lu-208075 and Hypertension--Pulmonary

Pediatric pulmonary hypertension (PAH) is a rare disease that carries a poor prognosis if left untreated. Although there are published guidelines for the treatment of children with pulmonary hypertension, due to the limited number of robust pediatric clinical trials, recommendations are often based on limited data or clinical experience. Furthermore, many practical aspects of care, particularly for the pediatric patient, are learned through experience and best navigated with a multidisciplinary team. While newer PAH therapies have been approved for adults, there is still limited but expanding experience in pediatrics. This new information will help improve the targets of goal-oriented therapy. Lastly, this review highlights practical aspects in the use of the different therapies available for the treatment of pediatric pulmonary hypertension.

Topics: Adolescent; Adult; Bosentan; Calcium Channel Blockers; Child; Child, Preschool; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Iloprost; Infant; Infant, Newborn; Phenotype; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Prognosis; Pulmonary Arterial Hypertension; Pyridazines; Pyrimidines; Receptors, Endothelin; Sildenafil Citrate; Sulfonamides; Tadalafil; Young Adult

It is commonly reported a limitation of therapeutic strategy in Eisenmenger syndrome (ES) historically. This qualitative systematic review is conducted to evaluate the safety and efficacy of pulmonary arterial hypertension-specific drug therapy (PAH-SDT) for ES patients for a clinical therapeutic strategy based on evidence.. PubMed, EMBASE, and the Cochrane Library databases have been systematically reviewed up to January 2019. Two reviewers independently conducted a literature search, quality evaluation, and data extraction. The occurrence of death, deterioration, and adverse events (AEs) has respectively been described as a count or percentage. Meta-analysis was conducted by Stata 15.1, and weighted mean differences (WMD) with 95% confidence intervals (CI) were recorded for continuous data. Randomized-effect model or fixed-effect model was applied according to the heterogeneity test.. Fifteen citations recruiting 456 patients associated with ES were eventually pooled, which involved 4 RCTs, 6 prospective studies, and 5 retrospective studies. Within the first year, it indicated PAH-SDT significantly ameliorated exercise capacity in 6-minute walk distance (6MWD) (I = 60.5%; WMD: 53.86 m, 95% CI [36.59, 71.13], P < .001), functional class (FC) (WMD = -0.71, 95% CI [-0.98, -0.44], P < .001) and Borg dyspnea index (WMD = -1.28, 95% CI [-1.86, -0.70], P < .001), in addition to hemodynamics, especially mean pulmonary arterial pressure by 5.70 mmHg (WMD = -5.70 mmHg, 95% CI [-8.19, -3.22], P < .001) and pulmonary vascular resistance by 4.20 wood U (WMD: -4.20, 95% CI [-7.32, -1.09], P = .008), but unsatisfactory effects in oxygen saturation at exercise (P = .747). In a prolonged medication, bosentan, a dual ERA, has been proved acting an important role in improving exercise tolerance of patients with ES (6MWD: I = 47.5%; WMD: 88.68 m, 95% CI [54.05, 123.3], P < .001; FC: I = 0.0%; WMD = -0.65, 95% CI [-1.10, -0.19], P = .006). While a nonsignificant change of 6MWD was noted in a long-term therapy of ambrisentan (P = .385). There existed rare evidence about the efficacy and safety of macitentan, phosphodiesterase-5 inhibitors (PDE5i), and prostanoids in a prolonged medication. Most AEs were recorded as mild to moderate with PAH-SDT, but about 4.3% individuals treated with endothelin receptor antagonists (ERAs) suffered from serious ones, and 3.9% suffered from death.. This systematic review and meta-analysis proved PAH-SDT as a safe and effective role in ES in an early stage. However, in a long-term treatment, bosentan has been supported for a lasting effect on exercise tolerance. A further multicenter research with a large sample about pharmacotherapy of ES is necessary.

Topics: Antihypertensive Agents; Bosentan; Eisenmenger Complex; Endothelin Receptor Antagonists; Exercise Tolerance; Hemodynamics; Humans; Hypertension, Pulmonary; Oxygen; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Prostaglandins; Pyridazines; Pyrimidines; Sulfonamides

Although many studies have reported on the cost-effectiveness of bosentan for treating pulmonary arterial hypertension (PAH), a systematic review of economic evaluations of bosentan is currently lacking. Objective evaluation of current pharmacoeconomic evidence can assist decision makers in determining the appropriate place in therapy of a new medication.. Systematic literature searches were conducted in English-language databases (MEDLINE, EMBASE, EconLit databases, and the Cochrane Library) and Chinese-language databases (China National Knowledge Infrastructure, WanFang Data, and Chongqing VIP) to identify studies assessing the cost-effectiveness of bosentan for PAH treatments.. A total of 8 published studies were selected for inclusion. Among them were two studies comparing bosentan with epoprostenol and treprostinil. Both results indicated that bosentan was more cost-effective than epoprostenol, while the results of bosentan and treprostinil were not consistent. Four studies compared bosentan with other endothelin receptor antagonists, which indicated ambrisentan might be the drug of choice for its economic advantages and improved safety profile. Only two economic evaluations provided data to compare bosentan versus sildenafil, and the results favored the use of sildenafil in PAH patients. Four studies compared bosentan with conventional, supportive, or palliative therapy, and whether bosentan was cost-effective was uncertain.. Bosentan may represent a more cost-effective option compared with epoprostenol and conventional or palliative therapy. There was unanimous agreement that bosentan was not a cost-effective front-line therapy compared with sildenafil and other endothelin receptor antagonists. However, high-quality cost-effectiveness analyses that utilize long-term follow-up data and have no conflicts of interest are still needed.

Topics: Antihypertensive Agents; Bosentan; Cost-Benefit Analysis; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Sildenafil Citrate; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a progressive disease defined by an elevation in pulmonary arterial pressure that can lead to right heart failure and death. Ambrisentan is a selective endothelin receptor antagonist approved for the treatment of idiopathic, heritable PAH and connective tissue disease-associated PAH. Ambrisentan has been shown to improve exercise capacity and hemodynamics with an acceptable side-effect profile. It has also proven to be safely used in combination with other PAH-specific medications, especially with phosphodiesterase-5 inhibitors. In the recent randomized trial, AMBITION, it was shown that upfront combination therapy of ambrisentan and tadalafil significantly decreased the risk of clinical failure compared with monotherapy. This review describes the drug profile of ambrisentan and its safety and efficacy in the treatment of PAH.

Topics: Animals; Antihypertensive Agents; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Randomized Controlled Trials as Topic; Tadalafil

Endothelin receptor antagonists (ERAs) such as ambrisentan, sitaxsentan, bosentan and macitentan are primary drug therapies for pulmonary arterial hypertension (PAH) patients. However, the optimal drugs for PAH remained controversial due to heterogeneous nature of randomized control trials (RCTs).. Apart from traditional meta-analysis, network meta-analysis (NMA) was performed in this study for multiple comparisons among PAH therapies. The 6 minute walking distance (6MWD) and clinical worsening were efficacy outcomes whereas serious adverse effects (SAE) and all-cause discontinuation were acceptability outcomes. The weighted mean difference (WMD) and odds ratio (OR) along with their 95% confidence interval (95% CI) or 95% credible interval (95% CrI) were used to evaluate the positive and negative effects of these therapies on PAH patients.. By synthesizing direct evidence from 10 studies with a total number of 2172 patients, we discovered that all of the four PAH therapies significantly increased the average 6MWD in comparison to the placebo (P-value<0.05). Moreover, bosentan and ambrisentan both showed significant association with a decrease in the risk of clinical worsening compared to placebo. Regarding of all-cause discontinuation, ambrisentan is the only therapy which was significantly associated with a risk decrease compared to placebo. However, there was no sufficient evidence suggesting significant difference in any efficacy or acceptability outcomes between any two of the PAH therapies (P-value>0.05).. Ambrisentan could be considered as the most appropriate therapy among the four ERAs for PAH patients. Bosentan also behaved well, but it is not as safe as ambrisentan.

Topics: Drug Monitoring; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Randomized Controlled Trials as Topic; Treatment Outcome; Walk Test

Pulmonary arterial hypertension (PAH) is a pathophysiological condition characterized by increased pulmonary vascular resistance (PVR), initially due to abnormal pulmonary vasoconstriction in response to endothelial injury. Recent studies confirmed the key role of endothelin (ET)-1 in the vasoconstriction and remodeling of pulmonary microcirculation during PAH. In responders patients, classical treatments for PAH are prostanoids, phosphodiesterase (PDE)-5 inhibitors and endothelin receptor antagonists (ERAs), which target prostaglandin I2, nitric oxide and endothelin pathways, respectively. Randomised, placebo-controlled trials have shown that ERAs improves haemodynamic parameters of the pulmonary circulation, functional capacity and clinical outcome in patients affected by PAH. Here, we will review the definition, classification and pathophysiology of PH. Furthermore, we will provide an up-to-date overview of currently recommended diagnostic and therapeutic work-up in PAH.

Topics: Bosentan; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Phenylpropionates; Prognosis; Pulmonary Circulation; Pyridazines; Randomized Controlled Trials as Topic; Sulfonamides; Treatment Outcome; Vascular Resistance

Pulmonary arterial hypertension (PAH) was previously considered a uniformly fatal disease, with patients succumbing to right heart failure and death at an average of 3 years after diagnosis. The past 20 years, however, have seen the development of numerous targeted therapies that have changed the natural history of PAH. As more pharmacologic agents have been approved and utilized, further advances in the design of and endpoints for clinical trials. This study will review some of these notable developments.. The successful design and completion of long-term, event-driven trials is exemplified in three recent studies: SERAPHIN, GRIPHON, and AMBITION. SERAPHIN and GRIPHON evaluated the newer agents, macitentan, an endothelin receptor antagonist, and selexipag, a prostacyclin receptor agonist, respectively. Both trials were large-scale studies that, in addition to showing marked effect on the primary endpoint of morbidity/mortality, clearly demonstrated that assessment of long-term effects of PAH therapies is feasible for new compounds. The AMBITION study evaluated a treatment strategy, namely up-front combination therapy with tadalafil and ambrisentan compared with monotherapy and showed the combination approach to be superior at decreasing the likelihood of clinical failure.. The evolution of clinical trials in PAH has direct implications for care of these patients. The short and long-term benefits of combination regimens suggest that the multidrug approach to PAH should, in fact, be standard of care for this disease.

Topics: Acetamides; Antihypertensive Agents; Clinical Trials as Topic; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Inositol 1,4,5-Trisphosphate Receptors; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Pyrazines; Pyridazines; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides

Pulmonary arterial hypertension (PAH) is a chronic disorder of the pulmonary vasculature characterized by elevated mean pulmonary arterial pressure eventually leading to right-sided heart failure and premature death. Macitentan is an oral, once-daily, dual endothelin (ET)A and ETB receptor antagonist with high affinity and sustained receptor binding that was approved in the USA, Europe, Canada, and Switzerland for the treatment of PAH.. This review discusses the pharmacokinetics (PK) and pharmacodynamics (PD) of macitentan and its drug interaction potential based on preclinical and clinical data.. Up to date, macitentan is the only registered treatment for PAH that significantly reduced morbidity and mortality as a combined endpoint in a long-term event-driven study. The safety profile of macitentan is favorable with respect to hepatic safety and edema/fluid retention and may be better than that of other ET receptor antagonists such as bosentan and ambrisentan. The PK profile supports a once-a-day dosing regimen. Macitentan has limited interactions with other drugs. Based on these characteristics macitentan is an important new addition to the treatment of PAH.

Topics: Animals; Bosentan; Drug Interactions; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Pyrimidines; Sulfonamides

Pulmonary arterial hypertension (PAH) is a condition that leads to progressive right heart failure and death unless recognized and treated early. Endothelin, a potent endogenous vasoconstrictor, has been identified as an important mediator of PAH. Endothelin receptor antagonists (ERAs) have been associated with an improvement in exercise capacity and time to clinical worsening in patients with Group 1 PAH, and three different ERAs are currently approved for use in this population: bosentan, ambrisentan, and macitentan. While all three ERAs are generally well-tolerated, they each have important adverse effects that need to be recognized and monitored. In particular, they may cause anemia, peripheral edema, and mild cardiac, respiratory, neurologic, and gastrointestinal adverse effects to varying degrees. Although bosentan increases a patient's risk of developing liver transaminitis, ambrisentan and macitentan do not appear to confer the same risk of hepatotoxicity at this time. Important drug-drug interactions, particularly involving other drugs metabolized via the cytochrome P450 pathway, are important to recognize when prescribing ERAs. In this review, we provide a brief overview of the current state of knowledge as it relates to the adverse effect profiles, tolerability, and drug-drug interactions of this class of medication as informed by the results of randomized clinical trials, drug surveillance programs, and regulatory agencies.

Topics: Animals; Antihypertensive Agents; Bosentan; Chemical and Drug Induced Liver Injury; Drug Interactions; Drug Monitoring; Endothelin Receptor Antagonists; Heart Failure; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Pyrimidines; Risk; Sulfonamides

Pulmonary hypertension (PH) is characterized by a significant increase in pulmonary vascular resistance, which results in ventricular failure and death. Ambrisentan appears to be an effective treatment in the pathogenesis and progression of ambrisentan, but some researchers disagree. Therefore, this meta-analysis aims to examine the clinical efficacy of ambrisentan in the treatment of PH.. A search of the scientific literature using the Embase, Cochrane, and CHINAHL databases retrieved published studies related to our topic of interest. Eight cohort studies related to ambrisentan and PH treatment were selected on the basis of our strict inclusion and exclusion criteria for a systematic meta-analysis. Statistical analyses were conducted using STATA version 12.0 statistical software (StataCorp LP, College Station, Texas).. Our meta-analysis retrieved 124 studies using our search criteria (90 studies in English and 34 studies in Chinese), and 8 studies (4 studies in English and 4 studies in Chinese) were eventually selected for this meta-analysis. The 8 studies contained data on a total of 172 PH patients. Pooled data in our meta-analysis revealed that 6-minute walking distance in PH patients significantly improved after ambrisentan treatment compared with before treatment. The mean pulmonary arterial pressure, brain natriuretic peptide level, and systolic pulmonary artery pressure in PH patients decreased measurably after ambrisentan treatment compared with before treatment. Sensitivity analysis results confirmed that the included studies had no publication bias (all P > 0.05).. Our meta-analysis results demonstrated that ambrisentan is highly effective in improving exercise tolerance and cardiac function in PH patients, and the mean pulmonary arterial pressure, systolic pulmonary artery pressure, and brain natriuretic peptide level levels in PH patients significantly decreased. However, with the limitations of small sample size, insufficient data, and ethnic difference in the study, further studies with larger sample sizes and sufficient information are essential to validate our findings of the high safety profile and efficacy of ambrisentan in treatment of PH.

Topics: Antihypertensive Agents; Arterial Pressure; Exercise Test; Exercise Tolerance; Heart; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Treatment Outcome; Walking

To provide an overview of the drug profile of the orally active, selective endothelin A receptor antagonist ambrisentan, and its efficacy and safety in the treatment of patients with pulmonary arterial hypertension (PAH).. Medical literature on the use of ambrisentan in PAH was identified using MEDLINE and EMBASE. Additional references were identified from the reference lists of published articles and from the authors' own bibliographies.. Significant improvements in exercise capacity were observed with approved dosages of ambrisentan (5 or 10 mg once daily) in the AMB-220 dose-ranging study and the pivotal ARIES-1 and ARIES-2 trials, with sustained effects up to 2 years observed in ARIES-E. Improvements in cardiopulmonary hemodynamic variables were reported in AMB-220 and ARIES-E (subset analysis). Ambrisentan had little or no effect on hepatic transporters in in vitro studies and displayed a low risk of potential drug-drug interactions, including those with other PAH therapies. Results from the VOLT post-marketing program confirmed the safety profile of ambrisentan observed in the ARIES studies, including the low incidence of liver function test abnormalities. Peripheral edema and anemia were common side effects of endothelin receptor antagonist therapies, including ambrisentan. In the recently completed AMBITION study (ClinicalTrials.gov Identifier: NCT01178073), upfront initial combination therapy with ambrisentan and tadalafil significantly reduced the risk of clinical failure (primary endpoint) by 50% compared with the pooled monotherapy groups.. The long-term efficacy and safety profile of ambrisentan in patients with PAH is supported by data from a comprehensive clinical trial program and real-life, post-marketing observations.

Topics: Endothelin A Receptor Antagonists; Exercise Tolerance; Humans; Hypertension, Pulmonary; Pharmacovigilance; Phenylpropionates; Pyridazines; Tadalafil; Treatment Outcome; Vasodilator Agents

Topics: Administration, Oral; Adult; Antihypertensive Agents; Bosentan; Carbolines; Endothelin Receptor Antagonists; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Male; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Artery; Purines; Pyridazines; Pyrimidines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfonamides; Sulfones; Tadalafil; Vascular Resistance; Vasodilator Agents

Since the discovery of endothelin (ET)-1 in 1988, the main components of the signalling pathway have become established, comprising three structurally similar endogenous 21-amino acid peptides, ET-1, ET-2 and ET-3, that activate two GPCRs, ETA and ETB . Our aim in this review is to highlight the recent progress in ET research. The ET-like domain peptide, corresponding to prepro-ET-193-166 , has been proposed to be co-synthesized and released with ET-1, to modulate the actions of the peptide. ET-1 remains the most potent vasoconstrictor in the human cardiovascular system with a particularly long-lasting action. To date, the major therapeutic strategy to block the unwanted actions of ET in disease, principally in pulmonary arterial hypertension, has been to use antagonists that are selective for the ETA receptor (ambrisentan) or that block both receptor subtypes (bosentan). Macitentan represents the next generation of antagonists, being more potent than bosentan, with longer receptor occupancy and it is converted to an active metabolite; properties contributing to greater pharmacodynamic and pharmacokinetic efficacy. A second strategy is now being more widely tested in clinical trials and uses combined inhibitors of ET-converting enzyme and neutral endopeptidase such as SLV306 (daglutril). A third strategy based on activating the ETB receptor, has led to the renaissance of the modified peptide agonist IRL1620 as a clinical candidate in delivering anti-tumour drugs and as a pharmacological tool to investigate experimental pathophysiological conditions. Finally, we discuss biased signalling, epigenetic regulation and targeting with monoclonal antibodies as prospective new areas for ET research.

Topics: Antineoplastic Agents; Aspartic Acid Endopeptidases; Benzazepines; Bosentan; Endothelin A Receptor Antagonists; Endothelin-1; Endothelin-2; Endothelin-3; Endothelin-Converting Enzymes; Endothelins; Epigenesis, Genetic; Humans; Hypertension, Pulmonary; Metalloendopeptidases; Neoplasms; Peptide Fragments; Phenylpropionates; Pyridazines; Pyrimidines; Receptor, Endothelin B; Sulfonamides; Vasodilator Agents

Since its identification in 1988 and the recognition of its primary role as a potent vasoconstrictor, endothelin has been extensively studied and is now considered as a ubiquitous protein, involved in important aspects of human homeostasis as well as in several pathophysiological pathways, mostly associated with cardiovascular disease. From an evolutionary point of view, endothelin consists a primitive molecule with the rare characteristic of being exactly the same in all mammals, thus permitting scientists to perform experiments in animals and doing predictions for humans. The understanding of its contribution to the genesis, evolution and maintenance of disease through activation of special receptor subtypes has led to the development of both selective and unselective receptor antagonists. Despite the disappointing results of these antagonists in the field of heart failure, almost from the initial animal trials of bosentan, a dual endothelin receptor antagonist, in pulmonary arterial hypertension, it has been demonstrated that the drug leads at least to hemodynamic and clinical improvement of the patients, thus receiving official approval for the management of this rare but eventually lethal disease. Resistant hypertension is another area where endothelin receptor blockers might potentially play a role, while the pathophysiological role of endothelin in atherosclerotic coronary artery disease is well-established and the relative research goes on. The main goal of this review is to describe the endothelin system and mostly to enlighten its role in pathophysiologic pathways, as well to state the relative research in the various fields of cardiovascular disease and also highlight its prognostic significance wherever there exists one.

Topics: Animals; Atherosclerosis; Atrial Fibrillation; Bosentan; Cardiovascular Diseases; Coronary Artery Disease; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Humans; Hypertension, Pulmonary; Phenylpropionates; Predictive Value of Tests; Pyridazines; Receptors, Endothelin; Sulfonamides

The authors review the basic pharmacology and potential for adverse drug-drug interactions (DDIs) of bosentan and ambrisentan, the 2 endothelin receptor antagonists currently approved for pulmonary arterial hypertension (PAH) treatment. Bosentan, an endothelin (ET) receptor-type ET(A) and ET(B) antagonist, is metabolized to active metabolites by and an inducer of cytochrome P450 (CYP)2C9 and CYP3A. Ambrisentan, a selective ET(A) receptor antagonist, is metabolized primarily by uridine 5'diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S and, to a lesser extent, by CYP3A and CYP2C19. Drug interactions observed with bosentan DDI studies have demonstrated a potential for significant clinical implications during PAH management: bosentan is contraindicated with cyclosporine A and glyburide, and additional monitoring/dose adjustments are required when coadministered with hormonal contraceptives, simvastatin, lopinavir/ritonavir, and rifampicin. As bosentan carries a boxed warning regarding risks of liver injury and showed dose-dependant increases in serum aminotransferase abnormalities, drug interactions that increase bosentan exposure are of particular clinical concern. Ambrisentan DDI studies performed to date have shown only one clinically relevant DDI, an interaction with cyclosporine A that requires ambrisentan dose reduction. As the treatment of PAH moves toward multimodal combination therapy, scrutiny should be placed on ensuring that drug combinations achieve maximal clinical benefit while minimizing side effects.

Topics: Animals; Antihypertensive Agents; Bosentan; Drug Interactions; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Sulfonamides

The demonstration that endothelin production is upregulated in pulmonary artery hypertension (PAH) served as the rationale for developing endothelin-receptor antagonists (ERAs) as a treatment for PAH. This article reviews the primary studies demonstrating efficacy of ERAs in PAH.. Multicenter, placebo-controlled trials and open-label extension studies.. Two orally active ERAs are currently approved for the treatment of PAH - the dual receptor antagonist bosentan, and the more selective ET(A) receptor antagonist ambrisentan-based on multicenter randomized clinical trials demonstrating efficacy and safety. Long-term experience with both agents supports maintenance of therapeutic effects in most patients. Adverse effects, including altered liver function and edema may occur and require careful monitoring.. Despite failure to demonstrate efficacy of ERAs in other cardiopulmonary conditions, ERAs have a major role in the treatment algorithm for PAH.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Bosentan; Drug Design; Drug Monitoring; Endothelin Receptor Antagonists; Endothelin-1; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Sulfonamides

The development of effective oral treatments that are capable of modulating the activity of endothelin receptor 1 (ET-1) represents a significant milestone in the field of pulmonary arterial hypertension (PAH). Randomized clinical trials confirm that endothelin receptor antagonist (ERA) treatments confer significant improvements on important clinical endpoints, such as exercise capacity, functional class, quality of life and pulmonary hemodynamics. Moreover, ERAs may prevent or delay clinical worsening and retard disease progression. Ambrisentan is a propanoic acid-based ERA, showing preferential affinity for the type A ET-1 over the type B receptor. It provides another valuable, effective treatment option in PAH. Two large, randomized-placebo controlled trials demonstrated the efficacy of ambrisentan in PAH at improving exercise tolerance as measured by the 6 min walk distance. Additional secondary measures of improvement including time to clinical worsening, survival, functional class, quality of life and hemodynamic variables have been reported in clinical trials. A favorably low incidence of aminotransferase elevation indicating lower hepatic toxicity than other ERAs has been observed. Ambrisentan can be safely administered with warfarin or sildenafil without the need for dose adjustment of either therapy. A once daily oral medication with relatively few side effects is an attractive option, especially as the use of therapies in combination continues to increase. Long-term data and hemodynamic data confirm the benefits can be compared with other ERAs with fewer drug-drug interactions and a better liver safety profile.

Topics: Antihypertensive Agents; Disease Progression; Drug Interactions; Endothelin Receptor Antagonists; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Quality of Life

Systemic sclerosis (SSc) is a multisystem connective tissue disease of unknown etiology that is characterized by inflammation, vascular dysfunction and fibrosis of the skin and visceral organs. SSc is clinically diverse both in terms of the burden of skin and organ involvement and the rate of progression of the disease. Recent studies indicate that the endothelin system, especially ET-1 and the ETA and ETB receptors may play a key role in the pathogenesis of SSc. A new class of drugs, endothelin receptor antagonists has been introduced for treatment of patients with pulmonary arterial hypertension (PAH). Bosentan, a dual endothelin receptor antagonist as well as Sitaxsentan and Ambrisentan, selective blockers of the ETA receptor have proven effective in SSc-PAH. This effect may be mediated through both a vasodilatory and antifibrotic effect, thus making these agents attractive as potential disease modifying agents for SSc.

