasma clearance following the intravenous administration of aliskiren to P-gp KO mice. Then the pharmacokinetics of aliskiren were evaluated and DDIs between aliskiren and P-gp inhibitors, such as cyclosporin A (CsA) and zosuquidar, examined in cynomolgus monkeys. The AUC for aliskiren were 8.3- and 42.1-fold higher after the oral administration of aliskiren with the concomitant oral administration of zosuquidar and CsA at doses of 10 and 30 mg/kg, respectively. In contrast, the AUC after the intravenous and oral administration of aliskiren was not significantly affected by the oral administration of zosuquidar or intravenous administration of CsA, respectively. These results indicated that P-gp strictly limited the intestinal absorption of aliskiren in mice and monkeys, and also that the effects of intestinal P-gp inhibition by CsA or zosuquidar on the pharmacokinetics of aliskiren were sensitively reproduced in monkeys. In conclusion, aliskiren can be used as a sensitive substrate to evaluate intestinal P-gp inhibition in monkeys.

Topics: Amides; Animals; Antihypertensive Agents; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Sub-Family B Member 4; Cyclosporine; Dibenzocycloheptenes; Dose-Response Relationship, Drug; Drug Interactions; Fumarates; Humans; Macaca fascicularis; Male; Mice; Mice, Knockout; Quinolines; Species Specificity

We aimed to analyze benefits and risks of aliskiren treatment in older adults (⩾ 65 years) in clinical practice. Patients (n = 14,986) were assigned to either aliskiren (ALIS), an angiotensin-converting-enzyme inhibitor or angiotensin receptor blocker (ACEi/ARB), or an agent not blocking the renin-angiotensin system (non-RAS). Older adults (n = 7396) had a longer history of hypertension (8.7 vs 4.7 years; P < 0.0001), lower mean diastolic blood pressure (DBP; 87.7 ± 11.0 vs 92.1 ± 11.0 mm Hg) and more renal (12.0 vs 5.6%; P < 0.0001) or cardiovascular disease (44.0 vs 18.9%; P < 0.0001); 4548 received aliskiren (68.8%), 1215 ACEi/ARBs (18.4%) and 850 non-RAS treatments (12.9%). Office BP at 1 year was reduced by 18.4 ± 21.5/7.2 ± 12.0 mm Hg. BP reductions were greater (19.5 ± 21.7/7.6 ± 12.1 mm Hg) in the aliskiren group than in the ACEi/ARB (15.6 ± 20.9/6.4 ± 11.9) and non-RAS groups (16.1 ± 20.7/6.5 ± 11.7 mm Hg), respectively (P<0.0001 for systolic BP (SBP) and <0.01 for DBP). After multivariable adjustment, differences in SBP reductions were clinically irrelevant and no differences were noted for DBP. Adverse effects were higher in older adults with no differences between treatment groups. In conclusion, the present analysis of a large, unselected cohort of patients in clinical practice from the 3A study, offers real-life evidence of the effectiveness and safety of aliskiren for the treatment of hypertension in older adults.

Topics: Age Factors; Aged; Amides; Antihypertensive Agents; Blood Pressure; Drug-Related Side Effects and Adverse Reactions; Female; Fumarates; Germany; Humans; Hypertension; Male; Middle Aged; Renin; Renin-Angiotensin System; Risk Assessment; Treatment Outcome

This study aimed to analyze the hemodynamic and cardiac effects of direct renin inhibitor (DRI) treatment and swimming training in hypertensive rats.. Seventy-seven rats were divide into eight groups: sedentary normotensive (SN), trained normotensive (TN), sedentary normotensive treated with DRI (SN_DRI), trained normotensive treated with DRI (TN_DRI), sedentary hypertensive (SH), trained hypertensive (TH), sedentary hypertensive treated with DRI (SH_DRI), trained hypertensive treated with DRI (TH_DRI). Swimming training occurred for up to 60 min, five times a week for four weeks. The hypertensive animals were treated with 20 mg ċ kg(-1) ċ day(-1) L-NAME for four weeks. Groups treated with DRI received 10 mg ċ kg(-1) ċ day(-1) of aliskiren for four weeks. After the treatment period, all the animals underwent femoral artery catheterization surgery for direct measurement of cardiovascular variables.. The SH group presented hypertension (136.4 ± 5.0 mmHg) compared to the SN (107.1 ± 1.7 mmHg). The TH group showed lower mean arterial pressure (MAP) than the SH (121.1 ± 1.3 mmHg), but the treatment with DRI did not attenuate hypertension (128.2 ± 4.9 mmHg). The analysis of collagen areas demonstrated that treatment with DRI may attenuate cardiac remodeling in situations of hypertension, in the condition of treatment alone or combined with physical training.. Both interventions in combination may be more effective at reducing cardiovascular risk in hypertensive subjects.

Topics: Amides; Animals; Blood Pressure; Disease Models, Animal; Enzyme Inhibitors; Fumarates; Heart; Hypertension; Male; NG-Nitroarginine Methyl Ester; Physical Conditioning, Animal; Rats; Rats, Wistar; Renin; Risk Factors; Swimming

The synthesis of aliskiren (1), a recently marketed drug for the treatment of hypertension, is presented. The focus of our synthetic effort is to develop an efficient pathway for the synthesis of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl)-N,N,8-trimethylnon-4-enamide (2a), which has been used as the advanced intermediate toward aliskiren. After an extensive investigation of three different strategies designed to construct the E-olefin functionality in 2a by employing the olefin cross-metathesis, Horner-Wadsworth-Emmons (HWE), and Julia-type olefinations, we have established a new protocol for the synthesis of 2a with a substantially improved overall efficiency in terms of the yield (ca. 33%), and diastereo- and E/Z-selectivity. The key transformations were the Evans chiral auxiliary-aided asymmetric allylation for the synthesis of the appropriate chiral intermediates in excellent enantiomeric purity of higher than 97% ee and a modified Julia-Kocienski olefination for the highly selective construction of E-2a with up to 13.6:1 E/Z ratio from the chiral intermediates. Consequently, the results provide an appealing option for the synthesis of aliskiren.

Topics: Alkenes; Amides; Chemistry Techniques, Synthetic; Fumarates; Stereoisomerism

To determine the protective effect of aliskiren on ischemia-reperfusion (I/R) injury in a rat renal (I/R) model.. Rats were randomly divided into five groups: sham control group; sham control with aliskiren pretreatment; I/R group and I/R with two doses of aliskiren pretreatment. Rats were unilaterally nephrectomized and subjected to 45 min of renal pedicle occlusion followed by 24 h reperfusion. Aliskiren (50 and 100 mg/kg) was administered orally by gavage 24 and 1 h prior to ischemia. After 24 h reperfusion, kidney samples were taken for the determination of malondialdehyde (MDA) level, superoxide dismutase (SOD), glutathione (GSH) activity and histological evaluation. The level of serum creatinine (SCR) and blood urea nitrogen (BUN), renin and angiotensin II (AT-2) was measured in serum samples.. Kidneys from I/R groups showed significant increase in MDA level and significant decrease in GSH, and SOD activity. IL-1β, iNOS and NFkB gene expression significantly increased in the I/R groups in the rat kidney tissue. Aliskiren treatment showed a significant down-regulatory effect on IL-1β, iNOS and NFkB mRNA expression. Compared with the sham group, SCR and BUN, renin and AT-2 were significantly increased in the I/R rats, accompanied by histopathological damage to the kidney.. Pretreatment with aliskiren ameliorated I/R-induced renal injury through decreasing nitric oxide and AT-2 levels and by the reduction of injury induced by I/R injury and ameliorated renal histopathological molecular and biochemical changes.

Topics: Amides; Angiotensin II; Animals; Antihypertensive Agents; Creatinine; Fumarates; Kidney; Kidney Diseases; Male; Malondialdehyde; Microscopy, Electron; Nitric Oxide; Oxidative Stress; Protective Agents; Rats; Rats, Wistar; Renin; Reperfusion Injury; Superoxide Dismutase; Treatment Outcome

The renin-angiotensin-aldosterone system (RAAS) plays a key role in the regulation of blood pressure. Renin is the rate limiting enzyme of the RAAS and aliskiren is a highly potent and selective inhibitor of the human renin. Renin is known to be active both in the circulating blood stream as well as locally, when bound to the (pro)-renin receptor ((P)RR). In this study we have investigated a possible mechanism of action of aliskiren, in which its accumulation in the plasma membrane is considered as an essential step for effective inhibition. Aliskiren's interactions with model membranes (cholesterol rich and poor) have been investigated by applying different complementary techniques: differential scanning calorimetry (DSC), Raman spectroscopy, magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy and small- and wide-angle X-ray scattering (SAXS and WAXS). In addition, in silico molecular dynamics (MD) calculations were applied for further confirmation of the experimental data. Aliskiren's thermal effects on the pre- and main transition of dipalmitoyl-phosphatidylcholine (DPPC) membranes as well as its topographical position in the bilayer show striking similarities to those of angiotensin II type 1 receptor (AT1R) antagonists. Moreover, at higher cholesterol concentrations aliskiren gets expelled from the membrane just as it has been recently demonstrated for the angiotensin receptor blocker (ARB) losartan. Thus, we propose that both the AT1R and the (P)RR-bound renin active sites can be efficiently blocked by membrane-bound ARBs and aliskiren when cholesterol rich membrane rafts/caveolae are formed in the vicinity of the receptors.

Topics: 1,2-Dipalmitoylphosphatidylcholine; Amides; Angiotensin II Type 1 Receptor Blockers; Calorimetry, Differential Scanning; Catalytic Domain; Caveolae; Cell Membrane; Cholesterol; Fumarates; Humans; Lipid Bilayers; Membrane Microdomains; Renin; Scattering, Small Angle; Spectrum Analysis, Raman; X-Ray Diffraction

Albuminuria change is often used to assess drug efficacy in intervention trials in nephrology. The change is often calculated using a variable number of urine samples collected at baseline and end of treatment. Yet more albuminuria measurements usually occur. Because albuminuria shows a large day-to-day variability, this study assessed to what extent the average and the precision of the antialbuminuric drug effect varies with the number of urine collections at each visit and the number of follow-up visits.. This study used data from three randomized intervention trials (Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy, Selective Vitamin D Receptor Activation for Albuminuria Lowering, and Residual Albuminuria Lowering with Endothelin Antagonist Atrasentan) including patients with type 2 diabetes and macroalbuminuria. Albuminuria-lowering drug effects were estimated from one, two, or three urine collections at consecutive days before each study visit and reported as albuminuria change from baseline to end of treatment or the change over time considering an average of all follow-up albuminuria measurements.. Increasing the number of urine collections for an albuminuria measurement at baseline and end of treatment or using all study visits during follow-up did not alter the average drug effect. The precision of the drug effect increased (decreased SEM) when the number of study visits and the number of urine collections per visit were increased. Using all albuminuria measurements at all study visits led to a 4- to 6-fold reduction in sample size to detect a 30% albuminuria-lowering treatment effect with 80% power compared with using baseline and end-of-treatment albuminuria measurements alone.. Increasing the number of urine collections per study visit and the number of visits over time does not change the average drug effect estimate but markedly increases the precision, thereby enhancing statistical power. Thus, clinical trial designs in diabetic nephropathy using albuminuria as an end point can be significantly improved, leading to smaller sample sizes and less complex trials.

Topics: Aged; Albuminuria; Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Atrasentan; Bone Density Conservation Agents; Diabetic Nephropathies; Endothelin Receptor Antagonists; Ergocalciferols; Female; Fumarates; Humans; Losartan; Male; Middle Aged; Office Visits; Pyrrolidines; Randomized Controlled Trials as Topic; Research Design; Statistics as Topic; Urine Specimen Collection

A sensitive UPLC-MS/MS method was developed and validated for simultaneous estimation of aliskiren hemifumarate (ALS), amlodipine besylate (AML) and hydrochlorothiazide (HCZ) in spiked human plasma using valsartan as an internal standard (IS). Liquid-liquid extraction was used for purification and pre-concentration of analytes. The mobile phase consisted of 0.1% formic acid in ammonium acetate buffer (0.02 M, pH 3.5) and methanol (25:75, v/v), flowing through XBridge BEH (50 × 2.1 mm ID, 5 µm) C18 column, at a flow rate of 0.6 mL min(-1). Multiple reaction monitoring (MRM) transitions were measured using an electrospray source in the positive ion mode for ALS and AML, whereas HCZ and IS were measured in negative ion mode. Validation of the method was performed as per US-FDA guidelines with linearity in the range of 2.0-400.0, 0.3-25.0 and 5.0-400.0 ng mL(-1) for ALS, AML and HCZ, respectively. In human plasma, ALS, AML and HCZ were stable for at least 1 month at -70 ± 5°C and for at least 6 h at ambient temperature. After extraction from plasma, the reconstituted samples of ALS, AML and HCZ were stable in the autosampler at ambient temperature for 6 h. The LC-MS/MS method is suitable for bioequivalence and pharmacokinetic studies of this combination.

Topics: Amides; Amlodipine; Antihypertensive Agents; Chromatography, High Pressure Liquid; Fumarates; Humans; Hydrochlorothiazide; Limit of Detection; Liquid-Liquid Extraction; Reproducibility of Results; Tandem Mass Spectrometry

Given the increasing popularity of aliskiren, particularly in combination with angiotensin converting enzyme inhibitor (e.g. enalapril), it is important to determine whether its use in combination with these agents is associated with potentially life threatening safety events. Analytical methods for the simultaneous determination of both drugs in plasma and urine utilized in clinical studies on efficacy and safety have not been fully described in the literature. In this work, a new, fast and reliable method using a digitally controlled microextraction by packed sorbent (eVol(®)-MEPS) followed by ultra-high performance liquid chromatography (UHPLC) coupled with tandem mass spectrometry (MS/MS) was developed and validated to quantify an aliskiren, enalapril and its active metabolite in both human plasma and urine. Chromatographic separation was accomplished on a Poroshell 120 EC-C18 column with a gradient elution system consisting of 0.1% formic acid in water and acetonitrile (1.5min of total analysis). Detection was performed by multiple reaction monitoring (MRM) mode using electrospray ionization in the positive ion mode. This assay method has been fully validated in terms of selectivity, linearity, accuracy, precision, stability, recovery and matrix effect. The developed method can be applied to the routine determination of selected compounds in human plasma and urine and can be useful to elucidate the mechanisms of the potential risks triggered by the combination of aliskiren and enalapril as well as its active metabolite enalaprilat.

Topics: Amides; Chromatography, High Pressure Liquid; Enalapril; Fumarates; Humans; Tandem Mass Spectrometry

The purpose of this study was to determine the prognostic significance and associated clinical profile of early post-discharge N-terminal pro-B-type natriuretic peptide (NT-proBNP) trajectory among patients hospitalized for worsening chronic heart failure (HHF).. This post-hoc analysis of the Aliskiren Trial in Acute Heart Failure Outcomes (ASTRONAUT) included 1351 HHF patients with ejection fraction (EF) ≤40%, elevated B-type natriuretic peptide ≥400 pg/mL or NT-proBNP ≥1600 pg/mL at admission, and available NT-proBNP measurements (from a central core laboratory) at baseline (median 5 days after admission) and 1-month follow-up. The co-primary endpoints were all-cause mortality and cardiovascular mortality or HHF within 12 months. Median follow-up was 11.3 months. Patients with decreasing post-discharge NT-proBNP trajectory tended to be younger and have non-ischaemic HF aetiology. The presence of baseline atrial fibrillation was associated with high NT-proBNP at 1 month (i.e. above the median), regardless of the baseline value. After adjustment for patient characteristics and 1-month NT-proBNP level, every twofold increase in continuous NT-proBNP change from baseline to 1 month was predictive of increased cardiovascular mortality or HHF (hazard ratio 1.14; 95% confidence interval 1.02-1.26), but not all-cause mortality (hazard ratio 0.95; 95% confidence interval 0.81-1.11).. In this cohort of HHF patients with reduced EF, early post-discharge NT-proBNP trajectory was associated with a distinct clinical profile and carried independent prognostic value after adjustment for patient characteristics and absolute NT-proBNP level. Future prospective study of serial NT-proBNP measurement during the hospital and early post-discharge periods is warranted to validate these findings and evaluate post-discharge NT-proBNP trajectory as a therapeutic target.

Topics: Aged; Amides; Chronic Disease; Cohort Studies; Disease Progression; Female; Fumarates; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Proportional Hazards Models; Renin

The objective of this study is to determine the effect of two angiotensin-converting enzyme inhibitors (ACEi) (Enalapril and Captopril), an angiotensin-II receptor inhibitor (Losartan) and a renin inhibitor (Aliskiren) on renin, TGF-β1 and collagen expressions in human lung fibroblast cultures through real-time PCR and ELISA.. Normal commercial fibroblasts (CCD25) were exposed to 10(-6) M of enalapril, captopril, losartan, or aliskiren for 6 h. Subsequently, media were recovered and proteins were concentrated; RNA was extracted from the cells. Real time-PCR and ELISA were performed.. ACEi and losartan-stimulated fibroblasts showed an increase in the expression of TGF-β1, Collagen-Iα1 (Col-Iα1), and renin (except losartan) vs PolR2A (p < 0.05), and upregulation of TGF-β1 protein (p < 0.01), except with aliskiren.. Results show that ACEis and losartan could play a profibrosing role by inducing the overexpression of molecules such TGF-β1 and Collagen.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Captopril; Cells, Cultured; Collagen Type I; Collagen Type I, alpha 1 Chain; Enalapril; Fibroblasts; Fibrosis; Fumarates; Humans; Losartan; Lung; Protein Biosynthesis; Renin; Transcription, Genetic; Transforming Growth Factor beta1

Ureteral obstruction is associated with reduced expression of renal aquaporins (AQPs), urinary concentrating defects, and an enhanced inflammatory response, in which the renin-angiotensin system (RAS) may play an important role. We evaluated whether RAS blockade by a direct renin inhibitor, aliskiren, would prevent the decreased renal protein expression of AQPs in a unilateral ureteral obstruction (UUO) model and what potential mechanisms may be involved. UUO was performed for 3 days (3UUO) and 7 days (7UUO) in C57BL/6 mice with or without aliskiren injection. In 3UUO and 7UUO mice, aliskiren abolished the reduction of AQP2 protein expression but not AQP1, AQP3, and AQP4. mRNA levels of renal AQP2 and vasopressin type 2 receptor were decreased in obstructed kidneys of 7UUO mice, which were prevented by aliskiren treatment. Aliskiren treatment was also associated with a reduced inflammatory response in obstructed kidneys of UUO mice. Aliskiren significantly decreased mRNA levels of several proinflammatory factors, such as transforming growth factor-β and tumor necrosis factor-α, seen in obstructed kidneys of UUO mice. Interestingly, mRNA and protein levels of the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome components apoptosis-associated speck-like protein containing a caspase recruitment domain, caspase-1, and IL-1β were dramatically increased in obstructed kidneys of 7UUO mice, which were significantly suppressed by aliskiren. In primary cultured inner medullary collecting duct cells, IL-1β significantly decreased AQP2 expression. In conclusions, RAS blockade with the direct renin inhibitor aliskiren increased water channel AQP2 expression in obstructed kidneys of UUO mice, at least partially by preventing NLRP3 inflammasome activation in association with ureteral obstruction.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Aquaporin 2; Carrier Proteins; Cells, Cultured; Cytoprotection; Disease Models, Animal; Fumarates; Inflammasomes; Inflammation Mediators; Kidney; Kidney Diseases; Male; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Renin; Renin-Angiotensin System; RNA, Messenger; Time Factors; Up-Regulation; Ureteral Obstruction

Aliskiren is the first orally active inhibitor of renin to be approved for clinical use as an antihypertensive agent. A number of studies show a link between aliskiren and intravascular thrombosis.. The goal of the present study was to investigate the impact of aliskiren on arterial thrombosis in normotensive and renovascular hypertensive rats. The contribution of each coagulation and fibrinolytic parameters in the mode of aliskiren action was determined. Six weeks after clipping of the left renal artery rats developed hypertension which was confirmed by the "tail cuff" method. Animals were treated with aliskiren (10, 30 and 100mg/kg/day) per os for 10 days. Arterial thrombosis was induced by electrical stimulation of the common carotid artery.. It was found that aliskiren in a dose-dependent manner decreased weight of the arterial thrombus in normotensive and hypertensive rats. It has been shown that this result was not associated with the effects on blood pressure, TF, PT, APTT, fibrinogen and hematological parameters. It was found that aliskiren caused increase of t-PA activity and decrease of its inhibitor activity.. The presented results indicate that aliskiren inhibits hemostasis in the arterial thrombosis in rats. The antithrombotic effect is related with improvement of the fibrinolytic balance, and also depends on antiplatelet action.

Topics: Amides; Animals; Antihypertensive Agents; Blood Coagulation; Blood Coagulation Factors; Blood Pressure; Disease Models, Animal; Fumarates; Hemostasis; Hypertension; Male; Plasminogen Activator Inhibitor 1; Platelet Aggregation; Rats; Thrombosis; Tissue Plasminogen Activator

This observational study evaluated the efficacy and tolerability of 3-month aliskiren/amlodipine therapy under outpatient conditions.. This Austria-wide observational study included 579 hypertensive patients (566 [98 %] who could be analyzed biometrically) under the care of 140 physicians. The average age of the patient collective was 64 ± 11 years and the mean duration of hypertension was 10 ± 7 years. Regarding 92 % of the study participants, an antihypertensive therapy already existed. Efficacy was assessed in accordance with the Austrian hypertension guidelines while tolerability was evaluated on the basis of adverse events. A descriptive physician judgment based on efficacy, tolerability, and compliance was available for 539 patients (95 %). Office blood pressure values were used for the evaluation.. On average, the systolic and diastolic blood pressures were reduced from 161 ± 14 to 135 ± 10 mmHg and 93 ± 9 to 81 ± 6 mmHg, respectively. Blood pressure values of < 140/90 mmHg and < 130/80 mmHg were achieved in 56 and 7 % patients, respectively. A subgroup analysis of 242 patients (43 %) with diabetes mellitus and/or renal disease, as well as those with a high cardiovascular risk, demonstrated nearly identical results compared to the total population. Overall, 44 adverse events were documented in 41 patients, and physicians reported that 94 % of patients were compliant in a final survey on evaluation of therapy.. The fixed-dose combination of aliskiren/amlodipine provided clinically relevant blood pressure reductions along with good tolerance and compliance. During the 3-month duration of observation under outpatient conditions, it was seen that aliskiren and amlodipine reduced the systolic and diastolic blood pressures on average by 26 and 13 mmHg, respectively.

Topics: Aged; Aged, 80 and over; Amides; Amlodipine; Antihypertensive Agents; Austria; Drug Combinations; Female; Fumarates; Humans; Hypertension; Longitudinal Studies; Male; Middle Aged; Treatment Outcome

Renovascular hypertension is characterized by increased renal sympathetic activity, angiotensin II and by endothelial dysfunction. The purpose of this study was to determine the role of renal sympathetic nerve activity (RSNA) in mediating the anti-hypertensive effects of aliskiren (ALSK) and L-arginine (L-ARG) in a rat renovascular hypertension model. Hypertension was induced by clipping the right renal artery, and the following five groups were divided: SHAM operated; 2-kidney, 1-clip (2K1C); 2K1C plus ALSK; 2K1C plus L-ARG; and 2K1C plus ALSK+ L-ARG. The systolic blood pressure (SBP) of 2K1C rats increased from 114.4±5.2 to 204±12.7 mm Hg (P<0.05) and was only reduced by ALSK+L-ARG treatment (138.4±4.37 mm Hg). The 2K1C hypertension increased the baseline RSNA (SHAM: 62.4±6.39 vs. 2K1C: 97.4±8.43%). L-ARG or ALSK+L-ARG treatment significantly decreased baseline RSNA (2K1C L-ARG:70.7±2.39; 2K1C ALSK+L-ARG: 69.3±4.23%), but ALSK treatment alone did not (2K1C ALSK: 84.2±2.5%). Urinary water, Na(+), Cl(-) and urea excretion were similar in the 2K1C L-ARG, 2K1C ALSK+L-ARG and SHAM groups. The combination of ALSK+L-ARG restored urine flow and increased the glomerular filtration rate. The nNOS expression in the non clipped kidney was significantly increased in 2K1C ALSK+L-ARG rats. In conclusion, combined ALSK+L-ARG treatment normalizes SBP and prevents renal dysfunction in 2K1C hypertensive rats.

Topics: Amides; Animals; Antihypertensive Agents; Arginine; Blood Pressure; Chlorides; Fumarates; Glomerular Filtration Rate; Hypertension, Renovascular; Kidney; Male; Nitric Oxide Synthase; Rats; Rats, Wistar; Sodium; Sympathetic Nervous System; Urea; Water

The efficient and selective formal total synthesis of aliskiren is described. Aliskiren, a renin inhibitor drug, has received considerable attention, primarily because it is the first of the renin inhibitor drugs to be approved by the FDA. Herein, the formal synthesis of aliskiren by iridium-catalyzed asymmetric hydrogenation of two allylic alcohol fragments is reported. Screening a number of N,P-ligated iridium catalysts yielded two catalysts that gave the highest enantioselectivity in the hydrogenation, which gave the saturated alcohols in 97 and 93 % ee. In only four steps after hydrogenation, the fragments were combined by using the Julia-Kocienski reaction to produce late-stage intermediate in an overall yield of 18 %.

Topics: Amides; Antihypertensive Agents; Catalysis; Fumarates; Hydrogenation; Iridium; Propanols; Renin; Stereoisomerism

Topics: Adult; Amides; Female; Fumarates; Humans; Juxtaglomerular Apparatus; Kidney Neoplasms; Renin

Testicular torsion is a urological emergency. Failure of timely intervention for this issue leads the testicles to go into necrosis. If left untreated, it can lead to loss of the reproductive organs. The aim of this study was to examine the role of aliskiren in testicular torsion and detorsion injuries.. Rats were divided into 8 groups of 12 each, including no torsion-detorsion, no torsion-detorsion plus 200 mg/kg aliskiren orally, torsion, torsion-detorsion, torsion plus 100 mg/kg aliskiren orally, torsion plus 200 mg/kg aliskiren orally, torsion-detorsion plus 100 mg/kg aliskiren orally and torsion-detorsion plus 200 mg/kg aliskiren orally. Aliskiren was administered 30 minutes before ischemia and reperfusion, and also 24 hours before the experimental protocol in all treatment groups. Ischemia and reperfusion were each applied for 2 hours.. Testicular damage decreased superoxide dismutase and glutathione, and increased malondialdehyde in the testis tissues of rats. Aliskiren administration increased superoxide dismutase and glutathione, and decreased malondialdehyde in the testis tissues. Values were measured by a biochemical autoanalyzer. In addition, this torsion-detorsion damage caused a significant increase in levels of the inflammatory cytokine and agents interleukin-1β and inducible nitric oxide synthase, as examined by real-time polymerase chain reaction. Aliskiren administration decreased these parameters. On pathological evaluation administration of a 200 mg/kg dose of aliskiren was found to protect the testis. Renin-angiotensin-aldosterone system inhibition by aliskiren caused an increase in serum renin levels and a decrease in serum angiotensin II levels.. It appears that aliskiren protects the testis from ischemia-reperfusion damage by regulating inflammation and the oxidant-antioxidant balance via renin-angiotensin-aldosterone system inhibition.

Topics: Amides; Animals; Fumarates; Ischemia; Male; Rats; Rats, Wistar; Renin-Angiotensin System; Spermatic Cord Torsion; Testis

Fructose is a commonly used sweetener associated with diets that increase the prevalence of metabolic syndrome (MS). Inhibition of the renin-angiotensin system (RAS) has been consistently demonstrated to reduce MS. However, there has been no direct comparison among different pharmacological modes of inhibiting the RAS concerning their effects on MS. This study investigated the effect of aliskiren, a direct renin inhibitor, versus telmisartan, an angiotensin II-receptor blocker, in the treatment of fructose-induced MS in rats. MS was induced by high fructose (FRC) diet feeding for 12 weeks. Oral administrations of telmisartan (TEL, 5 mg/kg), aliskiren (ALS, 30 mg/kg) or vehicle were started in the last 4 weeks. Results showed that administration of either TEL or ALS with FRC diet equally ameliorated the metabolic parameters (glucose level, oral glucose tolerance test, insulin resistance and serum lipids profile), systolic blood pressure and oxidative stress markers (malondialdehyde, nitric oxide, reduced glutathione levels and catalase activity). Additionally, the effects of TEL and ALS were associated with a decrease in body composition index and attenuation of liver index, serum liver enzyme activities and hepatic expressions of inflammatory and fibrotic markers (tumor necrosis factor-α, nuclear factor kappa-B and transforming growth factor-β) with a significant increase in hepatic glucose transporter-2 and peroxisome proliferator-activated receptors-alpha and gamma expressions. The results suggested that, at indicated dosage, ALS has ameliorative effect equal to that of TEL against FRC-induced metabolic and hepatic disorders; implying that drugs which inhibit the RAS, by different mode of inhibition, profoundly affect fructose-induced MS in rats.

Topics: Amides; Animals; Antihypertensive Agents; Benzimidazoles; Benzoates; Blood Glucose; Fructose; Fumarates; Insulin Resistance; Male; Metabolic Syndrome; Rats; Rats, Wistar; Telmisartan; Treatment Outcome

Aliskiren is a drug classified as a direct renin inhibitor. The renin-angiotensin system plays an important role in pulmonary fibrogeneses. This study aimed to investigate the impact of aliskiren on pulmonary fibrosis induced by bleomycin. Forty adult mice were divided into group I (control), group II (aliskiren 25mg/kg/day IP), group III (bleomycin 0.035U/g intraperitoneally twice weekly for 4 weeks) and group IV (aliskiren+bleomycin). Plasma renin activity (PRA), lung content of hydroxyproline and transforming growth factor-β1 (TGF-β1) were assayed. Lung paraffin sections were prepared for histological study and immunohistochemical detection of alpha smooth muscle actin (αSMA) as a marker for myofibroblasts activation and differentiation. Bleomycin induced a significant elevation of PRA with a significant increase in hydroxyproline and TGF-β1 in group III. Microscopically, pulmonary fibrosis was evident in the form of areas of collapsed alveoli, intense inflammatory cells infiltrations, excess accumulation of collagen, and excessively encountered αSMA positively immune-stained myofibroblasts, compared to a negative immune-reaction in groups I and II. In group IV, aliskiren resulted in a significant decrease in PRA, TGF-β1 and hydroxyproline, with an attenuation of pulmonary fibrosis and a decrease in αSMA positively immune-stained myofibroblasts. In conclusion, renin inhibition by aliskiren attenuated pulmonary fibrosis through decreasing TGF-β1 and myofibroblasts activation and differentiation.

Topics: Actins; Amides; Animals; Bleomycin; Cell Differentiation; Fumarates; Mice; Myofibroblasts; Pulmonary Fibrosis; Renin; Renin-Angiotensin System; Transforming Growth Factor beta

A comparative study was established between two signal processing techniques showing the theoretical algorithm for each method and making a comparison between them to indicate the advantages and limitations. The methods under study are Numerical Differentiation (ND) and Continuous Wavelet Transform (CWT). These methods were studied as spectrophotometric resolution tools for simultaneous analysis of binary and ternary mixtures. To present the comparison, the two methods were applied for the resolution of Bisoprolol (BIS) and Hydrochlorothiazide (HCT) in their binary mixture and for the analysis of Amlodipine (AML), Aliskiren (ALI) and Hydrochlorothiazide (HCT) as an example for ternary mixtures. By comparing the results in laboratory prepared mixtures, it was proven that CWT technique is more efficient and advantageous in analysis of mixtures with severe overlapped spectra than ND. The CWT was applied for quantitative determination of the drugs in their pharmaceutical formulations and validated according to the ICH guidelines where accuracy, precision, repeatability and robustness were found to be within the acceptable limit.

Topics: Algorithms; Amides; Amlodipine; Bisoprolol; Complex Mixtures; Fumarates; Hydrochlorothiazide; Reproducibility of Results; Signal Processing, Computer-Assisted; Signal-To-Noise Ratio; Spectrophotometry; Wavelet Analysis

Renin is the rate limiting step for the activation of the renin-angiotensin-aldosterone system, which is linked to the development of endothelial dysfunction, hypertension and atherosclerosis. However, the specific role of renin during physiological responses to tissue ischemia is currently unknown. Aliskiren is the only direct renin inhibitor that is clinically used as an orally active antihypertensive drug. Here we tested the hypothesis that aliskiren might improve neovascularization in response to ischemia.. At a dose that did not modulate blood pressure (10 mg/kg), aliskiren led to improved blood flow recovery after hindlimb ischemia in C57BL/6 mice (Doppler flow ratios 0.71 ± 0.07 vs. 0.55 ± 0.03; P < 0.05). In ischemic muscles, treatment with aliskiren was associated with a significant increase of vascular density, reduced oxidative stress levels and increased expression of VEGF and eNOS. Aliskiren treatment also significantly increased the number of bone marrow-derived endothelial progenitor cells (EPCs) after hindlimb ischemia. Moreover, the angiogenic properties of EPCs (migration, adhesion, integration into tubules) were significantly improved in mice treated with aliskiren. In vitro, aliskiren improves cellular migration and tubule formation in HUVECs. This is associated with an increased expression of nitric oxide (NO), and a significant reduction of oxidative stress levels. Importantly, the angiogenic properties of aliskiren in vitro and in vivo are completely abolished following treatment with the NOS inhibitor l-NAME.. Direct renin inhibition with aliskiren leads to improved ischemia-induced neovascularization that is not dependant on blood pressure lowering. The mechanism involves beneficial effects of aliskiren on oxidative stress and NO angiogenic pathway, together with an increase in the number and the functional activities of EPCs.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Bone Marrow Cells; Cell Adhesion; Cell Movement; Endothelial Cells; Endothelial Progenitor Cells; Fumarates; Human Umbilical Vein Endothelial Cells; Humans; Immunohistochemistry; Ischemia; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oxidative Stress; Oxygen; Reactive Oxygen Species; Renin; Renin-Angiotensin System; Superoxides

Aliskiren is a direct renin inhibitor which is suggested to modify proangiogenic cells in addition to lower blood pressure. Given that angiogenesis is impaired in the presence of diabetes mellitus, we would like to investigate whether and how aliskiren enhances endothelial progenitor cells (EPCs) and improves ischemic-induced neovasculogenesis by an effect independent of blood pressure reduction in diabetic animals.. Streptozotocin-induced diabetic mice were administered with either aliskiren (5 or 25 mg/kg/day) using an osmotic pump or hydralazine (2 or 10 mg/kg/day) given in drinking water for two weeks prior to a hind-limb ischemia surgery. Laser Doppler imaging and flow cytometry were used to evaluate the degree of neovasculogenesis and the circulating levels of EPCs, respectively.. In streptozotocin-induced diabetic mice, aliskiren enhanced the recovery of limb perfusion and capillary density, increased the number of circulating Sca-1+/Flk-1+ EPC-like cells, and elevated the levels of the plasma vascular endothelial growth factor (VEGF) and stromal cell-derived factor (SDF)-1α in a dose-dependent manner, whereas there were no such effects in hydralazine-treated mice. Intraperitoneal administration of anti-SDF-1 neutralizing monoclonal antibodies abolished the effects of aliskiren.. Independent of the reduction of blood pressure, aliskiren enhanced ischemia-induced neovasculogenesis in a dose-dependent manner via VEGF/SDF-1α related mechanisms in diabetic mice.

Topics: Amides; Animals; Antibodies, Monoclonal; Blood Pressure; Chemokine CXCL12; Diabetes Mellitus, Experimental; Endothelial Progenitor Cells; Fumarates; Humans; Hydralazine; Ischemia; Mice; Neovascularization, Physiologic; Renin; Vascular Endothelial Growth Factor A

Notch signaling is a conserved and widely expressed signaling pathway, which mediates various physiological processes including tumorigenesis. This study aims to explore the potential role and mechanism of notch1 interacting with KRT6B in the progression of RCC. The results indicated that the mRNA and protein expression of notch1 and KRT6 were significantly increased in tumor tissues, and highly positive correlation existed between notch1 and KRT6. Moreover, the patients with high notch1 expression had a significantly poorer prognosis than those of low expression patients. In vitro, KRT6 loss-of-function could inhibit the expression of notch1 and induce renal carcinoma cell death. Eventually, we found that renin inhibitor, aliskiren, could inhibit cell proliferation and decrease the expression of notch1 and KRT6 as well as regulate apoptosis-related protein expression in 786-O and ACHN renal carcinoma cell lines. These results suggested that the upregulation of notch1 and KRT6B might be involved in the development, progression and prognosis of human RCC, and aliskiren could suppress renal carcinoma cell proliferation, at least partially, through downregulation the expression of notch1 and KRT6.

Topics: Amides; Apoptosis; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Disease Progression; Female; Fumarates; Gene Silencing; Humans; Keratin-6; Kidney Neoplasms; Male; Middle Aged; Receptor, Notch1; RNA, Small Interfering; Signal Transduction; Up-Regulation

This antihypertensive has an unfavorable harm-benefit balance.

Topics: Amides; Antihypertensive Agents; Fumarates; Humans; Hyponatremia

This study aimed to examine the protective effects of aliskiren on gentamicin-induced nephropathy. Rats were injected with gentamicin (100 mg/kg per day) for 14 days. Aliskiren was infused for two weeks. Human proximal tubular epithelial cell lines (HK-2) were cultured with gentamicin in the absence or presence of aliskiren. Inflammatory profibrotic and apoptotic markers were evaluated in vivo and in vitro. Aliskiren treatment attenuated the decreased creatinine clearance, increased fractional sodium excretion, glomerulosclerosis and tubulointerstitial fibrosis and counteracted the increased ED-1 expression in gentamicin-treated rats. The levels of inflammatory cytokines (TNF-α, IL-1β and IFN-γ) and adhesion molecules (MCP-1, ICAM-1 and VCAM-1) increased in the gentamicin-treated kidneys. These changes were restored by aliskiren co-treatment. Aliskiren effectively reversed transforming growth factor-β-induced fibrotic responses such as induction of α-smooth muscle actin in gentamicin-treated rat kidneys. Along with these changes, aliskiren also attenuated the increase in nuclear factor κB and phosphorylated extracellular signal-regulated kinase (pERK 1/2) levels in HK-2 cells cultured with gentamicin. In addition, aliskiren decreased the number of TUNEL-positive nuclei and reduced the expression of proapoptotic markers in gentamicin-treated HK-2 cells. These findings suggest that aliskiren attenuates gentamicin-induced nephropathy by suppression of inflammatory, profibrotic and apoptotic factors through inhibition of the nuclear factor κB, Smads and mitogen-activated protein kinase signaling pathways.

Topics: Amides; Animals; Apoptosis; bcl-2-Associated X Protein; Cell Adhesion Molecules; Cytokines; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Fumarates; Gentamicins; Humans; Immunoblotting; Inflammation Mediators; Kidney; Kidney Diseases; Kidney Function Tests; Kidney Tubules; Male; NF-kappa B; Protective Agents; Proton-Translocating ATPases; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptors, Cell Surface; Renin; Smad Proteins; Transforming Growth Factor beta1; Vacuolar Proton-Translocating ATPases

We recently developed and validated in existing trials a novel algorithm (PRE score) to predict long-term drug efficacy based on short-term (month-6) drug-induced changes in multiple risk markers. To show the value of the PRE score for ongoing and planned clinical trials, we here report the predicted long-term cardio-renal efficacy of aliskiren in type 2 diabetes, which was investigated in the ALTITUDE trial, but unknown at the time this study was conducted.. We established the relation between multiple risk markers and cardio-renal endpoints (as defined in ALTITUDE) using a background database from past clinical trials. The short-term effect of aliskiren on multiple risk markers was taken from the AVOID trial. A PRE score was developed by multivariate Cox analysis in the background population and was then applied to the baseline and month-6 measurements of the aliskiren treatment arm of the AVOID trial to predict cardio-renal risk. The net risk difference at these time-points, after correction for placebo effects, was taken to indicate the estimated long-term cardio-renal risk change.. Based on the PRE score, we predicted that aliskiren treatment in ALTITUDE would confer a relative risk change of -7.9% (95% CI -2.5 to -13.4) for the cardio-renal endpoint, a risk change of -5.1% (-1.2 to -9.0) for the CV endpoint and a non-significant risk change of -19.9% (-42.1 to +2.1) for the renal endpoint.. PRE score estimations suggested that aliskiren has only a marginal additive protective effect on cardio-renal endpoints. These predictions were validated by the results of the ALTITUDE trial, confirming the potential of the PRE score to prospectively predict drug efficacy on cardio-renal outcomes.

Topics: Aged; Algorithms; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Cardiovascular Diseases; Decision Support Techniques; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Female; Fumarates; Humans; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Renin-Angiotensin System; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

The aspartic protease renin (REN) catalyses the rate-limiting step in the Renin-Angiotensin-Aldosterone System (RAAS), which regulates cardiovascular and renal homoeostasis in living organisms. Renin blockage is therefore an attractive therapeutic strategy for the treatment of hypertension. Herein, computational approaches were used to provide a structural characterization of the binding site, flap opening and dynamic rearrangements of REN in the key conserved residues and water molecules, with the binding of a dodecapeptide substrate or different inhibitors. All these structural insights during catalysis may assist future studies in developing novel strategies for REN inactivation. Our molecular dynamics simulations of several unbound-REN and bound-REN systems indicate similar flexible-segments plasticity with larger fluctuations in those belonging to the C-domain (exposed to the solvent). These segments are thought to assist the flap opening and closure to allow the binding of the substrate and catalytic water molecules. The unbound-REN simulation suggests that the flap can acquire three different conformations: closed, semi-open and open. Our results indicate that the semi-open conformation is already sufficient and appropriate for the binding of the angiotensinogen (Ang) tail, thus contributing to the high specificity of REN, and that both semi-open and open flap conformations are present in free and complexed enzymes. We additionally observed that the Tyr75-Trp39 H-bond has an important role in assisting flap movement, and we highlight several conserved water molecules and amino acids that are essential for the proper catalytic activity of REN.

Topics: Amides; Catalytic Domain; Fumarates; Imidazoles; Molecular Dynamics Simulation; Oligopeptides; Protein Binding; Protein Interaction Domains and Motifs; Renin

A new, simple, rapid and specific reversed-phase high-performance liquid chromatography (HPLC) method was developed and validated for the simultaneous determination of amlodipine besylate and aliskiren hemifumarate. The HPLC separation was achieved on an RP-18 column (250 × 4.6 mm) using a mobile phase of triethylamine-orthophosphoric acid buffer (50 mM, pH 3.0), acetonitrile and methanol (50:40:10, v/v/v) at a flow rate of 1 mL/min. The method was validated for specificity, linearity, precision, accuracy and robustness. The degree of linearity of the calibration curves, the percent recovery values of amlodipine and aliskiren and the limits of detection (LOD) and quantification (LOQ) for the HPLC method were determined. The linearity of the method was found to be in the concentration range of 5.0-50.0 µg/mL for aliskiren hemifumarate and 2.65-26.50 µg/mL for amlodipine besylate, LOD and LOQ values were 0.51, 0.95, 1.70 and 3.18 µg/mL for amlodipine besylate and aliskiren hemifumarate. The proposed method was successfully applied to amlodipine besylate and aliskiren hemifumarate in pharmaceutical dosage mixtures without any interference from the excipients. The method was found to be precise, accurate, reproducible and robust. The results agreed with those obtained using the developed reference method.

Topics: Amides; Amlodipine; Chromatography, High Pressure Liquid; Fumarates; Limit of Detection; Reproducibility of Results; Sensitivity and Specificity; Tablets

This study aimed to investigate the possible protective effects of aliskiren against doxorubicin (DXR)-induced cardiorenal injury and to identify the mechanisms involved. Intraperitoneal administration of DXR (15 mg/kg, body weight, as a single dose) caused significant induction in the levels of angiotensin I, caspase-3, lactate dehydrogenase (LDH), lipid peroxidation malondialdehyde (MDA), urea, and creatinine. Concomitant decline in the levels of albumin and total protein in plasma, reduction in reduced glutathione (GSH), and antiperoxidative enzyme superoxide dismutase (SOD) levels followed by ultrastructural alterations in the myocardial and renal tissues were also observed. Oral administration of aliskiren (100 mg/kg, for a period of 14 days) significantly prevented all these DXR-induced adverse effects and maintained the rats near to normal status. However, telmisartan (10 mg/kg) pretreatment has shown slight protection in DXR-induced renal injury as evidenced by broadening of podocyte foot process and narrowing of slit pore diameter. The results of aliskiren were compared with telmisartan which was used as reference in this study. These results suggested that aliskiren has protective effects against acute model of DXR-induced cardiotoxicity and nephrotoxicity, implying that plasma renin activity plays a role in DXR-induced cardio-renal injury.

Topics: Administration, Oral; Amides; Animals; Antihypertensive Agents; Cardiotoxicity; Disease Models, Animal; Doxorubicin; Fumarates; Injections, Intraperitoneal; Kidney Diseases; Myocardium; Rats; Rats, Wistar; Renin

Renal fibrosis, the major histopathological change in various renal disorders, is closely related to renal dysfunction. Unilateral ureteral obstruction is a well established model of experimental renal disease that results in tubulointerstitial fibrosis. Previous studies showed that aliskiren and mizoribine ameliorated unilateral ureteral obstruction induced renal fibrosis. However, to our knowledge the protective effect of combination therapy with aliskiren and mizoribine against renal fibrosis is unknown. We investigated the synergistic effects of aliskiren and mizoribine combination therapy on unilateral ureteral obstruction induced fibrosis in rats.. Male Sprague Dawley® rats underwent unilateral ureteral obstruction followed by aliskiren and/or mizoribine treatment. Kidney samples were fixed for histopathology and immunohistochemistry of myofibroblasts (α-SMA) and macrophages (ED-1). Real-time quantitative reverse transcription-polymerase chain reaction was performed to measure α-SMA, TGF-β1, osteopontin, MCP-1 and renin expression.. After unilateral ureteral obstruction the tubular dilatation, interstitial volume and α-SMA expression scores were significantly decreased by combination therapy compared with monotherapy with aliskiren or mizoribine. Combination therapy caused a significant decrease in the number of ED-1 positive cells and in TGF-β1 gene expression compared with monotherapy with either drug (each p <0.05). Combination therapy also decreased OPN and MCP-1 gene expression (p <0.05).. Aliskiren and mizoribine combination therapy provides increased renal protection against renal fibrosis and unilateral ureteral obstruction induced inflammation.

Topics: Amides; Animals; Drug Synergism; Drug Therapy, Combination; Fibrosis; Fumarates; Kidney; Male; Rats; Rats, Sprague-Dawley; Renin; Ribonucleosides; Transforming Growth Factor beta1; Ureteral Obstruction

The renin-angiotensin-aldosterone system (RAAS) plays pivotal roles in the pathogenesis of chronic kidney disease (CKD) progression. Aliskiren, a direct renin inhibitor, inhibits the rate-limiting step of the RAAS without any alternative pathway. It is proven to reduce albuminuria in CKD patients treated with angiotensin blockade. However, there are few reports which evaluate the advantage of aliskiren as the first-line drug against CKD progression in RAAS-activated hypertensive patients.. Tsukuba hypertensive mice (THM), double transgenic mice carrying both the human renin and human angiotensinogen genes, were fed a high-salt diet and treated with hydraladine, ramipril and aliskiren for 10 weeks. Blood pressure and urinary albumin excretion were measured every 2 weeks during the experimental period. We evaluated renal histological changes and gene expression. Plasma angiotensin concentration was measured to evaluate the RAAS inhibitory effect.. High-salt-loaded THM showed severe hypertension and renal injury. All antihypertensive drugs suppressed blood pressure and prevented renal disease progression. RAAS blockade showed a higher renoprotective effect than hydraladine despite an equivalent blood pressure lowering effect. Aliskiren exhibited even stronger renoprotection than ramipril. Plasma angiotensin concentration was increased in THM fed both normal salt and high salt. Hydraladine did not alter the plasma angiotensin concentration. Ramipril significantly decreased angiotensin II concentration. Aliskiren treatment almost completely suppressed angiotensin I and resulted in lower angiotensin II concentration than ramipril treatment.. Aliskiren prevents renal disease progression by suppressing both angiotensin I and II in RAAS-activated pathology. Our data suggest the application of a renin inhibitor for preventing kidney disease progression in CKD patients.

Topics: Albuminuria; Amides; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Antihypertensive Agents; Blood Pressure; Cytoprotection; Disease Models, Animal; Disease Progression; Down-Regulation; Fumarates; Humans; Hydralazine; Hypertension; Kidney; Kidney Diseases; Mice; Mice, Transgenic; Ramipril; Renin; Renin-Angiotensin System; Sodium Chloride, Dietary; Time Factors

The development of glomerulonephritis causes glomerular injury and renal dysfunction and is thought to increase renin release, thus activating the renin-angiotensin system (RAS). The aims of this study were to demonstrate activation of the intrarenal RAS and determine the effects of direct renin inhibition (DRI) on the progression of glomerulonephritis. Rats were treated with anti-Thy1.1 antibody with or without DRI, aliskiren (30 mg/kg/d). In the glomerulonephritic rats, protein, microalbumin excretion levels, urinary angiotensinogen excretion, glomerular expansion score and intrarenal transforming growth factor-β and plasminogen activator inhibitor-1 mRNA levels were augmented compared with control rats; however, hypertension was not observed in the glomerulonephritic rats, and aliskiren treatment did not modify their blood pressure. The increases in urinary protein (94.7 ± 13.0 mg/d) and microalbumin (7.52 ± 2.6 mg/d) excretion were reduced by aliskiren (43.6 ± 4.5 mg/d of protein and 2.57 ± 0.7 mg/d of microalbumin). Furthermore, the progression of glomerular expansion and elevation of intrarenal transforming growth factor-β and plasminogen activator inhibitor-1 levels were prevented by aliskiren. Importantly, aliskiren suppressed the augmentation of urinary angiotensinogen levels, the increased angiotensinogen expression in the kidneys and the increases in Ang II levels in renal medulla induced by the anti-Thy1.1 antibody. These results suggest that DRI with aliskiren prevents intrarenal RAS activation leading to mitigation of the development of glomerulonephritis. In addition, the renoprotective effects of DRI on glomerulonephritis occur in a blood pressure-independent manner. Accordingly, treatment with aliskiren may be an effective approach to treat glomerulonephritis and other intrarenal RAS-associated kidney diseases.

Topics: Amides; Animals; Fumarates; Glomerulonephritis; Kidney Glomerulus; Male; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System; Treatment Outcome

To report a case of difficult-to-treat hypertension ultimately managed with triple antirenin (anti-R) therapy using plasma renin activity (PRA) to guide medication selection.. A 66-year-old white man was referred to the cardiology pharmacotherapy clinic for difficult-to-treat hypertension. His initial office blood pressure (BP) was 152/71 mm Hg on diltiazem and chlorthalidone. After a series of medication adjustments based on serial PRA measurements, the patient achieved his target BP with a regimen that included 3 anti-R angiotensin system medications: carvedilol, valsartan, and aliskiren.. Despite continued progress in the understanding and advances in pharmacological therapy for hypertension, uncontrolled hypertension remains a major problem. The most common strategy to control hypertension is the stepped-care approach with progressive addition of medications to eventually reach BP goal. An alternative approach includes the use of PRA measurements to guide both the addition and removal of drugs in an attempt to effectively control BP. At times, this has the potential to result in a drug regimen that is incongruous with current guidelines and practice recommendations. However, if this results in more effective BP control with the same, or fewer, number of medications, it may represent a reasonable alternative.. This case report illustrates a real-world application of PRA-guided therapeutics in a patient with difficult-to-treat hypertension. It highlights how a personalized approach can lead to BP control with a more streamlined regimen than would likely result if a stepped-care approach was used.

Topics: Aged; Amides; Antihypertensive Agents; Carbazoles; Carvedilol; Fumarates; Humans; Hypertension; Male; Propanolamines; Renin; Tetrazoles; Valine; Valsartan

Juvenile rat toxicity studies with the direct renin inhibitor aliskiren were initiated to support treatment in the pediatric population. In Study 1, aliskiren was administered orally to juvenile rats at doses of 0, 30, 100 or 300 mg/kg/day with repeated dosing from postpartum day (PPD) 8 to PPD 35/36. In-life, clinical pathology, anatomic pathology, and toxicokinetics evaluations were performed. In Study 2, single oral doses of aliskiren (0, 100 or 300 mg/kg) were given to 14-, 21-, 24-, 28-, 31- or 36-day-old rats; in-life data and toxicokinetics were evaluated. Study 3 was a single dose (3 mg/kg i.v.) pharmacokinetic study in juvenile rats on PPD 8, 14, 21 and 28. In Study 4, naïve rats were used to investigate ontogenic changes of the multidrug-resistant protein 1 (MDR1) and the organic anion transporting polypeptide (OATP) mRNA in several organs. Oral administration of aliskiren at 100 and 300 mg/kg caused unexpected mortality and severe morbidity in 8-day-old rats. Aliskiren plasma and tissue concentrations were increased in rats aged 21days and younger. Expression of MDR1 and OATP mRNA in the intestine, liver and brain was significantly lower in very young rats. In conclusion, severe toxicity and increased exposure in very young rats after oral administration of aliskiren are considered to be the result of immature drug transporter systems. Immaturity of MDR1 in enterocytes appears to be the most important mechanism responsible for the high exposure.

Topics: Administration, Oral; Aging; Amides; Animals; Antihypertensive Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Dose-Response Relationship, Drug; Down-Regulation; Female; Fumarates; Injections, Intravenous; Jejunum; Liver; Male; Organic Anion Transporters; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Renin; Tissue Distribution; Toxicity Tests

This case represents an individual with accelerating hypertension and declining kidney function associated with atherosclerotic renal artery stenosis. Key features include loss of GFR (reaching stage V CKD) during intensified antihypertensive drug therapy including agents that block the renin-angiotensin system and failure to appreciate the extent to which moderate renal artery stenosis was affecting his better kidney. Interpretation of duplex ultrasound studies was complicated by a discrepancy between near-normal peak systolic velocities and markedly abnormal segmental arterial waveforms. It was essential to recognize that both kidneys were abnormal and focus on recovery of perfusion to the better of these kidneys. Successful revascularization of one kidney allowed major improvement in GFR and BP control.

Topics: Aged; Amides; Antihypertensive Agents; Atherosclerosis; Atrophy; Blood Pressure; Carbazoles; Carvedilol; Disease Progression; Drug Therapy, Combination; Fumarates; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Male; Propanolamines; Renal Artery Obstruction; Stents; Teaching Rounds

Angiotensin-converting enzyme inhibitors and angiotensin AT1 receptor blockers reduce myocardial ischemia-reperfusion injury via bradykinin B2 receptor- and angiotensin AT2 receptor-mediated mechanisms. The renin inhibitor aliskiren increases cardiac tissue kallikrein and bradykinin levels. In the present study, we investigated the effect of aliskiren on myocardial ischemia-reperfusion injury and the roles of B2 and AT2 receptors in this effect. Female Sprague-Dawley rats were treated with aliskiren (10 mg/kg per day) and valsartan (30 mg/kg per day), alone or in combination, together with the B2 receptor antagonist icatibant (0.5 mg/kg per day) or the AT2 receptor antagonist PD123319 (30 mg/kg per day), for 4 weeks before myocardial ischemia-reperfusion injury. Aliskiren increased cardiac bradykinin levels and attenuated valsartan-induced increases in plasma angiotensin II levels. In vehicle-treated rats, myocardial infarct size (% area at risk, mean±SEM, n=7-13) was 43±3%. This was reduced to a similar extent by aliskiren, valsartan, and their combination to 24±3%, 25±3%, and 22±2%, respectively. Icatibant reversed the cardioprotective effects of aliskiren and the combination of aliskiren plus valsartan, but not valsartan alone, indicating that valsartan-induced cardioprotection was not mediated by the B2 receptor. PD123319 reversed the cardioprotective effects of aliskiren, valsartan, and the combination of aliskiren plus valsartan. Aliskiren protects the heart from myocardial ischemia-reperfusion injury via a B2 receptor- and AT2 receptor-mediated mechanism, whereas cardioprotection by valsartan is mediated via the AT2 receptor. In addition, aliskiren attenuates valsartan-induced increases in angiotensin II levels, thus preventing AT2 receptor-mediated cardioprotection by valsartan.

Topics: Amides; Angiotensin II Type 2 Receptor Blockers; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Bradykinin; Bradykinin B2 Receptor Antagonists; Cardiotonic Agents; Drug Therapy, Combination; Female; Fumarates; Imidazoles; Models, Animal; Myocardial Infarction; Myocardial Reperfusion Injury; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 2; Receptor, Bradykinin B2; Tetrazoles; Valine; Valsartan

We tested the hypothesis that direct renin inhibition with aliskiren protects against myocardial ischemia/reperfusion (I/R) injury in spontaneously hypertensive rats (SHR), and examined the mechanism by which this occurs.. Male SHR were treated (orally, 4 weeks) with saline or aliskiren (30 or 60 mg kg(-1) day(-1)) and subjected to 30 minutes of left anterior descending coronary artery occlusion followed by 6 or 24 hours of reperfusion. Only the higher dose significantly lowered systolic blood pressure, the lower dose causing a smaller apparent lowering that was nonsignificant. Despite this difference in blood pressure-lowering effect, both doses increased the ejection fraction and fractional shortening and reduced myocardial infarct size equally. I/R decreased cardiac expression of phosphatidylinositol 3-kinase (PI3K), phospho-Akt and phospho-endothelial nitric oxide synthase (phospho-eNOS), but increased expression of inducible nitric oxide synthase (iNOS); these changes were all abrogated by aliskiren. Moreover, aliskiren decreased superoxide anion generation and increased cyclic guanosine-3',5'-monophosphate, an index of bioactive nitric oxide, in myocardium. It also decreased the expression of myocardial matrix metalloproteinase-2, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinases-1 (TIMP-1) following I/R. In a Langendorff heart preparation, the detrimental cardiac effects of I/R were abrogated by aliskiren, and these protective effects were abolished by NOS or PI3K inhibition. In a parallel study, although specific iNOS inhibition reduced plasma malondialdehyde and myocardial superoxide anion generation, it did not affect the deleterious effects of I/R on myocardial structure and function.. Direct renin inhibition protects against myocardial I/R injury through activation of the PI3K-Akt-eNOS pathway.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Fumarates; Hypertension; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Renin; Signal Transduction; Stroke Volume; Superoxides; Tissue Inhibitor of Metalloproteinase-1; Ventricular Function, Left

Aliskiren is a direct renin inhibitor developed to treat hypertension. Several clinical studies have suggested that aliskiren has beneficial effects on cardiovascular diseases beyond its antihypertensive effect. In the present study, we examined whether aliskiren limits the progression of AAA (abdominal aortic aneurysm), VH (ventricular hypertrophy) and atherosclerosis in an AngII (angiotensin II)-infused mouse model. ApoE-/- (apolipoprotein-E-deficient) mice were infused subcutaneously with AngII (1000 ng/kg of body weight per day; 4 weeks) to induce AAA and VH. At the completion of the AngII infusion, mice were randomly allocated to three groups to receive vehicle control, low-dose aliskiren (10 mg/kg of body weight per day) or high-dose aliskiren (50 mg/kg of body weight per day) for 4 weeks. Suprarenal aortic diameter assessed by ultrasound was significantly smaller in mice administered aliskiren at days 42 and 56. Aliskiren also significantly reduced the normalized heart weight, ventricular myocyte cell width and aortic arch atherosclerosis. Aliskiren lowered PRR (pro-renin receptor) expression and MAPK (mitogen-activated protein kinase) activity in the suprarenal aorta and heart. Aortic infiltration of T-lymphocytes and macrophages was reduced by aliskiren. In conclusion, aliskiren limits the progression of AAA, VH and atherosclerosis in an AngII-infused mouse model.

