Sitaxsentan sodium for pulmonary hypertension

Sitaxsentan is the first oral endothelin receptor antagonist (ETRA) with high selectivity for the endothelin-A (ET(A)) receptor to be approved for clinical use by regulatory agencies in Europe for the treatment of pulmonary arterial hypertension (PAH). Clinical trials have shown it to be well tolerated and to improve exercise tolerance, functional class and pulmonary hemodynamics in PAH, results which appear to be at least as good as those for the mixed ETRA bosentan. Importantly, compared to bosentan, sitaxsentan has a lower incidence of liver toxicity and no interaction with sildenafil, a drug commonly used in the management of PAH. Furthermore, there is increasing evidence to suggest that ETRAs may play an important role in the future management of a wide variety of other conditions, from hypertension and renal disease to connective tissue disease and cancer. In some of these conditions, ET(A) selectivity may be an advantage.     

Sitaxsentan, a selective endothelin-A receptor antagonist for the treatment of pulmonary arterial hypertension

Sitaxsentan, a highly selective endothelin-A (ET(A)) receptor antagonist (6500-fold more selective for ET(A) receptors than endothelin-B (ET(B)) receptors), may benefit patients with pulmonary artery hypertension (PAH) by blocking the vasoconstrictor effects of ET(A) receptors while maintaining the vasodilator/clearance functions of ET(B) receptors. In its first randomised, placebo-controlled study, Sitaxsentan to Relieve Impaired Exercise-1 (STRIDE-1), sitaxsentan improved exercise capacity assessed by 6 min walk, New York Heart Association functional class, cardiac index and pulmonary vascular resistance in New York Heart Association class II, III and IV patients with idiopathic PAH, PAH related to connective tissue disease or PAH related to congenital heart disease. In STRIDE-1, doses of 100 and 300 mg/day p.o. were evaluated. Although both doses showed equivalent efficacy, the lower dose had a more tolerable safety profile. Additional studies are ongoing to assess the relative safety and efficacy of 50 and 100 mg/day doses, both in de novo patients and in patients previously treated with the ET(A)/ET(B) receptor antagonist bosentan. Long-term comparative studies are necessary to determine whether there is a clinically meaningful difference between selective ET(A) receptor antagonism and ET(A)/ET(B) receptor antagonism.     

Sitaxsentan,a selective endothelin-A receptor antagonist for the treatment of pulmonary arterial hypertension

Sitaxsentan, a highly selective endothelin-A (ET_A) receptor antagonist (6500-fold more selective for ET_A receptors than endothelin-B (ET_B) receptors), may benefit patients with pulmonary artery hypertension (PAH) by blocking the vasoconstrictor effects of ET_A receptors while maintaining the vasodilator/clearance functions of ET_B receptors. In its first randomised, placebo-controlled study, Sitaxsentan to Relieve Impaired Exercise-1 (STRIDE-1), sitaxsentan improved exercise capacity assessed by 6 min walk, New York Heart Association functional class, cardiac index and pulmonary vascular resistance in New York Heart Association class II, III and IV patients with idiopathic PAH, PAH related to connective tissue disease or PAH related to congenital heart disease. In STRIDE-1, doses of 100 and 300 mg/day p.o. were evaluated. Although both doses showed equivalent efficacy, the lower dose had a more tolerable safety profile. Additional studies are ongoing to assess the relative safety and efficacy of 50 and 100 mg/day doses, both in de novo patients and in patients previously treated with the ET_A/ET_B receptor antagonist bosentan. Long-term comparative studies are necessary to determine whether there is a clinically meaningful difference between selective ET_A receptor antagonism and ET_A/ET_B receptor antagonism.     

Sitaxsentan: a selective endothelin-A receptor antagonist, for the treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive, life-threatening condition. Sitaxsentan, a selective endothelin-A receptor antagonist, is an effective, safe and well-tolerated endothelin receptor antagonist for the treatment of PAH in adult patients. Multi-center, randomized, placebo-controlled clinical trials have demonstrated that sitaxsentan has beneficial effects on exercise capacity (i.e., 6-min walk distance), functional class and hemodynamic parameters in PAH patients. Sitaxsentan has a low incidence of acute hepatotoxicity. Patients on concomitant warfarin require a decrease in warfarin dose to maintain a therapeutic international normalized ratio. The demonstration of clinical efficacy and low incidence of acute hepatotoxicity support the potential use of sitaxsentan for the treatment of PAH.     

