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 ET_A/ET_B 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.     

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.     

波生坦治疗成人肺动脉高压研究进展

肺动脉高压是临床上常见的一种致残率和致死率较高的疾病,内皮素受体拮抗剂是目前治疗肺动脉高压的常用靶向药物之一。波生坦作为第1个研发并应用于临床的内皮素受体拮抗剂,目前广泛应用于肺动脉高压的治疗。单药治疗方面,波生坦可以改善特发性肺动脉高压、结缔组织病相关性肺动脉高压患者的运动耐量、血流动力学状态和长期生存率;但其应用于先心病相关肺动脉高压患者的长期生存获益及慢性血栓栓塞性肺动脉高压患者的疗效仍缺乏证据。对于心功能Ⅲ~Ⅳ级的肺动脉高压患者,初始应用波生坦联合另一种靶向药物治疗可能优于单药治疗,而对于心功能Ⅱ~Ⅲ级的肺动脉高压患者,目前仍缺少联合用药优于单药治疗的证据。     

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.     

Pharmacokinetics of bosentan in routinely treated Japanese pediatric patients with pulmonary arterial hypertension

We evaluated the pharmacokinetics of routinely administered bosentan in 46 Japanese pediatric patients with pulmonary arterial hypertension. Plasma samples were taken twice at times corresponding to the peak and trough concentrations following repetitive oral administration. The population pharmacokinetic parameters of bosentan were estimated by use of the NONMEM program, in which a one-compartment model with repetitive bolus dosing was parameterized in terms of the oral clearance (CL/F) and elimination rate constant (k). Polymorphisms of CYP3A5, SLCO1B1, SLCO1B3, and SLCO2B1 had no significant effect on the disposition of bosentan. In addition, the pharmacokinetics of bosentan was not altered by heart failure or coadministration of sildenafil. In contrast, weight (WT)-normalized values of CL/F were correlated negatively with age (AGE). The final population mean values of CL/F and k were estimated to be 0.409 · (1 - 0.0377 · (AGE - 3.81)) · WT L/h and 0.175 h(-1), respectively.     

Effect of bosentan treatment on surrogate markers in pulmonary arterial hypertension

OBJECTIVE: The aim of this study was to evaluate the effect of the oral dual ET(A)/ET(B) receptor antagonist bosentan on different surrogate markers in patients with pulmonary arterial hypertension (PAH). DESIGN AND SETTING: Prospective, open label, uncontrolled study in a University Hospital in Brazil. POPULATION: Fifteen PAH patients (11 females) with mean age of 40 +/- 11 years (5 in WHO functional class II, 10 in class III). METHODS: All patients were investigated at baseline and after 16 weeks of bosentan treatment. We used the following surrogate markers for patients' evaluation: 6-min walk test, quality of life questionnaire (Short Form SF-36) and N-terminal proBNP (B type natriuretic peptide) fraction levels in blood. RESULTS: Between the evaluation at baseline and week 16, the 6-min walk test distance changed from 396 +/- 135 to 434 +/- 137 m (p < 0.05). Each of the eight domains of the SF-36 was significantly improved. Mean NT-proBNP levels were decreased from a mean of 1670 pg/mL to 1010 pg/mL (p = 0.01). CONCLUSION: The study suggests that bosentan treatment results in the improvement of different kinds of surrogate markers independently of their specificity to reflect functional capacity, quality of life and myocardial stress. It is concluded that the combined use of these different markers may be an alternative endpoint for future short duration clinical trials.     

Effect of bosentan treatment on surrogate markers in pulmonary arterial hypertension

ABSTRACT

Objective: The aim of this study was to evaluate the effect of the oral dual ET_A/ET_B receptor antagonist bosentan on different surrogate markers in patients with pulmonary arterial hypertension (PAH).

Design and setting: Prospective, open label, uncontrolled study in a University Hospital in Brazil.

Population: Fifteen PAH patients (11 females) with mean age of 40 ± 11 years (5 in WHO functional class II, 10 in class III).

Methods: All patients were investigated at baseline and after 16 weeks of bosentan treatment. We used the following surrogate markers for patients’ evaluation: 6‐min walk test, quality of life questionnaire (Short Form SF‐36) and N‐terminal proBNP (B type natriuretic peptide) fraction levels in blood.

Results: Between the evaluation at baseline and week 16, the 6‐min walk test distance changed from 396 ± 135 to 434 ± 137?m (?p < 0.05). Each of the eight domains of the SF‐36 was significantly improved. Mean NT‐proBNP levels were decreased from a mean of 1670?pg/mL to 1010?pg/mL (?p = 0.01).

Conclusion: The study suggests that bosentan treatment results in the improvement of different kinds of surrogate markers independently of their specificity to reflect functional capacity, quality of life and myocardial stress. It is concluded that the combined use of these different markers may be an alternative endpoint for future short duration clinical trials.     