Topics: Amides; Angiotensin II; Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Apolipoproteins E; Atherosclerosis; Blood Pressure; Disease Models, Animal; Fumarates; Hypertension; Hypertrophy; Mice; Mice, Inbred C57BL; Mice, Knockout

Aliskiren inhibits the activation of the renin-angiotensin system. Here, we investigated the effects of aliskiren on chronic atrial iron remodeling in the experimental canine model of rapid atrial pacing.. Twenty-eight dogs were assigned to sham (S), control paced (C), paced + aliskiren (10 mg Kg(-1) d(-1), A1), and paced + aliskiren (20 mg Kg(-1) d(-1), A2) groups. Rapid atrial pacing at 500 bpm was maintained for 2 weeks, while group S was not paced. Levels of serum angiotensin-converting enzyme and angiotensin II after pacing were determined by ELISA. Whole-cell patch-clamp technique, western blot, and RT-PCR were applied to assess atrial ionic remodeling.. The density of I CaL and I Na currents (pA/pF) was significantly lower in group C compared with group S (I CaL: -4.09 ± 1.46 vs. -6.12 ± 0.58,P < 0.05; I Na: 30.48 ± 6.08 vs. 46.31 ± 4.73, P < 0.05). However, the high dose of aliskiren elevated the density of I CaL and I Na currents compared with group C (I CaL: -6.23 ± 1.35 vs. -4.09 ± 1.46, P < 0.05; I Na: 58.62 ± 16.17 vs. 30.48 ± 6.08, P < 0.01). The relative mRNA and protein expression levels of Cav1.2 and Nav1.5α were downregulated in group C respectively (Cav1.2: 0.46 ± 0.08; Nav1.5α: 0.52 ± 0.08, P < 0.01; Cav1.2: 0.31 ± 0.03; Nav1.5α: 0.41 ± 0.04, P < 0.01;), but were upregulated by aliskiren.. Aliskiren has protective effects on atrial tachycardia-induced atrial ionic remodeling.

Topics: Amides; Angiotensin II; Animals; Atrial Remodeling; Calcium Channels, L-Type; Cardiac Pacing, Artificial; Dogs; Down-Regulation; Fumarates; Gene Expression; Heart Atria; Hemodynamics; NAV1.5 Voltage-Gated Sodium Channel; Renin; Up-Regulation

Adriamycin (ADR) is commonly used for many solid tumor treatments. Its clinical utility is, however, largely limited by the adverse reactions, are known to be nephrotoxic. The mechanism by which it induces kidney damage is still not completely understood, but its nephrotoxicity might relate to increase reactive oxidant status (ROS), mitochondrial dysfunction. Until now, neurohormonal activation of it is unclear. ADR might activate the renin angiotensin system. Angiotensin-II also induced ROS and mitochondrial dysfunction. The aim of this study was to investigate whether angiotensin-II production inhibition has the protective effect on attenuation of mitochondrial function in rats with acute ADR-nephrotoxicity or not. Rats were divided into five groups as a control, ADR, co-treated ADR with captopril (CAP), co-treated ADR with Aliskren, co-treated ADR with both CAP and Aliskren groups. Creatinine kinase (CK) levels were measured at the end of treatment period. The kidneys were homogenized and biochemical measurements were made in mitochondria, cytosol. Mitochondria membrane potential (MMP) and ATP levels were determined. ADR increased CK levels and oxidative stress in mitochondria too (p<0.05). ADR significantly decreased MMP and ATP level in kidney mitochondria (p<0.05). Co-administration with ADR and Aliskren and CAP improved the dissipation of MMP (p<0.05). The decrease in ATP level was restored by treatment with inhibitors of ACE and renin. We concluded that inhibitors of angiotensin-II are effective against acute ADR induced nephrotoxicity via the restoration of MMP and ATP production and prevention of mitochondrial damage in vivo.

Topics: Adenosine Triphosphate; Amides; Angiotensin II; Animals; Captopril; Creatine Kinase; Doxorubicin; Fumarates; Kidney; Kidney Diseases; Male; Membrane Potential, Mitochondrial; Mitochondria; Oxidative Stress; Rats, Sprague-Dawley; Reactive Oxygen Species; Renin; Renin-Angiotensin System

The activation of the renin-angiotensin system (RAS) has been related to various aspects of metabolic syndrome. The current study evaluated the effects of RAS blockers in a model of diet-induced insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD).. Male C57BL/6 mice were fed a standard chow (SC; 10% lipids, n=15) diet or a high-fat (HF; 50% lipids, n=60) diet for 8 weeks and then treated with aliskiren (HF-A; 50 mg/kg per day, n=15), enalapril (HF-E; 30 mg/kg per day, n=15), or losartan (HF-L; 10 mg/kg per day, n=15) for an additional 6 weeks. We assessed glucose and lipid metabolism, hepatic histopathology, the expression profile of genes and proteins affecting hepatic gluconeogenesis, RAS and insulin signaling, and lipid beta-oxidation and accumulation. The differences between the groups were tested via analysis of variance (ANOVA) and the post hoc Holm-Sidak test.. All treatments restored the up-regulation of hepatic RAS. The enalapril treatment, but not aliskiren or losartan, was effective in improving leptin, glucose intolerance, IR, hepatic steatosis, and triglycerides and in preventing increased hepatic protein levels of phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6Pase), and glucose transporter-2 (GLUT-2). Furthermore, enalapril improved the response to the deleterious effects of the HF diet by upregulating signal transduction through the insulin receptor substrate (IRS) 1/protein kinase B (Akt) pathway, as well as downregulating the protein levels and mRNA expression of peroxisome proliferator-activated receptor-γ (PPARγ), sterol regulatory element-binding protein-1c (SREBP-1c), and fatty acid synthase (FAS).. Enalapril was the most successful treatment in protecting against hepatic IR and NAFLD by enhancing hepatic insulin action, leptin, and gluconeogenesis and by reducing the lipogenic pathway and lipid accumulation in the liver.

Topics: Adipose Tissue; Amides; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Enalapril; Fumarates; Gene Expression Profiling; Gene Expression Regulation; Gluconeogenesis; Insulin Resistance; Leptin; Lipid Metabolism; Losartan; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Renin-Angiotensin System

A novel, specific, reliable, and accurate capillary zone electrophoretic method was developed and validated for the simultaneous determination of aliskiren hemifumarate, amlodipine besylate, and hydrochlorothiazide in their triple mixture dosage form. Separation was carried out in a fused-silica capillary (57.0 cm total length and 50.0 cm effective length, 75.6 μm internal diameter) by applying a potential of 17 kV and a running buffer consisting of 40 mM phosphate buffer at pH 6.0 with UV detection at 245 nm. The method was suitably validated with respect to specificity, linearity, LOD, and LOQ, accuracy, precision, and robustness. The method showed good linearity in the ranges 1-10, 2.5-25, and 30-300 μg/mL with LODs of 0.11, 0.33, and 5.83 μg/mL for amlodipine besylate, hydrochlorothiazide, and aliskiren hemifumarate, respectively. The proposed method was successfully applied for the analysis of the studied drugs in their coformulated tablets. The results of the proposed method were statistically compared with those obtained by the RP-HPLC reference method revealing no significant differences in the performance of the methods regarding accuracy and precision.

Topics: Amides; Amlodipine; Chromatography, High Pressure Liquid; Electrophoresis, Capillary; Fumarates; Hydrochlorothiazide

VTP-27999 is a renin inhibitor with an IC50 that is comparable to that of aliskiren, but with a higher bioavailability. Unexpectedly, VTP-27999, unlike aliskiren, did not unfold renin's precursor, prorenin, and increased the affinity of the antibodies applied in renin immunoassays.. Here we verified to what degree these differences affect intracellular renin inhibitor accumulation in renin-synthesizing human mast cells (HMC-1), and (pro)renin's signaling via the (pro)renin receptor ((P)RR) in rat vascular smooth muscle cells. We also addressed the consequences of (P)RR knockdown by small-interfering (si) RNA on (pro)renin release. Finally, making use of FRET(Bodipy-FL)-labeled aliskiren, we studied, by subcellular fractionation, the cellular distribution pattern of this renin inhibitor.. VTP-27999 accumulated at higher levels in HMC-1 cells than aliskiren, allowing this inhibitor to block intracellular renin at approximately five-fold lower medium levels. Labeled aliskiren accumulated in mitochondria and lysosomes, and its distribution pattern was different from that of renin. Moreover, the intracellular accumulation of both inhibitors in nonrenin-synthesizing HEK293 cells was not different from that in HMC-1 cells, suggesting that it is renin synthesis-independent. VTP-27999, but not aliskiren, blocked renin's capacity to stimulate extracellular signal-regulated kinase 1/2 phosphorylation in vascular smooth muscle cells, whereas neither inhibitor interfered with prorenin-induced signaling. (P)RR knockdown greatly increased renin (and to a lesser degree, prorenin) release, without affecting the capacity of forskolin or cAMP to stimulate renin release.. VTP-27999 differs from aliskiren regarding its level of intracellular accumulation and its capacity to interfere with renin signaling via the (P)RR, and the (P)RR determines prorenin-renin conversion and constitutive (but not regulated) (pro)renin release.

Topics: Amides; Animals; Antihypertensive Agents; Carbamates; Fluorescence Resonance Energy Transfer; Fumarates; HEK293 Cells; Humans; Inhibitory Concentration 50; Lysosomes; Mast Cells; Mitochondria; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Piperidines; Prorenin Receptor; Rats; Receptors, Cell Surface; Renin; RNA, Small Interfering

Topics: Amides; Captopril; Female; Fumarates; Humans; Kidney; Magnetic Resonance Imaging; Male; Oxygen; Renal Insufficiency, Chronic; Renin-Angiotensin System

Aliskiren hemifumarate (ALS) and amlodipine besylate (AML) were simultaneously determined by two different spectrofluorimetric techniques. The first technique depends on direct measurement of the steady-state fluorescence intensities of ALS and AML at 313 nm and 452 nm upon excitation at 290 and 375 nm, respectively, in a solvent composed of methanol and water (10: 90, v/v). The second technique utilizes synchronous fluorimetric quantitative screening of the emission spectra of ALS and AML at 272 and 366 nm, respectively using Δλ of 97 nm. Effects of different solvents and surfactants on relative fluorescence intensity were studied. The method was validated according to ICH guidelines. Linearity, accuracy and precision were found to be satisfactory in both techniques over the concentration ranges of 1-15 and 0.4-4 µg/mL for ALS and AML, respectively. In the first technique, limit of detection and limit of quantification were estimated and found to be 0.256 and 0.776 µg/mL for ALS as well as 0.067 and 0.204 µg/mL for AML, respectively. Also, limit of detection and limit of quantification were calculated in the synchronous method and found to be 0.293 and 0.887 µg/mL for ALS as well as 0.034 and 0.103 µg/mL for AML, respectively. The methods were successfully applied for the determination of the two drugs in their co-formulated tablets. The results were compared statistically with reference methods and no significant difference was found. The developed methods are rapid, sensitive, inexpensive and accurate for the quality control and routine analysis of the cited drugs in bulk and in pharmaceutical preparations without pre-separation.

Topics: Amides; Amlodipine; Chemistry, Pharmaceutical; Fumarates; Molecular Structure; Spectrometry, Fluorescence

Aliskiren is the first orally bioavailable direct renin inhibitor approved for the treatment of hypertension in adults. Juvenile toxicity studies in rats were initiated to support treatment in the pediatric population.. In Study 1, aliskiren oral administration was initiated on postpartum day (PPD) 14, after nephrogenesis was completed, and continued through PPD 70 at doses of 0, 30, 100, and 300 mg/kg/day. In-life, clinical pathology, anatomic pathology, developmental, behavioral, reproductive, and toxicokinetics evaluations were performed. In Study 2, oral administration was initiated on PPD 8, before completion of nephrogenesis, and continued through PPD 35/36. In-life, clinical pathology, anatomic pathology, developmental, and toxicokinetics evaluations were performed.. With dosing initiated on PPD 8, mortality at 100 and 300 mg/kg/day and slightly increased kidney weight at 100 mg/kg/day occurred. Decreased absolute lymphocyte count at 300 mg/kg/day at the end of dosing occurred with dosing initiated on PPD 14. There were clinical signs and transient effects on body weight gains in both studies. There were no changes in other parameters. Systemic exposure was much higher on PPD 8 and 14 compared with adult rats on PPD 64.. All effects produced by aliskiren, including kidney effects, were reversible. Increased exposure in very young animals is considered to be the result of immature drug transporter systems.

Topics: Administration, Oral; Amides; Animals; Antihypertensive Agents; Behavior, Animal; Body Weight; Dose-Response Relationship, Drug; Female; Fumarates; Hypertension; Kidney; Lymphocyte Count; Male; Maternal Exposure; Postpartum Period; Rats; Rats, Sprague-Dawley; Reproduction; Toxicity Tests; Toxicokinetics

Dual renin-angiotensin system (RAS) blockade in diabetic nephropathy is no longer feasible because of the profit/side effect imbalance. (Pro)renin receptor [(P)RR] blockade with handle region peptide (HRP) has been reported to exert beneficial effects in various diabetic models in a RAS-independent manner. To what degree (P)RR blockade adds benefits on top of RAS blockade is still unknown. In the present study, we treated diabetic TGR(mREN2)27 rats, a well-established nephropathy model with high prorenin levels [allowing continuous (P)RR stimulation in vivo], with HRP on top of renin inhibition with aliskiren. Aliskiren alone lowered blood pressure and exerted renoprotective effects, as evidenced by reduced glomerulosclerosis, diuresis, proteinuria, albuminuria, and urinary aldosterone levels as well as diminished renal (P)RR and ANG II type 1 receptor expression. It also suppressed plasma and tissue RAS activity and suppressed cardiac atrial natriuretic peptide and brain natriuretic peptide expression. HRP, when given on top of aliskiren, did not alter the effects of renin inhibition on blood pressure, RAS activity, or aldosterone. However, it counteracted the beneficial effects of aliskiren in the kidney, induced hyperkalemia, and increased plasma plasminogen activator-inhibitor 1, renal cyclooxygenase-2, and cardiac collagen content. All these effects have been linked to (P)RR stimulation, suggesting that HRP might, in fact, act as a partial agonist. Therefore, the use of HRP on top of RAS blockade in diabetic nephropathy is not advisable.

Topics: Aldosterone; Amides; Animals; Blood Pressure; Cyclooxygenase 2; Diabetes Mellitus, Experimental; Disease Models, Animal; Female; Fumarates; Kidney; Male; Oligopeptides; Plasminogen Activator Inhibitor 1; Potassium; Prorenin Receptor; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Streptozocin

Rasilez(®) tablets (RTs) contain the active ingredient aliskiren, which is a direct renin inhibitor of the renin-angiotensin system and used for the treatment of hypertension. We examined the influence of temperature and humidity on the physico-pharmaceutical characteristics (mass, volume, hardness, elution) of RTs. The RTs were preserved under conditions in which the temperature and humidity were altered using the second-order spherical composite experimental design for multi-objective problems. The characteristics of RTs were influenced more by the humidity than temperature, and differed markedly with over 55% relative humidity (RH). The mass and volume were increased with increasing humidity, and the tablets swelled. The hardness after vacuum-drying of the tablets, which preserved moisture conditions, was increased. Semitransparent particles were observed in the cross-section of the drying tablets in which aliskiren crystal forms were changed to amorphous forms. The mean dissolution time (MDT) of tablets was reduced with increasing humidity. The critical relative humidity (CRH) of the tablets was 36.1%RH at 30°C. These results suggest that RTs, on moisture absorption, showed changes in not their appearance and hardness, but also in crystal forms and the elution characteristics of aliskiren.

Topics: Amides; Chemical Phenomena; Drug Storage; Fumarates; Humidity; Renin-Angiotensin System; Tablets; Temperature

There are controversies about the mechanism of myocardium apoptosis in hypertensive heart disease. The aim of this study was to investigate the relationship among autophagy, Cx43 and apoptosis in aged spontaneously hypertensive rats (SHRs) and establish whether Aliskiren is effective or not for the treatment of myocardium apoptosis. Twenty-one SHRs aged 52 weeks were randomly divided into three groups, the first two receiving Aliskiren at a dose of 10 and 25 mg/kg/day respectively; the third, placebo for comparison with seven Wistar-Kyoto (WKY) as controls. After a 2-month treatment, systolic blood pressure (SBP), heart to bw ratios (HW/BW%) and angiotensin II (AngII) concentration were significantly enhanced in SHRs respectively. Apoptotic cardiomyocytes detected with TUNEL and immunofluorescent labelling for active caspase-3 increased nearly fourfolds in SHRs, with a decline in the expression of survivin and AKT activation, and an increase in caspase-3 activation and the ratio of Bax/Bcl-2. Myocardium autophagy, detected with immunofluorescent labelling for LC3-II, increased nearly threefolds in SHRs, with the up-regulation of Atg5, Atg16L1, Beclin-1 and LC3-II. The expression of Cx43 plaque was found to be down-regulated in SHRs. Aliskiren significantly reduced SBP, HW/BW%, AngII concentration and the expression of AT(1)R. Thus, Aliskiren protects myocardium against apoptosis by decreasing autophagy, up-regulating Cx43. These effects showed a dose-dependent tendency, but no significance. In conclusion, the myocardium apoptosis developed during the hypertensive end-stage of SHRs could be ameliorated by Aliskiren via the regulation of myocardium autophagy and maladaptive remodelling of Cx43.

Topics: Aging; Amides; Angiotensin II; Animals; Antihypertensive Agents; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Blood Pressure; Blotting, Western; Cell Proliferation; Cells, Cultured; Connexin 43; Fluorescent Antibody Technique; Fumarates; Immunoenzyme Techniques; Male; Myocytes, Cardiac; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Imaging of the kidney using blood oxygen level dependent (BOLD) magnetic resonance imaging (MRI) presents a major opportunity to examine differences in tissue oxygenation within the cortex and medulla applicable to human disease. The aim of this study was to evaluate BOLD signals before and after treatment with RAS inhibitors in hypertensive chronic kidney disease (CKD) patients. Ten patients with stable CKD and 5 healthy volunteers were included. Five CKD patients were subjected to BOLD MRI scan before and after chronic treatment with 300 mg/day aliskiren for at least 6 weeks. Five other CKD patients received BOLD MRI before and 1 hour after acute treatment with 50 mg captopril. A group of healthy volunteers (n=5) was scanned before and 1 hour after acute treatment with 50 mg captopril. The 10 patients had a mean age of 61±17 years; eGFR of 30±11 mL/min per 1.73 m(2) . Office systolic and diastolic blood pressures when on a RAS inhibito, were 130±10 and 86±5 mmHg in CKD patients. Control subjects had normal kidney function and were not on any medication. In untreated condition, systolic and diastolic arterial blood pressure elevated, 145±6 and 95±4 mmHg, respectively. After chronic treatment with aliskiren, arterial blood pressure decreased in all patients in this group, 127±3 mmHg and 77±3 mmHg. After acute treatment with captopril arterial blood pressure reduced to 125±4 and 71±8 mmHg. Tissue intensity signal (T2*) was increased in medulla after chronic treatment from 29±6 to 34±6 and after acute treatment with captopril from 34±9 to 38±11 in CKD patients. In addition, T2* ratio between cortex and medulla decreased in CKD patients after chronic treatment and acute treatment. This ratio remained stable in healthy volunteers before and after treatment with captopril 1.62±0.1 and 1.65±0.1, respectively. This study shows for the first time that RAS inhibitors change BOLD signal in CKD patients. Importantly, in healthy volunteers, a RAS inhibitor had no such effect. Further investigation is required.

Topics: Adult; Aged; Amides; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Captopril; Case-Control Studies; Comorbidity; Feasibility Studies; Female; Fumarates; Humans; Hypertension; Kidney; Magnetic Resonance Imaging; Male; Middle Aged; Oxygen; Pilot Projects; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Treatment Outcome

The purpose of this study was to investigate the effect of the renin inhibitor, aliskiren, on retinal ischemia-reperfusion injury. Retinal ischemia was induced by increasing intraocular pressure to 130 mmHg. At 7 days after ischemia, retinal damage was evaluated by measuring the retinal thickness and the number of retinal ganglion cells. Western blot was used to measure changes in the (pro)renin receptor expression. Retinal mRNA expressions of prorenin, angiotensinogen and angiotensin II type 1 receptor (AT1-R) were measured by real-time polymerase chain reaction. Rats were treated with the renin inhibitor, aliskiren. Although the number of retinal ganglion cells and the inner retinal thickness were significantly decreased at 7 days after ischemia, treatment with aliskiren significantly inhibited retinal ischemic injury. Administration of aliskiren increased mRNA expression of prorenin in the retina at 3 h after the reperfusion. The expression of the (pro)renin receptor was not changed after ischemia-reperfusion injury with or without aliskiren. Although there was an increase in the retinal expression of AT1-R at 3 h after the reperfusion, aliskiren administration suppressed this expression. A renin inhibitor attenuated subsequent ischemic damage in the rat retina via the inhibition of the prorenin-induced angiotensin generation.

Topics: Amides; Angiotensinogen; Animals; Blotting, Western; Cell Survival; Disease Models, Animal; Electroretinography; Fumarates; Infusion Pumps, Implantable; Intraocular Pressure; Male; Prorenin Receptor; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptor, Angiotensin, Type 1; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Reperfusion Injury; Retina; Retinal Diseases; Retinal Ganglion Cells; RNA, Messenger

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Coronary Artery Disease; Female; Fumarates; Humans; Hypertension; Male

Mammalian target of rapamycin (mTOR) has been reported to contribute to the development of HIV-associated nephropathy (HIVAN). We hypothesized that HIV may be activating renal tissue mTOR pathway through renin angiotensin system (RAS) via Angiotensin Receptor Type II receptor (AT2R). Renal tissues of Vpr transgenic and Tg26 (HIVAN) mice displayed enhanced phosphorylation of mTOR and p70S6K. Aliskiren, a renin inhibitor attenuated phosphorylation of both mTOR and p70S6K in renal tissues of HIVAN mice. Interestingly, Angiotensin Receptor Type I (AT1R) blockade did not modulate renal tissue phosphorylation of mTOR in HIVAN mice; on the other hand, AT2R blockade attenuated renal tissue phosphorylation of mTOR in HIVAN mice. In vitro studies, both renin and Ang II displayed enhanced mouse tubular cell (MTC) phosphorylation of p70S6K in a dose dependent manner. HIV/MTC also displayed enhanced phosphorylation of both mTOR and p70S6K; interestingly this effect of HIV was further enhanced by losartan (an AT1R blocker). On the other hand, AT2R blockade attenuated HIV-induced tubular cell phosphorylation of mTOR and p70S6K, whereas, AT2R agonist enhanced phosphorylation of mTOR and p70S6K. These findings indicate that HIV stimulates mTOR pathway in HIVAN through the activation of renin angiotensin system via AT2R.

Topics: AIDS-Associated Nephropathy; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin II Type 2 Receptor Blockers; Animals; Fumarates; HIV; Kidney Diseases; Losartan; Mice; Mice, Transgenic; Phosphorylation; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; TOR Serine-Threonine Kinases

We evaluated whether aliskiren, valsartan, or a combination of both was protective following myocardial infarction (MI) through effects on matrix metalloproteinase (MMP)-9. C57BL/6J wild type (WT, n=94) and MMP-9 null (null, n=85) mice were divided into 4 groups at 3h post-MI: saline (S), aliskiren (A; 50mg/kg/day), valsartan (V; 40mg/kg/day), or A+V and compared to no MI controls at 28days post-MI. All groups had similar infarct areas, and survival rates were higher in the null mice. The treatments influenced systolic function and hypertrophy index, as well as extracellular matrix (ECM) and inflammatory genes in the remote region, indicating that primary effects were on the viable myocardium. Saline treated WT mice showed increased end systolic and diastolic volumes and hypertrophy index, along with reduced ejection fraction. MMP-9 deletion improved LV function post-MI. Aliskiren attenuated the increase in end systolic volume and hypertrophy index, while valsartan improved end diastolic volumes and aliskiren+valsartan improved the hypertrophy index only when MMP-9 was absent. Extracellular matrix and inflammatory gene expression showed distinct patterns among the treatment groups, indicating a divergence in mechanisms of remodeling. This study shows that MMP-9 regulates aliskiren and valsartan effects in mice. These results in mice provide mechanistic insight to help translate these findings to post-MI patients.

Topics: Amides; Animals; Antihypertensive Agents; Drug Therapy, Combination; Extracellular Matrix; Female; Fumarates; Gene Expression; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; Myocardium; Stroke Volume; Survival Analysis; Systole; Tetrazoles; Valine; Valsartan; Ventricular Function, Left; Ventricular Remodeling

The benefit-risk ratio of combined blocking by the direct renin inhibitor aliskiren and an angiotensin-converting enzyme inhibitor (e.g. enalapril) on the renin-angiotensin-aldosterone system is discussed. No method was available for simultaneous determination of both drugs in urine. A novel sensitive method for simultaneous quantification in undiluted human urine was developed which enables systematic pharmacokinetic investigations, especially in poorly investigated populations like children. Matrix effects were clearly reduced by applying solid-phase extraction followed by a chromatographic separation on Xselect(TM) C18 CSH columns. Mobile phase consisted of methanol and water, both acidified with formic acid. Under gradient conditions and a flow rate of 0.4 mL/min the column effluent was monitored by tandem mass spectrometry with electrospray ionization. Calibration curves were constructed in the range of 9.4-9600 ng/mL regarding aliskiren, 11.6-12000 ng/mL for enalapril and 8.8-9000 ng/mL for enalaprilat. All curves were analyzed utilizing 1/x(2) -weighted quadratic squared regression. Intra-run and inter-run precision were 3.2-5.8% and 6.1-10.3% for aliskiren, 2.4-6.1% and 3.9-7.9% for enalapril as well as 3.1-9.4% and 4.7-12.7% regarding enalaprilat. Selectivity, accuracy and stability results comply with current international bioanalysis guidelines. The fully validated method was successfully applied to a pharmacokinetic investigation in healthy volunteers.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amides; Child; Child, Preschool; Chromatography, Liquid; Drug Stability; Enalapril; Enalaprilat; Female; Fumarates; Humans; Linear Models; Male; Middle Aged; Reproducibility of Results; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Young Adult

In the present study, we investigated the ameliorative potential of aliskiren in dextran sulfate sodium (DSS) induced colitis in mice. Aliskiren (3 and 10mg/kg, i.p.) was administered for 10 days from the day of DSS administration. The severity of colitis in mice was assessed using body weight loss, colon and spleen weight, hematological parameters, food intake, stool consistency, rectal bleeding and colon shortening. Colonic malondialdehyde (MDA), myeloperoxidase (MPO) and renin mRNA levels were also estimated. Furthermore, TNF-α and IL-6 in plasma and colon were analyzed. The results showed that aliskiren (10mg/kg, i.p.) significantly improved the severity of colitis by, decrease in weight loss, improvement in food intake and stool consistency, decrease in rectal bleeding, decrease in relative colon and spleen weight and improvement in colonic shortening. Aliskiren (10mg/kg, i.p.) improved blood hemoglobin, red blood cells (RBC) and hematocrit. Colonic malondialdehyde (MDA), MPO and histolopathological score were significantly diminished by aliskiren (10mg/kg, i.p.). Furthermore, aliskiren (10mg/kg, i.p.) significantly diminished the elevated levels of TNF-α, IL-6 and renin mRNA in inflammed colon. These results indicate involvement of renin in colitis and inhibition of renin by aliskiren ameliorates colitis.

Topics: Amides; Animals; Anti-Inflammatory Agents; Antioxidants; Body Weight; Colitis; Colon; Cytokines; Dextran Sulfate; Eating; Erythrocytes; Female; Fumarates; Gene Expression Regulation; Hematocrit; Hemoglobins; Malondialdehyde; Mice; Organ Size; Peroxidase; Renin; RNA, Messenger; Spleen

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cohort Studies; Disease-Free Survival; Drug Substitution; Enalapril; Female; Fumarates; Humans; Hypertension; Ovarian Neoplasms; Perindopril; Protein Kinase Inhibitors; Recurrence; Vascular Endothelial Growth Factor A

Hypertensive nephropathy is moving up the charts to number 2 after diabetic nephropathy in terms of diagnostic frequency cited as causing end stage renal disease (ESRD).. Hypertensive nephropathy was produced in mildly hypertensive C57BL/6-(hREN)/(hAGT) double transgenic (dTG) mice with 20 mg/kg of cyclosporine A (CsA) administered subcutaneously (sc) daily for 28 days. CsA dose 20 mg/kg was selected for the study as this dose offered significant alteration in blood pressure, biochemical parameters and moderate nephropathy in kidney. Effect of aliskiren oral treatment twice daily consequently for 28 days at 10 mg/kg body weight was evaluated against CsA induced hypertensive nephropathy. Systolic blood pressure (SBP) was measured by non invasive tail cuff method. Kidney function test (blood urea nitrogen, serum creatinine, urea and uric acid) and kidney injury biomarker (tumor necrosis factor-alpha (TNF-α) and interlekin-6) level was assessed in serum, TNF-α, IL-6, transforming growth factor-beta1 (TGF-β1) and kidney injury molecule-1 (KIM-1) was assayed in kidney homogenate. Urinary KIM-1 levels were assessed as an early biomarker of nephropathy.. Significant hypertensive nephropathy and increase in serum levels of biomarkers was observed in CsA treated animals when compared with Control group. Aliskiren treatment elicited significant renoprotection by preventing the increase in blood pressure and levels of serum biomarkers and also reduced the nephropathic alterations in the kidney histoarchitecture.. A correlation between pharmacological, biochemical and histological findings has been established in mouse model. The present findings have indicated the renoprotective activity of aliskiren in CsA induced hypertensive nephropathy, which may be due to its antihypertensive, anti-inflammatory as well as anti-apoptopic action.

Topics: Amides; Animals; Blood Pressure; Cyclosporine; Cytokines; Female; Fumarates; Hypertension, Renal; Kidney; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nephritis; Renin

Dysfunction of renin-angiotensin system (RAS) contributes to the pathogenesis of diabetic retinopathy (DR). Prorenin, the precursor of renin is highly elevated in ocular fluid of diabetic patients with proliferative retinopathy. Prorenin may exert local effects in the eye by binding to the so-called (pro)renin receptor ((P)RR). Here we investigated the combined effects of the renin inhibitor aliskiren and the putative (P)RR blocker handle-region peptide (HRP) on diabetic retinopathy in streptozotocin (STZ)-induced diabetic transgenic (mRen2)27 rats (a model with high plasma prorenin levels) as well as prorenin stimulated cytokine expression in cultured Müller cells. Adult (mRen2)27 rats were randomly divided into the following groups: (1) non-diabetic; (2) diabetic treated with vehicle; (3) diabetic treated with aliskiren (10 mg/kg per day); and (4) diabetic treated with aliskiren+HRP (1 mg/kg per day). Age-matched non-diabetic wildtype Sprague-Dawley rats were used as control. Drugs were administered by osmotic minipumps for three weeks. Transgenic (mRen2)27 rat retinas showed increased apoptotic cell death of both inner retinal neurons and photoreceptors, increased loss of capillaries, as well as increased expression of inflammatory cytokines. These pathological changes were further exacerbated by diabetes. Aliskiren treatment of diabetic (mRen2)27 rats prevented retinal gliosis, and reduced retinal apoptotic cell death, acellular capillaries and the expression of inflammatory cytokines. HRP on top of aliskiren did not provide additional protection. In cultured Müller cells, prorenin significantly increased the expression levels of IL-1α and TNF-α, and this was completely blocked by aliskiren or HRP, their combination, (P)RR siRNA and the AT1R blocker losartan, suggesting that these effects entirely depended on Ang II generation by (P)RR-bound prorenin. In conclusion, the lack of effect of HRP on top of aliskiren, and the Ang II-dependency of the ocular effects of prorenin in vitro, argue against the combined application of (P)RR blockade and renin inhibition in diabetic retinopathy.

Topics: Amides; Animals; Apoptosis; Blood Pressure; Cytokines; Diabetic Retinopathy; Disease Models, Animal; Fumarates; Gliosis; Inflammation Mediators; Mice, Transgenic; Oligopeptides; Prorenin Receptor; Rats; Receptors, Cell Surface; Renin; Retinal Ganglion Cells

Guidance regarding appropriate and cost-effective use of prescription drugs is published in the Ontario Drug Benefit Formulary in the form of "therapeutic notes." We conducted a cross-sectional study of all residents of Ontario aged 66 and older who received a new prescription for one of two drugs, aliskiren or sitagliptin, between December 1, 2008 and March 31, 2012 to determine how frequently such guidance is followed. Approximately half of initial prescriptions for aliskiren and sitagliptin were prescribed in a manner that did not conform to the therapeutic note recommendations (51.4% and 49.3%, respectively). Given this high rate of non-conformance, policy makers may wish to use other mechanisms to influence prescriber behaviour to improve the quality and efficiency of healthcare.

Topics: Aged; Aged, 80 and over; Amides; Antihypertensive Agents; Cross-Sectional Studies; Female; Fumarates; Guideline Adherence; Health Policy; Humans; Hypoglycemic Agents; Male; Ontario; Pharmacopoeias as Topic; Practice Guidelines as Topic; Practice Patterns, Physicians'; Pyrazines; Sitagliptin Phosphate; Triazoles

Aliskiren (ALK) is a renin inhibitor that has been used in the treatment of hypertension. The aim of this study was to determine whether ALK could ameliorate pressure overload-induced heart hypertrophy and fibrosis, and to elucidate the mechanisms of action.. Transverse aortic constriction (TAC) was performed in mice to induce heart pressure overload. ALK (150 mg·kg(-1)·d(-1), po), the autophagy inhibitor 3-methyladenine (10 mg·kg(-1) per week, ip) or the PKCβI inhibitor LY333531 (1 mg·kg(-1)·d-(1), po) was administered to the mice for 4 weeks. Heart hypertrophy, fibrosis and function were evaluated based on echocardiography, histological and biochemical measurements. Mechanically stretched cardiomyocytes of rats were used for in vitro experiments. The levels of signaling proteins were measured using Western blotting, while the expression of the relevant genes was analyzed using real-time QRT-PCR.. TAC induced marked heart hypertrophy and fibrosis, accompanied by high levels of Ang II in plasma and heart, and by PKCβI/α and ERK1/2 phosphorylation in heart. Meanwhile, TAC induced autophagic responses in heart, i.e. increases in autophagic structures, expression of Atg5 and Atg16 L1 mRNAs and LC3-II and Beclin-1 proteins. These pathological alterations in TAC-mice were significantly ameliorated or blocked by ALK administration. In TAC-mice, 3-methyladenine administration also ameliorated heart hypertrophy, fibrosis and dysfunction, while LY333531 administration inhibited ERK phosphorylation and autophagy in heart. In mechanically stretched cardiomyocytes, CGP53353 (a PKCβI inhibitor) prevented ERK phosphorylation and autophagic responses, while U0126 (an ERK inhibitor) blocked autophagic responses.. ALK ameliorates heart hypertrophy, fibrosis and dysfunction in the mouse model in setting of chronic pressure overload, via suppressing Ang II-PKCβI-ERK1/2-regulated autophagy.

Topics: Amides; Animals; Antihypertensive Agents; Autophagy; Cardiomegaly; Cells, Cultured; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Fumarates; Heart; Male; Mice; Mice, Inbred C57BL; Myocardium; Myocytes, Cardiac; Phosphorylation; Protein Kinase C; Rats; Rats, Sprague-Dawley; Stress, Mechanical

Sepsis and sepsis-related acute lung injuries (ALIs) are one of the main causes of death among hospitalized patients. Renin-angiotensin-aldosterone system (RAAS) has been reported to have role in sepsis. However, there is no study on aliskiren, a renin inhibitor, on sepsis-induced ALI. We aimed to investigate the potential protective effects of aliskiren in a model of cecal ligation and puncture (CLP)-induced lung injury. The rats were separated into five groups: sham, CLP, CLP + aliskiren 50 mg/kg (per orem (p.o.)), CLP + aliskiren 100 mg/kg (p.o.), and sham + aliskiren 100 mg/kg (p.o.). CLP model was applied via ligation of cecum and two punctures. After experiment, biochemical, molecular, and pathologic examinations were performed on lung and serum samples of rats. In our study, sepsis decreased superoxide dismutase (SOD) and glutathione (GSH) and increased malondialdehyde (MDA) in lung tissues of rats while aliskiren increased the SOD and GSH and decreased MDA. Also, sepsis caused a significant increase in pro-inflammatory cytokine levels (TNF-α, IL-1β, and IL-6) while aliskiren administration decreased these cytokines. Also, aliskiren administration at high dose protected lungs in pathologic evaluation. As a result of RAAS inhibition, aliskiren caused a decrease in serum angiotensin II level and increase in serum renin level. In light of these observations, we can suggest that the therapeutic administration of aliskiren prevented oxidative stress changes and cytokine changes and also protected lung tissues during CLP-induced sepsis by changing status of RAAS.

Topics: Amides; Angiotensin II; Animals; Fumarates; Glutathione; Lipid Peroxidation; Lung Injury; Male; Oxidative Stress; Rats; Rats, Wistar; Renin; Sepsis; Treatment Outcome

Glomerular filtration rate (GFR) is commonly calculated using the modification of diet in renal disease (MDRD) and Cockroft-Gault (CG) formulas and recently by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) algorithm and not directly measured, so that the real impact of antihypertensive therapy on GFR could not be well defined. In this study, the effect of Aliskiren on the GFR measured by radionuclide clearance of 99mTc-diethylene triamine penta-acetic acid (DTPA) was investigated.. In 106 hypertensive subjects (53% men) aged 61.9±12.7 years with uncontrolled blood pressure (BP) receiving at least 2 antihypertensive medications, Aliskiren was added once-daily at a dose of 150-300 mg for 12 months. Clinic BP measurements were taken at every follow-up visit (1st, 6th and 12th month), while 24-hours ambulatory BP and GFR (in mL/min/1.73 m2) were evaluated at baseline and at the end of the follow-up. Analysis of variance for repeated measures of BP, GFR and microalbuminuria was provided.. With the use of Aliskiren a significant reduction of BP and microalbuminuria was found (P<0.0001). Only in male population, a significant reduction in GFR calculated with CKD-EPI (82.4±15 vs. 78.6±18.2, P<0.01) and CG (81.6±29.5 vs. 74.2±28.4, P<0.0001) formulas was observed. This impairment of GFR was not found either with MDRD formula (70.5±19.6 vs. 68.3±23.4) or by radionuclide clearance (62.4±18.6 vs. 61.4±20.5).. This study seems to demonstrate that the efficacy on BP control of Aliskiren is not accompanied by an impairment of GFR. In order to evaluate the effect of Aliskiren on GFR scintigraphy technique or MDRD formula resulted to be the most accurate methods.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure; Female; Follow-Up Studies; Fumarates; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Radiopharmaceuticals; Sex Factors; Technetium Tc 99m Pentetate; Time Factors

Recently, the VA NEPHRON-D study was stopped early due to insignificant effects and increased adverse events. This was the last in a series of trials on the value of dual versus single blockade of the renin-angiotensin-aldosterone system in patients at risk for renal or cardiovascular complications. From these studies, the picture has emerged that dual blockade is hardly effective and increases the risk of hyperkalaemia and renal failure. Background use of beta blockers - little recognised indirect renin inhibitors - may play a role in the detrimental effects of dual blockade. Aldosterone antagonists in combination with one of the RAAS inhibitors may confer some benefit, but have not been studied sufficiently. For now, combining ACE inhibitors, angiotensin receptor blockers and aliskiren is to be discouraged.

Topics: Adrenergic beta-Antagonists; Amides; Angiotensin-Converting Enzyme Inhibitors; Fumarates; Humans; Mineralocorticoid Receptor Antagonists; Renin-Angiotensin System

We investigated whether aliskiren, a direct renin inhibitor, provided protection in a model of diabetic nephropathy in mice and compared its protective effects to valsartan, an angiotensin II type 1 receptor blocker.. Hyperglycemia was induced with streptozotocin (STZ, 40 mg/kg/day × 5 days) injection in DBA/2J mice fed on a high fat diet. Mice were treated with either aliskiren (25 mg/kg/day) or valsartan (8 mg/kg/day) for 6 weeks.. Aliskiren and/or valsartan treatment significantly attenuated albuminuria, urinary nephrin excretion and glomerulosclerosis. Aliskiren and/or valsartan prevented reduction of podocin and WT1 protein abundance in diabetic mice. Aliskiren and/or valsartan significantly prevented increased expression of profibrotic growth factors (TGFβ, CTGF and PAI-1), proinflammatory cytokines (MCP-1, TNFα and IL-1β), endoplasmic reticulum (ER) stress markers (CHOP and XBP-1) and lipid accumulation in the kidney of diabetic animals. Aliskiren showed similar efficacy compared to valsartan therapy and dual treatment in some aspects has synergistic protective effects.. Our study indicates that aliskiren and/or valsartan protects against diabetic kidney disease through multiple mechanisms, including decreasing podocyte injury, activation of profibrotic growth factors and proinflammatory cytokines, ER stress and accumulation of lipids.

Topics: Albumins; Amides; Animals; Creatinine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Endoplasmic Reticulum Stress; Fumarates; Inflammation; Lipid Metabolism; Male; Membrane Proteins; Mesangial Cells; Mice, Inbred DBA; Podocytes; Protective Agents; Proteinuria; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan

Regulatory guidelines for drug development suggest a strong control of the familywise error rate, when multiple hypotheses are simultaneously tested in confirmatory clinical trials. Accordingly, a variety of multiple test procedures exist for pharmaceutical trial applications, which are typically defined on a single structured family of null hypotheses. For some confirmatory clinical trials with multiple objectives, however, it is advantageous to address the arising multiplicity problems via grouped families of hypotheses. Graphical test procedures have been developed to construct, visualize, and perform multiple test procedures that are tailored to either a single or multiple families of structured hypotheses of interest. This note complements the existing literature by introducing a general algorithm to calculate adjusted p-values for any sequentially rejective graphical test procedure where the test procedures within the individual families of hypotheses are not necessarily graphical.

Topics: Algorithms; Amides; Antihypertensive Agents; Clinical Trials as Topic; Computer Graphics; Data Interpretation, Statistical; Drug Combinations; Enalapril; Endpoint Determination; Fumarates; Heart Failure; Humans

Tacrolimus (TAC), a calcineurin inhibitor, is commonly used as an immunosuppressive agent in organ transplantation, but its clinical use may be limited due to cardiotoxicity. Olmesartan (OLM; angiotensin receptor blocker) and aliskiren (ALK; renin inhibitor) may attenuate cardiotoxicity induced by TAC by inhibition of renin-angiotensin aldosterone system.. The aim of this study was to evaluate the effect of OLM and ALK on TAC-induced cardiotoxicity.. Male Wistar albino rats weighing 200-250 g (10-12 weeks old) were used in this study. Animals were divided into four groups. Group 1 received normal saline, group 2 received TAC (2 mg/kg, intraperitoneally for 14 d), group 3 received OLM (2 mg/kg, p.o. for 28 d) + TAC and group 4 received ALK (50 mg/kg, p.o. for 28 d) + TAC. TAC-induced cardiotoxicity was assessed biochemically and histopathologically.. Treatment with OLM or ALK decreased the TAC-induced changes in biochemical markers of cardiotoxicity such as serum aspartate transaminase, creatine kinase and lactate dehydrogenase. OLM or ALK also attenuated the effects of TAC on oxidant-antioxidant parameters such as malondialdehyde, reduced glutathione and catalase. Histopathological and ultrastructural studies showed that OLM or ALK also attenuated TAC-induced cardiotoxicity.. These results suggest that OLM as well as ALK has protective effects against TAC-induced cardiotoxicity; implying that angiotensin receptor blocker or renin inhibitor, respectively, may counteract cardiotoxicity associated with immunosuppressant use.

Topics: Amides; Animals; Fumarates; Heart; Imidazoles; Immunosuppressive Agents; Male; Myocardium; Rats; Rats, Wistar; Tacrolimus; Tetrazoles

The long-term relationship between 24-hour ambulatory blood pressure (ABP) and office BP in patients on therapy is not well documented. From a registry we included all patients in whom antihypertensive therapy needed to be uptitrated. Drug treatment included the direct renin inhibitor aliskiren or an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker or drugs not blocking the renin-angiotensin system, alone or on top of an existing drug regimen. In all patients, office BP and 24-hour ABP were obtained at baseline and after 1 year with validated devices. In the study population of 2722 patients, there was a good correlation between the change in office BP and 24-hour ABP (systolic: r=0.39; P<0.001; diastolic: r=0.34; P<0.001). However, the numeric decrease in office BP did not correspond to the decrease in ABP in a 1:1 fashion, for example, a decrease of 10, 20, and 30 mm Hg corresponded to a decrease of ≈7.2, 10.5, and 13.9 mm Hg in systolic ABP, respectively. The disproportionally greater decrease in systolic office BP compared with ABP was dependent on the level of the pretreatment BP, which was consistently higher for office BP than ABP. The white coat effect (difference between office BP and ABP) was on average 10/5 mm Hg lower 1 year after intensifying treatment and the magnitude of that was also dependent on pretreatment BP. There was a disproportionally greater decrease in systolic office BP than in ABP, which for both office BP and ABP seemed to depend on the pretreatment BP level.

Topics: Aged; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Circadian Rhythm; Follow-Up Studies; Fumarates; Humans; Male; Middle Aged; Office Visits; Prospective Studies; Registries; Treatment Outcome; White Coat Hypertension

A detailed account is given describing the approaches used toward the total synthesis of aliskiren. In particular, ring-closing metathesis with the Hoveyda-Grubbs catalyst accelerates the formation of a 9-membered lactone from an (R)-ester. The diastereomeric (S)-ester leads to the formation of dimeric dilactones, which were characterized by X-ray analysis and chemical conversions.

Topics: Amides; Caprylates; Catalysis; Crystallography, X-Ray; Esters; Fumarates; Lactones; Molecular Structure; Stereoisomerism

Current data on characteristics and outcomes of patients with high blood pressure (BP) managed under clinical practice conditions are limited.. The 3A registry is an open, prospective observational cohort study in German primary care offices, with a 4:1:1 inclusion ratio to either aliskiren (ALIS), an ACE inhibitor/angiotensin receptor blocker (ACEI/ARB), or to an antihypertensive agent not affecting the renin angiotensin system (non-RAS). A nonlinear mixed regression model was used to assess BP changes during follow-up regarding different BP values at inclusion in the various groups. ClinicalTrial.gov identifier is NCT01454583. In the total cohort of 13,433 patients with 1-year follow-up results, the mean age of patients was 64.7 years, 54% were men. Mean number of antihypertensive drugs was higher in the ALIS group compared to the other groups (3.0 drugs versus 2.5 in ACEI/ARB versus 1.6 in non-RAS; p<0.0001). Statistical regression analysis revealed baseline BP as the dominant covariate. After adjustment for baseline BP and 12 other confounders, no significant differences in BP reduction between the three groups were observed. The rate of major cardiac events (death, myocardial infarction, and stroke) was 1.3% in the total cohort, and did not differ across groups.. ALIS at beginning of the observation was mostly used by the physicians in patients with higher BP at entry and in higher risk populations. By study end, in all groups, stringent BP lowering measures, usually with combination therapy, led to significant improvements; more than half of these at-risk patients reached the BP targets.

Topics: Aged; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Female; Fumarates; Germany; Humans; Hypertension; Male; Middle Aged; Primary Health Care; Prospective Studies; Registries; Treatment Outcome

Dopamine (1 mg/kg, s.c.) causes 2.2-fold increase in diuresis (p < 0.05) in anesthetized rats, which is accompanied by an increase in the urinary excretion of sodium and potassium by a factor of 2.2 and 2.8, respectively (p < 0.05). Preliminary administration of the ACE inhibitor enalapril (1 mg/kg, p.o., for 7 days) enhances the renal dopamine response with 3.5-fold increase in its diuretic effect and increases natriuresis 3.2 times and urine potassium excretion 5 times (p < 0.05). After preliminary introduction of the AT1-angiotensin receptor antagonist losartan (1 mg/kg, p.o., for 7 days) dopamine causes 3.3-fold increase in diuresis, 3.1-fold increase in natriuresis, and 3-fold increase in kaliuresis (p < 0.05). Preliminary administration of the direct renin inhibitor aliskiren (4 mg/kg, p.o., for 7 days) is accompanied by 6-fold increase in the diuretic effect of dopamine and increases natriuresis 7.2 times and urine potassium excretion 7 times (p < 0.05). It is concluded that renin-angiotensin system (RAS) of renal tissues is involved in the mechanism of dopamine action in the kidney, acting as a modulator that prevents excessive loss of water and electrolytes with urine.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Animals; Dopamine; Dopamine Agents; Fumarates; Kidney; Losartan; Male; Natriuresis; Rats; Renin-Angiotensin System; Water-Electrolyte Balance

The interaction between the renin-angiotensin system and toll-like receptors (TLRs) in the pathogenesis of advanced atherosclerotic plaques is not well understood. We studied the effects of the renin inhibitor aliskiren on the progression of advanced atherosclerotic plaque in apolipoprotein E-deficient (ApoE(-/-)) mice with a special focus on plaque neovessel formation.. Four-wk-old ApoE(-/-) mice were fed a high-fat diet for 8 wks, and the mice were randomly assigned to one of three groups and administered a vehicle, hydralazine, or aliskiren for an additional 12 wks. Aliskiren reduced the atherosclerotic plaque area and plaque neovessel density. It increased the plaque collagen and elastin contents, and reduced plasma angiotensin II levels and plaque macrophage infiltration and cathepsin S (CatS) protein. Aliskiren also decreased the levels of AT1R, gp91phox, TLR2, monocyte chemotactic protein-1, and CatS mRNAs in the aortic roots. Hydralazine had no beneficial vascular effects, although its administration resulted in the same degree of blood pressure reduction as aliskiren. CatS deficiency mimicked the aliskiren-mediated vasculoprotective effect in the ApoE(-/-) mice, but aliskiren showed no further benefits in ApoE(-/-) CatS(-/-) mice. In vitro, TLR2 silencing reduced CatS expression induced by angiotensin II. Moreover, aliskiren or the inhibition of CatS impaired the endothelial cell angiogenic action in vitro or/and ex vivo.. Renin inhibition appears to inhibit advanced plaque neovessel formation in ApoE(-/-) mice and to decrease the vascular inflammatory action and extracellular matrix degradation, partly by reducing AT1R/TLR2-mediated CatS activation and activity, thus regressing advanced atherosclerosis.

Topics: Amides; Angiotensin II; Animals; Aorta; Apolipoproteins E; Atherosclerosis; Blood Pressure; Carrier Proteins; Cathepsins; Chemokine CCL2; Extracellular Matrix; Fumarates; Gene Silencing; Human Umbilical Vein Endothelial Cells; Humans; Hydralazine; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neovascularization, Pathologic; Nuclear Proteins; Plaque, Atherosclerotic; Receptor, Angiotensin, Type 1; Renin; Toll-Like Receptor 2; Treatment Outcome; Vascular Cell Adhesion Molecule-1

The aim of the present study was to investigate the effect of combination of aliskiren with paricalcitol on experimental diabetic nephropathy (DN) model in rats.. Forty male Sprague Dawley rats were divided into 5 groups of 8 rats each, namely the control (Group C), diabetes (Group D), aliskiren (Group A), paricalcitol (Group P), and aliskiren plus paricalcitol (Group A+P) groups. Aliskiren was given by oral-gavage at a dose of 50 mg/kg/day once daily for 12 weeks. Paricalcitol was given by intraperitoneally at a dose of 0,4 µg/kg/three day of week for 12 weeks. Renal function parameters, oxidative stress biomarkers, mRNA expression of renin-angiotensin system parameters and kidney histology were determined.. Group A+P had lower mean albümin-to-creatinine ratio (ACR) (p=0.004) as well as higher creatinine clearance (CCr) (p<0.005) than the diabetic rats (Group D). Combination therapy significantly increased CCr (Group A+P vs. Group A, p<0.005; Group A+P vs. Group P, p=0.022) and reduced ACR (Group A+P vs. Group A, p=0.018; Group A+P vs. Group P, p<0.005) when compared to monotherapy. Serum malondialdehyde levels were significantly lower (p=0.004); glutathion levels (p=0.003), glutathion peroxidase (p=0.004) and superoxide dismutase (p<0.005) activities were significantly higher in group A+P than in group D. The mean scores of mRNA expression of renin (p<0.005), angiotensin II (p=0.012) and angiotensin type 1 receptor (p=0.018) in group A+P were significantly lower. Although combination therapy showed no additional effect on oxidative system, renin-angiotensin system and renal histology, aliskiren plus paricalcitol significantly decreased interstitial fibrosis volume when compared to monotherapy (Group A+P vs. Group A, p<0.005; Group A+P vs. Group P, p=0.002).. Our data seem to suggest a potential role of aliskiren plus paricalcitol acting synergystically for reducing the progression of diabetic nephropathy in an experimental rat model.

Topics: Amides; Animals; Antihypertensive Agents; Antioxidants; Biomarkers; Bone Density Conservation Agents; Diabetic Nephropathies; Disease Progression; Drug Therapy, Combination; Ergocalciferols; Fumarates; Kidney; Kidney Function Tests; Lipid Peroxidation; Male; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System

The skeletal renin–angiotensin system (RAS) is involved in the progression of osteoporosis and the active peptide within the RAS, angiotensin II (ANG II), has deleterious effects on bones. This study was performed to investigate whether suppression of the rate-limiting step of the RAS cascade by the renin inhibitor aliskiren has a benefit on trabecular bone in osteoporotic mice. A postmenopausal osteoporosis model was induced by bilateral ovariectomy. The ovariectomized (OVX) mice were treated with a low (5 mg/kg) or high (25 mg/kg) dose of aliskiren for 6 weeks. Micro-computed tomography was performed to detect trabecular bone parameters of lumbar vertebra and to obtain 3-dimensional (3D) images. Treatment with aliskiren markedly increased bone volume over total volume (p<0.05), trabecular bone number (p<0.05), connectivity density (p<0.05), and bone mineral density (p<0.05) and reduced trabecular bone separation (p<0.05) compared to vehicle-treated OVX mice. Similarly, the 3D images were consistent with the quantitative data that showed aliskiren could markedly reverse the ovariectomy-induced pathological changes of trabecular bone. Thus, this study indicated that the treatment of estrogen-deficient mice with aliskiren could markedly increase bone mass and improve trabecular bone structure, suggesting its potential application in treating postmenopausal osteoporosis.

Topics: Amides; Animals; Antihypertensive Agents; Female; Fumarates; Lumbar Vertebrae; Mice; Osteoporosis; Ovariectomy; Renin; Renin-Angiotensin System; X-Ray Microtomography

The antihypertensive effects of the direct renin inhibitor aliskiren last substantially longer after treatment withdrawal than expected based upon its plasma half-life. This may be attributable to drug accumulation in the kidney as recently shown in rats and mice. Since aliskiren binds to renin we examined in the present study whether this accumulation depends on the renin content of the kidney.. For this we measured the aliskiren concentration in the kidney of wild-type as well as AT1a receptor(-/-) and Ren1c(-/-) mice. AT1a receptor(-/-) mice overexpress renin due to the lack of angiotensin II-mediated negative feedback, whereas Ren1c(-/-) mice lack renal renin expression.. Accumulation of aliskiren was found in the kidney of wild-type mice. However, renal accumulation was neither influenced by the overexpression nor by the absence of renin in the kidney. It was recently shown that the effects of aliskiren can be blocked by a handle region peptide, which inhibits the nonproteolytic activation of prorenin bound to the (pro)renin receptor. To investigate whether this putative (pro)renin receptor blocker influences renal aliskiren accumulation, we administered the blocker in addition to aliskiren. No influence on renal aliskiren accumulation was observed.. These data confirm accumulation of aliskiren in the murine kidney and demonstrate that neither renin nor (pro)renin receptor-bound prorenin are major players in this process.

Topics: Amides; Animals; Antihypertensive Agents; Fumarates; Humans; Immunohistochemistry; Kidney; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein Binding; Renin

Hypotension and syncopal attacks have been reported in association with drugs which block the renin-angiotensin-aldosterone system (RAAS). It has been proposed that the underlying mechanism is due to sensitisation of the Bezold-Jarisch reflex leading to withdrawal of sympathetic tone, profound and prolonged bradycardia, and hypotension. Sensitisation of this reflex occurs in the presence of blockade of the RAAS. In the ALTITUDE trial the use of the direct renin inhibitor, aliskiren, was associated with hypotensive episodes and an excess of ischaemic stroke. It is hypothesised that this is best explained by activation of the Bezold-Jarisch reflex, which may be particularly important in circumstances where there is dual blockade of the RAAS.