中国肺动脉高压药物治疗现状

肺动脉高压(PAH)是一类以肺血管阻力进行性升高和血管重构为特征的心肺血管疾病,最终可致右心衰竭甚至死亡。欧美有多种PAH治疗药物获得批准上市,我国PAH靶向治疗时代始于2006年,主要包括内皮素受体拮抗剂、5-型磷酸二酯酶抑制剂和前列环素类似物。本文综述中国PAH靶向药物治疗现状。     

Clinical value of prostacyclin and its analogs in the management of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is associated with changes in vascular tone as well as vascular structure, with the relative contribution of each dependent upon the etiology of the increased vascular resistance. Prostacyclin treatment has markedly improved both the therapeutic options and the prognosis of PAH. The beneficial effect of prostacyclin in PAH is linked to the powerful vasodilating capacity and, even more importantly, to the inhibition of platelet aggregation, smooth muscle proliferation and antiinflammatory actions. Since prostacyclin has a very short plasma half-life, continuous intravenous administration via a portable infusion pump must be carried out. Because of the complexity of the delivery and the associated complications, intravenous prostacyclin (epoprostenol) therapy is restricted to patients with late NYHA Class III and Class IV and thus alternative modes of delivery in less advanced PAH are desirable. Recent clinical studies with more stable prostacyclin analogs such as subcutaneously delivered treprostinil, orally active beraprost and aerosolized iloprost have demonstrated beneficial effects of each of these prostanoids, especially in NYHA Class II and III patients and, therefore, these agents should be considered first for prostanoid therapy in the early stages of PAH. Prostaglandins may be more effective in conjunction with endothelin receptor antagonists or phosphodiesterase inhibitors and an increasing number of studies are now addressing the combined efficiency and safety of these combinations. This update will focus on the current development status of PAH therapy with prostacyclin and its analogs. Special attention will be accorded to the selection of patients for prostanoid therapy, therapy monitoring and improvement of therapeutic efficacy by addition of other new therapeutic agents to prostaglandins. Survival benefits and special aspects of bridging-to-transplant therapy are also important aspects of the review.     

Key articles and guidelines in the management of pulmonary arterial hypertension: 2011 update

Pharmacotherapeutic approaches for the management of pulmonary arterial hypertension (PAH) have expanded greatly in the last 10?years. Pulmonary arterial hypertension is a relatively rare disease and is associated with myriad disease processes. The older term for PAH, primary PAH, has been changed to represent these differences and to distinguish it from postcapillary PAH associated with left-sided heart failure. Limitations in evaluating treatment approaches for PAH include its rarity, the small number of patients included in clinical trials, and issues regarding the use of placebo-controlled trials in a disease with such a high mortality rate if left untreated. Management options include the use of prostacyclin and prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase inhibitors, as well as traditional background therapy with diuretics, digoxin, calcium channel blockers, and warfarin. Numerous drugs are under investigation to evaluate their possible roles in management. Combination therapy is increasingly becoming a standard approach to therapy, with mounting literature to document effectiveness. Current or emerging roles for the pharmacist in the management of PAH largely involves ensuring access to drug therapy, facilitating specialty pharmacy dispensing, and providing patient counseling. Newer roles may include future drug development, optimized use of investigational drugs, and specialized disease management programs. This compilation includes a series of articles identifying important literature in cardiovascular pharmacotherapy. This bibliography focuses on pharmacotherapeutic management of pulmonary arterial hypertension (PAH). Most of the cited works present the results of significant human clinical studies that have shaped the management of patients with PAH. Limited primary literature is available for some topics, so in addition, consensus documents prepared by expert panels are reviewed. This compilation may serve as a teaching tool, reference resource, or update of the literature for pharmacy clinicians, physicians, and students.     

