Nebivolol in the treatment of arterial hypertension

This MiniReview reports the current knowledge about the treatment of arterial hypertension with the third‐generation beta‐adrenoceptor antagonist (BAA) nebivolol. Furthermore, it reviews the advantages of nebivolol compared to the earlier generation of BAAs with respect to their different pharmacological properties. Beta‐adrenoceptor antagonists are a class of drugs applied for several different conditions, including hypertension and heart failure. They differ significantly in their pharmacological properties, including varying β₁/β₂‐selectivity and/or exertion of additive effects on the heart and circulation. Although these drugs have been a part of hypertensive therapy for about 40 years, the outcome of large clinical trials has put the role of BAAs into question. However, most of these results were based on first‐ and second‐generation BAAs and cannot be translated directly into third‐generation drugs. The third‐generation BAA nebivolol has the highest β₁‐selectivity seen so far, together with additional vasodilating and anti‐oxidative properties. It is currently applied in the treatment of hypertension and congestive heart failure. Nebivolol has a unique pharmacological profile, despite showing similar blood pressure‐lowering effects, and has certain advantages in the treatment of hypertension compared to the previous generations of BAAs. This includes significant improvements in endothelial dysfunction, central haemodynamics and the degree of erectile dysfunction in men, a neutral/beneficial metabolic profile and lastly a more favourable side effect profile. It is widely beneficial for, for example, sexually active men and patients with comorbidities such as type II diabetes mellitus, metabolic syndrome and chronic obstructive lung disorders. Whether the advantages translate to an improved long‐term clinical outcome remains to be clarified, and ongoing prospective studies will show this in the future.     

Current pharmacological treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a disease characterized by an elevation in pulmonary artery pressure that can lead to right ventricular failure and death. Conventional treatment is based on non-specific drugs (warfarin, oxygen, diuretics). Pure vasodilators like calcium channel antagonists have little or no effect on the vast majority of patients. Although there is no cure for PAH, newer medical therapies have been shown to improve a variety of clinically relevant end-points including survival, functional class, exercise tolerance, haemodynamics, echocardiographic parameters and quality of life measures. Intravenous prostacyclin, was the first introduced drug for treatment of PAH and remains the first-line treatment for the most severe patients. Since then the list of approved drugs for PAH has expanded to include prostacyclin analogues with differing routes of administration, a dual endothelin receptor antagonist, and a phosphodiesterase-5 inhibitor. Novel drugs have also shown promise in experimental trials and are likely to be added to the list of options. This article reviews the current treatments strategies for PAH.     

The pharmacological treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a life-threatening and progressive disease of various origins characterized by pulmonary vascular remodeling that leads to increased pulmonary vascular resistance and pulmonary arterial pressure, most often resulting in right-sided heart failure. The most common symptom at presentation is breathlessness, with impaired exercise capacity as a hallmark of the disease. Advances in understanding the pathobiology over the last 2 decades have led to therapies (endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclins or analogs) initially directed at reversing the pulmonary vasoconstriction and more recently directed toward reversing endothelial cell dysfunction and smooth muscle cell proliferation. Despite these advances, disease progression is common even with use of combination regimens targeting multiple mechanistic pathways. Overall 5-year survival for PAH has increased significantly from approximately 30% in the 1980s to approximately 60% at present, yet remains abysmal. This review summarizes the mechanisms of action, clinical data, and regulatory histories of approved PAH therapies and describes the latest agents in late-stage clinical development.     

Current medical treatment of pulmonary arterial hypertension

Primary pulmonary hypertension is a rare disease of the pulmonary vasculature manifested by dyspnea on exertion, syncope, and signs and symptoms of right heart failure. In the absence of adequate treatment, primary pulmonary hypertension has a grave prognosis, with a median survival of 2.8 years. Pulmonary arterial hypertension develops in association with known risk factors and predisposing clinical conditions, and shares many clinical, pathological and therapeutic characteristics with primary pulmonary hypertension. Therapeutic choices in pulmonary arterial hypertension depend on the etiology of the disease, severity of functional impairment and hemodynamic response following acute vasodilator administration during right heart catheterization. Agents currently approved for the specific treatment of pulmonary arterial hypertension are continuous intravenous epoprostenol, subcutaneous treprostinil and oral bosentan. A small group of patients who demonstrate true acute vasoreactivity at right heart catheterization may be chronically treated with oral calcium channel blockers. In addition, most patients with pulmonary hypertension receive conventional treatment, represented by anticoagulants, diuretics, inotropic medication or oxygen supplementation. Treatment of pulmonary arterial hypertension has significantly altered the natural course of the disease, with pronounced symptomatic, functional and survival benefit. Current clinical research focuses on the discovery of new targets of therapy and the use of a combination treatment approach, which will offer hope and valuable insight into the pathogenetic basis of this devastating illness.     