波生坦治疗中重度特发性及先天性心脏病相关肺动脉高压40例

目的观察波生坦一线治疗先天性心脏病相关肺动脉高压(CHD-PAH)和特发性肺动脉高压(IPAH)患者疗效和用药前后生活质量(QOL)改善情况。方法 40例住院经右心导管检查确诊为CHDPAH和IPAH的患者给予波生坦62.5 mg,bid,4周后调整为125 mg,bid。比较用药前、3个月时患者QOL各维度的改善情况,分别记录并比较治疗前、治疗后1个月和3个月时患者的6 min步行距离(6MWD)、WHO心功能、Borg呼吸困难指数和超声心动图结果。结果波生坦能有效地提高患者QOL的生理机能、生理职能、躯体疼痛、一般状况、精力、情感职能和精神健康7个维度(P<0.01)。对CHDPAH和IPAH两个亚组分别进行比较,除社会功能外,治疗前后其他维度均有显著改善(P<0.01),且两亚组间均无显著差异(P>0.05)。治疗1个月后,患者的6MWD增至(393.1±63.4)m,治疗3个月后为(425.6±68.9)m,与治疗前(351.9±70.9)m相比均有非常显著差异(P<0.01)。治疗3个月后,26例(65%)患者WHO心功能降低1级,4例(10%)降低2级,10例患者维持原有分级不变;患者的肺血管收缩压明显改善,由治疗前(110.6±24.1)mmHg下降为(99.5±26.3)mmHg(P=0.011);对主要指标6MWD、Borg呼吸困难指数和心超指标等进行CHD-PAH和IPAH两亚组组间分析,除左室收缩末内径外,均无显著差异(P>0.05);总体患者的不良反应发生率低。结论波生坦短期治疗CHD-PAH和IPAH患者的疗效确定、结果相近,均可提高其运动能力、明显改善生活质量的7个维度,缓解呼吸困难的症状,且安全性、耐受性良好。     

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.     

波生坦对儿童先天性心脏病相关肺动脉高压的治疗作用

目的 观察波生坦在儿童先天性心脏病(CHD)相关肺动脉高压(PAH)患儿中应用的疗效及安全性,评价波生坦治疗儿童CHD-PAH的临床效果.方法 入选2008年1月至2011年5月首都医科大学附属北京安贞医院小儿心脏科入院≤18岁CHD-PAH患儿23例,给予波生坦口服治疗,进行开放性、观察性研究.随访评估服药前后6 min步行试验距离(6MWTD)、经皮血氧饱和度(SpO2)、纽约心脏病学会心功能分级(NYHA-FC)、心导管检查血流动力学参数(平均肺动脉压、肺小动脉阻力指数、肺体循环流量比、肺体循环阻力比)及肝功能变化.结果入选儿童患儿23例,平均年龄为(9.1±3.6)岁(2.1～14.7岁).口服波生坦治疗平均时间(13.3±7.5)个月(6 ～31个月).治疗后,11例患儿(年龄7岁以上)的6MWTD从(458±16)m增加至(496±49)m(P =0.035).23例患儿的SpO2 (89 ±6)％提高到(91±5)％(P=0.009).此外,所有患儿的NYHA心功能分级有不同程度改善或保持稳定.12例服药后再次接受心导管检查的患儿,肺、体循环比( Qp/Qs)由服药前平均(0.97 ±0.38)增至(1.16±0.39)(P =0.076),平均肺动脉压(mPAP)由(76±6)mm Hg(1 mm Hg=0.133 kPa)增至(78±12)mm Hg(P =0.649),肺小动脉阻力指数( PVRi)由平均(20.78±8.84) Woods units/m2降至( 18.13±7.71) Woods units/m2(P=0.165),肺、体循环阻力比(Rp/Rs)由(1.03±0.38)降至(0.83±0.29)(P=0.06),以上指标均有不同程度改善,但差异无统计学意义.所有患儿均对波生坦良好耐受,仅1例10岁男性患儿有一过性鲜血便.结论 服用波生坦可明显改善CHD-PAH患儿的6MWT、SpO2、NYHA-FC,降低PVR及Rp/Rs.波生坦在不符合手术适应证的儿童CHD-PAH患儿中的应用是安全、有效的.     

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.     

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.     

Tadalafil: the evidence for its clinical potential in the treatment of pulmonary arterial hypertension

Introduction:

Pulmonary arterial hypertension (PAH), characterized by increased pulmonary artery pressures in the absence of elevated pulmonary venous pressures, is a progressive disease associated with reduced exercise capacity and increased mortality risk. Current treatments for PAH include nonspecific vasodilators, prostacyclin and related analogs, and endothelin receptor antagonists. Since phosphodiesterase type 5 is highly expressed in pulmonary vascular tissues, agents that selectively inhibit phosphodiesterase type 5 activity induce pulmonary arterial vasodilatation, and are being developed for the treatment of PAH.

Aims:

The purpose of this review is to evaluate the existing evidence for the use of tadalafil, a selective phosphodiesterase type 5 inhibitor, in PAH.

