aliskiren and Chronic-Disease

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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