Tadalafil for the treatment of pulmonary arterial hypertension

Background: Tadalafil, a long-acting phosphodiesterase-5 inhibitor (PDE-5) is the most recent oral agent to receive FDA approval for the treatment of pulmonary arterial hypertension (PAH). Objective: With several new agents emerging for the treatment of PAH, this article reviews tadalafil, the compound and its properties, clinical evidence supporting its use, and the role of tadalafil in the current treatment approach for patients with PAH. Methods: A broad PubMed literature search was performed to identify the most current data on the use of tadalafil for PAH. Results: Tadalafil received FDA approval in 2009 following the recently published pivotal trial that demonstrated that the use of tadalafil 40 mg once daily was well tolerated, improved exercise capacity and quality of life measures and reduced time to clinical worsening in PAH patients. As the second PDE-5 inhibitor to gain approval for PAH, clinical properties such as its long half-life leading to once-daily dosing and possibly improved compliance, as well as potential cost benefit, may distinguish tadalafil from sildenafil in the widespread treatment of PAH.     

Tadalafil for the treatment of pulmonary arterial hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a progressive occlusive disease affecting the pulmonary vasculature; it carries a poor prognosis. Because right ventricular failure is the key feature of deterioration in PAH patients, vasodilator treatments relieving right ventricular afterload have gained ground in the treatment of this disorder. Phosphodiesterase-5 inhibitors are effective and well tolerated vasodilators that were originally developed for erectile dysfunction. Tadalafil, the first once-daily drug of this class, was approved by the USFDA in May 2009 for the treatment of patients suffering from PAH.

Areas covered: This review outlines the currently available data about tadalafil and its effects in patients with PAH. It also presents evidence from recent clinical trials of tadalafil and discusses potential improvements over existing therapy options and their impact on current treatment strategies.

Expert opinion: Tadalafil is an efficacious drug with a favorable side-effect profile and convenient mode of administration. More studies are needed to analyze its impact on survival and to substantiate its role in an upfront combination treatment strategy.     

肺动脉高压的药物治疗进展

肺动脉高压是一种严重的疾病，本文收集了近年来肺动脉高压药物治疗进展的国内外文献，重点介绍其药理特点，供临床医生参考。     

Selexipag for the treatment of pulmonary arterial hypertension

Introduction: Targeted pulmonary vasoactive substances are the cornerstone of treatment in pulmonary arterial hypertension (PAH). Approved drugs act on various receptors and molecules within the pulmonary arteries, mainly causing pulmonary vasodilation and potentially reversing remodeling with consequent improvement of right ventricular function. A key role is attributed to the prostacyclin pathway and especially the prostacyclin receptor (IP). Selexipag is a recently developed, non-prostanoid, oral IP receptor agonist for the treatment of PAH which has been approved in countries/regions including the USA and Europe.

Areas covered: We review the discovery and development of drugs targeting IP receptors in PAH and describe preclinical and phase I studies of selexipag. Furthermore, we review important phase II and III selexipag studies and place them into the clinical context of previously approved prostanoids.

Expert opinion: Oral selexipag offers a promising therapeutic option within the class of available drugs targeting IP receptors. However, its role as first-line therapy based on its efficacy/side-effect profile in current studies is questionable. Most likely, selexipag will be used in combination with other PAH-specific oral drugs. The potential of selexipag to replace or postpone the use of inhaled or parenteral prostanoids needs to be investigated in future trials.     

Selexipag for the treatment of pulmonary arterial hypertension

Chemotherapy-induced anaemia, with its important consequences on quality of life and social function of cancer patients, can be improved with erythropoietic therapy. Darbepoetin alfa is the first of a novel generation of erythropoietic proteins with a unique molecular structure and a circulating half-life that is threefold longer than that of the previous recombinant human erythropoietin. The efficacy and safety of weekly administration have been confirmed in different Phase II and III randomised trials. In order to optimise the efficacy profile of darbepoetin alfa, extended dosing intervals and front-loading regimens are evaluated, as well the optimal haemoglobin level to initiate therapy. Across all trials, darbepoetin alfa was shown to be a well-tolerated and safe therapy. The possible favourable effect on the outcome of cancer patients needs to be further elucidated.     

Macitentan for the treatment of pulmonary arterial hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a serious disease characterized by elevation of pulmonary artery pressures and right ventricular failure. It is a progressive disease with a poor 5-year survival despite recent advances in treatment. Endothelin plays an important role in the development and progression of the disease. Endothelin receptor blockers have been used to treat PAH since 2001. More recently, macitentan was approved for treatment of PAH.

Area covered: This review covers the preclinical and clinical data on macitentan.

Expert opinion: Macitentan is a more potent ERA and has been shown to delay progression of the disease. It does not appear to have any significant hepatotoxicity and has a convenient once-a-day dosing. In the large event driven trial, macitentan significantly reduced morbidity in patients with PAH. It was safe and well tolerated and the benefit was seen in treatment-naïve patients and those already receiving PAH therapy.     