Topics: Animals; Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Endothelins; Familial Primary Pulmonary Hypertension; Fibrosis; Humans; Hypertension, Pulmonary; Isoxazoles; Phenylpropionates; Pyridazines; Receptors, Endothelin; Scleroderma, Systemic; Sulfonamides; Thiophenes; Treatment Outcome

Pulmonary arterial hypertension (PAH) is a life-threatening and progressive disease characterized by increasing pulmonary vascular resistance leading to right ventricular failure and premature death. Current therapies target three major pathways involving endothelin, prostacyclin and NO. Ambrisentan is an oral, once daily, selective endothelin receptor antagonist.. This review focuses on, and critically appraises, the clinical efficacy and safety of ambrisentan as well as its pharmacokinetic and pharmacodynamic properties. The article also gives an expert perspective on the role of ambrisentan in the management of PAH.. Ambrisentan is an effective and safe treatment which is, in the authors' opinion, a valuable addition to the armamentarium against PAH. Ambrisentan offers a relative lack of drug interactions, once daily dosing and reassuring liver safety, offering safety and convenience advantages over bosentan. Presently, there is a lack of comparative studies between PDE5 inhibitors and endothelin receptor antagonists and a lack of data comparing bosentan with ambrisentan. This is hindering data-based conclusions regarding relative efficacy and further studies are needed to define the role of ambrisentan in the management of PAH.

Topics: Animals; Antihypertensive Agents; Clinical Trials as Topic; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Treatment Outcome

Endothelin is a key mediator in the pathophysiology of pulmonary arterial hypertension (PAH). Its effects are mediated through the activation of two associated receptor subtypes, termed A and B. Therapeutic strategies that modulate the activity of endothelin are, therefore, of interest to improve the functional status of patients with PAH.. The rationale for the use of endothelin receptor antagonists as a therapeutic class in PAH and pertinent data from important clinical studies are presented in this review. Areas for future research are also suggested.. The availability of the endothelin receptor antagonist class of agents represents a significant addition to the therapeutic armamentarium which is available for the treatment of PAH. Comparative studies are warranted to establish whether selective endothelin-A receptor antagonism is more advantageous than dual receptor antagonism. Future studies of endothelin receptor antagonists will increasingly focus on the potential of a combination of different PAH therapeutic classes and will employ 'harder' clinical end points. This is of crucial importance to ensure that future developments are both worthwhile and acceptable to patients, physicians, health system payers and regulatory authorities.

Topics: Animals; Antihypertensive Agents; Bosentan; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Sulfonamides

Ambrisentan, an orally active, highly selective antagonist of the endothelin-1 type A receptor, is indicated for the treatment of pulmonary arterial hypertension (PAH). It has a low potential for drug-drug interactions and requires only once-daily administration. Three months' treatment with ambrisentan 2.5-10 mg/day significantly improved exercise capacity, as determined by the distance walked in 6 minutes (6MWD; primary outcome measure), compared with placebo in two double-blind, multicenter studies in patients with PAH (ARIES-1 [n = 202] and -2 [n = 192]). A decrease in dyspnea and a delay in clinical worsening were among the improvements in secondary outcomes generally observed with ambrisentan versus placebo. In ARIES-E, a 2-year extension of ARIES-1 and -2, approved dosages of ambrisentan (5 and 10 mg/day) were associated with a sustained improvement in 6MWD, a generally sustained improvement in dyspnea, and a low risk of clinical worsening and of death. Six months' treatment with ambrisentan 5 mg/day significantly improved 6MWD (primary outcome measure) and dyspnea relative to baseline in an open-label, non-comparative, multicenter study in a diverse population of patients with PAH or non-PAH forms of pulmonary hypertension (ARIES-3 [n = 224]). Ambrisentan was associated with a low risk of clinical worsening and of death. Ambrisentan treatment was generally well tolerated in the various ARIES trials. All available pre-registration and post-marketing data indicate the drug poses only a very low risk of liver injury; the 'black box' warning regarding potential liver injury has been removed from the US prescribing information for ambrisentan.

Topics: Antihypertensive Agents; Clinical Trials as Topic; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Treatment Outcome

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by a progressive pulmonary vasculopathy with ensuing right heart failure if left untreated. In the 1980's, prior to the current treatment era, idiopathic pulmonary arterial hypertension (IPAH) carried a poor prognosis with a 10 month median survival for children after diagnosis. However, in 1995 continuous intravenous epoprostenol was approved for the treatment of severe PAH, improving hemodynamics, quality of life, exercise capacity, functional class and survival. In the past decade there have been further advances in the treatment of PAH; however, there is still no cure. While much of the groundbreaking clinical research has been performed in adults, children have also seen the benefits of PAH novel therapies. The target population among pediatric patients is expanding with the recent recognition of pulmonary hypertension as a risk factor for sickle cell disease patients. With rapid advances, navigating the literature becomes challenging. A comprehensive review of the most recent literature over the past year on available and emerging novel therapies as well as an approach to target pediatric populations provides insights into the management of pediatric PAH patients.

Topics: Anemia, Sickle Cell; Antihypertensive Agents; Child; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Pyridazines

In the field of nonpeptide NCEs with endothelin receptor antagonist activity, a burst in corporate IP filings occurred in the 1990s once the human endothelin system had been characterized, but patent activity has declined in the past decade. Universities have not been active in this area of research to a degree that would have led to many patent applications. While three endothelin receptor antagonists (bosentan, sitaxentan and ambrisentan) are already available for the treatment of pulmonary arterial hypertension, the use of such compounds for the larger therapy areas of heart failure, cancer and nephropathy is still being evaluated in late-stage clinical trials. Marketed and advanced-stage endothelin receptor blockers have remarkably little chemical diversity; thus, the substantially larger chemical space defined by patenting remains to be explored.

Topics: Animals; Antihypertensive Agents; Bosentan; Drug Design; Endothelin Receptor Antagonists; Endothelins; Humans; Hypertension, Pulmonary; Isoxazoles; Patents as Topic; Phenylpropionates; Pyridazines; Sulfonamides; Thiophenes

Pulmonary arterial hypertension (PAH) is a disease of the pulmonary vasculature characterized by vasoconstriction and vascular proliferation, which leads to right heart failure and death. Prostacyclin, NO and endothelin are felt to be key mediators in the development of PAH. We present the available published and presented data about ambrisentan, an ET(A)-selective endothelin receptor antagonist (ERA) and newest ERA agent to be approved by the FDA for the treatment of PAH in patients with WHO functional class II and III symptoms. Randomized, placebo-controlled trials have demonstrated a significant improvement in exercise capacity and decrease in time to clinical worsening, along with evidence to support an improvement in WHO functional class and quality of life for patients receiving ambrisentan. Long-term data have shown a 1-year survival of 95%; of the survivors, 94% remained on ambrisentan monotherapy. Endothelin receptor antagonists as a drug class have previously been associated with peripheral edema, aminotransferases abnormalities and a teratogenic risk to a developing fetus. Peripheral edema was observed in patients receiving ambrisentan; however, a greater percentage was experienced in patients aged > 65 years. In contrast, significant aminotransferase abnormalities were not observed with ambrisentan treatment in the placebo-controlled trials, and in all clinical trials combined the 1-year risk seems to be low (< 3%). Despite these data, the FDA requires monthly liver function tests monitoring. As with other ERAs, monthly pregnancy testing is required in all women of child bearing potential.

Topics: Animals; Antihypertensive Agents; Drug Monitoring; Endothelin A Receptor Antagonists; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Randomized Controlled Trials as Topic; Survival Rate

The last decade has seen significant advances in the understanding and treatment of pulmonary arterial hypertension (PAH). Three main pathways, involving endothelin, nitric oxide, and prostacyclin, have been identified in its pathogenesis and these have all led to the development of therapies in current use. While the nitric oxide and prostacyclin pathways require augmentation, the endothelin system is overactive in PAH, with increased endothelin synthesis and receptor expression and, therefore, requires blockade. There are two known endothelin receptors. The type A receptor, expressed in pulmonary artery media, mediates vasoconstriction and remodeling, whereas the function of the type B receptor is more complex. Like the type A receptor, the type B receptor mediates vasoconstriction and remodeling effects when expressed on smooth muscle cells and (myo)fibroblasts, yet functions to clear endothelin from the circulation and induce release of endogenous nitric oxide and prostacyclin, when activated in the pulmonary artery endothelium. Consequently, it is not clear from in vitro data whether the optimal strategy is to block only the type A receptor or both receptors. Phase III clinical studies show clear short-term physiologic benefit with both dual and selective endothelin blockade in PAH. Longer-term experience with bosentan, a dual receptor antagonist, has shown improved outcomes compared with historic control data and comparable survival to intravenous prostacyclin therapy. The newer selective blockers, sitaxsentan and ambrisentan, appear to have similar short-term efficacy, but long-term data are as yet either lacking or unpublished. They may be less hepatotoxic than bosentan, although long-term follow-up of patients receiving bosentan has shown this is not a significant problem. On the basis of available evidence, the endothelin receptor antagonists have become first-line therapy for patients with PAH, except in the most severely affected who still require treatment with intravenous prostacyclin. Although their use as part of combination therapy with other agents is widespread, the evidence for this is not as robust, but appropriate investigation is underway.

Topics: Antihypertensive Agents; Bosentan; Clinical Trials, Phase III as Topic; Drug Interactions; Endothelin Receptor Antagonists; Endothelins; Humans; Hypertension, Pulmonary; Isoxazoles; Phenylpropionates; Pyridazines; Sulfonamides; Thiophenes

Approved by the US Food and Drug Administration in 2007, ambrisentan is the second oral endothelin A-receptor antagonist available for the management of pulmonary arterial hypertension (PAH) in patients with World Health Organization class II or III symptoms.. This article examines the clinical pharmacology of ambrisentan, its efficacy and adverse effects, and future directions for research.. Pertinent articles and abstracts were identified through searches of MEDLINE and Current Contents from 1966 to January 15, 2008, using the term ambrisentan. The reference lists of identified articles were searched for additional publications. Abstracts presented at professional meetings from 2005 through 2007 were also reviewed.. The literature review identified 3 studies of ambrisentan in PAH: 1 dose-ranging study; 2 randomized, double-blind, placebo-controlled studies; and 1 drug-conversion study. In the dose-ranging study, ambrisentan at doses of 1 to 10 mg was associated with significant improvements from baseline in the 6-minute walk distance at 12 weeks that ranged from 33.9 m with ambrisentan 1 mg (P = 0.003) to 38.1 m with ambrisentan 5 mg (P = 0.001). In the placebo-controlled studies, ambrisentan at doses of 2.5 to 10 mg/d was associated with significant improvements versus placebo in the 6-minute walk distance at 12 weeks that ranged from 22 m with ambrisentan 2.5 mg (P = 0.022) to 59 m with ambrisentan 5 mg (P

Topics: Animals; Drug Interactions; Endothelin A Receptor Antagonists; Female; Hepatic Insufficiency; Humans; Hypertension, Pulmonary; Lactation; Male; Phenylpropionates; Pregnancy; Pyridazines; Renal Insufficiency

Treatment options for pulmonary arterial hypertension (PAH) have considerably improved in the past few years. Endothelin (ET)-receptor antagonism has been established as a first-line option for the majority of PAH patients. Endothelin-receptor antagonists (ETRAs) comprise sulfonamide and non-sulfonamide agents with different affinities for ET-receptor subtypes (ET(A) and ET(B)), and the focus of development has shifted from drugs with less selectivity to those with high selectivity. There is ongoing debate as to whether selective or non-selective ET-receptor antagonism is more beneficial in the treatment of PAH. This paper reviews the current evidence from experimental and clinical studies obtained from a thorough literature search focusing on the three marketed drugs bosentan, sitaxentan, and ambrisentan. A clinically meaningful difference among the three approved ETRAs with respect to their ET-receptor selectivity could not be demonstrated to date. Therefore, in clinical practice, other features are likely to be of greater relevance when considering treatment, such as the potential for serious drug-drug interactions, convenience of dosing schedule, or rates of limiting side effects. These characteristics bear more relation to the chemical or pharmacological properties of the drugs than to receptor selectivity itself.

Topics: Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Isoxazoles; Male; Phenylpropionates; Pulmonary Artery; Pyridazines; Randomized Controlled Trials as Topic; Sulfonamides; Thiophenes; Treatment Outcome; Vascular Resistance; Walking

Pulmonary arterial hypertension (PAH) is a devastating disease, which is associated with a 1-year survival of about 50% without specific treatment. Pulmonary vascular remodelling, thrombosis and vasoconstriction are thought to be directly involved in increasing pulmonary vascular resistance (PVR), which, left untreated, ultimately leads to right ventricular failure and death. A total of 10-12% of patients with systemic sclerosis (SSc) develop PAH, which is a leading cause of mortality in these patients. Targeted treatment regimens involving oral therapies, in particular endothelin receptor antagonists (ERAs), such as bosentan, sitaxsentan (sitaxentan) and ambrisentan, are now being used and this approach has improved symptoms as well as survival. 1-Year survival has improved to about 80%, while 3-year survival in advanced SSc-PAH has improved from 44% to 65% since the introduction of ERAs. Subanalysis of BREATHE-1, a pilot study and the STRIDE-2X randomized controlled trials has reported improvements in time to clinical worsening, 6-minute walk distance (6mwd) and right heart haemodynamics in SSc-PAH patients given bosentan and sitaxsentan, respectively, compared with placebo. The ARIES studies have also demonstrated a delay in the time to clinical worsening and improvement in 6mwd in connective tissue associated-PAH patients given ambrisentan compared with placebo. Unfortunately, these drugs are expensive and also have the potential for adverse interactions with other PAH and supportive therapies. Mandatory monthly liver function tests are required for safe administration of bosentan, ambrisentan and sitaxsentan, while dose adjustment of warfarin and careful monitoring are required when sitaxsentan is initiated. Earlier diagnosis and treatment of PAH may further improve outcomes with current ERAs. WHO functional class (FC) has traditionally been used to determine which patients with PAH will start therapy. The EARLY study has reported significant reductions in PVR and time to clinical worsening in mildly symptomatic PAH patients treated with bosentan, and many PAH clinicians now believe WHO FC should be used as a monitoring tool once targeted therapies have been initiated and not as a tool for deciding when to start PAH specific therapies.Many pathways are thought to be involved in the pathophysiology of the PAH. There is growing evidence that combination therapies targeting different pathophysiological steps may be necessary to effectively treat SSc-PAH

Topics: Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Isoxazoles; Phenylpropionates; Pyridazines; Receptors, Endothelin; Scleroderma, Systemic; Sulfonamides; Thiophenes; Treatment Outcome

For some years drugs of several different classes have been available in Germany for the treatment of pulmonary arterial hypertension (PHT): prostanoids, endothelin-receptor antagonists and phosphodiesterase inhibitors. To-date all relevant studies have consistently shown improvement in the 6-minute walking test (Iloprost, Treprostinil, Bosentan, Sitaxentan, Ambrisentan, Sildenafil). Results have not been consistent when the end-point has been an improvement in New York Heart Association (NYHA) class III or in the time to clinical worsening. Despite the good safety data for all drugs approved in Germany in the treatment of PHT, there are some clinically relevant interactions and significant contraindications. The availability of several options demands a detailed knowledge of studies to optimize safety and success in the treatment of PHT. Placebo-control mortality studies are not available for ethical reasons for those drugs that have been approved in Germany. But cohort analyses using historical survival rates have demonstrated a impressive improvement in survival of patients with PHT. Although there has been great progress in the treatment of PHT, a cure of this grave disease is not yet possible.

Topics: Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Isoxazoles; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Prostaglandins; Purines; Pyridazines; Sildenafil Citrate; Sulfonamides; Sulfones; Survival Rate; Thiophenes; Vasodilator Agents

Elevated endothelin (ET)-1 levels are strongly correlated with the pathogenesis and prognosis of pulmonary arterial hypertension (PAH). Ambrisentan is an orally active, highly selective ETA receptor antagonist with >4000-fold higher selectivity over the ETB receptor. In two large, well designed, 12-week, placebo-controlled, phase III trials (ARIES-1, n = 202 and ARIES-2, n = 192) in patients with PAH (WHO group I), ambrisentan 2.5-10 mg once daily significantly increased 6-minute walk distance by 31-59 m from baseline (primary outcome measure) versus placebo. The incidence of clinical worsening (secondary outcome measure) was significantly delayed for the combined ambrisentan 5 mg once daily groups versus the combined placebo groups from ARIES-1 and -2. At week 12, WHO functional class distribution was significantly improved with once-daily ambrisentan 5 mg, and Borg dyspnoea scores were significantly improved with ambrisentan 2.5-10 mg versus placebo in combined data from the ARIES-1 and -2 trials. The beneficial effects of ambrisentan on exercise capacity, WHO functional class and Borg dyspnoea scores seen at 12 weeks were maintained at 48 weeks in the ARIES-E phase III extension trial (n = 361). One-year survival rates with ambrisentan were 95-97%. Treatment with ambrisentan for up to 2.8 years was generally well tolerated in clinical trials.

Topics: Animals; Clinical Trials as Topic; Endothelin A Receptor Antagonists; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines

To review the role of ambrisentan in the treatment of pulmonary arterial hypertension (PAH).. Literature was accessed through MEDLINE (1950-June 2008), Iowa Drug Information Service (1966-March 2008), EMBASE (1966-June 2008), bibliographies of pertinent articles, and unpublished data provided by the manufacturer and the Food and Drug Administration (FDA). Search terms included ambrisentan, endothelin antagonist, pulmonary hypertension, and pulmonary arterial hypertension. Due to limited literature available, additional criteria to limit searches were not used.. Abstracts and original preclinical and clinical research reports available in the English language were identified for review. All manufacturer-provided data were also evaluated. Literature related to ambrisentan, endothelin antagonists, pulmonary hypertension, and pulmonary arterial hypertension were included. Four clinical trials evaluated the efficacy of ambrisentan in adults with symptomatic PAH.. Ambrisentan is the latest endothelin-receptor antagonist (ERA) to obtain FDA approval for the treatment of PAH. It joins the first FDA-approved ERA, bosentan. Like bosentan, ambrisentan is available orally (with once-daily dosing compared with bosentan's twice-daily dosing) and has been shown to improve exercise capacity and delay clinical worsening. As with bosentan, the most significant safety concerns with ambrisentan relate to potential liver injury and a contraindication in pregnancy. Although ambrisentan has higher affinity for the endothelin type A receptor than for the endothelin type B receptor, specific advantages of this selectivity, in terms of efficacy compared with bosentan, a nonselective agent, have not been demonstrated.. Ambrisentan has been shown to be an effective ERA in patients with PAH. A significant advantage of ambrisentan is the lack of any clinically important drug interactions with warfarin and sildenafil, which are frequently used by patients being treated for PAH.

Topics: Animals; Antihypertensive Agents; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines

Endothelin receptor antagonism has emerged as an important therapeutic approach in pulmonary arterial hypertension (PAH). Bench to bedside scientific research has shown that endothelin-1 (ET-1) is overexpressed in several forms of pulmonary vascular disease and may play an important pathogenetic role in the development and progression of PAH. Oral endothelin receptor antagonists (ERAs) improved exercise capacity, functional status, pulmonary hemodynamics, and delayed the time to clinical worsening in several randomized placebo-controlled trials. Two ERAs are currently approved by the US Food and Drug Administration: bosentan, a dual ERA for patients with class III and IV PAH, and ambrisentan, a selective ERA for patients with class II and III PAH. Sitaxsentan, another selective ERA, has been approved in Europe, Canada, and Australia. The objective of this review is to evaluate the available evidence describing the pharmacology, efficacy, safety, and tolerability, and patient-focused perspectives regarding the different types of endothelin receptor antagonists. Ongoing and forthcoming randomized trials are also highlighted including the approach of combining this class of drugs with other drugs that target different cellular pathways believed to be etiologically important in PAH.

Topics: Animals; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Isoxazoles; Patient Compliance; Patient Satisfaction; Phenylpropionates; Pyridazines; Quality of Life; Receptors, Endothelin; Sulfonamides; Thiophenes; Treatment Outcome

Ambrisentan is the second selective endothelin-A receptor antagonist to be licensed in Europe, and the first in the United States, for the management of pulmonary arterial hypertension (PAH). It has been shown to be clinically effective in improving exercise tolerance and functional class. Furthermore, ambrisentan is well tolerated and associated with low rates of liver toxicity and minimal interactions with other medicines commonly used to treat PAH. Overall, current data support a role for ambrisentan in the management of PAH. However, the results of longer-term follow-up studies are still required to fully assess efficacy and safety.

Topics: Animals; Antihypertensive Agents; Clinical Trials as Topic; Drug Interactions; Endothelin A Receptor Antagonists; Follow-Up Studies; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Receptor, Endothelin A

The endothelin (ET) system, especially ET-1 and the ET(A) and ET(B) receptors, has been implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Together with prostanoids and phosphodiesterase 5 inhibitors, ET receptor antagonists have become mainstays in the current treatment of PAH. Three substances are currently available for the treatment of PAH. One of these substances, bosentan, blocks both ET(A) and ET(B) receptors, whereas the two other compounds, sitaxsentan and ambrisentan, are more selective blockers of the ET(A) receptor. There is ongoing debate as to whether selective or nonselective ET receptor blockade is advantageous in the setting of PAH, although there is no clear evidence that receptor selectivity is relevant with regard to the clinical effects of these drugs. For the time being, other features, such as safety profiles and the potential for pharmacokinetic interactions with other drugs used in the treatment of PAH, may be more important than selectivity or nonselectivity when selecting treatments for individual patients.

Topics: Animals; Bosentan; Clinical Trials, Phase III as Topic; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Isoxazoles; Phenylpropionates; Prognosis; Pyridazines; Randomized Controlled Trials as Topic; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Severity of Illness Index; Sulfonamides; Survival Rate; Thiophenes; Treatment Outcome

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by an elevation of pulmonary-artery pressure and pulmonary-vascular resistance, leading to right-ventricular failure and death. Conventional therapy for PAH may include anticoagulation, digoxin, diuretics, supplemental oxygen and less often calcium-channel blockers. Protaglandins and sildenafil improve exercise capacity and hemodynamics.. Endothelin-1 (ET-1) has been recognized as a major mediator in the pathogenesis of PAH. ET-1 receptor antagonists have been recently developed. Selective ET(A) receptor antagonists, which preserve endothelial ET(B) receptor vasodilatory and clearance activity, may offer more benefit than nonselective ET(A) plus ET(B) antagonists. Two ET-1 receptor antagonists, orally active, can be used: bosentan (ET(A)/ET(B)=20) is nonselective and sitaxentan (ET(A)/ET(B)=6500) is highly selective. In short-term studies, these two treatments showed similar efficacy. In the Sitaxentan To Relieve ImpaireD Exercise-2X (STRIDE-2X) one-year trial, which compared the two treatments, sitaxentan caused less liver toxicity and showed trends to higher efficacy than bosentan.. Individualized treatment for PAH should take into account the type of PAH, the comorbidities (liver disease), treatment interactions, and long-term efficacy.

Topics: Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Isoxazoles; Phenylpropionates; Pyridazines; Sulfonamides; Thiophenes

The recognition that endothelin-1 contributes to the pathogenesis of pulmonary arterial hypertension has led to the development of clinically useful endothelin receptor antagonists that improve symptoms and functional capacity and alter the natural history of the disease in a beneficial way. The antagonists have varying degrees of selectivity for the two classes of endothelin receptor, termed ETA and ETB, and the varying degrees may translate into clinical differences. Endothelin receptor antagonists have become an integral part of therapy for pulmonary arterial hypertension, and the indications for their use are expanding.

Topics: Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Isoxazoles; Phenylpropionates; Pyridazines; Randomized Controlled Trials as Topic; Sulfonamides; Thiophenes

Pulmonary arterial hypertension (PAH) is a rare fatal disease. Current disease-specific therapeutic interventions in PAH target 1 of 3 established pathways in disease pathobiology: prostacyclin, nitric oxide, and endothelin-1. Endothelin receptor antagonists (ERAs) act on the endothelin pathway by blocking binding of endothelin-1 to its receptors (endothelin type-A [ET(A)] and/or type-B [ET(B)]) on the surface of endothelial and smooth muscle cells. Ambrisentan is an oral, once-daily, ET(A)-selective ERA in development for the treatment of PAH. In Phase 3 clinical trials in patients with PAH, ambrisentan (2.5-10 mg orally once-daily) improved exercise capacity, Borg dyspnea index, time to clinical worsening, WHO functional class, and quality of life compared with placebo. Ambrisentan provided durable (at least 2 years) improvement in exercise capacity in a Phase 2 long-term extension study. Ambrisentan was well tolerated with a lower incidence and severity of liver function test abnormalities compared with the ET(A)/ET(B) ERA, bosentan, and the ET(A)-selective ERA, sitaxsentan. Ambrisentan does not induce or inhibit P450 enzymes; therefore, ambrisentan is unlikely to affect the pharmacokinetics of P450-metabolized drugs. The demonstration of clinical efficacy, low incidence of acute hepatic toxicity, and low risk of drug-drug interactions support the role of ambrisentan for the treatment of PAH.