Topics: Amides; Brain Ischemia; Clinical Trials as Topic; Fumarates; Humans; Hypotension; Reflex; Renin-Angiotensin System; Risk Factors; Stroke

In the present study, we tested the hypothesis that chronic treatment with the direct rennin inhibitor aliskiren improves the remodelling of resistance arteries in dTGR (double-transgenic rats). dTGR (5 weeks) were treated with aliskiren (3 mg/kg of body mass per day) or ramipril (1 mg/kg of body mass per day) for 14 days and compared with age-matched vehicle-treated dTGR. BP (blood pressure) was similarly reduced in both aliskiren-treated and ramipril-treated rats compared with control dTGR (167±1 and 169±2 mmHg compared with 197±4 mmHg respectively; P<0.05). The M/L (media-to-lumen) ratio assessed on pressurized preparations was equally reduced in aliskiren-treated and ramipril-treated rats compared with controls (6.3±0.5 and 6.4±0.2% compared with 9.8±0.4% respectively; P<0.05). Endothelium-dependent and -independent relaxations were similar among the groups. L-NAME (N(G)-nitro-L-arginine methyl ester) significantly reduced acetylcholine-induced dilation in drug-treated dTGR. This effect was significantly more prominent in aliskiren-treated rats. eNOS (endothelial NO synthase) expression showed a 2-fold increase only in aliskiren-treated dTGR as compared with controls (P<0.01) and ramipril-treated dTGR (P<0.05). Plasma nitrite, as an index of NO production, was significantly increased in dTGR treated with either aliskiren or ramipril compared with controls. Only aliskiren induced a 2-fold increase in plasma nitrite, which was significantly greater than that induced by ramipril (P<0.05). gp91(phox) expression and ROS (reactive oxygen species) production in aorta were significantly and similarly reduced by both drugs. In conclusion, equieffective hypotensive doses of aliskiren or ramipril reduced the M/L ratio of mesenteric arteries and improved oxidative stress in dTGR. However, only aliskiren increased further NO production in the vasculature. Hence, in dTGR, direct renin inhibition induces favourable effects similar to that induced by ACE (angiotensin-converting enzyme) inhibition in improving vascular remodelling through different mechanisms.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Aorta; Blood Pressure; Fumarates; Humans; In Vitro Techniques; Male; Mesenteric Artery, Superior; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Nitric Oxide; Ramipril; Rats; Rats, Transgenic; Reactive Oxygen Species; Renin; Vascular Resistance

Aliskiren, a direct renin inhibitor, is a novel antihypertensive drug. To study whether aliskiren can reverse chronic kidney disease, we administered it to renin transgenic mice, a strain characterized by elevated blood pressure and a slow decline of renal function, mimicking well the progression of hypertensive chronic kidney disease. Ten-month-old transgenic mice were treated either with aliskiren or placebo for 28 days. Age-matched wild-type mice treated or not with aliskiren were considered as normotensive controls. Aliskiren reduced blood pressure to wild-type levels from as early as day 14. Proteinuria and cardiac hypertrophy and fibrosis were also normalized. Renal interstitial fibrosis and inflammation were significantly ameliorated in aliskiren-treated mice (shown by the decrease of proinflammatory and profibrotic markers), and the phenotypes of tubular epithelial cells and podocytes were restored as evidenced by the reappearance of cellular proteins characteristic of normal phenotype of these cells. Profibrotic p38 and Erk mitogen-activated protein kinases were highly activated in placebo-treated transgenic animals. Aliskiren treatment cancelled this activation. This nephroprotection was not attributed to the antihypertensive activity of aliskiren, because blood pressure normalization after treatment with hydralazine failed to induce the regression of renal fibrosis. Direct inhibition of renin can restore renal function and structure in aged hypertensive animals with existing proteinuria. This finding suggests that, in addition to antihypertensive action, aliskiren can be also used to treat chronic kidney disease.

Topics: Amides; Animals; Disease Models, Animal; Fibrosis; Fumarates; Hypertension; Kidney; Kidney Diseases; Mice; Mice, Transgenic; Renin

Topics: Amides; Animals; Antihypertensive Agents; Fumarates; Humans; Kidney; Renin

Acute coronary syndrome (ACS) activates neurohormonal pathways, including elevations in circulating aldosterone, with deleterious cardiovascular effects. We aimed to determine if early, more complete renin-angiotensin-aldosterone system inhibition (RAASI) in post-ACS patients without ventricular dysfunction or heart failure would result in a graded reduction in aldosterone concentrations.. We performed serial measurement of serum aldosterone within the Aliskiren and Valsartan to Reduce NT-proBNP via Renin-Angiotensin-Aldosterone-System Blockade (AVANT GARDE)-Thrombolysis in Myocardial Infarction (TIMI) 43 trial, a randomized double-blind, placebo controlled trial of RAASI by valsartan, aliskiren, or both in post-ACS patients with preserved ventricular function but increased natriuretic peptides. Aldosterone was measured at randomization and week 8.. Median aldosterone concentrations were comparable across treatment arms at baseline (9.26 ng/dL; interquartile range 7.12-12.76; n = 1073). In the placebo group, there was a significant increase in aldosterone over 8 weeks (19.7% rise, 2.20 (0.36) ng/dL, P < 0.0001) that was significantly reduced across active RAASI therapies (1.36 (0.39) ng/dL with aliskiren; 1.02 (0.37) ng/dL with valsartan; and 0.85 (0.37) ng/dL with combination therapy, P trend = 0.008). Compared to placebo, RAASI monotherapy resulted in a pooled relative absolute aldosterone change of -1.01 (0.45) ng/dL (P = 0.026 vs placebo), and combination therapy resulted in a relative absolute aldosterone change of -1.35 (0.52) ng/dL (P = 0.01 vs placebo). No significant difference in aldosterone concentrations was achieved between dual vs single RAASI (P = 0.47).. In ACS patients with preserved ventricular function but increased natriuretic peptides, serum aldosterone rises over time and is blunted by more complete RAASI. The clinical implications and role for RAASI in this population warrant further investigation.

Topics: Acute Coronary Syndrome; Aldosterone; Amides; Angiotensin-Converting Enzyme Inhibitors; Down-Regulation; Female; Fumarates; Humans; Male; Middle Aged; Renin-Angiotensin System; Retrospective Studies; Tetrazoles; Valine; Valsartan; Ventricular Function, Left

Our previous study indicated that the exchange from an angiotensin receptor blocker (ARB) to aliskiren reduced morning blood pressure and albuminuria in hypertensive patients with diabetic nephropathy. We extended the above study and assessed the effects of exchanging from an ARB to aliskiren on home blood pressure in hypertensive patients with diabetic nephropathy on chronic hemodialysis. The patients who were persistently hypertensive despite antihypertensive therapy, including ARB, were considered as candidates for the exchange from the ARB to aliskiren. Patients' age and durations of diabetes and hemodialysis were averaged as 62 ± 9 years old, 15 ± 8 and 7 ± 3 years, respectively. Aliskiren decreased morning systolic blood pressure (149 ± 14 to 144 ± 13 mm Hg, n = 30, P < .01) and plasma renin activity (3.5 ± 1.1 to 1.2 ± 0.6 ng/mL/h, P < .01) without changes in serum potassium. Aliskiren also reduced interdialytic weight gain (2.7 ± 0.6 to 2.5 ± 0.5 kg/interval, P < .05) and attenuated the magnitude of intradialytic declines in systolic (-20 ± 11 to -17 ± 10 mm Hg, P < .05) and diastolic blood pressure (-9 ± 6 to -5 ± 5 mm Hg, P < .01). The exchange from an ARB to aliskiren is safe and useful to control home blood pressure in hypertensive hemodialysis patients with diabetic nephropathy. Aliskiren reduced both intradialytic blood pressure drops and interdialytic weight gain in patients with DN.

Topics: Aged; Amides; Angiotensin Receptor Antagonists; Antihypertensive Agents; Blood Pressure; Circadian Rhythm; Diabetic Nephropathies; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Renal Dialysis; Renin; Retrospective Studies; Weight Gain

Topics: Acute Kidney Injury; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Female; Fumarates; Humans; Hyperkalemia; Male; Stroke

Some evidence suggests that the direct renin inhibitor aliskiren may increase the risk of severe hyperkalemia, stroke, or acute kidney injury (AKI) when prescribed with angiotensin-converting enzyme inhibitors (ACEi's) or angiotensin-receptor blockers (ARBs). The extent to which concomitant treatment increases the risk of these outcomes in routine clinical practice is unknown. We addressed this issue with the use of administrative databases.. We established a cohort of Ontarians treated with an ACEi or an ARB. Within this cohort, we conducted 3 case-control studies. Cases were patients hospitalized with 1 of 3 outcomes (hyperkalemia, AKI, or stroke). In each analysis, we identified up to 5 matched control subjects for each case. Conditional logistic regression was used to examine the association between hospitalization for each outcome and the use of aliskiren in the preceding 60 days.. Among 903,346 patients aged 66 years and older treated with an ACEi or ARB during the 28-month study period, we identified 4235 hospitalized with hyperkalemia, 18,231 hospitalized with AKI, and 8283 hospitalized with stroke. After extensive multivariable adjustment, aliskiren therapy was not associated with a significant increase in the risk of hospitalization for hyperkalemia, AKI, or stroke. We found similar results in stratified analyses of patients with and without a history of chronic kidney disease, diabetes, or heart failure.. Among community-dwelling patients aged 66 years and older receiving therapy with an ACEi or an ARB, aliskiren use was not associated with hospitalization for hyperkalemia, AKI, or stroke.

Topics: Acute Kidney Injury; Aged; Aged, 80 and over; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Case-Control Studies; Cohort Studies; Drug Therapy, Combination; Female; Fumarates; Hospitalization; Humans; Hyperkalemia; Logistic Models; Male; Ontario; Renin; Risk Factors; Stroke

In the present study, we have investigated the anti-nociceptive and anti-allodynic activity of the renin inhibitor, aliskiren, in various pain models. The anti-nociceptive activity of aliskiren was investigated in chemically-induced pain, orofacial pain and centrally mediated pain models. Anti-allodynic activity was evaluated in post-operative and neuropathic pain models. The levels of TNF-α and IL-6 were measured in homogenates of hind paw as markers of inflammation in formalin injected mice. Intraperitoneal administration of aliskiren (1-50mg/kg) showed anti-nociceptive activity in the writhing test, formalin hind paw test, capsaicin induced pain, and orofacial pain tests in ICR mice in a dose dependent manner. Aliskiren (50mg/kg, i.p.) reduced levels of TNF-α and IL-6 in hind paw homogenates of formalin-injected mice. Aliskiren (50mg/kg, i.p.) did not show any analgesic activity in hot-plate and tail-flick tests, indicating the absence of centrally mediated anti-nociceptive effects. On the other hand, intra-plantar administration of aliskiren (0.1, 0.5 and 1mg) showed analgesic activity in rat formalin tests, indicating a locally mediated effect. Aliskiren (30-100mg/kg, i.p.) showed anti-allodynic activity in post-operative pain and chronic constriction injury-induced neuropathic pain in Sprague Dawley rats. This data suggests that aliskiren may have the potential to be used as an anti-nociceptive and anti-allodynic agent.

Topics: Acetic Acid; Amides; Analgesics; Animals; Behavior, Animal; Capsaicin; Female; Formaldehyde; Fumarates; Hot Temperature; Hyperalgesia; Male; Mice; Mice, Inbred ICR; Motor Activity; Pain; Rats; Rats, Sprague-Dawley

Topics: Amides; Angioedema; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Data Interpretation, Statistical; Databases, Factual; Epidemiologic Research Design; Fumarates; Humans; Multicenter Studies as Topic; Product Surveillance, Postmarketing; Research Support as Topic; United States

Topics: Amides; Atherosclerosis; Endothelium; Fumarates; Humans; Renin; Stem Cells

Topics: Amides; Aorta, Thoracic; Benzimidazoles; Benzoates; Blood Pressure; Brachial Artery; Circadian Rhythm; Female; Fumarates; Humans; Hypertension; Male; Telmisartan

This paper describes a simple, rapid and sensitive liquid chromatography/tandem mass spectrometry assay for the determination of aliskiren in human plasma using nevirapine as an internal standard. Analyte and the internal standard were extracted from 100 μL of human plasma via liquid-liquid extraction using tert-butyl methyl ether. The chromatographic separation was achieved on a C18 column using a mixture of acetonitrile and 0.1% formic acid (90:10, v/v) as the mobile phase at a flow rate of 0.9 mL/min. The calibration curve obtained was linear (r(2) ≥ 0.99) over the concentration range of 0.10-1013 ng/mL. Method validation was performed as per US Food and Drug Administration guidelines and the results met the acceptance criteria. A run time of 2.2 min for each sample made it possible to analyze a greater number of samples in a short time, thus increasing the productivity. The proposed method was found to be applicable to clinical studies.

Topics: Amides; Chromatography, Liquid; Drug Stability; Fumarates; Humans; India; Liquid-Liquid Extraction; Male; Nevirapine; Renin; Reproducibility of Results; Sensitivity and Specificity; Tandem Mass Spectrometry

Aliskiren, the first in a new class of orally active renin inhibitors, is licensed for the treatment of hypertension. It inhibits plasma renin activity directly, thereby reducing generation of angiotensin II. In this study, we have explored the anti-Candida properties of aliskiren.. Candida albicans was cultured in the presence or absence of aliskiren for various time periods. Subsequently, inhibition of growth, germtube formation, adhesion, early/matured biofilm development and secreted aspartic protease (SAP) activity were studied.. When cultured in the presence of aliskiren, Candida showed significant reduction in the activity of aspartic proteases. Aliskiren impaired in vitro growth of C. albicans. It also affected two other virulence factors, germtube and adhesion. There is reduction in early and matured biofilm when treated with aliskiren.. Aliskiren could be considered as a candidate for antifungal drug development.

Topics: Amides; Antifungal Agents; Antihypertensive Agents; Aspartic Acid Proteases; Biofilms; Candida albicans; Cell Culture Techniques; Drug Repositioning; Fumarates; Microscopy, Electron, Scanning; Renin

Hypertension (HTN) is one of the major risk factors for cardiovascular disease in Western countries, and disease control is of major relevance in order to reduce cardiovascular morbidity and mortality. Different approaches have shown efficacy, and one of the proven therapies for HTN control is the blockade of the renin-angiotensin-aldosterone system, which may be accomplished by means of various drugs with different modes of action. Aliskiren is a novel direct renin inhibitor that reduces both angiotensin I and II blood levels. Different randomized clinical trials (phase II and III) have shown its safety and efficacy either alone or in combination with hydrochlorothiazide. However, although aliskiren has been on the market for some years, reports on the post-marketing experience with aliskiren in the real-world setting are lacking.. The Aliskiren in Latin America Study (ALAS) was designed with the aim of describing the effectiveness of aliskiren at reducing blood pressure (BP) values by prospectively assessing BP control in outpatient clinics in different countries in Latin America. A total of 435 sites in 5 Latin American countries (Mexico, Ecuador, Colombia, Argentina, and Venezuela) enrolled 4588 patients who had just been initiated on aliskiren (either alone or in combination with hydrochlorothiazide) based on their treating physicians' discretion, and they were followed for a 6-month period. Prior antihypertensive drugs could be continued if their doses were not modified along the study.. At the end of the follow-up period, a statistically significant reduction in BP values was observed, with a mean systolic BP reduction of 29.2 mmHg and a mean diastolic BP reduction of 13.78 mmHg from baseline at the 6-month visit.. The BP reduction levels and the low adverse event rate demonstrate the adequate efficacy and safety profile of aliskiren (alone or with hydrochlorothiazide).

Topics: Adult; Aged; Ambulatory Care; Amides; Antihypertensive Agents; Blood Pressure; Cohort Studies; Drug Therapy, Combination; Female; Follow-Up Studies; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Latin America; Male; Middle Aged; Prospective Studies; Renin; Young Adult

Aliskiren inhibits the first step in the renin-angiotensin system (RAS) and recently has been shown to modulate vascular diseases via RAS-dependent and independent pathways. This study aimed to determine the effect of aliskiren-associated direct renin inhibition on endothelial function in patients on hemodialysis via flow-mediated dilatation (FMD) and platelet-derived microparticles (PDMP), as biomarkers of atherosclerosis.. A 12-week prospective study was performed with 24 patients on hemodialysis who were administered 150 mg orally aliskiren once daily for 12 weeks.. No significant difference were observed between pre-dialysis, home, and weekly averaged blood pressure at baseline and at 12 weeks (151.5 ± 8.5/80.9 ± 12.9 mmHg vs 150.3 ± 15.3/78.9 ± 21.2 mmHg, 151.4 ± 9.7/82.3 ± 14.7 mmHg vs 151.2 ± 17.7/81.4 ± 10.6 mmHg, and 156.0 ± 18.3/81.9 ± 9.4 mmHg vs 152.5 ± 18.9/81.7 ± 12.3 mmHg, respectively). FMD significantly increased from 2.54% ± 1.45% at baseline to 3.11% ± 1.37% at 12 weeks (P = 0.0267), and PDMP significantly decreased from 13.9 ± 5.8 U/mL at baseline to 10.9 ± 4.5 U/mL at 12 weeks (P = 0.0002).. Aliskiren improved vascular endothelial function and platelet-endothelium activation in patients on hemodialysis independent of antihypertensive effect.

Topics: Aged; Amides; Antihypertensive Agents; Blood Platelets; Blood Pressure; C-Reactive Protein; Cell-Derived Microparticles; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Fumarates; Humans; Male; Middle Aged; Pilot Projects; Platelet Activation; Renal Dialysis; Renin; Renin-Angiotensin System; Vasodilation

The effect of blocking the first and rate-limiting step in renin-angiotensin cascade on the renal function in ischemia reperfusion injury has not been previously investigated. We investigated the effect of aliskiren, the first approved direct oral renin inhibitor, on the alterations in renal functional parameters in this condition. Wistar rats underwent left renal ischemia for 40 min. Group-1 received normal saline whereas Group-2 received aliskiren (30 mg/kg/day) by gavage for 6 days commencing one day before IRI. The hemodynamic and tubular functions and gene expression of neutrophil gelatinase-associated lipocalin (NGAL) and plasminogen activating inhibitor (PAI-1) in the right and left kidneys were measured five days following the IRI. Comparing Group-1 and Group-2, the left renal blood flow was significantly higher in Group-2 (1.28+/-0.36 vs. 0.39+/-0.05, P=0.007). Left kidney glomerular filtration rate was also higher in Group-2 but did not reach statistical significance (0.18+/-0.05 vs. 0.10+/-0.02, P=0.07). The left renal FE(Na) was significantly lower in Group-2 (29.9+/-6.4 vs. 49.7+/-7.8, P=0.03). Aliskiren also caused a significant decrease in the gene expression of both NGAL and PAI-1 in the left ischemic kidney. In conclusions, the administration of aliskiren before and after IRI appears to have ameliorated the IRI effect on the total renal artery blood flow, fractional excretion of sodium and gene expression of both NGAL and PAI-1 indicating a renoprotective effects in IRI.

Topics: Amides; Animals; Fumarates; Glomerular Filtration Rate; Kidney; Kidney Diseases; Male; Rats; Rats, Wistar; Renal Agents; Renal Circulation; Renin; Renin-Angiotensin System; Reperfusion Injury; Treatment Outcome

A simple and sensitive HPLC method has been developed for the determination of aliskiren in human plasma through derivatization with 1-naphthyl isocyanate. The separation was achieved on a C18 column using a mobile phase consisting of acetonitrile/water/phosphoric acid (45:55:0.01, v/v/v, pH 3.2) in a flow rate of 1mL/min with UV detection at 230nm. Caffeine was used as an internal standard. The factors influencing the derivatization reaction yields were carefully studied and optimized. The method was linear over the concentration range of 5-400ng/mL with a detection limit of 0.5ng/mL and a limit of quantification of 1.0ng/mL. The relative standard deviation was less than 4.2% for both intra-day assay and inter-day assay results. No interferences from endogenous compounds were encountered. The percentage recovery was in the range 97.1-98.6%. The method is suitable for routine therapeutic drug monitoring and for pharmacokinetic studies.

Topics: Amides; Antihypertensive Agents; Chromatography, High Pressure Liquid; Drug Monitoring; Fumarates; Humans; Isocyanates; Limit of Detection; Naphthalenes; Spectrophotometry, Ultraviolet

The aims of this study were to 1) determine whether renal localization of aliskiren and its antihypertensive and renoprotective effects persist after administration of the drug is stopped and 2) define the renal localization of aliskiren by light microscopy autoradiography. Hypertensive double transgenic rats (dTGR) overexpressing genes for human renin and angiotensinogen were treated with aliskiren (3 mg·kg(-1)·day(-1) sc; osmotic minipumps) or enalapril (18 mg/l in drinking water). After a 2-wk treatment, dTGR were assigned to either continued treatment with aliskiren ("continued"), or to cessation of their respective treatment ("stopped") for a 3-wk washout. One week of treatment with aliskiren and enalapril reduced blood pressure and albuminuria vs. baseline. After cessation of either treatment, blood pressure had returned to pretreatment levels and albuminuria remained relatively low for 1 wk, but rose thereafter similarly in both groups. In contrast, renal mRNA for transforming growth factor-β and renal collagen IV was reduced by aliskiren (continued and stopped groups), but not after cessation of enalapril. Similar patterns were found for collagen IV protein expression. Even 3 wk after stopping aliskiren treatment, renal levels of the drug exceeded its IC50, whereas enalaprilat was not detected. To localize aliskiren accumulation, Wistar rats were treated with [(3)H]-aliskiren for 7 days. Autoradiography demonstrated specific labeling in glomeruli, arterioles, and afferent arterioles as well as in the distal nephron. Labeling could still be observed even after 7 days' washout. These results suggest that the renophilic properties of aliskiren are different from enalapril and could have contributed to the renoprotective mechanism of this renin inhibitor.

Topics: Albuminuria; Amides; Animals; Antihypertensive Agents; Blood Pressure; Fumarates; Kidney; Male; Rats; Rats, Transgenic; Rats, Wistar; Renin

We have demonstrated that mesenchymal cells from spontaneously hypertensive rats genetically express complement 3 (C3). Mature tubular epithelial cells can undergo epithelial-to-mesenchymal transition (EMT) that is linked to the pathogenesis of renal fibrosis and injury. In this study, we investigated the contribution of C3 in EMT and in the renal renin-angiotensin (RA) systems associated with hypertension. C3a induced EMT in mouse TCMK-1 epithelial cells, which displayed increased expression of renin and Krüppel-like factor 5 (KLF5) and nuclear localization of liver X receptor α (LXRα). C3 and renin were strongly stained in the degenerated nephrotubulus and colocalized with LXRα and prorenin receptor in unilateral ureteral obstruction (UUO) kidneys from wild-type mice. In C3-deficient mice, hydronephrus and EMT were suppressed, with no expression of renin and C3. After UUO, systolic blood pressure was increased in wild-type but not C3-deficient mice. In wild-type mice, intrarenal angiotensin II (ANG II) levels were markedly higher in UUO kidneys than normal kidneys and decreased with aliskiren. There were no increases in intrarenal ANG II levels after UUO in C3-deficient mice. Thus C3 induces EMT and dedifferentiation of epithelial cells, which produce renin through induction of LXRα. These data indicate for the first time that C3 may be a primary factor to activate the renal RA systems to induce hypertension.

Topics: Aldosterone; Amides; Angiotensin II; Animals; Antihypertensive Agents; Complement C3; Epithelial-Mesenchymal Transition; Fumarates; Hypertension; Kidney; Kruppel-Like Transcription Factors; Liver X Receptors; Male; Mice; Mice, Inbred C57BL; Nephrosclerosis; Orphan Nuclear Receptors; Renin; Renin-Angiotensin System; Transforming Growth Factor beta1; Ureteral Obstruction

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Fumarates; Heart Failure; Humans; Renin; Stroke Volume; Ventricular Dysfunction, Left

Topics: Amides; Cardiotonic Agents; Diabetic Cardiomyopathies; Female; Fumarates; Heart Failure; Humans; Male

Topics: Amides; Coronary Artery Disease; Female; Fumarates; Humans; Male; Renin

Dopamine causes in anesthetized rats expressed diuretic response that is accompanied by an increase in GRF and a significant enhance of sodium and potassium excretion. Pretreatment the animals in diclofenac sodium or contrical in doses, that inhibit respectively activity of renal PG-system and kallikrein-kinin system, don't prevent of renal effects of dopamine. Preliminary assignment a direct renin inhibitor aliskiren enhances the diuretic, natriuretic and kaliyuretic effects of the drug. It is concluded that renal PG-system and kallikrein-kinin system are not involved in the formation of renal effects of dopamine. Renal tissue RAS directly included in the mechanism of action of dopamine in the kidney, acting as a modulator, preventing excessive loss of water and electrolytes with urine.

Topics: Amides; Animals; Animals, Outbred Strains; Aprotinin; Cations, Monovalent; Diclofenac; Dopamine; Fumarates; Glomerular Filtration Rate; Ion Transport; Kallikrein-Kinin System; Kidney; Male; Natriuresis; Potassium; Rats; Renin-Angiotensin System; Sodium; Water-Electrolyte Balance

The aim of this French observational study was to evaluate how the direct renin inhibitor aliskiren is being prescribed to treat hypertension by primary care providers (PCPs) and office-based cardiologists.. Each participating physician included the first three consecutive hypertensive patients who had been prescribed aliskiren at least 4 weeks beforehand and noted whether aliskiren was prescribed: alone or as part of a combination; as first-line therapy, to replace another drug or as an add-on therapy.. Five thousand, four hundred and eleven patients were analyzed [mean age, 63; 58% men; 24% diabetic; mean blood pressure (BP) 148/85 mmHg]. A total of 23.6% of patients had a controlled BP. Aliskiren was prescribed alone in 49.4% patients and as part of a combination in 50.6% (bitherapy 28.3%, tritherapy 14.7%, and quadri+therapy 7.6%), at the higher recommended dosage (300 mg daily) to two-thirds of cases. Aliskiren replaced another drug in 71.9% [mainly an angiotensin receptor blocker (ARB) or an angiotensin-converting enzyme inhibitor (ACEi)] and was added to an existing regimen in 22.5%. For bitherapy, aliskiren was combined with a diuretic (D; 39%) or a calcium channel blocker (CCB; 32%). For tritherapy, it was prescribed with CCB and D in 28% and β-blocker and D in 26%. In 8.9% of patients, aliskiren was prescribed with an ACEi or an ARB.. French physicians are generally following the current prescribing recommendations for aliskiren, but the place of this new class of antihypertensive in the management of essential hypertension will become clearer with longer experience, especially concerning effective doses and combinations.

Topics: Aged; Amides; Antihypertensive Agents; Cross-Sectional Studies; Female; France; Fumarates; Humans; Hypertension; Male; Middle Aged; Practice Patterns, Physicians'; Renin

The protective effect of aliskiren on ischemia-reperfusion (I/R) injury in the heart and brain has been reported. Whether or not this protective effect extends into the alleviation of renal I/R injury is not known. Therefore, we investigated the protective effect of aliskiren in the kidney in this study. Sprague-Dawley rats were randomly divided into four groups: sham control group; sham control with aliskiren pretreatment; I/R group and I/R with aliskiren pretreatment. Aliskiren (3mg/kg) or vehicle was administrated intravenously via vena cava. Blood samples and the left kidneys were then collected to check for renal function, angiotensin II (Ang II), apoptosis and oxidative stress levels. Compared with the sham rats, serum creatinine (SCR) and blood urea nitrogen (BUN) were significantly increased in the I/R rats, accompanied by histopathological damage to the kidney, which included tubular cell swelling, desquamation, and cast formation. There were also more apoptotic cells and leukocyte infiltration in the I/R rats than in the sham rats. Pretreatment with aliskiren ameliorated I/R induced renal injury, i.e. reduced SCR and BUN levels, ameliorated renal histopathological changes, and decreased the apoptosis of cells and leukocyte infiltration in kidney. I/R injury also decreased superoxide dismutase (SOD) and glutathione (GSH-reduced form) levels, which were blocked with the aliskiren pretreatment. Aliskiren pretreatment exerts a protective effect on ischemia/reperfusion injury in the kidney, via amelioration of oxidative stress, and reduction in leukocyte infiltration and cellular apoptosis.

Topics: Amides; Animals; Apoptosis; Cytoprotection; Fumarates; Kidney; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion Injury

A series of tubes: The continuous manufacture of a finished drug product starting from chemical intermediates is reported. The continuous pilot-scale plant used a novel route that incorporated many advantages of continuous-flow processes to produce active pharmaceutical ingredients and the drug product in one integrated system.

Topics: Acids; Amides; Catalysis; Crystallization; Drug Compounding; Fumarates; Pharmaceutical Preparations; Technology, Pharmaceutical

This study focuses on the impact of aliskiren and (or) glucagon-like peptide-1 analogue on the binding affinity/regulation of endothelin-1 (ET-1) to its receptor subtypes A (ETAR) and B (ETBR) at the level of the coronary endothelium and the cardiomyocytes in a type-1 diabetic rat model. Seven groups were used: (i) normal rats, (ii) rats with induced diabetes, (iii) rats with induced diabetes that were treated with insulin, (iv) rats with induced diabetes that were treated with exendin-4, (v) rats with induced diabetes that were treated with aliskiren, (vi) rats with induced diabetes that were co-treated with insulin plus aliskiren, and (vii) rats with induced diabetes that were co-treated with exendin-4 plus aliskiren. Heart perfusion with [(125)I]-ET-1 was employed to estimate ET-1 binding affinity (τ = 1/K-n) to ETAR and ETBR at the level of the coronary endothelium and the cardiomyocytes. Plasma ET-1 levels were measured using enzyme immunoassay, whereas densities of ETAR and ETBR were detected using Western blot. No significance differences were detected in the τ of ETAR and ETBR between normal and diabetic in cardiomyocytes and the coronary endothelium. Exendin-4 normalized the τ value for ETAR and ETBR on coronary endothelium, while aliskiren normalized it on cardiomyocytes. Furthermore, ETAR and ETBR densities were normalized with monotreatments of aliskiren and exendin-4, compared with up-regulated ETAR and down-regulated ETBR band densities in the diabetic animals. Our data indicate that aliskiren alleviates diabetes-associated hypertrophy in type 1 diabetes mellitus.

Topics: Amides; Animals; Cardiomegaly; Coronary Vessels; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Endothelin-1; Endothelium, Vascular; Exenatide; Fumarates; Hypoglycemic Agents; Insulin; Male; Myocytes, Cardiac; Peptides; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Streptozocin; Time Factors; Venoms

Activation of the renin-angiotensin-system is known to play a role in nonalcoholic steatohepatitis. Renin knockout mice manifest decreased hepatic steatosis. Aliskiren is the first direct renin inhibitor to be approved for clinical use. Our study aims to evaluate the possible therapeutic effects and mechanism of the chronic administration of aliskiren in a dietary steatohepatitis murine model.. Male C57BL/6 mice were fed with a methionine and choline-deficient (MCD) diet to induce steatohepatitis. After 8 weeks of feeding, the injured mice were randomly assigned to receive aliskiren (50 mg·kg(-1) per day) or vehicle administration for 4 weeks. Normal controls were also administered aliskiren (50 mg·kg(-1) per day) or a vehicle for 4 weeks.. In the MCD mice, aliskiren attenuated hepatic steatosis, inflammation and fibrosis. Aliskiren did not change expression of lipogenic genes but increase turnover of hepatic fat by up-regulating peroxisome proliferator-activated receptor α, carnitine palmitoyltransferase 1a, cytochrome P450-4A14 and phosphorylated AMP-activated protein kinase. Furthermore, aliskiren decreased the hepatic expression of angiotensin II and nuclear factor κB. The levels of oxidative stress, hepatocyte apoptosis, activation of Kupffer cells and hepatic stellate cells, and pro-fibrotic markers were also reduced in the livers of the MCD mice receiving aliskiren.. Aliskiren attenuates steatohepatitis and fibrosis in mice fed with a MCD diet. Thus, the noted therapeutic effects might come from not only the reduction of angiotensin II but also the up-regulation of fatty acid oxidation-related genes.

Topics: Amides; Angiotensin II; Animals; Blotting, Western; Choline; Diet; Fatty Liver; Fumarates; Immunoenzyme Techniques; Inflammation; Insulin; Liver; Male; Methionine; Mice; Mice, Inbred C57BL; Oxidative Stress; Real-Time Polymerase Chain Reaction; Renin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thiobarbituric Acid Reactive Substances; Triglycerides

Diabetes-induced organ damage is significantly associated with the activation of the renin-angiotensin system (RAS). Recently, several studies have demonstrated a change in the RAS from an extracellular to an intracellular system, in several cell types, in response to high ambient glucose levels. In cardiac myocytes, intracellular angiotensin (ANG) II synthesis and actions are ACE and AT1 independent, respectively. However, a role of this system in diabetes-induced organ damage is not clear.. To determine a role of the intracellular ANG II in diabetic cardiomyopathy, we induced diabetes using streptozotocin in AT1a receptor deficient (AT1a-KO) mice to exclude any effects of extracellular ANG II. Further, diabetic animals were treated with a renin inhibitor aliskiren, an ACE inhibitor benazeprilat, and an AT1 receptor blocker valsartan.. AT1a-KO mice developed significant diastolic and systolic dysfunction following 10 wks of diabetes, as determined by echocardiography. All three drugs prevented the development of cardiac dysfunction in these animals, without affecting blood pressure or glucose levels. A significant down regulation of components of the kallikrein-kinin system (KKS) was observed in diabetic animals, which was largely prevented by benazeprilat and valsartan, while aliskiren normalized kininogen expression.. These data indicated that the AT1a receptor, thus extracellular ANG II, are not required for the development of diabetic cardiomyopathy. The KKS might contribute to the beneficial effects of benazeprilat and valsartan in diabetic cardiomyopathy. A role of intracellular ANG II is suggested by the inhibitory effects of aliskiren, which needs confirmation in future studies.

Topics: Amides; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Disease Models, Animal; Down-Regulation; Fumarates; Kallikreins; Kininogens; Kinins; Mice; Mice, Knockout; Myocytes, Cardiac; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Tetrazoles; Ultrasonography; Valine; Valsartan

To report a case of difficult-to-treat hypertension ultimately managed with triple antirenin (anti-R) therapy using plasma renin activity (PRA) to guide medication selection.. A 66-year-old white man was referred to the cardiology pharmacotherapy clinic for difficult-to-treat hypertension. His initial office blood pressure (BP) was 152/71 mm Hg on diltiazem and chlorthalidone. After a series of medication adjustments based on serial PRA measurements, the patient achieved his target BP with a regimen that included 3 anti-R angiotensin system medications: carvedilol, valsartan, and aliskiren.. Despite continued progress in the understanding and pharmacological therapy for hypertension, uncontrolled hypertension remains a major problem. The most common strategy to control hypertension is the stepped-care approach, with progressive addition of medications to eventually reach the BP goal. An alternative approach includes the use of PRA measurements to guide both the addition and removal of drugs in an attempt to effectively control BP. At times, this has the potential to result in a drug regimen that is incongruous with current guidelines and practice recommendations. However, if this results in more effective BP control with the same, or fewer, number of medications, it may represent a reasonable alternative.. This case report illustrates a real-world application of PRA-guided therapeutics in a patient with difficult-to-treat hypertension. It highlights how a personalized approach can lead to BP control with a more streamlined regimen than would likely result if a stepped-care approach was used.

Topics: Aged; Amides; Antihypertensive Agents; Blood Pressure; Carbazoles; Carvedilol; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Male; Practice Guidelines as Topic; Precision Medicine; Predictive Value of Tests; Propanolamines; Renin; Renin-Angiotensin System; Tetrazoles; Treatment Outcome; Valine; Valsartan

Topics: Amides; Antihypertensive Agents; Cardiovascular Diseases; Fumarates; Humans; Hypertension; Renin; Sodium Chloride Symporter Inhibitors

Aliskiren is an oral renin inhibitor, which inhibits the first rate limiting step in the renin angiotensin aldosterone system. In this study, sympathetic nerve sprouting and the inducibility of ventricular fibrillation after aliskiren treatment in myocardial infarction were investigated.. Male Sprague Dawley rats after coronary artery ligation were randomly allocated to four groups: angiotensin converting enzyme inhibitor enalapril, angiotensin receptor blocker valsartan, β adrenergic receptor blocker carvedilol and rennin inhibitor aliskiren treatment for six weeks. Electrophysiological study, histological examination and Western blotting were performed.. The plasma norepinephrine level and sympathetic nerve innervation significantly increased in treated infarcted rats compared to untreated rats. Aliskiren treatment reduced the sympathetic nerve innervations after myocardial infarction. There is no significant difference in sympathetic nerve innervations after myocardial infarction among the enalapril, valsartan, carvediloand or aliskiren treated groups. Programmed electrical stimulation study showed that inducible ventricular arrhythmia was reduced, ventricular fibrillation threshold was increased and ventricular effective refractory period was prolonged in enalapril, valsartan, carvedilol and aliskiren treated infarcted rats compared to untreated infarcted rats. Cardiomyocytic apoptosis in infarcted region was significantly decreased in enalapril, valsartan, carvedilol and aliskiren treated infarcted rats.. Aliskiren ameliorated cardiomyocytic apoptosis, attenuated the sympathetic nerve innervations and reduced the vulnerability of ventricular arrhythmias after myocardial infarction. Enalapril, valsartan and carvedilol have similar effects as aliskiren on cardiomyocytic apoptosis, sympathetic nerve innervations and vulnerability of ventricular arrhythmias after myocardial infarction.

Topics: Amides; Animals; Fumarates; Male; Myocardial Infarction; Norepinephrine; Rats; Rats, Sprague-Dawley; Renin; Sympathetic Nervous System; Tachycardia, Ventricular

Myocardial fibrosis, a major pathophysiologic substrate of heart failure with preserved ejection fraction (HFPEF), is modulated by multiple pathways including the renin-angiotensin system. Direct renin inhibition is a promising anti-fibrotic therapy since it attenuates the pro-fibrotic effects of renin in addition to that of other effectors of the renin-angiotensin cascade. Here we show that the oral renin inhibitor aliskiren has direct effects on collagen metabolism in cardiac fibroblasts and prevented myocardial collagen deposition in a non-hypertrophic mouse model of myocardial fibrosis. Adult mice were fed hyperhomocysteinemia-inducing diet to induce myocardial fibrosis and treated concomitantly with either vehicle or aliskiren for 12 weeks. Blood pressure and plasma angiotensin II levels were normal in control and hyperhomocysteinemic mice and reduced to levels lower than observed in the control group in the groups treated with aliskiren. Homocysteine-induced myocardial matrix gene expression and fibrosis were also prevented by aliskiren. In vitro studies using adult rat cardiac fibroblasts also showed that aliskiren attenuated the pro-fibrotic pattern of matrix gene and protein expression induced by D,L, homocysteine. Both in vivo and in vitro studies demonstrated that the Akt pathway was activated by homocysteine, and that treatment with aliskiren attenuated Akt activation. In conclusion, aliskiren as mono-therapy has potent and direct effects on myocardial matrix turnover and beneficial effects on diastolic function.

Topics: Amides; Angiotensin II; Animals; Antihypertensive Agents; Cardiomyopathies; Collagen; Diet; Extracellular Matrix; Fibroblasts; Fibrosis; Fumarates; Homocysteine; Mice; Myocardium; Proto-Oncogene Proteins c-akt; Renin; Renin-Angiotensin System; Signal Transduction

An alternative method for analysis of aliskiren (ALI) and hydrochlorothiazde (HCT) in combined dosage forms by ion-pair reversed phase high performance liquid chromatography was developed and validated. The pharmaceutical preparations were analyzed using a C18 column (250 mm x 4.6 mm, 3 microm) with a mobile phase consisting of 25% methanol, 50% sodium monobasic phosphate aqueous solution containing 6 mM tetrabutylammonium bromide and 25% water at pH 7.2. Isocratic analysis was performed at a flow rate of 1 mL/min and a column temperature of 30 degrees C under direct UV detection at 210 nm. Paracetamol was used as internal standard. The validation was performed according to the ICH guidelines. The proposed method was linear over the concentration range of 0.250 to 60 and 0.1 to 10 microg/mL for ALI and HCT, respectively. The limits of detection and quantitation (LOD and LOQ) were 0.075 and 0.198 microg/mL, respectively, for ALI and 0.04 and 0.062 microg/mL, respectively, for HCT. The method proved to be specific, sensitive, precise and accurate with mean recovery values of 101.1 +/- 0.32% and 100.9 +/- 0.41% for ALI and HCT, respectively. The method robustness was evaluated by means of an experimental design. The proposed method was applied successfully to spiked human urine samples with mean recoveries of 98.8 +/- 0.36% and 98.1 +/- 0.21% for ALI and HCT, respectively.

Topics: Amides; Antihypertensive Agents; Calibration; Chromatography, High Pressure Liquid; Diuretics; Fumarates; Humans; Hydrochlorothiazide; Hydrogen-Ion Concentration; Indicators and Reagents; Limit of Detection; Quality Control; Reference Standards; Reproducibility of Results; Spectrophotometry, Ultraviolet; Tablets

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Fumarates; Humans; Renin; Renin-Angiotensin System; Risk Assessment; Stroke

Diminishing the activity of the renin-angiotensin system (RAS) plays a pivotal role in the treatment of heart failure. In addition to angiotensin converting enzyme (ACE) inhibitors and angiotensin-receptor blockers, direct renin inhibition has emerged as a potential adjunctive treatment to conventional RAS blockade. We sought to determine the effectiveness of this strategy after myocardial infarction (MI) in the setting of preexisting hypertension, a common premorbid condition in patients with ischemic heart disease.. Ten-week-old female heterozygous hypertensive (mRen-2)27 transgenic rats (Ren-2), were randomized to one of five groups (n = 8 per group); sham, MI, MI + aliskiren, MI + lisinopril and MI + combination lisinopril and aliskiren. Cardiac function was assessed by echocardiography and in vivo cardiac catheterization. Untreated MI animals developed heart failure with hypotension, dilation, reduced ejection fraction (EF), and raised left ventricular end-diastolic pressure (LVEDP). Treatment with single agent treatment had only modest effect on cardiac function though combination therapy was associated with significant improvements in EF and LVEDP when compared to untreated MI animals (P < 0.05). Histologic analysis demonstrated increase extracellular matrix deposition and cardiomyocyte hypertrophy in the noninfarct region of all MI groups when compared with sham operated animals (P < 0.05) that was reduced by ACE inhibitor monotherapy and combination treatment but not by aliskiren alone.. In a hypertensive rat model that underwent experimental MI, EF, and LVEDP, key functional indices of heart failure, were improved by treatment with combination ACE and direct renin inhibition when compared with either agent used alone.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiac Catheterization; Disease Models, Animal; Drug Therapy, Combination; Echocardiography; Female; Fumarates; Heart Failure; Hypertension; Lisinopril; Myocardial Infarction; Myocardium; Random Allocation; Rats; Rats, Transgenic; Recovery of Function; Renin; Renin-Angiotensin System; Stroke Volume; Ventricular Function, Left; Ventricular Pressure; Ventricular Remodeling

Aliskiren is a novel blood pressure-lowering agent acting as an oral direct renin inhibitor. We evaluated the effects of aliskiren on the fibrinolytic system in patients with coronary artery disease who were receiving angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs). We studied 17 patients with coronary artery disease whose systolic blood pressure was more than 130 mmHg despite treatment with ACEIs or ARBs. Aliskiren (150 mg) was added to ACEIs or ARBs, and was continued for 6 weeks. Aliskiren significantly decreased systolic blood pressure (140 ± 6-128 ± 8 mmHg, P < 0.001) and plasma renin activity (1.8 ± 2.3-0.6 ± 0.9 ng/ml/h, P < 0.01) after 6 weeks. However, it did not affect plasminogen activator inhibitor-1 (28.8 ± 14.5-30.6 ± 13.6 ng/ml, P = 0.84), fibrinogen (305 ± 72 vs 301 ± 71 mg/dl, P = 0.33), or D-dimer (0.49 ± 0.24-0.51 ± 0.28 μg/ml, P = 0.70) levels. Our data suggested that patients receiving ACEIs or ARBs would not be expected to have any changes in biomarkers of the fibrinolytic system with additional pharmacologic inhibition of the renin-angiotensin-aldosterone system.

Topics: Aged; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Coronary Artery Disease; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fibrinolysis; Follow-Up Studies; Fumarates; Humans; Male; Renin; Treatment Outcome

Hyperactivation of the renin-angiotensin system contributes to hypertension-induced upregulation of vascular matrix metalloproteinases (MMPs) and remodeling, especially in the two kidney, one clip (2K1C) hypertension model. We hypothesized that the AT1R antagonist losartan or the renin inhibitor aliskiren, given at doses allowing similar antihypertensive effects, could prevent in vivo vascular MMPs upregulation and remodeling, and collagen/elastin deposition found in 2K1C hypertension by preventing the activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) and transforming growth factor-β1 (TGF-β1). We also hypothesized that aliskiren could enhance the effects of losartan.. 2K1C rats were treated with aliskiren (50mg.kg(-1).day(-1)), or losartan (10mg.kg(-1).day(-1)), or both by gavage during 4 weeks.. Aliskiren, losartan, or both drugs exerted similar antihypertensive effects when compared with 2K-1C rats treated with water. Aliskiren reduced plasma renin activity in both sham and 2K-1C rats. Losartan alone or combined with aliskiren, but not aliskiren alone, abolished 2K1C-induced aortic hypertrophy and hyperplasia, and prevented the increases in aortic collagen/elastin content, MMP-2 levels, gelatinolytic activity, and expression of phospho-ERK 1/2 and TGF-β1. No significant differences were found in the aortic expression of the (pro)renin receptor.. These findings show that although losartan and aliskiren exerted similar antihypertensive effects, only losartan prevented the activation of vascular profibrotic mechanisms and MMP upregulation associated with vascular remodeling in 2K1C hypertension. Our findings also suggest that aliskiren does not enhance the protective effects exerted by losartan.

Topics: Amides; Animals; Antihypertensive Agents; Aorta; Fumarates; Hypertension; Losartan; Male; Random Allocation; Rats; Rats, Wistar; Treatment Outcome; Ventricular Remodeling

Aliskiren, a direct renin inhibitor (DRI), has therapeutic effects in patients with hypertension and associated complications, but its potential mechanism in diabetic nephropathy is lacking. The effects of aliskiren in Streptozotocin (STZ)-induced renal complication in diabetic rats were investigated. Aliskiren treatment for eight weeks at the dose of 10 mg/kg/day, via osmotic mini-pump, induced improvement in blood glucose levels, systolic blood pressure (BP) and serum creatinine. Improvement of insulin resistance by aliskiren was confirmed by increased glucose translocation in liver and muscle and hence insulin levels. The treated group also showed improvement in glomerulosclerosis and tubulointerstitial injury. Aliskiren treatment also improved albumin levels in plasma, suppressed profibrotic and proinflammatory cytokine synthesis viz TNF-α and TGF-β and angiogenesis by a decrease in VEGF. In addition, the level of total proteins and GFR via cystatin c and beta-2microglobulin along with adiponectin and erythropoietin were also improved. These results suggest that the beneficial organ protective effect of aliskiren is mediated by improvement in insulin resistance as well as a direct anti-fibrotic effect in the target organ in STZ-induced diabetic rats with a slight effect on blood pressure. Aliskiren may be a useful therapeutic agent in the treatment of type 2 diabetes and diabetic nephropathy.

Topics: Amides; Animals; Biomarkers; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Diabetic Nephropathies; DNA Fragmentation; Extracellular Matrix; Fumarates; Glomerular Filtration Rate; Glucose Transporter Type 2; Glucose Transporter Type 4; Hemodynamics; Humans; Inflammation; Insulin; Insulin Resistance; Liver; Mice; Muscles; Rats; Rats, Wistar; ROC Curve

Angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers can improve insulin resistance and vascular dysfunction in insulin-resistant rats; however, there are few reports on the effects of direct renin inhibitors on these conditions. We investigated the effects of a direct renin inhibitor, aliskiren, on insulin resistance, aortic endothelial dysfunction and vascular remodeling in fructose-fed hypertensive rats. Male Wistar-Kyoto rats were divided into four groups (n=6 per group) and studied for 8 weeks: Group Con: standard chow diet; group Fru: high-fructose diet (60% fructose); Group FruA: high-fructose diet with concurrent aliskiren treatment (100 mg kg(-1) per day); and Group FruB: high-fructose diet with subsequent aliskiren treatment 4 weeks later. Blood was collected for biochemical assays, and isolated rings of the thoracic aorta were obtained for analysis of vascular reactivity, vascular structure and lipid peroxide. Rats fed with high-fructose diets developed significant systolic hypertension, decreased plasma nitrite (NO(2); nitric oxide metabolite) levels and increased plasma glucose, insulin, triglyceride, total cholesterol and aortic lipid peroxide levels, and aortic wall thickness compared with control rats. Aliskiren treatment, either concurrent or subsequent, elevated plasma NO(2) levels and reduced systolic hypertension, insulin resistance, dyslipidemia, aortic lipid peroxide levels and aortic wall hypertrophy in FHR. The peak endothelium-dependent aortic relaxations were significantly higher in rats that received aliskiren treatment than in those that did not. In conclusion, our findings suggest that aliskiren prevents and ameliorates insulin resistance, aortic endothelial dysfunction and oxidative vascular remodeling in fructose-fed hypertensive rats.

Topics: Amides; Animals; Aorta, Thoracic; Dietary Carbohydrates; Disease Models, Animal; Endothelium, Vascular; Fructose; Fumarates; Hypertension; Insulin Resistance; Lipid Peroxides; Male; Nitrites; Oxidative Stress; Rats; Rats, Inbred WKY; Renin; Vasodilation

To test the hypothesis that aliskiren improves the metabolic phenotype in a genetic mouse model of the metabolic syndrome (the caveolin-1 (cav-1) knock out (KO) mouse).. Eleven-week-old cav-1 KO and genetically matched wild-type (WT) mice were randomized to three treatment groups: placebo (n=8/group), amlodipine (6 mg/kg/day, n=18/ group), and aliskiren (50 mg/kg/day, n=18/ group). After three weeks of treatment, all treatment groups were assessed for several measures of insulin resistance (fasting insulin and glucose, HOMA-IR, and the response to an intraperitoneal glucose tolerance test (ipGTT)) as well as for triglyceride levels and the blood pressure response to treatment.. Treatment with aliskiren did not affect the ipGTT response but significantly lowered the HOMA-IR and insulin levels in cav-1 KO mice. However, treatment with amlodipine significantly degraded the ipGTT response, as well as the HOMA-IR and insulin levels in the cav-1 KO mice. Aliskiren also significantly lowered triglyceride levels in the cav-1 KO but not in the WT mice. Moreover, aliskiren treatment had a significantly greater effect on blood pressure readings in the cav-1 KO vs. WT mice, and was marginally more effective than amlodipine.. Our results support the hypothesis that aliskiren reduces insulin resistance as indicated by improved HOMA-IR in cav-1 KO mice whereas amlodipine treatment resulted in changes consistent with increased insulin resistance. In addition, aliskiren was substantially more effective in lowering blood pressure in the cav-1 KO mouse model than in WT mice and marginally more effective than amlodipine.

Topics: Amides; Animals; Antihypertensive Agents; Blood Glucose; Blood Pressure; Caveolin 1; Disease Models, Animal; Fumarates; Glucose Tolerance Test; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Mice; Mice, Knockout; Random Allocation; Renin; Triglycerides

Aldosterone is increased in diabetes and contributes to the development of diabetic nephropathy. The authors hypothesized that reduction in aldosterone production in diabetes by amlodipine or aliskiren improves diabetic kidney disease by attenuating renal oxidative stress and fibrosis. Normoglycemic and streptozotocin-induced diabetic Sprague-Dawley rats were given vehicle, amlodipine, or aliskiren alone and combined for 6 weeks. At the end of study, we evaluated blood pressure (BP), 24-hour urinary sodium (UNaV) and aldosterone excretion rates, renal interstitial fluid (RIF) levels of nitric oxide (NO), cyclic guanosine 3',5'-monophosphate (cGMP), and 8-isoprostane, and renal morphology. BP was not significantly different between any of experimental groups. UNaV increased in diabetic animals and was not affected by different treatments. Urinary aldosterone excretion increased in diabetic rats receiving vehicle and decreased with amlodipine and aliskiren alone or combined. RIF NO and cGMP levels were reduced in vehicle-treated diabetic rats and increased with amlodipine or aliskiren given alone and combined. RIF 8-isoprostane levels and renal immunostaining for periodic acid-Schiff and fibronectin were increased in vehicle-treated diabetic rats and decreased with aliskiren alone or combined with amlodipine. The authors conclude that inhibition of aldosterone by amlodipine or aliskiren ameliorates diabetes induced renal injury via improvement of NO-cGMP pathway and reduction in oxidative stress and fibrosis, independent of BP changes.

Topics: Aldosterone; Amides; Amlodipine; Animals; Antihypertensive Agents; Blood Glucose; Blood Pressure; Cyclic GMP; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Dinoprost; Down-Regulation; Fibronectins; Fibrosis; Fumarates; Immunohistochemistry; Kidney; Male; Natriuresis; Nitric Oxide; Oxidative Stress; Rats; Rats, Sprague-Dawley; Time Factors

The orally active direct renin inhibitor aliskiren is approved for the treatment of essential hypertension in adults. Analytical methods utilized in clinical studies on efficacy and safety have not been fully described in the literature but need a large sample volume ranging from 200 to 700 μL, rendering them unsuitable particularly for pediatric applications. In the assay presented only 100 μL of serum is needed for mixed-mode solid-phase extraction. The chromatographic separation was performed on Xselect(TM) C18 CSH columns with mobile phase consisting of methanol-water-formic acid (75:25:0.005, v/v/v) and a flow rate of 0.4 mL/min. Running in positive electrospray ionization and multiple reaction monitoring the mass spectrometer was set to analyze precursor ion 552.2 m/z [M + H](+) to product ion 436.2 m/z during a total run time of 5 min. The method covers a linear calibration range of 0.146-1200 ng/mL. Intra-run and inter-run precisions were 0.4-7.2 and 0.6-12.9%. Mean recovery was at least 89%. Selectivity, accuracy and stability results comply with current European Medicines Agency and Food and Drug Administration guidelines. This successfully validated LC-MS/MS method with a wide linear calibration range requiring small serum amounts is suitable for pharmacokinetic investigations of aliskiren in pediatrics, adults and the elderly.

Topics: Adult; Amides; Antihypertensive Agents; Child; Chromatography, High Pressure Liquid; Fumarates; Humans; Limit of Detection; Male; Renin; Solid Phase Extraction; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

Doxorubicin (DXR) is one of the most effective and widely used anthracycline antibiotics. However, its clinical application is hampered by toxic effects in many organs. Nephrotoxicity is one of the major side effects of anthracycline antibiotics. This study was designed to investigate the possible protective effects of aliskiren (a direct renin inhibitor) in DXR-induced nephrotoxicity in rats.. Wistar albino rats were intraperitoneally (ip) injected with DXR and renin activity, albumin, total protein, urea, creatinine levels in plasma and ultrastructural changes in podocytes were assessed.. Rats subjected to DXR administration had significant (p<0.01) increases in systolic blood pressure, plasma renin activity, plasma concentration of urea, creatinine and tissue malondialdehyde and significant (p<0.01) reductions in plasma concentrations of albumin, total protein and antioxidant defense (reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT)) in renal tissues. Furthermore, DXR-induced nephrotoxicity has also been characterized by broadening of podocyte foot processes, enlargement of glomerular basement membrane width and reduction in slit pore diameter. The above effects of DXR were significantly (p<0.01) prevented by aliskiren treatment.. These findings revealed that the blockade of renin activity by aliskiren is a promising approach in the treatment of DXR-induced nephrotoxicity.

Topics: Amides; Animals; Antioxidants; Benzimidazoles; Benzoates; Blood Pressure; Body Weight; Creatinine; Doxorubicin; Fumarates; Kidney Diseases; Lipid Peroxidation; Organ Size; Oxidative Stress; Podocytes; Rats; Rats, Wistar; Renin; Serum Albumin; Systole; Telmisartan; Urea

The present study was designed to investigate the potential of aliskiren, a direct renin inhibitor, in chronic constriction injury (CCI)-induced neuropathic pain in rats. Neuropathic pain was induced by placing four loose ligatures around the sciatic nerve. Acetone drop, von Frey hair, pin-prick and hot plate tests were performed to assess cold allodynia, mechanical allodynia, mechanical and heat hyperalgesia, respectively. The levels of Tumor necrosis factor-alpha (TNF-α) were measured in the sciatic nerve as an inflammatory marker. CCI was associated with the development of cold allodynia, mechanical allodynia, mechanical and heat hyperalgesia along with a rise in the levels of Tumor necrosis factor-alpha (TNF-α). Administration of aliskiren (25 or 50 mg/kg intraperitoneal (i.p.)) for 14 days in CCI-subjected rats significantly attenuated CCI-induced pain-related behavior and rise in TNF-α level. It may be concluded that aliskiren-mediated anti-inflammatory actions may be responsible for its beneficial effects in neuropathic pain in rats.