Tadalafil for the treatment of pulmonary arterial hypertension

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a progressive occlusive disease affecting the pulmonary vasculature; it carries a poor prognosis. Because right ventricular failure is the key feature of deterioration in PAH patients, vasodilator treatments relieving right ventricular afterload have gained ground in the treatment of this disorder. Phosphodiesterase-5 inhibitors are effective and well tolerated vasodilators that were originally developed for erectile dysfunction. Tadalafil , the first once-daily drug of this class, was approved by the USFDA in May 2009 for the treatment of patients suffering from PAH. AREAS COVERED: This review outlines the currently available data about tadalafil and its effects in patients with PAH. It also presents evidence from recent clinical trials of tadalafil and discusses potential improvements over existing therapy options and their impact on current treatment strategies. EXPERT OPINION: Tadalafil is an efficacious drug with a favorable side-effect profile and convenient mode of administration. More studies are needed to analyze its impact on survival and to substantiate its role in an upfront combination treatment strategy.     

Combined labetalol plus flunarizine treatment for arterial hypertension

Forty-one patients (21 males and 20 females) suffering from arterial hypertension associated with peripheral and cerebral vascular distress were treated for a period of 60 days with an extempore combination of labetalol (an antihypertensive drug with an alpha- and beta-blocking action) and flunarizine (a calcium-antagonist). Changes in supine and standing arterial blood pressure and in supine heart rate were evaluated periodically. Haematological and urinary controls of a number of biomedical indices were performed in basal conditions and after 60 days. The combination was found to show a rapid efficacy in the entire patient group: both supine and standing systolic and diastolic blood were significantly reduced as early as the tenth day of treatment. No significant changes in heart rate were observed. The combination revealed neither orthostatic hypotensive effects nor side-effects of such a degree of severity as to require reduction of the dose or discontinuation of the treatment.     

Imatinib mesylate for the treatment of pulmonary arterial hypertension

INTRODUCTION: Despite recent advances, pulmonary arterial hypertension (PAH) remains a devastating disease which harbors a poor prognosis. Novel therapeutic approaches directly targeting pulmonary vascular remodeling are warranted. AREAS COVERED: This review delineates the current limitations in the management of PAH and focuses on a novel, anti-proliferative therapeutic concept. It will help readers understand the mechanisms of receptor tyrosine kinase signaling, with a special focus on platelet-derived growth factor (PDGF) receptors and their role in the pathobiology of PAH. Furthermore, it provides a comprehensive summary regarding the rationale, efficacy and safety of the tyrosine kinase inhibitor imatinib mesylate , which potently inhibits the PDGF receptor, as an additional treatment option in PAH. EXPERT OPINION: PDGF is a potent mitogen for pulmonary vascular smooth muscle cells and represents an important mediator of pulmonary vascular remodeling. Imatinib mesylate, a compound that inhibits the Bcr-Abl kinase and was developed for the treatment of chronic myeloid leukemia, also targets PDGF receptors. Both experimental and clinical data indicate that it reverses the vascular remodeling process even when it is fully established. Results from Phase II and III clinical trials suggest potent and prolonged efficacy in patients with severe PAH (i.e., pulmonary vascular resistance > 800 dynes*s*cm(-5)). Future studies should evaluate the long-term clinical efficacy and safety of imatinib, including patients with less impaired hemodynamics. Based on the current knowledge, this compound is likely to become an additional treatment option for patients with PAH and has the potential to at least partially correct the pathology of the disease.     

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.     

Sildenafil citrate for the treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension is a life-threatening, progressive disease that is characterised by an increase of pulmonary artery pressure leading to right heart failure and death. Conventional therapy (e.g., anticoagulants, diuretics, cardiac glycoside) has until recently represented the mainstay of pulmonary arterial hypertension treatment, but newer specific therapies have become available in the meantime. Among them, are the endothelin receptor antagonists (e.g., bosentan), prostacyclin and prostanoid derivatives (e.g., epoprostenol, iloprost, beraprost, treprostinil) or phosphodiesterase-5 inhibitors (e.g. sildenafil citrate). Sildenafil citrate has recently been approved for pulmonary arterial hypertension therapy, and the two discussed clinical studies assessed its safety and efficacy.     

盐酸法舒地尔治疗肺动脉高压疗效观察

目的评价盐酸法舒地尔治疗肺动脉高压的临床近期疗效及安全性。方法将60例各型肺动脉高压患者随机分为治疗组和对照组,对照组30例作常规治疗,治疗组30例在常规治疗基础上加法舒地尔治疗。结果治疗组临床症状、动脉血氧饱和度、动脉氧分压、超声心动图估测肺动脉收缩压（SPAP）、6 min步行试验距离有改善（P〈0.05）,且优于对照组（P〈0.05）。结论盐酸法舒地尔能改善运动耐量,提高肺动脉氧分压和动脉血氧饱和度,降低SPAP,增加6 min步行试验距离,对肺动脉高压治疗安全、有效。