Topics: Endothelin Receptor Antagonists; Endothelin-1; Exercise; Humans; Hypertension, Pulmonary; Muscle, Smooth, Vascular; Phenylpropionates; Pulmonary Wedge Pressure; Pyridazines; Receptors, Endothelin; Treatment Outcome; Vascular Resistance

Topics: Animals; Endothelin A Receptor Antagonists; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Receptor, Endothelin A

In a series of articles the authors discuss literature data concerning epidemiology of pulmonary arterial hypertension (PAH), its current classification; peculiarities of its pathogenesis and treatment in various diseases and conditions. In the eleventh communication the authors discuss literature data related to the role of endothelin system in pathogenesis of primary (idiopathic) PAH, as well as PAH associated with diffuse diseases of connective tissue and congenital heart disease. This communication also contains presentation of clinical pharmacology of three available endothelin receptor blockers - bosentan, sitaxsentan, ambrisentan, and analysis of results of randomized controlled trials of efficacy and safety of these agents in patients with idiopathic PAH and PAH associated with diffuse diseases of connective tissue and congenital heart disease.

Topics: Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Isoxazoles; Phenylpropionates; Pyridazines; Sulfonamides; Thiophenes; Ventricular Dysfunction, Right

Endothelin-1 (ET-1) is of significance in the pathophysiology and prognosis of pulmonary hypertension (PHT). Bosentan, an endothelin-receptor antagonist, currently plays a central role in the treatment of PHT, because it improves exercise capacity, hemodynamics, clinical symptoms and right ventricular function, achieving a survival duration of 2- 3 years. Bosentan causes an increase of transaminases in about 10% of patients, but this effect is reversible on dosage reduction or discontinuing the medication. However, transaminases should be measured every 4 weeks while patients are on bosentan. Almost all current guidelines list bosentan as of equal value to sildenafil or prostacyclin analogues in the first-line treatment of patients in NYHA functional class III and also, with narrower indications, of those in class IV.

Topics: Algorithms; Antihypertensive Agents; Bosentan; Drug Interactions; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Isoxazoles; Phenylpropionates; Pyridazines; Sulfonamides; Survival Rate; Thiophenes

Rapid advances in the understanding of endothelin as a naturally occurring peptide with developmental and regulatory roles in normal physiology, along with a number of deleterious effects under pathologic conditions (including vasoconstriction, fibrosis, vascular hypertrophy, and inflammation) have led to the development of endothelin-receptor antagonists (ERAs). Bosentan, an antagonist with dual specificity for the endothelin-receptor subtypes A and B, has been shown to be efficacious and well tolerated in placebo-controlled clinical trials and is now approved in many countries, including the US, Canada, and Europe, for treatment of pulmonary arterial hypertension (PAH), including PAH associated with rheumatic diseases. ERAs with specificity for the endothelin-receptor subtype A, including sitaxsentan and ambrisentan, are currently undergoing investigation. This article reviews PAH associated with systemic rheumatic diseases and describes the role of ERAs in this setting.

Topics: Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Isoxazoles; Phenylpropionates; Pulmonary Wedge Pressure; Pyridazines; Rheumatic Diseases; Thiophenes; Treatment Outcome

Initial combination therapy with an endothelin receptor antagonist (ERA) and riociguat in pulmonary arterial hypertension (PAH) has limited supporting data.. We performed a prospective, single-arm, open-label trial of riociguat, and ambrisentan for incident PAH patients in functional class III. The primary endpoint was pulmonary vascular resistance (PVR) at 4-months.. Twenty patients (59 ± 13 years old, 85% female) enrolled and 1 died before their 4-month follow-up. Fifteen patients completed a 4-month and 13 completed the 12-month follow-up. At 4-months PVR decreased 54% with an absolute change of -5.8 Wood units (95% CI -4.0; -7.5, p < 0.001). Other hemodynamic variables and risk scores also improved. Six patients discontinued riociguat and 8 discontinued ambrisentan, with 5 (25%) discontinuing both.. These results do not support the routine use of riociguat plus ambrisentan in initial regimens. Future studies are needed to compare this strategy with phosphodiesterase-5 inhibitors and an ERA with respect to tolerability and long-term outcomes.

Topics: Aged; Antihypertensive Agents; Endothelin Receptor Antagonists; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Prospective Studies; Pulmonary Arterial Hypertension; Pyrazoles; Pyridazines; Pyrimidines; Treatment Outcome

Ambrisentan has shown effectiveness in the treatment of Group 1 pulmonary arterial hypertension (PAH). Although portopulmonary hypertension (PoPH) is a subset of Group 1 PAH, few clinical trials have been testing PAH therapies in patients with PoPH. The objective of this study is to evaluate the efficacy and safety of ambrisentan in PoPH.. This study is a prospective, multicenter, open-label trial in which treatment-naive patients with PoPH with Child-Pugh class A/B were administered with ambrisentan for 24 weeks, followed by a long-term extension (24-28 weeks). The primary end-points were change in pulmonary vascular resistance (PVR) and 6-minutes walk distance (6MWD) at 24 weeks, whereas secondary end-points included safety, World Health Organization (WHO) functional class (FC) and echocardiographic assessments.. Of the 31 patients, 23 finished 24 weeks of ambrisentan therapy and 19 finished the extension. PVR decreased significantly (mean ± SD) (7.1 ± 5 vs 3.8 ± 1.8 Wood units, p < 0.001), whereas 6MWD remained unchanged (314 ± 94 vs 336 ± 108 m). Other hemodynamic parameters such as right atrial pressure (13 ± 8 vs 9 ± 4 mm Hg, p < 0.05), mean pulmonary arterial pressure (46 ± 13 vs. 38 ± 8 mm Hg, p < 0.01), cardiac index (2.6 ± 0.6 vs. 3.5 ± 0.7 liter/min/m. Ambrisentan monotherapy in PoPH improves hemodynamics and FC at 24 weeks; however, it did not show any improvement in 6MWD. These preliminary outcomes should be interpreted with caution (Clinicaltrials.Gov:NCT01224210).

Topics: Antihypertensive Agents; Echocardiography; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Prospective Studies; Pulmonary Wedge Pressure; Pyridazines; Treatment Outcome; Vascular Resistance

Topics: Aged; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Myocardial Contraction; Observer Variation; Phenylpropionates; Prospective Studies; Pyridazines; Scleroderma, Limited; Tadalafil; Treatment Outcome; Ventricular Dysfunction, Right

The multinational AMBITION study demonstrated a 50% risk reduction in time to first clinical failure event (TtCF, a composite of death, hospitalization for worsening pulmonary arterial hypertension [PAH], disease progression, or unsatisfactory long-term clinical response) in treatment-naive Functional Class II and III PAH patients initiated on combination therapy (ambrisentan and tadalafil) vs monotherapy. A post-hoc analysis of AMBITION data by risk stratification, as determined by baseline REVEAL risk score, was undertaken to better assess the impact of combination therapy.. Patients were randomized 2:1:1 to initial combination therapy with ambrisentan 10 mg plus tadalafil 40 mg vs either drug plus placebo, respectively. Baseline REVEAL risk scores in the 605 patients were grouped by low, intermediate, or high risk. Adjudicated outcomes (TtCF and post-hoc composite end-point of time to first PAH hospitalization or death) were assessed by risk group and treatment assignment.. At baseline, risk groups were similarly represented across treatment assignments as low (16%), intermediate (46%), and high (38%) risk. Greater risk was associated with worse outcome. At each level of risk, patients on combination therapy had significantly fewer TtCF or PAH hospitalization/death events relative to those on monotherapy, and discontinuations due to adverse events were not higher on combination therapy.. This post-hoc analysis comparing outcomes by REVEAL risk group has shown that, at all levels of risk, patients enrolled in AMBITION receiving initial combination therapy have superior outcomes and, even in those assessed as low risk, initial combination therapy was clinically beneficial.

Topics: Aged; Drug Therapy, Combination; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Pyridazines; Registries; Risk Assessment; Survival Rate; Tadalafil

Pulmonary arterial hypertension (PAH) is a condition which may lead to right ventricular failure and premature death. While recent data supports the initial combination of ambrisentan (a selective ERA) and tadalafil (a PDE5i) in functional class II or III patients, there is no published data describing the safety and efficacy of ambrisentan when added to patients currently receiving a PDE5i and exhibiting a suboptimal response. The ATHENA-1 study describes the safety and efficacy of the addition of ambrisentan in this patient population.. PAH patients with a suboptimal response to current PDE5i monotherapy were assigned ambrisentan in an open-label fashion and evaluated for up to 48 weeks. Cardiopulmonary hemodynamics (change in PVR as primary endpoint) were evaluated at week 24 and functional parameters and biomarkers were measured through week 48. Time to clinical worsening (TTCW) and survival are also described.. Thirty-three subjects were included in the analysis. At week 24, statistically significant improvements in PVR (-32%), mPAP (-11%), and CI (+25%) were observed. Hemodynamic improvements at week 24 were further supported by improvements in the secondary endpoints: 6-min walk distance (+18 m), NT-proBNP (-31%), and maintenance or improvement in WHO FC in 97% of patients. Adverse events were consistent with known effects of ambrisentan.. The hemodynamic, functional, and biomarker improvements observed in the ATHENA-1 study suggests that the sequential addition of ambrisentan to patients not having a satisfactory response to established PDE5i monotherapy is a reasonable option.

Topics: Adult; Antihypertensive Agents; Biomarkers; Dose-Response Relationship, Drug; Drug Therapy, Combination; Elapid Venoms; Endothelin A Receptor Antagonists; Exercise Tolerance; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, C-Type; Outcome Assessment, Health Care; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Pyridazines; Survival; Tadalafil; Treatment Outcome

Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH.. To explore the safety and efficacy of initial combination therapy with ambrisentan and tadalafil versus ambrisentan or tadalafil monotherapy in patients with CTD-PAH and SSc-PAH enrolled in the AMBITION trial.. This was a post hoc analysis of patients with CTD-PAH and SSc-PAH from AMBITION, an event-driven, double-blind trial in patients with WHO functional class II/III PAH. Treatment-naive patients were randomised 2:1:1 to once-daily initial combination therapy with ambrisentan plus tadalafil or monotherapy with ambrisentan or tadalafil, respectively. The primary endpoint was time to the first clinical failure event (first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response).. In the primary analysis set (N=500), 187 patients had CTD-PAH, of whom 118 had SSc-PAH. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in each subgroup: CTD-PAH (HR 0.43 (95% CI 0.24 to 0.77)) and SSc-PAH (0.44 (0.22 to 0.89)). The most common AE was peripheral oedema, which was reported more frequently with initial combination therapy than monotherapy in the two PAH subgroups. The relative frequency of adverse events between those on combination therapy versus monotherapy was similar across subgroups.. This post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial ambrisentan and tadalafil combination therapy.. NCT01178073, post results.

Topics: Adult; Aged; Antihypertensive Agents; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Edema; Female; Humans; Hypertension, Pulmonary; Lupus Erythematosus, Systemic; Male; Middle Aged; Mixed Connective Tissue Disease; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Pyridazines; Scleroderma, Systemic; Tadalafil

To elucidate whether the pharmacokinetics (PK) and pharmacodynamics (PD) of sildenafil are influenced differently when it is coadministered with bosentan (S+B) or with ambrisentan (S+A), we evaluated the PK and PD profiles of sildenafil before and after 4-5 weeks of S+A or S+B treatment in patients with pulmonary arterial hypertension. The area under the plasma concentration-time curve of sildenafil was significantly higher in S+A treatment than in S+B treatment (165.8 ng•h/mL vs. 396.8 ng•h/mL, P = 0.018) and the oral clearance of sildenafil was significantly lower after S+A treatment than after S+B treatment (120.6 L/h/kg vs. 50.4 L/h/kg, P = 0.018). In the PD study, incremental shuttle walking distance was superior during treatment with S+A than during treatment with S+B (S+B; 280 m vs. S+A; 340 m, P = 0.042). There were no concerns about safety with either combination therapy regime.

Topics: Adult; Bosentan; Drug Therapy, Combination; Exercise; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Pyridazines; Sildenafil Citrate; Sulfonamides

Pulmonary arterial hypertension (PAH) is a condition which may lead to right ventricular failure and early mortality and is an important complication in patients with connective tissue disease (CTD). Previously, the endothelin A selective receptor antagonist, ambrisentan, demonstrated efficacy and safety in treating patients with PAH due to WHO Group I etiologies. These analyses describe the 3-year efficacy and safety of ambrisentan in patients specifically with CTD associated PAH (CTD-PAH).. Patients with CTD-PAH participating in the ARIES-1 and -2 clinical trials and their long-term extension were evaluated. Efficacy evaluations including 6-min walk distance (6MWD), clinical worsening, and survival were collected at routine study visits. Additional analyses of 6MWD categorical (30 m) breakpoints were conducted to determine any relationship between 6MWD and a prognostic threshold for survival.. 124 patients with CTD-PAH were evaluated. 62.6%, 57.3%, and 58.2% of CTD-PAH patients treated with ambrisentan exhibited increases in 6MWD at 1-, 2-, and 3- years respectively. At 3 years, 64% of patients were free from clinical worsening and 76% of patients were still alive (Kaplan-Meier estimates). Identified factors holding prognostic relevance for survival include: baseline functional class, CTD-PAH subgroup, patient sex, improvement in 6MWD ≥30 m over the first 12 weeks of treatment, the most recent 6MWD, and a 6MWD absolute threshold of 222 m.. These first analyses of the 3-year treatment of CTD-PAH patients with ambrisentan revealed fewer clinical worsening events and improved survival compared to historical controls. Key exercise parameters were also identified which appear important in guiding treatment.

Topics: Adult; Aged; Antihypertensive Agents; Connective Tissue Diseases; Double-Blind Method; Endothelin A Receptor Antagonists; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Outcome Assessment, Health Care; Phenylpropionates; Predictive Value of Tests; Prevalence; Pyridazines; Survival Analysis; Treatment Outcome; Walk Test

In treatment-naive patients with pulmonary arterial hypertension, initial combination therapy with ambrisentan and tadalafil reduces the risk of clinical failure events compared with monotherapy. We did this secondary analysis to further investigate the effect of combination therapy on survival.. We analysed survival data from the modified intention-to-treat population of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial. AMBITION was a multicentre, randomised, double-blind study, in which treatment-naive patients with pulmonary arterial hypertension were randomly assigned in a 2:1:1 ratio and received combination therapy with ambrisentan and tadalafil, ambrisentan and placebo, or tadalafil and placebo. We did a prespecified analysis of all mortality events from randomisation to the end of the study, including patients who discontinued their assigned treatment. In a post-hoc analysis, we analysed survival at 7 days after the termination of each individual patient's randomised treatment. We used Cox proportional hazard regression, Kaplan-Meier survival estimates, and the stratified log-rank test to compare the survival of patients receiving initial combination therapy or initial monotherapy.. The study population consisted of 605 patients with pulmonary arterial hypertension who were randomly assigned and received combination therapy (n=302) or monotherapy (n=303; 152 patients assigned to ambrisentan monotherapy and 151 patients to tadalafil monotherapy). At the end of the study, 29 (10%) of 302 patients in the combination therapy group had died compared with 41 (14%) of 303 patients in the monotherapy group (hazard ratio 0·67, 95% CI 0·42-1·08; stratified log-rank p=0·10). At 7 days after the end of randomised treatment, fewer patients had died in the combination therapy group (3 [1%] of 302 patients) compared with the monotherapy group (13 [4%] of 303 patients; hazard ratio 0·21, 95% CI 0·06-0·73).. These data indicate that initial combination therapy might be associated with a survival advantage compared with initial monotherapy in patients with newly diagnosed pulmonary arterial hypertension. This hypothesis needs to be addressed in future studies.. Gilead, GlaxoSmithKline.

Topics: Adult; Aged; Antihypertensive Agents; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypertension, Pulmonary; Intention to Treat Analysis; Kaplan-Meier Estimate; Male; Middle Aged; Phenylpropionates; Proportional Hazards Models; Pulmonary Artery; Pyridazines; Tadalafil; Treatment Outcome

Although several new drugs have been approved in recent years, pulmonary arterial hypertension (PAH) remains a rapidly progressive disease with a poor prognosis. Ambrisentan, a selective endothelin type A antagonist, has been approved for treatment of PAH. This open label study assessed the efficacy and safety of ambrisentan in Chinese subjects with PAH.. Eligible patients with PAH (World Health Organisation [WHO] functional class [FC] II orIII) were enrolled and received Ambrisentan (5 mg) once daily for a 12-week preliminary evaluation period, and a 12-week dose-adjustment period (dose titration to 10 mgallowed). Endpoints included: change from baseline in 6-Minute Walk Distance (6-MWD), N-Terminal Pro B-Type Natriuretic Peptide (NT-pro-BNP), WHO FC, Borg Dyspnoea Index (BDI), clinical worsening of PAH and incidences of adverse events (AE).. One hundred thirty-three subjects (85 % women, mean age: 36 years) with PAH (WHOFC II or III) were enrolled and received ambrisentan (5 mg) once daily for a 12-week preliminary evaluation period, and a 12-week dose-adjustment period. Mean (SD) duration of drug exposure was 161.7 (27.13) days. Ambrisentan (average daily dose of 6.27 mg) significantly improved exercise capacity (6MWD) from baseline (mean: 377.1 m [m]) at week 12 (+53.6 m, p < 0.001) (primary endpoint). Improvement in exercise capacity was noted as early as week 4, and was sustained up to week 24 (+ 64.4 m, p < 0.001). NT-pro-BNP plasma levels decreased significantly (p < 0.001) at week 12 (-861.4 ng/L) and week 24 (-806 ng/L) from baseline (mean: 1600.7 ng/L). The WHO FC showed improvements for 44 subjects at week 12 and 51 subjects at week 24. BDI scores decreased significantly at week 12 (-0.3, p < 0.001) and week 24 (-0.2, p = 0.003) from baseline (mean: 2.5). Four patients died during the study (sudden cardiac death [n = 2], cerebral haemorrhage [n = 1], cardiac failure [n = 1]). Drug related adverse events occurred in 34.3 % of subjects; peripheral oedema (11.2 %) and flushing (8.2 %) occurred most frequently.. Ambrisentan (5 and 10 mg, orally) significantly improved the exercise capacity in Chinese PAH subjects with a safety profile similar to that observed in global studies.. NCT No. (ClinicalTrials.gov): NCT01808313 ; Registration date (first time): February 28, 2013.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antihypertensive Agents; China; Dose-Response Relationship, Drug; Exercise Test; Exercise Tolerance; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Middle Aged; Morbidity; Phenylpropionates; Prospective Studies; Pyridazines; Treatment Outcome; Young Adult

The clinical course of pulmonary hypertension (PH) in idiopathic pulmonary fibrosis (IPF) is not known except in advanced disease.488 subjects in a placebo-controlled study of ambrisentan in IPF with mild-moderate restriction in lung volume, underwent right heart catheterisation (RHC) at baseline and 117 subjects (24%) had repeated haemodynamic measurements at 48 weeks. The subjects were categorised into a) World Health Organization (WHO) Group 3 PH (PH associated with pulmonary disease), n=68 (14%); b) WHO Group 2 PH (PH associated with left-sided cardiac disease), n=25 (5%); c) no PH but elevated pulmonary artery wedge pressure (PAWP), n=21 (4%); and d) no PH but without elevation of PAWP, n=374 (77%). The WHO Group 3 PH subjects had a lower diffusion capacity, 6MWD and oxygen saturation compared to the subjects with no PH. There was no significant change in mean pulmonary arterial pressure with ambrisenten or placebo after 12 months. Subjects with IPF associated with WHO Group 3 PH had impaired gas exchange and exercise capacity compared to patients without PH. An additional 9% of the subjects had haemodynamic evidence of subclinical left-ventricular dysfunction. Pulmonary artery pressures remained stable over 1 year in the majority of the cohort.

Topics: Aged; Arterial Pressure; Cardiac Catheterization; Double-Blind Method; Female; Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Lung; Male; Middle Aged; Phenylpropionates; Pulmonary Wedge Pressure; Pyridazines; Ventricular Dysfunction, Left; World Health Organization

Data on the effect of initial combination therapy with ambrisentan and tadalafil on long-term outcomes in patients with pulmonary arterial hypertension are scarce.. In this event-driven, double-blind study, we randomly assigned, in a 2:1:1 ratio, participants with World Health Organization functional class II or III symptoms of pulmonary arterial hypertension who had not previously received treatment to receive initial combination therapy with 10 mg of ambrisentan plus 40 mg of tadalafil (combination-therapy group), 10 mg of ambrisentan plus placebo (ambrisentan-monotherapy group), or 40 mg of tadalafil plus placebo (tadalafil-monotherapy group), all administered once daily. The primary end point in a time-to-event analysis was the first event of clinical failure, which was defined as the first occurrence of a composite of death, hospitalization for worsening pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response.. The primary analysis included 500 participants; 253 were assigned to the combination-therapy group, 126 to the ambrisentan-monotherapy group, and 121 to the tadalafil-monotherapy group. A primary end-point event occurred in 18%, 34%, and 28% of the participants in these groups, respectively, and in 31% of the pooled-monotherapy group (the two monotherapy groups combined). The hazard ratio for the primary end point in the combination-therapy group versus the pooled-monotherapy group was 0.50 (95% confidence interval [CI], 0.35 to 0.72; P<0.001). At week 24, the combination-therapy group had greater reductions from baseline in N-terminal pro-brain natriuretic peptide levels than did the pooled-monotherapy group (mean change, -67.2% vs. -50.4%; P<0.001), as well as a higher percentage of patients with a satisfactory clinical response (39% vs. 29%; odds ratio, 1.56 [95% CI, 1.05 to 2.32]; P=0.03) and a greater improvement in the 6-minute walk distance (median change from baseline, 48.98 m vs. 23.80 m; P<0.001). The adverse events that occurred more frequently in the combination-therapy group than in either monotherapy group included peripheral edema, headache, nasal congestion, and anemia.. Among participants with pulmonary arterial hypertension who had not received previous treatment, initial combination therapy with ambrisentan and tadalafil resulted in a significantly lower risk of clinical-failure events than the risk with ambrisentan or tadalafil monotherapy. (Funded by Gilead Sciences and GlaxoSmithKline; AMBITION ClinicalTrials.gov number, NCT01178073.).

Topics: Adult; Aged; Carbolines; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; Hospitalization; Humans; Hypertension, Pulmonary; Kaplan-Meier Estimate; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Phenylpropionates; Pyridazines; Risk Factors; Tadalafil

This prospective, double-blinded, randomized controlled study aimed to investigate the efficacy and safety of oral tadalafil in patients receiving background ambrisentan therapy. Current treatments for pulmonary arterial hypertension (PAH) remain insufficient, resulting in high mortality rates. The addition of oral tadalafil, a phosphodiesterase-5 inhibitor, to background ambrisentan may provide a safe and effective therapeutic strategy. A total of 124 patients who had been treated with ambrisentan for at least 4 months and had a stable 6-min walking distance (6MWD) and World Health Organization (WHO) functional class (FC) for at least 1 month were randomized to either the oral tadalafil or placebo group. Treatment differences in 6MWD, changes in FC, clinical worsening (CW) and adverse events were analyzed after 16 weeks of treatment. At week 16, the tadalafil group showed a significantly improved exercise capacity as assessed by the 6MWD (P<0.05). In addition, 5 (8.3%) patients receiving tadalafil add-on therapy had CW vs. 15 (23.4%) with placebo (P<0.05). No significant differences were found in adverse events or changes in hemodynamic parameters between the placebo and tadalafil groups. Tadalafil 40 mg was well-tolerated as add-on therapy to background ambrisentan. However, the data from this study are insufficient to prove the additional therapeutic benefits of tadalafil add-on therapy.