Topics: Amides; Animals; Constriction; Disease Models, Animal; Female; Fumarates; Hyperalgesia; Male; Neuralgia; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Tumor Necrosis Factor-alpha

To investigate the combined effect of aliskiren, a renin inhibitor, and AVE 0991, a Mas-receptor agonist, in experimental hypertension (HT) in rats. HT was produced by administration of deoxycorticosterone acetate (DOCA) and mean arterial blood pressure (MABP) was assessed by tail-cuff method. Treatments were started from 4th week onwards and were continued for 9 days. A significant increase in MABP was noted after 1 week in DOCA control rats, as compared with the base line value. A stable HT developed after 4 weeks of DOCA administration. Treatments with aliskiren and AVE 0991 alone, dose-dependently decreased MABP in DOCA-treated rats. Further, combination of low doses of aliskiren and AVE 0991 significantly reduced MABP, as compared with DOCA control rats and with either drug alone in low doses. It may be concluded that treatment with aliskiren produced down-regulation of both harmful Ang II-AT1-receptor and survival Ang(1-7)/Mas-receptor axis of RAAS. Treatment with combination of low doses of aliskiren and AVE 0991, for the first time, has been shown to produce synergistic blood pressure lowering effect. Therefore, combination of renin inhibitor with Mas-receptor agonist may prove beneficial for the treatment of hypertensive patients.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Desoxycorticosterone; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Fumarates; Hypertension; Imidazoles; Male; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Renin

Hyperglycaemia up-regulates intracellular AngII (angiotensin II) production in cardiac myocytes, effects of which are blocked more effectively by renin inhibition than ARBs (angiotensin receptor blockers) or ACEis (angiotensin-converting enzyme inhibitors). In the present study, we determined whether renin inhibition is more effective at preventing diabetic cardiomyopathy than an ARB or ACEi. Diabetes was induced in adult mice for 10 weeks by STZ (streptozotocin). Diabetic mice were treated with insulin, aliskiren (a renin inhibitor), benazeprilat (an ACEi) or valsartan (an ARB) via subcutaneous mini-pumps. Significant impairment in diastolic and systolic cardiac functions was observed in diabetic mice, which was completely prevented by all three RAS (renin-angiotensin system) inhibitors. Hyperglycaemia significantly increased cardiac oxidative stress and circulating inflammatory cytokines, which were blocked by aliskiren and benazeprilat, whereas valsartan was partially effective. Diabetes increased cardiac PRR (prorenin receptor) expression and nuclear translocation of PLZF (promyelocytic zinc finger protein), which was completely prevented by aliskiren and valsartan, and partially by benazeprilat. Renin inhibition provided similar protection of cardiac function to ARBs and ACEis. Activation of PLZF by PRR represented a novel mechanism in diabetic cardiomyopathy. Differential effects of the three agents on oxidative stress, cytokines and PRR expression suggested subtle differences in their mechanisms of action.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Blood Pressure; Diabetes Mellitus, Experimental; Fumarates; Heart; Humans; Male; Mice; Mice, Inbred C57BL; Myocardium; Oxidative Stress; Prorenin Receptor; Receptors, Cell Surface; Renin; Tetrazoles; Valine; Valsartan

The influence of chronic administration of low doses of aliskiren (5 mg/kg/day, i.p.) for a period of eight weeks on cardiac electrophysiological and structural remodeling was investigated in transgenic (TGR)(mRen-2)27 rats. Cardiac and plasma angiotensin II (Ang II) levels were determined by ELISA before and after administration of the drug. Moreover, histological, electrophysiological and echocardiographic studies were performed in controls and at the end of eight weeks of aliskiren administration.. 1) The cardiac Ang II levels were significantly reduced while the plasma Ang II levels were not significantly decreased in rats treated with low doses of aliskiren; 2) echocardographic studies showed a decrease of left ventricle diameter (LVD), left ventricle posterior wall thickness (LVPW), left ventricle end diastolic volume (LVEDV) and increased ejection fraction (EF); 3) aliskiren improved the impulse propagation, increased the cardiac refractoriness and reduced the incidence of triggered activity; 4) perivascular and interstitial fibrosis were greatly reduced, which explains the increase in conduction velocity. All these effects of aliskiren were found independently of blood pressure, suggesting that the beneficial effect of aliskiren was related to an inhibition of the local cardiac renin angiotensin system; and 5) the effect of mechanical stretch on action potential duration, conduction velocity and spontaneous rhythmicity was changed by aliskiren, supporting the hypothesis presented here that the beneficial effect of the drug on cardiac remodeling is related to a decreased sensitivity of cardiac muscle to mechanical stress.

Topics: Action Potentials; Amides; Animals; Blood Pressure; Dose-Response Relationship, Drug; Electrocardiography; Electrophysiological Phenomena; Fibrosis; Fumarates; Heart; Heart Ventricles; Male; Myocardium; Rats; Rats, Transgenic; Receptor, Angiotensin, Type 1; Stress, Mechanical; Systole; Ventricular Remodeling

A nonsynonymous single nucleotide polymorphism (SNP) in the SLCO2B1 gene encoding organic anion transporting polypeptide 2B1 (OATP2B1), c.935G>A (p.R312Q; rs12422149), has been associated with reduced plasma concentrations of montelukast in patients with asthma. Our aim was to examine the possible effects of the SLCO2B1 c.935G>A SNP on the single-dose pharmacokinetics of the suggested OATP2B1 substrates montelukast and aliskiren.. Sixteen healthy volunteers with the SLCO2B1 c.935GG genotype, 12 with the c.935GA genotype, and five with the c.935AA genotype ingested a single 10 mg dose of montelukast or a 150 mg dose of aliskiren, with a washout period of 1 week. Plasma montelukast concentrations were measured up to 24 h. Plasma and urine aliskiren concentrations were measured up to 72 and 12 h, respectively, and plasma renin activity up to 24 h after aliskiren intake.. The SLCO2B1 genotypes had no significant effect on the pharmacokinetics of montelukast or aliskiren. The geometric mean ratios with 90% confidence intervals of montelukast area under the plasma concentration-time curve from 0 h to infinity (AUC(0-∞)) in participants with the c.935GA or the c.935AA genotype to those with the c.935GG genotype were 1.02 (0.87, 1.21) or 0.88 (0.71, 1.10), respectively (P=0.557). The geometric mean ratios (90% confidence interval) of aliskiren AUC(0-∞) in participants with the c.935GA or the c.935AA genotype to those with the c.935GG genotype were 0.98 (0.74, 1.30) or 1.24 (0.85, 1.80), respectively (P=0.576).. These data do not support the suggested functional significance of the SLCO2B1 c.935G>A SNP on OATP2B1 activity in vivo.

Topics: Acetates; Adult; Amides; Antihypertensive Agents; Chromatography, Liquid; Cross-Over Studies; Cyclopropanes; Female; Fumarates; Genotype; Humans; Leukotriene Antagonists; Male; Middle Aged; Organic Anion Transporters; Polymorphism, Single Nucleotide; Quinolines; Radioimmunoassay; Renin; Sulfides; Tandem Mass Spectrometry; Tissue Distribution; Young Adult

A substantial amount of evidence links the renin-angiotensin system with thrombosis. For example, ACE inhibitors and angiotensin receptor blockers possess independent of the hemodynamic changes, antithrombotic activity. Aliskiren direct renin inhibitor belongs to a new very promising antihypertensive drug that effectively inhibits the renin-angiotensin system. The aim of study was to determine the influence of aliskiren on stasis-induced venous thrombosis in renovascular hypertensive and normotensive rats. The involvement of nitric oxide and prostacyclin in the potential antithrombotic action was also elucidated. Six weeks after clipping of the left renal artery rats developed hypertension which was confirmed by the "tail cuff" method. Hypertensive and normotensive rats were treated with aliskiren (10, 30 and 100mg/kg/day) per os for 10days. Venous thrombosis was induced by stasis of vena cava inferior. Aliskiren at the highest dose induced a significant decrease in systolic blood pressure in hypertensive, but did not change this parameter in normotensive rats. Oral administration of aliskiren resulted in dose-dependent decrease of venous thrombus weight in hypertensive and normotensive rats. The antithrombotic activity of aliskiren was abolished both by NO synthase inhibitor and prostacyclin synthesis inhibitor. Aliskiren decreased collagen-induced platelet aggregation, increased plasma level of tissue plasminogen activator activity whereas no changes in plasminogen activator inhibitor activity and coagulation parameters were found. We showed that aliskiren prevents the development of venous thrombosis by enhanced fibrinolysis and the blood platelet inhibition via nitric oxide and/or prostacyclin-dependent mechanism.

Topics: Administration, Oral; Amides; Animals; Biomarkers; Blood Platelets; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Epoprostenol; Fibrinolysis; Fibrinolytic Agents; Fumarates; Hypertension, Renovascular; Hypoglycemic Agents; Kidney; Ligation; Male; Nitric Oxide; Nitric Oxide Synthase; Plasminogen Activator Inhibitor 1; Platelet Activation; Rats; Rats, Wistar; Renal Artery; Tissue Plasminogen Activator; Venous Thrombosis

We examined the antihypertensive effects of valsartan, aliskiren, or both drugs combined on circulating, cardiac, and renal components of the renin-angiotensin system in congenic mRen2.Lewis hypertensive rats assigned to: vehicle (n=9), valsartan (via drinking water, 30 mg/kg per day; n=10), aliskiren (SC by osmotic mini-pumps, 50 mg/kg per day; n=10), or valsartan (30 mg/kg per day) combined with aliskiren (50 mg/kg per day; n=10). Arterial pressure and heart rate were measured by telemetry before and during 2 weeks of treatment; trunk blood, heart, urine, and kidneys were collected for measures of renin-angiotensin system components. Arterial pressure and left-ventricular weight/tibia length ratio were reduced by monotherapy of valsartan, aliskiren, and further reduced by the combination therapy. Urinary protein excretion was reduced by valsartan and further reduced by the combination. The increases in plasma angiotensin (Ang) II induced by valsartan were reversed by the treatment of aliskiren and partially suppressed by the combination. The decreases in plasma Ang-(1-7) induced by aliskiren recovered in the combination group. Kidney Ang-(1-12) was increased by the combination therapy whereas the increases in urinary creatinine mediated by valsartan were reversed by addition of aliskiren. The antihypertensive and antiproteinuric actions of the combined therapy were associated with marked worsening of renal parenchymal disease and increased peritubular fibrosis. The data show that despite improvements in the surrogate end points of blood pressure, ventricular mass, and proteinuria, dual blockade of Ang II receptors and renin activity is accompanied by worsening of renal parenchymal disease reflecting a renal homeostatic stress response attributable to loss of tubuloglomerular feedback by Ang II.

Topics: Amides; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Fumarates; Heart Rate; Hemodynamics; Hypertension; Kidney; Male; Rats; Renin; Renin-Angiotensin System; Telemetry; Tetrazoles; Valine; Valsartan

This study revealed that low-dose aliskiren treatment could attenuate proteinuria by interrupting the renin-angiotensin system in mice with lupus nephritis, and the beneficial effect was beyond blood pressure control. An in and ex vivo fluorescence imaging (using a non-invasion in vivo imaging system) showed intense labeling of renin in the kidneys of female MRL/lpr mice. In the study, Alzet mini-osmotic pumps were implanted into 6-week-old female MRL/lpr mice. Pumps were filled with either phosphate-buffered saline or a solution of aliskiren dissolved in phosphate-buffered saline (20 mg/kg/day) and replaced at 28-day intervals. Mice were sacrificed at four and eight weeks. To label cells for DNA synthesis, bromodeoxyuridine (BrdU) (50 mg/kg) was injected intraperitoneally an hour prior to sacrifice. The level of renin inhibition was adequate, as aliskiren-treated mice demonstrated higher renal renin mRNA expression than controls (p < 0.05). Although there were no significant differences in the systolic blood pressure (control versus aliskiren-treated: 127.20 ± 4.44 mmHg versus 103.80 ± 7.40 mmHg, p > 0.05) and heart rate (control versus aliskiren-treated: 680.50 ± 11.71 versus 647.80 ± 13.90, p > 0.05) of both groups after eight weeks, there was significant reduction of inflammatory cytokines (transforming growth factor-beta1, regulated on activation normal T cell expressed, monocyte chemoattractant protein-1 and osteopontin, p < 0.05), reduction of innate immunity (toll-like receptor 7, p < 0.05), as well as a reduction of glomerular proliferation and inflammation (BrdU-, CD45-, CD3- and F4/80-positive glomerular cells, p < 0.01) after aliskiren infusion, which might translate into an improvement in proteinuria (control versus aliskiren-treated: 493.7 versus 843.7 mg/g, p < 0.01) or weight gain (control versus aliskiren-treated: 5.65 ± 1.61 versus 8.67 ± 0.97%, p < 0.05).

Topics: Amides; Animals; Blood Pressure; Disease Models, Animal; Female; Fumarates; Lupus Nephritis; Mice; Mice, Inbred Strains; Proteinuria; Renal Agents; Renin

Elevated prorenin levels associate with microvascular complications in patients with diabetes mellitus, possibly because prorenin affects vascular function in diabetes mellitus, for example by generating angiotensins following its binding to the (pro)renin receptor [(P)RR]. Here we evaluated whether the renin inhibitor aliskiren, with or without the putative (P)RR antagonist handle region peptide (HRP) improved the disturbed vascular function in diabetic TGR(mREN2)27 rats, a high-prorenin, high-(P)RR hypertensive model.. Telemetry transmitters were implanted to monitor blood pressure. After 3 weeks of treatment, rats were sacrificed, and iliac and mesenteric arteries were removed to evaluate vascular reactivity.. Diabetes mellitus enhanced the contractile response to nitric oxide synthase (NOS) blockade, potentiated the response to phenylephrine, diminished the effectiveness of endothelin type A (ETA) receptor blockade and allowed acetylcholine to display constrictor, cyclo-oxygenase-2 mediated, endothelium-dependent responses in the presence of NOS inhibition and blockers of endothelium-derived hyperpolarizing factors. Aliskiren normalized blood pressure, suppressed renin activity, and reversed the above vascular effects, with the exception of the altered effectiveness of ETA receptor blockade. Remarkably, when adding HRP on top of aliskiren, its beneficial vascular effects either disappeared or were greatly diminished, although HRP did not alter the effect of aliskiren on blood pressure and renin activity.. Renin inhibition improves vascular dysfunction in diabetic hypertensive rats, and HRP counteracts this effect independently of blood pressure and angiotensin. (P)RR blockade therefore is unlikely to be a new tool to further suppress the renin-angiotensin system (RAS) on top of existing RAS blockers.

Topics: Amides; Animals; Base Sequence; Diabetes Mellitus, Experimental; DNA Primers; Endothelium, Vascular; Fumarates; Muscle Contraction; Peptides; Prorenin Receptor; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Receptors, Cell Surface; Up-Regulation

Strategies that block angiotensin II actions on its angiotensin type 1 receptor or inhibit actions of aldosterone have been shown to reduce myocardial hypertrophy and interstitial fibrosis in states of insulin resistance. Thereby, we sought to determine if combination of direct renin inhibition with angiotensin type 1 receptor blockade in vivo, through greater reductions in systolic blood pressure (SBP) and aldosterone would attenuate left ventricular hypertrophy and interstitial fibrosis to a greater extent than either intervention alone.. We utilized the transgenic Ren2 rat which manifests increased tissue expression of murine renin which, in turn, results in increased renin-angiotensin system activity, aldosterone secretion and insulin resistance. Ren2 rats were treated with aliskiren, valsartan, the combination (aliskiren+valsartan), or vehicle for 21 days.. Compared to Sprague-Dawley controls, Ren2 rats displayed increased systolic blood pressure, elevated serum aldosterone levels, cardiac tissue hypertrophy, interstitial fibrosis and ultrastructural remodeling. These biochemical and functional alterations were accompanied by increases in the NADPH oxidase subunit Nox2 and 3-nitrotyrosine content along with increases in mammalian target of rapamycin and reductions in protein kinase B phosphorylation. Combination therapy contributed to greater reductions in systolic blood pressure and serum aldosterone but did not result in greater improvement in metabolic signaling or markers of oxidative stress, fibrosis or hypertrophy beyond either intervention alone.. Thereby, our data suggest that the greater impact of combination therapy on reductions in aldosterone does not translate into greater reductions in myocardial fibrosis or hypertrophy in this transgenic model of tissue renin overexpression.

Topics: Aldosterone; Amides; Angiotensin II Type 1 Receptor Blockers; Animals; Blood Pressure; Cell Size; Drug Interactions; Fibrosis; Fumarates; Mice; Myocardium; Myocytes, Cardiac; Oxidative Stress; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Receptor, Angiotensin, Type 1; Renin; Signal Transduction; Tetrazoles; Valine; Valsartan; Ventricular Remodeling

Numerous randomized clinical trials have demonstrated the efficacy and tolerability of aliskiren and aliskiren hydrochlorothiazide (aliskiren HCT) single-pill combination therapy in patients with hypertension. The objective of the present study was to evaluate the effectiveness and safety of aliskiren-based therapy under daily life conditions in a multiethnic population.. This observational, multicenter, noninterventional study, conducted at 420 centers in Asia and the Middle East, included adult patients with hypertension who received treatment with aliskiren or aliskiren HCT as single or add-on therapy for a planned treatment period of at least 26 weeks. The main effectiveness assessments included the proportion of patients achieving therapeutic blood pressure (BP) goal (defined as systolic BP [SBP]/diastolic BP [DBP]<140/90 mmHg, or <130/80 mmHg in patients with diabetes) and BP response, and change in mean sitting BP from baseline to study end.. Of 4,826 patients (mean age 51.4 years, 65.9% male, 64.5% Asian, 41.5% diabetic) included in the study, 3,473 received aliskiren and 1,353 received aliskiren HCT. Almost half the study population (48.1%) received aliskiren or aliskiren HCT as add-on therapy. The therapeutic BP goal was achieved in 49.5% of patients treated with aliskiren and 48.3% of patients receiving aliskiren HCT; attainment of BP goal increased to more than 70% when a classic BP target of <140/90 mmHg was applied for all patients. Reductions in mean sitting SBP/DBP were significantly lower versus baseline for both aliskiren (24.1/12.2 mmHg) and aliskiren HCT (27.6/14.1 mmHg) and BP response rates were consistently achieved in more than 80% of all patients during the study. Aliskiren treatment was well tolerated with only a small proportion of patients experiencing adverse events (AEs; 2.1%) and serious AEs (0.3%).. In this real-world, naturalistic setting, antihypertensive treatment with an aliskiren-based regimen was effective and well-tolerated in this multiethnic population with arterial hypertension.

Topics: Adult; Amides; Antihypertensive Agents; Asian People; Drug Combinations; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Prospective Studies; Treatment Outcome

Topics: Amides; Animals; Aorta, Thoracic; Endothelium, Vascular; Fructose; Fumarates; Hypertension; Insulin Resistance; Male; Renin

Diabetic nephropathy is one of the major causes of chronic kidney disease (CKD), consequently progression to end stage renal disease. The previous studies demonstrated that the inhibition on renin-angiotensin-aldosterone system (RAAS) such as by angiotensin converting enzyme inhibitor (ACEI) and angiotensin type I receptor blocker (ARB) reduced proteinuria and slow progression of CKD. Direct renin inhibitor (DRI) theoretical complete block RAAS by reducing plama renin activity angiotensin I and angiotensin II. The present study aimed to determine the efficacy of aliskiren (DRI) monotherapy on blood pressure control and proteinuria reduction.. Diabetic mellitus patients with estimated glomerular filtration rate (eGFR) > or = 30 ml/min who had proteinuria > 300 mg/day were enrolled to receive aliskiren 150 mg/day for 2 weeks then 300 mg/day until 24 weeks.. The SBP were significantly decreased form 137.8 to 123.7 (p = 0.01) at 2 weeks, 137.8 to 126.26 (p = 0.04) at 4 weeks and 137.8 to 121 mmHg (p = 0.002) at 24 weeks after treatment, respectively. Similar to SBP, the DBP was significantly decreased from 84.08 to 73.66 (p = 0.04) at 4 weeks and 84.08 to 75.85 mmHg (p = 0.002) at the end of study. Reduction of UPCR showed significantly reduced for 32.65% (p = 0.007) and 45% (p = 0.004) from baseline at 2 weeks and 24 weeks after DRI treatment respectively. Serum creatinine, eGFR and serum potassium were no significant changed from the baseline. There were no harmful adverse reaction in patients who receiving aliskirin.. Aliskiren monotherapy showed significantly reduced proteinuria, good blood pressure control without harmful side effect in overt diabetic nephropathy patients.

Topics: Aged; Amides; Antihypertensive Agents; Diabetic Nephropathies; Female; Fumarates; Humans; Male; Middle Aged; Prospective Studies; Proteinuria; Renin

Treatment strategies to improve blood pressure control, reduce end-organ damage, and improve cardiovascular outcomes are more important today than ever before. Most patients will require combination therapy to achieve target blood pressure; early initiation of combination therapy may help patients achieve blood pressure control more rapidly. Low-dose combinations may be more effective with fewer adverse effects than higher doses of single agents. Dysregulation of the renin-angiotensin-aldosterone system (RAAS) is an important contributor in the pathogenesis of hypertension and its sequelae. Treatment with a direct renin inhibitor blocks the rate-limiting step in the RAAS, resulting in decreased angiotensin I and II production and decreased urinary aldosterone excretion. Like the angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, treatment with a direct renin inhibitor increases plasma renin concentration, but unlike the other RAAS inhibitors, treatment with a direct renin inhibitor decreases plasma renin activity. This unique combination of effects on the RAAS make a direct renin inhibitor an attractive option to combine with other antihypertensive agents for the management of hypertension and its comorbidities. Clinical studies have shown that combining the direct renin inhibitor, aliskiren, with drugs representing each of the major classes of antihypertensive agents (thiazide diuretics, beta blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, and calcium-channel blockers) reduces blood pressure, improves markers for cardiovascular outcomes, or does both. Results of several ongoing randomized clinical trials should provide additional insights into the potential of therapeutic combinations that include aliskiren to improve cardiovascular morbidity and mortality in patients with hypertension and related comorbidities.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Clinical Trials as Topic; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

The efficacy of aliskiren, a direct renin inhibitor, in ventricular remodeling after myocardial infarction (MI) compared with conventional renin-angiotensin system (RAS) inhibitors remains to be defined. This study was performed to examine the protective effects of aliskiren and its addition to valsartan, an angiotensin-II receptor blocker, against ventricular remodeling after MI. MI was induced in 8- to 12-week-old C57BL/6 mice by ligating the left anterior descending artery. At 3 days after MI, mice were divided into five groups and were treated with the following: (1) phosphate-buffered saline (PBS); (2) hydralazine (10 mg kg(-1) day(-1)); (3) valsartan (8 mg kg(-1) day(-1)); (4) aliskiren (25 mg kg(-1) day(-1)); and (5) combined aliskiren (25 mg kg(-1) day(-1)) and valsartan (8 mg kg(-1) day(-1)). With these doses of drugs, blood pressure-lowering effects compared with the PBS group were similar among the treated groups in sham-operated mice. At 28 days after MI, echocardiographic, hemodynamic and histological assessments demonstrated that monotherapy with valsartan or aliskiren alone significantly and similarly ameliorated ventricular remodeling after MI compared with the PBS and the hydralazine groups. Combination therapy of valsartan and aliskiren more greatly improved ventricular remodeling after MI with enhancement of angiogenesis and greater attenuation of tissue oxidative stress and inflammation. Our results indicate that aliskiren can be an alternative to conventional RAS inhibitors in the treatment of post-MI patients. Moreover, the dual therapy of valsartan and aliskiren may be more beneficial than either monotherapy. Further clinical trials will be warranted to sufficiently assess the safety and the efficacy of the use of aliskiren in post-MI patients.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Blood Pressure; Drug Synergism; Fumarates; Heart; Lipid Peroxidation; Male; Mice; Myocardial Infarction; Myocardium; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan; Ventricular Remodeling

Topics: Amides; Antihypertensive Agents; Blood Pressure; Female; Fumarates; Humans; Hypertension; Male; Ramipril

A simple and sensitive method has been developed and validated for the determination of aliskiren (ALS) in its dosage forms and spiked plasma. The method was based on the reaction of the drug with dansyl chloride in the presence of bicarbonate solution of pH 10.5 to give a highly fluorescent derivative which was measured at 501 nm with excitition at 378 nm in dichloromethane. Different experimental parameters affecting the development of the method and stability were carefully studied and optimized. The calibration curves were linear over the concentration ranges of 100-700 and 50-150 ng/mL for standard solution and plasma, respectively. The limits of detection were 27.52 ng/mL in standard solution, 4.91 ng/mL in plasma. The developed method was successfully applied to the analysis the drug in the commercial tablets and spiked plasma samples. The mean recovery of ALS from tablets and plasma was 100.10 and 97.81%, respectively. A proposal of the reaction pathway was presented.

Topics: Amides; Calibration; Dansyl Compounds; Fumarates; Humans; Hydrogen-Ion Concentration; Sensitivity and Specificity; Spectrometry, Fluorescence; Spectrophotometry, Ultraviolet; Tablets

Hypokalemic hypertension is a common condition leading to the diagnosis of secondary hypertension. We report the case of a 60-year-old woman for whom the diagnosis of autosomal dominant polycystic kidney disease arose during the investigation of possible hyperaldosteronism. Activation of the renin system, as supported by recent studies, can explain the mechanism of hypokalemia and hypertension in this inherited cystic kidney disorder. Clinicians should be aware of this relatively uncommon clinical phenomenon of secondary hypertension in polycystic kidney disease. Increased understanding of the disorder's underlying mechanism should lay the foundation for better appreciation of potentially effective blood pressure treatments. The availability of a direct renin inhibitor may redirect research toward finding a remedy for this troublesome disease.

Topics: Amides; Female; Fumarates; Humans; Hypertension; Hypokalemia; Middle Aged; Polycystic Kidney, Autosomal Dominant; Potassium Chloride; Renin; Treatment Outcome

Angiotensin (ANG) II-dependent hypertension is characterized by increases in intrarenal ANG II levels, derangement in renal hemodynamics, and augmented tubular sodium reabsorptive capability. Increased nephron expression of renin-angiotensin system components, such as angiotensinogen by proximal tubule cells and renin by collecting duct principal cells, has been associated with an augmented ability of the kidney to form ANG II in hypertensive states. However, the contribution of de novo intrarenal ANG II production to the development and maintenance of ANG II-dependent hypertension remains unclear. The present study was performed to determine the effects of selective intrarenal renin inhibition on whole kidney hemodynamics and renal excretory function in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension in the absence of the confounding influence of associated reductions in mean arterial pressure (MAP). Male Cyp1a1-Ren2 transgenic rats were induced to develop malignant hypertension, anesthetized, and surgically prepared for intrarenal administration of the direct renin inhibitor aliskiren (0.01 mg/kg). Following acute aliskiren treatment, urine flow and sodium excretion increased (10.5 ± 1.1 to 15.9 ± 1.9 μl/min, P < 0.001; 550 ± 160 to 1,370 ± 320 neq/min, P < 0.001, respectively) and ANG II excretion decreased (120 ± 30 to 63 ± 17 fmol/h, P < 0.05). There were no significant changes in MAP, glomerular filtration rate, estimated renal plasma flow, plasma ANG II levels, or protein excretion. The present findings demonstrate that selective renal renin inhibition elicits diuretic and natriuretic responses in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension. Elevated intraluminal ANG II levels likely act to augment tubular reabsorptive function and, thereby, contribute to the elevated blood pressure in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension.

Topics: Amides; Animals; Blood Pressure; Cytochrome P-450 CYP1A1; Fumarates; Hypertension, Malignant; Kidney; Male; Rats; Rats, Transgenic; Renin; Sodium

Inhibition of the renin angiotensin system (RAS) has been consistently demonstrated to reduce atherosclerosis. However, there has been no direct comparison among the three available pharmacological modes of inhibiting the RAS, which are inhibitors of renin, ACE and angiotensin II type 1 receptor. The purpose of this study was to determine the relative effects of these three modes of pharmacological RAS inhibition in reducing atherosclerosis by determining the dose-response relationships.. Male LDL receptor -/- mice were administered either vehicle or any of three doses of aliskiren, enalapril or losartan through s.c. infusion for 12 weeks. All mice were fed a saturated fat-enriched diet during drug infusions. Systolic and diastolic BPs were measured during the study using a non-invasive tail-cuff system. Plasma cholesterol and renin concentrations, atherosclerotic lesions, and renal angiotensin II concentrations were determined at the termination of the study.. Plasma renin concentrations were increased by all three drugs. None of the drugs changed plasma cholesterol concentrations. All drugs produced a dose-related decrease in BP. All three drugs also profoundly reduced atherosclerosis in a dose-dependent manner. The highest dose of each drug markedly attenuated lesion size, with no significant differences between the different drugs. The highest dose of each drug also similarly reduced renal angiotensin II concentrations.. Drugs that inhibit the RAS, irrespective of their mode of inhibition, profoundly affect atherosclerotic lesion development in a dose-dependent manner.

Topics: Amides; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Atherosclerosis; Blood Pressure; Cholesterol; Diet, High-Fat; Enalapril; Fumarates; Hypercholesterolemia; Kidney; Losartan; Male; Mice; Mice, Knockout; Receptor, Angiotensin, Type 1; Receptors, LDL; Renin; Renin-Angiotensin System

Aliskiren is a direct renin inhibitor used in the treatment for arterial hypertension. It can also augment nitric oxide (NO) production, which plays a crucial role in the pathogenesis of portal hypertension and modulation of porto-systemic collaterals. This study investigated the effects of aliskiren on portal pressure and porto-systemic collaterals of portal vein-ligated (PVL) rats.. Sham-operated and PVL rats received aliskiren (50 mg/kg per day) or distilled water (control) treatment for 10 days. The mean arterial pressure and portal pressure were measured by catheterization of the right femoral artery and mesenteric vein, while the superior mesenteric arterial blood flow was measured by Doppler technique. The left adrenal vein and superior mesentery artery were dissected for mRNA study. The PVL rats also underwent preincubation with (i) Krebs solution (control); (ii) 10(-4) M aliskiren; or (iii) 10(-4) M aliskiren plus nonselective NO inhibitor N(ω)-nitro-L-arginine (10(-4) M), followed by the addition of arginine vasopressin (AVP) to evaluate the collateral vascular responsiveness.. Aliskiren had systemic arterial pressure- and portal pressure-lowering effects in PVL rats. Superior mesentery arterial resistance also decreased. The constitutive NO synthase was enhanced in the left adrenal vein and superior mesentery artery after aliskiren treatment. Aliskiren attenuated the collateral vasoconstrictive effects of AVP, but the vasodilatory effects were abolished after nonselective NO synthase inhibition.. Chronic aliskiren use reduces portal pressure in portal hypertensive rats partly due to the modulation of splanchnic and collateral NO synthase.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Collateral Circulation; Disease Models, Animal; Dose-Response Relationship, Drug; Fumarates; Hypertension, Portal; Male; Nitric Oxide; Nitric Oxide Synthase; Portal Pressure; Portal System; Rats; Rats, Sprague-Dawley; Renin

We have demonstrated previously that overactivity of the renin-angiotensin system (RAS) is associated with whole body and skeletal muscle insulin resistance in obese Zucker (fa/fa) rats. Moreover, this obesity-associated insulin resistance is reduced by treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor (type 1) blockers. However, it is currently unknown whether specific inhibition of renin itself, the rate-limiting step in RAS functionality, improves insulin action in obesity-associated insulin resistance. Therefore, the present study assessed the effect of chronic, selective renin inhibition using aliskiren on glucose tolerance, whole body insulin sensitivity, and insulin action on the glucose transport system in skeletal muscle of obese Zucker rats. Obese Zucker rats were treated for 21 days with either vehicle or aliskiren (50 mg/kg body wt ip). Renin inhibition was associated with a significant lowering (10%, P < 0.05) of resting systolic blood pressure and induced reductions in fasting plasma glucose (11%) and free fatty acids (46%) and homeostatic model assessment for insulin resistance (13%). Glucose tolerance (glucose area under the curve) and whole body insulin sensitivity (inverse of the glucose-insulin index) during an oral glucose tolerance test were improved by 15% and 16%, respectively, following chronic renin inhibition. Moreover, insulin-stimulated glucose transport activity in isolated soleus muscle of renin inhibitor-treated animals was increased by 36% and was associated with a 2.2-fold greater Akt Ser(473) phosphorylation. These data provide evidence that chronic selective inhibition of renin activity leads to improvements in glucose tolerance and whole body insulin sensitivity in the insulin-resistant obese Zucker rat. Importantly, chronic renin inhibition is associated with upregulation of insulin action on skeletal muscle glucose transport, and it may involve improved Akt signaling. These data support the strategy of targeting the RAS to improve both blood pressure regulation and insulin action in conditions of insulin resistance.

Topics: Amides; Animals; Biological Transport; Blood Pressure; Body Weight; Disease Models, Animal; Fatty Acids, Nonesterified; Female; Fumarates; Glucose; Insulin; Insulin Resistance; Muscle, Skeletal; Obesity; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Zucker; Renin; Signal Transduction

We hypothesized that compared with hydrochlorothiazide (HCTZ), the renin inhibitor aliskiren (ALISK) or amlodipine (AMLO) and their combination reduce albuminuria via reduction in renal inflammation, independent of blood pressure (BP) changes. We studied normal and streptozotocin-induced diabetic (DM) Sprague-Dawley rats treated for 6 weeks with vehicle, ALISK, HCTZ, or AMLO individually and combined and evaluated the effects of treatments on BP, urine albumin to creatinine ratio, renal interstitial fluid levels of angiotensin II, tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6) and renal expression of TNF-α, IL-6, transforming growth factor beta 1, and nuclear factor kappa B. There were no differences in BP between treatments. Only ALISK and its combinations reduced renal interstitial fluid angiotensin II. Urine albumin to creatinine ratio increased in DM rats and decreased with ALISK alone or combined with HCTZ or AMLO. HCTZ or AMLO individually and combined did not influence urine albumin to creatinine ratio. Renal interstitial fluid TNF-α and IL-6, and the renal expression of TNF-α, IL-6, transforming growth factor beta 1, and nuclear factor kappa B were increased in DM rats. These renal inflammatory markers were reduced only with ALISK or AMLO individually or combined with other treatments. We conclude that ALISK alone and combined with HCTZ or AMLO reduced albuminuria in diabetes via reduction in renal inflammation, independent of BP changes.

Topics: Albuminuria; Amides; Amlodipine; Animals; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Experimental; Drug Therapy, Combination; Fumarates; Hydrochlorothiazide; Inflammation; Kidney; Male; Rats; Rats, Sprague-Dawley; Renin; Streptozocin

Chronic renal ischemia leads to renal fibrosis and atrophy. Activation of the renin-angiotensin-aldosterone system is one of the main mechanisms driving chronic renal ischemic injury. The aim of the present study was to define the effect of aliskiren in chronic ischemia of the kidney. Two-kidney, one-clip mice were used to study chronic renal ischemia. Aliskiren significantly lowered the blood pressure in mice with renal artery constriction (92.1±1.1 vs. 81.0±1.8 mm Hg, P<0.05). Renin expression was significantly increased in ischemic kidneys when treated with aliskiren. In addition, (Pro)renin receptor expression was decreased by aliskiren in ischemic kidneys. Aliskiren treatment significantly increased klotho expression and reduced the expression of fibrogenic cystokines, caspase-3 and Bax in ischemic kidneys. Histological examination revealed that aliskiren significantly reduced the nephrosclerosis score (4.5±1.9 vs. 7.3±0.4, P<0.05). Immunofluorescence staining also showed that aliskiren decreased the deposition of interstitial collagen I in ischemic kidneys. In conclusion, direct renin inhibition significantly reduced renal fibrosis and apoptosis following chronic renal ischemia.

Topics: Amides; Animals; Antihypertensive Agents; Caspase 3; Collagen Type I; Disease Models, Animal; Female; Fibrosis; Fumarates; Glucuronidase; Ischemia; Kidney; Kidney Failure, Chronic; Klotho Proteins; Mice; Mice, Inbred Strains; Renal Artery; Renin; Surgical Instruments

We report a case of acute kidney injury (AKI) caused by a novel direct renin inhibitor, aliskiren. A 43-year-old Japanese man with dilated cardiomyopathy on cardiac resynchronization therapy with defibrillator and chronic kidney disease (CKD) was started on aliskiren in addition to enalapril, carvedilol, furosemide, and spironolactone for worsening cardiac function suggested by the elevation of serum brain natriuretic peptide. After 1 month, he noticed general malaise, loss of appetite and his serum creatinine level increased from 2.0 to 7.24 mg/dL. He had no evidence of exacerbation of hemodynamic instability (heart failure or hypotension) or post-renal cause of AKI. Although a cessation of aliskiren did not ameliorate AKI, renal function returned to baseline after withholding enalapril. Careful monitoring is necessary when aliskiren is used in patients with CKD and/or significant systolic dysfunction since it can cause normotensive ischemic AKI, especially when there is a concomitant use of other renin-angiotensin-aldosterone system inhibitors.

Topics: Acute Kidney Injury; Adult; Amides; Antihypertensive Agents; Cardiomyopathy, Dilated; Fumarates; Humans; Kidney Failure, Chronic; Male; Natriuretic Peptide, Brain

Topics: Amides; Animals; Bile Ducts; Blood Pressure; Body Weight; Fumarates; Hemodynamics; Hypertension, Portal; Ligation; Liver Cirrhosis, Experimental; Male; Nitric Oxide Synthase Type III; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System

Aliskiren is the first commercially available, orally active, direct renin inhibitor approved to treat hypertension. The renin-angiotensin system has been shown to be a significant contributor to the development of hypercholesterolemia-induced atherosclerosis. The aim of this study was to evaluate the antiatherosclerotic and plaque stabilization effects of aliskiren alone and in combination with atorvastatin.. APOE*3Leiden.CETP mice (n = 14-17/group) were fed a western-type diet (containing 0.25% cholesterol) alone or were treated with either aliskiren (15 mg/kg per day), atorvastatin (3.6 mg/kg per day) or a combination of aliskiren and atorvastatin. Effects on SBP, total cholesterol, inflammation markers and atherosclerotic size and composition were assessed.. Aliskiren reduced SBP (-19%, P < 0.001) and atorvastatin reduced total cholesterol (-24%, P < 0.001). Atherosclerotic lesion area was reduced by aliskiren (-40%, P < 0.01), atorvastatin (-61%, P < 0.001) and the combination treatment (-69%, P < 0.001). Aliskiren alone and together with atorvastatin decreased the number of T cells in the aortic root area (-60%, P < 0.01; -41%, P < 0.05), as well as macrophage (-64%, P < 0.001; -72%, P < 0.001) and necrotic area (-52%, P = 0.071; -84%, P < 0.001) in the lesion. Atorvastatin alone and together with aliskiren decreased monocyte adherence (-43%, P < 0.05 and -51%, P < 0.01) and monocyte chemoattractant protein-1 (both -36%, P < 0.01). The combination treatment decreased the number of lesions (-17%, P < 0.05) and E-selectin (-17%, P < 0.05).. Aliskiren inhibited atherosclerosis development and improved plaque stability alone and in combination with atorvastatin, possibly via a mechanism involving T cells. These results suggest a potential benefit of using aliskiren in a clinical setting, particularly in combination with statin treatment.

Topics: Amides; Animals; Apolipoproteins E; Atherosclerosis; Atorvastatin; Female; Fumarates; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mice; Mice, Transgenic; Pyrroles

In Italy, prescriptions of the direct renin inhibitor aliskiren (aliskiren) to high-risk hypertensive patients must be electronically filled by specialized physicians only when at least two antihypertensive drug classes (independently of the dosages), fails to normalize blood pressure (BP) levels.. To analyze the effects of the addition of aliskiren 150-300 mg daily to antihypertensive therapy in a population of high cardiovascular risk hypertensive patients with uncontrolled BP levels.. Clinical data were derived from patients included in the national Web-based drug-monitoring system. Follow-up visits were required for measuring BP levels, and collecting data on drug safety and tolerability.. Between March 2009 and February 2010, aliskiren was prescribed by 6464 specialized physicians to 11 511 treated, uncontrolled hypertensive patients (47.6% women, aged 68.0 ± 11.1 years, BMI 28.4 ± 4.9 kg/m) with organ damage or comorbidities. During 6-month observation, only a few drug-related side-effects were reported (n = 33). At the entry and 1-month follow-up visits (n = 8197; 70.6%), BP levels were 158.9 ± 16.8 and 142.1 ± 15.2 mmHg for SBP and 90.8 ± 9.6 and 83.1 ± 8.5 mmHg for DBP, respectively. At 6-month (n = 4907; 42.3%), SBP and DBP levels were 137.9 ± 13.9 and 81.3 ± 8.0 mmHg, respectively. A consistent reduction in the use of all classes of concomitant antihypertensive drugs was recorded.. Although data derived from national registries need to be interpreted with caution, the Italian Web-based drug-monitoring system provided information on 'real-life' use of aliskiren in hypertension. In this uncontrolled, high-risk treated hypertensive population, SBP and DBP levels recorded during treatment with aliskiren were consistently lower than those recorded at entry visits in a context of a very low rate of reported side-effects.

Topics: Aged; Amides; Antihypertensive Agents; Drug Monitoring; Female; Fumarates; Humans; Internet; Italy; Male; Middle Aged; Models, Theoretical

Topics: Amides; Animals; Apolipoproteins E; Atherosclerosis; Atorvastatin; Female; Fumarates; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pyrroles

Topics: Amides; Antihypertensive Agents; Drug Monitoring; Female; Fumarates; Humans; Internet; Male

Renal hemodynamic effects of inhibitors of the renin-angiotensin system can increase the risk of acute kidney injury under certain conditions. The BP-lowering effects of the renin inhibitor aliskiren are sustained 3-4 weeks after withdrawal. In this study, the reversibility of the renal hemodynamic effects of aliskiren was tested.. In this open-label study, renal perfusion was measured by 1.5-T magnetic resonance imaging-arterial spin labeling in 34 subjects with arterial hypertension before aliskiren (pre-aliskiren), after 4 weeks of aliskiren treatment (300 mg), and 4-5 days (∼2.5-3.0× plasma half-life) after withdrawal (post-aliskiren).. Aliskiren reduced systolic BP from 152 ± 14 to 139 ± 16 mmHg (P<0.0001), which was sustained post-aliskiren (136 ± 13 mmHg, P=1.00 versus aliskiren). Aliskiren significantly altered renal perfusion (P=0.005), increasing from 272 ± 25 pre-aliskiren to 287 ± 29 ml/min per 100 g during aliskiren (P=0.03). This increase in renal perfusion was completely reversed post-aliskiren (272 ± 26 ml/min per 100 g, P=0.03 versus aliskiren, P=0.63 versus pre-aliskiren). No changes were noted in urinary angiotensinogen levels. Plasma renin activity was reduced by aliskiren, which was sustained post-aliskiren. Angiotensin II and aldosterone were reduced by aliskiren but recovered post-aliskiren to pre-aliskiren levels.. After withdrawal of aliskiren, the effects on BP were sustained, whereas increase in renal perfusion was reversed, which was associated with recovery of angiotensin II and aldosterone to pretreatment levels. Renal hemodynamic effects are more readily reversible than systemic effects of aliskiren.

Topics: Adult; Aged; Aldosterone; Amides; Analysis of Variance; Angiotensin II; Antihypertensive Agents; Blood Pressure; Female; Fumarates; Germany; Half-Life; Humans; Hypertension; Magnetic Resonance Imaging; Male; Middle Aged; Perfusion Imaging; Renal Circulation; Renin; Renin-Angiotensin System; Time Factors; Treatment Outcome; Vasodilation; Vasodilator Agents

Aliskiren is a selective renin inhibitor recently approved for use in hypertension. Efficacy duration appears longer than what would be expected based on its circulating half-life. The aim was therefore to characterize the kinetics of the interaction between aliskiren and renin. The interaction was evaluated in three assays and compared with two other renin inhibitors including remikiren. First, the inhibition of recombinant human renin was assessed by monitoring the cleavage of fluorescent substrate. Second, human plasma renin activity (PRA) was monitored by measuring generated angiotensin I over 1 h in the presence or absence of inhibitor. Finally, the affinity, association and dissociation rate constants were determined by using a surface plasmon resonance (SPR) biosensor assay. Aliskiren and remikiren were found to be equipotent inhibitors of recombinant renin activity (K(i) ≤ 0.04 nM) while compound 1 displayed a K (i) value of 1 nM. PRA was efficiently inhibited by both aliskiren and remikiren with IC₅₀ values of 0.2-0.3 nM. Remikiren and aliskiren also displayed long-lasting interactions with immobilized renin having k (off) values of 0.18 and 0.11 × 10⁻³ s⁻¹ respectively. These dissociation rate constants corresponded to residence times of 1.5 and 2.5 h, respectively, while compound 1 had a residence time lasting only 3 min. It is therefore concluded that the long-lasting interaction between aliskiren and human renin may contribute to the 24 h anti-hypertensive effect seen in clinical trials and possibly also to target-mediated drug disposition.

Topics: Amides; Antihypertensive Agents; Biosensing Techniques; Fumarates; Humans; Imidazoles; Kinetics; Recombinant Proteins; Renin

A major focus area in improving pharmaceutical manufacturing is decreasing powder-handling steps such as milling, granulation, and blending. One approach to go directly from active pharmaceutical ingredients (API) and excipients in solution to a formulated drug product is to use electrospinning to make solid formulations of API in a polymer. Because of the rapid evaporation rate in electrospinning, the process usually results in a well-mixed solid dispersion of drugs in the polymer. In this study, solid-state nuclear magnetic resonance is used to examine phase separation in formulations of aliskiren (SPP) and indomethacin (IND) with polyvinylpyrrolidone (PVP) prepared by electrospinning and hot-melt extrusion. It was found that 1:1 SPP-PVP, 1:1 IND-PVP, and 4:1 SPP-PVP formulations prepared by electrospinning are homogeneous solid solutions down to a 2-11 nm length scale, whereas a 4:1 SPP-PVP formulation prepared by hot-melt extrusion exhibits phase separation with domain sizes of 20-100 nm or larger.

Topics: Amides; Chemistry, Pharmaceutical; Drug Compounding; Excipients; Fumarates; Indomethacin; Magnetic Resonance Spectroscopy; Povidone; Solutions

Alterations in the circadian arterial pressure rhythm predict cardiovascular mortality. We examined the circadian arterial pressure rhythm and the effect of renin-angiotensin system blockade in congenic mRen2.Lewis hypertensive rats, a renin-dependent model of hypertension derived from the backcross of transgenic hypertensive [mRen-2]27 rats with Lewis normotensive ones.. Twenty-nine mRen2.Lewis hypertensive rats were randomly assigned to drink tap water (vehicle; n = 9), valsartan (30 mg/kg/day; n = 10), or valsartan (30 mg/kg/day) combined with aliskiren given subcutaneously (50 mg/kg/day; n = 10) for 2 weeks. Arterial pressure, heart rate, and locomotive activity were recorded with chronically implanted radiotelemetry probes. The awake/asleep ratio was calculated as [awake mean arterial pressure (MAP) mean - asleep MAP mean)] / (awake MAP mean) x 100. Plasma renin activity (PRA) and concentration (PRC), and plasma and kidney angiotensin II (Ang II) were measured by radioimmunoassay (RIAs).. Untreated hypertensive rats showed an inverse arterial pressure rhythm, higher at day and lower at night, accompanied by normal rhythms of heart rate and locomotive activity. Treatment with valsartan or aliskiren and valsartan normalized the elevated arterial pressure and the arterial pressure rhythm, with the combination therapy being more effective in reducing MAP and in restoring the awake/asleep ratio. While PRA and PRC increased with the treatments, the addition of aliskiren to valsartan partially reversed the increases in plasma Ang II levels. Valsartan and the aliskiren and valsartan combination markedly reduced the renal cortical content of Ang II.. The altered circadian arterial pressure rhythm in this renin-dependent hypertension model uncovers a significant role of Ang II in the desynchronization of the circadian rhythm of arterial pressure, heart rate, and locomotive activity.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Blood Pressure; Circadian Rhythm; Disease Models, Animal; Drug Therapy, Combination; Fumarates; Heart Rate; Male; Motor Activity; Random Allocation; Rats; Rats, Inbred Lew; Rats, Transgenic; Receptors, Angiotensin; Renin; Tetrazoles; Valine; Valsartan

Sclerosing encapsulated peritonitis (SEP) is a rare complication of long term peritoneal dialysis. Renin-angiotensin-aldosterone system (RAAS) may play a role in the development of peritoneal fibrosis in CAPD patients. We aimed to evaluate the effect of aliskiren, valsartan, and aliskiren + valsartan therapy on SEP. The study included 30 Wistar albino rats which were divided into five groups: I (Control) SF solution i.p.; II (CG group) chlorhexidine gluconate i.p.; III aliskiren oral plus CG i.p.; IV valsartan oral plus CG i.p.; and V aliskiren oral, valsartan oral and CG i.p. On the twenty-first day, all of the rats were sacrificed. All of the groups were analyzed in terms of peritoneal thickness, degree of inflammation, vasculopathy, neovascularization and fibrosis. Also, the parietal peritoneal tissue samples were evaluated for matrix metalloproteinase 2 (MMP-2) using the ELISA method. Peritoneal thickness and fibrosis scores were lower in the valsartan group compared to the CG group (P < 0.05). Peritoneal fibrosis scores were lower in the aliskiren group compared to CG group (P < 0.05) but no difference was observed between the peritoneal thickness scores of the two groups (P > 0.05). Tissue MMP-2 levels were significantly higher in the CG group compared other groups (P < 0.05). There were no statistically significant differences between the aliskiren, valsartan and aliskiren + valsartan groups according to the tissue MMP-2 levels. Due to the antifibrotic properties of valsartan, it is thought to be a possible choice to prevent SEP development. We found no positive impact of aliskiren or aliskiren + valsartan combination compared to valsartan alone.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Animals; Chlorhexidine; Fumarates; Matrix Metalloproteinase 2; Peritoneum; Peritonitis; Rats; Rats, Wistar; Renin; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan

Topics: Amides; Animals; Cardiovascular Agents; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Female; Fumarates; Humans; Male; Myocardial Infarction; Renin; Ventricular Dysfunction, Left; Ventricular Remodeling

Topics: Amides; Animals; Female; Fumarates; Ischemia; Kidney; Kidney Failure, Chronic; Renin

Aliskiren, a novel direct renin inhibitor, is hypothesized to inhibit the renin-angiotensin- system. This study attempted to provide insight into this mechanism by examining the antihypertensive and renoprotective effects of aliskiren in hypertensive chronic kidney disease (CKD) patients.. After recruitment, 43 hypertensive CKD patients (mean age, 53.7 years) began treatment of aliskiren. The patients were classified into high (over 30 mL/min/1.73 m(2)) estimated glomerular filtration rate (eGFR) group or low (under 30 mL/min/1.73 m(2)) eGFR group for comparison of measurements of various parameters over the 6-month observation period.. Systolic blood pressure/diastolic blood pressure of 150 mg/day group decreased to an average of 126.8 ± 21.6 mmHg/69.3 ± 15.1 mmHg (average decrease: -7.4/-8.3 mmHg) over the 6-month observation period, while that of 300 mg/day group significantly decreased to an average of 133.5 ± 14.0 mmHg/71.5 ± 11.7 mmHg (average decrease: -21.1/-14.6 mmHg). Urinary protein of all patients decreased slightly and insignificantly to 1.1 ± 1.7 g/gCr from 1.4 ± 2.5 g/gCr. The serum creatinine (Cr) level of all patients decreased from 1.81 ± 1.10 mg/dL to 1.78 ± 0.82 mg/dL. Although the serum Cr level of the high eGFR group decreased from 1.28 ± 0.45 mg/dL to 1.27 ± 0.57 mg/dL, that of the low eGFR group slightly but insignificantly increased from 2.49 ± 0.64 mg/dL to 2.69 ± 1.11 mg/dL.. Administration of aliskiren exerts an antihypertensive effect on hypertensive CKD patients that may lead to a decrease in urinary protein and an improvement in renal functioning.

Topics: Aged; Amides; Blood Pressure; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Fumarates; Glomerular Filtration Rate; Humans; Hypertension; Japan; Kidney Failure, Chronic; Male; Middle Aged; Prevalence; Renin; Renin-Angiotensin System; Treatment Outcome

This study was performed to determine whether chronic direct renin inhibition can prevent the development of slowly progressive angiotensin (ANG) II-dependent hypertension and the associated derangements in renal function in Cyplal-Ren2 transgenic rats with inducible expression of the Ren2 gene.. Male Cyplal-Ren2 rats (n = 6) were fed a normal diet containing 0.15% indole-3-carbinol (I3C) for 16 days to induce slowly progressive ANG II-dependent hypertension. Conscious systolic blood pressure was measured daily using tail-cuff plethysmography. The rats were then anesthetized with pentobarbital sodium and surgically prepared for the measurement of mean arterial pressure (MAP) and renal hemodynamics and excretory function.. In rats induced with I3C, systolic blood pressure increased by day 3 (130 ± 7-160 ± 5 mm Hg, P < 0.01) and continued to increase to 191 ± 6 mm Hg (P < 0.001) by day 16. In a separate group of rats (n = 6), chronic administration of the direct renin inhibitor, aliskiren (30 mg/kg/d, sc), prevented the development of hypertension (113 ± 5 versus 114 ± 5 mm Hg, not significant). Rats treated with aliskiren exhibited significantly lower mean arterial pressure (138 ± 4 versus 201 ± 6 mm Hg, P < 0.001), renal vascular resistance (23 ± 4 versus 38 ± 3 mm Hg/mL/min · g, P < 0.01), urine flow (17.6 ± 1.4 versus 25.1 ± 2.9 μL/min, P < 0.05) and urinary sodium excretion (1.11 ± 0.32 versus 2.35 ± 0.28 μEq/min, P < 0.05) and higher renal plasma flow (4.22 ± 0.23 versus 2.56 ± 0.21 mL/min · g, P < 0.01) and glomerular filtration rate (1.19 ± 0.07 versus 0.78 ± 0.08 mL/min · g, P< 0.01), compared with induced rats not treated chronically with aliskiren.. The present findings demonstrate that chronic direct renin inhibition with aliskiren prevents the development of ANG II-dependent hypertension and the associated derangements in renal hemodynamics and excretory function in Cyplal-Ren2 transgenic rats.

Topics: Amides; Angiotensin II; Animals; Arterial Pressure; Cytochrome P-450 CYP1A1; Fumarates; Hypertension; Kidney; Male; Rats; Rats, Transgenic; Renin

Central infusion of an angiotensin type 1 (AT(1)) receptor blocker prevents sympathetic hyperactivity and hypertension in Dahl salt-sensitive (S) rats on high salt. In the present study, we examined whether central infusion of a direct renin inhibitor exerts similar effects. Intracerebroventricular infusion of aliskiren at the rate of 0.05 mg/day markedly inhibited the increase in ANG II levels in the cerebrospinal fluid and in blood pressure (BP) caused by intracerebroventricular infusion of rat renin. In Dahl S rats on high salt, intracerebroventricular infusion of aliskiren at 0.05 and 0.25 mg/day for 2 wk similarly decreased resting BP in Dahl S rats on high salt. In other groups of Dahl S rats, high salt intake for 2 wk increased resting BP by ∼25 mmHg, enhanced pressor and sympathoexcitatory responses to air-stress, and desensitized arterial baroreflex function. All of these effects were largely prevented by intracerebroventricular infusion of aliskiren at 0.05 mg/day. Aliskiren had no effects in rats on regular salt. Neither high salt nor aliskiren affected hypothalamic ANG II content. These results indicate that intracerebroventricular infusions of aliskiren and an AT(1) receptor blocker are similarly effective in preventing salt-induced sympathetic hyperactivity and hypertension in Dahl S rats, suggesting that renin in the brain plays an essential role in the salt-induced hypertension. The absence of an obvious increase in hypothalamic ANG II by high salt, or decrease in ANG II by aliskiren, suggests that tissue levels do not reflect renin-dependent ANG II production in sympathoexcitatory angiotensinergic neurons.

Topics: Amides; Angiotensin II; Animals; Baroreflex; Blood Pressure; Fumarates; Heart Rate; Hyperkinesis; Hypertension; Infusions, Intraventricular; Male; Rats; Rats, Inbred Dahl; Rats, Wistar; Renin; Sodium Chloride, Dietary; Sympathetic Nervous System

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Early Termination of Clinical Trials; Fumarates; Humans; Randomized Controlled Trials as Topic; Renal Insufficiency

Topics: Adipose Tissue; Amides; Antihypertensive Agents; Female; Fumarates; Humans; Hypertension; Male; Muscle, Skeletal; Renin-Angiotensin System

Increasing evidence indicates that locally blocking renin-angiotensin system activity exerts a beneficial effect on glomerulonephritis (GN) progression leading to irreversible glomerulosclerosis. This is the first study on the pharmacological effect of the renal delivery of aliskiren, a direct renin inhibitor, in a progressive model of anti-Thy-1 GN.. Local blockade of renin activity was accomplished by subrenal capsular implantation of a collagen sponge with aliskiren. The pharmacological effect was evaluated by semiquantitative and quantitative analysis of immunohistological findings and by analysis of glomerular microcirculation using an intravital microscope system.. Quantitative mesangial matrix analysis showed that local treatment with aliskiren significantly suppressed mesangial matrix expansion and ameliorated the glomerular sclerotic index in the progressive model of ATS GN. Immunofluorescent studies revealed that renin expression at the juxtaglomerular region was enhanced in the ATS + aliskiren group, and pathological expressions of α-smooth muscle cell actin and type I collagen in ATS GN were remarkably decreased by local treatment with aliskiren. Furthermore, local delivery of aliskiren significantly improved glomerular blood flow levels.. This study revealed that renally delivered aliskiren has a renoprotective effect on potentially progressive glomerulosclerosis.

