Short and long term anti-inflammatory effects of bosentan therapy in patients with pulmonary arterial hypertension: relation to clinical and hemodynamic responses

Objective: We sought to investigate the short- and long- term effects of bosentan therapy on endothelial, inflammatory and fibrotic markers in patients with pulmonary arterial hypertension (PAH) and the relation to clinical and hemodynamic responses.

Methods: We studied 16 patients with moderate-severe idiopathic PAH, in WHO functional class II-IV, despite conventional treatment. Patients received additional treatment with bosentan, 62.5 mg twice daily for 1 month, followed by 125 mg twice daily for 11 months. Study endpoints included 6-min walking distance (6MWD), mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR) and plasma levels of intracellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), IL-6 and brain natriuretic peptide (BNP). Patients were assessed at baseline, 2 months and 12 months after initiation of bosentan.

Results: At 2 months there was an improvement in 6MWD (p < 0.001) and functional class (p < 0.001) and a marked fall in PVR (p < 0.001), ICAM-1 (p < 0.001), IL-6 (p < 0.001)and BNP (p = 0.001). At 12 months, 6MWD was further improved (p < 0.001), PVR remained significantly improved (p < 0.001), mPAP was significantly decreased (p < 0.001) and ICAM-1, IL-6 and BNP remained significantly lower (p < 0.001). Significant correlations were found between changes in ICAM-1 and cardiac index (r = 0.59, p = 0.01), IL-6 and PVR (r = 0.51, p = 0.04), BNP and 6MWD (r = ?0.53, p = 0.03) and BNP and PAP (r = 0.51, p = 0.04) between 2- and 12-months treatment.

Conclusions: In patients with moderate-severe PAH, the addition of bosentan to therapy, exerts favorable anti-inflammatory effects, which are associated with clinical and hemodynamic improvement.     

内皮素受体拮抗剂用于肺动脉高压的治疗进展

肺动脉高压（PAH）是一类以肺血管阻力进行性升高为主要特征的心肺血管疾病,最终可导致右心衰竭甚至死亡。早期发现PAH患者中内皮素明显高于正常,可引起肺血管的持续收缩及重构。内皮素受体拮抗剂可阻断该通路进而起到降低肺高压的作用。但目前国内临床上对于该类药物了解甚少。本文参考国内外文献对内皮素受体拮抗剂在PAH中的作用机制及临床应用作简要综述,旨在指导临床用药,使更多患者获益。     

Treatment of pulmonary arterial hypertension with bosentan: from pathophysiology to clinical evidence

In addition to its potent vasoconstricting effect, endothelin (ET)-1 induces proliferation of pulmonary vascular cells and appears to play a pathogenic role in the development of pulmonary arterial hypertension (PAH). Blockade of the ET receptors has been proposed for the treatment of this condition. Bosentan (Tracleer, Actelion Pharmaceuticals), an oral ETA/ETB receptor antagonist, has been shown to improve exercise capacity, quality of life, haemodynamics and time to clinical worsening of patients with PAH in short-term placebo-controlled trials. These improvements were sustained, and a long-term observational study on idiopathic PAH patients suggested a favourable effect on survival in this subset. In the present report, the pharmacology, clinical efficacy and safety profile of bosentan are summarised. The place of bosentan among the current therapies available for the treatment of PAH is also discussed.     

Endothelin receptor antagonists for the treatment of pulmonary arterial hypertension

Introduction: 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.

Areas covered: 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.

Expert opinion: 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.     

Pharmacokinetic and clinical profile of a novel formulation of bosentan in children with pulmonary arterial hypertension: the FUTURE-1 study

AIM

To show equivalent bosentan exposure in paediatric patients with pulmonary arterial hypertension (PAH) when compared with a cohort of historical controls of adult PAH patients using a newly developed paediatric formulation.

METHODS

Thirty-six paediatric PAH patients were enrolled in this multicentre, prospective, open-label, noncontrolled study and treated for 4 weeks with bosentan 2 mg kg⁻¹ b.i.d. and then for 8 weeks with 4 mg kg⁻¹ b.i.d. Blood samples were taken for pharmacokinetic purposes. Exploratory efficacy measurements included World Health Organization (WHO) functional class and parent''s and clinician''s Global Clinical Impression scales.

RESULTS

Comparing children with a historical group of adults, the geometric mean ratio (90% confidence interval) of the area under the plasma concentration–time curve was 0.54 (0.37, 0.78), i.e. children had lower exposure to bosentan than adults. Bosentan concentrations following doses of 2 and 4 mg kg⁻¹ were similar. Improvements in WHO functional class and the Global Clinical Impression scales occurred mainly in bosentan-naive patients, whereas the rare worsenings occurred in patients already on bosentan prior to study initiation. The paediatric formulation was well accepted and bosentan well tolerated in this study. No cases of elevated liver enzymes or anaemia were reported.