Topics: Adolescent; Adult; Aged; Carbolines; Dose-Response Relationship, Drug; Drug Therapy, Combination; Endothelin Receptor Antagonists; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Outcome Assessment, Health Care; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Pyridazines; Tadalafil; Treatment Outcome; Young Adult

In translational models of pulmonary arterial hypertension (PAH), spironolactone improves cardiopulmonary hemodynamics by attenuating the adverse effects of hyperaldosteronism on endothelin type-B receptor function in pulmonary endothelial cells. This observation suggests that coupling spironolactone with inhibition of endothelin type-A receptor-mediated pulmonary vasoconstriction may be a useful treatment strategy for patients with PAH. We examined clinical data from patients randomized to placebo or the selective endothelin type-A receptor antagonist ambrisentan (10 mg/day) and in whom spironolactone use was reported during ARIES-1 and -2, which were randomized, double-blind, placebo-controlled trials assessing the effect of ambrisentan for 12 weeks on clinical outcome in PAH. From patients randomized to placebo (n = 132) or ambrisentan (n = 67), we identified concurrent spironolactone use in 21 (15.9%) and 10 (14.9%) patients, respectively. Compared with patients treated with ambrisentan alone (n = 57), therapy with ambrisentan + spironolactone improved change in 6-minute walk distance by 94% at week 12 (mean ± SE, +38.2 ± 8.1 vs +74.2 ± 27.4 m, p = 0.11), improved plasma B-type natriuretic peptide concentration by 1.7-fold (p = 0.08), and resulted in a 90% relative increase in the number of patients improving ≥1 World Health Organization functional class (p = 0.08). Progressive illness, PAH-associated hospitalizations, or death occurred as an end point for 5.3% of ambrisentan-treated patients; however, no patient treated with ambrisentan + spironolactone reached any of these end points. In conclusion, these pilot data suggest that coupling spironolactone and endothelin type-A receptor antagonism may be clinically beneficial in PAH. Prospective clinical trials are required to further characterize our findings.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Diuretics; Double-Blind Method; Drug Therapy, Combination; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Phenylpropionates; Pilot Projects; Pyridazines; Severity of Illness Index; Spironolactone; Treatment Outcome; Young Adult

To investigate the preliminary efficacy and safety of ambrisentan, a selective endothelin receptor antagonist, in patients with pulmonary arterial hypertension (PAH).. A total of 15 patients with PAH, including 10 patients with idiopathic PAH and 5 patients with associated connective-tissue disease, received 2.5 mg or 5 mg of ambrisentan once daily for 12 weeks. Before and after 12 weeks treatment, 6-minute walk test (6-MWD), WHO functional classification (WHO FC) and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured.. After 12 weeks treatment, the 6-MWD was significantly increased [(376.5 ± 108.2) m vs.(460.3 ± 95.7) m, P = 0.021] and the systolic pulmonary artery was significantly decreased [(85.0 ± 33.3) mm Hg (1 mm Hg = 0.133 kPa)vs. (70.5 ± 30.5) mm Hg,P = 0.015] and NT-proBNP was significantly reduced [892.0 (99.0-2245.0) ng/L vs. 205.0 (56.0-534.0) ng/L, P = 0.026] than before treatment. WHO FC was improved in 4 patients after 12 weeks treatment. No patient was withdrawn from this study for safety reasons.. Ambrisentan treatment can effectively improve the exercise capacity, and reduce systolic pulmonary artery pressure and NT-proBNP in PAH patients. Ambrisentan use is safe and could be well tolerated in Chinese PAH patients.

Topics: Adult; Antihypertensive Agents; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Prospective Studies; Pyridazines; Treatment Outcome

To explore the efficacy, safety and tolerance of ambrisentan, a high-selective endothelin receptor antagonist, in Chinese patients with pulmonary hypertension (PH).. Twenty-eight PH patients (Group 1+Group 4) came from Shanghai East Hospital, Zhongshan Hospital of Fudan University and Fifth People's Hospital of Shanghai were recruited into this open-label, prospective multi-center trial between August 2012 and February 2013. They received 2.5-5.0 mg ambrisentan once daily for 12 weeks. The primary endpoint was the change in exercise capacity showed by six-minute walk distance (6MWD) from baseline to 12 weeks. Secondary endpoints included the changes in World Health Organization (WHO) function class, N-terminal brain natriuretic peptide (NT-proBNP) and liver function test results.. There were 9 males and 19 females with an average age of (35 ± 17) years. The value of 6MWD increased from (372 ± 86) m at baseline to (443 ± 96) m (P = 0.000) after 12 weeks. WHO functional class improved after a 12-week therapy compared to the baseline level (P = 0.000). NT-proBNP decreased from a median of 732 ng/L at baseline to 329 ng/L after 12 weeks (P = 0.046). The baseline liver function test was normal. And liver function test didn't significantly change after a 12-week therapy.. Ambrisentan therapy is well-tolerated and it improves the exercise capacity and WHO function class in Chinese PH patients.

Topics: Adolescent; Adult; Antihypertensive Agents; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Prospective Studies; Pyridazines; Treatment Outcome; Young Adult

Ambrisentan is an oral, once daily, endothelin receptor antagonist approved for treatment of pulmonary arterial hypertension (PAH). Previous studies of ambrisentan were limited to patients with Group 1 PAH and often excluded patients receiving other pulmonary hypertension (PH) therapies.. ARIES-3 was an open-label study evaluating efficacy and safety of ambrisentan in patients with various PH etiologies and background PH medications. Patients received 5 mg ambrisentan once daily for 24 weeks. The primary endpoint was change from baseline in 6-minute walk distance (6MWD) at week 24.. A total of 224 patients with PH due to idiopathic and familial PAH (31%), connective tissue disease (18%), chronic hypoxemia (22%), chronic thromboembolic disease (13%), or other etiologies (16%) were enrolled and 53% of patients received stable background PAH therapies. After 24 weeks of therapy, an increase in 6MWD (+21 m; 95% CI: 12-29) and a decrease in B-type natriuretic peptide (-26%; 95% CI: -34 to -16%) was observed in the overall population compared to baseline; however, increases in 6MWD were not observed in several non-Group 1 PH subpopulations. Peripheral edema, headache, and dyspnea were the most common adverse events.. This study reconfirms the results of previous placebo-controlled studies, which demonstrate that ambrisentan is well tolerated and provides benefit in patients with PAH. Definitive conclusions regarding the safety and efficacy of ambrisentan in specific non-Group 1 PH etiologies cannot be determined and larger, controlled studies will be necessary to determine the efficacy and safety of ambrisentan in these populations.

Topics: Adult; Aged; Double-Blind Method; Endothelin A Receptor Antagonists; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Long-Term Care; Male; Middle Aged; Natriuretic Peptide, Brain; Phenylpropionates; Pyridazines; Survival; Treatment Outcome; Walking

Recently studied therapies for pulmonary arterial hypertension (PAH) have improved outcomes among populations of patients, but little is known about which patients are most likely to respond to specific treatments. Differences in endothelin-1 biology between sexes and between whites and blacks may lead to differences in patients' responses to treatment with endothelin receptor antagonists (ERAs).. We conducted pooled analyses of deidentified, patient-level data from six randomized placebo-controlled trials of ERAs submitted to the US Food and Drug Administration to elucidate heterogeneity in treatment response. We estimated the interaction between treatment assignment (ERA vs placebo) and sex and between treatment and white or black race in terms of the change in 6-min walk distance from baseline to 12 weeks.. Trials included 1,130 participants with a mean age of 49 years; 21% were men, 74% were white, and 6% were black. The placebo-adjusted response to ERAs was 29.7 m (95% CI, 3.7-55.7 m) greater in women than in men (P = .03). The placebo-adjusted response was 42.2 m for whites and -1.4 m for blacks, a difference of 43.6 m (95% CI, -3.5-90.7 m) (P = .07). Similar results were found in sensitivity analyses and in secondary analyses using the outcome of absolute distance walked.. Women with PAH obtain greater responses to ERAs than do men, and whites may experience a greater treatment benefit than do blacks. This heterogeneity in treatment-response may reflect pathophysiologic differences between sexes and races or distinct disease phenotypes.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Bosentan; Child; Double-Blind Method; Endothelin Receptor Antagonists; Ethnicity; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Isoxazoles; Male; Middle Aged; Phenylpropionates; Prevalence; Prospective Studies; Pulmonary Wedge Pressure; Pyridazines; Sex Factors; Sulfonamides; Thiophenes; Treatment Outcome; United States; Walking; Young Adult

To investigate the safety and efficacy of long-term administration of ambrisentan in Japanese adults with pulmonary arterial hypertension (PAH).. In this open-label extension of a preceding multicenter dose-escalation study, 21 Japanese patients with PAH received treatment with 5 or 10 mg of ambrisentan once daily and were comprehensively evaluated every 12 weeks. The primary endpoint was the safety of long-term ambrisentan administration, as defined by the incidence and severity of adverse events. The secondary (efficacy) endpoints were change in exercise capacity (as indicated by 6-minute walk distance), World Health Organization functional class, Borg dyspnea index, plasma brain natriuretic peptide level, cardiopulmonary hemodynamics, and time to clinical worsening of PAH.. NCT00554619.. The mean total duration of treatment (i.e., including the preceding dose-escalation study) was approximately 139 weeks. There were fewer adverse events related to ambrisentan in this study than in the preceding study, and we identified no new safety signals that might preclude the long-term use of ambrisentan among Japanese adults with PAH. Improvements observed in efficacy endpoints in the preceding study were maintained in the present study.. This study did not include a control group and lacked the statistical power to reach definite conclusions regarding the efficacy of ambrisentan.. Our results suggest that long-term administration of ambrisentan is well tolerated and efficacious for Japanese adults with PAH.

Topics: Adult; Aged; Antihypertensive Agents; Asian People; Drug Administration Schedule; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Pyridazines; Time Factors; Treatment Outcome

Exercise-induced pulmonary hypertension (ePH) may represent an early, clinically relevant phase in the spectrum of pulmonary vascular disease. The purpose of this pilot study was to describe the changes in hemodynamics and exercise capacity in patients with systemic sclerosis (SSc) spectrum-associated ePH treated with open-label daily ambrisentan.. Patients were treated with ambrisentan, 5 mg or 10 mg once daily, for 24 weeks. At baseline and 24 weeks, patients with SSc spectrum disorders exercised in a supine position, on a lower extremity cycle ergometer. All patients had normal hemodynamics at rest. We defined baseline ePH as a mean pulmonary artery pressure of >30 mm Hg with maximum exercise and a transpulmonary gradient (TPG) of >15 mm Hg. The primary end point was change in pulmonary vascular resistance (PVR) with exercise. Secondary end points included an improvement from baseline in 6-minute walking distance, health-related quality of life assessments, and cardiopulmonary hemodynamics.. Of the 12 enrolled patients, 11 completed the study. At 24 weeks there were improvements in mean exercise PVR (85.8 dynes × second/cm(5) ; P = 0.003) and mean distance covered during 6-minute walk (44.5 meters; P = 0.0007). Improvements were also observed in mean exercise cardiac output (1.4 liters/minute; P = 0.006), mean pulmonary artery pressure (-4.1 mm Hg; P = 0.02), and total pulmonary resistance (-93.0 dynes × seconds/cm(5) ; P = 0.0008). Three patients developed resting pulmonary arterial hypertension during the 24 weeks.. Exercise hemodynamics and exercise capacity in patients with SSc spectrum-associated ePH improved over 24 weeks with exposure to ambrisentan. Placebo-controlled studies are needed to confirm whether this is a drug-related effect and to determine optimal therapeutic regimens for patients with ePH.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Cardiac Output; Dose-Response Relationship, Drug; Exercise; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Physical Endurance; Pilot Projects; Prospective Studies; Pyridazines; Quality of Life; Scleroderma, Systemic; Treatment Outcome

Edema is a common side effect of endothelin receptor antagonists. Ambrisentan is an endothelin type A-selective endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension. We examined the clinical outcomes of patients who developed edema with and without ambrisentan treatment in 2 phase III, randomized placebo-controlled trials, ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2 (ARIES-1 and ARIES-2) (n = 393). Edema-related adverse events were extracted using broad adverse event search terms. The present post hoc analysis included 132 placebo patients and 261 ambrisentan patients. Of these patients, 14% of the placebo patients and 23% of the ambrisentan patients experienced edema-related adverse events. Overall, the patients who experienced edema tended to have a worse baseline World Health Organization (WHO) functional class (edema 76%, WHO functional class III-IV; no edema 56%, WHO functional class III-IV). In the ambrisentan patients, those with edema were older (mean age 58 ± 13 years) and heavier (mean weight 75 ± 19 kg) than those without edema (mean age 49 ± 15 years; mean weight 70 ± 17 kg). At week 12 of treatment, the ambrisentan patients had significantly increased their 6-minute walk distance (6MWD) by 34.4 m compared to the placebo patients in whom the 6MWD had deteriorated by -9.0 m (p <0.001). Among the ambrisentan patients, those without edema had a 6MWD increase of 38.9 m and those with edema had a 6MWD increase of 19.4 m. Ambrisentan significantly improved the brain natriuretic peptide levels by -34% compared to the brain natriuretic peptide levels in the placebo group that had worsened by +11% (p <0.001). Ambrisentan reduced the brain natriuretic peptide concentrations similarly in patients with and without edema. In conclusion, the present subanalysis of patients with pulmonary arterial hypertension has revealed that ambrisentan therapy provides clinical benefit compared to placebo, even in the presence of edema.

Topics: Adult; Age Factors; Aged; Analysis of Variance; Confidence Intervals; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Edema; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Incidence; Male; Middle Aged; Natriuretic Peptide, Brain; Phenylpropionates; Pyridazines; Reference Values; Risk Assessment; Safety Management; Severity of Illness Index; Sex Factors; Treatment Outcome

To investigate the efficacy, safety, and pharmacokinetics of ambrisentan in Japanese adults with pulmonary arterial hypertension (PAH).. In this open-label, uncontrolled, dose-escalation study, 25 Japanese patients with PAH were scheduled to receive 5 mg of ambrisentan once daily for the first 12 weeks, and 10 mg once daily for an additional 12 weeks. The primary endpoint was improvement in exercise capacity from baseline which was indicated by 6-minute walk distance; the secondary endpoints included World Health Organization functional class, Borg dyspnea index, plasma brain natriuretic peptide level, and cardiopulmonary hemodynamics.. NCT00540436.. At week 24, improvements were noted in all endpoints, with no clinically significant elevation of serum aminotransferase level. Pharmacokinetics in these Japanese patients was similar to that of non-Japanese populations, suggesting that once-daily dosing is appropriate in Japanese patients. Ambrisentan was generally well tolerated. No new safety signals were identified.. This study lacked a control group and was insufficiently powered to reach definitive conclusions on the efficacy of ambrisentan.. Ambrisentan is considered as safe and effective for Japanese adults with PAH.

Topics: Adult; Aged; Antihypertensive Agents; Asian People; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Platelet Aggregation Inhibitors; Pyridazines; Treatment Outcome

Sarcoidosis associated pulmonary hypertension (SAPH) is associated with significant morbidity and mortality. There is a paucity of information concerning therapy for this condition.. We performed a prospective, open-label, proof of concept trial of ambrisentan for SAPH. 21 subjects with SAPH received 5 mg/day of ambrisentan for 4 weeks and then 10/mg day for 20 subsequent weeks.. No significant change was noted in the 6-minute walk distance over the course of the study (mean change between week 0 and 24: 9.8 +/- 54.6 meters, p: NS). There were also no significant differences between weeks 0 and 24 in terms of dyspnea as measured by the modified Borg scale, serum brain naturetic peptide, diffusing capacity, and quality of life as measured by the Short Form-36. There was a high dropout rate: overall: 11/21, 52%; social reasons: 3/21, 14%; medical reasons: 8/21, 38% because of dyspnea: 6/21, 29% and/or edema: 4/21, 19%. Of those who completed the 24 week study (10/21, 48%), there was an improvement in their WHO functional class and a marked improvement in their health related quality of life as measured by the St. George Respiratory questionnaire (-15.3 +/- 25.0). However both these improvments did not reach statistical significance possibly because of the small sample size.. Although ambrisentan was not well tolerated by many of these subjects with SAPH, in those who remained in this 24-week trial, improvements in WHO functional class and in health related quality of life suggested a possible benefit of this drug in selected patients.

Topics: Adult; Antihypertensive Agents; Exercise Test; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Lung; Male; Middle Aged; North Carolina; Phenylpropionates; Prospective Studies; Pyridazines; Quality of Life; Recovery of Function; Respiratory Function Tests; Sarcoidosis; South Carolina; Surveys and Questionnaires; Time Factors; Treatment Outcome

This study evaluated long-term outcomes in patients with pulmonary arterial hypertension (PAH) undergoing treatment with ambrisentan monotherapy, a selective oral endothelin-1 receptor antagonist.. Patients who participated in the Ambrisentan in Pulmonary Arterial Hypertension: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Multicenter Efficacy Study (ARIES-1) clinical trial and extension phase at our institution were included. Cardiac catheterization, 6-minute walk distance (6MWD), and cardiac magnetic resonance (MRI) data were retrospectively reviewed. Twelve patients with PAH (11 idiopathic, 1 fenfluramine) had follow-up from 3 to 5.5 years from the initiation of ARIES-1. Patients received ambrisentan therapy throughout the study period and were on ambrisentan monotherapy for the first 2 years. At year 1, improvements in median mean pulmonary arterial pressure (PA), cardiac output, and pulmonary vascular resistance (PVR) were seen (P = .02, P = .03, P < .01), and the improvement in PVR persisted at 2 years. 6MWD also improved significantly between baseline (350 m) and 1 and 2 years (397 m, P < .01 and 393 m, P = .01). Cardiac MRI results were more varied, with an increase in RV ejection fraction from 29% at baseline to 46% at 2 years (P = .02), but other MRI variables did not improve.. Ambrisentan monotherapy led to improvements in catheterization, 6MWD, and RV ejection fraction, and shows promise as a long-term treatment for pulmonary arterial hypertension.

Topics: Adolescent; Adult; Aged; Double-Blind Method; Exercise Test; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Pyridazines; Survival Rate; Time Factors; Treatment Outcome; Young Adult

Some endothelin receptor antagonists (ERAs) are associated with liver function test (LFT) result abnormalities. However, ambrisentan has an incidence of serum aminotransferase levels more than three times the upper limit of normal (ULN), similar to that observed in PAH patients who are not receiving ERAs. Because ambrisentan may provide benefits in PAH patients who have discontinued ERA therapy due to LFT abnormalities, we evaluated the safety and efficacy of ambrisentan in this patient population.. Patients who previously discontinued bosentan and/or sitaxsentan due to LFT abnormalities received ambrisentan, 2.5 mg qd, for 4 weeks followed by 5 mg/d for 8 weeks. The primary end point was the incidence of aminotransferase levels more than three times ULN considered by the investigator to be related to ambrisentan and resulting in drug discontinuation. Secondary end points included aminotransferase levels more than five times ULN requiring drug discontinuation and more than three times ULN requiring dose reduction, as well as changes in 6-min walk distance (6MWD), Borg dyspnea index, World Health Organization functional class, and Short Form-36 health survey score. Patients continued treatment beyond the 12-week end point with monthly monitoring of LFTs.. Thirty-six patients who previously discontinued bosentan (n = 31), sitaxsentan (n = 2), or both (n = 3) were enrolled. At baseline, 69.4% of patients were receiving prostanoid and/or sildenafil therapy. No patient had an aminotransferase level more than three times ULN that required ambrisentan discontinuation. One patient had a transient aminotransferase level more than three times ULN that resolved following a temporary dose reduction. No additional aminotransferase levels more than three times ULN were observed with long-term treatment (median exposure, 102 weeks), despite dose increases to 10 mg qd in more than half of the patients. Significant improvements in 6MWD and other efficacy assessments were observed.. Ambrisentan treatment may be an option for patients who have discontinued bosentan and/or sitaxsentan therapy due to LFT result abnormalities.. Clinicaltrials.gov Identifier NCT00423592.

Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Bosentan; Child; Disease-Free Survival; Endothelin Receptor Antagonists; Female; Humans; Hypertension, Pulmonary; Isoxazoles; Liver Function Tests; Male; Middle Aged; Phenylpropionates; Pyridazines; Sulfonamides; Thiophenes; Transaminases; Treatment Outcome; Young Adult

This study evaluated the safety and efficacy of ambrisentan for a period of 2 years in patients with pulmonary arterial hypertension (PAH).. Ambrisentan is an oral, once-daily endothelin receptor antagonist that is selective for the endothelin type A receptor. The ARIES-1 (Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies) and ARIES-2 trials were the pivotal 12-week, placebo-controlled studies that led to the regulatory approval of ambrisentan (5 and 10 mg) for the treatment of PAH.. In the ARIES-1 and -2 studies, and the subsequent long-term extension protocol, the ARIES-E study, 383 patients received ambrisentan (2.5, 5, or 10 mg). Efficacy and safety assessments are presented from the time of the first dose of ambrisentan for all patients with post-baseline data.. After 2 years of ambrisentan exposure, the mean change from baseline in 6-min walk distance was improved for the 5-mg (+23 m; 95% confidence interval: 9 to 38 m) and 10-mg (+28 m; 95% confidence interval: 11 to 45 m) groups. Estimates of survival and freedom from clinical worsening for the combined dose group were 94% and 83%, respectively, at 1 year and 88% and 72%, respectively, at 2 years. The annualized risk of aminotransferase abnormalities >3x the upper limit of normal was approximately 2% per year; most of these events were mild and did not lead to discontinuation of drug.. Two years of ambrisentan treatment was associated with sustained improvements in exercise capacity and a low risk of clinical worsening and death in patients with PAH. Ambrisentan was generally well tolerated and had a low risk of aminotransferase abnormalities over the 2-year study period. (A Long Term Study of Ambrisentan in Pulmonary Arterial Hypertension Subjects Having Completed AMB-320 or AMB-321; NCT00578786).

Topics: Administration, Oral; Dose-Response Relationship, Drug; Double-Blind Method; Exercise Tolerance; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Pulmonary Wedge Pressure; Pyridazines; Survival Rate; Time Factors; Treatment Outcome

Ambrisentan is a propanoic acid-based, A-selective endothelin receptor antagonist for the once-daily treatment of pulmonary arterial hypertension.. Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study 1 and 2 (ARIES-1 and ARIES-2) were concurrent, double-blind, placebo-controlled studies that randomized 202 and 192 patients with pulmonary arterial hypertension, respectively, to placebo or ambrisentan (ARIES-1, 5 or 10 mg; ARIES-2, 2.5 or 5 mg) orally once daily for 12 weeks. The primary end point for each study was change in 6-minute walk distance from baseline to week 12. Clinical worsening, World Health Organization functional class, Short Form-36 Health Survey score, Borg dyspnea score, and B-type natriuretic peptide plasma concentrations also were assessed. In addition, a long-term extension study was performed. The 6-minute walk distance increased in all ambrisentan groups; mean placebo-corrected treatment effects were 31 m (P=0.008) and 51 m (P<0.001) in ARIES-1 for 5 and 10 mg ambrisentan, respectively, and 32 m (P=0.022) and 59 m (P<0.001) in ARIES-2 for 2.5 and 5 mg ambrisentan, respectively. Improvements in time to clinical worsening (ARIES-2), World Health Organization functional class (ARIES-1), Short Form-36 score (ARIES-2), Borg dyspnea score (both studies), and B-type natriuretic peptide (both studies) were observed. No patient treated with ambrisentan developed aminotransferase concentrations >3 times the upper limit of normal. In 280 patients completing 48 weeks of treatment with ambrisentan monotherapy, the improvement from baseline in 6-minute walk at 48 weeks was 39 m.. Ambrisentan improves exercise capacity in patients with pulmonary arterial hypertension. Improvements were observed for several secondary end points in each of the studies, although statistical significance was more variable. Ambrisentan is well tolerated and is associated with a low risk of aminotransferase abnormalities.

Topics: Activities of Daily Living; Administration, Oral; Aged; Double-Blind Method; Dyspnea; Endothelin Receptor Antagonists; Exercise; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Kaplan-Meier Estimate; Male; Middle Aged; Natriuretic Peptide, Brain; Phenylpropionates; Placebos; Pyridazines; Quality of Life; Treatment Outcome

The purpose of this study was to examine the efficacy and safety of four doses of ambrisentan, an oral endothelin type A receptor-selective antagonist, in patients with pulmonary arterial hypertension (PAH).. Pulmonary arterial hypertension is a life-threatening and progressive disease with limited treatment options. Endothelin is a vasoconstrictor and smooth muscle cell mitogen that plays a critical role in the pathogenesis and progression of PAH.. In this double-blind, dose-ranging study, 64 patients with idiopathic PAH or PAH associated with collagen vascular disease, anorexigen use, or human immunodeficiency virus infection were randomized to receive 1, 2.5, 5, or 10 mg of ambrisentan once daily for 12 weeks followed by 12 weeks of open-label ambrisentan. The primary end point was an improvement from baseline in 6-min walk distance (6MWD); secondary end points included Borg dyspnea index, World Health Organization (WHO) functional class, a subject global assessment, and cardiopulmonary hemodynamics.. At 12 weeks, ambrisentan increased 6MWD (+36.1 m, p < 0.0001) with similar and statistically significant increases for each dose group (range, +33.9 to +38.1 m). Improvements were also observed in Borg dyspnea index, WHO functional class, subject global assessment, mean pulmonary arterial pressure (-5.2 mm Hg, p < 0.0001), and cardiac index (+0.33 l/min/m2, p < 0.0008). Adverse events were mild and unrelated to dose, including the incidence of elevated serum aminotransferase concentrations >3 times the upper limit of normal (3.1%).. Ambrisentan appears to improve exercise capacity, symptoms, and hemodynamics in patients with PAH. The incidence and severity of liver enzyme abnormalities appear to be low.

Topics: Adult; Aged; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Exercise Tolerance; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Maximum Tolerated Dose; Middle Aged; Phenylpropionates; Probability; Pyridazines; Reference Values; Risk Assessment; Severity of Illness Index; Treatment Outcome; Vascular Resistance

Pulmonary arterial hypertension (PAH) is a progressive and inevitably fatal disease characterized by the progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling, which lead to right-sided heart failure and premature death. Many of the genetically modified mouse models do not develop severe PH and occlusive vascular remodeling.