Topics: Actins; Amides; Animals; Antibodies, Monoclonal; Collagen Type I; Disease Models, Animal; Disease Progression; Fumarates; Glomerulonephritis; Infusion Pumps, Implantable; Injections, Intravenous; Kidney; Male; Mesangial Cells; Pilot Projects; Rats; Rats, Wistar; Renin

The present study aims to investigate the combined and individual treatment of aliskiren and olmesartan for 8 weeks in streptozotocin induced diabetic rats provide an effective blockade of RAAS by improving glucose homeostasis, glomerular filtration rate along with renal variables thereby delaying the progression of the disease. Streptozotocin induced diabetic rats were administered with aliskiren (10mg/kg/day), olmesartan (6mg/kg/day) alone and in combination. To identify the glucose homeostasis, translocation of glucose transporter proteins in liver and muscle was observed by their expression after treatment. Glomerular filtration rate is estimated using serum creatinine, cystatin C and beta 2 microglobulin. This study also examined the effects of combination and monotherapy on various renal variables viz. albumin, total proteins, TGF-β, TNF-α, VEGF, nitric oxide, adiponectin and erythropoeitin. In addition, histopathological and anti-apoptotic profile of kidney was also investigated. The present study indicates that dual blockade of RAAS improved glucose homeostasis and confirms the nephroprotective effects of the combined treatment of aliskiren and olmesartan independent of their antihypertensive property in the STZ induced diabetes. In addition, its antifibrotic, antiproteinuric effects indicate that combination treatment might be potential as an important therapeutic option for chronic fibrotic diseases in renal complications.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Blood Glucose; Diabetes Mellitus, Experimental; Drug Therapy, Combination; Fumarates; Glomerular Filtration Rate; Glucose Transporter Type 2; Glucose Transporter Type 4; Humans; Imidazoles; Insulin; Kidney; Liver; Muscle, Skeletal; Rats; Rats, Wistar; Renin-Angiotensin System; Serum Albumin; Tetrazoles; Time Factors

Topics: Adult; Amides; Female; Fumarates; Humans; Juxtaglomerular Apparatus; Kidney Neoplasms; Renin

Chronic activation of the renin-angiotensin-aldosterone system is a major contributing factor to the pathogenesis and progression of cardiovascular and renal diseases.. To evaluate the role of renin-angiotensin-aldosterone system blockade with aliskiren, a direct renin inhibitor, in the development and progression of dilated cardiomyopathy in the Syrian cardiomyopathic hamster (SCH) model, we treated 1-month-old SCH with aliskiren (10 mg·kg·d) over a 4-month period. For comparative purposes, we also evaluated the effects of the angiotensin receptor blocker valsartan (10 mg·kg·d) and the combination of both drugs. Age-matched golden hamsters were used as controls. Left ventricular end-diastolic volume and end-systolic volume, ejection fraction, and diastolic function were determined by echocardiography. Systolic blood pressure (SBP) was also measured in the left femoral artery by sphygmomanometry.. Results indicate that at 2 months of age, SBP is higher in SCH than in controls, and administration for 1 month of aliskiren, valsartan, or the combination of these drugs normalized SBP in SCH to a similar extent. In 5-month-old SCH, aliskiren improved ejection fraction (from 48.6% ± 5.8% to 69.4% ± 3.2%, n = 5, P < 0.05), left ventricular end-systolic volume (from 0.28 ± 0.06 to 0.10 ± 0.01 mL/100 g body weight), left ventricular end-diastolic volume (from 0.61 ± 0.05 to 0.34 ± 0.02 mL/100 g body weight), and normalized diastolic function (E:A ratio increases from 0.93 ± 0.13 to 1.70 ± 0.03, n = 5, P < 0.05). Similar results were observed with valsartan or the combination of aliskiren and valsartan.. Our results indicate that in this animal model, aliskiren is as effective as valsartan, or the combination of both drugs, in improving diastolic function and in preventing the development of dilated cardiomyopathy. These findings suggest that aliskiren may be used as a monotherapy in heart failure management. Clinical studies, however, are needed to assess the effectiveness of this drug in patients with heart failure.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Animals; Blood Pressure; Cardiomyopathy, Dilated; Cricetinae; Disease Models, Animal; Disease Progression; Drug Therapy, Combination; Fumarates; Male; Renin; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan; Ventricular Dysfunction, Left

Topics: Amides; Anti-Arrhythmia Agents; Antihypertensive Agents; Arrhythmias, Cardiac; Fumarates; Humans; Pulmonary Veins

Doxorubicin (DXR) is one of the most effective antineoplastic agents. However, the optimal clinical use of this agent is limited because of marked cardiomyopathy and congestive heart failure. Renin angiotensin system (RAS) plays an important role in the development of cardiac hypertrophy, reperfusion injury and congestive heart failure. Aliskiren (ALK) is a direct inhibitor of renin and does not affect other systems involved in cardiovascular regulation. This study was designed to explore the possible protective effects of ALK (30 and 100 mg/kg, per oral [p.o.] respectively for 42 days) in chronic model of DXR (1.25 mg/kg, intraperitoneally (i.p.) sixteen equal cumulative doses) induced cardiomyopathy in rats. DXR treatment significantly (P<0.01) increased the activities of serum creatine kinase (CK-MB), lactate dehydrogenase (LDH), cardiomyocyte caspase-3 and catalase (CAT). ALK (100 mg/kg) treatment prevented the animals significantly (P<0.01) from rise in the above indices. Furthermore ALK (100 mg/kg) significantly restores the DXR-induced decrease in antioxidant defense, reduced glutathione (GSH) and superoxide dismutase (SOD). Transmission electron microscopic studies showed that DXR caused apoptosis in myocardium, manifested as condensation of chromatin network at the margins and rupture of nuclear membrane which was well protected by ALK (100 mg/kg) treatment. The present study indicates that ALK protected rats from DXR-induced cardiomyopathy.

Topics: Amides; Animals; Antibiotics, Antineoplastic; Antioxidants; Apoptosis; Cardiomyopathies; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Doxorubicin; Fumarates; Microscopy, Electron, Transmission; Myocardium; Oxidative Stress; Rats; Rats, Wistar; Renin; Renin-Angiotensin System

It remains unclear whether angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs) have fully delivered the expected reduction in cardiovascular diseases. We investigated the effects of adding the direct renin inhibitor (DRI), aliskiren, to an ACEI or an ARB on monocyte subsets and myocardial salvage in patients with primary acute myocardial infarction (AMI).. Twenty-one consecutive patients were treated with an ACEI or an ARB (non-DRI group), and another 21 consecutive patients received aliskiren combined with an ACEI or an ARB (DRI group). Two monocyte subsets (CD14(+)CD16(-) and CD14(+)CD16(+)) were measured by flow cytometry. The extent of myocardial salvage 7 days after AMI was evaluated by cardiac magnetic resonance imaging. Both plasma renin activity and aldosterone levels were significantly lower in the DRI group than in the non-DRI group. Peak levels of CD14(+)CD16(-) monocyte number and ratio were also significantly lower in the DRI group. The extent of myocardial salvage was significantly higher in the DRI group than in the non-DRI group (44.8 [41.2-53.1] vs. 36.0 [28.5-42.6], P=0.001).. A DRI combined with an ACEI or an ARB can better improve the extent of myocardial salvage after AMI than an ACEI or an ARB alone in association with the decrease in circulating CD14(+)CD16(-) monocytes.

Topics: Aged; Aldosterone; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Chi-Square Distribution; Drug Therapy, Combination; Female; Flow Cytometry; Fumarates; GPI-Linked Proteins; Humans; Japan; Lipopolysaccharide Receptors; Magnetic Resonance Imaging; Male; Middle Aged; Monocytes; Myocardial Infarction; Myocardium; Prospective Studies; Receptors, IgG; Renin; Renin-Angiotensin System; Time Factors; Treatment Outcome

Enhanced renin-angiotensin-aldosterone system (RAAS) activation contributes to proteinuria and chronic kidney disease by increasing glomerular and tubulointerstitial oxidative stress, promotion of fibrosis. Renin activation is the rate limiting step in angiotensin (Ang II) and aldosterone generation, and recent work suggests direct renin inhibition improves proteinuria comparable to that seen with Ang type 1 receptor (AT(1)R) blockade. This is important as, even with contemporary use of AT(1)R blockade, the burden of kidney disease remains high. Thereby, we sought to determine if combination of direct renin inhibition with AT(1)R blockade in vivo, via greater attenuation of kidney oxidative stress, would attenuate glomerular and proximal tubule injury to a greater extent than either intervention alone. We utilized the transgenic Ren2 rat with increased tissue RAS activity and higher serum levels of aldosterone, which manifests hypertension and proteinuria. Ren2 rats were treated with renin inhibition (aliskiren), AT(1)R blockade (valsartan), the combination (aliskiren+valsartan), or vehicle for 21days. Compared to Sprague-Dawley controls, Ren2 rats displayed increased systolic pressure (SBP), circulating aldosterone, proteinuria and greater urine levels of the proximal tubule protein excretory marker beta-N-acetylglucosaminidase (β-NAG). These functional and biochemical alterations were accompanied by increases in kidney tissue NADPH oxidase subunit Rac1 and 3-nitrotyrosine (3-NT) content as well as fibronectin and collagen type III. These findings occurred in conjunction with reductions in the podocyte-specific protein podocin as well as the proximal tubule-specific megalin. Further, in transgenic animals there was increased tubulointerstitial fibrosis on light microscopy as well as ultrastructural findings of glomerular podocyte foot-process effacement and reduced tubular apical endosomal/lysosomal activity. Combination therapy led to greater reductions in SBP and serum aldosterone, but did not result in greater improvement in markers of glomerular and tubular injury (i.e. β-NAG) compared to either intervention alone. Further, combination therapy did not improve markers of oxidative stress and podocyte and proximal tubule integrity in this transgenic model of RAAS-mediated kidney damage despite greater reductions in serum aldosterone and BP levels.

Topics: Acute Kidney Injury; Aldosterone; Amides; Angiotensin II Type 1 Receptor Blockers; Animals; Fumarates; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Receptor, Angiotensin, Type 1; Renin; Tetrazoles; Valine; Valsartan

Aliskiren combined with other inhibitors of the renin–angiotensin system increases the risk of hyperkalemia. This risk does not translate into an increased incidence of acute kidney injury, suggest the results of a meta-analysis. However, further research is needed to fully evaluate the safety of combination therapy with aliskiren.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Glomerular Filtration Rate; Humans; Hyperkalemia; Renin; Renin-Angiotensin System

A rapid procedure based on direct extraction and HILIC separation of aliskiren (ALI) degradation product - 3-amino-2,2-dimethylpropanamide (ADPA) with fluorescence detection has been developed. The formation of ADPA from ALI under different conditions was studied. The evaluation of HILIC method robustness was performed using multifactorial experiments with fixed factors (one-level Plackett-Burman design). XBridge HILIC column with isocratic elution using mobile phase 10 mM K(2)HPO(4) pH 7.2-acetonitrile (26:74; v/v) was employed. Fluorescence detection after post column derivatization using o-phthaldialdehyde (OPA) reagent was performed at excitation and emission wavelength of 345 nm and 450 nm, respectively. The reported method has an advantage of a simple sample pre-treatment and quick and very sensitive measurement. The method was successfully applied for the analysis of commercially available ALI samples.

Topics: Amides; Amino Acids; Antihypertensive Agents; Chromatography, Liquid; Fumarates; Mass Spectrometry; o-Phthalaldehyde; Sensitivity and Specificity; Spectrometry, Fluorescence; Time Factors

Drugs acting on the renin angiotensin system (RAS), such as angiotensin converting enzyme (ACE) inhibitors and sartans, have been used for hypertension treatment in the HIV-negative population. These drugs reduce hypertension related cardiovascular diseases such as renal impairment in the general population. Limited data show similar findings also in the HIV-positive population. A new drug called aliskiren has recently become available on the market: it is able to block the RAS by a different mechanism acting as direct renin inhibitor. No data are available about the use of aliskiren in HIV-positive patients.. A 61-year-old HIV-infected Caucasian male (CDC C3) patient with hypertension for ten years and cardiovascular complications took carvedilol 25 mg twice a day, plus daily administration of irbesartan 300 mg, hydroclorotiazide 25 mg, doxazosin 4 mg, lacidipine 6 mg, and simvastatin 40 mg. He took AZT+ 3TC + RAL with a good profile on HIV replication and immunological parameters. We found a non-optimal blood pressure value and decided to start aliskiren 150 mg a day to improve blood pressure control. After one month blood pressure control and proteinuria improved. In our case the use of low doses of aliskiren appeared to improve the level of blood pressure, although five antihypertensive agents had already been used on the patient. Finally, although aliskiren would appear to have no direct effect on viro-immunological parameters and does not seem to interfere with cART, further studies are warranted in this context.

Topics: Amides; Antihypertensive Agents; Fumarates; HIV Seropositivity; Humans; Hypertension; Male; Middle Aged; Renin; Renin-Angiotensin System; Treatment Outcome

This pooled analysis of ambulatory blood pressure (BP) monitoring data from two 8-week randomized controlled trials compared the antihypertensive efficacy and safety of combination aliskiren/valsartan vs valsartan alone in hypertensive patients (nocturnal dippers or nondippers). At study end, patients were taking aliskiren/valsartan 300/320 mg or valsartan 320 mg. In dippers (n=138) and nondippers (n=132), aliskiren/valsartan provided significantly (P<.05) greater reductions from baseline to week 8 than valsartan in 24-hour, daytime, and last-4-hour mean ambulatory systolic BP (maSBP). Treatment differences were more pronounced in nondippers. Nighttime maSBP reductions with aliskiren/valsartan were significantly greater vs valsartan in nondippers (-17.0 mm Hg vs -8.9 mm Hg; P<.05) but not dippers (-7.6 mm Hg vs -4.5 mm Hg; P=.16). In all time periods, combination therapy was generally associated with BP reductions that were greater in nondippers than dippers. Conversion from nondipper to dipper status was 32% vs 22% for aliskiren/valsartan vs valsartan (P=.48). Both treatments were similarly well tolerated. Although the addition of aliskiren to valsartan did not significantly alter dipper status, our data suggest an increased contribution of the renin-angiotensin-aldosterone system to the nondipper status of hypertensive patients.

Topics: Adult; Aged; Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Circadian Rhythm; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Tetrazoles; Treatment Outcome; Valine; Valsartan

Failure to intensify therapy when indicated is a serious problem in the management of hypertension. Patients having an antihypertensive prescription rejected because of utilization management tools may be at a high risk of failing to intensify their therapy when it is warranted.. The goal of this study was to investigate the patterns of therapy change after rejected aliskiren claims because of utilization management tools such as prior authorization, step therapy, and restrictive formulary.. A retrospective study was conducted using data from a large national pharmacy benefits manager. Patients with a rejected aliskiren claim because of utilization management and who were naive to aliskiren treatment before having a rejected aliskiren claim were included. Patients were followed up for 6 months after the initial rejected aliskiren claim to see whether there was a therapy change. Therapy change was defined as titration of old regimens, fulfillment of aliskiren, or fulfillment of a new antihypertensive medication not used previously.. A total of 1955 patients were identified (mean age, 64.5 years; 54.4% female). Six months after having rejected aliskiren claims, 36.8% overcame the utilization management and filled aliskiren; 45.1% filled a new antihypertensive medication not used previously; and 10.8% patients titrated old antihypertensive medications. More than one quarter of patients (28.4%) had no change in their antihypertensive treatment. Logistic regression analysis revealed that patients rejected because of prior authorization (odds ratio = 4.00 [95% CI, 1.89-8.44]) or step therapy (odds ratio = 2.59 [95% CI, 1.26-5.32]) were more likely to have a therapy change compared with patients rejected because of a restrictive formulary.. A significant number of patients had no therapy change 6 months after having rejected aliskiren claims because of utilization management tools, indicating potential clinical inertia or lack of therapy intensification in hypertension management. Patients with restrictive formularies were least likely to have a therapy change. More aggressive follow-up with patients with a rejected claim may be warranted to reduce treatment gaps.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amides; Antihypertensive Agents; Female; Follow-Up Studies; Formularies as Topic; Fumarates; Humans; Hypertension; Insurance, Pharmaceutical Services; Logistic Models; Male; Middle Aged; Practice Patterns, Physicians'; Retrospective Studies; Young Adult

The benefits of long-term peritoneal dialysis (PD) in patients with end-stage renal failure are short-lived due to structural and functional changes in the peritoneal membrane. In this report, we provide evidence for the in vitro and in vivo participation of the renin-angiotensin-aldosterone system (RAAS) in the signaling pathway leading to peritoneal fibrosis during PD. Exposure to high-glucose PD fluids (PDFs) increases damage and fibrosis markers in both isolated rat peritoneal mesothelial cells and in the peritoneum of rats after chronic dialysis. In both cases, the addition of the RAAS inhibitor aliskiren markedly improved damage and fibrosis markers, and prevented functional modifications in the peritoneal transport, as measured by the peritoneal equilibrium test. These data suggest that inhibition of the RAAS may be a novel way to improve the efficacy of PD by preventing inflammation and fibrosis following peritoneal exposure to high-glucose PDFs.

Topics: Amides; Animals; Biological Transport; Biomarkers; Cytoprotection; Dose-Response Relationship, Drug; Epithelial Cells; Fibrosis; Fumarates; Glucose; Inflammation; Male; Peritoneal Dialysis; Peritoneum; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Time Factors

Diabetic nephropathy (DN) is a leading disease that requires renal replacement therapy. The progression of renal dysfunction in DN is faster than the other renal diseases. While antihypertensive therapy reduces albuminuria, a good indicator for the progression, hypertension in DN is treatment resistant. Among patients with DN who took angiotensin receptor blockers (ARBs), 27 patients who exhibited poor control of albuminuria were enrolled into the study. Angiotensin receptor blocker was exchanged to aliskiren (150-300 mg/d) and clinical parameters were followed for 6 months. Exchange to aliskiren decreased albuminuria (1.57 ± 0.68 to 0.89 ± 0.45 g/gCr, P < .01) without changes in estimated glomerular filtration rate and office blood pressure (BP). Body weight and hemoglobin A1c were not altered. Aliskiren also reduced plasma renin activity (2.0 ± 0.9 to 1.2 ± 0.6 ng/mL/h, P < .01). While evening BP was unchanged, morning systolic BP (139 ± 8 to 132 ± 7 mm Hg, P < .01) and diastolic BP (81 ± 7 to 76 ± 6 mm Hg, P < .05) were decreased significantly after 6 months. Our results indicated that aliskiren decreased BP, especially morning BP in hypertensive patients with DN. The present data suggest that aliskiren exerts renoprotective actions including reduction in albumin excretion for patients with DN.

Topics: Aged; Albuminuria; Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Blood Pressure; Circadian Rhythm; Diabetic Nephropathies; Disease Progression; Female; Fumarates; Glomerular Filtration Rate; Humans; Male; Middle Aged; Prospective Studies; Renin

Aliskiren is the first in a new class of orally active direct renin inhibitors, approved for the treatment of hypertension. However, the efficacy of aliskiren in diabetic cardiovascular complications remains to be defined. This study aimed to test the hypothesis that aliskiren may enhance the beneficial effects of pioglitazone against cardiovascular injury associated with diabetic nephropathy.. Diabetic nephropathy was induced in rats by unilateral nephrectomy followed by streptozotocin injection. Diabetic nephropathic rats were orally given vehicle, pioglitazone, aliskiren, or combined pioglitazone and aliskiren for four weeks to compare their effects on cardiovascular injury, particularly myocardial fibrosis.. Pioglitazone treatment significantly attenuated cardiac lipid peroxidation, oxidative injury and myocardial fibrosis in diabetic nephropathic rats. This was associated with up-regulation of transforming growth factor-β1 and matrix metalloproteinase-2 genes, along with down-regulation of tissue inhibitor of metalloproteinase-2 gene in cardiac tissue. The combination of aliskiren with pioglitazone exerted greater beneficial effect than monotherapy with either drug, on all the aforementioned parameters.. Our findings suggested that aliskiren enhanced the protective effects of pioglitazone against myocardial fibrosis, in experimental diabetic nephropathy. Thus, the combination of aliskiren and pioglitazone may be a potential therapeutic strategy for cardiovascular injury associated with diabetic nephropathy.

Topics: Amides; Animals; Antihypertensive Agents; Cardiomyopathies; Diabetic Nephropathies; Disease Models, Animal; Drug Therapy, Combination; Fibrosis; Fumarates; Gene Expression Regulation; Hypoglycemic Agents; Lipid Peroxidation; Male; Matrix Metalloproteinase 2; Myocardium; Nephrectomy; Oxidative Stress; Pioglitazone; Rats; Rats, Wistar; Streptozocin; Thiazolidinediones; Tissue Inhibitor of Metalloproteinase-2; Transforming Growth Factor beta1

Activity of renin substrate cleavage (renin-like activity) was measured in vitro in plasma samples obtained from healthy human volunteers.. Renin-like activity was determined using FRET (Fluorescence Resonance Energy Transfer) human renin substrate. Recombinant human renin and human plasma showed dose-dependent cleavage activity of FRET human renin substrate.. Activity of recombinant human renin was completely inhibited by either a peptidergic or a non-peptidergic renin inhibitor. However, renin-like activity in human plasma was not inhibited by these renin inhibitors. In a mixture of recombinant renin and human plasma, renin inhibitors inhibited only that part of the activity caused by recombinant renin, while the activity in plasma still remained. Human plasma did not show cleavage activity of rat FRET renin substrate. Native human prorenin showed cleavage activity of human renin substrate. This activety was also completely inhibited by renin inhibitors. Immunoprecipitation with anti-renin or anti-prorenin antibodies did not reduce the activity in human plasma. Renin-like activity in human plasma was abolished by degeneration of protein when sample was heated to 95 degrees C. Activity of both recombinant renin and human plasma was significantly inhibited by a protease inhibitor cocktail.. These results suggest that the activity of renin substrate cleavage in human plasma is not mainly caused by the renin or prorenin molecule, but probably by other proteases.

Topics: Adult; Amides; Angiotensinogen; Animals; Enzyme Precursors; Fumarates; Humans; Middle Aged; Oligopeptides; Protease Inhibitors; Rats; Recombinant Proteins; Renin; Young Adult

Renin has recently attracted much attention in the antihypertensive community, since this enzyme starts the angiotensin-converting cascade and forms the rate-limiting step in this cascade. In the present study, we describe a new method called active-site spatial partitioning (ASSP) for quantitatively characterizing the nonbonding interaction profile between renin and the substructures of indole-3-carboxamide derivatives-a novel class of achiral renin inhibitors that exhibit both high affinity and strong specificity for renin, thus blocking its active state-on the basis of structural models of protein-ligand complexes. It is shown that the ASSP-derived potential parameters are highly correlated with the experimentally measured activities of indole-3-carboxamides; the statistical models linking the parameters and activities using a sophisticated partial least squares regression technique show much promise as an effective and powerful tool for generalizing and predicting the pharmaceutical potencies and the physicochemical properties of other modified derivatives. Furthermore, by visually examining substructure-color plots generated by the ASSP procedure, it is found that the relative importance of nonbonding contributions to the recognition and binding of a ligand by renin is as follows: steric < hydrophobic < electrostatic. The polar and charged moieties that float on the surface of the ligand molecule play a critical role in conferring electrostatic stability and specificity to renin-ligand complexes, whereas the aromatic rings embedded in the core region of the ligand are the main source of hydrophobic and steric potentials that lead to substantial stabilization of the complex architecture.

Topics: Amides; Catalytic Domain; Fumarates; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Indoles; Inhibitory Concentration 50; Least-Squares Analysis; Ligands; Models, Molecular; Protein Structure, Secondary; Renin; Static Electricity

Accumulation of amyloid β-peptide (Aβ) in senile plaques, a pathological hallmark of Alzheimer's disease (AD), has been implicated in neuronal degeneration. Renin-angiotensin system (RAS) blockers, including the renin inhibitor aliskiren, are a group of clinically relevant anti-hypertensive agents. The present study was initiated to investigate whether aliskiren may modulate Aβ neurotoxicity as an additional function aside from its established property of lowering blood pressure. We found aliskiren conferred neuronal resistance to Aβ toxicity in primary rat cortical cultures. Moreover, both Aβ25-35 and Aβ1-42 induced renin expression in cortical neurons; in parallel, a heightened expression of renin was detected in the cerebral cortices of 9-month-old AD transgenic mice. Notably, aliskiren blocked Aβ-mediated neuronal induction of renin. We therefore concluded that aliskiren may carry neuroprotective action against Aβ toxicity. Furthermore, the aliskiren effects may involve downregulation of renin expression induced by Aβ.

Topics: Amides; Amyloid beta-Peptides; Animals; Blotting, Western; Cerebral Cortex; Fumarates; Immunohistochemistry; Mice; Mice, Transgenic; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Renin

In addition to hypertension control, direct renin inhibition has been shown to exert direct beneficial effects on the heart in post-infarction cardiac remodeling. This study elucidates the possible contribution of mitochondria to the anti-hypertrophic effects of the direct renin inhibitor aliskiren in post-infarction heart failure complicated with diabetes in rats.. Diabetes was induced in male Sprague-Dawley rats by a single injection of streptozotocin (IP, 65 mg/kg body weight). After 7 days, the animals were randomly assigned to 4 groups: sham, heart failure, sham+aliskiren, and heart failure+aliskiren. Post-infarction HF was induced by coronary artery ligation for 4 weeks.. showed that heart failure reduced ejection fraction and cardiac output by 41% (P<0.01) and 42% (P<0.05), respectively, compared to sham-operated hearts. Cardiac dysfunction was associated with suppressed state 3 respiration rates and respiratory control index in mitochondria, and increased mitochondrial permeability transition pore (PTP) opening. In addition, heart failure reduced expression of the major mitochondrial sirtuin, SIRT3 and increased acetylation of cyclophilin D, a regulatory component of the PTP. Aliskiren significantly improved cardiac function and abrogated mitochondrial perturbations.. Our results demonstrate that aliskiren attenuates post-infarction remodeling which is associated with its beneficial effects on mitochondria.

Topics: Amides; Animals; Blotting, Western; Diabetes Mellitus, Experimental; Echocardiography; Electrophoresis, Polyacrylamide Gel; Fumarates; Heart Failure; Male; Mitochondria, Heart; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Renin; Reverse Transcriptase Polymerase Chain Reaction

Although vitamin D has been implicated in cardiovascular protection, few studies have addressed the role of vitamin D receptor (VDR) in atherosclerosis. Here we investigate the effect of inactivation of the VDR signaling on atherogenesis and the antiatherosclerotic mechanism of vitamin D. Low density lipoprotein receptor (LDLR)(-/-)/VDR(-/-) mice exhibited site-specific accelerated atherogenesis, accompanied by increases in adhesion molecules and proinflammatory cytokines in the aorta and cholesterol influx in macrophages. Macrophages showed marked renin up-regulation in the absence of VDR, and inhibition of renin by aliskiren reduced atherosclerosis in LDLR(-/-)/VDR(-/-) mice, suggesting that the renin-angiotensin system (RAS) promotes atherosclerosis in the absence of VDR. LDLR(-/-) mice receiving LDLR(-/-)/VDR(-/-) BMT developed larger lesions than LDLR(-/-) BMT controls. Moreover, LDLR(-/-) mice receiving Rag-1(-/-)/VDR(-/-) BMT, which were unable to generate functional T and B lymphocytes, still had more severe atherosclerosis than Rag-1(-/-) BMT controls, suggesting a critical role of macrophage VDR signaling in atherosclerotic suppression. Aliskiren treatment eliminated the difference in lesions between Rag-1(-/-)/VDR(-/-) BMT and Rag-1(-/-) BMT recipients, indicating that local RAS activation in macrophages contributes to the enhanced atherogenesis seen in Rag-1(-/-)/VDR(-/-) BMT mice. Taken together, these observations provide evidence that macrophage VDR signaling, in part by suppressing the local RAS, inhibits atherosclerosis in mice.

Topics: Amides; Animals; Antihypertensive Agents; Aorta; Atherosclerosis; B-Lymphocytes; Bone Marrow Cells; Cell Adhesion Molecules; Cholesterol; Fumarates; Homeodomain Proteins; Lipids; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Calcitriol; Receptors, LDL; Renin; Renin-Angiotensin System; Signal Transduction; T-Lymphocytes; Up-Regulation

The objective of our study was to investigate the effect of Aliskiren, a renin inhibitor, on the deoxycorticosterone (DOCA) induced myocardial fibrosis in a rat model and its underlying mechanism. A total of 45 Sprague-Dawley (SD) rats underwent right nephrectomy and were randomly assigned into 3 groups: control group (CON group: silicone tube was embedded subcutaneously); DOCA treated group (DOC group: 200 mg of DOCA was subcutaneously administered); DOCA and Aliskiren (ALI) treated group (ALI group: 200 mg of DOCA and 50 mg/kg/d ALI were subcutaneously and intragastrically given, respectively). Treatment was done for 4 weeks. Sirius red staining was employed to detect the expression of myocardial collagen, and the myocardial collagen volume fraction (CVF) and perivascular collagen volume area (PVCA) were calculated. Radioimmunoassay was carried out to measure the renin activity (RA) and content of angiotensin II (Ang II) in the plasma and ventricle. Western blot assay was done to detect the expressions of extracellular signal-regulated kinase 1/2 (ERK1/2), phosphorylated ERK1/2 (PERK1/2) and matrix metalloproteinase 9 (MMP-9). In the DOC group and ALI group, the CVF and PVCA were significantly increased; the RA and Ang II levels in the plasma and ventricle were remarkably lowered when compared with the CON group. The RA and Ang II levels in the ventricle of the ALI group were significantly lower than those in the DOC group. Moreover, the expressions of ERK1/2, PERK1/2 and MMP9 were the lowest in the CON group, but those in the ALI group were significantly reduced as compared to the DOC group. ALI can inhibit the DOCA induced myocardial fibrosis independent of its pressure-lowing effect, which may be related to the suppression of RA and Ang II production, inhibition of ERK1/2 phosphorylation and MMP9 expression in the heart.

Topics: Amides; Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Blotting, Western; Cardiomyopathies; Cardiotonic Agents; Collagen; Desoxycorticosterone; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Fumarates; Heart Ventricles; Indicators and Reagents; Male; Matrix Metalloproteinase 9; Myocardium; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Renin

We hypothesized that aliskiren provides renoprotection in diabetic animals that did not receive sufficient renoprotection by AT1-receptor antagonist treatment. Type 2 diabetic KKAy mice were treated with group 1: vehicle or group 2: valsartan (15 mg/kg per day) from 12 to 16 weeks of age. The mice were subsequently divided into 4 groups and treated with the following combinations of drugs for another 6 weeks: 1: group 1 kept receiving vehicle, 2: group 2 continuously received 15 mg/kg per day of valsartan (Val-Val15), 3: group 2 received 50 mg/kg per day of valsartan (Val-Val50), 4: group 2 continuously received 15 mg/kg per day of valsartan with 25 mg/kg per day of aliskiren (Val-Val+Ali). Aliskiren exerted significant anti-albuminuric effects, whereas valsartan failed to ameliorate the albuminuria in the first four weeks. Surprisingly, the increasing dosage of valsartan in the Val-Val50 group showed non-significant tendencies to attenuate the albuminuria compared with vehicle infusion. Val-Val+Ali significantly suppressed the development of albuminuria and podocyte injury. Val-Val50 and Val-Val+Ali showed similar suppression of angiotensin II contents in the kidney of KKAy mice. In conclusion, the anti-albuminuric effect that was observed in the type 2 diabetic mice showing no anti-albuminuric effect by valsartan can be attributed to the add-on aliskiren.

Topics: Albuminuria; Amides; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Fumarates; Kidney; Male; Mice; Mice, Inbred C57BL; Renin; RNA, Messenger; Tetrazoles; Valine; Valsartan

Renal vasoconstriction, activated by the renin-angiotensin system, plays a pivotal role in the pathogenesis of contrast-induced nephropathy (CIN). The purpose of this study was to evaluate the effect of aliskiren, a direct renin inhibitor, for the prophylaxis of experimental CIN in the rat.. Thirty-two Wistar albino rats were divided into four groups of 8 rats each, namely the control (C), aliskiren (A), contrast media (CM) and aliskiren plus contrast media (ACM) groups. Aliskiren was given orally at a dose of 50 mg/kg/day once daily for 5 consecutive days. CIN was induced by intravenous administration of indomethacin, N-nitro-L-arginine methyl ester and high-osmolar contrast medium meglumine amidotrizoate. Renal function parameters, kidney histology and tubular expression of vascular endothelial growth factor were determined.. Mean serum creatinine was significantly lower (p < 0.001) and mean creatinine clearance was higher (p < 0.001) in the ACM group compared with the CM group. However, there were no differences between the ACM and CM groups in terms of tubular necrosis, proteinaceous casts, medullary congestion and vascular endothelial growth factor expression.. Our preliminary data seem to suggest a potential role of aliskiren for the prophylaxis of CIN in an experimental rat model.

Topics: Amides; Animals; Contrast Media; Fumarates; Kidney Diseases; Male; Random Allocation; Rats; Rats, Wistar; Renin; Treatment Outcome

In the present study, we evaluated the effect of inhibition of renin activity (aliskiren) on the progression of renal lesions in two different mouse models (Vpr and Tg26) of human immunodeficiency virus (HIV)-associated nephropathy (HIVAN). In protocol A, Vpr mice were fed either water (C-VprA) or doxycycline [Doxy (D-VprA)] in their drinking water for 6 wk. In protocols B and C, Vpr mice received either normal saline (C-VprB/C), Doxy + normal saline (D-VprB/C), or Doxy + aliskiren (AD-VprB/C) for 6 wk (protocol B) or 12 wk (protocol C). In protocols D and E, Vpr mice were fed Doxy for 6 wk followed by kidney biopsy. Subsequently, half of the mice were administered either normal saline (D-VprD/E) or aliskiren (AD-VprD/E) for 4 wk (protocol D) or 8 (protocol E) wk. All D-VprA mice showed renal lesions in the form of focal segmental glomerular sclerosis and dilatation of tubules. In protocols B and C, aliskiren diminished both progression of renal lesions and proteinuria. In protocol C, aliskiren also diminished (P < 0.01) the rise in blood urea. In all groups, Doxy-treated mice displayed increased serum ANG I levels (the product of plasma renin activity); on the other hand, all aliskiren-treated mice displayed diminished serum ANG I levels. Renal tissues of D-VprC displayed increased ANG II content; however, aliskiren attenuated renal tissue ANG II production in AD-VprC. In protocol D, AD-VprD showed a 24.2% increase in the number of sclerosed glomeruli compared with 139.2% increase in sclerosed glomeruli in D-VprD (P < 0.01) from their baseline. The attenuating effect of aliskiren on the progression of renal lesions continued in AD-VprE. Aliskiren also diminished blood pressure, proteinuria, and progression of renal lesions in Tg26 mice. These findings indicate that inhibition of renin activity has a potential to slow down the progression of HIVAN.

Topics: AIDS-Associated Nephropathy; Amides; Animals; Biopsy; Disease Progression; Doxycycline; Fumarates; Glomerulosclerosis, Focal Segmental; Kidney; Mice; Mice, Transgenic; Renin; Renin-Angiotensin System

High-performance liquid chromatography enantioseparation of aliskiren hemifumarate was accomplished on an immobilized-type Chiralpak IC chiral stationary phase under both polar organic and reversed-phase modes. A simple analytical method was developed and validated using a mixture of acetonitrile-n-butylamine 100:0.1 (v/v/) as a mobile phase with a flow rate maintained at 1.0 mL/min. Ultraviolet detection was carried out at 228 nm. Resolution between the two enantiomers was greater than 3.0. This method was capable of detecting the R-isomer to a level of 0.2 μg/mL. The method was validated as per International Conference on Harmonization guidelines and found to be robust. The method is very useful for routine evaluation of the quality of aliskiren hemifumarate in bulk drug manufacturing units.

Topics: Amides; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Drug Contamination; Fumarates; Limit of Detection; Reproducibility of Results; Spectrophotometry, Ultraviolet; Stereoisomerism

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Female; Fumarates; Humans; Male; Monocytes; Myocardial Infarction; Myocardium; Renin; Renin-Angiotensin System

The use of nanotechnology in medicine and more specifically in drug delivery systems is set to spread rapidly. In order to broaden the range of matrices and implicitly to develop the class of drug delivery systems based on diffusion mechanism, in this study the starting materials, SBA-15 powder matrices, were engineered by MgO modification for antihypertensive drugs intercalation. Captopril and aliskiren were used as drug models. All powders, unmodified and MgO-modified silica matrices, and their corresponding drug-loaded samples were characterized by X-ray diffraction, N(2) adsorption and desorption, FTIR spectroscopy and scanning electron microscopy. The studied drug carriers were tested in the controlled drug release process and the influence of the silica pore morphology and geometry on drug release profiles was extensively studied. In order to analyze the data obtained from the in vitro release studies and to evaluate the kinetic release mechanism, the Korsmeyer and Peppas equation was used. The obtained drug delivery system based on MgO-SBA-15 matrix exhibits exciting structural features and is therefore promising for its use as antihypertensive drug delivery system, having potential therapeutic benefits resulting in safe and effective management of captopril and aliskiren adsorption and in vitro release.

Topics: Amides; Antihypertensive Agents; Captopril; Delayed-Action Preparations; Drug Carriers; Fumarates; Magnesium Oxide; Nanoparticles; Silicon Dioxide; Spectroscopy, Fourier Transform Infrared; Surface Properties; X-Ray Diffraction

Most hypertensive dialysis patients are currently treated with angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB). Aliskiren, the direct renin inhibitor, has not been specifically studied in peritoneal dialysis patients. The aim of the study was to compare hypotensive effects of aliskiren and ramipril and their influence on serum potassium and inflammatory parameters in hypertensive peritoneal dialysis patients. Eighteen hypertensive patients on chronic peritoneal dialysis were enrolled in an open-label comparative fixed-order study. The patients had been off RAAS blocking drugs for ≥4 weeks prior to an inclusion. At each of 3 study visits (baseline and after each of the treatment periods) blood pressure, serum lipids, potassium, renin, aldosterone, C-reactive protein (CRP) and monocyte chemotactic protein-1 (MCP-1) were measured. After the baseline visit aliskiren was started (150 mg/d) and after 12 weeks replaced with ramipril (5 mg/d) for the next 12 weeks. Blood pressure was 142/88±15/11 mmHg at baseline, 137/84±10/8 mmHg after aliskiren (ns) and 126/81±11/7 mmHg after ramipril (p<0.05 vs baseline and aliskiren). No incidents of hyperkalemia were observed. Plasma renin concentration increased significantly during aliskiren treatment compared to ramipril (227,6±844 vs. 58,3±765 pg/mL). CRP was similar after both therapies (8,8±34 vs. 8,4±32 µg/mL) but MCP-1 concentration was significantly lower after aliskiren than after ramipril (294,0±172,6 vs. 358,9±183,3 pg/mL). Aliskiren 150 mg/day decreases blood pressure less effectively than ramipril 5 mg/day in peritoneal dialysis patients. It does not influence serum potassium. The decrease of MCP-1 concentration after aliskiren treatment may provide an indirect evidence for its blood pressure independent cardioprotective and anti-inflammatory effects.

Topics: Adult; Aged; Amides; Anti-Inflammatory Agents; Antihypertensive Agents; Blood Pressure; C-Reactive Protein; Chemokine CCL2; Combined Modality Therapy; Comorbidity; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Peritoneal Dialysis; Pilot Projects; Potassium; Ramipril; Renal Insufficiency, Chronic; Renin; Treatment Outcome

The role of the renin-angiotensin system in chronic kidney disease involves multiple peptides and receptors. Exerting antipodal pathophysiological mechanisms, renin inhibition and AT(1) antagonism ameliorate renal damage. However, it is unclear which mechanism exerts better nephroprotection. We compared the renin inhibitor aliskiren with the AT(1) antagonist losartan in mice with chronic kidney disease due to renal ablation. Doses were adjusted to equipotent inhibition of the renin-angiotensin system, determined via a dose-response quantifying plasma and renal renin expression. Six-week treatment with either 500 mg/l drinking water losartan or 50 mg·kg(-1)·day(-1) aliskiren significantly decreased albuminuria, glomerular damage, and transcription rates of renal injury markers to a similar extent. An array analysis comparing renal gene expression of losartan- and aliskiren-treated mice evaluating >34,000 transcripts demonstrated regulation for 14 genes only, with small differences. No superior nephroprotection was found by combining losartan and aliskiren. Compared with plasma concentrations, aliskiren accumulated ∼7- to 29-fold in the heart, liver, lung, and spleen and ∼156-fold in the kidney. After withdrawal, plasma concentrations dropped to zero within 24 h, whereas renal tissue concentrations declined slowly over days. Withdrawal of aliskiren in mice with chronic kidney disease revealed a significantly delayed re-increase in albuminuria compared with withdrawal of losartan. This study demonstrates equieffective nephroprotection of renin inhibition and AT(1) antagonism in mice with chronic kidney disease without additional benefit of combination therapy. These observations underscore the pivotal role of targeting ANG II to reduce renal injury.

Topics: Albuminuria; Amides; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Blood Pressure; Dose-Response Relationship, Drug; Fumarates; Gene Expression; Kidney; Losartan; Male; Mice; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Treatment Outcome

Heart failure with preserved systolic function (HFPSF) has attained epidemic proportions; however evidence-based therapeutic interventions have not advanced despite continued research over the past three decades. We propose the combined use of direct renin inhibitor and carvedilol for this condition.. The Renin Angiotensin Aldosterone System (RAAS) plays a central role in myocyte hypertrophy, fibrosis and ventricular remodeling which is responsible for the diastolic dysfunction in HFPSF. Rising serum aldosterone levels with age have been implicated as a cause of myocardial fibrosis in the elderly. The sole use of Angiotensin Converting Enzyme Inhibitors or Angiotensin Receptor Blockers is associated with angiotensin-II and aldosterone escape and increased plasma renin activity. Carvedilol is a novel third generation non-selective β-blocker. The use of combination therapy will facilitate in better blood pressure control, reduce afterload, improve ventricular relaxation, cause regression of ventricular remodeling/fibrosis, maintain atrioventricular synchrony and enhance cardio-metabolic profile. The individual benefits of direct renin inhibitor and carvedilol could plausibly have a supra-additive effect when used in combination. Besides this, carvedilol can further reduce generation of free radicals, decrease LDL oxidation, improve Doppler echo diastolic parameters and decrease cardiac norepinephrine and density of cardiac β-receptors.. Evidence suggests that patients with HFPSF are treated less aggressively as compared to patients with heart failure with systolic dysfunction. Aggressive therapy with concurrent use of direct renin inhibitor and carvedilol will help in improving outcomes in this vulnerable patient sub-population. No prior trial has evaluated the combined use of these drugs for the treatment of HFPSF.

Topics: Adrenergic beta-Antagonists; Amides; Carbazoles; Carvedilol; Fumarates; Heart Failure; Humans; Propanolamines; Protease Inhibitors; Renin; Renin-Angiotensin System; Systole

Diabetes is associated with renin-angiotensin system (RAS) activation, leading to renal and systemic vascular dysfunction that contribute to end-organ injury and significant morbidity. RAS blockade with ACE inhibitors reduces, but does not abolish, RAS effects. Accordingly, our aim was to determine if direct renin inhibition alone, and in combination with an ACE inhibitor, corrects early hemodynamic abnormalities associated with type 1 diabetes.. Arterial stiffness (augmentation index), flow-mediated vasodilatation (FMD), and renal hemodynamic function (inulin and paraaminohippurate clearance) were measured at baseline under clamped euglycemic and hyperglycemic conditions (n = 21). Measures were repeated after 4 weeks of aliskiren therapy and again after aliskiren plus ramipril.. Blood pressure-lowering effects of aliskiren were similar during clamped euglycemia and hyperglycemia. Combination therapy augmented this effect under both glycemic conditions (P = 0.0005). Aliskiren reduced arterial stiffness under clamped euglycemic and hyperglycemic conditions, and the effects were augmented by dual RAS blockade (-3.4 ± 11.2 to -8.0 ± 11.5 to -14.3 ± 8.4%, respectively, during euglycemia, P = 0.0001). During clamped euglycemia, aliskiren increased FMD; dual therapy exaggerated this effect (5.1 ± 3.3 to 7.5 ± 3.0 to 10.8 ± 3.5%, repeated-measures ANOVA, P = 0.0001). Aliskiren monotherapy caused renal vasodilatation during clamped hyperglycemia only. In contrast, dual therapy augmented renal vasodilatory effects during clamped euglycemia and hyperglycemia.. In patients with uncomplicated type 1 diabetes, aliskiren-based dual RAS blockade is associated with greater arterial compliance, FMD, and renal vasodilatation.

Topics: Adult; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 1; Female; Fumarates; Humans; Kidney; Male; Renin; Renin-Angiotensin System; Vascular Stiffness; Young Adult

Topics: Amides; Antihypertensive Agents; Fumarates; Humans; Renin

Topics: Amides; Antihypertensive Agents; Fumarates; Humans; Renin

Topics: Amides; Amlodipine; Drug Combinations; Fumarates; Humans; Hypertension

The addition of the direct renin inhibitor aliskiren is demonstrated to improve blood pressure (BP) control rate and reduce progression of organ damage in treated hypertensive patients in clinical trials with a relatively short follow-up period.. The objective of this study was to assess the effectiveness, safety and tolerability of aliskiren as an add-on antihypertensive therapy in high-risk, treated, hypertensive patients, who were not controlled with concomitant treatment with at least two antihypertensive drugs under 'real-life' conditions, during a planned observation and treatment period of at least 12 months in Italy.. Clinical data were derived from medical databases of treated, uncontrolled, hypertensive patients followed by specialized physicians operating in different clinical settings (hospital divisions or outpatient clinics) in Italy. Aliskiren was added to stable antihypertensive treatment, including at least two drug classes (independently of class or dosage) and unable to achieve BP control. Follow-up visits for measuring clinic BP levels and collecting data on drug safety and tolerability were planned at time intervals of 1, 6 and 12 months. At each predefined follow-up visit, aliskiren could be up-titrated from 150 to 300 mg daily if BP control was not achieved.. From May 2009 to June 2011, a total of 1186 treated, uncontrolled, hypertensive patients (46.3% female, aged 65.2 ± 11.7 years, mean duration of hypertension 13.2 ± 9.3 years, mean clinic BP levels 156.5 ± 15.9/90.3 ± 9.5 mmHg) were enrolled. Systolic and diastolic BP levels were 141.1/82.4, 134.9/79.8 and 133.6/78.9 mmHg at 1-, 6- and 12-month follow-up visits, respectively (p < 0.0001 vs baseline for all comparisons). These effects were consistent in all predefined subgroups, including those with left ventricular hypertrophy, renal disease, diabetes mellitus, coronary artery disease or cerebrovascular disease. Reduced levels of microalbuminuria were also reported, without affecting other renal and electrolyte parameters. Overall, compliance to study medication was high (93.0%), with a very low proportion of patients experiencing adverse events leading to drug discontinuation (3.6%).. In this observational, prospective, open-label, multicentre study, we reported the 12-month clinical effectiveness, safety and tolerability of adding aliskiren to treated, uncontrolled, hypertensive patients in a 'real-life' setting in Italy. This strategy leads to a significantly improved BP control rate and low incidence of drug-related side effects or discontinuations.

Topics: Adrenergic beta-Antagonists; Adult; Age Factors; Aged; Albuminuria; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diastole; Diuretics; Drug Therapy, Combination; Female; Follow-Up Studies; Fumarates; Humans; Hypertension; Italy; Male; Medication Adherence; Middle Aged; Prospective Studies; Renin; Systole

The renin-angiotensin-aldosterone system (RAAS) plays an important role in the progression of chronic kidney disease (CKD). Although dual RAAS inhibition results in worse renal outcomes than monotherapy in high risk type 2 diabetes patients, the effect of dual RAAS inhibition in patients with non-DM CKD is unclear. The aim of this study was to evaluate the potential renoprotective effect of add-on direct renin inhibitor in non-DM CKD patients.. We retrospectively enrolled 189 non-DM CKD patients who had been taking angiotensin II receptor blockers (ARBs) for more than six months. Patients were divided into an add-on aliskiren group and an ARB monotherapy group. The primary outcomes were a decline in glomerular filtration rate (GFR) and a reduction in urinary protein-to-creatinine ratio at six months.. The baseline characteristics of the two groups were similar. Aliskiren 150 mg daily reduced the urinary protein-to-creatinine ratio by 26% (95% confidence interval, 15 to 37%; p < 0.001). The decline in GFR was smaller in the add-on aliskiren group (-2.1 vs. -4.0 ml/min, p = 0.038). Add-on aliskiren had a neutral effect on serum potassium in the non-DM CKD patients. In subgroup analysis, the proteinuria-reducing effect of aliskiren was more prominent in patients with a GFR less than 60 ml/min, and in patients with a urinary protein-to-creatinine ratio greater than 1.8. The effect of aliskiren in retarding the decline in GFR was more prominent in patients with hypertensive nephropathy than in those with glomerulonephritis.. Add-on direct renin inhibitor aliskiren (150 mg daily) safely reduced proteinuria and attenuated the decline in GFR in the non-DM CKD patients who were receiving ARBs.

Topics: Adult; Aged; Aged, 80 and over; Amides; Angiotensin Receptor Antagonists; Antihypertensive Agents; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Follow-Up Studies; Fumarates; Humans; Male; Middle Aged; Renal Insufficiency, Chronic; Renin; Retrospective Studies; Treatment Outcome

Topics: Amides; Antihypertensive Agents; Diabetes Mellitus, Type 2; Endpoint Determination; Female; Fumarates; Humans; Kidney; Male; Myocardium

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Clinical Trials Data Monitoring Committees; Congresses as Topic; Diabetes Mellitus, Type 2; Endpoint Determination; Fumarates; Heart Failure; Humans; Randomized Controlled Trials as Topic; Rats; Renin; Renin-Angiotensin System

The complex pathophysiological interactions between heart and kidney diseases are collectively known as cardiorenal syndrome. The renin-angiotensin system (RAS) may have a pivotal role in the development of cardiorenal syndrome. The aim of this study was to elucidate the RAS activity responsible for adverse post-infarction remodeling and prognosis in mice with renal failure. To establish the type IV cardiorenal syndrome model, 5/6 nephrectomy (NTX) was performed in a surgical procedure, followed by the induction of myocardial ischemia (MI) by a coronary artery ligation 4 weeks later. NTX and MI resulted in deteriorated left ventricular remodeling and RAS activation, which was improved by an aliskiren that appeared to be independent of renal function and blood pressure (BP). Moreover, MI induced in renin and angiotensinogen double-transgenic (Tg) mice showed comparable effects to MI plus NTX mice, including advanced ventricular remodeling and enhancement of RAS, oxidative stress, and monocytes chemoattractant protein (MCP)-1. Aliskiren suppressed these changes in the MI-induced Tg mice. In in vitro study, Nox2 expression was elevated by the stimulation of plasma from NTX mice in isolated neonatal cardiomyocytes. However, Nox2 upregulation was negated when we administered plasma from aliskiren-treated-NTX mice or isolated cardiomyocytes from AT1-deficient mice. Primary mononuclear cells also showed an upregulation in the expression of Nox2 and MCP-1 by stimulation with plasma from NTX mice. Our data suggest that renal disorder results in ventricular dysfunction and deteriorates remodeling after MI through excessive RAS activation. Moreover, renin inhibition improved the changes caused by cardiorenal syndrome.

Topics: Amides; Analysis of Variance; Animals; Atrial Natriuretic Factor; Chemokine CCL2; Disease Models, Animal; Fumarates; Humans; Hypertension; Kaplan-Meier Estimate; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Infarction; Myocardium; Nephrectomy; Oxidative Stress; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Ventricular Remodeling

The blockade of the renin-angiotensin system (RAS) improves the prognosis of patients with complications related to diabetes, hypertension or, in general, atherosclerosis. Several observational studies have suggested the use of a dual blockade of the RAS to benefit from a better cardiorenal protection. However, recent randomized controlled studies failed to demonstrate that a dual blockade exert a better protection than single blockade, but showed a higher risk for renal complications and hyperkalemia. To decrease the residual risk, other opportunities may be recommended such as reinforcement of low salt diet, use of supraphysiological dose of a monotherapy inhibiting the RAS (perhaps prescribed at the evening) or addition of an aldosterone antagonist. However, all these approaches, as dual therapy, may also increase the risk of hypotension and renal insufficiency and thus require to be used under strict medical supervision.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Renin; Renin-Angiotensin System

Increased angiotensin II (Ang II) plays an important role in liver inflammation and fibrogenesis. Chronic administration of aliskiren, a newly developed direct renin inhibitor, decreases Ang II in the hypertensive patients and animals.. Our study aims to evaluate the possible protective effects of chronic administration of aliskiren in a chronic liver injury model.. C57BL6 mice were injected intraperitoneally with carbon tetrachloride (CCl(4)) to induce chronic liver injury. The injured mice were randomly assigned to aliskiren-treated (25 mg/kg per day for 2 weeks, the CCl(4) + Ali group) or untreated group (the CCl(4) group). Mice without CCl(4) and aliskiren administration served as the normal control.. In the CCl(4)-injured mice, aliskiren attenuated liver inflammation and fibrosis. The levels of hepatocyte apoptosis, lipid peroxidation production, the activation of hepatic stellate cells and Kupffer cells, hepatic expression of p47 phox, inflammatory mediators and profibrotic markers were reduced in the CCl(4) + Ali group. Furthermore, aliskiren decreased Ang II, activated the renal expression of renin, but down-regulated the hepatic expression of renin and renin receptor in the CCl(4)-injected mice.. Aliskiren attenuates chronic liver injury in the CCl(4)-treated mice by reducing Ang II. Direct renin inhibition may serve as a potential treatment for chronic liver injury.

Topics: Amides; Angiotensin II; Animals; Antihypertensive Agents; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury, Chronic; Drug Interactions; Fumarates; Liver; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Random Allocation; Renin

Topics: Amides; Angioedema; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Fumarates; Humans; Renin

It is a well-accepted fact that angiotensin II (Ang II) contributes to increased vascular tone in cirrhotic livers. However, aliskiren attenuates the effect of Ang II through direct renin inhibition. Our study aimed to evaluate the effects of aliskiren on portal pressure and intrahepatic resistance in bile duct ligated (BDL) rats.. The effects of acute intravenous infusion (1 mg or 3 mg) or a course of 2-day oral administration of aliskiren (20 mg/kg/day) on blood pressure and portal pressure were evaluated in BDL and sham rats. Intrahepatic resistance was evaluated by a liver perfusion study isolated in situ. Ang II efflux was measured by Enzyme-linked immunosorbent assay (ELISA). The hepatic gene expression of angiotensinogen, renin, angiotensin-converting enzyme (ACE), Ang II type 1 receptor (AT(1)R) was analyzed with quantitative reverse transcription polymerase chain reaction.. Aliskiren infusion intravenously reduced portal pressure with a minimal effect on blood pressure in BDL rats. Direct infusion of aliskiren in an isolated cirrhotic liver caused greater vasorelaxation and decreased hepatic production of Ang II. Two days of aliskiren treatment reduced portal pressure and hepatic ACE mRNA; in addition, it improved the vasodilator response to acetylcholine in the cirrhotic livers and decreased Ang II efflux.. Aliskiren reduced portal pressure in cirrhotic rats. The portal hypotensive effect of aliskiren was related to the amelioration of the Ang II induced intrahepatic vasoconstriction.

Topics: Administration, Oral; Amides; Animals; Fumarates; Infusions, Intravenous; Liver Circulation; Liver Cirrhosis, Experimental; Male; Portal Pressure; Rats; Rats, Sprague-Dawley; Vascular Resistance

Despite significant advances in pharmacological and non-pharmacological therapy, epidemiological data from European and US hospitals show that the prevalence of heart failure (HF) hospitalization, especially for patients >65 years, continues to rise. Hospitalization for worsening HF is one of the most important predictors of short- and long-term outcomes in patients with chronic HF. There is therefore a clear need for new therapies that can work synergistically with standard medications to reverse the progression of the disease and improve myocardial efficiency. In the last years, researches in chronic HF focused on drugs that can exert a greater attenuation of neurohormonal activation and that can improve cardiac energy and substrate utilization.

Topics: Algorithms; Amides; Benzazepines; Chronic Disease; Fumarates; Heart Failure; Heart Rate; Humans; Ivabradine

In this issue of Curr Vasc Pharmacol, Pfeiffer et al. [1] and Glorioso et al. [2] report the efficacy and tolerability of aliskiren/amlodipine single-pill combinations (SPCs) in patients with inadequate blood pressure (BP) response to amlodipine or aliskiren monotherapy, respectively.

Topics: Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Female; Fumarates; Humans; Hypertension; Male; Vasodilator Agents

Topics: Amides; Angioedema; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cough; Drug Interactions; Fumarates; Humans

Topics: Amides; Animals; Antihypertensive Agents; Fumarates; Hypertension, Portal; Rats; Renin

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Coronary Vasospasm; Drug Therapy, Combination; Early Termination of Clinical Trials; Fumarates; Humans; Hypertension; Ramipril; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System; Telmisartan

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Consumer Advocacy; Drug Labeling; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Hypotension; Kidney; Randomized Controlled Trials as Topic; Renin; United States; United States Food and Drug Administration

We herein report the first case of remarkable hypertriglyceridemia induced by aliskiren. A 42-year-old man with chronic kidney disease who had been taking antihypertensive medication for approximately 10 years was treated with aliskiren at a dose of 150 mg/day due to uncontrolled hypertension. Six weeks later, although the patient's blood pressure decreased, a laboratory examination revealed remarkable hypertriglyceridemia and an elevated creatinine level. We suspected the occurrence of an adverse event of aliskiren, and the medication was discontinued. Thereafter, the hypertriglyceridemia and elevated creatinine level spontaneously improved. Transient eosinophilia and a strong-positive response of drug lymphocyte stimulation test (DLST) to aliskiren occurred during the patient's clinical course, and we determined the remarkable hypertriglyceridemia to be an adverse event of aliskiren.

Topics: Adult; Amides; Antihypertensive Agents; Fumarates; Humans; Hypertriglyceridemia; Male

In this study, effect of aliskiren (ALK) on doxorubicin (DXR)-induced cardiomyopathy in rats was evaluated. ALK (50 and 100 mg/kg/day) was administered for 7 days and a single intraperitoneal injection of DXR (20 mg/kg) on day 5. The animals were sacrificed 48 h after DXR administration. DXR produced significant elevation in malondialdehyde (MDA) and significantly inhibited the activity of glutathione (GSH) in heart tissue, with a significant rise in the serum levels of lactate dehydrogenase (LDH), total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL) and reduction in high-density lipoprotein (HDL), indicating acute cardiac toxicity. ALK pretreatment significantly reduced the MDA concentration and ameliorated the inhibition of cardiac GSH activity. ALK also significantly improved the serum levels of LDH, TC, TG, LDL and reduction in HDL in DXR-treated rats. Furthermore, histological examination of the heart sections confirmed the myocardial injury with DXR administration and the near-normal pattern with ALK pretreatment. The results provide clear evidence that the ALK pretreatment offered significant protection against DXR-induced enzymatic changes and cardiac tissue damage.