Evidence review:

Data from erectile dysfunction populations indicate that tadalafil is well tolerated with an elimination half-life of 17.5 hours. Small pilot studies in patients with PAH of mixed etiology demonstrate that tadalafil reduces pulmonary vascular resistance and is associated with improved clinical status. A multicenter, randomized, placebo-controlled clinical trial in patients with PAH is currently recruiting patients.

Clinical potential:

Based on existing studies of sildenafil, a related selective phosphodiesterase type 5 inhibitor in PAH, and the findings of initial pilot studies, tadalafil appears to have excellent potential to provide therapeutic benefit in patients with pulmonary hypertension. The long elimination half-life of tadalafil makes it suitable for once-daily dosing.     

波生坦联合伐地那非治疗先天性心脏病术后肺动脉高压的疗效观察

目的探讨波生坦联合伐地那非治疗先天性心脏病术后肺动脉高压的临床疗效。方法选取2013年1月—2015年1月在聊城市第二人民医院心胸外科接受治疗的先天性心脏病术后肺动脉高压患者76例,随机分为对照组和治疗组,每组各38例。对照组口服盐酸伐地那非片,20 mg/次,1次/d。治疗组在对照组的基础上口服波生坦片,根据患者体质量给药,体质量10 kg:15.625 mg/次;体质量10~20 kg:31.25 mg/次;体质量21~40 kg:62.5 mg/次,1次/d。两组患儿均治疗6个月。观察两组的临床疗效,同时比较治疗前后两组呼吸困难评分(Borg评分)、脑钠尿肽(BNP)、心脏功能分级(NYHAFC)、血氧饱和度(SpO_2)、6 min步行实验距离(6 MWTD)及右心导管检查结果变化情况。结果治疗后,对照组和治疗组的总有效率分别为73.68%、92.11%,两组比较差异有统计学意义(P0.05)。治疗后,两组患者Borg评分、BNP及NYHAFC均明显降低,同组治疗前后比较差异有统计学意义(P0.05);且治疗组这些观察指标的下降幅度优于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组患者肺动脉收缩压(s PAP)、肺动脉平均压(mPAP)、肺动脉收缩压/体循环动脉收缩压(Pp/Ps)均明显降低,而肺循环血流量/体循环血流量(Qp/Qs)明显增高,同组治疗前后比较差异有统计学意义(P0.05);且治疗组这些观察指标的改善程度优于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组患者Sp O2和6 MWTD均明显增加,同组治疗前后比较差异有统计学意义(P0.05);且治疗组这些观察指标的改善程度优于对照组,两组比较差异具有统计学意义(P0.05)。结论波生坦联合伐地那非治疗先天性心脏病术后肺动脉高压具有较好的临床疗效,可提高患者的运动能力,改善患者的心脏功能,缓解呼吸困难症状,具有一定的临床推广应用价值。     

肺动脉高压的免疫调节治疗

肺动脉高压是临床上常见的疾病,其发病机制尚未完全清楚。免疫因素在肺动脉高压的发病机制中起重要作用。免疫抑制疗法为肺动脉高压治疗提供了新的途径。本文就机体免疫紊乱对肺动脉高压的影响机制及其免疫调节治疗的临床应用及研究现状进行综述。     

肺动脉高压治疗进展

肺动脉高压（Pulmonary Arterial Hypertension,PAH）是以肺小动脉的血管痉挛、内膜增生及重构和微血栓病灶形成为主要特征的一种疾病[1]。患者最终往往死于右心衰竭。PAH是一种进展性疾病,预后较差,目前缺乏有效的治疗方案。近年来,一些新的药物和治疗方法开始应用于临床,使患者的生活质量和临床预后不断改善,现将最近的治疗进展综述如下。     

波生坦治疗结缔组织病相关肺动脉高压临床疗效观察及安全性分析

目的观察波生坦治疗结缔组织病相关肺动脉高压(CTD-PAH)的有效性及安全性。方法分析和比较42例经波生坦治疗的CTD-PAH患者4周的6 min步行距离(6MWD),Borg呼吸困难评分,生活质量调查表评分(SF-36),肺动脉高压心功能分级及超声心动图指标较基线变化情况。结果与基线时相比,波生坦治疗4周6MWD从(328±68)m增加至(402±62)m(P<0.05)。Borg评分由(3.1±1.3)减少至(2.5±1.4)(P<0.05)。SF-36量表中除社会功能外其他7项维度评分均有改善(P<0.05)。肺动脉高压心功能分级较前改善(P<0.05)。并发心包积液由基线19例(45%)减少至8例(19%)(P<0.05)。超声心动图中左房内径、左室舒张末期内径、三尖瓣反流速率和肺动脉压力分别由基线状态时的(35±7)mm、(41±9)mm、(4.4±0.6)m/s和(63±23)mmHg减少至治疗4周后的(37±7)mm、(40±7)mm、(4.2±0.5)和(54±12)(P<0.05)。治疗组无药物不良反应发生。结论波生坦有效改善CTD-PAH患者心脏功能,是治疗CTD-PAH安全有效靶向药物。