Topics: Animals; Familial Primary Pulmonary Hypertension; Heart Failure; Hypertension, Pulmonary; Hypoxia-Inducible Factor-Proline Dioxygenases; Mice; Pulmonary Arterial Hypertension; Pulmonary Artery; Sildenafil Citrate; Vascular Remodeling; Vasodilator Agents

Despite the growing evidence of efficacy, little is known regarding the efficiency of ambrisentan to decrease cost and improve the functional classes of pediatric patients with pulmonary arterial hypertension. This study aims to determine the cost-utility of ambrisentan regarding sildenafil to treat pediatric patients with pulmonary arterial hypertension in Colombia.. A decision tree model was used to estimate the cost and quality-adjusted life-years (QALYs) of ambrisentan, or sildenafil in pediatric patients with pulmonary arterial hypertension. Multiple sensitivity analyses were conducted to evaluate the robustness of the model. Cost-effectiveness was evaluated at a willingness-to-pay (WTP) value of US$5180.. The base-case analysis showed that compared with sildenafil, ambrisentan was associated with higher costs and higher QALYs. The expected annual cost per patient with ambrisentan was US$16,105 and with sildenafil was US$1431. The QALYs per person estimated with ambrisentan was 0.40 and for sildenafil was 0.39. The estimated improvement in quality of life and reduced costs results in an estimate of economic dominance for sildenafil over ambrisentan.. Our economic evaluation shows that ambrisentan is not cost-effective regarding sildenafil to treat pediatric patients with pulmonary arterial hypertension in Colombia. Our study provides evidence that should be used by decision-makers to improve clinical practice guidelines.

Topics: Child; Cost-Benefit Analysis; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Quality of Life; Sildenafil Citrate

Use of endothelin receptor antagonists (ERAs) and riociguat, approved for treatment of pulmonary hypertension (PH), is contraindicated during pregnancy due to reported teratogenicity in animals. We aimed to investigate prescribing of these drugs in girls/women of childbearing age and to explore - as a secondary aim - the occurrence of pregnancies exposed to these drugs. Using the German Pharmacoepidemiological Research Database (GePaRD, claims data from 20% of the German population) we conducted cross-sectional analyses to determine prescribing prevalence of ERAs and riociguat between 2004 and 2019 and to characterize users and prescribing patterns. In a cohort analysis, we assessed the occurrence of pregnancies exposed to these drugs in the critical time window. Overall, we identified 407 women with ≥ 1 dispensation of bosentan between 2004 and 2019; the respective number was 73 for ambrisentan, 182 for macitentan, 31 for sitaxentan, and 63 for riociguat. In nearly all years, more than 50% of the girls/women were ≤ 40 years. Age-standardized prevalence was highest for bosentan (0.04/1000) in 2012 and 2013, followed by macitentan (0.03/1000) in 2018 and 2019. We observed 10 exposed pregnancies: 5 to bosentan, 3 to ambrisentan, and 2 to macitentan. The increased prevalence of macitentan and riociguat from 2014 onwards might reflect changes in PH treatment. Even though PH is a rare disease and pregnancy should be avoided in women with PH, particularly if they use ERAs, we identified pregnancies exposed to ERAs. Multi-database studies will be needed to assess the risk of these drugs on the unborn child.

Topics: Animals; Bosentan; Cross-Sectional Studies; Endothelin Receptor Antagonists; Female; Hypertension, Pulmonary

This regulatory post-marketing surveillance (PMS) was organized to identify the safety and effectiveness of ambrisentan in the Korean population.. This was an open-label, multi-center PMS conducted from 31 institutions in Korea for 6 years from August 2015 to 2021, to evaluate the use of ambrisentan for the treatment of pulmonary arterial hypertension (PAH). Inclusion criteria are Korean subjects with the World Health Organization functional classification (WHO Fc) II or III PAH who are new users or repeated users with ambrisentan (Volibris®) Tablet 5 or 10 mg per day (age >18 years old).. A total of 293 cases were analyzed. The overall incidence of adverse events (AE) was 52.22% and adverse drug reactions (ADR) was 10.92%. Severe AEs occurred in 20.82% of patients. However, only 2 subjects (0.68%) reported serious ADR. The difference in AE incidence was statistically significant for concomitant medications other than PAH medications in the safety analysis and the new users (p = 0.0041 and p = 0.0299, respectively) and elderly population in the repeated users (p = 0.0319). Among the long-term 223 subjects, the WHO Fc II and III were 41.26% and 58.74% before ambrisentan, and changed after treatment to 3.09%, 66.05%, and 30.86% for Fc I/II/III, respectively. 217 of 249 subjects (87.15%) considered their symptoms to have 'improved' after the last administration.. In real-world practice, ambrisentan demonstrated tolerable safety and favorable effectiveness in PAH patients in Korea. Age and concomitant drug use can affect the occurrence of AE.

Topics: Adult; Aged; Antihypertensive Agents; Humans; Hypertension, Pulmonary; Phenylpropionates; Product Surveillance, Postmarketing; Pulmonary Arterial Hypertension; Republic of Korea; Treatment Outcome

To describe the safety and tolerability of treatment with ambrisentan and tadalafil in pediatric pulmonary hypertension (PH).. This retrospective observational two-center study included subjects (≤18 years of age) with PH receiving combination therapy with ambrisentan and tadalafil. Before initiating this therapy, many patients were on other therapies for PH. At baseline, patients either received no therapy or monotherapy with a phosphodiesterase 5 inhibitor (PDE5i) or endothelin receptor antagonist (ERA) (Group A), switched from a different PDE5i and ERA (Group B), or were on prostanoid therapy with or without a PDE5i and/or ERA (Group C and D). Demographics, symptoms, and adverse effects were collected. Pre- and postvalues for exercise capacity, hemodynamics, and biomarkers were compared.. There were 43 subjects (26 F, 17 M) ages 4-17.5 years (median 9.3) with World Symposium of PH group 1, 3, and 5. Significant improvements were seen in change scores at follow-up in the entire sample and Group A for 6-min walk distance: +37.0 (6.5-71.0) [p = 0.022], mean pulmonary artery pressure: -6.0 (-14.0 to -3.5) [p = .002], pulmonary vascular resistance: -1.7 (-6.2 to -1.0) [p = .003], NT-proBNP -32.9 (-148.9 to -6.7) [p = .025]. WHO functional class improved in 39.5% and was unchanged in 53.5%; PH risk scores improved in 16%; were unchanged in 56%; and declined in 14%. Three patients discontinued therapy (two headaches, one peripheral edema). Seven patients were hospitalized for worsening disease (2/7 had a Potts shunt placed, 2/7 had an atrial septostomy). There were no deaths or lung transplantation.. Combination therapy with ambrisentan and tadalafil was well-tolerated, with an acceptable safety profile in a select group of children. This therapy was associated with improved exercise capacity and hemodynamics in children who were treatment naïve or on monotherapy with a PH medication before the initiation of ambrisentan and tadalafil. Based on these early data, further study of combination therapy in pediatric PH is warranted.

Topics: Adolescent; Antihypertensive Agents; Child; Child, Preschool; Drug Therapy, Combination; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Pulmonary Arterial Hypertension; Pyridazines; Retrospective Studies; Tadalafil; Treatment Outcome

Although sildenafil is used in dogs with severe pulmonary hypertension, they sometimes become resistant and clinical signs deteriorate over time. The objective of this study was to determine the benefits of adjunct ambrisentan therapy in dogs with sildenafil-refractory pulmonary hypertension. In 5 dogs with severe pulmonary hypertension with deteriorating clinical signs despite ongoing sildenafil treatment, adding ambrisentan improved appetite, activity, and respiratory functions. Although peak tricuspid valve regurgitation velocity, as measured by Doppler echocardiography, did not necessarily decrease after ambrisentan administration, there was improved partial pressure of arterial oxygen and the alveolar-arterial oxygen gradient, with no apparent side effects. We concluded that ambrisentan has potential as an adjunct treatment in dogs with pulmonary hypertension that are refractory to sildenafil therapy. Key clinical message: Ambrisentan improved clinical signs in dogs with sildenafil-refractory pulmonary hypertension.

Topics: Animals; Dog Diseases; Dogs; Hypertension, Pulmonary; Oxygen; Phenylpropionates; Pyridazines; Sildenafil Citrate

Pulmonary arterial hypertension is a progressive, debilitating condition characterized by increased resistance in the pulmonary arterial circulation. Current treatments for pulmonary arterial hypertension include endothelin receptor antagonists such as bosentan, sitaxentan, ambrisentan, macitentan, and oral prostacyclin receptor agonists such as selexipag. Endothelin receptor antagonists have been associated with liver injury, while hepatotoxicity was not reported for selexipag. Although genetic variability has been indisputably associated with variability in drug response, no study has been designed until now to assess its effects on the pharmacokinetics of endothelin receptor antagonists or selexipag.. We report the case of a 58-year-old female Caucasian patient with a dramatic increase in plasma levels of transaminases after treatment with macitentan and selexipag, drugs whose risk of causing liver injury has so far been considered limited. After therapy discontinuation, plasma levels of transaminases returned to baseline, thus suggesting a role of these drugs in the observed hepatotoxicity. After pharmacological counseling, we decided to introduce ambrisentan for the patient's treatment. After 7 months of treatment, no liver injury has been reported. To evaluate the role of genetic factors in the observed hepatotoxicity, we genotyped the patient for single-nucleotide polymorphisms previously associated with macitentan, ambrisentan, or selexipag metabolism. We found a genetic profile associated with a poor metabolizer (PM) phenotype for CYP2C8 and CYP2C9, key enzymes for elimination of both macitentan and selexipag. The reported results suggest that an allelic profile associated with low activity for CYP2C8 and CYP2C9 enzyme could be a potential risk factor for macitentan and selexipag-induced liver injury and could provide a possible marker for early identification of subjects at higher risk of developing hepatotoxicity.. A multidisciplinary approach based on clinical evaluation, as well as pharmacological counseling and evaluation of the patient's genetic profile, might be useful for identification of patients with a high chance of drug-induced liver injury, avoiding unnecessary risks in therapy selection and prescription.

Topics: Bosentan; Counseling; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP2C9; Endothelin Receptor Antagonists; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Middle Aged; Pulmonary Arterial Hypertension; Receptors, Epoprostenol; Transaminases

Ambrisentan (AMB) is an orphan drug approved for oral administration that has been developed for the treatment of pulmonary arterial hypertension (PAH), a chronic and progressive pathophysiological state that might result in death if left untreated. Lipid-core nanocapsules (LNCs) are versatile nanoformulations capable of loading lipophilic drugs for topical, vaginal, oral, intravenous, pulmonary, and nasal administration. Our hypothesis was to load AMB into these nanocapsules (LNC

Topics: Animals; Female; Hypertension, Pulmonary; Lipids; Nanocapsules; Phenylpropionates; Pulmonary Arterial Hypertension; Pyridazines; Rats

We present a 10-year-old boy with syncope who was found to have long-QT syndrome and severe Pulmonary Hypertension (PH) both in the absence of a secondary cause; to our knowledge, this is the first report with this unusual coexistence. His genetic tests were positive for hereditary hemorrhagic telangiectasia and Long QT Syndrome (LQTS) without any family history of PH or LQTS. We demonstrated that digital subtraction pulmonary angiography was more useful compared to CT angiogram to demonstrate pulmonary vascular changes which correlated with a noresponse to acute vasoreactivity testing during right heart catheterization. He has been stable for the last 2 years on Ambrisentan, Sildenafil, and Nadolol without recurrence of symptoms.

Topics: Angiography; Child; Echocardiography; Electrocardiography; Genetic Testing; Humans; Hypertension, Pulmonary; Long QT Syndrome; Male; Nadolol; Phenylpropionates; Pyridazines; Sildenafil Citrate; Syncope; Telangiectasia, Hereditary Hemorrhagic; Tomography, X-Ray Computed

Ambrisentan is a selective endothelin receptor antagonist used for the treatment of pulmonary arterial hypertension (PAH). Little is known about ambrisentan removal by hemodialysis in patients with end-stage renal disease (ESRD).. A 53-year-old woman with HIV/hepatitis C virus (HCV) co-infection, PAH and ESRD on regular hemodialyis was admitted in our hospital due to refractory heart failure while on treatment with bosentan (125 mg twice daily) and tadalafil (20 mg once daily) for PAH and antiretroviral treatment (cART) including darunavir/cobicistat (800/150 mg once daily). Excessive exposure to bosentan due to drug interactions between bosentan and darunavir/cobicistat was suspected. Bosentan was replaced by ambrisentan, with progressive improvement in her clinical condition. Pre- and postdialyzer cocentrations of ambrisentan in plasma were determined and hemodialysis extraction ratio for ambrisentan was 2%.. Our results suggest that hemodialysis results in minimal ambrisentan removal, and therefore no specific ambrisentan dosage adjustment seems to be required in ESRD patients undergoing hemodialysis.

Topics: Antihypertensive Agents; Female; Hemodialysis Solutions; Hepatitis C, Chronic; HIV Infections; Humans; Hypertension, Pulmonary; Kidney Failure, Chronic; Middle Aged; Phenylpropionates; Pyridazines; Renal Dialysis

Topics: Aged; Antihypertensive Agents; Coronary Artery Disease; Female; Fibromuscular Dysplasia; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Sildenafil Citrate; Tadalafil; Vascular Fistula; Vasodilator Agents

Topics: Adult; Antihypertensive Agents; Arrhythmias, Cardiac; Humans; Hypertension, Pulmonary; Male; Myocardial Ischemia; Phenylpropionates; Pyridazines

Topics: Bosentan; Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Insurance Coverage; Japan; Phenylpropionates; Prevalence; Prognosis; Pulmonary Disease, Chronic Obstructive; Pyrazoles; Pyridazines; Pyrimidines; Sildenafil Citrate; Sulfonamides; Treatment Outcome; Universal Health Insurance

Topics: Antihypertensive Agents; Diagnosis, Differential; Dyspnea; Female; Humans; Hypertension, Pulmonary; Middle Aged; Phenylpropionates; Pyridazines; Thrombocytopenia

Sarcoid Associated Pulmonary Hypertension (SAPH) is a common complication of sarcoidosis and is associated with poor prognosis. SAPH can be due to multiple synergistic mechanisms and current therapeutic strategies treat systemic sarcoidosis and pulmonary hypertension separately. Several studies have been performed to develop an effective therapy for SAPH but have been met with mixed results. The AMBITION trial successfully treated incident patients with pulmonary arterial hypertension (PAH) with the upfront combination of ambrisentan and tadalafil; however combination therapy has not yet been studied in patients with SAPH. Here we report a cohort of patients with newly diagnosed SAPH who were treated with upfront combination therapy per the AMBITION study protocol. We report three subjects with newly diagnosed SAPH who were treated with combination ambrisentan and tadalafil. Baseline hemodynamics were compared with those from surveillance right heart catheterization while on therapy. Mean follow up period was 17 months. Each subject demonstrated clinical and hemodynamic improvement with combination therapy. This series is the first to evaluate upfront combination ambrisentan and tadalafil therapy for treatment of newly diagnosed SAPH. Despite the impressive clinical and hemodynamic improvement, the study is limited by its small size and retrospective nature. While these initial results are promising, further work is needed to fully evaluate this regimen for treatment of SAPH.

Topics: Adult; Aged; Antihypertensive Agents; Arterial Pressure; Drug Therapy, Combination; Endothelin A Receptor Antagonists; Female; Humans; Hypertension, Pulmonary; Lung Transplantation; Male; Middle Aged; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Pulmonary Artery; Pyridazines; Retrospective Studies; Sarcoidosis, Pulmonary; Tadalafil; Treatment Outcome

4-Aminopyridine (4-AP) is a recent treatment indicated to improve walking in patient with multiple sclerosis. We report the first case of pulmonary arterial hypertension (PAH) that we attribute to the use of 4-AP. A 64-year-old woman with multiple sclerosis presented with dyspnea. After excluding other secondary causes of pulmonary hypertension, a diagnosis of severe PAH due to 4-AP was made based on right heart catheterization. History revealed that the dyspnea began with the initiation of 4-AP. After discontinuation of 4-AP therapy and initiation of ambrisentan and tadalafil, dyspnea and pulmonary arterial pressure have improved significantly and one specific PAH treatment was stopped. 4-AP is an outward rectifying potassium channel blocker with a vasoconstrictor effect in animal's pulmonary artery. According to the chronological sequence of events, the lack of other etiology, and its pharmacological plausibility, 4-AP is highly suspected to have induced our patient's PAH.

Topics: 4-Aminopyridine; Antihypertensive Agents; Dyspnea; Female; Humans; Hypertension, Pulmonary; Middle Aged; Multiple Sclerosis; Phenylpropionates; Potassium Channel Blockers; Pyridazines; Tadalafil

Pulmonary arterial hypertension (PAH) is a female predominant disease in which progressive vascular remodeling and vasoconstriction result in right ventricular (RV) failure and death. Most PAH patients utilize multiple therapies. In contrast, the majority of preclinical therapeutic studies are performed in male rats with a single novel drug often markedly reversing disease in the model. We sought to differentiate single drug therapy from combination therapy in female rats with severe disease. One week after left pneumonectomy, we induced PH in young female Sprague-Dawley rats with an injection of monocrotaline (45 mg/kg). Female rats were then randomized to receive combination therapy (ambrisentan plus tadalafil), ambrisentan monotherapy, tadalafil monotherapy, or vehicle. We measured RV size and function on two serial echocardiograms during the development of disease. We measured RV systolic pressure (RVSP) invasively at

Topics: Animals; Antihypertensive Agents; Disease Models, Animal; Drug Therapy, Combination; Echocardiography; Female; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Lung; Monocrotaline; Phenylpropionates; Pneumonectomy; Pulmonary Artery; Pyridazines; Rats; Rats, Sprague-Dawley; Tadalafil; Vascular Remodeling; Vasoconstriction; Ventricular Dysfunction, Right; X-Ray Microtomography

Initial combination therapy with ambrisentan and tadalafil (upfront therapy) offers clinical benefits in pulmonary arterial hypertension (PAH) and reduces the risk of clinical failure compared with monotherapy in naïve patients. The aim of study is to assess the efficacy of a 12-month upfront therapy with ambrisentan and tadalafil in improving haemodynamics in incident PAH patients.. This is a multicentre retrospective analysis of real-world Italian clinical data in 56 patients with newly diagnosed PAH. Clinical evaluations, including demographics, medical history, WHO functional class, 6-min walk distance, and right heart catheterization, were collected from the patients' medical records at baseline and at 12-month follow-up.. At baseline, there were 16, 34, and 6 patients in WHO functional class II, III, and IV, respectively. Over a median follow-up of 12 months, 54 (96%) patients were still alive, 6 (11%) of whom received parenteral prostanoids. Ambrisentan-tadalafil combination was associated with significant improvements in WHO functional class (2.2 ± 0.8 vs. 2.8 ± 0.6, P < 0.001, improved in 29 patients), exercise capacity (395 ± 123 vs. 353 ± 101 m, P = 0.039), N-terminal probrain natriuretic peptide (528 ± 493 vs. 829 ± 620 pg/ml; P = 0.009), and haemodynamics (right atrial pressure 7 ± 4 vs. 9 ± 5 mmHg, P = 0.02; mean pulmonary artery pressure 45 ± 15 vs. 50 ± 13 mmHg, P = 0.03; cardiac index 3.0 ± 1.0 vs. 2.5 ± 0.9 l/min/m, P = 0.001; pulmonary vascular resistance 8 ± 4 vs. 11 ± 6 Wood units, P = 0.001) compared with baseline.. Initial combination therapy with ambrisentan and tadalafil offers clinical benefits and significant haemodynamic improvement in newly diagnosed PAH patients.

Topics: Adult; Aged; Antihypertensive Agents; Drug Therapy, Combination; Female; Humans; Hypertension, Pulmonary; Italy; Male; Middle Aged; Phenylpropionates; Pyridazines; Retrospective Studies; Tadalafil; Treatment Outcome; Vascular Resistance

Pulmonary arterial hypertension (PAH) is an intractable and rare disease and the accumulation of clinical evidence under real-world setting is needed. A post-marketing surveillance for the endothelin receptor antagonist ambrisentan (Volibris tablet) has been conducted by all-case investigation since September 2010. This paper is an interim report on the safety and efficacy of ambrisentan in 702 patients with PAH.. PAH patients aged 15 years or older were subjected to the analysis. The safety analysis by overall cases or stratification of patient backgrounds and the efficacy analysis were investigated.. Regarding patient characteristics, the 702 patients subjected to safety analysis included 543 (77.4%) women and 546 (77.8%) patients at WHO functional class II/III. The mean observational time was 392.7 days. A total of 324 adverse drug reaction (ADR) occurred in 204 (29.1%) patients. Common ADRs (≥ 2%) included anemia (4.6%), peripheral edema (4.1%), headache (3.6%), edema and face edema (2.6% each), abnormal hepatic function (2.3%), and epistaxis (2.1%). There were 82 serious ADRs occurring in 44 (6.3%) patients (385 serious adverse events in 184 (26.2%) patients). Although 11 (1.6%) interstitial lung disease (ILD) cases were reported, all were observed in patients with disease that may contribute to ILD and therefore it is difficult to assess if ambrisentan was associated with these events. There was no difference in safety in relation to the presence/absence of connective tissue disease-related PAH (CTD-PAH) or combination therapy. Among 677 patients subjected to efficacy analysis, those in whom hemodynamic status was determined before and after treatment showed improvement in the mean pulmonary arterial pressure and pulmonary vascular resistance after treatment.. The interim results showed safety consistent with the known profile of ambrisentan in terms of the types and frequencies of ADRs in patients with PAH in real clinical practice, in comparison with previous clinical trials in Japan and the rest of the world. Thus, these results provided another corroboration of the tolerability of ambrisentan and we continue to monitor proper use information via the post-marketing surveillance to ensure any new safety signals are identified in a timely manner (ClinTrial.gov: NCT01406327).

Topics: Adult; Aged; Antihypertensive Agents; Edema; Endothelin Receptor Antagonists; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Japan; Male; Middle Aged; Phenylpropionates; Product Surveillance, Postmarketing; Pyridazines; Research Report; Tablets; Treatment Outcome

Newer endothelin receptor antagonists (ERAs) used to treat patients with pulmonary arterial hypertension (PAH) are associated with fewer drug-drug interactions than bosentan and require less monitoring. This, combined with a pharmacokinetic basis for improved efficacy, means there may be a clinical rationale for changing therapies. However, this can be challenging and few data on its safety in patients with PAH are available.. At the Royal Free Hospital in London, UK, home-based medication transitioning has been standard practice since 2009 to avoid unnecessary hospital visits for patients, unless there is a clinical imperative. In this audit of standard practice we evaluated the consequences of adopting such a strategy when transitioning PAH patients between ERA therapies.. Using a Clinical Nurse Specialist-led, home-based transitioning strategy, 92 patients with PAH were transitioned from bosentan to macitentan or ambrisentan. Observational data were analysed retrospectively. The majority of patients were female with PAH associated with connective tissue disease and their ERA was changed in the hope of improving efficacy. The process was well tolerated with no adverse events associated with the process. Seventeen patients died during the study (macitentan, n = 5; ambrisentan, n = 12). None of the deaths was considered related to ERA treatment. The majority of patients remained clinically stable, based on WHO functional class and exercise capacity.. An established home-based transitioning strategy can be adopted safely for patients with PAH changing ERA therapies. Most patients remained stable and the therapy change was well tolerated.

Topics: Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Pyridazines; Pyrimidines; Retrospective Studies; Sulfonamides; Treatment Outcome

Topics: Angioplasty, Balloon; Cyclic Nucleotide Phosphodiesterases, Type 1; Drug Therapy, Combination; Endarterectomy; Epoprostenol; Genome-Wide Association Study; Hemodynamics; Humans; Hypertension, Pulmonary; Japan; Molecular Targeted Therapy; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Practice Guidelines as Topic; Pulmonary Embolism; Pyridazines; Randomized Controlled Trials as Topic; Registries; Sildenafil Citrate; Tadalafil

There were no significant differences in echocardiogram, WHO-FC, hemodynamics, demographics and liver function at baseline, 1-and 2-year points in both arms. 6MWD in bosentan group was significantly shorter at baseline. But there were no significant differences of 6MWD at 1- and 2-year points.. It is safe for stable PAH patients to transition from ambrisentan to bosentan without hemodynamic or hematologic deterioration.

Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Bosentan; Cardiac Catheterization; Drug Substitution; Echocardiography; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Prospective Studies; Pyridazines; Walk Test; Young Adult

Topics: Administration, Oral; Age Factors; Bosentan; Drug Therapy, Combination; Endothelin Receptor Antagonists; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Pyridazines; Pyrimidines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Tadalafil

Combination therapy with the phosphodiesterase type 5 inhibitors (PDE-5i) sildenafil or tadalafil and the endothelin receptor antagonists (ERA) bosentan, ambrisentan, or macitentan may cause mutual pharmacokinetic interactions in patients with pulmonary arterial hypertension (PAH).. The objective of this study was to analyze plasma drug concentrations in PAH patients receiving different combination treatments.. PAH patients receiving a stable combination treatment with ERA and PDE-5i with targeted dosage for at least 1 month were routinely assessed, including clinical parameters and plasma drug concentrations. Concentrations were normalized considering dose and time from last medication intake and presented as multiples of the expected mean (MoM) of the respective monotherapies.. A total of 125 PAH patients (84 female, 41 male, 57% idiopathic/heritable) were included. Sildenafil and tadalafil concentrations were lowest in combination with bosentan (MoM 0.44 ± 0.42, 95% confidence interval [CI] 0.30-0.57, and MoM 0.89 ± 0.53, 95% CI 0.50-1.28, respectively) compared to the combination with ambrisentan (MoM 1.3 ± 0.97, 95% CI 0.86-1.73, and MoM 1.67 ± 0.63, 95% CI 1.40-1.94, respectively) and macitentan (MoM 1.16 ± 0.87, 95% CI 0.86-1.46, and MoM 1.59 ± 0.99, 95% CI 0.80-2.38, respectively). The combination of sildenafil and bosentan led to more than twice the expected bosentan concentrations in 53.8%. Patients switching from sildenafil-bosentan to macitentan showed a significant increase in sildenafil concentrations (p < 0.001).. Only the combination with macitentan or ambrisentan led to targeted mean PDE-5i plasma concentrations and should therefore be preferred to combination with bosentan. Sildenafil-bosentan showed the strongest interaction, with low sildenafil and high bosentan concentrations. The study was not powered to analyze whether lower PDE-5i concentrations cause unsatisfying clinical response. However, plasma concentrations within a targeted range are desirable and may become of increasing importance.

Topics: Adult; Aged; Bosentan; Case-Control Studies; Drug Interactions; Drug Therapy, Combination; Endothelin Receptor Antagonists; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Pyridazines; Pyrimidines; Sildenafil Citrate; Sulfonamides; Tadalafil

The VOLibris Tracking (VOLT) Study was an open-label, prospective, observational, multicenter, post-marketing registry program designed to more fully characterize the safety profile of ambrisentan for the treatment of pulmonary arterial hypertension (PAH). The key outcome was the incidence of aminotransferase elevations >3× the upper limit of normal (ULN).. In total, 999 patients from 115 centers in 15 countries, who were prescribed ambrisentan for the treatment of PAH (Functional Class II and III) between 30 June 2008 and 13 May 2011, were enrolled. Of these, 238 had PAH associated with connective tissue disease (PAH-CTD) and 220 had no prior PAH-specific therapy. Routine clinical monitoring data were collected by physicians.. The incidence of both alanine and aspartate aminotransferase events (>3× ULN) was 0.02 per patient-year (95% confidence interval 0.015 to 0.027). Similar results were reported for the PAH-CTD and PAH-specific-therapy-naive subgroups. Overall, 514 (52%) patients reported treatment-emergent adverse events of special interest, most commonly edema/fluid retention (249, or 25%) and anemia (143, or 14%).. Data from the VOLT study indicate no new ambrisentan-related safety signals. Ambrisentan was not associated with increases in liver function test abnormalities above the assumed background incidence of 1.5% per year, and the observed safety profile of ambrisentan was consistent with previously published data.

Topics: Adult; Aged; Antihypertensive Agents; Female; Hospitalization; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Product Surveillance, Postmarketing; Prospective Studies; Pyridazines; Registries; Transaminases; Treatment Outcome

Endothelin receptor antagonists are approved for pulmonary arterial hypertension. Development of selective ET. Human isolated pulmonary (i.d. 5.5mm) and human radial (i.d. 3.23mm) artery ring segments were mounted in organ baths for isometric force measurement. Single concentration-contraction curves to endothelin-1 were constructed in the absence or presence of bosentan (1-10µM), macitentan (0.03-0.3µM) or ambrisentan (0.1-1µM).. All 3 endothelin antagonists caused competitive rightward shifts in the endothelin-1 concentration-response curves in both arteries. The Clark plot and analysis gave the following pK. Noting the maximum plasma levels attained from recommended oral doses of each antagonist in volunteers, the pK

Topics: Bosentan; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Phenylpropionates; Pulmonary Artery; Pyridazines; Pyrimidines; Radial Artery; Receptor, Endothelin A; Sulfonamides; Tissue Survival; Vasoconstriction

Tetralogy of Fallot (TOF) with pulmonary atresia (PA) and multiple aortopulmonary collaterals (MAPCAs) is a rare and severe form of congenital heart disease with poor prognosis. Aortopulmonary collaterals expose pulmonary arterioles to systemic pressure resulting in pulmonary hypertension (PH). To date, reports regarding the role of PH medications in this population are sparse. The objective of this study was to assess the effect of PH medications in patients with TOF, PA and MAPCAs or similar anatomy, with emphasis on symptoms, echocardiography and invasive hemodynamics. A retrospective review was performed for patients at a single tertiary care pediatric center. Twelve of 66 patients were treated with PH medications (18 %), and eight of these patients had adequate follow-up for further analysis. Median age at last follow-up was 6 years (range 1.4-21 years). Median length of therapy with PH medication was 4 years (range 0.3-17 years). PH medications included sildenafil, bosentan, ambrisentan, inhaled treprostinil and prostacyclin infusion. PH therapy was associated with improvement in symptoms in all patients and improvement in PH by hemodynamic measures in the majority of patients. All patients underwent at least one cardiac intervention by catheterization or surgery while taking PH medication. Two patients died from non-PH-related causes. The remaining six patients are alive and remain on PH medication. This review indicates that PH medications are well tolerated by this patient group and provide symptomatic improvement. Further studies are required to determine whether PH medications provide long-term survival benefit for patients with complex congenital heart disease.

Topics: Abnormalities, Multiple; Adolescent; Antihypertensive Agents; Bosentan; Catheterization; Child; Child, Preschool; District of Columbia; Echocardiography; Female; Hemodynamics; Hospitals, Pediatric; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Lung; Male; Phenylpropionates; Pulmonary Artery; Pulmonary Atresia; Pyridazines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Tertiary Care Centers; Tetralogy of Fallot; Young Adult

Topics: Antihypertensive Agents; Drug Approval; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Tadalafil; United States; United States Food and Drug Administration

Topics: Adult; Age Distribution; Aged; Anticoagulants; Bosentan; Chronic Disease; Female; Humans; Hypertension, Pulmonary; Incidence; Latvia; Male; Middle Aged; Phenylpropionates; Prevalence; Pulmonary Embolism; Pyrazoles; Pyridazines; Pyridones; Registries; Rivaroxaban; Sex Distribution; Sildenafil Citrate; Sulfonamides; Vasodilator Agents; Warfarin; Young Adult

Treatment for pulmonary arterial hypertension (PAH) has been underpinned by single-agent therapy to which concomitant drugs are added sequentially when pre-defined treatment goals are not met.This retrospective analysis of real-world clinical data in 97 patients with newly diagnosed PAH (86% in New York Heart Association functional class III-IV) explored initial dual oral combination treatment with bosentan plus sildenafil (n=61), bosentan plus tadalafil (n=17), ambrisentan plus tadalafil (n=11) or ambrisentan plus sildenafil (n=8).All regimens were associated with significant improvements in functional class, exercise capacity, dyspnoea and haemodynamic indices after 4 months of therapy. Over a median follow-up period of 30 months, 75 (82%) patients were still alive, 53 (71%) of whom received only dual oral combination therapy. Overall survival rates were 97%, 94% and 83% at 1, 2 and 3 years, respectively, and 96%, 94% and 84%, respectively, for the patients with idiopathic PAH, heritable PAH and anorexigen-induced PAH. Expected survival rates calculated from the French equation for the latter were 86%, 75% and 66% at 1, 2 and 3 years, respectively.Initial combination of oral PAH-targeted medications may offer clinical benefits, especially in PAH patients with severe haemodynamic impairment.

Topics: Adult; Aged; Antihypertensive Agents; Bosentan; Diethylpropion; Drug Therapy, Combination; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Patient Safety; Phenylpropionates; Pyridazines; Retrospective Studies; Severity of Illness Index; Sildenafil Citrate; Sulfonamides; Tadalafil; Time Factors; Treatment Outcome

Pulmonary arterial hypertension (PAH) is a known risk factor of perioperative complications, but the risks for non-cardiac operations have not yet been examined sufficiently. We report a case of a right lower lobectomy in a patient with PAH. A 73-year-old woman with Sjögren's syndrome was scheduled for right lowr lobectomy for primary lung cancer under general anesthesia. She was diagnosed with symptomatic PAH (estimated mean pulmonary arterial pressure, 40 mmHg) and medicated with ambrisentan. After induction of general anesthesia with propofol and fentanyl, a pulmonary artery catheter was placed to measure pulmonary artery pressure. The Pp/Ps was roughly 0.4 and the pulmonary artery clamp elevated it to 0.5. Milrinone administration gradually improved the Pp/Ps to 0.3. To avoid pulmonary artery pressure elevation during emergence of anesthesia, continuous dexmedetomidine was administered. The double-lumen tracheal tube was extubated uneventfully with minimal elevation in pulmonary arterial pressure.

Topics: Aged; Anesthesia; Dexmedetomidine; Female; Fentanyl; Humans; Hypertension, Pulmonary; Lung Neoplasms; Phenylpropionates; Pneumonectomy; Propofol; Pyridazines

Pulmonary arterial hypertension (PAH) is characterized by obstructive lesions and vasoconstriction of the pulmonary arteries. Early therapeutic interventions with vasodilator drugs are thought to be beneficial in PAH. However, it remains unknown whether the severity of intimal obstruction is associated with increased pulmonary arterial pressure and whether reduction of vasoconstriction in the earlier stage by these drugs has a beneficial effect. Therefore, the aims of this study were to investigate these issues in a rat model of severe PAH. Methods A rat model of severe PAH was created by injection of a vascular endothelial growth factor receptor blocker in combination with hypoxia for the first 3 weeks followed by normoxia for the next 9 weeks. To assess intimal obstruction, "the pulmonary artery occlusion index (PAOI)" was developed to digitize all lesions. The small pulmonary arteries were assessed by this index, and the association between right ventricular systolic pressure (RVSP) and PAOI was investigated. An endothelin receptor antagonist, ambrisentan, was administered by gavage to rats during either hypoxia (Prevention study group, n=25) or normoxia (Early treatment group, n=15).. PAOI showed a positive correlation with RVSP, and both RVSP and PAOI increased gradually over time. There were no severe occlusive lesions in either group, but the density of partially occlusive lesions was significantly decreased in the Prevention study group.. A novel PAOI index was developed, and this index was strongly correlated with RVSP. Furthermore, ambrisentan reduced luminal occlusive lesions more effectively when treatment was given during the first 2 weeks of hypoxia.

Topics: Animals; Antihypertensive Agents; Disease Models, Animal; Hemodynamics; Hypertension, Pulmonary; Male; Phenylpropionates; Pyridazines; Rats; Rats, Sprague-Dawley; Tunica Intima; Vascular Remodeling

Adult onset of Still's disease (AOSD) is a rare systemic inflammatory disease. Cardiorespiratory complications are mainly represented by pleural and pericardial disorders and are less frequent than cutaneous and articular complaints. Pulmonary arterial hypertension (PAH) occurring in AOSD is rarely described in literature.. We present the case of a young patient who developed severe PAH 2 years after diagnosis of AOSD. This is a rare and severe complication which is probably underestimated.. PAH in AOSD can be lethal, and unfortunately its occurrence is unpredictable. Echocardiographic screening of AOSD patients should be evaluated in further trials. Currently, the most suitable treatment is still unknown.

Topics: Adrenal Cortex Hormones; Adult; Antihypertensive Agents; Antirheumatic Agents; Echocardiography; Female; Humans; Hypertension, Pulmonary; Interleukin 1 Receptor Antagonist Protein; Phenylpropionates; Pyridazines; Still's Disease, Adult-Onset; Tadalafil; Tomography, X-Ray Computed; Young Adult

Sarcoidosis is a pleomorphic disease that can present with pulmonary hypertension (PH). What little information is available about the association of these two diseases comes mainly from small series of patients scheduled for transplant. We present 4 cases of mild pulmonary involvement in whom right catheterisation was performed and PH-specific therapy was administered. After obtaining written consent, a genetic study was performed that showed mutations in PH-related genes in 3 of the patients. This is the first study of its kind to yield genetic information for this type of PH.

Topics: Bone Morphogenetic Protein Receptors, Type II; Bosentan; Disease Progression; Epoprostenol; Fatal Outcome; Female; Humans; Hypertension, Pulmonary; Kv1.5 Potassium Channel; Male; Middle Aged; Mutation; Phenylpropionates; Point Mutation; Pyridazines; Respiratory Function Tests; RNA, Messenger; Sarcoidosis; Sildenafil Citrate; Sulfonamides; Tadalafil; Treatment Outcome

Previous studies examining the use of pulmonary arterial hypertension (PAH) drugs in patients with Eisenmenger syndrome (ES) have shown that it may have beneficial effects in some patients with ES; however, experience with additional cases is necessary to confirm its efficacy and appropriate clinical use. We herein report our experience of an adult patient with ES who benefitted from treatment with PAH drugs. A 32-year-old Japanese man with severe ES induced by a ventricular septal defect associated with Down syndrome began treatment with bosentan at 62.5 mg. Eleven months later, he was admitted for tadalafil (40 mg) add-on therapy because his 6-minute walking distance and brain natriuretic peptide (BNP) level had not improved and his hepatic enzyme levels had increased. However, marked hypotension developed, and the tadalafil dose was decreased. His BNP level subsequently increased, so the bosentan dose was increased to 125 mg. The bosentan was then abruptly stopped because of a low platelet count and high liver enzyme levels. Ambrisentan was then administered for these side effects, but because severe dyspnea developed, the bosentan was started again at 62.5 mg. This resulted in immediate clinical improvement. The patient was finally switched to ambrisentan (5 mg), which was well tolerated. The findings in this particular case show that although it should be used with caution, bosentan may be beneficial in select patients with ES. In addition, ambrisentan may be considered as first-line treatment in some patients as long as liver enzymes and platelets are carefully monitored.

Topics: Adult; Antihypertensive Agents; Bosentan; Down Syndrome; Eisenmenger Complex; Endothelin Receptor Antagonists; Heart Septal Defects, Ventricular; Humans; Hypertension, Pulmonary; Male; Phenylpropionates; Pyridazines; Sulfonamides

Recent vasodilating drugs have improved prognosis of Pulmonary arterial hypertension (PAH). Some reports describe the merits of combination therapies for PAH, and this study evaluated the efficacy and safety of phosphodiesterase type 5 inhibitors (PDE5i) combination therapy, using sildenafil and tadalafil, for multi-drug-resistant PAH.. We retrospectively analyzed 7 consecutive refractory patients with PAH administered either sildenafil 60 mg or tadalafil 40 mg as well as both ERA and prostanoid as combination therapies. All were started on the dual PDE5i (sildenafil and tadalafil at maximum dose).. Treatment was generally well tolerated without severe adverse events. On completion of the study, the seven patients received right heart catheterization and the 6-minute walk test (6WMT) 9.6 ± 1.4 months after initiation of the dual PDE5i therapy, showing significant improvements in hemodynamic parameters and exercise tolerance. Mean pulmonary arterial pressure and pulmonary vascular resistance decreased from 47.9 ± 9.7 to 41.7 ± 9.2 mmHg (P = 0.004) and 9.3 ± 2.7 to 6.7 ± 2.9 mmHg (P = 0.018), respectively. Cardiac index and 6MWT also increased from 2.8 ± 0.9 to 3.1 ± 0.8 L/min/m(2) (P = 0.026) and 353 ± 60 to 382 ± 62 m (P = 0.014), respectively.. The findings support dual PDE5i therapy as a new treatment option for refractory PAH.

Topics: Adult; Antihypertensive Agents; Bosentan; Cardiac Catheterization; Drug Therapy, Combination; Endothelin Receptor Antagonists; Epoprostenol; Exercise Test; Female; Humans; Hypertension, Pulmonary; Middle Aged; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Pilot Projects; Prostaglandins; Pulmonary Wedge Pressure; Pyridazines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Tadalafil; Treatment Outcome; Vascular Resistance; Young Adult

Although endothelin receptor antagonists (ERAs) including bosentan and ambrisentan are essential tools for the treatment of pulmonary arterial hypertension (PAH), each agent has a specific adverse effect with non-negligible frequency, ie, liver dysfunction for bosentan and peripheral edema for ambrisentan. These adverse effects often hinder the titration of the doses of ERAs up to the therapeutic levels. Portopulmonary hypertension, which is complicated with liver cirrhosis and successive portal hypertension, is one of the PAHs refractory to general anti-PAH agents because of the underlying progressed liver dysfunction and poor systemic condition. We here present a patient with portopulmonary hypertension, which was treated safely by combination therapy that included low-dose bosentan and ambrisentan, minimizing the adverse effects of each ERA. Combination therapy including different types of ERAs at each optimal dose may become a breakthrough to overcome portopulmonary hypertension in the future.

Topics: Antihypertensive Agents; Bosentan; Combined Modality Therapy; Diagnosis, Differential; Dose-Response Relationship, Drug; Echocardiography; Hemodynamics; Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Cirrhosis; Male; Middle Aged; Phenylpropionates; Pyridazines; Sulfonamides; Treatment Outcome

Hoarseness is a common phenomenon that can be caused by uncommon pathology. One seldom cause is Ortner's syndrome, a rare cardiovocal disease that can lead to hoarseness due to left recurrent laryngeal nerve palsy induced by mechanical compression of the nerve by cardiovascular structures. This case report describes a case of a 41-year-old woman with sudden onset of hoarseness. The patient had known pulmonary hypertension and Eisenmenger's syndrome.

Topics: Adult; Antihypertensive Agents; Cardiac Catheterization; Eisenmenger Complex; Female; Hoarseness; Humans; Hypertension, Pulmonary; Laryngoscopy; Phenylpropionates; Piperazines; Pulmonary Artery; Purines; Pyridazines; Recurrent Laryngeal Nerve; Sildenafil Citrate; Sulfonamides; Syndrome; Tomography, X-Ray Computed; Vocal Cord Paralysis

Scleroderma-associated pulmonary arterial hypertension (SSc-PAH) is a rare disease characterized by a very dismal response to therapy and poor survival. We assessed the effects of up-front combination PAH therapy in patients with SSc-PAH.. In this prospective, multicenter, open-label trial, 24 treatment-naive patients with SSc-PAH received ambrisentan 10 mg and tadalafil 40 mg daily for 36 weeks. Functional, hemodynamic, and imaging (cardiac magnetic resonance imaging and echocardiography) assessments at baseline and 36 weeks included changes in right ventricular (RV) mass and pulmonary vascular resistance as co-primary endpoints and stroke volume/pulmonary pulse pressure ratio, tricuspid annular plane systolic excursion, 6-minute walk distance, and N-terminal pro-brain natriuretic peptide as secondary endpoints.. At 36 weeks, we found that treatment had resulted in significant reductions in median (interquartile range [IQR]) RV mass (28.0 g [IQR, 20.6-32.9] vs. 32.5 g [IQR, 23.2-41.4]; P < 0.05) and median pulmonary vascular resistance (3.1 Wood units [IQR, 2.0-5.7] vs. 6.9 Wood units [IQR, 4.0-12.9]; P < 0.0001) and in improvements in median stroke volume/pulmonary pulse pressure ratio (2.6 ml/mm Hg [IQR, 1.8-3.5] vs. 1.4 ml/mm Hg [IQR 8.9-2.4]; P < 0.0001) and mean ( ± SD) tricuspid annular plane systolic excursion (2.2 ± 0.12 cm vs. 1.65 ± 0.11 cm; P < 0.0001), 6-minute walk distance (395 ± 99 m vs. 343 ± 131 m; P = 0.001), and serum N-terminal pro-brain natriuretic peptide (647 ± 1,127 pg/ml vs. 1,578 ± 2,647 pg/ml; P < 0.05).. Up-front combination therapy with ambrisentan and tadalafil significantly improved hemodynamics, RV structure and function, and functional status in treatment-naive patients with SSc-PAH and may represent a very effective therapy for this patient population. In addition, we identified novel hemodynamic and imaging biomarkers that could have potential value in future clinical trials. Clinical trial registered with www.clinicaltrials.gov (NCT01042158).

Topics: Drug Therapy, Combination; Female; Heart Ventricles; Humans; Hypertension, Pulmonary; Magnetic Resonance Imaging; Male; Middle Aged; Natriuretic Peptide, Brain; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Prospective Studies; Pyridazines; Scleroderma, Systemic; Stroke Volume; Tadalafil; Ultrasonography; Vascular Resistance

Endothelin receptor antagonists (ERA) and phosphodiesterase 5 inhibitors (PDE5I) are long-term therapeutics for the treatment of pulmonary arterial hypertension (PAH). Their interindividual pharmacokinetic variability is remarkably large, and despite the seriousness of the disease, nonadherence is occurring. Therefore, methods to monitor sufficient circulating drug levels are essential. The objectives of this study were to develop and validate dried blood spot (DBS) assays for the quantification of ambrisentan, bosentan, sildenafil, tadalafil, and their main metabolites. We also quantified the influence of different hematocrit levels and assessed the correlation of simultaneously taken capillary whole blood (DBS) and venous plasma samples. The aliquot punches were extracted by liquid/liquid extraction followed by liquid chromatography/tandem mass spectrometry (LC/MS/MS) quantification methods. All assays fulfilled the requirements of the FDA and EMA guidelines for assay validation with a lower limit of quantification of 2.5 ng/mL for the ERAs, 5 ng/mL for sildenafil, and 10 ng/mL for tadalafil. All analytes were stable for at least 147 days when stored on DBS filter paper cards at room temperature in the dark. Due to poor distribution into erythrocytes, drug concentrations in DBS were always lower than in plasma, resulting in conversion factors of 1.58 for ambrisentan and sildenafil and 1.52 for bosentan and tadalafil.

Topics: Bosentan; Chromatography, Liquid; Dried Blood Spot Testing; Humans; Hypertension, Pulmonary; Limit of Detection; Phenylpropionates; Pyridazines; Reproducibility of Results; Sildenafil Citrate; Sulfonamides; Tadalafil; Tandem Mass Spectrometry

A simultaneous, selective, sensitive, and rapid liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of bosentan, ambrisentan, sildenafil, and tadalafil in 50μL of human blood plasma. Diluted plasma samples were extracted using a solid-phase extraction procedure with 2% formic acid and methanol. The four drugs were separated by high-performance liquid chromatography using a C18 column and an isocratic mobile phase running at a flow rate of 0.2mL/min for 5min. The drugs were detected by a tandem mass spectrometer with electrospray ionization using deuterated compounds as internal standards. Calibration curves were generated over the linear concentration range of 2-1000ng/mL in plasma with a lower limit of quantification of 2ng/mL for all compounds. Finally, this validated method was applied to a clinical pharmacokinetic study in pediatric patients with pulmonary arterial hypertension (PAH) following the oral administration of PAH drugs. These results indicate that this method is suitable for assessing the risk/benefit of combination therapy in the pediatric population and useful for therapeutic drug monitoring for PAH treatment.

Topics: Bosentan; Carbolines; Child; Child, Preschool; Chromatography, Liquid; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Infant; Male; Phenylpropionates; Piperazines; Purines; Pyridazines; Sildenafil Citrate; Sulfonamides; Sulfones; Tadalafil; Tandem Mass Spectrometry

Recent clinical trials in pulmonary arterial hypertension have included World Health Organization functional classes I and II patients. However, the impact of baseline functional class and other measures of severity on outcomes has not been evaluated in detail.. Outcomes at 12 weeks for patients grouped by functional class, haemodynamics, brain natriuretic peptide (BNP) level and 6-min walk distance (6MWD) were evaluated for patients in the Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter Efficacy Study 1 and 2 (ARIES)-1 and 2 pivotal trials of ambrisentan, a once-daily oral endothelin-1 antagonist. Long-term outcomes in the ARIES-E extension study were also evaluated.. At 12 weeks, ambrisentan-treated patients with both early and late functional class showed similar improvement in 6MWD relative to placebo. However, patients with more severe disease tended to have greater improvement in 6MWD after grouping by other measures of severity. This included higher baseline BNP level, shorter baseline 6MWD and more severe baseline haemodynamics (p < 0.05 for BNP and p = NS for other comparisons, analysed as interaction terms). During long-term open label follow-up, maintenance of 6MWD improvement, freedom from clinical worsening and survival were also numerically worse for patients who were functional class III/IV at baseline.. Patients with both less severe and more severe PAH benefited from ambrisentan therapy vs. placebo in 12-week clinical trials and during long-term follow up, but greater improvement vs. placebo was seen for those with higher BNP levels.