Topics: Amides; Animals; Antibiotics, Antineoplastic; Cardiomyopathies; Doxorubicin; Fumarates; Lipid Peroxidation; Lipids; Myocardium; Rats; Rats, Wistar; Renin; Renin-Angiotensin System

Aliskiren is a direct renin inhibitor (DRI) and provides an organ-protective effect in human and animal experiments. However, there is no current evidence of the effect of DRI on insulin resistance and metabolic abnormalities in type 2 diabetic animals. Methods. We investigated the effects and molecular mechanism of aliskiren in db/db mice and cultured mesangial cells (MCs).. Aliskiren treatment for 3 months at a dose of 25 mg/kg/day via an osmotic mini-pump did not induce significant changes in blood glucose levels, systolic blood pressure, serum creatinine and electrolyte levels. However, aliskiren treatment improved insulin resistance confirmed by insulin tolerance test and various biomarkers including homeostasis model assessment index levels and lipid abnormalities. The treated group also exhibited significant improvement in cardiac functional and morphological abnormalities including left ventricular hypertrophy, and induced phenotypic changes in adipose tissue. Aliskiren treatment also markedly decreased urinary albumin excretion, glomerulosclerosis and suppressed profibrotic and proinflammatory cytokine synthesis and improved renal lipid metabolism. In cultured MCs, high glucose stimulation increased MC renin concentration. Furthermore, renin treatment directly up-regulates synthesis of proinflammatory and profibrotic cytokines, which were abolished by prior treatment with aliskiren and angiotensin receptor (AT1) antagonist. These results suggest that the beneficial effect of aliskiren is mediated by an angiotensin-dependent mechanism.. Together, these results imply that aliskiren provides an organ-protective effect through improvement in insulin resistance and lipid abnormality, as well as direct anti-fibrotic effect in target organ in db/db mice. Aliskiren may be a useful new therapeutic agent in the treatment of type 2 diabetes mellitus and diabetic nephropathy.

Topics: Amides; Animals; Biomarkers, Tumor; Blood Glucose; Blood Pressure; Blotting, Western; Body Weight; Cells, Cultured; Diabetes Complications; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Fumarates; Gene Expression Profiling; Humans; Immunoenzyme Techniques; Insulin; Insulin Resistance; Male; Mesangial Cells; Mice; Mice, Mutant Strains; Oligonucleotide Array Sequence Analysis; Renin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Spontaneously hypertensive rats (SHRs) are characterized by capillary rarefaction, which may contribute to blood pressure elevation. We hypothesized that capillary rarefaction involves a suppressed angiogenesis; renin inhibition influences anti-angiogenesis homeostasis by acting on angiopoietins; transient renin blockade reduces anti-angiogenesis thereby ameliorating long-lasting blood pressure and cardiac hypertrophy in SHRs.. First, serum angiopoietin-1 and angiopoietin-2 were measured in 2-month old normotensive Wistar-Kyoto rats (WKYs) and SHRs after renin inhibition (aliskiren: 1 and 10 mg/kg per day) or placebo. Second, 4-week old SHRs were prehypertensively treated with aliskiren (1 and 10 mg/kg per day) or placebo for 4 weeks. After 4 weeks of 'drug holiday' 12-week old SHRs were given L-nitro-arginine methyl ester (L-NAME) (25 mg/kg per day) for a 4-week interval to promote capillary rarefaction. Thereafter, mean arterial pressure (MAP), cardiac remodeling, capillary density, pAkt/Akt as marker for cellular survival, pro-angiogenic genes and systemic angiopoietins were investigated.. Baseline angiopoietin levels were similar between WKYs and SHRs. Renin inhibition increased angiopoietin-1 in SHR and reduced angiopoietin-2 in both WKY and SHR blood pressure independently. Prehypertensive renin inhibition reduced MAP and cardiac hypertrophy in adult SHRs. This was associated with higher cardiac capillary density, pAkt/Akt, pro-angiogenic expression pattern and serum angiopoietin-1, whereas angiopoietin-2 was lower as compared to vehicle-pretreated SHRs. These results were independent of prehypertensive blood pressure lowering by aliskiren.. We conclude that renin inhibition modulates anti-angiogenesis signaling independently of blood pressure by increasing angiopoietin-1/angiopoietin-2 ratio. This promotes in SHR stabilization of endothelial cells, favors pro-angiogenic action and consequently results in higher capillary density.

Topics: Amides; Angiopoietin-1; Angiopoietin-2; Animals; Antihypertensive Agents; Blood Pressure; Capillaries; Fumarates; Hypertension; Male; Neovascularization, Physiologic; NG-Nitroarginine Methyl Ester; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; Signal Transduction; Ventricular Remodeling

The direct renin inhibitor aliskiren is known to exhibit a strong antihypertensive effect. However, the organoprotective potential of aliskiren beyond its antihypertensive properties is less clear. This study investigates the antifibrotic nephroprotective effects of aliskiren in a nonhypertensive mouse model for progressive renal fibrosis.. COL4A3(-/-) mice received aliskiren via osmotic minipumps. Placebo-treated animals served as controls. Therapy was initiated in 6-week-old animals already showing renal damage (proteinuria ~1 g/l, starting renal fibrosis) and lasted for 4 weeks. Six animals were sacrificed after 9.5 weeks; serum urea and proteinuria were measured. Kidneys were further investigated using histological, immunohistological, and western blot techniques. Survival until end-stage renal failure was monitored in the remaining animals.. COL4A3(-/-) mice did not develop hypertension. Aliskiren serum levels were in the therapeutic range (288 ± 44 ng/ml). Therapy significantly prolonged lifespan until death from renal failure by 18% compared with placebo-treated controls (78.6 ± 8.2 vs. 66.6 ± 4.9 days, P < 0.05). Similarly, therapy reduced the amount of proteinuria and serum urea. Compared with placebo-treated controls, the accumulation of extracellular matrix and renal scarring and the levels of transforming growth factor-β (TGFβ) and connective tissue growth factor (CTGF) were decreased in treated mice.. Despite the late onset of therapy, our results indicate nephroprotective effects of the renin inhibitor aliskiren beyond its antihypertensive property in this animal model of progressive renal fibrosis. In addition to the recognized antihypertensive action of aliskiren, its antifibrotic, antiproteinuric effects demonstrated in the present study indicate that aliskiren may have potential as an important therapeutic option for chronic fibrotic diseases in humans.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Autoantigens; Collagen Type IV; Connective Tissue Growth Factor; Disease Models, Animal; Extracellular Matrix; Fibrosis; Fumarates; Kidney; Mice; Proteinuria; Transforming Growth Factor beta1; Uremia

Evidence is currently equivocal on the added benefits of dual blockade of the renin-angiotensin-aldosterone system with the combination of either an ACE inhibitor (ACEI) plus an angiotensin II type 1 receptor antagonist (angiotensin receptor blocker [ARB]) or aliskiren, the first-in-class direct renin inhibitor, plus an ARB.. To compare the compliance, persistence, healthcare resource utilization, and healthcare costs associated with aliskiren plus ARB versus ACEI plus ARB combination therapies among adult patients diagnosed with hypertension.. Patients (aged ≥18 years) initiated on either combination therapy were identified in the MarketScan Commercial and Medicare Supplemental Databases (1 July 2007 to 30 June 2008). The ARB components considered were candesartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan. The ACEI components included benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril. Outcomes measured during the 6-month study period included the proportion of days covered (PDC), treatment discontinuation, healthcare resource utilization, and changes in healthcare costs (study period minus 6-month baseline values). Risk-adjusted differences in outcomes between treatments and associated 95% confidence intervals (CIs) were estimated using multivariate regression models, controlling for demographics, region, co-morbidities, prescription drug use, and resource utilization during the baseline period.. Adjusting for baseline characteristics, aliskiren plus ARB patients (n = 1395) demonstrated a significantly higher PDC (67.0% vs 54.3%; difference 12.7%; 95% CI 10.6, 14.7) and a significantly lower discontinuation rate (50.4% vs 68.6%; odds ratio 0.46; 95% CI 0.40, 0.54) than ACEI plus ARB patients (n = 16 507). Aliskiren plus ARB patients had significantly fewer all-cause hospitalizations (adjusted incidence rate ratio [IRR] 0.73; 95% CI 0.61, 0.86) and significantly fewer all-cause emergency room (ER) visits (adjusted IRR 0.72; 95% CI 0.61, 0.85) than ACEI plus ARB patients. Compared with ACEI plus ARB therapy, aliskiren plus ARB therapy was associated with significantly larger increases in prescription costs by $US264 post therapy initiation (95% CI 153, 375), but with non-significantly greater reductions in total healthcare costs by -$583 (95% CI -2409, 1242).[2008 values].. In adult hypertensive patients, treatment with aliskiren plus ARB was associated with significantly better compliance/persistence and fewer hospitalizations and ER visits compared with ACEI plus ARB therapy. Reductions in total healthcare costs were non-significantly different between patients treated with aliskiren plus ARB versus ACEI plus ARB, despite the increased prescription costs associated with aliskiren plus ARB therapy.

Topics: Adult; Aged; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Drug Therapy, Combination; Female; Fumarates; Health Care Costs; Health Resources; Humans; Hypertension; Male; Medication Adherence; Middle Aged

The objective of this case series was to review the safety and efficacy of aliskiren in combination with losartan in pediatric chronic kidney disease (CKD) patients. This was a retrospective study in which the medical files of all patients who had received aliskiren were reviewed. Four patients were identified between 5 and 18 years of age who had received aliskiren and losartan for the reduction of refractory proteinuria. While proteinuria was reduced in all four of these patients by 45, 96, 53, and 64%, respectively, three patients experienced side effects requiring changes in the aliskiren dose. A significant side effect occurred in the patient with CKD stage 3 who suffered accelerated loss of kidney function leading to dialysis after only a short course of therapy. The data from this preliminary trial strongly suggest that clinicians should exercise caution when prescribing aliskiren in combination with losartan until appropriate pediatric trials establish dosing, efficacy, and safety.

Topics: Adolescent; Age Factors; Amides; Angiotensin II Type 1 Receptor Blockers; Child, Preschool; Chronic Disease; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fumarates; Humans; Kidney Diseases; Losartan; Male; Off-Label Use; Patient Selection; Proteinuria; Renin; Renin-Angiotensin System; Risk Assessment; Risk Factors; Treatment Outcome

Topics: 8-Hydroxy-2'-Deoxyguanosine; Albuminuria; Amides; Antihypertensive Agents; Asian People; Blood Pressure; Chemokine CCL2; Creatinine; Deoxyguanosine; Diabetic Nephropathies; Female; Fumarates; Glomerular Filtration Rate; Humans; Interleukin-6; Male; Middle Aged; Oxidative Stress; Treatment Outcome

Topics: Adolescent; Age Factors; Amides; Antihypertensive Agents; Child; Child, Preschool; Evidence-Based Medicine; Fumarates; Humans; Hypertension; Off-Label Use; Patient Selection; Proteinuria; Renin; Renin-Angiotensin System; Risk Assessment; Risk Factors

The renin-angiotensin-aldosterone system (RAAS) represents a key therapeutic target in heart failure (HF) management. However, conventional agents that block this system induce a reflex increase in plasma renin activity (PRA), which may lead to RAAS 'escape'. Direct renin inhibitors (DRIs) have been developed that decrease PRA and thus may provide a greater RAAS blockade. Aliskiren is the first orally active DRI. Plasma levels of B-type natriuretic peptide (BNP) have been observed to be reduced with aliskiren compared with placebo. The aim of the Aliskiren Trial of Minimizing OutcomeS for Patients with HEart failuRE (ATMOSPHERE) study is to evaluate the effect of both aliskiren and enalapril monotherapy and aliskiren/enalapril combination therapy on cardiovascular death and HF hospitalization in patients with chronic systolic HF, NYHA functional class II-IV symptoms, and elevated plasma levels of BNP. Methods Patients tolerant to at least 10 mg or equivalent of enalapril will undergo an open-label run-in period where they receive enalapril then aliskiren. Approximately 7000 patients tolerating this run-in period will then be randomized 1:1:1 to aliskiren monotherapy, enalapril monotherapy, or the combination. The primary endpoints of ATMOSPHERE are (i) whether the aliskiren/enalapril combination is superior to enalapril monotherapy in delaying time to first occurrence of cardiovascular death or HF hospitalization and (ii) whether aliskiren monotherapy is superior or at least non-inferior to enalapril monotherapy on this endpoint. Perspective The ATMOSPHERE study will definitively determine the role of a DRI strategy additional to or as an alternative to conventional RAAS blockade in patients with chronic systolic HF.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Enalapril; Fumarates; Heart Failure, Systolic; Humans; Natriuretic Peptide, Brain; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System; Research Design; Stroke Volume; Ventricular Function, Left

A reversed-phase liquid chromatography (RP-LC) method is validated for the determination of aliskiren in tablet dosage form. The LC method is carried out on a Waters XBridge C(18) column (150 × 4.6 mm i.d.), maintained at 25°C. The mobile phase consisted of acetonitrile:water (95:5, v/v)/phosphoric acid (25 mM, pH 3.0) (40:60, v/v), run at a flow rate of 1.0 mL/min, with photodiode array detector set at 229 nm. The chromatographic separation is obtained with aliskiren retention time of 3.68 min, and it is linear in the range of 10-300 μg/mL (r = 0.9999). The limits of detection and quantitation are 2.38 and 7.93 μg/mL, respectively. The specificity and stability-indicating capability of the method are proven through degradation studies, which also showed that there is no interference of the formulation excipients, showing that peak is free from any coeluting peak. The method showed adequate precision, with a relative standard deviation (RSD) values lower than 0.92%. Good values of accuracy were also obtained, with a mean value of 99.55%. Experimental design is used during validation to calculate method robustness. The proposed method is applied for the analysis of the tablet dosage forms, contributing to improve the quality control and to assure the therapeutic efficacy.

Topics: Amides; Analysis of Variance; Chromatography, Reverse-Phase; Fumarates; Linear Models; Reproducibility of Results; Sensitivity and Specificity; Tablets

Altered extracellular matrix (ECM) remodeling and podocyte apoptosis are characteristic features of diabetic nephropathy (DN). Aliskiren (ALI) inhibits the renin-catalyzed conversion of angiotensinogen to angiotensin I. This study tested ALI's effect on podocyte ECM accretion and survival in a high-glucose environment in vitro.. Conditionally immortalized mouse podocytes were incubated in normal glucose (NG; 5.5 mM) or high glucose (HG; 40 mM) for 24-48 h with and without ALI (20 nM). Real-time RT-PCR was performed for fibronectin (FN), collagen α5(type IV) (Cola5IV), matrix metalloproteinases 2 and 9 (MMP2 and MMP9), and tissue inhibitor of metalloproteinases 1 and 2 (TIMP1 and TIMP2). Western blots were performed for FN, Cola5IV, MMP2, MMP9, TIMP1 and cleaved (activated) caspase-3.. ALI significantly reduced the mRNA and protein levels of FN, Cola5IV and TIMP1, and the mRNA of TIMP2 and cleaved caspase-3. ALI had no effect on MMP2 mRNA or protein or MMP9 mRNA tested under HG conditions. Under NG conditions, ALI had no effect on FN, Cola5IV, MMP2, MMP9 and activated caspase-3 proteins. ALI decreased the activated caspase-3 protein and evidence of apoptosis by TUNEL staining observed in podocytes cultured under HG conditions.. These results show for the first time that renin inhibition with ALI mitigates the profibrotic and apoptotic effects of HG in cultured podocytes. These data strengthen the therapeutic rationale for renin inhibition with ALI beyond its hemodynamic effects.

Topics: Amides; Animals; Apoptosis; Cells, Cultured; Collagen Type IV; Diabetic Nephropathies; Extracellular Matrix; Fibronectins; Fumarates; Glucose; Matrix Metalloproteinases; Podocytes; Renin; RNA, Messenger

Topics: Amides; Amlodipine; Antihypertensive Agents; Calcium Channel Blockers; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Practice Guidelines as Topic; Randomized Controlled Trials as Topic

To investigate whether the putative (pro)renin receptor blocker, the handle region peptide (HRP), exerts effects on top of the blood pressure-lowering and cardioprotective effects of the renin inhibitor aliskiren, spontaneously hypertensive rats were implanted with telemetry transmitters to monitor heart rate and mean arterial pressure (MAP). After a 2-week recovery period, vehicle, aliskiren, HRP (100 and 1 mg/kg per day, respectively), and HRP+aliskiren were infused for 3 weeks using osmotic minipumps. Subsequently, the heart was removed to study coronary function according to Langendorff. Baseline MAP and heart rate in vehicle-treated rats were 146±3 mm Hg and 326±4 bpm. HRP did not affect MAP, whereas aliskiren and HRP+aliskiren lowered MAP (by maximally 29±2 and 20±1 mm Hg, respectively) without affecting heart rate. Aliskiren significantly reduced MAP throughout the 3-week infusion period, whereas the blood pressure-lowering effect of HRP+aliskiren returned to baseline within 2 weeks of treatment. In comparison with vehicle, aliskiren increased the endothelium-dependent response to bradykinin and decreased the response to angiotensin II in the coronary circulation, whereas these responses were not altered after treatment with HRP or HRP+aliskiren. HRP did not alter plasma renin activity, plasma angiotensin levels, or the renal angiotensin content, either alone or on top of aliskiren, nor did it alter the aliskiren-induced decrease in renal Ang II type 1 receptor expression. Yet, it did reverse the aliskiren-induced reduction in cardiomyocyte area, without affecting this area when given alone. In conclusion, HRP counteracts the beneficial effects of aliskiren on blood pressure, coronary function, and cardiac hypertrophy in an angiotensin-independent manner.

Topics: Amides; Analysis of Variance; Animals; Antihypertensive Agents; Blood Pressure; Bradykinin; Drug Interactions; Endothelium, Vascular; Fumarates; Heart Rate; Hypertension; Infusion Pumps, Implantable; Male; Oligopeptides; Rats; Rats, Inbred SHR; Renin; Reverse Transcriptase Polymerase Chain Reaction; Telemetry

Cyp1a1-Ren2 transgenic rats [strain name: TGR(Cyp1a1Ren2)], administered indole-3-carbinol (I3C) develop angiotensin (ANG) II-dependent hypertension due to hepatic expression of the Ren2 renin gene. Although AT1 receptor blockade prevents the development of hypertension and normalizes the elevated arterial blood pressure of Cyp1-Ren2 rats, little information is available regarding the blood pressure and renal functional responses to direct inhibition of renin in this high circulating renin model of ANG II-dependent hypertension. This study was performed to determine the effects of acute direct renin inhibition with aliskiren on blood pressure and renal hemodynamics in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension.. Mean arterial pressure (MAP) and renal hemodynamics were measured in pentobarbital-anesthetized male Cyp1a1-Ren2 rats during control conditions and after administration of the renin inhibitor, aliskiren (10 mg/kg, intravenous).. Rats induced with I3C had higher MAP (194 ± 7 versus 141 ± 2 mm Hg, P < 0.001), lower renal plasma flow (RPF; 2.47 ± 0.23 versus 4.17 ± 0.35 mL/min/g, P < 0.001) and lower glomerular filtration rate (GFR; 1.01 ± 0.07 versus 1.34 ± 0.06 mL/min/g, P = 0.01) than noninduced Cyp1a1-Ren2 rats (n = 5). Aliskiren administration decreased MAP (194 ± 7 to 136 ± 2 mm Hg, P < 0.001) and increased RPF (2.47 ± 0.23 versus 4.31 ± 0.20 mL/min/g, P < 0.001) in hypertensive but not in normotensive rats, without altering GFR.. Acute renin inhibition with aliskiren normalizes MAP and RPF in Cyp1a1-Ren2 rats with malignant hypertension. The normalization of MAP and RPF after acute renin inhibition indicates that renin generated by expression of the Ren2 gene is responsible for the maintenance of malignant hypertension and the associated reduction in renal hemodynamic function in Cyp1a1-Ren2 rats.

Topics: Amides; Angiotensin II; Animals; Blood Pressure; Cytochrome P-450 CYP1A1; Disease Models, Animal; Fumarates; Glomerular Filtration Rate; Hypertension, Malignant; Kidney; Male; Rats; Rats, Transgenic; Regional Blood Flow; Renin; Vascular Resistance

The hypertensive double-transgenic (dTG) rat strain, expressing human renin and angiotensinogen, develops severe hypertension and organ damage and 50% of individuals die by 7 weeks of age. Here, we characterise a variation of this model in which animals present stable hypertension.. The effect of renin-angiotensin system blockers on blood pressure was determined with adult dTG rats treated with enalapril from 3 to 12 weeks of age. Tissue expression levels of renin and angiotensinogen were determined in dTG rats and rhesus monkeys by quantitative PCR.. Upon withdrawal from enalapril, mean arterial pressure (MAP) rose to 160-180 mmHg, with 95% of the female dTG rats surviving for 6 to 12 months, In Sprague-Dawley (SD) rats and rhesus monkeys, renin mRNA was absent or weakly expressed in most tissues, except for the kidneys and adrenals. In dTG rats, human renin expression was high in many additional tissues. The expression of human angiotensinogen in dTG rats followed a similar tissue pattern to SD and rhesus monkey angiotensinogen. Oral dosing of aliskiren, enalapril or losartan provided a similar maximal reduction in MAP and duration of efficacy in telemetrised dTG rats.. Enalapril-pretreated dTG rats are suitable for long-term MAP monitoring and sequential evaluation of human renin inhibitors.

Topics: Amides; Angiotensinogen; Animals; Blood Pressure; Disease Models, Animal; Enalapril; Female; Fumarates; Gene Expression Regulation; Heart Rate; Humans; Hypertension; Macaca mulatta; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Renin; RNA, Messenger; Tissue Distribution

Topics: Adrenergic beta-Antagonists; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Drug Therapy, Combination; Fumarates; Humans; Molecular Targeted Therapy; Myocardial Infarction; Myocardium; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System; Treatment Outcome; Ventricular Remodeling

Hypertensive chronic kidney disease (CKD) patients often have sympathetic hyperactivity. In this pilot study, we evaluated the effect of 6 weeks treatment with aliskiren on sympathetic activity in hypertensive Stages 2-4 CKD patients.. In 10 CKD patients (8 males, aged 44 ± 11 years, estimated glomerular filtration rate ( 57 ± 22 mL/min/1.73 m(2)), blood pressure and sympathetic activity [quantified by assessment of muscle sympathetic nerve activity (MSNA)] were assessed, while taken off renin-angiotensin blocker, and during the 6 weeks of treatment with aliskiren 300 mg/day. Ten other CKD patients served as control and were studied twice with an interval of 6 weeks without any change in medication, to quantify within subject reproducibility.. In the aliskiren study group, MSNA was reduced from 36 ± 8 to 26 ± 8 bursts/min (P = 0.01). Aliskiren lowered supine systolic and diastolic blood pressure from 147 ± 10 to 120 ± 8 and from 96 ± 7 to 83 ± 7 mmHg, respectively (both P < 0.05). MSNA changed in patients treated with aliskiren [-9.6 bursts/min with 95% confidence interval (CI) -4.0 to -15.0; P-value = 0.003] but not in controls (-0.7 bursts/min with 95% CI -2.2 to 4.0; P-value = 0.6). The mean difference in change between aliskiren group and the control group was -8.9 with 95% CI of -15 to -3; P = 0.005.. In hypertensive CKD patients, 6 weeks aliskiren treatment lowers blood pressure and MSNA (Clinical trial government identifier number: NCT00719316).

Topics: Adult; Amides; Antihypertensive Agents; Blood Pressure; Case-Control Studies; Female; Follow-Up Studies; Fumarates; Glomerular Filtration Rate; Humans; Hypertension; Kidney Failure, Chronic; Male; Prognosis; Survival Rate; Sympathetic Nervous System

Topics: Amides; Follow-Up Studies; Fumarates; Humans; Middle Aged; Prospective Studies; Proteinuria; Renin-Angiotensin System; Treatment Outcome

Topics: Amides; Amlodipine; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Neoplasms; Renin

Topics: Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Fumarates; Humans; Hypertension

Topics: Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Fumarates; Humans; Hypertension

Increasing evidence suggests that local renin-angiotensin system (RAS) plays an important role in cardiac diseases. Elevated p90 ribosomal S6 kinase (RSK) activity has been observed in diabetic animal, as well as in human failing hearts. We hypothesize that RSK mediates cardiac dysfunction by up regulating local RAS signaling. In the present study, we show that the prorenin mRNA level was significantly increased (~5.6-fold) in transgenic mouse hearts with cardiac specific expression of RSK (RSK-Tg). The RSK-Tg mice were more vulnerable to ischemia/reperfusion (I/R) injury than non-transgenic littermate controls (NLC). To further understand the direct contribution of cardiac renin to I/R injury, we used a Langendorff system to evaluate the effect of renin inhibition by aliskiren in RSK-Tg mouse hearts. In the vehicle-perfused group, I/R significantly decreased left ventricular developed pressure (LVDP) in RSK-Tg hearts compared to NLC (7% versus 60% of the baseline). However, aliskiren perfusion significantly increased LVDP in RSK-Tg (7% to 61%, p<0.01) but not in NLC hearts (60% to 62%, n.s.). The protective effect of aliskiren in RSK-Tg hearts was further demonstrated with positive (contraction) dp/dt (6.5% to 63%, p<0.01) and rate pressure product (RPP) (5% to 51%, p<0.01). Moreover, aliskiren significantly decreased I/R induced infarction in RSK-Tg (60% to 32%, p<0.01), compared to NLC hearts (37% to 32%, n.s.). These results suggest that RSK plays a crucial role in regulating local cardiac renin, which contributes to I/R induced cardiac injury and dysfunction. Thus, renin inhibition may provide an alternative therapeutic strategy under conditions of increased RAS.

Topics: Amides; Animals; Fumarates; Gene Expression Regulation; Heart; Mice; Mice, Transgenic; Myocardial Infarction; Myocardium; Renin; Renin-Angiotensin System; Reperfusion Injury; Ribosomal Protein S6 Kinases; RNA, Messenger

Topics: Amides; Amlodipine; Antihypertensive Agents; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Combinations; Drug Synergism; Fumarates; Humans; Hypertension; Overweight

The recent discovery of a specific receptor for renin/prorenin (PRR) has added new interest to the potential pharmacological actions of aliskiren, the first direct renin inhibitor.. In the present study, to gain new insights into the pharmacological properties of aliskiren, we investigated the effect of aliskiren on PRR expression and activity in cultured human smooth muscle cells (HSMCs).. Co-incubation of HSMCs with angiotensinogen (ANG) (1.5 × 10(-7)M) and prorenin (10(-8)-10(-7)M) resulted in an efficient production (within 4h) of angiotensin I, almost completely inhibited by 10(-5)M aliskiren (-86.0 ± 14.0%). In HSMCs stimulated with both ANG and prorenin, a 24h incubation with aliskiren (10(-6)-10(-5)M) resulted in a concentration-dependent reduction of PRR mRNA levels (IC(50) 4.6 × 10(-6)M). The cell surface expression of PRR determined by flow cytometry analysis was also reduced after incubation with aliskiren in a concentration-dependent manner. The lower levels of PRR were associated with a reduced expression of TGF-β, PAI-1 and type I collagen mRNA.. These results suggest a direct pharmacological action of aliskiren on PRR expression and its signalling pathway in HSMCs. This reported action of aliskiren may reveal a new scenario of the pharmacological properties of aliskiren.

Topics: Amides; Angiotensin I; Angiotensinogen; Aorta; Cells, Cultured; Fumarates; Gene Expression Regulation; Humans; Myocytes, Smooth Muscle; Prorenin Receptor; Protein Binding; Receptors, Cell Surface; Renin

We investigated whether the direct renin inhibitor aliskiren can affect metabolism in cardiomyocytes from rat, mouse and human sources.. At 10-50 μmol/L, aliskiren significantly increased medium-chain-fatty-acid uptake in primary-cultured neonatal-rat and HL-1 adult-mouse-derived cardiomyocytes (BODIPY-induced fluorescence intensity). The fatty-acid transporter CD-36 was correspondingly translocated to, but the glucose transporter Glut-4 away from, the sarcoplasmic reticulum/plasma membrane, in primary-cultured neonatal-rat (CD-36, Glut-4) and adult-human (CD-36) cardiomyocytes (confocal immunocytochemistry). Immunoblotting showed that aliskiren induced phosphorylation of ERK1/2 in cardiomyocytes from all three sources; responses were dose- and time-dependent, unaffected by renin treatment, and did not cause alterations in expression of (P)R or Igf2/M6P receptors. Microarray analysis of the complete genome of aliskiren-treated neonatal-rat cardiomyocytes, with RT-qPCR and immunoblot confirmation assays in rat and human primary cardiomyocytes, showed that aliskiren up-regulated mRNA and increased protein expression of several enzymes important in lipid and glucose metabolism and in cholesterol biosynthesis. Cardiomyocyte cell-cycle and viability were unaffected by aliskiren.. Aliskiren can induce changes in fatty-acid and glucose uptake and expression of key enzymes of lipid and cholesterol metabolism, which are not associated with increased expression of (P)R or Igf2/M6P receptors, in cultured cardiomyocytes.

Topics: Amides; Animals; CD36 Antigens; Cell Cycle; Cell Survival; Cells, Cultured; Cholesterol; Extracellular Signal-Regulated MAP Kinases; Fatty Acids; Fumarates; Glucose Transporter Type 4; Humans; Lauric Acids; Lipid Metabolism; Myocytes, Cardiac; Oligonucleotide Array Sequence Analysis; Rats; Receptor, IGF Type 2; Renin

Topics: Amides; Antihypertensive Agents; Benzopyrans; Chlorthalidone; Ethanolamines; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Impotence, Vasculogenic; Losartan; Male; Middle Aged; Nebivolol; Risk Factors

The hyperactivation of renin-angiotensin-aldosterone system (RAAS) underlies the development and the progression of arterial hypertension and chronic kidney diseases. Aldosterone is the main unit of RAAS and self-sufficient predictor of the development of cardiovascular events. In this study, the angiotensin receptor blocker valsartan, ACE inhibitor enalapril, and direct renin inhibitor aliskiren were used for the correction of blood pressure and aldosterone levels in patients with hypertension and chronic kidney diseases. The data obtained suggest that the proposed complex therapy provides the most complete blood pressure reduction and aldosterone level correction (as evidence of RAAS activity recovery), greatly improves the prognoses, and ensures maximum nephroprotection in the patients with arterial hypertension and chronic kidney diseases.

Topics: Aged; Aldosterone; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Drug Therapy, Combination; Enalapril; Female; Fumarates; Humans; Hypertension; Indapamide; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan

Renin-angiotensin system activation is involved in inflammation and fibrosis in the kidney. Aliskiren, a direct renin inhibitor, decreases renin-angiotensin system activation, including plasma renin activity and angiotensin II, but increases the prorenin level, which may promote inflammation and fibrosis in renal tissue. Thus, we evaluated whether inhibiting the renin-angiotensin system by aliskiren would decrease renal inflammation and fibrosis in a mouse model of unilateral ureteral obstruction.. Ten-week-old male C57BL/6 mice (Samtako, Kyoung Gi-Do, Korea) weighing 30 to 33 gm were divided into 4 groups, including vehicle or aliskiren treated sham operated and vehicle or aliskiren treated unilateral ureteral obstruction groups. We evaluated plasma renin activity, and plasma renin and renal mRNA expression levels of renin and (pro)renin receptor. To evaluate inflammation and fibrosis renal mRNA expression of monocyte chemotactic protein-1, osteopontin and transforming growth factor-β was measured. Hematoxylin and eosin, Masson's trichrome staining, and immunohistochemical staining for CD68, transforming growth factor-β and α-smooth muscle actin were performed.. Plasma renin activity was significantly lower in the aliskiren treated obstruction group than in the vehicle treated obstruction group. Aliskiren treatment increased renal mRNA expression of renin. The number of CD68 positive cells, and renal monocyte chemotactic protein-1 and osteopontin mRNA levels were significantly higher in mice with unilateral ureteral obstruction than in sham operated mice. Aliskiren decreased the increased levels of these inflammation markers. Aliskiren also decreased renal transforming growth factor-β mRNA expression, transforming growth factor-β and α-smooth muscle actin immunostaining, and Masson's trichrome stained areas of unilateral ureteral obstruction kidneys.. Aliskiren has anti-inflammatory and antifibrotic effects in an experimental unilateral ureteral obstruction mouse model.

Topics: Amides; Animals; Fibrosis; Fumarates; Kidney; Male; Mice; Mice, Inbred C57BL; Nephritis; Renin; Ureteral Obstruction

The challenge of managing hypertension is exemplified by the limited success of monotherapy and necessity for multiple drug regimens targeting complimentary pathways. Recent evidence suggests that combination therapy including angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers (CCBs) provides blood pressure control while reducing cardiovascular mortality and morbidity over ACE inhibitor/diuretic therapy. However, CCBs, ACE inhibitors and angiotensin receptor blockers all increase plasma renin activity (PRA), promoting angiotensin I accumulation and angiotensin II production through alternative pathways. While the clinical ramifications of this and other compensatory pathways activating the renin-angiotensin-aldosterone system are unclear, the recently approved aliskiren/amlodipine antihypertensive combination pill has been shown to decrease PRA via aliskiren's direct inhibition of renin. The purpose of this monograph is to review the mechanisms of action, pharmacodynamics, and safety and efficacy profile of the aliskiren/amlodipine combination pill.

Topics: Amides; Amlodipine; Antihypertensive Agents; Clinical Trials as Topic; Drug Combinations; Drug Interactions; Fumarates; Humans; Hypertension; Renin

A stability-indicating MEKC method was developed and validated for the simultaneous determination of aliskiren (ALI) and hydrochlorothiazide (HCTZ) in pharmaceutical formulations using ranitidine as an internal standard (IS). Optimal conditions for the separation of ALI, HCTZ and its major impurity chlorothiazide (CTZ), IS and degradation products were investigated. The method employed 47 mM Tris buffer and 47 mM anionic detergent SDS solution at pH 10.2 as the background electrolyte. MEKC method was performed on a fused-silica capillary (40 cm) at 28°C. Applied voltage was 26 kV (positive polarity) and photodiode array (PDA) detector was set at 217 nm. The method was validated in accordance with the ICH requirements. The method was linear over the concentration range of 5-100 and 60-1200 μg/mL for HCTZ and ALI, respectively (r(2) >0.9997). The stability-indicating capability of the method was established by enforced degradation studies combined with peak purity assessment using the PDA detection. Precision and accuracy evaluated by RSD were lower than 2%. The method proved to be robust by a fractional factorial design evaluation. The proposed MEKC method was successfully applied for the quantitative analysis of ALI and HCTZ both individually and in a combined dosage tablet formulation to support the quality control.

Topics: Amides; Chromatography, Micellar Electrokinetic Capillary; Fumarates; Hydrochlorothiazide; Pharmaceutical Preparations; Reproducibility of Results

1. Aliskiren is a renin inhibitor with an IC(50) of 0.6 nmol/L for human renin, 4.5 nmol/L for mouse renin and 80 nmol/L for rat renin. 2. In the present study, we compared the effects of aliskiren (10 mg/kg per day), the angiotensin-converting enzyme inhibitor perindopril (0.2 mg/kg per day) and their combination on angiotensin and bradykinin peptides in female heterozygous (mRen-2)27 rats, transgenic for the mouse renin gene. 3. All three treatments produced similar reductions in systolic blood pressure, heart weight and plasma aldosterone levels and reduced angiotensin II levels in lung, but only perindopril and the combination reduced angiotensin II levels in kidney of (mRen-2)27 rats. In contrast, aliskiren and the combination, but not perindopril alone, increased cardiac bradykinin levels. Aliskiren increased immunostaining for tissue kallikrein in the heart and reduced cardiac fibrosis. 4. We investigated the mechanism underlying the increase in bradykinin levels following aliskiren treatment in Sprague-Dawley rats, in which aliskiren has a lower potency for renin inhibition. Aliskiren (10 mg/kg per day) reduced renal angiotensin levels within 24 h, but treatment for > 24 h was required to increase cardiac bradykinin levels. Moreover, 3 mg/kg per day aliskiren increased cardiac bradykinin levels, but did not reduce renal angiotensin levels. Aliskiren did not potentiate the hypotensive effects of bradykinin; however, it increased tissue kallikrein, but not plasma kallikrein, mRNA levels in the heart. 5. These data demonstrate that the aliskiren-induced increase in cardiac bradykinin levels is independent of renin inhibition and changes in bradykinin metabolism, but is associated with increased tissue kallikrein gene expression.

Topics: Aldosterone; Amides; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Bradykinin; Female; Fumarates; Heart; Kallikreins; Kidney; Lung; Mice; Myocytes, Cardiac; Perindopril; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger; Tissue Kallikreins

This study focuses on the effects of long-term renin-angiotensin system suppression and/or incretin mimetic therapies on the regulation and binding affinity of GLP-1 to its receptor in the coronary endothelium (CE) and cardiomyocytes (CMs) of type 1 diabetic male Sprague-Dawley rats. The groups assessed are normal (N), streptozotocin-induced diabetic (D), Insulin treated (DI), Exendin-4 treated (DE), Aliskiren treated (DA), cotreated with Insulin and Aliskiren (DIA) and cotreated with exendin-4 and Aliskiren (DEA). Heart perfusion with (125)I-GLP-1 was performed to estimate GLP-1 binding affinity (τ = 1/k-n) to its receptor in the heart. Western Blotting was assessed to determine the expression variation of GLP-1 receptor in the heart. Plasma GLP-1 levels were measured using Enzyme-Linked Immunosorbent Assay (ELISA). Diabetes decreased the τ value on CE and increased it on CMs compared to normal. The combination of Exendin-4 with Aliskiren showed a normalizing effect on the binding affinity of GLP-1 at the coronary endothelium, while at the cardiomyocyte level Exendin-4 treatment alone was the most effective.

Topics: Amides; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Drug Evaluation, Preclinical; Exenatide; Fumarates; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart; Hypoglycemic Agents; Male; Myocardium; Peptides; Protein Binding; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Renin; Streptozocin; Venoms

We examined whether the renin inhibitor, aliskiren, provides similar or greater protection than ACE inhibition from non-proliferative diabetic retinopathy and from the proliferative neoangiogenesis of oxygen-induced retinopathy.. Transgenic (mRen-2)27 rats, which overexpress mouse renin and angiotensin in extra-renal tissues, were studied. For diabetic studies, non-diabetic, diabetic (streptozotocin, 55 mg/kg), diabetic + aliskiren (10 mg kg(-1) day(-1), pump), or diabetic + lisinopril (10 mg kg(-1) day(-1), drinking water) rats were evaluated over 16 weeks. For oxygen-induced retinopathy studies, rats were exposed to 80% oxygen (22 h/day) from postnatal days 0 to 11, and then room air from postnatal days 12 to 18. Aliskiren (10 or 30 mg kg(-1) day(-1), pump) or lisinopril (10 mg kg(-1) day(-1), drinking water) was administered during retinopathy development between postnatal days 12 and 18.. Systolic BP in diabetic (mRen-2)27 rats was reduced with 10 mg kg(-1) day(-1) aliskiren, but only lisinopril normalised systolic blood pressure. In diabetic (mRen-2)27 rats, 10 mg kg(-1) day(-1) aliskiren and lisinopril reduced retinal acellular capillaries and leucostasis to non-diabetic levels. In oxygen-induced retinopathy, neoangiogenesis and retinal inflammation (leucostasis, ED-1 immunolabelling) were partially reduced by 10 mg kg(-1) day(-1) aliskiren and normalised by 30 mg kg(-1) day(-1) aliskiren, whereas lisinopril normalised neoangiogenesis and reduced leucostasis and ED-1 immunolabelling. Aliskiren and lisinopril normalised retinal vascular endothelial growth factor expression; however, only aliskiren reduced intercellular adhesion molecule-1 to control levels.. Aliskiren provided similar or greater retinal protection than ACE inhibition and may be a potential treatment for diabetic retinopathy.

Topics: Amides; Animals; Animals, Genetically Modified; Diabetic Retinopathy; Female; Fumarates; Lisinopril; Mice; Neovascularization, Pathologic; Oxygen; Rats; Renin

Aliskiren is a nonpeptide antihypertensive drug that potently inhibits the human enzyme renin in vitro and in vivo. Many clinical trials have shown the efficacy of aliskiren to lower blood pressure in correlation with other antihypertensive agents. In this report, the conformational behavior of aliskiren is studied in water, trifluoroethanol, and dimethylformamide solutions by means of 2D-NMR spectroscopy and molecular dynamics simulations. The stereochemical characteristics of aliskiren in different solutions, in combination with the previously published crystal structure of the renin-aliskiren complex have been investigated. The aim of this study was to explore the conformational behavior of this first successful renin inhibitor in relation to its environment. In aqueous solution, aliskiren adapts a U-shape conformation, whereas in DMF, the molecule is basically endowed with an "extended" conformation, which has more similarities to the one bound to the receptor.

Topics: Amides; Crystallography, X-Ray; Fumarates; Magnetic Resonance Spectroscopy; Molecular Conformation; Molecular Dynamics Simulation; Renin; Stereoisomerism

To compare the effect of the direct renin inhibitor aliskiren on neurohumoral activity in heart failure patients treated with low-dose and high-dose ACE inhibitor.. A retrospective analysis of the ALOFT trial. Comparison of the effects of 6 months treatment with aliskiren (versus placebo) in patients receiving

Topics: Aged; Aldosterone; Amides; Angiotensin-Converting Enzyme Inhibitors; Female; Fumarates; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Randomized Controlled Trials as Topic; Renin; Retrospective Studies; Single-Blind Method

Activation of the atrial renin-angiotensin system plays an important role in the pathophysiology of atrial fibrillation (AF). The pulmonary vein (PV) and left atrium (LA) are important trigger and substrate for the genesis of AF. We investigate the effects of a direct renin inhibitor, aliskiren, on the PV and LA arrhythmogenic activity and the underlying electromechanical mechanisms. Conventional microelectrodes were used to record action potentials and contractility in isolated rabbit PVs and LA tissues before and after the administration of aliskiren (0.1, 1, 3 and 10 μM). By the whole-cell patch clamp and indo-1 fluorimetric ratio techniques, ionic currents and intracellular calcium transient were studied in isolated single PV and LA cardiomyocyte before and after the administration of aliskiren (3 μM). Aliskiren (0.1, 1, 3 and 10 μM) reduced PV firing rate in a concentration-dependent manner (6, 10, 14 and 17%) and decreased PV diastolic tension, which could be attenuated in the presence of 100 μM L-N(G)-Nitroarginine Methyl Ester (L-NAME). Aliskiren induced PV automatic rhythm exit block causing slow and irregular PV activity with variable pauses. Aliskiren increased PV and LA contractility, which could be abolished by pre-treating with 0.1 μM ryanodine. Aliskiren (3 μM) decreased L-type calcium currents, but increased reverse-mode of Na( + )/Ca(2+ ) exchanger currents, intracellular calcium transients, and sarcoplasmic reticulum calcium content in PV and LA cardiomyocytes. Pretreatment with renin, losartan or angiotensin II did not alter the effect of aliskiren on sarcolemmal calcium flux. In conclusion, aliskiren reduces PV arrhythmogenic activity with a direct vasodilatory property and has a positive inotropic effect on cardiomyocytes. These findings may reveal the anti-arrhythmic and anti-heart failure potentials of aliskiren.

Topics: Action Potentials; Amides; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Calcium; Excitation Contraction Coupling; Fumarates; Heart Atria; Myocardial Contraction; Organ Culture Techniques; Patch-Clamp Techniques; Pulmonary Veins; Rabbits; Renin

The role of the renin-angiotensin system in cognitive impairment is unclear. This work was undertaken to test our hypothesis that renin-angiotensin system may contribute to cognitive decline and brain damage caused by chronic cerebral ischemia. C57BL/6J mice were subjected to bilateral common carotid artery stenosis with microcoil to prepare mice with chronic cerebral hypoperfusion, a model of subcortical vascular dementia. The effects of aliskiren, a direct renin inhibitor, or Tempol, a superoxide scavenger, on brain damage and working memory in these mice were examined. Chronic cerebral hypoperfusion significantly increased brain renin activity and angiotensinogen expression in C57BL/6J mice, which was attributed to the increased renin in activated astrocytes and microvessels and the increased angiotensinogen in activated astrocytes in white matter. Aliskiren pretreatment significantly inhibited brain renin activity and ameliorated brain p67(phox)-related NADPH oxidase activity, oxidative stress, glial activation, white matter lesion, and spatial working memory deficits in C57BL/6J mice with bilateral common carotid artery stenosis. To elucidate the role of oxidative stress in brain protective effects of aliskiren, we also examined the effect of Tempol in the same mice with bilateral common carotid artery stenosis. Tempol pretreatment mimicked the brain protective effects of aliskiren in this mouse model. Posttreatment of mice with aliskiren or Tempol after bilateral common carotid artery stenosis also prevented cognitive decline. In conclusion, chronic cerebral hypoperfusion induced the activation of the brain renin-angiotensin system. Aliskiren ameliorated brain damage and working memory deficits in the model of chronic cerebral ischemia through the attenuation of oxidative stress. Thus, direct renin inhibition seems to be a promising therapeutic strategy for subcortical vascular dementia.

Topics: Amides; Angiotensinogen; Animals; Antihypertensive Agents; Blood Pressure; Brain Damage, Chronic; Brain Ischemia; Cognition Disorders; Cyclic N-Oxides; Dementia, Vascular; Disease Models, Animal; Fumarates; Hypertension; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Oxidative Stress; Renin; Renin-Angiotensin System; Risk Factors; Spin Labels

Hypertensive chronic kidney disease (CKD) patients often have sympathetic hyperactivity, which appears to contribute to the pathogenesis of hypertension and cardiovascular organ damage. Experimental studies and some clinical studies have shown that statin therapy can reduce central sympathetic activity. Blockade of the renin-angiotensin system (RAS), which is standard treatment for CKD, is known to lower sympathetic activity. We hypothesized that adding a statin for 6 weeks to RAS blockade would further lower sympathetic activity in hypertensive stage 2-4 CKD patients.. In 10 stable CKD patients (eight men, aged 45 ± 11 years, estimated glomerular filtration rate 56 ± 22 ml/min per 1.73 m2), who were on chronic treatment with aliskiren 300 mg, blood pressure and sympathetic activity (quantified by assessment of muscle sympathetic nerve activity, MSNA) were assessed at baseline and 6 weeks after atorvastatin 20 mg/day was added. Ten other CKD patients served as time control and were studied twice with an interval of 6 weeks without any change in medication, to quantify within participant reproducibility.. Mean arterial blood pressure remained stable throughout the study (93 ± 5 versus 94 ± 5 mmHg). MSNA was reduced from 28 ± 8 to 20 ± 6 bursts/min (P = 0.01), while heart rate remained stable during the study. In the control CKD group, MSNA did not change: 26 ± 5 to 25 ± 6 bursts/min. Atorvastatin reduced total and low-density lipoprotein cholesterol.. Atorvastatin has a further sympatholytic effect in CKD patients, who are on chronic aliskiren, which is independent of blood pressure and heart rate.

Topics: Adult; Amides; Arteries; Atorvastatin; Blood Pressure; Case-Control Studies; Female; Fumarates; Glomerular Filtration Rate; Heart Rate; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney Failure, Chronic; Male; Middle Aged; Pyrroles; Sympathetic Nervous System; Sympatholytics; Time Factors

Topics: Adult; Aged; Amides; Antihypertensive Agents; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Patient Compliance; Prospective Studies; Renin

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS, decreases NO synthesis. Plasma ADMA concentrations increase markedly in hypertension. We tested whether the development of hypertension and the increases in ADMA in spontaneously hypertensive rats (SHR) are prevented by aliskiren, a renin inhibitor. Male SHRs and normotensive Wistar Kyoto (WKY) control rats, aged 4 weeks (pre-hypertensive stage), were assigned to 4 groups: untreated SHRs and WKY rats, and SHRs that received oral aliskiren 10 and 30 mg/kg/day for 6 weeks. All rats were sacrificed at age 10 weeks. Blood pressure decreased at age 6, 8, and 10 weeks in SHRs that received high-dose aliskiren. Aliskiren mitigated the increases in plasma ADMA in SHRs. Renal ADMA levels were lower in SHRs that received high-dose aliskiren versus SHRs. SHRs experienced decreased plasma and kidney l-Arg-to-ADMA ratios versus control rats, which were reverted by 30 mg/kg aliskiren. Renal cortical neuronal NOS-α and -β levels increased in SHRs fed with high-dose aliskiren. Early aliskiren treatment mitigates increases in ADMA, restores l-Arg-to-ADMA ratios, enhances neuronal NOS-α, prevents decreased nNOS-β levels in the kidney-which might restore NO bioavailability and contribute to the decrease of blood pressure in young SHRs. Our findings suggest that aliskiren is a therapeutic agent for prehypertension that regulates the ADMA/NO pathway.

Topics: Amides; Animals; Antihypertensive Agents; Arginine; Blood Pressure; Dose-Response Relationship, Drug; Fumarates; Gene Expression Regulation, Enzymologic; Hypertension; Kidney Cortex; Male; Nitric Oxide; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Rats; Rats, Inbred SHR; Renin

Blockade of the renin-angiotensin system (RAS) with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II (Ang II) receptor blockers (ARBs) slow the progression of various chronic kidney diseases and chronic allograft dysfunction. RAS inhibition can be achieved also by directly blocking renin upstream from ACE. However, direct renin inhibition can have additional effects since formation of renoprotective Ang II breakdown products such as angiotensin (Ang) (1-7) that are produced by ACE2 are also inhibited.. Using a Fischer-to-Lewis renal transplantation model, the effect of the renin inhibitor aliskiren (10 mg/kg/day) was assessed on the development of chronic allograft dysfunction compared with vehicle treatment and Ang II receptor blockers candesartan.. Aliskiren had no effect on renal function (proteinuria, creatinine clearance) or on renal morphological changes (glomerulosclerosis collagen deposition, myofibroblast accumulation and macrophage infiltration) compared with the vehicle- and candesartan-treated animals determined 24 weeks after transplantation. On the other hand, atrophy of tubular cells was significantly attenuated. Candesartan reduced both proteinuria and structural injury of the kidney. In aliskiren-treated animals reduced serum Ang II and Ang (1-7) levels were detected, whereas the level of urine angiotensinogen was unchanged.. The renin inhibitor aliskiren does not slow the progression of chronic allograft dysfunction. We suggest that the lack of protection might be due to reduced formation of the protective Ang II breakdown products such as Ang (1-7) or due to unchanged intrarenal RAS activity demonstrated by urinary angiotensinogen levels.

Topics: Amides; Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Biphenyl Compounds; Fumarates; Kidney; Kidney Transplantation; Male; Models, Animal; Peptide Fragments; Rats; Rats, Inbred F344; Rats, Inbred Lew; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Tetrazoles; Transplantation, Homologous

We assessed the ability of Aliskiren (AL), a direct renin inhibitor, and Valsartan (VA), an angiotensin receptor blocker, to limit myocardial infarct size (IS) in mice with type-2 diabetes mellitus.. Db/Db mice, fed Western Diet, received 15-day pretreatment with: 1) vehicle; 2) AL 25 mg/kg/d; 3) AL 50 mg/kg/d; 4) VA 8 mg/kg/d; 5) VA 16 mg/kg/d; 6) AL 25+VA 16 mg/kg/d; or 7) AL 50+VA 16 mg/kg/d. Mice underwent 30 min coronary artery occlusion and 24 h reperfusion. Area at risk (AR) was assessed by blue dye and IS by TTC staining. Protein expression was assessed by immunobloting.. IS in the control group was 42.9 ± 2.1% of the AR. AL at 25 (21.9 ± 2.9%) and 50 mg/kg/d (15.5 ± 1.3%) reduced IS. VA at 16 mg/kg/d (18.8 ± 1.2%), but not at 8 mg/kg/d (35.2 ± 4.0%), limited IS. IS was the smallest in the AL50+VA16 group (6.3 ± 0.9%). Both AL and VA reduced myocardial AT1R levels, without affecting AT2R levels, and increased the expression of Sirt1 and PGC-1α with increased phosphorylation of Akt and eNOS.. AL, dose dependently limited myocardial IS in mice with type-2 diabetes mellitus. At doses shown to limit IS in non-diabetic animals, VA failed to reduce IS in Db/Db mice. However, at higher dose (16 mg/kg/d), VA reduced IS. Both drugs reduced the expression of AT1R and increased myocardial levels of the longevity genes Sirt1 and PGC-1α along with increased Akt and eNOS phosphorylation.

Topics: Administration, Oral; Amides; Angiotensin II Type 1 Receptor Blockers; Animals; Diabetes Mellitus, Experimental; Drug Therapy, Combination; Fumarates; Hemodynamics; Immunoblotting; Male; Mice; Mice, Inbred Strains; Myocardial Infarction; Myocardial Reperfusion Injury; Receptor, Angiotensin, Type 1; Renin; Tetrazoles; Valine; Valsartan

Topics: Amides; Animals; Fumarates; Kidney; Kidney Transplantation; Male; Renin

The Bartter syndrome is a rare hereditary salt-wasting tubulopathy, characterized by metabolic alkalosis, hypokalemia, hyperreninemia and hyperaldosteronemia of varying severity. Indomethacin and high doses of oral potassium have been until now the therapeutic strategies used, with high risk of gastrointestinal injury. Since April 2009, aliskiren--renin inhibitor--has been used in individual cases of Bartter syndrome in adults, by ignoring its use in pediatrics. The authors present the case of an eight year old child with Bartter syndrome, treated with oral potassium chloride and oral indomethacin, whom has been diagnosed a giant gastric ulcer. To enable the reduction of the amount of potassium administered, we chose to start the aliskiren.

Topics: Amides; Anti-Inflammatory Agents, Non-Steroidal; Bartter Syndrome; Child; Fumarates; Humans; Indomethacin; Male; Potassium Chloride; Renin

The effect of renin inhibition on type 2 diabetes is still unclear. The present study was undertaken to examine the efficacy of aliskiren, a direct renin inhibitor, on cardiovascular injuries, glucose intolerance and pancreatic injury in a mouse model of type 2 diabetes.. Groups of db/db mice, with obesity and type 2 diabetes, were treated with aliskiren (3, 6, 12 and 25 mg kg(-1) day(-1)) or hydralazine (80 mg kg(-1) day(-1)) for 6 weeks, and the protective effects were extensively compared among groups.. All sub-pressor and hypotensive doses of aliskiren significantly attenuated cardiac fibrosis, macrophage infiltration and coronary remodelling, and improved vascular endothelial function in db/db mice. These protective effects of aliskiren were attributed to the attenuation of cardiac p22(phox)-related NADPH oxidase-induced superoxide and the restoration of vascular endothelial nitric oxide synthase (eNOS) production. Aliskiren at the highest dose (25 mg kg(-1) day(-1)), but not at lower doses, partially reduced glucose intolerance in db/db mice. Furthermore, the highest dose of aliskiren significantly attenuated the decreases in pancreatic islet insulin content and beta cell mass, and prevented pancreatic islet fibrosis in db/db mice, being associated with the reduction of 8-hydroxy-2'-deoxyguanosine-positive cells and Nox2 (also known as Cybb) expression in pancreatic islets by aliskiren.. Our work provides the first evidence that direct renin inhibition with aliskiren protects against cardiovascular complications and pancreatic injury, through the attenuation of oxidative stress. Thus, we propose that aliskiren may be a promising therapeutic agent for type 2 diabetes.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Fumarates; Glucose Intolerance; Hydralazine; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Obesity; Organ Size; Pancreas; Renin

Renin-angiotensin system (RAS) activation contributes to kidney injury through oxidative stress. Renin is the rate-limiting step in angiotensin (ANG II) generation. Recent work suggests renin inhibition improves proteinuria comparable to ANG type 1 receptor (AT1R) blockade (ARB). Thereby, we investigated the relative impact of treatment with a renin inhibitor vs. an ARB on renal oxidative stress and associated glomerular structural and functional changes in the transgenic Ren2 rat, which manifests hypertension, albuminuria, and increased tissue RAS activity. Young Ren2 and age-matched Sprague-Dawley (SD) controls (age 6-9 wk) were treated with a renin inhibitor (aliskiren), an ARB (irbesartan), or vehicle for 21 days. Ren2 rats exhibited increases in systolic pressure (SBP), albuminuria, and renal 3-nitrotyrosine content as well as ultrastructural podocyte foot-process effacement and diminution of the podocyte-specific protein nephrin. Structural and functional alterations were accompanied by increased renal cortical ANG II, AT1R, as well as NADPH oxidase subunit (Nox2) expression compared with SD controls. Abnormalities were attenuated to a similar extent with both aliskiren and irbesartan treatment. Despite the fact the dose of irbesartan used caused a greater reduction in SBP than aliskerin treatment (P < 0.05), the effects on proteinuria, nephrin, and oxidative stress were similar between the two treatments. Our results highlight both the importance of pressor-related reductions on podocyte integrity and albuminuria as well as RAS-mediated oxidant stress largely comparable between ARB and renin inhibition treatment.

Topics: Albuminuria; Amides; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Biphenyl Compounds; Blood Pressure; Fumarates; Glomerular Filtration Rate; Hypertension; Irbesartan; Kidney; Membrane Glycoproteins; Membrane Proteins; NADPH Oxidase 2; NADPH Oxidases; Oxidative Stress; Podocytes; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Tetrazoles; Tyrosine

A direct renin inhibitor (DRI) had a benefit in decreasing albuminuria in type 2 diabetic patients having already been treated with angiotensin (Ang) II type 1 receptor blocker (ARB), suggesting that aliskiren may have another effect other than blockade of the traditional renin-angiotensin system (RAS). Recently, prorenin bound to (pro)renin receptor ((P)RR) was found and shown to evoke two pathways; the generation of Ang peptides and the receptor-dependent activation of extracellular signal-related protein kinase (ERK). Because (P)RR is present in the podocytes, a central component of the glomerular filtration barrier, we hypothesized that aliskiren influences the (P)RR-induced two pathways in human podocytes.. Human podocytes were treated with 2 nmol/l prorenin in the presence and absence of an angiotensin-converting enzyme inhibitor (ACEi) imidaprilat, an ARB candesartan, a DRI aliskiren, or the siRNA knocking down the (P)RR mRNA and the intracellular AngII levels and the phosphorylation of ERK were determined.. The expression of (P)RR mRNA of human podocytes was unaffected by the treatment with RAS inhibitors, but decreased by 69% with the siRNA treatment. The basal levels of intracellular AngII and the prorenin-induced increase in intracellular AngII were significantly reduced by aliskiren and siRNA treatment, compared with imidaprilat and candesartan. The prorenin-induced ERK activation was reduced to control level by the siRNA treatment, but it was unaffected by imidaprilat, candesartan, or aliskiren.. Aliskiren is the most potent inhibitor of intracellular AngII levels of human podocytes among RAS inhibitors, although it is incapable of inhibiting the (P)RR-dependent ERK phosphorylation.

