波生坦治疗肺动脉高压42例临床疗效观察

目的 观察波生坦治疗肺动脉高压临床疗效.方法 42例患者口服波生坦14d前、后观察6min步行距离(6MWD),彩色多普勒超声心动图(UCG)测定肺动脉收缩压(PAP)、动脉血气分析,评估心功能的变化.结果 治疗后相关结果均有明显改善,6MWD增加37-139.5(72.3±39.5)m,肺动脉压下降8-37(16.5±8.2)mmHg(1mmHg=0.133kPa),动脉血氧分压(PaO2)上升16-31(22.3±5.8)mmHg;二氧化碳分压(PaCO2)平均下降8-23(14.8±6.7)mmHg,心功能改善提高1级.结论 口服波生坦可以显著改善患者耐力及降低肺动脉压.     

波生坦治疗特发性肺动脉高压的临床研究

目的观察波生坦治疗特发性肺动脉高压的临床疗效及安全性。方法选择我院收治的15例特发性肺动脉高压患者,口服波生坦进行治疗,对比治疗前后患者的各项指标变化情况。结果治疗后,患者心功能得到了明显改善;6WMD、NT-proBNP、LVEDD、mPAP等指标均较治疗前明显改善(P<0.05);患者血常规及肝肾功能检查结果均无明显变化(P>0.05)。结论波生坦是治疗特发性动脉高血压的安全有效的药物,值得向临床推荐。     

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研究进展

近年来肺动脉高压的药物治疗多从调控内源性血管收缩因子（如内皮素-1、血栓素A2）和增殖介质（前列腺素和一氧化氮）的失衡入手。本文综述了基于内皮素-1途径的内皮素受体拮抗剂,如波生坦、安立生坦以及新近上市的macitentan,该类药物具有全身副作用小和口服优势,日益受到关注。     

Bosentan, a selective and more potent antagonist for Atractaspis envenomation than the specific antivenom

Preparation of an antivenom against Atractaspis had been done for the first time in the year 2007 in NAVPC in Riyadh, however, it was a lengthy and expensive process.In this study, an alternative treatment was tested using: 1- Nitroglycerin to antagonize the coronary vasospasm induced by the venom, 2- Bosentan to block the endothelin receptors since there is a similarity in structure and effect between the toxic fraction of venom (Sarafotoxins) and endothelins and 3- The specific Antivenom in comparison to nitroglycerin and bosentan.Pretreatment of rabbits with nitroglycerin, antivenom or bosentan completely protected all rabbits from the minimal lethal doses of venom or its toxic fraction. On the other hand, injecting any of the three drugs a few minutes (min) after injecting one minimal lethal dose (MLD) of the venom or the toxic fraction and at the first signs of ischemia, just before death, showed that bosentan completely saved all rabbits. In case of nitroglycerin all rabbits died and in case of antivenom, only 5 out of 10 rabbits were rescued.It is clear that bosentan is superior to the specific antivenom in protecting rabbits; this may be due to its higher affinity to endothelin receptors than sarafotoxins.This preclinical study shows a good potential in using bosentan as a selective antidote for atractaspis envenomation, especially in the African continent.     

Prophylactic bosentan does not improve exercise capacity or lower pulmonary artery systolic pressure at high altitude

Hypoxic pulmonary vasoconstriction in response to high altitude ascent may contribute to decreased exercise capacity. Endothelin receptor antagonists reduce pulmonary artery pressure and improve exercise capacity in patients with pulmonary arterial hypertension, but their effects on exercise capacity at altitude are unknown. We studied the efficacy of bosentan started 5 days prior to ascent on exercise capacity and pulmonary artery systolic pressure (PASP) at 3800 m altitude. Eight healthy subjects completed a double-blinded, randomized, placebo-controlled, crossover study. The end-points were time to complete a cycle ergometer time trial, PASP, and hemoglobin oxygen saturation (SpO₂). The time to complete the time trial at altitude in subjects on placebo and bosentan was 527 ± 159 and 525 ± 156 s respectively (P = 0.90). PASP was not different on bosentan compared with placebo. Mean SpO₂ during the altitude time trial was lower in subjects taking bosentan compared to placebo (78 ± 6 vs. 85 ± 8% respectively, P = 0.03). Bosentan initiated 5 days prior to ascent to high altitude did not improve exercise capacity or reduce PASP, and worsened SpO₂ during high intensity exercise at altitude.     

Does rapid dose titration affect the hepatic safety profile of Bosentan?