Topics: Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Phenylpropionates; Pyridazines; Randomized Controlled Trials as Topic; Research Design; Severity of Illness Index; Survival Analysis; Treatment Outcome

Topics: Carbolines; Endothelin Receptor Antagonists; Female; Humans; Hypertension, Pulmonary; Male; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Pyridazines; Tadalafil

Topics: Adult; Anticoagulants; Antihypertensive Agents; Drug Interactions; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenprocoumon; Phenylpropionates; Prospective Studies; Pyridazines; Retrospective Studies

Topics: Cardiac Catheterization; Ductus Arteriosus, Patent; Endothelin Receptor Antagonists; Female; Humans; Hypertension, Pulmonary; Middle Aged; Phenylpropionates; Pyridazines; Radiography; Septal Occluder Device; Severity of Illness Index; Ultrasonography

Pulmonary arterial hypertension (PAH) is characterized by elevations in the pulmonary arterial pressure and the vascular resistance in pulmonary placenta. One of the kinds of the pulmonary hypertension is the idiopathic arterial pulmonary hypertension, which etiology is not known. Below we present the case of 51 year old woman with idiopathic arterial pulmonary hypertension. Due to worsening shortness of breath occurring at night and heart palpitations, the noninvasive and invasive diagnostics were conducted. The diagnostics have shown a dilatation of the right atrium and ventricle, widening of the pulmonary vessels with the pressure in the pulmonary artery 108 mmHg, and moderate regurgitation of tricuspid valve and pulmonary artery. In spite of the treatment, increasing right sided heart failure was the cause of patient's further hospitalization. After the introduction of Ambrisentan therapy, her condition has improved. She waited for a lung transplant. The last exacerbation of ascites was probably a result of the cessation of the use of the above mentioned drug. Then there was a sudden cardiac arrest and, despite of the treatment the patient has died.

Topics: Echocardiography; Electrocardiography; Familial Primary Pulmonary Hypertension; Fatal Outcome; Female; Heart Arrest; Humans; Hypertension, Pulmonary; Middle Aged; Patient Compliance; Phenylpropionates; Pyridazines

To investigate long-term efficacy and safety of ambrisentan monotherapy in patients with pulmonary arterial hypertension (PAH).. Patients with PAH who received 2.5 mg or 5 mg of ambrisentan once daily between July 10, 2011 and August 30, 2012 for at least 6 months were enrolled. The efficacy endpoints were change in exercise capacity, World Health Organization (WHO) functional class and N-terminal pro-brain natriuretic peptide (NT-proBNP) level, echocardiographic parameters. The safety endpoint was the safety of long-term ambrisentan administration, as defined by the incidence and severity of adverse events.. A total of 18 patients with PAH were enrolled. Mean age was (39 ± 17) years, 8 (55.6%) were female, and 11 (61.1%) patients were in WHO functional class III. The median duration of treatment was 17 months (range: 6-26 months). After treatment, the 6MWD was significantly increased[ (495 ± 97) m vs. (400 ± 91) m, P < 0.001], NT-proBNP was significantly reduced [308 (53-1 645) ng/L vs. 80(22-454) ng/L, P = 0.005], the systolic pulmonary artery was significantly decreased [(62 ± 30) mmHg vs. (82 ± 41) mmHg, P = 0.001] and left ventricular end diastolic diameter was significantly increased [(44 ± 6) mm vs. (40 ± 6) mm, P < 0.004] compared to pre-treatment. WHO functional class was improved compared with baseline in 11(61.1%) patients, stable in 7(38.9%) patients. No patient died during the treatment period. No patient was withdrawn from this study for safety reasons.. Long-term treatment of ambrisentan can effectively improve the exercise capacity, reduce systolic pulmonary artery pressure and NT-proBNP in PAH patients. Ambrisentan is safe and well tolerated in Chinese PAH patients.

Topics: Adult; Blood Pressure; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Phenylpropionates; Pyridazines; Treatment Outcome; Young Adult

Interferon-alpha treatment is a rare cause of pulmonary arterial hypertension (PAH). We report a case of a 43-year-old man treated for chronic hepatitis C infection complicated by decompensated right heart failure diagnosed with PAH and external coronary artery compression secondary to a dilated pulmonary trunk. The novel complication of extrinsic coronary artery compression should be considered in PAH patients presenting with chest pain or acute coronary syndrome. Establishing a diagnosis has clinical value as pulmonary vasodilator therapy may improve symptoms.

Topics: Adult; Antiviral Agents; Chest Pain; Coronary Stenosis; Hepatitis C, Chronic; Humans; Hypertension, Pulmonary; Interferon-alpha; Male; Phenylpropionates; Pulmonary Artery; Pyridazines; Treatment Outcome; Vasodilator Agents

Endothelin receptor antagonists (ETRAs), authorized for pulmonary hypertension, have failed to prove their utility in chronic lung diseases with corticosteroid-resistant airway inflammation when applied at late disease stages with emphysema/fibrosis. Earlier administration might prove effective by targeting the interaction between airway inflammation and tissue remodeling. We hypothesized that human airway smooth muscle cells (HASMCs) participate in linking inflammation with remodeling and that associated genes become differentially suppressed by ambrisentan (A-receptor selective ETRA) and bosentan (nonselective/dual ETRA). Inflammatory responses of ex vivo-cultivated HASMCs to TNF-α were investigated by whole-genome microarray analyses. qRT-PCR and ELISA were used to test inflammatory and remodeling genes for sensitivity to bosentan and ambrisentan and to investigate differential sensitivities mechanistically. ETRA and corticosteroid effects were compared in HASMCs from patients with chronic obstructive pulmonary disease. TNF-α induced the expression of 18 cytokines/chemokines and five tissue remodeling genes involved in severe, corticosteroid-insensitive asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and/or pulmonary hypertension. Thirteen cytokines/chemokines, MMP13, and WISP1 were suppressed by ETRAs. Eight genes had differential sensitivity to bosentan and ambrisentan depending on the endothelin-B receptor impact on transcriptional regulation and mRNA stabilization. Chemokine (C-C motif) ligands 2 and 5, granulocyte macrophage colony-stimulating factor, and MMP13 had increased sensitivity to bosentan or bosentan/dexamethasone combination versus dexamethasone alone. Suppression of cytokine and remodeling gene expression by ETRAs was confirmed in TNF-α-activated human bronchial epithelial cells. HASMCs and human bronchial epithelial cells participate in the interaction of inflammation and tissue remodeling. This interaction is targeted differentially by selective and nonselective ETRAs, which could be used in therapies of chronic lung diseases with corticosteroid-resistant airway inflammation at early disease stages to attenuate inflammation-induced airway remodeling.

Topics: Airway Remodeling; Bosentan; Chemokines; Endothelin Receptor Antagonists; Gene Expression Regulation; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Hypertension, Pulmonary; Inflammation; Matrix Metalloproteinase 13; Myocytes, Smooth Muscle; Oligonucleotide Array Sequence Analysis; Phenylpropionates; Pulmonary Disease, Chronic Obstructive; Pyridazines; Receptors, Endothelin; RNA Stability; RNA, Messenger; Sulfonamides; Transcription, Genetic; Tumor Necrosis Factor-alpha

Combined pulmonary fibrosis and emphysema (CPFE) is a computed tomography (CT)-defined syndrome of combined pulmonary fibrosis and emphysema, characterized by subnormal spirometry, impairment of gas exchange, and high prevalence of pulmonary hypertension. Although endothelin-1 (ET-1) plays an important role in the development of lung fibrosis as well as in pulmonary hypertension, no ET-1-targeted therapy is currently recommended. Here we report a case of CPFE successfully treated with ambrisentan, an endothelin-A receptor antagonist, and also discuss the biologic mechanisms underlying the observed therapeutic effects. A 79-year-old man with chronic obstructive pulmonary disease (COPD) was referred to our respiratory unit as an outpatient for dyspnea. Clinical, radiologic, and laboratory findings suggested a diagnosis of chronic hypoxemic, type 1 respiratory failure, due to combined pulmonary fibrosis and emphysema, complicated by severe, precapillary pulmonary hypertension. Pharmacologic treatment with ambrisentan induced an initial improvement in clinical symptoms that proved to be very relevant 9 months later. In order to investigate the biologic mechanisms underlying the clinical effects of ambrisentan, we performed an "in vitro" study on primary cultures of fibrotic human lung fibroblasts, as well as on human umbilical vein endothelial cells, incubated for 24 and 48 h with ET-1, in the absence or presence of an overnight treatment with ambrisentan. ET-1 significantly increased cell proliferation and mitogen-activated protein kinase activation (P < 0.01). These effects were significantly (P < 0.01) inhibited by ambrisentan in both cell cultures. In conclusion, we hypothesize that the clinical benefits induced by ambrisentan in this patient with CPFE can be attributed to its vasodilator and anti-proliferative actions, exerted on pulmonary the vascular bed and lung fibroblasts.

Topics: Aged; Emphysema; Endothelin A Receptor Antagonists; Endothelin-1; Human Umbilical Vein Endothelial Cells; Humans; Hypertension, Pulmonary; Male; Phenylpropionates; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Pyridazines; Severity of Illness Index; Tomography, X-Ray Computed; Treatment Outcome

Combined idiopathic pulmonary fibrosis (IPF) with pulmonary emphysema (CPFE) is a syndrome with a characteristic presentation of upper lobe emphysema and lower lobe fibrosis. While CPFE is a strong determinant of secondary precapillary pulmonary hypertension (PH), there is limited evidence regarding the management of patients with CPFE and PH.. A 63 year-old male presented in 2006 with dyspnoea on exertion having quit smoking in 2003. Clinical examination, together with high resolution computed tomography, bronchoalveolar lavage, and echocardiographic assessments, suggested a diagnosis of CPFE without PH. In 2007, the patient received intravenous cyclophosphamide, N-acetylcysteine, and short-term anticoagulation treatment. Due to remission of acute exacerbations, the patient received triple combination therapy (prednisone, N-acetylcysteine and azathioprine). Upon progressive clinical worsening, long-term supplemental oxygen therapy was initiated in 2009. Repeated right heart catheterisation in 2011 confirmed PH and worsening pulmonary haemodynamics, and off-label ambrisentan therapy was initiated. Dyspnoea remained at follow-up, although significant haemodynamic improvement was observed.. CFPE is a distinct but under-recognized and common syndrome with a characteristic presentation. Further studies are needed to ascertain the etiology, morbidity, and mortality of CPEF with or without PH, and to evaluate novel management options.

Topics: Acetylcysteine; Azathioprine; Disease Management; Humans; Hypertension, Pulmonary; Lung; Male; Middle Aged; Oxygen Inhalation Therapy; Phenylpropionates; Prednisolone; Pulmonary Emphysema; Pulmonary Fibrosis; Pyridazines; Radiography; Smoking

Idiopathic pulmonary arterial hypertension (IPAH), formerly called primary pulmonary hypertension, is a rare disease (incidence and prevalence rates of approximately one and six cases per million inhabitants, respectively) with different clinical phenotypes. A group of diverse conditions manifest pulmonary arterial hypertension (PAH) and share similar pathological and/or clinical findings with IPAH. By definition, IPAH is diagnosed only after alternative diagnoses have been ruled out. Extensive investigation is needed to determine if PAH is associated with thyroid diseases, infectious diseases, autoimmune conditions, exposure to certain drugs (particularly anorexigens), certain genetic mutations, and so on. The presence of genetic abnormalities and risk factors (such as specific drug exposures) reinforces the "multiple hit" concept for the development of pulmonary hypertension. Fortunately, within the past two decades, therapeutic options have become available for IPAH, resulting in improved survival and clinical outcomes. At least seven different compounds have been registered for PAH treatment. However, even with aggressive PAH-specific therapy, mortality rates remain high (∼40% at 5 years). Given the high mortality rates, the use of combinations of agents that work by different pathways has been advocated (either as "add-on" therapy or initial "up front" therapy). Further, new therapeutic agents and treatment strategies are on the near horizon, aiming to further improve survival from the remarkable progress already seen.

Topics: Aminorex; Antihypertensive Agents; Appetite Depressants; Bosentan; Dasatinib; Epoprostenol; Familial Primary Pulmonary Hypertension; Fenfluramine; Genetic Predisposition to Disease; Humans; Hypertension, Pulmonary; Iloprost; Phenylpropionates; Piperazines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyridazines; Pyrimidines; Risk Factors; Sildenafil Citrate; Sulfonamides; Sulfones; Thiazoles; Vasodilator Agents

Pulmonary hypertension (PH) may complicate connective tissue disease (CTD), particularly systemic sclerosis (SSc, scleroderma), and markedly increases mortality. More than 70% of cases of PH complicating CTD occur in SSc, which is the major focus of this article. Pulmonary complications (i.e., interstitial lung disease [ILD] and PH) are the leading causes of scleroderma-related deaths. "Isolated" PH (i.e., without ILD) complicates SSc in 7.5 to 20% of cases; secondary PH may also occur in patients with SSc-associated ILD. Several clinical markers and specific autoantibody profiles have been associated with PH in SSc. The role of PH-specific therapy is controversial, as prognosis and responsiveness to therapy are worse in SSc-associated PH compared with idiopathic pulmonary arterial hypertension. We discuss medical therapies for CTD-associated PH and the role of lung transplantation for patients failing medical therapy.

Topics: Antihypertensive Agents; Bosentan; Connective Tissue Diseases; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Lung Transplantation; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Prognosis; Pyridazines; Scleroderma, Systemic; Sulfonamides

Topics: Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Phenylpropionates; Pyridazines; Receptors, Endothelin

Recent trials in adult PAH revealed the efficacy of ambrisentan. However, in children with PAH, the clinical safety and pharmacokinetics of ambrisentan has not been well studied. Our aim was to investigate the clinical safety, pharmacokinetics, tolerability, and efficacy of endothelin receptor antagonist therapy with ambrisentan in children with pulmonary arterial hypertension (PAH). This retrospective cohort study provides clinical data from pediatric patients with PAH receiving ambrisentan as add-on therapy or transition from bosentan. Safety included evaluation of adverse events including aminotransferase abnormalities. The clinical impact was evaluated by improvement from baseline in clinical variables. A total of 38 pediatric patients with PAH received ambrisentan. Fifteen of 38 patients were switched from bosentan to ambrisentan. The remaining 23 children were treated with ambrisentan as an add-on therapy due to disease progression. In both transition and add-on cases, mean pulmonary artery pressure significantly improved (transition; 55 ± 18 vs. 45 ± 20 mmHg, n = 13, P = 0.04, add-on; 52 ± 17 vs. 45 ± 19 mmHg, n = 13, P = 0.03) during the follow-up. World Health Organization functional class improved in 31% of patients, but one patient required an atrial septostomy due to disease progression during the follow-up period (median, range; 20, 4-44 months). Five patients (13%) discontinued ambrisentan due to severe headache, lack of clinical efficacy, or near syncope. Ten patients (26%) had side effects associated with ambrisentan treatment, including nasal congestion, headache, and flushing. However, no patients had aminotransferase abnormalities and there were no deaths after initiation of ambrisentan during follow-up. Pharmacokinetics were evaluated in sixteen children treated with ambrisentan from 2.5 mg to 10.0 mg; the mean peak plasma concentration was 738 ± 452 ng/ml, mean time to peak plasma concentration was 3.2 ± 2.1 hours, and mean area under the curve plasma concentration was 6657 ± 4246 ng·hour/ml. In conclusion, initial experience with ambrisentan in children suggests that treatment is safe with similar pharmacokinetics to those in adults and may improve PAH in some children.

Topics: Adolescent; Antihypertensive Agents; Bosentan; Child; Child, Preschool; Cohort Studies; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Phenylpropionates; Pyridazines; Retrospective Studies; Sulfonamides

Six-minute walk distance (6MWD) and brain natriuretic peptide (BNP) levels at baseline and after initiation of treatment have been associated with survival in patients with pulmonary arterial hypertension. Our objective was to determine the individual and additive ability of pretreatment and posttreatment 6MWD and BNP to discriminate 2-year survival in patients with pulmonary arterial hypertension.. We included patients enrolled in two randomized clinical trials of ambrisentan who had 2-year follow-up (N 5 370). 6MWD and BNP were assessed before and after 12 weeks of treatment. Receiver operating characteristic curve analyses were performed to identify optimal cutoffs that defi ned subgroups with a high 2-year mortality. Classifi cation and regression tree analysis was used to determine the incremental prognostic value of combined assessments.. 6MWD at baseline and after 12 weeks of therapy were similarly discriminatory of 2-year survival (c-statistics 5 0.77 [95% CI 0.70-0.84] and 0.82 [95% CI 0.75-0.88], respectively), whereas change in 6MWD from baseline to week 12 was not discriminating. The same observation was true of BNP at baseline and after 12 weeks of therapy (c-statistics 5 0.68 [95% CI 0.60-0.76] and 0.74 [95% CI 0.66-0.82], respectively). After consideration of baseline 6MWD, there was no prognostic information added by the week 12 6MWD or BNP at either time point.. 6MWD and BNP values at baseline or week 12 identifi ed a population with an elevated risk of death at 2 years. A repeat assessment of 6MWD or BNP after 12 weeks of ambrisentan therapy did not provide additional prognostic information beyond that obtained from baseline values.

Topics: Adult; Aged; Antihypertensive Agents; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Kaplan-Meier Estimate; Longitudinal Studies; Male; Middle Aged; Natriuretic Peptide, Brain; Phenylpropionates; Predictive Value of Tests; Prognosis; Pyridazines; Survival Rate; Treatment Outcome; Walking

Maintenance of a favourable hemodynamic profile is central to therapeutic success in pulmonary arterial hypertension (PAH). There is little information about the safety of transitioning patients between oral therapies for PAH. Endothelin receptor antagonists (ERAs) have been a therapeutic mainstay in PAH, providing benefit to many patients. Three ERAs, bosentan, sitaxsentan, and ambrisentan have been approved for clinical use. Sitaxsentan was voluntarily withdrawn from the market in late 2010 resulting in the need to quickly transition a large number of stable patients.. We transitioned 30 clinically stable patients to either ambrisentan or bosentan. Patients underwent a right heart catheterization, measurement of serum N-terminal pro-brain natriuretic peptide (NT-proBNP), and assessment of functional class before changing ERA and again 4 months later. We present a retrospective analysis of those data.. Of the 30 patients transitioned (15 to ambrisentan, 15 to bosentan), 23 had complete hemodynamic data. No significant change was observed in the groups in right atrial, mean pulmonary artery, and pulmonary artery wedge pressures, or in cardiac output, pulmonary vascular resistance, or NT-proBNP levels. There was no change in World Health Organization functional class. Four ambrisentan and 2 bosentan-treated patients reported fluid retention, and 3 bosentan-treated patients had elevation of hepatic transaminases. Two of the patients had a right atrial pressure increase of ≥5 mm Hg, and 4 had pulmonary artery wedge pressure increase of ≥5 mm Hg.. Transitioning between ERAs in stable PAH patients does not result in hemodynamic or clinical deterioration during the first 4 months posttransition. A minority of patients have developed increased cardiac filling pressures.

Topics: Administration, Oral; Aged; Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Isoxazoles; Middle Aged; Phenylpropionates; Pulmonary Wedge Pressure; Pyridazines; Retrospective Studies; Sulfonamides; Thiophenes; Treatment Outcome; Vascular Resistance

Topics: Bosentan; Endothelin Receptor Antagonists; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Isoxazoles; Phenylpropionates; Pulmonary Wedge Pressure; Pyridazines; Sulfonamides; Thiophenes; Vascular Resistance

Portopulmonary hypertension (POPH) is a part of group 1 pulmonary hypertension (pulmonary hypertension associated with portal hypertension). Liver transplantation (LTx) may be curative, but is usually restricted to patients with mild-to-moderate POPH. The presence of severe POPH may be a contraindication to transplantation because of the elevated risk of peritransplantation and post-transplantation morbidity and mortality. This report describes a series of seven patients with onset of moderate (two patients) or severe (five patients) POPH before LTx, of whom six were treated with oral vasodilator therapy for POPH. Although previous studies recommend aggressive parenteral prostacyclin therapy (epoprostenol), we describe the opportunity to treat cases of severe POPH with an oral phosphodiesterase type 5 inhibitor (sildenafil) and/or an endothelin receptor antagonist (bosentan/ambrisentan) as a bridge to successful LTx in selected patients.

Topics: Administration, Oral; Adult; Antihypertensive Agents; Bosentan; Combined Modality Therapy; Exercise Test; Female; Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Transplantation; Male; Middle Aged; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Pyridazines; Sulfonamides; Vasodilator Agents

Ambrisentan, an endothelin receptor type A antagonist, may be a novel therapeutic agent in neonatal chronic lung disease (CLD) by blocking the adverse effects of the vasoconstrictor endothelin-1, especially pulmonary arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH). We determined the cardiopulmonary effects of ambrisentan treatment (1-20 mg·kg(-1)·day(-1)) in neonatal rats with CLD in 2 models: early treatment during continuous exposure to hyperoxia for 10 days and late treatment starting on day 6 in rat pups exposed postnatally to hyperoxia for 9 days, followed by a 9-day recovery period in room air. Parameters investigated included survival, lung and heart histopathology, right ventricular function, fibrin deposition, and differential mRNA expression in the lungs. In the early treatment model, we investigated the role of nitric oxide synthase (NOS) inhibition with N(ω)-nitro-L-arginine methyl ester (L-NAME; 25 mg·kg(-1)·day(-1)) during ambrisentan treatment. In the early treatment model, ambrisentan improved survival with reduced lung fibrin and collagen III deposition, arterial medial wall thickness, and RVH. These changes were not affected by L-NAME administration. Ambrisentan did not reduce the influx of macrophages and neutrophils or prevent reduced irregular elastin expression. In the late treatment model, ambrisentan diminished PAH, RVH, and right ventricular peak pressure, demonstrating that RVH is reversible in the neonatal period. Alveolarization and vascularization were not affected by ambrisentan. In conclusion, ambrisentan prolongs survival and reduces lung injury, PAH, and RVH via a NOS-independent mechanism but does not affect inflammation and alveolar and vascular development in neonatal rats with CLD.

Topics: Animals; Animals, Newborn; Familial Primary Pulmonary Hypertension; Heart; Hyperoxia; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Lung; NG-Nitroarginine Methyl Ester; Phenylpropionates; Pulmonary Alveoli; Pyridazines; Rats; Time Factors

Endothelin receptor antagonists and phosphodiesterase type 5 inhibitors are used to treat pulmonary arterial hypertension. We tested the hypothesis that a selective endothelin type A receptor antagonist (ambrisentan) and a phosphodiesterase type 5 inhibitor (tadalafil) may act synergistically to relax endothelin-constricted pulmonary arteries. Rat isolated intrapulmonary arterial rings contracted with 8 nmol/L endothelin-1 were relaxed by 10 nmol/L ambrisentan and 30 nmol/L tadalafil alone by 26±3% and 21±1%, respectively, whereas both drugs in combination acted synergistically to relax arterial rings by 83±6%. The nonselective endothelin type A and B receptor antagonists bosentan (100 nmol/L) and macitentan (30 nmol/L) alone relaxed endothelin-contracted rings by 30±5% and 24±3%, respectively. Combinations of 30 nmol/L tadalafil with 100 nmol/L bosentan or 30 nmol/L macitentan relaxed endothelin-contracted rings by 53±5% or 46±7%, respectively; these values are similar to the calculated sums of the individual effects of these compounds. Denudation of endothelium from pulmonary arterial rings abolished the vasodilator response to 30 nmol/L tadalafil and the synergistic vasorelaxant effect of tadalafil with ambrisentan. In the presence of 1 μmol/L BQ-788, a selective endothelin type B receptor antagonist, the vasorelaxant effects of 10 nmol/L ambrisentan and 30 nmol/L tadalafil were additive but not synergistic. These data can be interpreted to suggest that ambrisentan and tadalafil synergistically inhibit endothelin-1-induced constriction of rat intrapulmonary arteries and that endothelin type B receptors in endothelium are necessary to enable a synergistic vasorelaxant effect of the drug combination.

Topics: Animals; Blotting, Western; Carbolines; Disease Models, Animal; Drug Synergism; Endothelin-1; Hypertension, Pulmonary; Male; Phenylpropionates; Pulmonary Artery; Pyridazines; Rats; Rats, Sprague-Dawley; Tadalafil; Vasoconstriction; Vasodilator Agents

Topics: Adult; Exercise; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Physical Endurance; Prospective Studies; Pyridazines; Time

Topics: Adult; Aged; Alanine Transaminase; Antihypertensive Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Endothelin A Receptor Antagonists; Endothelins; Female; Humans; Hypertension, Pulmonary; Incidence; Liver; Liver Function Tests; Male; Middle Aged; Phenylpropionates; Pyridazines; Risk Factors; United States

Pulmonary arterial hypertension (PAH) is characterized by an increase in pulmonary vascular resistance, which can lead to right heart failure and death. Endothelin-1 binding ETA and ETB receptors seem to play a critical role in the pathogenesis and progression of the disease, and oral endothelin receptor antagonists (ERAs) have been shown to be an effective treatment. Bosentan and ETA-selective ambrisentan are the ERAs currently available for PAH treatment.. On the basis of the analysis of the literature, this paper addresses the efficacy and safety of ambrisentan in the treatment for PAH.. Ambrisentan has shown an efficacy comparable with other ERAs. Compared with bosentan, ambrisentan seems to have a better safety profile with regards to hepatic safety and drug-drug interactions. On the other hand, ambrisentan shows a higher rate of other adverse events, such as nasal congestion and peripheral edema. Ambrisentan is a viable option for PAH treatment. However, there is still a need for more robust data about long-term mortality, treatment in non-PAH pulmonary hypertension (PH) (such as PH due to left heart disease and PH due to chronic hypoxic lung diseases) and combination therapy.