Topics: Amides; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Cells, Cultured; Extracellular Signal-Regulated MAP Kinases; Fumarates; Humans; Imidazolidines; Phosphorylation; Podocytes; Prorenin Receptor; Receptors, Cell Surface; Renin; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Tetrazoles

Topics: Ambulatory Care; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Body Mass Index; Clinical Trials as Topic; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Obesity, Abdominal; Perindopril; Ramipril; Renin; Time Factors

Gender and body weight influence the pharmacokinetics and pharmacodynamics of many drugs. This pooled analysis of 17 clinical studies evaluated the effect of gender, body mass index (BMI), body weight, and lean body weight (LBW) on the pharmacokinetics of the direct renin inhibitor aliskiren in healthy volunteers (n = 392). A separate pooled analysis of 5 clinical studies in patients with hypertension (n = 2327) assessed the influence of gender and BMI on the effects of aliskiren on plasma renin activity and blood pressure. Area under the aliskiren plasma concentration-time curve (AUC(τ)) was 22% lower and the peak aliskiren plasma concentration (C(max)) was 24% lower in men than women (P < .05). BMI was not significantly correlated with AUC(τ) (r = 0.005; P = .917); AUC(τ) was negatively correlated with body weight (r = -0.235; P < .0001) and LBW (r = -0.295; P < .0001). Results were similar for C(max). Adjusting individual aliskiren AUC(τ) and C(max) values for overall mean body weight or LBW abolished gender differences. Based on r(2) values, LBW variation accounted for 8.9% of aliskiren AUC(τ) variation. In patients with hypertension, gender and BMI did not significantly influence the effects of aliskiren on plasma renin activity or blood pressure. It was concluded that lower systemic exposure to aliskiren in men versus women relates to differences in body weight; neither gender nor body weight has clinically relevant effects on the pharmacokinetics or pharmacodynamics of aliskiren.

Topics: Adult; Amides; Antihypertensive Agents; Blood Pressure; Body Composition; Body Mass Index; Body Weight; Clinical Trials as Topic; Female; Fumarates; Humans; Hypertension; Male; Renin; Sex Characteristics

The renin-angiotensin-aldosterone system plays a key role in the development of hypertension-related target organ damage. Nonetheless, compensatory increases in plasma renin levels that lead to adjustments in angiotensin production and conversion limit the potential benefits of both angiotensin converting enzyme inhibitors and angiotensin receptor blockers. On the other hand, the ONTARGET trial reported that the combination of two renin-angiotensin system inhibitors was associated with more adverse events without an increase in benefit. Aliskiren is a novel direct renin inhibitor with promising results. In this manuscript the current evidence about aliskiren, alone or in combination, is analyzed.

Topics: Amides; Antihypertensive Agents; Cardiovascular System; Clinical Trials as Topic; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

We report a "macrocycle route" toward aliskiren, a drug presently marketed for the treatment of hypertension, using a highly stereocontrolled approach starting from a common "isopropyl chiron". Highlights of the synthesis include a challenging RCM reaction to produce a nine-membered unsaturated lactone, a highly stereoselective catalytic Du Bois aziridination, and a regio- and diastereoselective aziridine ring-opening to a vicinal amino alcohol.

Topics: Amides; Antihypertensive Agents; Fumarates; Hypertension; Protease Inhibitors; Renin; Stereoisomerism; Substrate Specificity

The present drug utilization research project was conducted in order to evaluate the current status of antihypertensive drug treatment at launch of aliskiren - a drug targeting a completely new pharmacological mode of action - and to investigate the potential therapeutic value of this new therapeutic principle.. In 1,431 primary care practices in Germany, general practitioners and internal specialists were requested to determine the therapeutic value of different antihypertensive drugs (3rd and 4th quarter of 2007). Physicians were also requested to expose potential advantages of the new therapeutic principle of direct renin inhibition. Additional epidemiologic data such as age, gender and comorbidities were collected for each antihypertensive patient considered an optimal candidate to receive aliskiren in the respective medical practice due to an unfavorable response to the current antihypertensive treatment by using a second questionnaire.. On a scale between 1 (very important) and 6 (unimportant), the therapeutic value of antihypertensive drugs was judged as follows: angiotensin-inhibiting enzyme (ACE) inhibitors (98.8%), angiotensin (AT)(1) receptor blockers (87.4%), beta-receptor blockers (71.2%), calcium channel blockers (58.9%), thiazide diuretics (56,3%), and loop diuretics (32.3%) were judged with the mark 1 (very important) and 2 (important). From a total of 14,358 patients included in the present survey, age, gender, severity and duration of arterial hypertension, complications and comorbidities, and a detailed drug history were collected. 50.3% of the patients received an ACE inhibitor, 27.9% an AT(1) receptor blocker, 45.7% a beta-receptor blocker, 37.5% a calcium channel blocker, and 53.2% a diuretic. Dominating comorbidities up to the time of data collection were diabetes mellitus (43.8%), coronary heart disease (37.3%), and chronic heart failure (20.7%). 89.4% of patients with diabetes received either an ACE inhibitor or an AT(1) receptor blocker compared to 69.6% of patients not suffering from diabetes.. According to the evaluation of primary care physicians participating in this study, aliskiren might be useful for antihypertensive treatment in patients with severe arterial hypertension, in patients with an already long-lasting course of disease, and in the presence of comorbidities such as diabetes mellitus. The high percentage of patients in this study cohort already treated with an ACE inhibitor or an AT(1) receptor blocker represents good adherence of primary care physicians to current treatment guidelines. The evaluation of loop diuretics as important antihypertensive drugs by 32.3% of attending physicians in this study requires critical discussion.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Comorbidity; Drug Approval; Drug Therapy, Combination; Drug Utilization; Female; Fumarates; Germany; Humans; Hypertension; Male; Middle Aged; Practice Patterns, Physicians'; Primary Health Care; Renin; Treatment Outcome

Addition of aliskiren, a direct renin inhibitor, to losartan provides additive reduction of urinary albumin excretion in type 2 diabetic patients. However, the detailed effect of aliskiren on type 2 diabetic nephropathy is still unknown. This study was undertaken to examine the efficacy of aliskiren and the combination of aliskiren with valsartan on type 2 diabetic nephropathy.. db/db mice were treated with aliskiren (3 mg/kg per day), valsartan (5 or 10 mg/kg per day), combined aliskiren (3 mg/kg per day) and valsartan (5 mg/kg per day), and hydralazine (80 mg/kg per day), for 6 weeks, and the protective effects against diabetic nephropathy were compared among each group.. Aliskiren significantly attenuated albuminuria and glomerular mesangial matrix expansion in db/db mice, which was associated with the improvement of the increased glomerular transforming growth factor-beta and type IV collagen expressions, the increased macrophage infiltration, and the decreased glomerular nephrin expression of db/db mice. These protective effects of aliskiren in db/db mice were attributed to the attenuation of p22(phox)-related nicotinamide adenine dinucleotide phosphate oxidase-induced superoxide. Addition of aliskiren to valsartan treatment provided more beneficial effects on all the above-mentioned parameters than valsartan monotherapy.. Aliskiren protected against type 2 diabetic nephropathy, through pleiotropic effects, and significantly enhanced the protective effects of valsartan against diabetic nephropathy in db/db mice.

Topics: Albuminuria; Amides; Animals; Collagen Type IV; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Synergism; Fumarates; Kidney Glomerulus; Losartan; Male; Mice; Mice, Inbred C57BL; Tetrazoles; Transforming Growth Factor beta; Valine; Valsartan

To verify the recently proposed concept that mast cell-derived renin facilitates angiotensin II-induced bronchoconstriction bronchial rings from male Sprague-Dawley rats were mounted in Mulvany myographs, and exposed to the mast cell degranulator compound 48/80 (300 microg/ml), angiotensin I, angiotensin II, bradykinin or serotonin (5-hydroxytryptamine, 5-HT), in the absence or presence of the renin inhibitor aliskiren (10 micromol/l), the ACE inhibitor captopril (10 micromol/l), the angiotensin II type 1 (AT1) receptor blocker irbesartan (1 micromol/l), the mast cell stabilizer cromolyn (0.3 mmol/l), the 5-HT2A/2C receptor antagonist ketanserin (0.1 micromol/l) or the alpha1-adrenoceptor antagonist phentolamine (1 micromol/l). Bath fluid was collected to verify angiotensin generation. Bronchial tissue was homogenized to determine renin, angiotensinogen and serotonin content. Compound 48/80 contracted bronchi to 24+/-4% of the KCl-induced contraction. Ketanserin fully abolished this effect, while cromolyn reduced the contraction to 16+/-5%. Aliskiren, captopril, irbesartan and phentolamine did not affect this response, and the angiotensin I and II levels in the bath fluid after 48/80 exposure were below the detection limit. Angiotensin I and II equipotently contracted bronchi. Captopril shifted the angiotensin I curve approximately 10-fold to the right, whereas irbesartan fully blocked the effect of angiotensin II. Bradykinin-induced constriction was shifted approximately 100-fold to the left with captopril. Serotonin contracted bronchi, and ketanserin fully blocked this effect. Finally, bronchial tissue contained serotonin at micromolar levels, whereas renin and angiotensinogen were undetectable in this preparation. In conclusion, mast cell degranulation results in serotonin-induced bronchoconstriction, and is unlikely to involve renin-induced angiotensin generation.

Topics: Amides; Angiotensinogen; Animals; Biphenyl Compounds; Bronchi; Bronchoconstriction; Captopril; Cell Degranulation; Fumarates; In Vitro Techniques; Irbesartan; Male; Mast Cells; Methacholine Chloride; p-Methoxy-N-methylphenethylamine; Rats; Rats, Sprague-Dawley; Renin; Serotonin; Tetrazoles

Peritoneal fibrosis (PF) is a recognized complication of long-term peritoneal dialysis (PD) and can lead to ultrafiltration failure. The present study was designed to investigate the protective effects of aliskiren on chlorhexidine digluconate-induced PF in rats.. The PF was induced in Sprague-Dawley rats by daily administration of 0.5 mL 0.1% chlorhexidine digluconate in normal saline via PD tube for 1 week. Rats received daily intravenous injections of low-dose aliskiren (1 mg kg(-1)) or high-dose aliskiren (10 mg kg(-1)) for 1 week. After 7 days, conventional 4.25% Dianeal (30 mL) was administered via a PD catheter with a dwell time of 4 h and assessed of peritoneal function. At the end of dialysis, rats were sacrificed and the liver peritoneum was harvested for microscopically and immunohistochemistry.. There was no significant difference in mean arterial pressure and heart rate between groups. After 4 h of PD, the D(4)/P(4) urea level was reduced, the D(4)/D(0) glucose level, serum and dialysate transforming growth factor-beta1 (TGF-beta1) level was increased, the liver peritoneum was markedly thicker, and the expression of TGF-beta1, alpha-smooth muscle actin (alpha-SMA), fibronectin, collagen, and vascular endothelial growth factor (VEGF) were elevated in the PS group compared with the vehicle group. Aliskiren decreased the serum and dialysate TGF-beta1 level, decreased the thickness of the liver peritoneum, and decreased the expression of TGF-beta1, alpha-SMA, fibronectin, collagen, and VEGF-positive cells in liver peritoneum. Moreover, high-dose aliskiren had better protective effects against PF than low dose in rats.. Aliskiren protected against chlorhexidine digluconate-induced PF in rats by decreasing TGF-beta1 production.

Topics: Amides; Animals; Anti-Infective Agents; Chlorhexidine; Fumarates; Peritoneal Dialysis; Peritoneal Fibrosis; Rats; Rats, Sprague-Dawley; Renin; Transforming Growth Factor beta1; Treatment Outcome

This study aimed to investigate the possible effects of ABCB1 haplotypes on the pharmacokinetics and renin-inhibiting effect of aliskiren.. Eleven healthy volunteers homozygous for the ABCB1 c.1236C-c.2677G-c.3435C (CGC) haplotype and 11 homozygous for the c.1236T-c.2677T-c.3435T (TTT) haplotype ingested a single 150-mg dose of aliskiren. Plasma aliskiren concentrations were measured up to 72 h, its excretion into urine up to 12 h, and plasma renin activity up to 24 h.. The ABCB1 haplotypes had no significant effect on the pharmacokinetics or renin-inhibiting effect of aliskiren. The geometric mean ratio (95% confidence interval) of aliskiren peak plasma concentration and area under the plasma concentration-time curve from 0 h to infinity in participants homozygous for the TTT haplotype to those in participants homozygous for the CGC haplotype were 1.14 (0.66, 1.96; P = 0.631) and 1.01 (0.58, 1.76; P = 0.960) respectively.. These data suggest that the ABCB1 c.1236C-c.2677G-c.3435C and c.1236T-c.2677T-c.3435T haplotypes have no clinically meaningful effect on the pharmacokinetics of aliskiren.

Topics: Adult; Amides; Antihypertensive Agents; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Female; Fumarates; Haplotypes; Humans; Male; Renin

The renin-angiotensin system affects insulin sensitivity mainly through the angiotensin II type 1 receptor. In this study, the effects of renin inhibition on insulin resistance and adipose tissue dysfunction were explored in type 2 diabetic KK-A(y) mice.. Male KK-A mice were treated with a direct renin inhibitor, aliskiren, administered subcutaneously at a dose of 50 mg/kg per day for 14 days using an osmotic minipump. This dose of aliskiren strongly inhibited plasma renin activity and lowered blood pressure about 17% in KK-A(y) mice. Aliskiren decreased body weight and plasma glucose level, and increased plasma insulin level in a fed condition. Aliskiren also lowered the plasma levels of cholesterol, fatty acids and triglycerides. In the oral glucose tolerant test, the plasma glucose elevation after glucose load was reduced by aliskiren, without a significant change in insulin level. Insulin tolerance test showed that aliskiren enhanced insulin's effect on plasma glucose. Aliskiren also reduced the epididymal adipose tissue mass by 25% and retroperitoneal adipose tissue mass by 35%. In adipose tissue, expression of the insulin receptor was not changed by aliskiren; however, expression of insulin receptor substrate-1, glucose transporter type 4, adiponectin, peroxisome proliferator-activated receptor-gamma and CCAAT/enhancer-binding proteindelta was increased by aliskiren. Moreover, NADPH oxidase activity and expression of inflammatory factors were reduced in adipose tissue. Aliskiren increased the pancreatic beta-cell area in KK-A(y) mice.. These results suggest that renin inhibition by aliskiren improved insulin resistance and adipose tissue dysfunction in type 2 diabetic mice through an increase in insulin sensitivity, insulin secretion and adipocyte differentiation, and a reduction of oxidative stress.

Topics: Adiponectin; Adipose Tissue; Amides; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Fumarates; Glucose; Glucose Transporter Type 4; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Male; Mice; PPAR gamma; Renin; Renin-Angiotensin System

Topics: Amides; Antihypertensive Agents; Drug Combinations; Fumarates; Humans; Hydrochlorothiazide; Hypertension

The blood pressure-lowering effect of the renin inhibitor aliskiren equals that of angiotensin-converting enzyme (ACE) inhibitors and angiotensin (Ang) II type 1 (AT1) receptor blockers. Whether aliskiren offers end-organ protection remains to be investigated. Here, we compared the cardiac effects of aliskiren, the AT1 receptor blocker irbesartan and the ACE inhibitor captopril in spontaneously hypertensive rats (SHR) at equi-hypotensive doses.. SHR were treated for 1-3 weeks with vehicle, aliskiren, captopril or irbesartan (100, 3 and 15 mg/kg per day, respectively) using an osmotic minipump, and compared to vehicle-treated Wistar-Kyoto (WKY) controls. All drugs lowered (but not normalized) mean arterial pressure in SHR equi-effectively, as monitored by radiotelemetry, without altering heart rate. All drugs also reduced the increased cardiomyocyte area in SHR, and tended to normalize the elevated brain natriuretic peptide plasma levels. In the Langendorff set-up, all drugs normalized the diminished endothelium-dependent vasodilator response to bradykinin in SHR. Moreover, aliskiren and irbesartan, but not captopril, decreased the enhanced coronary Ang II response in SHR. Aliskiren reduced plasma renin activity and the plasma and tissue angiotensin levels at 1 week of treatment; yet, after 3 weeks of aliskiren treatment only the cardiac angiotensin levels remained suppressed, whereas no tissue angiotensin reductions were seen with captopril or irbesartan.. For a given decrease in blood pressure, aliskiren improves coronary endothelial function and decreases cardiac hypertrophy in SHR to at least the same degree as ACE inhibition and AT1 receptor blockade. In addition, aliskiren diminishes the enhanced Ang II response in the coronary circulation of SHR and offers superior long-term cardiac angiotensin suppression.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Animals; Biphenyl Compounds; Blood Pressure; Captopril; Disease Models, Animal; Dose-Response Relationship, Drug; Fumarates; Heart; Heart Ventricles; Hypertension; Hypertrophy; Irbesartan; Male; Natriuretic Peptide, Brain; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; Tetrazoles

Human (pro)renin receptor ((P)RR) has been implicated in the augmentation of many biological and cellular processes through bindings to its ligands, renin and prorenin. In this study, we investigated the effects of aliskiren, a direct oral renin inhibitor, on the activities of free and (P)RR-bound forms of human mature renin. We also elucidated the effect of aliskiren on the 'renin activity' of the receptor-bound form of prorenin. Aliskiren had an IC(50) of 0.72 nmol l(-1) against renin. The compound competitively inhibited renin activity with an inhibitory constant (K(i)) of 0.18 nmol  l(-1). Furthermore, the dissociation constants (K(D)) for aliskiren from renin and prorenin bound to (P)RR were determined using surface plasmon resonance in a BIAcore assay system (Uppsala, Sweden). These values were estimated to be 0.46 ± 0.03 and 0.25 ± 0.01 nmol  l(-1), respectively. The compound competitively inhibited the renin activities of (P)RR-bound forms of both renin and prorenin with a K(i) of 0.14 and 0.15 nmol  l(-1), respectively. These results indicate that aliskiren could be a potent inhibitor of the free forms of mature renin and of the receptor-bound forms of renin and prorenin.

Topics: Amides; Fumarates; Humans; In Vitro Techniques; Ligands; Prorenin Receptor; Protein Binding; Receptors, Cell Surface; Renin; Time Factors; Vacuolar Proton-Translocating ATPases

The relationship between angiotensin II (ANG II) and endothelin-1 (ET-1) is known to be complex; both peptides can initiate and potentiate the gene expression of each other. This pilot study investigated the effects of the AT(1) receptor blocker losartan or the direct renin inhibitor aliskiren on mean arterial pressure (MAP) and albuminuria and the renal ANG II and ET-1 levels. 3-month-old male Ren-2 transgenic rats (TGR) were treated either with losartan (5 mg kg(-1) day(-1)) or aliskiren (10 mg kg(-1) day(-1)) for 10 weeks. At the end of the experiment, rats were decapitated and cortical and papillary parts of kidneys were separated. Plasma and tissue ANG II levels were measured by RIA and tissue ET-1 concentrations by ELISA. In all four groups of animals ET-1 levels were lowest in renal cortex and more than 100-fold higher in the papilla. Cortical and papillary ET-1 concentrations in untreated TGR significantly exceeded those of control HanSD rats and were significantly depressed by both drugs. In both strains, papillary ANG II concentrations were moderately but significantly higher than cortical ANG II, TGR exhibited higher ANG II levels both in cortex and papilla as compared to control HanSD rats. Aliskiren and losartan at the doses used depressed similarly the levels of ANG II in cortex and papilla and reduced ET-1 significantly in the renal cortex and papilla below control levels in HanSD rats. Albuminuria, which was more than twice as high in TGR as in HanSD rats, was normalized with aliskiren and reduced by 28% with losartan, although MAP was reduced to a similar degree by both drugs. Despite similar reductions of MAP and renal ET-1 and ANG II levels aliskiren appears to be more effective than losartan, at the doses used, in reducing albuminuria in heterozygous hypertensive Ren-2 rats.

Topics: Albuminuria; Amides; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Down-Regulation; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Fumarates; Hypertension; Kidney; Losartan; Male; Mice; Pilot Projects; Radioimmunoassay; Rats; Rats, Transgenic; Renin; Time Factors

Angiotensin I-converting enzyme (ACE; kininase II) levels in humans are genetically determined. ACE levels have been linked to risk of myocardial infarction, but the association has been inconsistent, and the causality underlying it remains undocumented. We tested the hypothesis that genetic variation in ACE levels influences myocardial tolerance to ischemia. We studied ischemia-reperfusion injury in mice bearing 1 (ACE1c), 2 (ACE2c, wild type), or 3 (ACE3c) functional copies of the ACE gene and displaying an ACE level range similar to humans. Infarct size in ACE1c was 29% lower than in ACE2c (P<0.05). Pretreatment with a kinin B2 receptor antagonist suppressed this reduction. In ACE3c, infarct size was the same as in ACE2c. But ischemic preconditioning, which reduced infarct size in ACE2c (-63%, P<0.001) and ACE1c (-52%, P<0.05), was not efficient in ACE3c (-2%, NS, P<0.01 vs. ACE2c). In ACE3c, ischemic preconditioning did not decrease myocardial inflammation or cardiomyocyte apoptosis. Pretreatment with a renin inhibitor had no cardioprotective effect in ACE2c, but in ACE3c partially restored (38%) the cardioprotection of ischemic preconditioning. Thus, a modest genetic increase in ACE impairs myocardial tolerance to ischemia. ACE level plays a critical role in cardiac ischemia, through both kinin and angiotensin mediated mechanisms.

Topics: Amides; Angiotensin I; Angiotensin II; Animals; Apoptosis; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Fumarates; Heart; Kinins; Lung; Mice; Mice, Mutant Strains; Myocardial Infarction; Myocardial Ischemia; Myocardium; Peptidyl-Dipeptidase A; Renin; Reperfusion Injury

The effects of the human renin inhibitor aliskiren on blood pressure (BP), end-organ damage, proteinuria, and tissue and plasma angiotensin (ANG) II levels in young and adult heterozygous Ren-2 transgenic rats (TGR) were evaluated and compared with the effect of the ANG type 1 (AT(1)) receptor blocker losartan during treatment and after 12 days after the withdrawal of drug treatments. BP was monitored by telemetry from the age of 32 days on (young rats) and at 100 days (adult rats). Aliskiren (10 mg·kg(-1)·day(-1) in osmotic minipumps) or losartan (5 mg·kg(-1)·day(-1) in drinking water) treatment was applied for 28 days in young rats and for 70 days in adult rats. In young untreated TGR, severe hypertension rapidly evolved. Adult untreated TGR exhibited stable established hypertension. Both aliskiren and losartan fully prevented the development of hypertension and cardiac hypertrophy in young TGR and normalized BP and cardiac hypertrophy in adult TGR. After cessation of aliskiren treatment in both young and adult TGR BP and cardiac hypertrophy were persistently reduced, while after losartan withdrawal BP and cardiac hypertrophy rapidly increased. In adult aliskiren-treated rats proteinuria was significantly reduced compared with losartan (the effect persisting after withdrawal of treatment), and this decrease strongly correlated with normalization of glomerular size in these animals. In conclusion, aliskiren and losartan had similar antihypertensive effects during chronic treatment, but the antihypertensive and organoprotective effects of aliskiren were persistent even after the 12-day washout period. The durable effect on proteinuria can possibly be attributed to the normalization of glomerular morphology.

Topics: Amides; Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Cardiomegaly; Disease Models, Animal; Fumarates; Heart Rate; Hypertension; Kidney Glomerulus; Losartan; Male; Proteinuria; Rats; Rats, Transgenic; Renin; Time Factors

The protective effect of combination therapy with valsartan and aliskiren against renal fibrosis remains to be defined. This study was undertaken to examine the protective effects of the combination of valsartan and aliskiren against renal fibrosis induced by unilateral ureteral obstruction (UUO). Combination therapy with valsartan (15 mg·kg(-1)·day(-1)) and aliskiren (10 mg·kg(-1)·day(-1)), valsartan monotherapy (30 mg·kg(-1)·day(-1)), and aliskiren monotherapy (20 mg·kg(-1)·day(-1)) all significantly ameliorated the increase in blood urea nitrogen and the degree of hydronephrosis determined by the increase in weight and length of the obstructed kidney. The dose titration study and blood pressure measurement confirmed that the combination therapy provided a greater benefit independent of the vasodilatory effect. There were no significant changes in serum levels of creatinine, sodium, and potassium in UUO rats and any treatment groups. Combination therapy also attenuated UUO-related increases in the scores of tubular dilatation, interstitial volume, interstitial collagen deposition, α-smooth muscle actin, the activation of ERK 1/2, the infiltration of monocytes/macrophages, the mRNA expression of snail-1, and transforming growth factor-β1 to a greater extent compared with aliskiren or valsartan used alone. The mRNA expression of renin and the (pro)renin receptor significantly increased after UUO. Combination therapy and monotherapy of valsartan and aliskiren had a comparable enhancing effect on the mRNA expression of renin, whereas all these treatments did not affect the expression of the (pro)renin receptor. In conclusion, a direct renin inhibitor in conjunction with an angiotensin II receptor blocker exerts increased renal protection against renal fibrosis and inflammation during obstruction over either agent alone.

Topics: Actins; Amides; Anatomy, Cross-Sectional; Animals; Antihypertensive Agents; Blood Pressure; Blotting, Western; Collagen; Drug Therapy, Combination; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Fumarates; Immunohistochemistry; Kidney; Kidney Diseases; Kidney Function Tests; Male; Neutrophil Infiltration; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Snail Family Transcription Factors; Tetrazoles; Transcription Factors; Ureteral Obstruction; Valine; Valsartan

Angiotensin (Ang)II, the effector arm of the locally active renin-angiotensin system (RAS), modulates Tissue Factor (TF), the principal initiator of blood coagulation and a key promoter of atherothrombotic events. Consistent with that knowledge, previous data showed inhibitory properties of angiotensin-converting enzyme inhibitor (ACEI)s and angiotensin II type-1 receptor blocker (ARB)s, but no data are available about the effect of renin inhibition. We aimed to evaluate whether aliskiren, a direct renin inhibitor (DRI), modulates TNF-α-stimulated TF expression in cultured human umbilical vein endothelial cells (HUVECs). Zofenopril, an ACEI, and olmesartan, an ARB, were the controls. HUVECs were incubated with experimental drugs (1 nM) 30 min prior to TNF-α stimulation (0.1 ng/ml × 4 h). Main evaluation variables were procoagulant activity (single-stage clotting assay), TF antigen (ELISA) and mRNA expression (real-time polymerase chain reaction) in cell lysates. TNF-α stimulated procoagulant activity and increased TF antigen and mRNA expression. Aliskiren inhibited TNF-α-mediated TF stimulation; zofenopril and olmesartan exerted a comparable effect. We conclude that aliskiren, a DRI, downregulates TNF-α-stimulated TF expression in HUVECs, possibly as a reflection of endothelial renin activation by the cytokine.

Topics: Amides; Captopril; Down-Regulation; Endothelial Cells; Fumarates; Humans; Imidazoles; Renin; Tetrazoles; Thromboplastin; Tumor Necrosis Factor-alpha; Umbilical Veins

Topics: Amides; Angiotensin II; Fumarates; Humans; Renin; Renin-Angiotensin System; Vaccination

Sca-1 and VEGFR-2 positive pro-angiogenic cells (PAC) predict outcome of patients with vascular disease. Activation of the renin-angiotensin-aldosterone system impairs PAC function. The effects of the direct renin inhibitor aliskiren on PAC numbers and function are not known. Treatment of C57Bl/6 mice and Apo E(-/-) mice on high-cholesterol diet with aliskiren, 25 mg/kg/day s.c. for 3-6 weeks, reduced systolic and diastolic blood pressure by -11.5 and -13.7% compared to vehicle. Aliskiren increased Sca-1/VEGFR-2 positive PAC in the blood (159 ± 14%) and spleen-derived DiLDL/lectin positive PAC (180 ± 21%). Migratory capacity of PAC was increased to 165 ± 16%. In cultured human PAC, aliskiren dose-dependently increased the number of colony forming units to 152 ± 9% (1 μmol/l) and 187 ± 7% (10 μmol/l), which was prevented by the eNOS inhibitor LNMA. H₂O₂-induced apoptosis of cultured human PAC was reduced to 77 ± 23%. In Apo E(-/-) mice, aliskiren reduced atherosclerotic plaque area in the aortic sinus by 58 ± 4%. Circulating Sca-1/VEGFR-2 positive PAC were upregulated to 180 ± 25% and migratory capacity of PAC was increased to 127 ± 7%. Aliskiren reduced vascular NADPH oxidase activity to 41.6 ± 6.7%. Despite similar blood pressure lowering, treatment with hydralazine (25 mg/kg/day) did not significantly influence atherogenesis or PAC. Treatment of C57Bl/6 mice with a lower dose of aliskiren (15 mg/kg/day) did not affect blood pressure but increased cultured DiLDL/lectin positive PAC to 229 ± 30% and their migratory capacity to 214 ± 24%. Aliskiren increased number and function of PAC in mice and prevented atherosclerotic lesion formation. The effects were observed independent of blood pressure lowering.

Topics: Amides; Angiogenesis Inducing Agents; Animals; Antigens, Ly; Apolipoproteins E; Apoptosis; Atherosclerosis; Blood Pressure; Cell Movement; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Fumarates; Humans; Infusions, Subcutaneous; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; NADPH Oxidases; Neovascularization, Physiologic; Oxidative Stress; Renin; Stem Cells; Time Factors; Vascular Endothelial Growth Factor Receptor-2

Renin-angiotensin system (RAS) blockade has cardioprotective and renoprotective effects in the general population; however, whether dual blockade using angiotensin-receptor blockade (ARB) plus a renin inhibitor, aliskiren, can minimize severe proteinuria in kidney transplant recipients remains undetermined.. To analyze the efficacy and safety of dual blockade of the RAS with an ARB and aliskiren in kidney transplant recipients with severe proteinuria and creatinine concentration 2.5 mg/dL or less.. This prospective study included 16 patients (mean age 56 years; 10 men [62%] who had undergone cadaveric renal transplantation between 1992 and 2004. Immunosuppression therapy included a calcineurin inhibitor in 9 patients (56%) or mammalian target of rapamycin inhibitor in 7 (44%), and mycophenolate mofetil in 15 (94%). All received high-dose ARB II (1.0-3.5 g/24 h) because of marked proteinuria, with poor response. Accordingly, 11 patients also received aliskiren, and in 5 who were receiving an angiotensin-converting enzyme inhibitor, therapy was changed to aliskiren. Mean (range) follow-up was 11 (3-18) months.. At 3 months, proteinuria decreased by 40%, and at 6 months by 60%. In addition, mean blood pressure was decreased significantly. Renal function remained stable, as did the serum potassium concentration. A slight but significant decrease in hemoglobin concentration was observed, with no clinical repercussions.. Dual blockade of the RAS with ARB II plus aliskiren therapy demonstrated an additive effect to decrease severe proteinuria and blood pressure in kidney transplant recipients. Neither relevant adverse effects in renal function nor anemia or hyperkalemia were observed. These findings might contribute to prolonging long-term kidney graft survival.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Female; Fumarates; Humans; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Proteinuria; Renin-Angiotensin System

While the safety of renin-angiotensin system (RAS)-blocking drugs such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers is well known, less is known about the new direct renin inhibitor aliskiren. The authors pooled data from 12 randomized controlled trials of aliskiren in patients with hypertension and analyzed the incidence and types of adverse events (AEs) and laboratory abnormalities. Studies were characterized as short-term (≤2 months) placebo-controlled or long-term (>2 months) active-controlled. Relative risks for AEs of particular interest for RAS blockers were calculated. In short-term studies, AEs occurred in similar proportions of aliskiren 150 mg and 300 mg (33.6% and 31.6%, respectively) and placebo treatment groups (36.8%). In long-term studies, a lower proportion of patients treated with aliskiren 150 mg and 300 mg had AEs (33.7% and 43.2%, respectively) than those treated with ACE inhibitors (60.1%), angiotensin receptor blockers (53.9%), and thiazide diuretics (48.9%). Events of special interest, including angioedema, hyperkalemia, and diarrhea occurred in similar proportions of patients taking aliskiren, placebo, and comparator agents. In studies of up to 36 weeks, patients treated with aliskiren were significantly less likely to develop cough than those treated with ACE inhibitors. At the registered doses of 150 mg and 300 mg daily, aliskiren has safety and tolerability profiles similar to placebo, other RAS blockers, and diuretics. Cough rates are lower with aliskiren compared with ACE inhibitors.

Topics: Aged; Amides; Antihypertensive Agents; Female; Fumarates; Humans; Hypertension; Incidence; Male; Middle Aged; Renin; Renin-Angiotensin System; Risk

Topics: Amides; Amlodipine; Antihypertensive Agents; Calcium Channel Blockers; Drug Combinations; Drug Interactions; Fumarates; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin

Pre-treatment with angiotensin receptor blockers is known to improve neurological outcome after stroke. This study investigated for the first time, whether the renin inhibitor aliskiren has similar neuroprotective effects.. Since aliskiren specifically blocks human renin, double transgenic rats expressing human renin and angiotensinogen genes were used. To achieve a systolic blood pressure of 150 or 130 mmHg animals were treated with aliskiren (7.5 or 12.5 mg/kg*d) or candesartan (1.5 or 10 mg/kg*d) via osmotic minipump starting five days before middle cerebral artery occlusion with reperfusion. Infarct size was determined by magnetic resonance imaging. mRNA of inflammatory marker genes was studied in different brain regions.. The mortality of 33.3% (7 of 21 animals) in the vehicle group was reduced to below 10% by treatment with candesartan or aliskiren (p<0.05). Aliskiren-treated animals had a better neurological outcome 7 days post-ischemia, compared to candesartan (Garcia scale: 9.9±0.7 vs. 7.3±0.7; p<0.05). The reduction of infarct size in the aliskiren group did not reach statistical significance compared to candesartan and vehicle (24 h post-ischemia: 314±81 vs. 377±70 and 403±70 mm(3) respectively). Only aliskiren was able to significantly reduce stroke-induced gene expression of CXC chemokine ligand 1, interleukin-6 and tumor necrosis factor-alpha in the ischemic core.. Head-to-head comparison suggests that treatment with aliskiren before and during cerebral ischemia is at least as effective as candesartan in double transgenic rats. The improved neurological outcome in the aliskiren group was blood pressure independent. Whether this effect is due to primary anti-inflammatory mechanisms has to be investigated further.

Topics: Amides; Angiotensinogen; Animals; Animals, Genetically Modified; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Brain; Brain Ischemia; Cerebral Arterial Diseases; Cerebrovascular Disorders; Chemokine CXCL1; Fumarates; Gene Expression; Humans; Interleukin-6; Rats; Renin; Reverse Transcriptase Polymerase Chain Reaction; Stroke; Tetrazoles; Tumor Necrosis Factor-alpha

Aliskiren is the first direct oral renin inhibitor approved for the treatment of hypertension. It acts by binding to the active site of renin and blocking its catalytic function, as a result preventing the formation of the angiotensin I and II. Used in monotherapy or in combination, this molecule proved its antihypertensive efficacy without showing, however, a clear superiority on the other antihypertensive drugs. Its benefit on cardiovascular morbidity and mortality and on target organ damage should be proved before aliskiren may be recommended as a first line therapy in essential hypertension. Data on cardiac insufficiency and diabetic nephropathy are preliminary.

Topics: Amides; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin

Topics: Amides; Antihypertensive Agents; Fumarates; Heart Diseases; Humans; Randomized Controlled Trials as Topic

Topics: Amides; Angiotensinogen; Animals; Antihypertensive Agents; Cell Line, Tumor; Colforsin; Dose-Response Relationship, Drug; Fumarates; Humans; Juxtaglomerular Apparatus; Leukemia, Mast-Cell; Mast Cells; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Renin

Renin initiates angiotensin II formation and has no other known functions. We observed that transgenic rats (TGR) overexpressing the human renin gene (hREN) developed moderate obesity with increased body fat mass and glucose intolerance compared with nontransgenic Sprague-Dawley (SD) rats. The metabolic changes were not reversed by an angiotensin-converting enzyme inhibitor, a direct renin inhibitor, or by (pro)renin receptor blocker treatment. The obese phenotype in TGR(hREN) originated from higher food intake, which was partly compensated by increases in resting energy expenditure, total thermogenesis (postprandial and exercise activity), and lipid oxidation during the first 8 weeks of life. Once established, the difference in body weight between TGR(hREN) and SD rats remained constant over time. When restricted to the caloric intake of SD, TGR(hREN) developed an even lower body weight than nontransgenic controls. We did not observe significant changes in the cocaine and amphetamine-regulated transcript, pro-opiomelanocortin, both anorexigenic, or neuropeptide Y, orexigenic, mRNA levels in TGR(hREN) versus SD controls. However, the mRNA level of the agouti-related peptide, orexigenic, was significantly reduced in TGR(hREN) versus SD controls at the end of the study, which indicates a compensatory mechanism. We suggest that the human renin transgene initiates a process leading to increased and early appetite, obesity, and metabolic changes not related to angiotensin II. The mechanisms are independent of any currently known renin-related effects.

Topics: Adipocytes; Amides; Angiotensin II; Animals; Cells, Cultured; Disease Models, Animal; Energy Metabolism; Fumarates; Humans; Leptin; Lipid Metabolism; Male; Obesity; Phenotype; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Renin; Thermogenesis

Topics: Amides; Antihypertensive Agents; Benchmarking; Fumarates; Humans; Hydrochlorothiazide; Hypertension

Renin is the rate-limiting enzyme in renin-angiotensin system (RAS) activation. We sought to determine the impact of renin inhibition on whole-body insulin sensitivity and skeletal muscle RAS, oxidative stress, insulin signaling, and glucose transport in the transgenic TG(mRen2)27 rat (Ren2), which manifests increased tissue RAS activity, elevated serum aldosterone, hypertension, and insulin resistance. Young (aged 6-9 wk) Ren2 and age-matched Sprague Dawley control rats were treated with aliskiren [50 mg/kg . d, ip] or placebo for 21 d and administered an ip glucose tolerance test. Insulin metabolic signaling and 2-deoxyglucose uptake in soleus muscle were examined in relation to tissue renin-angiotensin-aldosterone system [angiotensin (Ang) II, mineralocorticoid receptor (MR), and Ang type I receptor (AT(1)R)] and measures of oxidative stress as well as structural changes evaluated by light and transmission electron microscopy. Ren2 rats demonstrated systemic insulin resistance with decreased skeletal muscle insulin metabolic signaling and glucose uptake. This was associated with increased Ang II, MR, AT(1)R, oxidative stress, and reduced tyrosine insulin receptor substrate-1 phosphorylation, protein kinase B/(Akt) phosphorylation and glucose transporter-4 immunostaining. The Ren2 also demonstrated perivascular fibrosis and mitochondrial remodeling. Renin inhibition improved systemic insulin sensitivity, insulin metabolic signaling, and glucose transport along with normalization of Ang II, AT(1)R, and MR levels, oxidative stress markers, fibrosis, and mitochondrial structural abnormalities. Our data suggest that renin inhibition improves systemic insulin sensitivity, skeletal muscle insulin metabolic signaling, and glucose transport in Ren2 rats. This is associated with reductions in skeletal muscle tissue Ang II, AT(1)R, and MR expression; oxidative stress; fibrosis; and mitochondrial abnormalities.

Topics: Amides; Angiotensin II; Animals; Animals, Genetically Modified; Disease Models, Animal; Fumarates; Gene Expression Regulation; Glucose; Glucose Transporter Type 4; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Muscle, Skeletal; Oxidative Stress; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Reactive Nitrogen Species; Receptor, Angiotensin, Type 1; Receptors, Mineralocorticoid; Renin

Topics: Adult; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Drug Therapy, Combination; Female; Fumarates; Glomerulonephritis, Membranous; Humans; Male; Middle Aged; Proteinuria; Renin-Angiotensin System; Time Factors; Treatment Outcome; Young Adult

Most patients with hypertension require antihypertensive combination therapy to achieve BP control. This study investigated the safety and efficacy of the direct renin inhibitor aliskiren combined with the calcium channel blocker amlodipine.. Overall, 556 patients with hypertension (msDBP > or =95-<110 mmHg) received open-label aliskiren/amlodipine 150/5 mg for 2 weeks, followed by forced titration to aliskiren/amlodipine 300/10 mg for 52 weeks. Add-on hydrochlorothiazide (HCT) was permitted from week 10 to achieve BP control (<140/90 mmHg). The primary objective of the study was to evaluate the long-term safety and tolerability of aliskiren/amlodipine combination therapy; the BP-lowering efficacy of the combination was also assessed (week 54 endpoint; last observation carried forward).. ClinicalTrials.gov identifier NCT00402103.. In total, 452 patients completed 54 weeks' treatment with aliskiren/amlodipine 300/10 mg, with or without add-on HCT. The most frequently reported adverse events (AEs) were peripheral edema, upper respiratory tract infection, headache and bronchitis. Peripheral edema (the most common AE), occurred in 22.7% of treated patients, and was generally mild or moderate in intensity and transient in nature. Few patients exhibited laboratory abnormalities. Aliskiren/amlodipine combination therapy provided a mean BP reduction from baseline to week 54 of 24.2/15.5 mmHg; 74.3% of patients achieved BP control. In the subgroup of patients with stage 2 hypertension (baseline msSBP > or =160 mmHg and/or msDBP > or =100 mmHg), the mean BP reduction at week 54 was 29.1/17.1 mmHg, and 67.0% of patients achieved BP control.. In this open-label study, aliskiren/amlodipine 300/10 mg combination therapy, with or without add-on HCT, effectively reduced BP, particularly in patients with stage 2 hypertension. The most common AE was peripheral edema, consistent with the known AE profile of high-dose (10 mg) amlodipine. Further studies comparing the aliskiren/amlodipine combination with the component monotherapies and other antihypertensive combinations are warranted.

Topics: Adult; Aged; Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Diastole; Drug Therapy, Combination; Drug Tolerance; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Patient Selection; Safety; Systole

Bartter syndrome is traditionally treated with large doses of oral potassium with or without suppression of the renin-angiotensin system. Since plasma renin activity is invariably elevated in Bartter syndrome, the availability of the direct renin inhibitor aliskiren should lead to the ability to maintain potassium levels without utilizing large doses of oral potassium. This case report is, to my knowledge, the first to show the efficacy of a renin receptor blocker in Bartter syndrome.

Topics: Amides; Antihypertensive Agents; Bartter Syndrome; Female; Fumarates; Humans; Middle Aged; Renin-Angiotensin System

Topics: Amides; Anti-Arrhythmia Agents; Antihypertensive Agents; Fumarates; Humans; Long QT Syndrome; Sotalol

Aliskiren gained FDA approval for the treatment of hypertension in 2007. It is the first approved pharmaceutical to manage hypertension by direct renin inhibition. With the introduction of novel drugs and mechanisms of action comes the challenge of monitoring for new unreported adverse events. The side effect profile for aliskiren has not yet been fully described. We describe the first apparent report of aliskiren-induced QT prolongation resulting in torsades de pointes.

Topics: Aged; Amides; Anti-Arrhythmia Agents; Antihypertensive Agents; Female; Fumarates; Humans; Long QT Syndrome; Sotalol

We report the first case of acute renal failure with hyperkalemia associated with the recently marketed direct renin inhibitor aliskiren. To optimize blood pressure control, the antihypertensive medication of a 76-year-old hypertensive female patient was changed from the angiotensin II receptor antagonist irbesartan to aliskiren. Spironolactone was continued, as serum creatinine and potassium levels were initially normal. Two weeks later the patient presented with acute oliguric renal failure, symptomatic hyperkalemia and metabolic acidosis, necessitating emergency dialytic treatment. Unrecognized pre-existing renal insufficiency (CKD Stage 2 - 3) and the continuation of spironolactone were identified as predisposing risk factors.

Topics: Acute Kidney Injury; Aged; Amides; Antihypertensive Agents; Female; Fumarates; Humans; Hyperkalemia; Hypertension; Renal Dialysis

Aliskiren is the first in a new class of orally effective direct renin inhibitors. Initial results of clinical efficacy studies have demonstrated at least equivalent or superior blood pressure-lowering efficacy when compared with existing drugs, and a favorable side-effect profile either as monotherapy or as a component of combination therapy. This report aims to introduce and provide a critical appraisal of the initial results of the ASPIRE HIGHER program, evaluating the potential cardio-renal protective effects of aliskiren.

Topics: Administration, Oral; Amides; Antihypertensive Agents; Blood Pressure; Clinical Trials as Topic; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin

Scleroderma renal crisis (SRC) is an important complication of scleroderma associated with significant morbidity and mortality. Current treatment of patients with SRC focuses on renin-angiotensin-aldosterone system (RAAS) blockade, ideally using angiotensin-converting enzyme inhibitors. We present a case of SRC in a patient established on maximal tolerable RAAS-blocking treatment. Introduction of a selective endothelin-A receptor antagonist followed by a direct renin inhibitor provided excellent blood pressure control and complete abrogation of heavy proteinuria. This was associated with a decrease in kidney function, with serum creatinine level increasing by approximately 30%. This increase is considered acceptable after the introduction of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, is regarded as an indicator of drug efficacy, and confers longer term renal protection. Both endothelin receptor antagonism and direct renin inhibition offer alternate novel therapies for patients with SRC. Their ability to preserve or improve kidney function is unclear.

Topics: Amides; Antihypertensive Agents; Atrophy; Biomarkers; Biopsy; Endothelin Receptor Antagonists; Female; Fibrosis; Fumarates; Humans; Hypertension, Renal; Isoxazoles; Kidney; Middle Aged; Proteinuria; Pulmonary Fibrosis; Renal Insufficiency, Chronic; Renin; Scleroderma, Systemic; Thiophenes; Treatment Outcome

Aliskiren/hydrochlorothiazide is a single-pill combination of the first in the new class of non-peptide direct renin inhibitors (aliskiren) and a thiazide diuretic (hydrochlorothiazide [HCTZ]) that achieves blood pressure (BP) reductions greater than those seen with either component alone. In double-blind, 8-week clinical trials, aliskiren and HCTZ (as a combination of the individual components or as single-pill combinations) reduced mean sitting systolic and diastolic BP from baseline to a significantly greater extent than placebo, aliskiren monotherapy and HCTZ monotherapy. Aliskiren/HCTZ produced additional BP reductions in patients inadequately responsive to 4 weeks' prior treatment with aliskiren or HCTZ alone. Responder rates and BP control rates further demonstrated the benefits of aliskiren/HCTZ combination therapy over monotherapy with individual components in patients with mild to moderate hypertension. Aliskiren plus HCTZ appeared to be effective as long-term (up to 1 year) combination treatment in an open-label trial. In a 12-week placebo-controlled trial in obese patients with hypertension, BP reductions and responder and control rates were significantly greater with aliskiren/HCTZ than with HCTZ alone. Aliskiren/HCTZ was generally well tolerated in clinical trials, with most adverse events being mild and transient in nature.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Drug Combinations; Fumarates; Humans; Hydrochlorothiazide; Hypertension

Recurrent focal segmental glomerulosclerosis (FSGS) after renal transplantation with nephrotic syndrome is a serious problem with a high risk of graft loss. The therapeutic role of renin-angiotensin-system (RAS) blockers in recurrent FSGS is not clear. We present the safety and efficacy of an intensified triple RAS blockade with an ACE-inhibitor, an AT 1 receptor blocker and the direct renin inhibitor aliskiren in a 29-year-old renal transplant recipient with biopsy proven recurrence of FSGS and relapsing severe nephrotic syndrome. We subsequently used full dose ramipril, candesartan and aliskiren under a close monitoring of kidney function and electrolytes and examined the effect on proteinuria, clinical course and tolerability over 12 months. We found a significant and sustained antiproteinuric effect under triple RAS blockade. RAS blockade was generally well tolerated. This can offer a new therapeutic approach in selected hypertensive patients with recurrent FSGS.

Topics: Adult; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Benzimidazoles; Biphenyl Compounds; Drug Therapy, Combination; Female; Fumarates; Glomerulosclerosis, Focal Segmental; Humans; Hypertension, Renal; Kidney Transplantation; Nephrotic Syndrome; Plasma Exchange; Proteinuria; Ramipril; Recurrence; Renin; Renin-Angiotensin System; Rituximab; Tetrazoles

The protective effect of aliskiren, a direct renin inhibitor, against hypertensive cardiovascular and renal injury remains to be defined. This study was undertaken to examine the protective effects of the combination of aliskiren and valsartan, an angiotensin receptor blocker, against cardiovascular and renal injury. Endothelial NO synthase-deficient mice, subjected to cuff injury of femoral artery, were divided into 5 groups and were treated with the following: (1) vehicle; (2) aliskiren (25 mg/kg per day); (3) valsartan (8 mg/kg per day); (4) combined aliskiren (12.5 mg/kg per day) and valsartan (4 mg/kg per day); and (5) hydralazine (10 mg/kg per day) for 4 weeks. Aliskiren and valsartan alone markedly and similarly suppressed cardiac hypertrophy, inflammation and fibrosis, and coronary remodeling; prevented cuff injury-induced arterial intimal thickening; and reduced urinary albumin excretion, glomerular inflammation, and glomerulosclerosis in endothelial NO synthase-deficient mice. These beneficial effects of aliskiren and valsartan were associated with the significant attenuation of oxidative stress in these tissues. Hence, aliskiren and valsartan markedly exert the protective effects against cardiovascular and renal injury through the reduction of oxidative stress. Furthermore, compared with monotherapy with aliskiren or valsartan, the combination of a half dose of these drugs more greatly improved the above-mentioned cardiovascular and renal injuries of endothelial NO synthase-deficient mice, which were associated with greater attenuation of tissue oxidative stress by the combination therapy. Thus, the combination of aliskiren and valsartan exerts the synergistic organ-protective effects through synergistic attenuation of oxidative stress. The combination of aliskiren and valsartan seems to be a promising therapeutic strategy for hypertensive organ injury caused by endothelial NO synthase dysfunction.

Topics: Amides; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Blood Pressure; Cardiomegaly; Cardiovascular Diseases; Cardiovascular System; Drug Synergism; Drug Therapy, Combination; Fumarates; Gene Expression; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NADPH Oxidases; Nitric Oxide Synthase Type III; Receptor, Angiotensin, Type 1; Renin; RNA, Messenger; Superoxides; Tetrazoles; Tunica Intima; Valine; Valsartan

Novel nonpeptide small molecule renin inhibitors bearing an N-isopropyl P(1) motif were designed based on initial lead structures 1 and aliskiren (2). (P(3)-P(1))-Benzamide derivatives such as 9a and 34, as well as the corresponding P(1) basic tertiary amine derivatives 10 and 35 were found to display low nanomolar inhibition against human renin in vitro.

Topics: Administration, Oral; Amides; Animals; Antihypertensive Agents; Benzamides; Callithrix; Ethylenes; Fumarates; Humans; Protease Inhibitors; Renin; Stereoisomerism; Structure-Activity Relationship

Combining an angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB) lowers blood pressure (BP) by 4/3 mmHg compared to either agent alone, although this additive effect may be abolished with maximal monotherapy dosing. The recent ONTARGET study showed no reduction in primary outcomes when an ACE-I-ARB combination was compared to an ACE-I alone, despite 2.4/1.4 mmHg lower BP in the former group. In proteinuric chronic kidney disease, an ACE-I-ARB combination reduces proteinuria and disease progression more than monotherapy, but the ONTARGET study showed an increase in renal endpoints in the combined group. Aliskiren offers a novel approach to renin-angiotensin system (RAS) inhibition. As monotherapy in hypertension, aliskiren is of similar efficacy to thiazides, calcium channel blockers and ARBs. In combination with other RAS inhibitors at maximal dosage aliskiren has a small synergistic effect on BP (additional 4/2 mmHg reduction). Early data suggest a role for aliskiren in preventing end-organ damage but, considering the ONTARGET results with an ACE-I-ARB combination, outcome studies are needed before the use of aliskiren can be recommended in combination with other RAS inhibitors. As monotherapy, aliskiren should probably be reserved for use as an alternative to ACE-Is or ARBs, where these are ineffective or poorly tolerated.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

Overfeeding increases adipose tissue mass and leptin production and up-regulates the renin-angiotensin system in adipose tissue in rodents. Here, we determined the effect of chronic treatment with the renin inhibitor, aliskiren, in a model of diet-induced obesity in mice, on: (i) body weight, adipose tissue weight and plasma leptin; (ii) food intake and caloric efficiency; and (iii) angiotensin II (Ang II) in adipose tissue.. Four-week-old C57BL/6J mice (n= 40) received aliskiren (50 mg.kg(-1).day(-1); 6 weeks) by means of a subcutaneous osmotic Alzet minipump. Animals were given either a low-fat (10% kcal from fat) or a high-fat diet (45% kcal from fat) during this period. Food-intake and body-weight variation were monitored during treatment.. In addition to a decrease of plasma renin activity, aliskiren reduced body-weight gain, adipose pads and plasma leptin concentration, independent of the diet. In adipose tissue, local concentrations of Ang II were also reduced by aliskiren.. Aliskiren limited the gain of adiposity in young mice. This effect was not due to changes in food intake or caloric efficiency and might be related to a down-regulation of the local renin-angiotensin system in adipose tissue. These effects were accompanied by reduced plasma leptin levels. As Ang II favours differentiation of adipocytes, it is possible that the decreased adipose tissue was linked to changes in adipocyte size and number.

Topics: Adipose Tissue; Adiposity; Amides; Animals; Dietary Fats; Eating; Energy Intake; Fumarates; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Organ Size; Renin; Renin-Angiotensin System; Weight Gain

Topics: Amides; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin

Angiotensin II is the principle effector molecule of the renin angiotensin system (RAS). It exerts its various actions on the cardiovascular and renal system, mainly via interaction with the angiotensin II type-1 receptor (AT1R), which contributes to blood pressure regulation and development of hypertension but may also mediate effects on the immune system. Here we study the role of the RAS in myelin-oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE), a model mimicking many aspects of multiple sclerosis. Quantitative RT-PCR analyses showed an up-regulation of renin, angiotensin-converting enzyme, as well as AT1R in the inflamed spinal cord and the immune system, including antigen presenting cells (APC). Treatment with the renin inhibitor aliskiren, the angiotensin II converting-enzyme inhibitor enalapril, as well as preventive or therapeutic application of the AT1R antagonist losartan, resulted in a significantly ameliorated course of MOG-EAE. Blockade of AT1R did not directly impact on T-cell responses, but significantly reduced numbers of CD11b+ or CD11c+ APC in immune organs and in the inflamed spinal cord. Additionally, AT1R blockade impaired the expression of CCL2, CCL3, and CXCL10, and reduced CCL2-induced APC migration. Our findings suggest a pivotal role of the RAS in autoimmune inflammation of the central nervous system and identify RAS blockade as a potential new target for multiple sclerosis therapy.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antigen-Presenting Cells; Cell Movement; Cells, Cultured; Chemokines; Enalapril; Encephalomyelitis, Autoimmune, Experimental; Fumarates; Losartan; Mice; Mice, Inbred C57BL; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System

A 47-year-old woman with family history of autosomal-dominant polycystic kidney disease (ADPKD), who underwent living-donor kidney transplantation in 2000, presented with recurrent edema, hyperreninemia, and hyperaldosteronism. Since 2002, her antihypertensive therapy comprised ramipril and spironolactone. The post-transplantation kidney function was stable. Based on the clinical picture and reports of renin secretion by renal cysts in ADPKD, we performed a trial of aliskiren therapy (300 mg/day). The patient showed excellent blood pressure control and reduction of edema, with aldosterone levels normalizing within 2 months. This is a novel report of aliskiren therapy for treatment of edema, hyperreninemia, and hyperaldosteronism in ADPKD.

Topics: Amides; Female; Fumarates; Humans; Hyperaldosteronism; Middle Aged; Polycystic Kidney, Autosomal Dominant; Recurrence; Remission Induction; Renin

The Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) trial demonstrated that adding aliskiren, an oral direct renin inhibitor, at a dosage of 300 mg/d to the highest approved dosage of losartan and optimal antihypertensive therapy reduces albuminuria over 6 mo among patients with type 2 diabetes, hypertension, and albuminuria. The cost-effectiveness of this therapy, however, is unknown. Here, we used a Markov model to project progression to ESRD, life years, quality-adjusted life years, and lifetime costs for aliskiren plus losartan versus losartan. We used data from the AVOID study and the Irbesartan in Diabetic Nephropathy Trial (IDNT) to estimate probabilities of progression of renal disease. We estimated probabilities of mortality for ESRD and other comorbidities using data from the US Renal Data System, US Vital Statistics, and published studies. We based pharmacy costs on wholesale acquisition costs and based costs of ESRD and transplantation on data from the US Renal Data System. We found that adding aliskiren to losartan increased time free of ESRD, life expectancy, and quality-adjusted life expectancy by 0.1772, 0.1021, and 0.0967 yr, respectively. Total expected lifetime health care costs increased by $2952, reflecting the higher pharmacy costs of aliskiren and losartan ($7769), which were partially offset by savings in costs of ESRD ($4860). We estimated the cost-effectiveness of aliskiren to be $30,500 per quality-adjusted life year gained. In conclusion, adding aliskiren to losartan and optimal therapy in patients with type 2 diabetes, hypertension, and albuminuria may be cost-effective from a US health care system perspective.

Topics: Albuminuria; Amides; Biphenyl Compounds; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Fumarates; Health Care Costs; Humans; Hypertension; Irbesartan; Losartan; Quality-Adjusted Life Years; Tetrazoles

The renin-angiotensin-aldosterone system (RAS) plays a central role in atherosclerosis. To investigate the effects of a direct renin inhibitor aliskiren on vascular inflammation, we conducted leukocyte adhesion assays in vivo and in vitro using a novel real-time imaging system.. Aliskiren (10 mg/kg/d) or PBS was administered to C57BL/6 mice (6-7 weeks of age; Oriental Yeast, Tokyo, Japan) for 2 weeks via an osmotic pump. Blood pressure was not significantly changed in the 2 groups throughout the experimental period. A perivascular cuff injury was then introduced to the femoral artery and real-time intravital microscopic observation was conducted 24 hours after injury. The number of adherent leukocytes was elevated in the injured mice without aliskiren (43.8+/-9.3/10(-2) mm(2)), whereas that was significantly reduced in the mice with aliskiren (18.4+/-4.4, P<0.05). Treatment of human umbilical vein endothelial cells (HUVECs) with aliskiren significantly reduced the adhesion of THP-1 cells to TNF-alpha-activated HUVECs (P<0.05). Interestingly, TNF-alpha-induced renin activity and angiotensin II production in HUVECs were also blunted by aliskiren. Furthermore, exogenous renin and angiotensin II abrogated the aliskiren-mediated reduction of THP-1 cell adhesion to HUVECs.. Our in vivo and in vitro findings indicate a pivotal role for renin inhibition in vascular inflammation independent of blood pressure.