CONCLUSIONS

Exposure to bosentan, as shown comparing the results from this study with those from a study in adults, was different in paediatric and adult PAH patients. Since FUTURE-1 and past studies suggest a favourable benefit–risk profile for bosentan at 2 mg kg⁻¹ b.i.d., this dose is recommended for children with PAH. The new paediatric formulation was well tolerated.     

Ambrisentan,an endothelin receptor type A-selective endothelin receptor antagonist,for the treatment of pulmonary arterial hypertension

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.     

波生坦治疗特发性肺动脉高压的临床疗效

目的 探讨口服波生坦治疗特发性肺动脉高压( IPAH)的临床效果.方法 将45例特发性肺动脉高压患者随机分为治疗组23例和对照组22例;两组均采取常规治疗,治疗组在此基础上口服波生坦;根据观察结果,分析、探讨两组的治疗效果.结果 经过14d治疗,治疗组PaO2和6MWD分别为(81.0±3.7)mm Hg(1 mm Hg=0.133 kPa)和(331.0±81.2)m,较对照组的(57.0±3.9) mmHg和(263.0±58.9)m高;PaCO2、PAP分别为(43.0±5.9) mm Hg和(63.0±17.1) mm Hg,较对照组的(66.0±7.2) mm Hg和(78.0±16.7)mm Hg低;两组比较差异均有显著性(P＜0.05).结论 口服波生坦能有效治疗特发性肺动脉高压,显著降低肺动脉压.     

内皮素受体拮抗剂治疗肺动脉高压的临床应用进展

内皮素（ET）-1是强有力的内源性血管收缩剂，在肺动脉高压的发病机制中发挥重要作用。ET受体分为两种类型：ETA和ETB。本文综述近年来非选择性ET受体拮抗剂和选择性ETA受体拮抗剂治疗肺动脉高压的临床应用进展。证明ET受体拮抗剂可以改善肺动脉高压患者的运动耐量，降低肺血管阻力，增加心输出量，改善心功能。其主要副作用是血清转氨酶增高。     

治疗肺动脉高压新药安贝生坦的药理与临床研究

安贝生坦为一种选择性内皮素A受体阻滞剂,临床用于治疗肺动脉高压.它能有效改善症状,且耐受性良好.与抗凝剂发生药物相互作用较少,肝功能损伤等不良反应发生率也较低.现对其药理作用、药动学、临床研究、安全性评价等方面做一综述.     

Long-term trial of bosentan monotherapy for pulmonary arterial hypertension in Japanese patients

ABSTRACT

Objective: To determine the efficacy and safety of long-term bosentan monotherapy in Japanese patients with pulmonary arterial hypertension (PAH).

Research design and methods: The present study was an extension to a 12?week open-label trial of bosentan in which 21 Japanese patients with PAH received bosentan, 125?mg twice daily. Of the 21 patients in the initial trial, 20 elected to participate in the long-term study and to continue to receive bosentan for up to 3 years.

Main outcome measures: The primary efficacy measure was comparison of World Health Organization (WHO) functional class for pulmonary arterial hypertension following long-term (> 2.5 years) therapy compared with baseline (prior to initiation of bosentan). Secondary outcomes included time from initiation of bosentan therapy to clinical worsening and safety assessments.

Results: Bosentan treatment was continued for a median of 2.7 years (range 0.4–3.0 years); 12 patients received bosentan monotherapy for at least 2.5 years. Following long-term treatment, improvement of WHO functional class compared with baseline was observed in 9/12 patients (75.0%) and in 3/12 patients (25.0%) the functional class remained stable; no patient experienced a worsening of WHO functional class compared with baseline. Overall, long-term treatment with bosentan was well tolerated.

Conclusions: Long-term treatment with bosentan is well tolerated and is associated with sustained clinical improvement in Japanese patients with PAH. Bosentan, therefore, represents a valuable treatment option for Japanese patients with this devastating disease.     