Topics: Animals; Antihypertensive Agents; Bosentan; Disease Progression; Drug Interactions; Endothelin A Receptor Antagonists; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Receptor, Endothelin B; Sulfonamides

Two endothelin receptor antagonists (ERAs), bosentan and ambrisentan, are currently approved for the treatment of pulmonary arterial hypertension (PAH), a devastating disease involving an activated endothelin system and aberrant contraction and proliferation of pulmonary arterial smooth muscle cells (PASMC). The novel ERA macitentan has recently concluded testing in a Phase III morbidity/mortality clinical trial in PAH patients. Since the association and dissociation rates of G protein-coupled receptor antagonists can influence their pharmacological activity in vivo, we used human PASMC to characterize inhibitory potency and receptor inhibition kinetics of macitentan, ambrisentan and bosentan using calcium release and inositol-1-phosphate (IP(1)) assays. In calcium release assays macitentan, ambrisentan and bosentan were highly potent ERAs with K(b) values of 0.14 nM, 0.12 nM and 1.1 nM, respectively. Macitentan, but not ambrisentan and bosentan, displayed slow apparent receptor association kinetics as evidenced by increased antagonistic potency upon prolongation of antagonist pre-incubation times. In compound washout experiments, macitentan displayed a significantly lower receptor dissociation rate and longer receptor occupancy half-life (ROt(1/2)) compared to bosentan and ambrisentan (ROt(1/2):17 minutes versus 70 seconds and 40 seconds, respectively). Because of its lower dissociation rate macitentan behaved as an insurmountable antagonist in calcium release and IP(1) assays, and unlike bosentan and ambrisentan it blocked endothelin receptor activation across a wide range of endothelin-1 (ET-1) concentrations. However, prolongation of the ET-1 stimulation time beyond ROt(1/2) rendered macitentan a surmountable antagonist, revealing its competitive binding mode. Bosentan and ambrisentan behaved as surmountable antagonists irrespective of the assay duration and they lacked inhibitory activity at high ET-1 concentrations. Thus, macitentan is a competitive ERA with significantly slower receptor dissociation kinetics than the currently approved ERAs. Slow dissociation caused insurmountable antagonism in functional PASMC-based assays and this could contribute to an enhanced pharmacological activity of macitentan in ET-1-dependent pathologies.

Topics: Animals; Bosentan; Calcium; CHO Cells; Clinical Trials, Phase III as Topic; Cricetinae; Endothelin Receptor Antagonists; Endothelin-1; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Inositol Phosphates; Myocytes, Smooth Muscle; Phenylpropionates; Pulmonary Artery; Pyridazines; Pyrimidines; Receptors, Endothelin; Sulfonamides

Ambrisentan is a selective endothelin-receptor antagonist that is approved by the US Food and Drug Administration for the treatment of pulmonary arterial hypertension. We describe hemodynamic responses and clinical outcomes of patients with portopulmonary hypertension (POPH) treated with ambrisentan.. In this observational study, we prospectively identified and followed consecutive adult patients with POPH who received monotherapy with ambrisentan ≤ 10 mg daily from January 2007 until December 2009. Liver enzymes were assessed monthly. Pulmonary hemodynamic responses were assessed using echocardiograms and right-sided heart catheterizations.. We identified 13 patients (seven men) with POPH and began monotherapy with ambrisentan. The median age was 57 (interquartile range [IQR], 52-60). Patients were followed for a median of 613 days (IQR, 385-1,011). The median model for end-stage liver disease score was 10 (IQR, 8.5-15); eight patients had Child-Turcotte-Pugh A classification. Median time on ambrisentan therapy was 390 days (IQR, 363-611). Two patients died, one of advanced hepatocellular carcinoma and one of septic shock following pneumonia. The mean pulmonary artery pressure decreased from a baseline median of 58 mm Hg (IQR, 37-63) to 41 mm Hg (IQR, 27-48) (P = .004). The pulmonary vascular resistance median was reduced from 445 dynes/s/cm(5) (IQR, 329-834) to 174 dynes/s/cm(5) (IQR, 121-361) (P = .008). There was no difference in the longitudinal analysis of liver function tests (aspartate aminotransferase, alanine aminotransferase, total bilirubin, and international normalized ratio) after 12 months of therapy. One patient underwent successful liver transplantation and normalized pulmonary hemodynamic responses after transplantation.. In this small cohort of patients with moderate to severe pulmonary hypertension in the setting of POPH, we have shown that ambrisentan monotherapy can significantly improve pulmonary hemodynamic responses without adverse effect on hepatic function.

Topics: Administration, Oral; Cardiac Catheterization; Central Venous Pressure; Dose-Response Relationship, Drug; Echocardiography; Female; Follow-Up Studies; Humans; Hypertension, Portal; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Prospective Studies; Pyridazines; Treatment Outcome

  Several cellular pathways are implicated in the pathogenesis of pulmonary arterial hypertension (PAH) and attempts to arrest disease progression with a single drug would not be expected to succeed in the medium term. In clinical practice, combination therapy is often used in patients deteriorating on monotherapy, despite the absence of firm evidence from randomized controlled controls..   From January 2005 to August 2009, 112 patients with World Health Organisation Functional Class (FC) II-IV PAH deteriorating on monotherapy received non-parenteral combination therapy at six Australian PAH expert hospitals. Combination therapy included bosentan, sitaxentan, ambrisentan, iloprost and sildenafil. Data were prospectively collected for survival status, 6-min walk distance, FC and echocardiographic parameters at the start of monotherapy through to commencement of combination therapy and at 6-monthly intervals thereafter..   After varying periods of monotherapy (18.7±13.4onths), survival estimates on combination therapy were 88%, 71% and 61% for the additional 1, 2 and 3years respectively. Survival on dual therapy in patients with idiopathic PAH/familial PAH was 93% at 1year and 79% at 2years, and for scleroderma-related PAH, 72% at 1 year and 48% at year 2 after initiation of combination therapy. In survivors, dual therapy reversed the deterioration in FC, from 3.1±0.6 on monotherapy to 2.2±0.6 at 12months. Similarly, dual therapy improved 6-min walk distance from 316±119m to 406±129m at 12months, and sequential echocardiography demonstrated a fall in pulmonary artery systolic pressure and improved right ventricular function..   Dual non-parenteral therapy appears safe and effective and should be considered for PAH patients who are deteriorating on monotherapy to improve long-term outcomes.

Topics: Adult; Aged; Australia; Bosentan; Cooperative Behavior; Drug Therapy, Combination; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Piperazines; Prospective Studies; Purines; Pyridazines; Sildenafil Citrate; Sulfonamides; Sulfones; Survival Rate; Young Adult

Eisenmenger syndrome (ES) is a known complication of congenital heart disease associated with unrepaired systemic to pulmonary shunts. Evidence for use of targeted pulmonary arterial hypertension therapy in ES is limited. The early experience using ambrisentan was evaluated in a cohort of consecutive patients with ES who initiated ambrisentan at Columbia University's Pulmonary Hypertension Center from January 1, 2007, to August 1, 2008. Effects of ambrisentan on rest and exercise systemic arterial oxygen saturation (S(a)O(2)), exercise capacity, functional status, hemoglobin levels, and hemodynamics were evaluated and compared using paired Student's t tests. Seventeen patients were evaluated at short-term (mean 163 ± 57 days) and longer term (mean 2.5 ± 0.5 years) follow-up. At short-term follow-up, there was an improvement in exercise capacity (6-minute walking distance 389 ± 74 vs 417 ± 77 m, p=0.03, n=11) and maintenance of rest S(a)O(2) (89 ± 7% vs 89% ± 6%, p=0.75, n=15), exercise S(a)O(2) (75 ± 15% vs 77% ± 15%, p=0.33, n=11), functional class (improvement in 2 patients, no change in 13), and hemoglobin (16.5 ± 2.8 vs 15.8 ± 1.8 g/dl, p=0.11, n=14). At longer term follow-up compared to baseline and short-term follow-up, there was stability of exercise capacity, S(a)O(2), functional class, and hemoglobin. In conclusion, in this single-center cohort of patients with ES, ambrisentan was safe and was associated with increasing exercise capacity at short-term follow-up, with patients maintaining S(a)O(2), functional class, and hemoglobin, and with no significant evidence of clinical deterioration at longer term follow-up. Additional studies are required to further assess the efficacy of ambrisentan in patients with ES.

Topics: Adult; Eisenmenger Complex; Familial Primary Pulmonary Hypertension; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; Phenylpropionates; Pyridazines; Retrospective Studies; Treatment Outcome

Currently available endothelin receptor antagonists for treating pulmonary arterial hypertension block either the endothelin (ET) receptor A or both A and B receptors. Transition from one endothelin receptor antagonist to another may theoretically alter side-effects or efficacy. We report our experience of a transition from sitaxsentan to ambrisentan, both predominant ET(A) receptor antagonists, in pulmonary arterial hypertension patients.. At Baylor Pulmonary Hypertension Center, 18 patients enrolled in the open-label extension phase of the original sitaxsentan studies (Sitaxsentan To Relieve ImpaireD Exercise) were transitioned to ambrisentan (from July 2007 to September 2007) at the time of study closure. Pre-transition (PreT), 1 month (1Mth) and 1 year (1Yr) post-transition assessments of 6-minute walk distance (6MWD), brain naturetic peptide (BNP) levels, WHO functional class (WHO FC), Borg dyspnea score (BDS), oxygen saturation, liver function, and peripheral edema were compared.. 6MWD was 356 ± 126 m at PreT, 361 ± 125 m at 1Mth, and 394 ± 114 m at 1Yr (mean ± SD). There was no difference in the walk distance at 1Mth and 1Yr post transition compared with PreT (P=0.92, 0.41 respectively). Oxygen saturation was no different at 1Mth and 1Yr to PreT level (P=0.49 and P=0.06 respectively). BNP was 178 ± 44 pg/mL at PreT, 129 ± 144 pg/mL at 1Mth and 157 ± 201 at 1Yr. Peripheral edema was present in 7/18 patients at PreT, in 8/16 patients at 1Mth, and in 6/13 patients at 1Yr post transition. Proportions of patients with edema over these 3 time points did not change significantly (P=0.803). At 1Yr, 2 patients had died, 1 had undergone lung transplantation, 1 had relocated, and 1 patient was started on intravenous prostacyclin therapy. Over 3 points (baseline, 1 month, and 1 year), there was no significant change in function class (P=0.672).. Our limited data suggest that ET(A) receptor antagonists can be switched from one to another with sustained exercise capacity and maintained WHO FC with no increase in incidence of peripheral edema.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Drug Substitution; Dyspnea; Edema; Endothelin A Receptor Antagonists; Exercise Test; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Isoxazoles; Liver Function Tests; Male; Middle Aged; Natriuretic Peptide, Brain; Oxygen; Phenylpropionates; Pyridazines; Retrospective Studies; Texas; Thiophenes; Time Factors; Treatment Outcome; Walking

The long-term effects of endothelin receptor antagonists on pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) in patients with pulmonary arterial hypertension (PAH) are not well studied. This post hoc analysis examined changes in pulmonary hemodynamics in a cohort of patients with PAH who underwent follow-up right heart catheterization (RHC) in a long-term ambrisentan study (ARIES-E). A retrospective review was conducted of patients who underwent RHC after >3 months of ambrisentan therapy. Changes from baseline in mean PAP, mean right atrial pressure, cardiac index, and PVR were assessed and correlations between these hemodynamic changes and exercise capacity were examined. Sixty-eight patients who received ambrisentan in the ARIES studies had ≥1 follow-up RHC while receiving ambrisentan. Fifty-eight patients were on ambrisentan alone at the time of the first RHC. Median time from initiation of ambrisentan therapy to follow-up RHC was 60 weeks (range 14 to 158). Significant improvements compared to baseline were observed for mean PAP (-7.6 mm Hg, 95% confidence interval [CI] -10.0 to -5.1), PVR (-266 dyne × s/cm(5), 95% CI -350 to -180), and cardiac index (0.4 L/min/m(2), 95% CI 0.2 to 0.6 L/min/m(2)); for patients on ambrisentan alone, changes in mean PAP and PVR were inversely correlated with change from baseline 6-minute walking distance (r = -0.41 and -0.43, respectively, p <0.001 for the 2 comparisons) at time of follow-up RHC. In conclusion, ambrisentan may provide sustained improvements in pulmonary hemodynamics in patients with PAH who receive long-term treatment and these changes correlate with improvements in exercise capacity.

Topics: Antihypertensive Agents; Atrial Function, Right; Cardiac Catheterization; Cardiac Output; Dose-Response Relationship, Drug; Exercise Test; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Pulmonary Wedge Pressure; Pyridazines; Randomized Controlled Trials as Topic; Retrospective Studies; Vascular Resistance

In the past 5-10 years, drug treatment of idiopathic pulmonary arterial hypertension has evolved considerably. Experience and results from use of such updated treatment in Norway has not been reported.. 32 patients newly diagnosed with idiopathic pulmonary arterial hypertension, were consecutively assessed with respect to hemodynamics and physical capacity. The results after three months were compared with those after 12 months. Observed survival was compared with estimated survival from the time when only conventional treatment was available.. The patients (78% women) were 42 ± 14 years, had dyspnea in NYHA class 2.9 ± 0.4 and a maximal oxygen uptake of 12.0 ± 3.9 ml/kg/min (37 ± 13% of the expected). Updated treatment led to significantly improved hemodynamics and physical capacity, which persisted during follow-up. During 43 ± 31 months follow-up, seven patients died while two underwent bilateral lung transplantation. Observed transplantation-free survival was 81% after one, two and three years, while that for estimated transplantation-free survival was 70%, 58% and 49% respectively.. Treatment of idiopathic pulmonary arterial hypertension with updated treatment improves hemodynamics and thereby symptoms. Mortality remains high, but is probably lower than it was when only conventional treatment was available.

Topics: Adult; Airway Resistance; Antihypertensive Agents; Bosentan; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Iloprost; Lung Transplantation; Lung Volume Measurements; Male; Middle Aged; Oxygen Consumption; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Pyridazines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Ambrisentan, a selective endothelin receptor antagonist has been approved in several countries for pulmonary arterial hypertension. No data have been published on the efficacy of ambrisentan on improvement of exercise capacity in patients with portopulmonary hypertension (PoPH).. We retrospectively analyzed the safety and efficacy of ambrisentan in patients with PoPH in four German university hospitals.. 14 patients with moderate to severe PoPH were included. The median follow-up was 16 months (IQR, 12 - 21). 6 minute walk tests after 6 and 12 months improved from 376 meters (IQR, 207 - 440) at baseline to 415 meters (IQR, 393 - 475; p = 0.011) and 413 meters (IQR, 362 - 473, p = 0.005), respectively. WHO- functional class after 1 year of therapy with ambrisentan also improved significantly (p = 0.014). No significant changes in blood gas analysis and liver function tests (aspartate aminotransferase, alanine aminotransferase, total bilirubin, and international normalized ratio) during therapy with ambrisentan were detectable.. The present study demonstrates significant improvement of exercise capacity and clinical symptoms without relevant safety concerns during ambrisentan treatment in patients with PoPH.

Topics: Antihypertensive Agents; Dose-Response Relationship, Drug; Exercise; Exercise Test; Follow-Up Studies; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Retrospective Studies; Treatment Outcome

Congenital heart disease (CHD) is a common structural defect of the heart or major blood vessels. Patients with adult congenital heart disease (ACHD) have medical needs that are distinct from those of pediatric patients with CHD, and the transition into adult health care is important for management of the patient with ACHD. A large proportion of patients with CHD develop diseases and complications associated with the long-term stress of intracardiac shunts. Pulmonary arterial hypertension (PAH) is a significant complication of some CHD lesions. The treatment of these patients remains challenging due to their combined heart and lung disease, and multidisciplinary care is ofen necessitated for a variety of secondary conditions. A number of treatment options are available for the management of PAH associated with CHD, including prostanoids, phosphodiesterase type-5 inhibitors, and endothelin receptor antagonists. This article discusses the diagnosis and management of such ACHD patients with PAH.

Topics: Adult; Algorithms; Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Epoprostenol; Familial Primary Pulmonary Hypertension; Heart Defects, Congenital; Hospitals, Pediatric; Humans; Hypertension, Pulmonary; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Prevalence; Pyridazines; Sulfonamides; Texas; Transition to Adult Care

Topics: Administration, Oral; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Endothelin Receptor Antagonists; Europe; Evidence-Based Medicine; Humans; Hypertension, Pulmonary; Isoxazoles; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Practice Guidelines as Topic; Purines; Pyridazines; Sildenafil Citrate; Sulfonamides; Sulfones; Thiophenes

Topics: Administration, Oral; Antihypertensive Agents; Bosentan; Canada; Cost Control; Drug Costs; Humans; Hypertension, Pulmonary; Isoxazoles; Phenylpropionates; Piperazines; Purines; Pyridazines; Sildenafil Citrate; Sulfonamides; Sulfones; Thiophenes

There are only a few reports of pulmonary hypertension (PH) in hypersensitivity pneumonitis (HP) and an approved vasomodulatory therapy for PH does not exist at all for interstitial lung disease (ILD), particularly for HP.. The case of a 53-year-old woman with chronic HP and severe life-threatening PH treated with a combined specific vasomodulatory therapy is reported. Sustained clinical and hemodynamic improvement was achieved.. Further investigation of PH in HP and specific vasomodulatory therapy is necessary.

Topics: Alveolitis, Extrinsic Allergic; Chronic Disease; Drug Therapy, Combination; Female; Humans; Hypertension, Pulmonary; Iloprost; Middle Aged; Phenylpropionates; Piperazines; Purines; Pyridazines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a rare but life-threatening condition that is characterized by progressive elevation of pulmonary artery pressure and pulmonary vascular resistance, leading to right-sided heart failure and frequently death. Orally administered agents used for the treatment of symptomatic, moderate-to-severe PAH include sildenafil and the endothelin (ET) receptor antagonists (ERAs), bosentan and sitaxentan (sitaxsentan). Ambrisentan is a new oral ET(A) receptor-selective ERA, with higher ET receptor affinity than bosentan. Placebo-controlled, randomized clinical trials (RCTs) have demonstrated that ambrisentan (5 or 10 mg/day) is safe and effective. To provide health economic data on the multiple oral PAH therapies currently available, a population-based cost-minimization analysis (CMA) was conducted for Canada.. The primary requirement for a CMA is that all clinical outcomes be equivalent between comparator treatments. To provide such supporting data, a literature search was conducted for RCTs of oral agents used to treat symptomatic PAH. This was followed by application of direct and indirect statistical methods to support the hypothesis of clinical equivalence between the oral agents. Estimates for PAH prevalence, incidence and death rates were then used to build a population-based CMA model. The base-case analysis considered costs for drug therapy, outpatient pharmacy costs, medical consultations and visits, laboratory and diagnostic procedures and other healthcare-related resources. In addition, costs for secondary pharmacotherapy in cases where the primary agent had to be discontinued because of adverse effects were also included. The time horizon for evaluating pharmacotherapy was 3 years, all costs were in 2008 Canadian dollars ($Can) and the costs were discounted at a rate of 3% annually. The study perspective was the Canadian healthcare system.. There were no double-blind RCTs comparing ambrisentan with any of the other oral agents. Therefore, an indirect comparison of placebo-controlled trials of PAH drugs had to be used to support the clinical equivalence. This included a calculation of standardized mean differences (SMD) between agents (vs placebo) and a meta-regression analysis on the primary and secondary trial endpoints. Keeping in mind the caveats associated with indirect trial comparisons, the data suggested similar clinical efficacy over 12-16 weeks between agents, as indicated by the identical magnitude of the SMD between the active agent and placebo and the non-significant differences between drugs as determined by the meta-regression analysis. The population-based model projected that the number of PAH patients clinically suitable for these drugs in Canada would be 931 in the first full-budget year (i.e. 2009) with an increase to 1114 by the third full year. The CMA revealed the following rank order of the least to most costly agent; sildenafil, ambrisentan, sitaxentan and bosentan. Sildenafil was the least costly, primarily because of the lower daily drug-acquisition cost. Of the three ERAs, ambrisentan would be associated with annual cost savings of $Can3.4 and $Can5.6 million when used as an alternative to sitaxentan or bosentan, respectively.. Ambrisentan is less costly than other available ERAs, including bosentan and sitaxentan, but is more costly than sildenafil. In PAH patients in whom an ERA is the preferred agent, ambrisentan may be the drug of choice because of its economic advantages and improved safety profile.

Topics: Administration, Oral; Antihypertensive Agents; Bosentan; Canada; Costs and Cost Analysis; Drug Costs; Humans; Hypertension, Pulmonary; Isoxazoles; Phenylpropionates; Piperazines; Placebos; Purines; Pyridazines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfonamides; Sulfones; Thiophenes; Treatment Outcome

Pulmonary Hypertension is a serious complication of sickle cell disease (SCD), with high morbidity and mortality. Endothelin (ET)-1, a potent vasoconstrictor elevated in SCD, acts through the ET receptors (ETR), ETR-A and ETR-B. Bosentan and ambrisentan are ETR blockers used in primary pulmonary hypertension. We report on the use of ETR blocking agents in a cohort of 14 high-risk SCD adult patients with pulmonary hypertension. Patients underwent right heart catheterization, 6-min walk test, echocardiogram, physical examination and blood work-up before starting ETR blockers. Eight patients received ETR blockers as initial therapy; six patients were already taking sildenafil. Over more than 6 months of therapy, sequential measurements of 6-min walk distance increased significantly (baseline 357 +/- 22 to 398 +/- 18 m at 5-6 months, P < 0.05). Downward trends were observed for amino-terminal brain natriuretic peptide and tricuspid regurgitant velocity. Pulmonary artery mean pressures decreased in three patients that had repeat right heart catheterization (44-38 mmHg). Adverse events were: increased serum alanine aminotransferase (2), peripheral oedema (4), rash (1), headache (3), decreased haemoglobin (2). Therapy was stopped in two patients who were switched then to the other ETR blocker agent. These data suggest preliminary evidence for the benefit of bosentan and ambrisentan in pulmonary hypertension in SCD.

Topics: Adult; Anemia, Sickle Cell; Antihypertensive Agents; Bosentan; Cardiac Catheterization; Drug Evaluation; Drug Therapy, Combination; Endothelin Receptor Antagonists; Exercise Test; Humans; Hypertension, Pulmonary; Middle Aged; Phenylpropionates; Piperazines; Purines; Pyridazines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome

Topics: Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Randomized Controlled Trials as Topic; Vasodilator Agents

Compared to the unselective endothelin (ET) receptor antagonist (Bosentan), superior effects of selective ET-A-receptor blockage (Ambrisentan) for the treatment of pulmonary hypertension (PH) are expected due to ET-B-receptor mediated beneficial effects. Our hypothesis was that treatment with Ambrisentan leads to an increase in prostacyclin synthase I (PGIS) expression compared to Bosentan.. To test this hypothesis, rats were treated with either monocrotaline (MCT) only, MCT+Ambrisentan or MCT+Bosentan. After 4 weeks, right ventricular systolic pressure (RVSP), pulmonary vascular remodelling and right ventricular hypertrophy (RV/(LV+S)) were measured.. In MCT only treated animals, significantly greater expression of PGIS mRNA was found in the lungs compared to control animals, and this was confirmed by immunohistochemical analysis indicating increased staining of PGIS in the very small pulmonary arteries (17 % greater expression of PGIS mRNA in MCT versus control, p = 0.002; Remmele score (RS): 51 versus 102, p = 0.009). Treatment with Bosentan resulted in a significantly lower expression of PGIS mRNA compared to Ambrisentan and MCT only (7 % versus 18 %, p = 0.003 and 7 % versus 17 %, p = 0.004). This observation was also confirmed by immunohistochemical analysis (RS very small arteries: 45 versus 81, p = 0.003; RS small arteries: 45 versus 108, p = 0.014). No difference was observed in RVSP, RV/(LV+S) or pulmonary vascular remodelling between the two treatment groups (RVSP: 28 versus 39 mmHg, p = 0.189; RV/(LV+S) 0.46 versus 0.48, p = 0.818; medial area: 78.3 % versus 75.2 %, p = 0.823).. Treatment with Bosentan leads to lower PGIS expression in pulmonary arteries compared to Ambrisentan, although the greater PGIS expression by Ambrisentan treatment had no benefical effect on pulmonary haemodynamics.

Topics: Animals; Bosentan; Cytochrome P-450 Enzyme System; Endothelin Receptor Antagonists; Gene Expression Regulation, Enzymologic; Heart Ventricles; Hemodynamics; Hypertension, Pulmonary; Hypertrophy; Immunohistochemistry; Intramolecular Oxidoreductases; Lung; Male; Organ Size; Phenylpropionates; Pulmonary Artery; Pyridazines; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sulfonamides

Topics: Drug Approval; Drug Labeling; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines

Topics: Endothelin A Receptor Antagonists; Humans; Hypertension, Pulmonary; Models, Molecular; Molecular Structure; Phenylpropionates; Pyridazines; Randomized Controlled Trials as Topic; Treatment Outcome