Role of the endothelium in pulmonary arterial hypertension

Pulmonary hypertension represents a significant disease burden in both the developed and developing worlds. Certain forms of pulmonary hypertension are more common in some countries than others but people of all races, all ages and both sexes are affected. Treatment options are limited and expensive. The development of new therapies will be determined by improved understanding of endothelial cell biology.     

Sitaxentan: in pulmonary arterial hypertension

Sitaxentan is a highly selective endothelin (ET)(A) receptor antagonist, with an approximately 6500 higher affinity for ET(A) than ET(B) receptors. In pulmonary arterial hypertension (PAH), elevated ET-1 levels are strongly correlated with disease severity and prognosis. Sitaxentan 100 mg once daily was efficacious in the management of moderate to severe PAH in the pivotal, 12-18 week, large (n > or = 98), well designed, placebo-controlled STRIDE-1, -2 and -4 trials. In the STRIDE-1 and -2 trials (the majority of patients had New York Heart Association [NYHA]/WHO functional class III PAH), sitaxentan-treated patients experienced significantly greater improvements from baseline in distance walked over 6 minutes (6MWD; primary endpoint in STRIDE-2) and in NYHA/WHO functional class than placebo recipients. In STRIDE-4, although there was no between-group difference in terms of improvements in 6MWD in the primary analysis of patients across all WHO functional classes (61% were functional class II) [primary endpoint], improvements in 6MWD significantly favoured sitaxentan versus placebo-treated patients in a post hoc subgroup analysis of those with WHO functional class III or IV disease. The beneficial effects of sitaxentan therapy on exercise capacity and NYHA/WHO functional class were maintained after up to 2 years' treatment. Treatment with sitaxentan for up to 2 years was generally well tolerated in clinical trials.     

西他生坦治疗肺动脉高压

肺动脉高压是一种以肺小动脉痉挛、内膜增生和重构为特征的恶性血管疾病。近年来随着对肺动脉高压发病机制深入研究和选择性肺血管舒张药物的研发,肺动脉高压的治疗已经取得极大进步。西他生坦作为一个新型的高选择性内皮素受体拮抗药也因此备受临床关注。西他生坦通过阻断A型内皮素受体,抑制内皮素-1的缩血管效应,舒张血管。本文综述了西他生坦的药理学特点、相关基础及临床研究进展。     

Prevalence of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension in the United States

Abstract

Background:

The prevalence of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) in the US is largely unknown. Prior research has estimated PAH prevalence in Europe at ～15–52 per million.     

Bosentan for pulmonary arterial hypertension

Pulmonary arterial hypertension is an uncommon but disabling and often fatal condition, in which there is a sustained rise in pulmonary arterial pressure due to progressive obliteration of the pulmonary vascular bed. [symbol: see text] Bosentan (Tracleer-Actelion), which belongs to a new class of drugs called endothelin receptor antagonists, is now available for treating patients with pulmonary arterial hypertension. Here we assess whether bosentan offers worthwhile benefits in the management of patients with this condition.     

Current management of primary pulmonary hypertension.

Primary pulmonary hypertension (PPH) is a rare disorder with an annual incidence of 1 to 2 per million people. The aetiology of this disorder is unknown, but it appears to result from an abnormal interaction of environmental and genetic factors leading to a vasculopathy. The pulmonary arteries in these patients exhibit a spectrum of pathological lesions ranging from the early medial hypertrophy to the end-stage fibrotic plexiform lesions. This characteristic pathology is also observed in pulmonary hypertension resulting from connective tissue disease (particularly systemic sclerosis), HIV infection, portal hypertension and certain toxins. PPH is a condition that is difficult to diagnose and treat, with a median survival of 2.8 years in historical studies. One of the difficulties in treating patients with PHH is that the subacute nature of disease presentation often prevents an accurate diagnosis during the early stages of the illness. Progressive dyspnoea on exertion is the most common presenting symptom. Diagnostic evaluation should include electrocardiography, chest radiograph and echocardiography, and laboratory and other studies to evaluate for secondary causes (e.g. pulmonary function tests, chest computed tomography and ventilation/perfusion scans, pulmonary arteriogram, cardiopulmonary testing, right heart catherisation). PHH is a disorder for which there is no known cure. Current medical and surgical treatment options for patients with PHH include anticoagulation, vasodilators and transplantation. Calcium channel antagonists are currently the oral drugs of choice for the treatment of patients with New York Heart Association (NYHA) Class II disease. These agents, in particular the dihydropyridine compounds, have beneficial effects on haemodynamics and right ventricular function, and possibly increased survival. Epoprostenol is administered by intravenous infusion, and studies have demonstrated short- and long-term improvements in symptoms, haemodynamics and survival. It is well tolerated and has become the treatment of choice for patients with NYHA Class III and IV disease. Inotropic agents are used as a bridge to transplant, which is indicated in patients who do not respond to maximal medical therapy. Experience has shown that single lung, double lung and heart-lung transplantation are approximately of equal efficacy. Currently, single lung transplant appears to be the procedure of choice. Newer agents, such as sildenafil, beraprost and bosentan, are presently being evaluated for the treatment of this disorder. Future study should include elucidation of the pathogenic mechanisms in the development of this vasculopathy, which will hopefully lead to the development of improved treatment options for patients with PHH.     