Topics: Amides; Animals; Blotting, Western; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Femoral Artery; Fumarates; Humans; In Vitro Techniques; Mice; Mice, Inbred C57BL; Oxidative Stress; Random Allocation; Reactive Oxygen Species; Renin; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; Sensitivity and Specificity; Tumor Necrosis Factor-alpha

Renin is a basic component of renin-angiotensin-aldosteron system which contributes much to the activity of this system. Renin and its precursor prorenin can interact with prorenin receptors thus inducing hypertrophy and fibrogenesis in target tissues. Many variants of arterial hypertension are associated with plasmic renin activation suggesting high efficacy of direct renin inhibitors. Large controlled clinical trials demonstrated that one of such inhibitors, aliskiren, reduces high blood pressure and damage to target organs.

Topics: Amides; Antihypertensive Agents; Clinical Trials as Topic; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

The purposes of this study are to investigate the cost-effectiveness of an implantable carotid body stimulator (Rheos; CVRx, Inc, Minneapolis, MN) for treating resistant hypertension and determine the range of starting systolic blood pressure (SBP) values where the device remains cost-effective. A Markov model compared a 20-mm Hg drop in SBP from an initial level of 180 mm Hg with Rheos to failed medical management in a hypothetical 50-year-old cohort. Direct costs (2007$), utilities, and event rates for future myocardial infarction, stroke, heart failure, and end-stage renal disease were modeled. Sensitivity analyses tested the assumptions in the model. The incremental cost-effectiveness ratio (ICER) for Rheos was $64,400 per quality-adjusted life-years (QALYs) using Framingham-derived event probabilities. The ICER was <$100,000 per QALYs for SBPs > or =142 mm Hg. A probability of device removal of <1% per year or SBP reductions of > or =24 mm Hg were variables that decreased the ICER below $50,000 per QALY. For cohort characteristics similar to Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure-Lowering Arm (ASCOT-BPLA) participants, the ICER became $26,700 per QALY. Two-way sensitivity analyses demonstrated that lowering SBP 12 mm Hg from 220 mm Hg or 21 mm Hg from 140 mm Hg were required. Rheos may be cost-effective, with an ICER between $50,000 and $100,000 per QALYs. Cohort characteristics and efficacy are key to the cost-effectiveness of new therapies for resistant hypertension .

Topics: Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure; Carotid Body; Cohort Studies; Cost-Benefit Analysis; Drug Resistance; Electric Stimulation Therapy; Electrodes, Implanted; Fumarates; Humans; Hypertension; Markov Chains; Middle Aged; Quality-Adjusted Life Years; Sensitivity and Specificity; Treatment Outcome

Topics: Aged; Aged, 80 and over; Amides; Antihypertensive Agents; Blood Pressure; Catheter Ablation; Clinical Trials as Topic; Diastole; Dissection; Female; Fumarates; Humans; Hypertension; Kidney Transplantation; Life Expectancy; Male; Primary Prevention; Renal Artery; Renin; Risk Factors; Secondary Prevention; Smoking; Sympathectomy; Sympathetic Nervous System; Systole

Topics: Amides; Antihypertensive Agents; Fumarates; Humans

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Fumarates; Heart Failure; Humans; Hypertension; Kidney Failure, Chronic; Myocardial Infarction; Patient Readmission; Renin; Renin-Angiotensin System; Treatment Outcome

Aliskiren is a novel molecule which blocks the renin-angiotensin-aldosterone system in its rate limiting step by renin inhibition. Aliskiren is validated as an antihypertensive drug in many countries based on its efficacy data. Although some surrogate endpoint trials suggest that its potential advantages based on its mechanism of action provide clinical benefit beyond its blood pressure-lowering effect, hard endpoint clinical trials to reveal its long-term effects are yet to be completed.

Topics: Amides; Antihypertensive Agents; Clinical Trials as Topic; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

The inhibition of renin-angiotensin system (RAS) has an effect beyond reducing blood pressure in the treatment of cardiovascular diseases; it also reduces mortality and morbidity. Although the classic RAS blockage is effective, due to blockage of negative feedback inhibition, it increases plasma renin activity and as a result generates a residual cardiovascular risk. Different from ACE-i and ARB treatments, aliskiren, a direct renin inhibitor, is the only pharmacologic agent that noticeably reduces the plasma renin activity, an independent cardiovascular risk factor. This creates a new option in RAS blockage. The efficacy and safety of aliskiren in the treatment of hypertension has been well established. The effect of aliskiren on cardiovascular mortality and morbidity is being researched. At this point there are many experimental and clinical studies to answer questions on this subject.

Topics: Amides; Antihypertensive Agents; Atherosclerosis; Cardiovascular Diseases; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

Renin-angiotensin aldosterone system has a detrimental effect on the progression of renal failure in patients with chronic kidney disease. Drugs inhibiting the renin-angiotensin aldosterone system, such as angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers have been shown to slow the progression of kidney disease in patients with diabetic and nondiabetic renal diseases. Aliskiren is a direct renin inhibitor that blocks the renin-angiotensin system at its initial step. Several experimental studies have demonstrated the renoprotective effects of aliskiren. Aliskiren, added to standard therapy, shows additional and significant antiproteinuric effects in patients with diabetic nephropathy. The optimal therapeutic approach to patients with target organ damage will be better understood as the ongoing large clinical studies with direct renin inhibitors conclude.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diabetic Nephropathies; Fumarates; Humans; Kidney Diseases; Proteinuria; Renin; Renin-Angiotensin System

Although antihypertensive drugs currently used provide significant decreases in blood pressure and improve clinical results, cardiovascular morbidity and mortality are not sufficiently decreased; therefore, there is still a need for new approaches to the treatment of hypertension and related cardiovascular diseases. However, when a new blood-pressure lowering therapy is introduced, the question of whether this will be superior over other drug classes in terms of its advantages in hypertensive patients is frequently asked. In 1898, Tigerstedt and Bergman discovered "renin" as a consequence of an observation of blood-pressure elevation following the injection of rabbit renal extracts to rabbits; however, the first member of the renin system pharmacology, ACE inhibitors, could be developed in 1970's. This was followed by the development of angiotensin-receptor blockers (ARB) and, during the last 30 years, it has been shown that the pharmacologic blockage of renin-angiotensin system (RAS) improves the prognosis in hypertensive patients. It has been shown that renin system is the key system in the treatment of hypertension and related comorbidities and that the drugs which target renin system, such as ACE inhibitors and ARB, reduce the cardiovascular events to a large extent. In contrast, as the inhibition of angiotensin II (Ang II) production and effect prevents the negative feedback which helps Ang II to inhibit the renin release from the kidney, elevated Ang II levels suggest that renin enzyme, which can be considered to be the center of renin system, can be the optimal tool in the treatment. Aliskiren, which is the first oral direct renin inhibitor developed based on these ideas, was approved by the FDA in March 2007. During all this period, clinical studies have shown that aliskiren is as efficient as other antihypertensive drugs, and preclinical studies have shown that, in genetically modified rats, aliskiren is efficient in healing the cardiovascular damage associated with Ang II. The fact that the plasma renin activity (PRA), which increases with other antihypertensive therapies and is associated with increased cardiovascular complications, decreases with the use of direct renin inhibitors raises the question as to whether aliskiren may provide additional benefit in reducing cardiovascular morbidity and mortality. The ASPIRE HIGHER program designed to find an answer to this question includes several studies which investigate how aliskiren impacts the c

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Cardiovascular Diseases; Clinical Trials as Topic; Fumarates; Humans; Hypertension; Rabbits; Rats; Renin; Renin-Angiotensin System

Aliskiren (Rasilez), a direct renin inhibitor, is currently indicated for the treatment of essential hypertension, as monotherapy or in combination, especially with hydrochlorothiazide (Rasilez HCT). It may also be use to obtain a more complete blockade of the renin-angiotensin-aldosterone system (RAAS) when it is associated with an angiotensin converting enzyme inhibitor (ACEI) (or an AT1 angiotensin receptor antagonist) (ARA). There is some room for agents that may be more efficacious in reducing the progression of diabetic nephropathy than ACEI or ARA. In this context, the dual blockade of RAAS most probably offers a better efficacy than the simple blockade, but also exposes to a higher risk. Should ongoing trials confirm the preliminary favourable results, aliskiren might reach a forefront position among the armamentarium now available to optimize the RAAS blockade. The present article will summarize advances concerning the biochemical effects of the specific mode of action of aliskiren, especially the potential interferences related to increased renin/pro-renin levels, as well as results of recent clinical trials, not only in hypertension, but also in the fields of diabetes, renal insufficiency and cardiology. The objectives and design of the landmark study ALTITUDE will also be briefly presented.

Topics: Amides; Antihypertensive Agents; Cardiovascular Diseases; Clinical Trials as Topic; Diabetic Nephropathies; Fumarates; Humans; Renin

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Fumarates; Humans; Losartan; Proteinuria; Renin; Renin-Angiotensin System

The blockade of the renin-angiotensin-aldosterone system (RAAS) has been shown to be useful, or even mandatory, in the management of arterial hypertension, congestive heart failure, post-myocardial infarction and nephropathy with albuminuria, due to diabetes or not. Such blockade can be obtained with an angiotensin converting enzyme inhibitor, a specific antagonist of angiotensin II AT1 receptors and/or recently a direct inhibitor of renin such as aliskiren. Various studies have demonstrated the advantage of optimising RAAS blockade in order to benefit of the best cardiorenal protection. The present article describes the various modalities to optimize the RAAS blockade, either by using a maximal dosage of a monotherapy, or by choosing a double inhibition of RAAS. New prospects for the RAAS blockade will be also briefly considered.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Fumarates; Heart Failure; Humans; Hypertension; Kidney Diseases; Renin; Renin-Angiotensin System

Topics: Amides; Antihypertensive Agents; Fumarates; Humans; Hypertension; Treatment Outcome

Topics: Amides; Fumarates; Humans; Hypertension; Inhibitory Concentration 50; Renin

Topics: Amides; Antihypertensive Agents; Blood Pressure; Child; Follow-Up Studies; Fumarates; Humans; Hypotension; Male; Medication Errors; Time Factors

Topics: Amides; Animals; Antihypertensive Agents; Atherosclerosis; Fumarates; Humans; Hypertension; Nitric Oxide

We investigated whether aliskiren, a direct renin inhibitor, improves NO bioavailability and protects against spontaneous atherosclerotic changes. We also examined the effects of cotreatment with aliskiren and valsartan, an angiotensin II receptor blocker, on the above-mentioned outcomes. Watanabe heritable hyperlipidemic rabbits were treated with vehicle (control), aliskiren, valsartan, or aliskiren plus valsartan for 8 weeks. Then, acetylcholine-induced NO production was measured as a surrogate index of endothelium protective function, and both superoxide and vascular peroxynitrite were measured. Tetrahydrobiopterin in aortic segments was assessed by high-performance liquid chromatography with fluorescence detection. Plaque area was quantified by histology. Increase in plasma NO concentration in response to intra-aortic acetylcholine infusion was significantly greater in all of the test groups than in controls. Aliskiren+valsartan cotreatment increased acetylcholine-induced NO by 6.2 nmol/L, which was significantly higher than that with either aliskiren or valsartan alone. Vascular superoxide and peroxynitrite levels were both significantly higher in controls and significantly lower in the aliskiren+valsartan group than in the aliskiren or valsartan group. The highest tetrahydrobiopterin levels were observed after aliskiren+valsartan cotreatment. Histology of the thoracic aorta revealed that the plaque area was significantly decreased with combination therapy compared with monotherapy. Treatment with a direct renin inhibitor has protective effects on endothelial function and atherosclerotic changes. Furthermore, cotreatment with a direct renin inhibitor and an angiotensin II receptor blocker has additive protective effects on both.

Topics: Acetylcholine; Amides; Animals; Antihypertensive Agents; Atherosclerosis; Biopterins; Blood Pressure; Drug Therapy, Combination; Endothelium, Vascular; Fumarates; Heart Rate; HSP90 Heat-Shock Proteins; Hyperlipidemias; Inflammation Mediators; Lipids; Male; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Proto-Oncogene Proteins c-akt; Rabbits; Renin; Tetrazoles; Tyrosine; Valine; Valsartan; Vasodilation; Vasodilator Agents

Emerging evidence indicates that pancreatic tissue expresses all components of the renin-angiotensin system. However, the functional role is not well understood. This investigation examined renin inhibition on pancreas structure/function in the transgenic Ren2 rat harboring the mouse renin gene, a model of tissue renin overexpression. Renin is the rate-limiting step in the generation of angiotensin II (Ang II), which stimulates the generation of reactive oxygen species in a variety of tissues. Overexpression of renin in Ren2 rats results in hypertension, insulin resistance, and cardiovascular and renal damage. Young (6-7 wk old) insulin-resistant male Ren2 and age-matched insulin sensitive Sprague Dawley rats were treated with the renin inhibitor, aliskiren (50 mg/kg.d by ip injection), or placebo for 21 d. At 21 d, the Ren2 demonstrated insulin resistance with increased islet insulin, Ang II, and reduced total insulin receptor substrate (IRS)-1, IRS-2, and Akt immunostaining. There was increased islet nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and subunits (p47(phox) and Rac1) as well as increased nitrotyrosine immunostaining (each P < 0.05). These functional abnormalities were associated with a disordered islet architecture; increased islet-exocrine interface, pericapillary fibrosis, and structurally abnormal mitochondria and content in endocrine and exocrine pancreas. In vivo treatment with aliskiren normalized systemic insulin resistance and islet insulin, Ang II, NADPH oxidase activity/subunits, and nitrotyrosine and improved total IRS-1 and Akt phosphorylation (each P < 0.05) as well as islet/exocrine structural abnormalities. Collectively, these data suggest that pancreatic functional/structural changes are driven, in part, by tissue renin-angiotensin system-mediated increases in NADPH oxidase and reactive oxygen species generation, abnormalities attenuated with direct renin inhibition.

Topics: Amides; Animals; Animals, Genetically Modified; Antihypertensive Agents; Blood Pressure; Fumarates; Glucose Tolerance Test; Insulin Receptor Substrate Proteins; Insulin Resistance; Male; Oxidative Stress; Pancreas; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Regeneration; Renin

Professor Hans Rudolf Brunner Born in 1937, Professor Brunner is a Swiss citizen. He is a Professor Emeritus of Medicine at the University of Lausanne, Switzerland. He has been at the forefront of research on the role of renin and the renin-angiotensin system in blood pressure regulation. He has been involved in the development of drugs such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. He was among the first medical practitioners to introduce the use of angiotensin-converting enzyme inhibitors in the treatment of hypertension and congestive heart failure. Professor Brunner has been a medical advisor to Speedel since 1999.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hypertension; Patient Selection; Renin

Aliskiren is the first orally active inhibitor of renin to be approved for clinical use as an antihypertensive agent. The development program has established that at the licensed doses of 150 mg and 300 mg, there are dose-related falls in blood pressure comparable to those seen with other major classes of antihypertensive drugs and that these falls are associated with a placebo level of side effects. Aliskiren was found to be effective either as monotherapy or in combination with drugs from the other major classes. As expected, there was a greater benefit from adding aliskiren to natriuretic drugs than to other blockers of the renin system. However, there was also some consistent benefit from dual renin blockade. Aliskiren is likely to be of most value in patients uncontrolled by, or intolerant of, other classes. Rational understanding of the renin system will maximize its value, for instance, by encouraging greater use of natriuretic agents in patients with resistant hypertension to render their hypertension renin dependent. Whether there are cardiovascular benefits other than blood pressure control in blocking the renin system remains to be demonstrated. It is hoped that long-term outcome studies with aliskiren will finally allow this question to be answered.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hypertension; Renin

Inhibition of (pro)renin receptor activation was demonstrated to inhibit or even abolish the development of end-organ damage in animal models. The new renin inhibitor, aliskiren, markedly increases the plasma concentration of the (pro)renin receptor ligands prorenin and renin in patients. The effects of prorenin and of renin inhibitors on the signal transduction cascade of the (pro)renin receptor are currently unknown.. Our results indicate that renin and prorenin were equally potent in (pro)renin receptor activation by decreasing (pro)renin receptor mRNA, increasing phosphatidylinositol-3 kinase p85alpha mRNA and augmenting viable cell number, respectively. These effects of renin and prorenin are both abolished using small-interfering RNA against the (pro)renin receptor or its adaptor promyelocytic zinc finger protein. The renin inhibitor aliskiren did not inhibit the renin-induced or prorenin-induced activation of the (pro)renin receptor.. This is the first report demonstrating equal ligand activities of both, renin and prorenin, on the (pro)renin receptor - promyelocytic zinc finger protein-phosphatidylinositol-3 kinase-p85alpha pathway. The failure of aliskiren to inhibit the noncatalytic effects of renin and prorenin may be of clinical relevance considering the increase in plasma concentrations of (pro)renin under aliskiren treatment.

Topics: Amides; Antihypertensive Agents; Cell Survival; Cells, Cultured; Fumarates; Humans; Kidney; Kruppel-Like Transcription Factors; Ligands; Phosphatidylinositol 3-Kinases; Promyelocytic Leukemia Zinc Finger Protein; Prorenin Receptor; Protein Binding; Receptors, Cell Surface; Renin; RNA, Messenger; RNA, Small Interfering

Topics: Adult; Amides; Antihypertensive Agents; Double-Blind Method; Drug Therapy, Combination; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Randomized Controlled Trials as Topic; Renin

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Benzimidazoles; Benzoates; Drug Therapy, Combination; Fumarates; Humans; Losartan; Proteinuria; Renin; Telmisartan

Topics: Amides; Blood Pressure; Blood Pressure Determination; Drug Therapy, Combination; Fumarates; Humans; Proteinuria; Renin

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Losartan; Mineralocorticoid Receptor Antagonists; Proteinuria; Renin; Spironolactone

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diuretics; Drug Therapy, Combination; Fumarates; Humans; Losartan; Proteinuria; Renin; Renin-Angiotensin System

Topics: Amides; Antidepressive Agents; Antihypertensive Agents; Contraindications; Diabetic Nephropathies; Female; Fumarates; Health Promotion; Heart Diseases; Humans; Natriuretic Peptide, Brain; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Renin; Smoking; Smoking Prevention

Hypertension and type 2 diabetes are common comorbidities, thus many patients receiving antihypertensive medication require concomitant therapy with hypoglycemic or lipid-lowering drugs. The aim of these three studies was to investigate the pharmacokinetics, safety and tolerability of aliskiren, a direct renin inhibitor for the treatment of hypertension, co-administered with the glucose-lowering agents metformin or pioglitazone or the lipid-lowering agent fenofibrate in healthy volunteers.. In three open-label, multiple-dose studies, healthy volunteers (ages 18 to 45 years) received once-daily treatment with either metformin 1000 mg (n = 22), pioglitazone 45 mg (n = 30) or fenofibrate 200 mg (n = 21) and aliskiren 300 mg, administered alone or co-administered in a two-period study design. Blood samples were taken frequently on the last day of each treatment period to determine plasma drug concentrations.. Co-administration of aliskiren with metformin decreased aliskiren area under the plasma concentration- time curve during the dose interval (AUC(tau)) by 27% (geometric mean ratio [GMR] 0.73; 90% confidence interval [CI] 0.64, 0.84) and maximum observed plasma concentration (C(max)) by 29% (GMR 0.71; 90% CI 0.56, 0.89) but these changes were not considered clinically relevant. Co-administration of aliskiren with fenofibrate had no effect on aliskiren AUC (GMR 1.05; 90% CI 0.96, 1.16) or C(max) (GMR 1.05; 90% CI 0.80, 1.38); similarly, co-administration of aliskiren with pioglitazone had no effect on aliskiren AUC(tau) (GMR 1.05; 90% CI 0.98, 1.13) or C(max) (GMR 1.01; 90% CI 0.84, 1.20). All other AUC and C(max) GMRs for aliskiren, metformin, pioglitazone, ketopioglitazone, hydroxypioglita-zone and fenofibrate were close to unity and the 90% CI were contained within the bioequivalence range of 0.80 to 1.25.. Co-administration of aliskiren with metformin, pioglitazone or fenofibrate had no significant effect on the pharmacokinetics of these drugs in healthy volunteers. These findings indicate that aliskiren can be co-administered with metformin, pioglitazone or fenofibrate without the need for dose adjustment.

Topics: Adolescent; Adult; Amides; Antihypertensive Agents; Area Under Curve; Chromatography, Liquid; Drug Interactions; Female; Fenofibrate; Fumarates; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Male; Metformin; Middle Aged; Pioglitazone; Renin; Tandem Mass Spectrometry; Thiazolidinediones

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Kidney Failure, Chronic; Renin-Angiotensin System

Many of the effects of angiotensin (Ang) II are mediated through specific plasma membrane receptors. However, Ang II also elicits biological effects from the interior of the cell (intracrine), some of which are not inhibited by Ang receptor blockers (ARBs). Recent in vitro studies have identified high glucose as a potent stimulus for the intracellular synthesis of Ang II, the production of which is mainly chymase dependent. In the present study, we determined whether hyperglycemia activates the cardiac intracellular renin-Ang system (RAS) in vivo and whether ARBs, ACE, or renin inhibitors block synthesis and effects of intracellular Ang II (iAng II).. Diabetes was induced in adult male rats by streptozotocin. Diabetic rats were treated with insulin, candesartan (ARB), benazepril (ACE inhibitor), or aliskiren (renin inhibitor).. One week of diabetes significantly increased iAng II levels in cardiac myocytes, which were not normalized by candesartan, suggesting that Ang II was synthesized intracellularly, not internalized through AT(1) receptor. Increased intracellular levels of Ang II, angiotensinogen, and renin were observed by confocal microscopy. iAng II synthesis was blocked by aliskiren but not by benazepril. Diabetes-induced superoxide production and cardiac fibrosis were partially inhibited by candesartan and benazepril, whereas aliskiren produced complete inhibition. Myocyte apoptosis was partially inhibited by all three agents.. Diabetes activates the cardiac intracellular RAS, which increases oxidative stress and cardiac fibrosis. Renin inhibition has a more pronounced effect than ARBs and ACE inhibitors on these diabetes complications and may be clinically more efficacious.

Topics: Amides; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Benzazepines; Benzimidazoles; Biphenyl Compounds; Diabetes Mellitus, Experimental; Endomyocardial Fibrosis; Fumarates; Insulin; Myocytes, Cardiac; Oxidative Stress; Rats; Renin; Tetrazoles

High blood pressure is a major risk factor for cardiovascular disease worldwide. Drug treatments include those that target the renin-angiotensin system, a key hormone cascade in the regulation of blood pressure. One of these is aliskiren (Rasilez - Novartis), which belongs to a new class of drugs, direct renin inhibitors. Here we assess its place in managing adults with hypertension.

Topics: Adult; Amides; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Drug Combinations; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Renin; Treatment Outcome

Pharmacological renin inhibition with aliskiren is an effective antihypertensive drug treatment, but it is currently unknown whether aliskiren is able to attenuate cardiac failure independent of its blood pressure-lowering effects. We investigated the effect of aliskiren on cardiac remodeling, apoptosis, and left ventricular (LV) function after experimental myocardial infarction (MI). C57J/bl6 mice were subjected to coronary artery ligation and were treated for 10 days with vehicle or aliskiren (50 mg/kg per day via an SC osmopump), whereas sham-operated animals served as controls. This dose of aliskiren, which did not affect systemic blood pressure, improved systolic and diastolic LV function, as measured by the assessment of pressure-volume loops after MI. Furthermore, after MI LV dilatation, cardiac hypertrophy and lung weights were decreased in mice treated with aliskiren compared with placebo-treated mice after MI. This was associated with a normalization of the mitogen-activated protein kinase P38 and extracellular signal-regulated kinases 1/2, AKT, and the apoptotic markers bax and bcl-2 (all measured by Western blots), as well as the number of TUNEL-positive cells in histology. LV dilatation, as well as the associated upregulation of gene expression (mRNA abundance) and activity (by zymography) of the cardiac metalloproteinase 9 in the placebo group after MI, was also attenuated in the aliskiren-treated group. Aliskiren improved LV dysfunction after MI in a dose that did not affect blood pressure. This was associated with the amelioration of cardiac remodelling, hypertrophy, and apoptosis.

Topics: Amides; Animals; Antihypertensive Agents; Apoptosis; Blood Pressure; Cardiomegaly; Collagen; Extracellular Matrix; Fumarates; Hypertension, Renal; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myocardium; Renin; RNA, Messenger; Tissue Inhibitor of Metalloproteinase-1; Ventricular Function, Left; Ventricular Remodeling

Topics: Amides; Cough; Fumarates; Humans; Hypertension; Incidence; Ramipril; Randomized Controlled Trials as Topic

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Fumarates; Heart Failure; Humans; Renin; Renin-Angiotensin System

Aliskiren (Rasilez) is the first oral renin inhibitor. Its present indication is essential hypertension, as monotherapy or in combination with other antihypertensive agents (diuretic, calcium antagonist, ...). It may also be associated with an angiotensin converting enzyme inhibitor (or an AT1 angiotensin receptor antagonist) in order to benefit of a dual blockade of the renin-angiotensin-aldosterone system. The usual daily dose is 150 mg, to be increased up to 300 mg if necessary. New clinical trials are ongoing to validate this novel therapeutic approach in other indications such as congestive heart failure and diabetic nephropathy.

Topics: Amides; Fumarates; Humans; Hypertension; Renin

Topics: Amides; Antihypertensive Agents; Biological Availability; Blood Pressure; Drug Interactions; Fumarates; Humans; Hypertension; Renal Insufficiency; Renin; Renin-Angiotensin System

We compared the effect n-3 polyunsaturated fatty acids (PUFAs) with direct renin inhibition on electrophysiological remodeling in angiotensin II-induced cardiac injury. We treated double-transgenic rats expressing the human renin and angiotensinogen genes (dTGRs) from week 4 to 7 with n-3 PUFA ethyl-esters (Omacor; 25-g/kg diet) or a direct renin inhibitor (aliskiren; 3 mg/kg per day). Sprague-Dawley rats were controls. We performed electrocardiographic, magnetocardiographic, and programmed electrical stimulation. Dietary n-3 PUFAs increased the cardiac content of eicosapentaenoic and docosahexaenoic acid. At week 7, mortality in dTGRs was 31%, whereas none of the n-3 PUFA- or aliskiren-treated dTGRs died. Systolic blood pressure was modestly reduced in n-3 PUFA-treated (180+/-3 mm Hg) compared with dTGRs (208+/-5 mm Hg). Aliskiren-treated dTGRs and Sprague-Dawley rats were normotensive (110+/-3 and 119+/-6 mm Hg, respectively). Both n-3 PUFA-treated and untreated dTGRs showed cardiac hypertrophy and increased atrial natriuretic peptide levels. Prolonged QRS and QT(c) intervals and increased T-wave dispersion in dTGRs were reduced by n-3 PUFAs or aliskiren. Both treatments reduced arrhythmia induction from 75% in dTGRs to 17% versus 0% in Sprague-Dawley rats. Macrophage infiltration and fibrosis were reduced by n-3 PUFAs and aliskiren. Connexin 43, a mediator of intermyocyte conduction, was redistributed to the lateral cell membranes in dTGRs. n-3 PUFAs and aliskiren restored normal localization to the intercalated disks. Thus, n-3 PUFAs and aliskiren improved electrical remodeling, arrhythmia induction, and connexin 43 expression, despite a 70-mm Hg difference in blood pressure and the development of cardiac hypertrophy.

Topics: Amides; Angiotensinogen; Animals; Animals, Genetically Modified; Antihypertensive Agents; Arrhythmias, Cardiac; Blood Pressure; Cardiac Pacing, Artificial; Cardiomegaly; Connexin 43; Dietary Fats; Disease Models, Animal; Electrocardiography; Electrophysiology; Fatty Acids, Omega-3; Fumarates; Humans; Hypertension; Magnetocardiography; Male; Rats; Rats, Sprague-Dawley; Renin; Up-Regulation

The recently cloned (pro)renin receptor [(P)RR] mediates renin-stimulated cellular effects by activating mitogen-activated protein kinases and promotes nonproteolytic prorenin activation. In vivo, (P)RR is said to be blocked with a peptide consisting of 10 amino acids from the prorenin prosegment called the "handle-region" peptide (HRP). We tested whether human prorenin and renin induce extracellular signal-regulated kinase (ERK) 1/2 activation and whether the direct renin inhibitor aliskiren or the HRP inhibits the receptor. We detected the (P)RR mRNA and protein in isolated human monocytes and in U937 monocytes. In U937 cells, we found that both human renin and prorenin induced a long-lasting ERK 1/2 phosphorylation despite angiotensin II type 1 and 2 receptor blockade. In contrast to angiotensin II-ERK signaling, renin and prorenin signaling did not involve the epidermal growth factor receptor. A mitogen-activated protein kinase kinase 1/2 inhibitor inhibited both renin and prorenin-induced ERK 1/2 phosphorylation. Neither aliskiren nor HRP inhibited binding of (125)I-renin or (125)I-prorenin to (P)RR. Aliskiren did not inhibit renin and prorenin-induced ERK 1/2 phosphorylation and kinase activity. Fluorescence-activated cell sorter analysis showed that, although fluorescein isothiocyanate-labeled HRP bound to U937 cells, HRP did not inhibit renin or prorenin-induced ERK 1/2 activation. In conclusion, prorenin and renin-induced ERK 1/2 activation are independent of angiotensin II. The signal transduction is different from that evoked by angiotensin II. Aliskiren has no (P)RR blocking effect and did not inhibit ERK 1/2 phosphorylation or kinase activity. Finally, we found no evidence that HRP affects renin or prorenin binding and signaling.

Topics: Amides; Angiotensin II; Cells, Cultured; Enzyme Activation; Fumarates; Humans; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Monocytes; Oligopeptides; Peptides; Phosphorylation; Protein Binding; Renin; Signal Transduction; U937 Cells

The prorenin/renin receptor is a recently discovered component of the renin-angiotensin system. The effects of aliskiren, a direct inhibitor of human renin, were compared with the handle region decoy peptide (HRP), which blocks the prorenin/renin receptor, in double-transgenic rats overexpressing the human renin and angiotensinogen genes. After 7 wk, all aliskiren-treated rats were alive, whereas mortality was 40% in vehicle-treated and 58% in HRP-treated rats. Aliskiren but not the HRP reduced BP and normalized albuminuria, cystatin C, and neutrophil gelatinase-associated lipocalin, a marker of renal tubular damage, to the levels of nontransgenic controls. In vitro, human renin and prorenin induced extracellular signal-regulated kinase 1/2 phosphorylation, independent of angiotensin II (AngII), in vascular smooth muscle cells. Preincubation with the HRP or aliskiren did not prevent renin- and prorenin-induced extracellular signal-regulated kinase 1/2 phosphorylation, whereas the MAP kinase kinase (MEK1/2) inhibitor PD98059 prevented both. In conclusion, renin inhibition but not treatment with the HRP protects against AngII-induced renal damage in double-transgenic rats. In addition, the in vitro data do not support the use of the HRP to block AngII-independent prorenin- or renin-mediated effects.

Topics: Amides; Angiotensin II; Animals; Blood Pressure; Fumarates; Humans; Hypertension; Muscle, Smooth, Vascular; Oligopeptides; Rats; Renin

Aliskiren, an octanamide, is nonpeptide, low molecular weight, orally active renin inhibitor effectively preventing angiotensin and aldosterone release. This drug has been recently approved for the treatment of hypertension. Considering potential links between hypertension, platelets, the coagulation cascade and fibrinolysis we sought to evaluate the effect of aliskiren on human biomarkers of hemostasis. In vitro effects of whole blood preincubation with escalating concentrations of aliskiren (500, 1,000 and 2,000 ng ml(-1)) were assessed in 20 aspirin-naive volunteers with multiple risk factors for vascular disease. A total of 33 biomarkers were measured, of which 18 are related to platelet function, 12 to coagulation and 3 to fibrinolysis. Pretreatment of blood samples with aliskiren 500 ng ml(-1) resulted in a significant increase of antithrombin-III (AT-III) activity (P=0.003). All other tested biomarkers were not significantly affected. Spiking whole blood with the higher aliskiren doses was associated with various trends in biomarker activity, where 1000 ng ml(-1) concentration mostly decreased (7/33), and 2,000 ng ml(-1) mostly increased (6/33) some biomarkers. In the therapeutic concentration of 500 ng ml(-1) aliskiren does not affect hemostatic biomarkers, except for a moderate but highly significant (P=0.003) increase of AT-III activity. Higher aliskiren doses were associated with more profound biomarker changes, but they are likely not to be clinically relevant since they show diverging (that is, both mild antiplatelet and platelet-activating) trends, and considering the 2- to 4-fold safety margin. It is suggested that antithrombotic properties of aliskiren be explored further in an ex vivo clinical setting.

Topics: Adult; Amides; Analysis of Variance; Antihypertensive Agents; Biomarkers; Blood Coagulation; Blood Platelets; Cardiovascular Diseases; Female; Fibrinolysis; Flow Cytometry; Fumarates; Humans; Hypertension; Male; Renin; Renin-Angiotensin System; Risk Factors; Statistics, Nonparametric

The role of the renin angiotensin system (RAS) in atherosclerosis is complex because of the involvement of multiple peptides and receptors. Renin is the rate-limiting enzyme in the production of all angiotensin peptides. To determine the effects of renin inhibition on atherosclerosis, we administered the novel renin inhibitor aliskiren over a broad dose range to fat-fed LDL receptor-deficient (Ldlr(-/-)) mice. Renin inhibition resulted in striking reductions of atherosclerotic lesion size in both the aortic arch and the root. Subsequent studies demonstrated that cultured macrophages expressed all components of the RAS. To determine the role of macrophage-derived angiotensin in the development of atherosclerosis, we transplanted renin-deficient bone marrow to irradiated Ldlr(-/-) mice and observed a profound decrease in the size of atherosclerotic lesions. In similar experiments, transplantation of bone marrow deficient for angiotensin II type 1a receptors failed to influence lesion development. We conclude that renin-dependent angiotensin production in macrophages does not act in an autocrine/paracrine manner. Furthermore, in vitro studies demonstrated that coculture with renin-expressing macrophages augmented monocyte adhesion to endothelial cells. Therefore, although previous work suggests that angiotensin peptides have conflicting effects on atherogenesis, we found that renin inhibition profoundly decreased lesion development in mice.

Topics: Amides; Animals; Atherosclerosis; Bone Marrow Transplantation; Cell Adhesion; Cells, Cultured; Fumarates; Hypercholesterolemia; Macrophages; Mice; Mice, Inbred C57BL; Monocytes; Receptor, Angiotensin, Type 1; Receptors, LDL; Renin; Systole

Topics: Amides; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin

A semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was developed to evaluate the effects of aliskiren on the renin-angiotensin system (RAS) in humans. Mean data were extracted from a three-way crossover, placebo-controlled study. Outcome measures included the time-course of plasma renin activity (PRA) and plasma concentrations of aliskiren, active renin (AR), angiotensin I (ANG I), and angiotensin II (ANG II). The disposition of aliskiren may be best described as a two-compartment model with nonlinear elimination and distribution. The four biomarkers of RAS inhibition were co-modeled, and the AR showed a dose-dependent increase after the administration of aliskiren. This effect was described in terms of an indirect stimulatory response model in conjunction with an empirical submodel of functional adaptation. The estimated concentration of aliskiren necessary for producing 50% inhibition of PRA is 0.66 ng/ml, which is similar to in vitro estimates (0.33 ng/ml) after correction for plasma protein binding. The final and reduced models test the current hypothesis that RAS is inhibited by direct renin antagonism, and also provide suitable platforms for future clinical study design and analysis.

Topics: Amides; Biomarkers; Controlled Clinical Trials as Topic; Cross-Over Studies; Dose-Response Relationship, Drug; Fumarates; Humans; Male; Models, Biological; Renin; Renin-Angiotensin System

Topics: Adult; Amides; Angioedema; Antihypertensive Agents; Female; Fumarates; Humans; Hypertension; Renin

The occurrence of a functional intracellular renin-angiotensin system (RAS) has emerged as a new paradigm. Recently, we and others demonstrated intracellular synthesis of ANG II in cardiac myocytes and vascular smooth muscle cells that was dramatically stimulated in high glucose conditions. Cardiac fibroblasts significantly contribute to diabetes-induced diastolic dysfunction. The objective of the present study was to determine the existence of the intracellular RAS in cardiac fibroblasts and its role in extracellular matrix deposition. Neonatal rat ventricular fibroblasts were serum starved and exposed to isoproterenol or high glucose in the absence or presence of candesartan, which was used to prevent receptor-mediated uptake of ANG II. Under these conditions, an increase in ANG II levels in the cell lysate represented intracellular synthesis. Both isoproterenol and high glucose significantly increased intracellular ANG II levels. Confocal microscopy revealed perinuclear and nuclear distribution of intracellular ANG II. Consistent with intracellular synthesis, Western analysis showed increased intracellular levels of renin following stimulation with isoproterenol and high glucose. ANG II synthesis was catalyzed by renin and angiotensin-converting enzyme (ACE), but not chymase, as determined using specific inhibitors. High glucose resulted in increased transforming growth factor-beta and collagen-1 synthesis by cardiac fibroblasts that was partially inhibited by candesartan but completely prevented by renin and ACE inhibitors. In conclusion, cardiac fibroblasts contain a functional intracellular RAS that participates in extracellular matrix formation in high glucose conditions, an observation that may be helpful in developing an appropriate therapeutic strategy in diabetic conditions.

Topics: Adrenergic beta-Agonists; Amides; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Newborn; Benzazepines; Benzimidazoles; Biphenyl Compounds; Blotting, Western; Cells, Cultured; Collagen Type I; Dose-Response Relationship, Drug; Extracellular Matrix; Fibroblasts; Fumarates; Glucose; Heart Ventricles; Isoproterenol; Microscopy, Confocal; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System; Tetrazoles; Time Factors; Transforming Growth Factor beta; Up-Regulation

1. Initial attempts to inhibit renin in humans have faced numerous difficulties. Molecular modelling and X-ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors, such as aliskiren. 2. Aliskiren has a low bioavailability (between 2.6 and 5.0%) compensated by its high potency to inhibit renin (IC50: 0.6 nmol/L) and a long plasma half-life (23-36 h), which makes it suitable for once-daily dosing. 3. The once-daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 (AT1) receptor blockers (losartan, valsartan, irbesartan), hydrochlorothiazide, angiotensin converting enzyme inhibitors (ramipril and lisinopril) or long acting calcium channel blockers (amlodipine). In combination therapy, aliskiren further decreases blood pressure when combined with either hydrochlorothiazide, amlodipine, irbesartan or ramipril. 4. The biochemical consequences of renin inhibition differ from those of angiotensin I-converting enzyme (ACE) inhibition and Ang II antagonism, particularly in terms of angiotensin profiles and interactions with the bradykinin-nitric oxide-cyclic guanosine monophosphate pathway and possibly the (pro)renin receptor. 5. Blockade of the renin angiotensin system (RAS) with ACE inhibitors, AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine. However, it remains unclear how to optimize RAS blockade to maximize cardiovascular and renal benefits. In this context, renin inhibition to render the RAS fully quiescent is a new possibility requiring further study.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fumarates; Humans; Hypertension

Renin-angiotensin system (RAS) blockade with ACE inhibitor and/or angiotensin receptor blocker therapy can lead to increased potassium levels, hence the need to assess dual blockade involving a direct renin inhibitor. Here we report the results of a pre-planned 6-month interim analysis of a long-term, open-label study examining the safety, tolerability and efficacy of the aliskiren/valsartan 300/320-mg combination in patients with hypertension.. A total of 601 patients with hypertension (msDBP > or = 90 and < 110 mmHg) received a combination of aliskiren/valsartan 150/160 mg for 2 weeks followed by forced titration to aliskiren/valsartan 300/320 mg once daily for a targeted duration of 52 weeks. Optional hydrochlorothiazide (HCTZ) addition was allowed from week 8 for inadequate BP control (> or = 140/90 mmHg). The primary objective was to assess the safety of combination therapy; potassium elevations were a predefined safety outcome. BP was measured at regular intervals during the study.. At the 6-month cut-off date, 512 patients (85.2%) were still ongoing with study treatment, and 192 patients had received at least one dose of HCTZ add-on during this period. Combination therapy was generally well-tolerated; the most commonly reported adverse events were headache (7.5%), dizziness (7.3%) and nasopharyngitis (7.2%). Ten patients (2.5%) receiving aliskiren/valsartan and two patients (1.0%) receiving aliskiren/valsartan/HCTZ had serum potassium elevations > 5.5 mmol/L. Only one patient (0.2%) exhibited potassium levels > or = 6.0 mmol/L during this period and the patient was treated with aliskiren/valsartan. Mean msSBP/DBP reductions of 22.3/14.4 mmHg were observed at 6-month endpoint (LOCF analysis) and 73.4% of patients achieved BP control (< 140/90 mmHg; LOCF).. Although lack of an active comparator group is a limitation of the study, our findings show that long-term treatment with the aliskiren/valsartan 300/320-mg combination provided clinically significant BP lowering, was well-tolerated and was associated with a very low rate of potassium elevations in patients with hypertension.

Topics: Aged; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hyperkalemia; Hypertension; Male; Middle Aged; Renin; Renin-Angiotensin System; Risk Factors; Tetrazoles; Time Factors; Valine; Valsartan

Renin inhibition with aliskiren has been reported to cause a greater rise in renin than other types of renin-angiotensin system blockade, thereby potentially leading to angiotensin generation or stimulation of the human (pro)renin receptor (h(P)RR). Here we studied whether this rise in renin is attributable to an aliskiren-induced change in the prorenin conformation, allowing its detection in renin assays, or a change in renin/prorenin clearance. We also investigated whether aliskiren affects (pro)renin binding to its receptors, using rat aortic vascular smooth muscle cells (VSMCs) overexpressing the h(P)RR.. A 48-hour incubation with aliskiren at 4 degrees C converted the prorenin conformation from "closed" to "open," thus allowing its recognition in active site-directed renin assays. VSMCs accumulated (pro)renin through binding to mannose 6-phosphate receptors (M6PRs) and h(P)RRs. Aliskiren did not affect binding at 4 degrees C. At 37 degrees C, aliskiren increased (pro)renin accumulation up to 40-fold, and M6PR blockade prevented this. Aliskiren increased the intracellular half life of prorenin 2 to 3 times.. Aliskiren allows the detection of prorenin as renin, and decreases renin/prorenin clearance. Both phenomena may contribute to the "renin" surge during aliskiren treatment, but because they depend on aliskiren binding, they will not result in angiotensin generation. Aliskiren does not affect (pro)renin binding to its receptors.

Topics: Adult; Aged; Aged, 80 and over; Amides; Animals; Animals, Genetically Modified; Antihypertensive Agents; Aorta; Cells, Cultured; Female; Fumarates; Half-Life; Humans; Male; Middle Aged; Muscle, Smooth, Vascular; Prorenin Receptor; Protein Binding; Rats; Receptor, IGF Type 2; Receptors, Cell Surface; Renin; Vacuolar Proton-Translocating ATPases

Hypertension is associated with increased risk of cardiovascular diseases. Antihypertensive treatment, particularly blockade of the renin-angiotensin system, contributes to prevent atherosclerosis-mediated cardiovascular events. Direct comparison of different antihypertensive treatments on atherosclerosis and particularly plaque stabilization is sparse. ApoE(-/-) mice with vulnerable (2-kidney, 1-clip renovascular hypertension model) or stable (1-kidney, 1-clip renovascular hypertension model) atherosclerotic plaques were used. Mice were treated with aliskiren (renin inhibitor), irbesartan (angiotensin-receptor blocker), atenolol (beta-blocker), or amlodipine (calcium channel blocker). Atherosclerosis characteristics were assessed. Hemodynamic and hormonal parameters were measured. Aliskiren and irbesartan significantly prevented atherosclerosis progression in 2-kidney, 1-clip mice. Indeed, compared with untreated animals, plaques showed thinner fibrous cap (P<0.05); smaller lipid core (P<0.05); decreased media degeneration, layering, and macrophage content (P<0.05); and increased smooth muscle cell content (P<0.05). Interestingly, aliskiren significantly increased the smooth muscle cell compared with irbesartan. Despite similar blood pressure lowering, only partial plaque stabilization was attained by atenolol and amlodipine. Amlodipine increased plaque smooth muscle cell content (P<0.05), whereas atenolol decreased plaque inflammation (P<0.05). This divergent effect was also observed in 1-kidney, 1-clip mice. Normalizing blood pressure by irbesartan increased the plasma renin concentration (5932+/-1512 ng/mL per hour) more than normalizing it by aliskiren (16085+/-5628 ng/mL per hour). Specific renin-angiotensin system blockade prevents atherosclerosis progression. First, evidence is provided that direct renin inhibition mediates atherosclerotic plaque stabilization. In contrast, beta-blocker and calcium channel blocker treatment only partially stabilize plaques differently influencing atherogenesis. Angiotensin II decisively mediates plaque vulnerability. The plasma renin concentration measurement by an indirect method did not confirm the excessive increase of plasma renin concentration reported in the literature during aliskiren compared with irbesartan or amlodipine treatment.

Topics: Amides; Amlodipine; Animals; Antihypertensive Agents; Apolipoproteins E; Atenolol; Atherosclerosis; Biphenyl Compounds; Blood Pressure; Cholesterol; Disease Models, Animal; Disease Progression; Female; Fumarates; Heart Rate; Irbesartan; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Renin; Renin-Angiotensin System; Tetrazoles

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Atherosclerosis; Fumarates; Humans; Mice; Mice, Knockout; Models, Biological; Receptors, LDL; Renin; Renin-Angiotensin System

A unique rating system compares five new drugs with existing therapies and evaluates the uses and most important properties of each new agent. Advantages, disadvantages, and other important information regarding the new drug are considered and identified, including their use in the elderly.

Topics: Aged; Amides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antihypertensive Agents; Antiparkinson Agents; Antipsychotic Agents; Drug Approval; Fumarates; Humans; Hypoglycemic Agents; Isoxazoles; Macular Degeneration; Paliperidone Palmitate; Pyrazines; Pyrimidines; Ranibizumab; Sitagliptin Phosphate; Tetrahydronaphthalenes; Thiophenes; Triazoles; United States

Angiotensin II (Ang II) stimulation of the Ang type 1 receptor (AT(1)R) facilitates myocardial remodeling through NADPH oxidase-mediated generation of oxidative stress. Components of the renin-angiotensin system constitute an autocrine/paracrine unit in the myocardium, including renin, which is the rate-limiting step in the generation of Ang II. This investigation sought to determine whether cardiac oxidative stress and cellular remodeling could be attenuated by in vivo renin inhibition and/or AT(1)R blockade in a rodent model of chronically elevated tissue Ang II levels, the transgenic (mRen2)27 rat (Ren2). The Ren2 overexpresses the mouse renin transgene with resultant hypertension, insulin resistance, and cardiovascular damage. Young (6- to 7-wk-old) heterozygous (+/-) male Ren2 and age-matched Sprague-Dawley rats were treated with the renin inhibitor aliskiren, which has high preferential affinity for human and mouse renin, an AT(1)R blocker, irbesartan, or placebo for 3 wk. Myocardial NADPH oxidase activity and immunostaining for NADPH oxidase subunits and 3-nitrotyrosine were evaluated and remodeling changes assessed by light and transmission electron microscopy. Blood pressure, myocardial NADPH oxidase activity and subunit immunostaining, 3-nitrotyrosine, perivascular fibrosis, mitochondrial content, and markers of activity were significantly increased in Ren2 compared with SD littermates. Both renin inhibition and blockade of the AT(1)R significantly attenuated cardiac functional and structural alterations, although irbesartan treatment resulted in greater reductions of both blood pressure and markers of oxidative stress. Collectively, these data suggest that both reduce changes driven, in part, by Ang II-mediated increases in NADPH oxidase and, in part, increases in blood pressure.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Animals; Animals, Genetically Modified; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Fumarates; Irbesartan; Male; Myocardium; NADPH Oxidases; Oxidative Stress; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Renin; Tetrazoles; Tyrosine; Ventricular Remodeling

Hypertension is one of the major risk factors for cardiovascular morbidity and mortality. Lowering blood pressure (BP) may reduce the risk of stroke by 40% and the risk of ischemic heart disease by 20%. Despite the varied drugs available to lower BP, more than 50% of the hypertensive patients are not well-controlled. The major reason for the failure to control BP is noncompliance which is related to the side effects and inconvenience of drug administration. Aliskiren, a new oral direct renin inhibitor is very effective in BP reduction. It is given once daily and has very few side effects, almost like a placebo. It is well combined with diuretics, angiotensin converting enzyme (ACE) inhibitors and calcium channel blockers. Unlike ACE inhibitors and angiotensin receptor blockers that block the renin angiotensin axis in its last part and thereby raise the rein-levels, the direct renin inhibitor block the renin-angiotensin axis in its beginning and keep the renin levels suppressed. Aliskiren is a promising agent but further prospective studies with morbidity and mortality data as endpoints are required, before the drug can be recommended as a first choice agent.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hypertension; Renin

The aim of this study was to explore the effects of the renin inhibitor aliskiren in streptozotocin-diabetic TG(mRen-2)27 rats. Furthermore, we investigated in vitro the effect of aliskiren on the interactions between renin and the (pro)renin receptor and between aliskiren and prorenin. Aliskiren distributed extensively to the kidneys of normotensive (non)diabetic rats, localizing in the glomeruli and vessel walls after 2 hours exposure. In diabetic TG(mRen-2)27 rats, aliskiren (10 or 30 mg/kg per day, 10 weeks) lowered blood pressure, prevented albuminuria, and suppressed renal transforming growth factor-beta and collagen I expression versus vehicle. Aliskiren reduced (pro)renin receptor expression in glomeruli, tubules, and cortical vessels compared to vehicle (in situ hybridization). In human mesangial cells, aliskiren (0.1 micromol/L to 10 micromol/L) did not inhibit binding of (125)I-renin to the (pro)renin receptor, nor did it alter the activation of extracellular signal-regulated kinase 1/2 by renin (20 nmol/L) preincubated with aliskiren (100 nmol/L) or affect gene expression of the (pro)renin receptor. Evidence was obtained that aliskiren binds to the active site of prorenin. The above results demonstrate the antihypertensive and renoprotective effects of aliskiren in experimental diabetic nephropathy. The evidence that aliskiren can reduce in vivo gene expression for the (pro)renin receptor and that it may block prorenin-induced angiotensin generation supports the need for additional work to reveal the mechanism of the observed renoprotection by this renin inhibitor.

Topics: Albuminuria; Amides; Animals; Antihypertensive Agents; Blood Pressure; Collagen Type I; Collagen Type III; Collagen Type IV; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Fumarates; Gene Expression; Humans; Male; Prorenin Receptor; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Renin; Transforming Growth Factor beta

Topics: Amides; Animals; Antihypertensive Agents; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Fumarates; Hypertension; Rats; Renin

Here we apply the computational solvent mapping (CS-Map) algorithm toward the in silico identification of hot spots, that is, regions of protein binding sites that are major contributors to the binding energy and, hence, are prime targets in drug design. The CS-Map algorithm, developed for binding site characterization, moves small organic functional groups around the protein surface and determines their most energetically favorable binding positions. The utility of CS-Map algorithm toward the prediction of hot spot regions in druggable binding pockets is illustrated by three test systems: (1) renin aspartic protease, (2) a set of previously characterized druggable proteins, and (3) E. coli ketopantoate reductase. In each of the three studies, existing literature was used to verify our results. Based on our analyses, we conclude that the information provided by CS-Map can contribute substantially to the identification of hot spots, a necessary predecessor of fragment-based drug discovery efforts.

Topics: Alcohol Oxidoreductases; Algorithms; Amides; Binding Sites; Computers, Molecular; Drug Design; Escherichia coli Proteins; Fumarates; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Protein Binding; Proteins; Renin; Thermodynamics

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Female; Forecasting; Fumarates; Humans; Hypertension; Male; Needs Assessment; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Risk Factors; Sensitivity and Specificity

Topics: Amides; Anemia; Antihypertensive Agents; Benzazepines; Drug Administration Schedule; Drug Approval; Drug Combinations; Drug Delivery Systems; Erythropoietin; Ferrosoferric Oxide; Fumarates; Humans; Hyponatremia; Immunosuppressive Agents; Kidney Diseases; Nanoparticles; Nephrology; Renal Dialysis; Renin; Tacrolimus; Tolvaptan

Topics: Amides; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hypertension; Kidney; Renin

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Fumarates; Humans; Hypertension; Lisinopril; Renin; Renin-Angiotensin System; Treatment Outcome

Renin catalyzes the rate-limiting step of the renin-angiotensin system. A T allele variant at position -5312 within a distal enhancer region has been reported to increase in vitro renin gene transcription. Among 387 White bank employees, ambulatory blood pressures were higher in 133 -5312T allele carriers than in 254 CC homozygotes-mean differences [99% confidence interval] between carriers and homozygotes for daytime and night-time systolic/diastolic pressure were 2.5[0.4,4.6]/1.7[0.2,3.2] and 2.4[0.5,4.4]/1.5[0.1,2.9] respectively. Ambulatory pressure estimates for the only common renin haplotype including the -5312T variant (-5312T, 5090C, 5912A, 9479A, 10194G), were statistically significantly higher than estimates for all other haplotypes. Among 259 White hypertensive participants in a randomized double-blind clinical trial comparing a renin antagonist, aliskiren, with an angiotensin receptor blocker, losartan, plasma renin activity did not differ with renin -5312C/T genotype. Nocturnal blood pressure reductions with losartan 100 mg daily were significantly greater in -5312T allele carriers than in CC homozygotes (mean[standard error]; -12.9[3.7]/-7.9[2.4] versus -7.1[2.5]/-4.2[1.6]) whereas with aliskiren 150 and 300 mg daily, lesser reductions were observed in -5312T allele carriers than in CC homozygotes (-5.4[2.0]/-4.1[1.3] versus -10.1[1.4]/-6.5[1.1]; P<0.03 for treatmentxgenotype interaction for night-time systolic and diastolic pressures). Hence, the -5312 renin C/T enhancer polymorphism does contribute to blood pressure variation in Whites and also appears to predict responses to inhibition of the renin-angiotensin system. These findings suggest that genotyping at this locus may aid in the identification of susceptibility to hypertension and in the selection of optimal therapy for individual hypertensive patients.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Chi-Square Distribution; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Fumarates; Genetic Predisposition to Disease; Haplotypes; Humans; Hypertension; Linear Models; Losartan; Male; Middle Aged; Multivariate Analysis; Polymorphism, Genetic; Renin; Renin-Angiotensin System; Severity of Illness Index; Treatment Outcome

Topics: Amides; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin

Aliskiren is an orally active direct renin inhibitor approved for the treatment of hypertension. This study assessed the effects of renal impairment on the pharmacokinetics and safety of aliskiren alone and in combination with the angiotensin receptor antagonist irbesartan.. This open-label study enrolled 17 males with mild, moderate or severe renal impairment (creatinine clearance [CL(CR)] 50-80, 30-49 and <30 mL/minute, respectively) and 17 healthy males matched for age and bodyweight. Subjects received oral aliskiren 300 mg once daily on days 1-7 and aliskiren coadministered with irbesartan 300 mg on days 8-14. Plasma aliskiren concentrations were determined by high-performance liquid chromatography/tandem mass spectrometry at frequent intervals up to 24 hours after dosing on days 1, 7 and 14.. Renal clearance of aliskiren averaged 1280 +/- 500 mL/hour (mean +/- SD) in healthy subjects and 559 +/- 220, 312 +/- 75 and 243 +/- 186 mL/hour in patients with mild, moderate and severe renal impairment, respectively. At steady state (day 7), the geometric mean ratios (renal impairment : matched healthy volunteers) ranged from 1.21 to 2.05 for the area under the plasma concentration-time curve (AUC) over the dosage interval tau (24h) [AUC(tau)]) and from 0.83 to 2.25 for the maximum observed plasma concentration of aliskiren at steady state. Changes in exposure did not correlate with CL(CR), consistent with an effect of renal impairment on non-renal drug disposition. The observed large intersubject variability in aliskiren pharmacokinetic parameters was unrelated to the degree of renal impairment. Accumulation of aliskiren at steady state (indicated by the AUC from 0 and 24 hours [AUC(24)] on day 7 vs day 1) was similar in healthy subjects (1.79 [95% CI 1.24, 2.60]) and those with renal impairment (range 1.39-1.99). Coadministration with irbesartan did not alter the pharmacokinetics of aliskiren. Aliskiren was well tolerated when administered alone or with irbesartan.. Exposure to aliskiren is increased by renal impairment but does not correlate with the severity of renal impairment (CL(CR)). This is consistent with previous data indicating that renal clearance of aliskiren represents only a small fraction of total clearance. Initial dose adjustment of aliskiren is unlikely to be required in patients with renal impairment.

Topics: Administration, Oral; Amides; Biphenyl Compounds; Drug Therapy, Combination; Fumarates; Humans; Irbesartan; Kidney Diseases; Pharmacokinetics; Renin; Tetrazoles

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan

Topics: Amides; Fumarates; Hypertension, Renovascular; Renin

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin

We studied the effects of extremely low-dose human renin inhibition (aliskiren) with low angiotensin II receptor blockade (losartan) in a novel double-transgenic rat model harbouring both human renin and angiotensinogen genes. We found that low-dose aliskiren and low-dose losartan effectively reduced mortality and target-organ damage with minimal, non-significant, effects on blood pressure (BP). Our data suggest that renin-angiotensin system (RAS) inhibition ameliorates target-organ damage in an Ang II-driven model of hypertension. Direct renin inhibition is equally efficacious in this regard. Our study does not fully answer the question of BP-lowering versus RAS inhibition. This question is important and was at least partially addressed with our low-dose model.

Topics: Amides; Angiotensinogen; Animals; Animals, Genetically Modified; Antihypertensive Agents; Fumarates; Humans; Hypertension; Rats; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System

Topics: Amides; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin; Treatment Outcome

Topics: Amides; Antihypertensive Agents; Blood Pressure; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diuretics; Drug Design; Drug Industry; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Renin; Tetrazoles; Valine; Valsartan