Expert opinion on available options treating pulmonary arterial hypertension

Until in the early nineties, pulmonary arterial hypertension (PAH) was a uniformly fatal disease, with a median life expectancy of ～ 2.5 years. Uncontrolled studies showed that a small proportion of patients responded to high-dose calcium channel blockers, retrospective studies supported the use of anticoagulant therapy and heart–lung or lung transplantation remained the only option. In 1996, a 3-month randomised, placebo-controlled trial showed that chronic intravenous epoprostenol (synthetic prostacyclin) improved functional state, exercise capacity, haemodynamics, and even survival in patients with idiopathic PAH. Similar benefits were subsequently reported and extended to all PAH categories, and confirmed with more stable prostacyclin analogues administered subcutaneously (treprostinil), by inhalation (iloprost), or even orally (beraprost). In the early 2000s, two randomised controlled trials showed efficacy of the oral intake of the dual endothelin A/B receptor antagonist bosentan. Two selective endothelin-A receptor antagonists, sitaxsentan and ambrisentan, are being developed. Finally, a randomised controlled trial has established the therapeutic efficacy of phosphodiesterase-5 inhibition with sildenafil, introducing a third signalling pathway to be targeted by the pharmacological treatment of PAH. Another phosphodiesterase-5 inhibitor, tadalafil, is already being evaluated. While all these treatments have markedly improved the lives of PAH patients, they have not offered yet a cure of the disease. Multi-drug approaches are now under evaluation, with more ambitious therapeutic goals. Alternative approaches with stem cells, RhoA-Rho-kinase inhibitors, platelet derived growth factor inhibitors and vasoactive intestinal peptides are being considered.     

波生坦用于儿童CHD相关PAH治疗的临床效果观察

目的 探讨非选择性内皮素受体拮抗剂波生坦用于治疗儿童先天性心脏病(congenital heart disease,CHD)相关性肺动脉高压(puhmonary arterial hypertension,PAH)的临床效果及安全性.方法 选取2011年4月～2012年3月山东省莱芜市人民医院收治的32例先天心脏病患儿,随机分为治疗组和对照组(n=16).对照组进行常规强心利尿治疗,治疗组在对照组的基础上应用波生坦进行治疗,治疗6个月后观察2组患者肺动脉压、肺血管阻力、6 min步行实验、心率(heart rate,HR)、心功能及肝肾功能指标的变化情况差异.结果 治疗前对照组和治疗组的肺动脉收缩压、肺动脉舒张压、肺动脉阻力、HR比较差异不显著;治疗后对照组和治疗组肺动脉收缩压、舒张压均显著降低(P＜0.05),肺动脉阻力、HR无显著性差异,且治疗后治疗组患儿肺动脉收缩压、舒张压显著低于对照组,差异有统计学意义(P＜0.05).治疗前2组6 m in步行距离差异不显著,治疗后治疗组的步行距离显著长于对照组(P＜0.05).治疗前后2组尿素氮(urea nitrogen,BUN)、肌酐(ereatinine,CREA)、谷丙转氨酶(alanine aminotransferase,AST)、谷草转氨酶(aspartate aminotransferase,ALT)差异均不显著.结论 非选择性内皮素受体拮抗剂用于治疗CHD相关性PAH能改善肺动脉压及提高肺活动耐量,具有较好的安全性.     

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.     

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.     

Pharmacokinetic interactions among imatinib,bosentan and sildenafil,and their clinical implications in severe pulmonary arterial hypertension

AimsThis study characterized the population pharmacokinetics (PK) of imatinib in patients with severe pulmonary arterial hypertension (PAH), investigated drug–drug interactions (DDI) among imatinib, sildenafil and bosentan, and evaluated their clinical implications.MethodsPlasma concentrations of imatinib, bosentan and sildenafil were collected in a phase III study and were used to characterize the PK of imatinib in this population. DDIs among the three drugs were quantified using a linear mixed model and log-transformed drug concentrations.ResultsThe population mean estimates of apparent clearance (CL/F) and volume (V/F) were 10.8 l h^–1 (95% CI 9.2, 12.4 l h^–1) and 267 l (95% CI 208, 326 l), respectively. It was estimated that sildenafil concentrations increased, on average, by 64% (95% CI 32%, 103%) and bosentan concentrations by 51% (95% CI 12%, 104%), in the presence of imatinib. Despite increased concentrations of co-medications, treatment differences between imatinib and placebo for change in 6 min walk distance and pulmonary vascular resistance were relatively constant across the entire concentration range for sildenafil and bosentan. Overall, higher concentrations of imatinib and bosentan were not associated with increasing liver enzymes (serum glutamic oxaloacetic transaminases [SGOT]/serum glutamic-pyruvic transaminase [SGPT]).ConclusionsPopulation PKs of imatinib in patients with severe PAH were found comparable with those of patients with chronic myeloid leukemia. Imatinib was found effective regardless of the co-medications and showed intrinsic efficacy beyond merely elevating the concentrations of the co-medications due to DDIs. There was no evidence of increased risk of liver toxicity upon co-administration with bosentan.     