Role of the serotonin transporter in pulmonary arterial hypertension

Pulmonary arterial hypertension is a disease in which pulmonary arterial pressure is raised, leading to right heart failure. Survival is poor despite current therapeutic strategies. The ‘serotonin hypothesis of pulmonary arterial hypertension’ arose in the 1960s following an ‘epidemic’ of pulmonary arterial hypertension in women taking the indirect serotinergic agonist aminorex as an anorexigen. In the 1980s, the hypothesis was revisited following the occurrence of pulmonary arterial hypertension associated with the use of fenfluramines as anorexigens; these are also indirect serotinergic agents. Research has identified changes in serotonin synthesis, serotonin receptor activation and serotonin uptake via the serotonin transporter in experimental and clinical pulmonary arterial hypertension. This review will discuss our current understanding of this serotonin hypothesis with particular reference to the role of the serotonin transporter.     

Oral treprostinil in the treatment of pulmonary arterial hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a rare disease resulting in progressive remodeling of the pulmonary vasculature and eventual right ventricular failure. Despite the development of 13 therapies for PAH since 2000, the use of continuously infused prostanoids retains a special role. Infused medications present unique challenges, and the search for an efficacious oral prostanoid culminated in the FDA approval of oral treprostinil – a first in class oral prostanoid medication approved to treat pulmonary arterial hypertension (PAH).

Areas covered: In this discussion, we review the pharmacologic properties of oral treprostinil, and discuss three original major registration studies that resulted in the approval and widespread use of the drug. We also review several post-approval analyses and transitional studies. We discuss administration issues including side effects, transitioning, cost, and comparative analysis with selexipag.

Expert opinion: Though the prospects of harnessing the benefits of continuously infused prostanoid therapy in a pill form are tantalizing, the gap in efficacy between oral and infused treatment is substantial. Major side effects and exorbitant cost are further barriers to broad uptake. Competition from oral prostaglandin receptor agonist selexipag challenges the commercial success of oral treprostinil. The long-term viability of oral treprostinil rests largely on the outcome of the long-term event-driven study of the molecule added to background approved ERA or PDE5 inhibitor monotherapy.     

Biomarkers in systemic sclerosis-related pulmonary arterial hypertension

Systemic sclerosis (SSc) is a complex multisystem disease characterized by vascular involvement and generalized disturbance of the microcirculation. Pulmonary vascular disease leads to systemic sclerosis-related pulmonary arterial hypertension (SScPAH). SScPAH is a devastating complication with a considerable impact on prognosis, being a common cause of disease-related death. The ability to detect this process at an early stage by simple means would be of great value, since effective treatment is now available. There is increasing evidence that several biomarkers increase in proportion to the extent of right ventricular dysfunction and correlate with hemodynamic, echocardiographic and functional measurements of pulmonary vascular disease. Biomarkers may be used to identify high-risk patients for more invasive procedures, provide prognostic information, and guide vasodilator therapy. In this article, we review potential biomarkers in SScPAH as tools for screening, diagnostic evaluation, risk stratification, prediction of disease severity and indicators of treatment efficacy.