RATIONALE: Bosentan, a dual endothelin receptor antagonist, has proven efficacy in pulmonary hypertension. Due to an association with hepatic dysfunction, it is typically initiated at a sub-therapeutic dose for 4 weeks before titration to a therapeutic dose. At our institution some patients have undergone rapid titration, to potentially benefit from therapy earlier. This study assesses the impact of this practice on hepatic safety. METHOD: All patients initiated on bosentan therapy before April 2005 were included. Rapidly titrated patients achieved a therapeutic dose by 3 days, whereas standard titration patients were titrated at 4 weeks. All patients were monitored with monthly liver function tests. RESULTS: 149 patients commenced bosentan, of which 55 were rapidly titrated. At baseline, the two groups were similar in age, BMI, diagnosis, 6-min walking distance, alanine aminotransferase (ALT), cardiac index and pulmonary artery pressures. The rapid group had elevated right atrial pressures (9.7 mm Hg versus 7.4 mm Hg, p = 0.016) and worse WHO functional class (p = 0.008) and included less females (31% versus 69%, p = 0.024). The incidence of hepatic dysfunction in all patients was 12.8% at 12 months. There was no statistical difference in incidence between the rapid and standard groups (4% versus 11% at 3 months, p = 0.211 and 6% versus 15% at 12 months, p = 0.219). Of all patients on bosentan, hepatic dysfunction was most significantly associated with a higher baseline ALT (p = 0.021), female sex (p = 0.003) and underlying connective tissue disease (p = 0.025). Subgroup analysis suggested these factors were not confounders when comparing rapid and standard titration. CONCLUSIONS: Rapid and standard titration of bosentan resulted in similar hepatic safety profiles. Baseline ALT, female sex and the presence of connective tissue disease increased the risk of hepatic dysfunction independent of the titration method used.     

The effect of endothelin receptor blockade on the development of the Sephadex-induced inflammation in the rat lung

The non-peptide ET-receptor antagonist Bosentan was used to investigate the role of endogenous endothelin-1 (ET-1) in the development of the Sephadex-induced lung inflammation in the rat. Intratracheal instillation of Sephadex caused a 60-fold rise in endothelin-1-like-immunoreactivity (ET-1-LI) in bronchoalveolar lavage fluid (BALF) concomitant with development of lung oedema, an influx of inflammatory cells into the airways and a rise in the protein content in BALF. The ET-1-LI level in lung homogenate was not significantly affected. Pre-treatment with Bosentan reduced ET-1-LI content in the lung parenchyma but increased ET-1-LI levels in BALF, possibly indicating an effective displacement of ET-1 from its receptors. In Bosentan-treated animals there was an enhancement of the lung oedema formation following Sephadex instillation, but no significant change in the number of leucocytes or protein concentration in BALF. The present data thus do not support the hypothesis that endogenous ET-1 mediates oedema formation or leucocyte influx in this model. If anything, Bosentan enhanced the oedema formation in parallel with increased ET-1-LI in BALF.     

Respirable controlled release polymeric colloid (RCRPC) of bosentan for the management of pulmonary hypertension: in vitro aerosolization,histological examination and in vivo pulmonary absorption

Bosentan is an endothelin receptor antagonist (ERA) prescribed for patients with pulmonary arterial hypertension (PAH). The oral delivery of bosentan possesses several drawbacks such as low bioavailability (about 50%), short duration of action, frequent administration, hepatotoxicity and systemic hypotension. The pulmonary administration would circumvent the pre-systemic metabolism thus improving the bioavailability and avoids the systemic adverse effects of oral bosentan. However, the short duration of action and the frequent administration are the major drawbacks of inhalation therapy. Thus, the aim of this work is to explore the potential of respirable controlled release polymeric colloid (RCRPC) for effective, safe and sustained pulmonary delivery of bosentan. Central composite design was adopted to study the influence of formulation and process variables on nanoparticles properties. The particle size, polydispersity index (PDI), entrapment efficiency (EE) and in vitro bosentan released were selected as dependent variables. The optimized RCRPC showed particle size of 420?nm, PDI of 0.39, EE of 60.5% and sustained release pattern where only 31.0% was released after 16?h. The in vitro nebulization of RCRPC indicated that PLGA nanoparticles could be incorporated into respirable nebulized droplets better than drug solution. Pharmacokinetics and histopathological examination were determined after intratracheal administration of the developed RCRPC to male albino rats compared to the oral bosentan suspension. Results revealed the great improvement of bioavailability (12.71 folds) and sustained vasodilation effect on the pulmonary blood vessels (more than 12?h). Bosentan-loaded RCRPC administered via the pulmonary route may therefore constitute an advance in the management of PAH.