Long-term treatment of pulmonary arterial hypertension with macitentan in Japanese patients

Abstract

Objective: Macitentan, a novel dual endothelin receptor antagonist, was approved for the treatment of pulmonary arterial hypertension (PAH) in Japan. However, long-term effects in Japanese patients of macitentan are currently unavailable. This study sought to assess the long-term efficacy and safety of macitentan in Japanese patients with PAH.

Methods: In this multicenter, open-label, clinical extension study (JapicCTI-121986), efficacy was evaluated based on the change from baseline at 24, 48, 72, 96 and 120-week in the 6-minute walk distance (6MWD), World Health Organization (WHO) functional class, and serum N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels. In addition, the time to a hospitalization related to PAH and a morbidity/mortality event was determined. As for safety, the incidence of adverse events and changes in laboratory data and vital signs were assessed.

Results: Macitentan was administered at a once-daily dose of 10?mg in 30 PAH patients with a median treatment period of 2.4?years (range, 229–1037?days). The improvements in 6MWD, WHO functional class and NT-pro-BNP at week 24 were maintained throughout the long-term follow-up. Hospitalization related to PAH occurred in 2 patients. Levels of liver enzyme and hemoglobin remained unchanged throughout the study period.

Conclusions: This study suggests that the long-term use of macitentan is well tolerated and effective in Japanese patients with PAH. We concluded that macitentan can be a possible approach to reduce morbidity/mortality in Japanese PAH patients.     

Current understanding of the role of bosentan in inoperable chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension may occur in the context of incomplete lysis of acute pulmonary emboli, resulting in the obstruction of pulmonary blood flow, as well as progressive right ventricular dysfunction and failure. The treatment of choice for this condition is surgical removal of the obstructing material. However, in many patients, surgery is not possible due to either an unfavourable distribution of the disease, the development of a concurrent small vessel pulmonary arteriopathy, or the presence of significant comorbid conditions. There is increasing evidence that the medical therapies that are used in other forms of pulmonary hypertension may also be effective in inoperable chronic thromboembolic pulmonary hypertension. This article examines the rationale for the use of the oral dual endothelin receptor antagonist bosentan in this life-threatening condition.     

Efficacy,safety and clinical pharmacology of macitentan in comparison to other endothelin receptor antagonists in the treatment of pulmonary arterial hypertension

Introduction: Macitentan is a novel dual endothelin receptor antagonist (ERA) showing sustained receptor occupancy. In vitro and in vivo animal studies have demonstrated its potency in antagonizing endothelin-induced disorders. A large morbidity/mortality study in patients with pulmonary arterial hypertension (PAH) taking macitentan has been completed recently.

Areas covered: This drug evaluation reviews the efficacy, safety and clinical pharmacology of macitentan in the treatment of PAH.

Expert opinion: The large Phase III study (SERAPHIN) tested macitentan in more than 700 PAH patients and has provided unique long-term outcome data for this ERA, not available for other members of this class. The effect on a composite clinically relevant morbidity/mortality end point was highly significant at a 10 mg/day dose. The safety profile of macitentan appears to be superior with respect to hepatic safety and edema/fluid retention than bosentan and ambrisentan, respectively, and is similar when considering decrease in hemoglobin concentration. The drug has a low propensity for drug–drug interactions and has one circulating pharmacologically active metabolite. The pharmacokinetics of macitentan in patients with renal or hepatic impairment does not require dose adjustments. Based on its characteristics, macitentan is an important addition to the therapeutic armamentarium in the long-term treatment of PAH. Its potential use in other disorders is under investigation.     

Novel therapeutics for the treatment of paediatric pulmonary arterial hypertension

The treatment of paediatric pulmonary arterial hypertension is challenging due to the serious nature of the disease, its rapid progression and the limited treatment options available. However, recent advances in the treatment of pulmonary arterial hypertension may offer significant improvements for patients suffering from this condition. Novel treatment options include prostacyclin analogues and endothelin receptor antagonists. A comprehensive review of the newer agents, with an emphasis on the pathobiology/pathophysiology of pulmonary arterial hypertension provides insight into future management of paediatric pulmonary arterial hypertension.     

肺动脉高压药物及新靶点研究进展

肺动脉高压(PAH)为一种少见的慢性疾病,其危害性大、致死率高,多发于老年人和妇女。随着我国步入老龄化社会,对PAH的防治越发重视。综述了包括CCBs、PDE-5抑制剂、ERAs和PGI2类常规靶点和鸟苷酸环化酶激动剂,5-羟色胺,Bcr-Abl蛋白络氨酸激酶抑制剂,Rho-激酶抑制剂,内皮祖细胞和基因等治疗该疾病的新型作用靶点在内的最新靶点与药物的研究进展,以及新一代药物的发展方向。