Bosentan

Importance to the field: Pulmonary arterial hypertension (PAH) is a morbid condition with high mortality if left untreated. Bosentan is an effective treatment option for group 1 pulmonary arterial hypertension. Bosentan improves exercise tolerance and functional class and delays the time to clinical worsening in these patients. Investigation is ongoing to determine its efficacy in other groups of pulmonary hypertension.

Areas covered in this review: This review provides a background on endothelin activity in PAH, as a rationale for the use of bosentan in this disease. It also presents evidence from key clinical trials of bosentan and discusses future directions in the study of bosentan to help the clinician better understand the role of bosentan in PAH management.

What the reader will gain: i) An understanding of the rationale for using endothelin receptor antagonists in treating PAH; ii) an understanding of the clinical evidence to support bosentan for the treatment of PAH; and iii) an understanding of how to use bosentan optimally in the treatment of PAH.

Take home message: Bosentan is an effective and safe treatment for patients with PAH. Patients with suspected PAH should be evaluated carefully as the use of bosentan in non-group 1 pulmonary hypertension is still being investigated. Patients on bosentan should be monitored with monthly liver transaminase testing. Coadministration with other drugs should be reviewed carefully as drug–drug interactions may be important.     

Bosentan

? Bosentan is a nonpeptide, specific, competitive, dual antagonist at both endothelin receptor subtypes (ET_A and ET_B). Orally administered bosentan effectively prevents endothelin 1-induced vasoconstriction in pulmonary vessels in patients with pulmonary arterial hypertension. ? Improvement in exercise capacity from baseline was significantly greater with bosentan than with placebo in two phase III trials in patients with WHO functional class III or IV pulmonary arterial hypertension (primary or associated with connective tissue disease) despite treatment with vasodilators, diuretics, anticoagulants, cardiac glycosides, or supplemental oxygen. The beneficial effects of bosentan on exercise capacity were maintained for at least 20 weeks. ? Compared with placebo, bosentan led to a significantly greater improvement from pretreatment values in secondary efficacy end-points such as the Borg dyspnea index, WHO functional class, and cardiopulmonary hemodynamic parameters (cardiac index, pulmonary vascular resistance, pulmonary artery pressure, pulmonary capillary wedge pressure, mean right atrial pressure). ? Bosentan significantly reduced the incidence, and delayed the onset, of clinical worsening of pulmonary arterial hypertension compared with placebo. ? In published clinical trials, adverse events that occurred with similar or greater frequency with bosentan 125mg twice daily than with placebo included headache, syncope, flushing and abnormal hepatic function. Those that occurred less frequently with bosentan 125mg twice daily than with placebo included dizziness, worsening of symptoms of pulmonary arterial hypertension, cough and dyspnea.     

波生坦片的制备

目的 优化波生坦片的制剂处方,以解决波生坦溶出度不高,制剂不稳定的共性难题。方法 采用湿法制粒后压片的工艺,以片剂的性状、溶出度、有关物质、晶型稳定性等为评价指标,比较不同处方制得的波生坦片,并与原研药相比较。结果 优化后的处方制得的波生坦片,片面光洁美观,溶出效果好,晶型稳定,有关物质符合要求,且溶出行为和质量与原研药一致。结论 该新处方增加了波生坦的溶出度,提高了制剂晶型的稳定性,制剂质量与原研药一致,且制备方法简单、可行、易于实现产业化大生产,值得推广。     

Bosentan in systemic sclerosis

Systemic sclerosis (SSc) is a relatively rare chronic connective tissue disease characterized by varying degrees of skin fibrosis and visceral organ involvement. Pulmonary compromise, including pulmonary arterial hypertension and interstitial lung disease, is currently the leading cause of death in patients with SSc. Digital ulcers are common complications which lead to substantial morbidity and functional limitation. Until recently, treatment options for these complications were quite limited. Endothelin-1 (ET-1) is a peptide that has a role in promoting both vascular injury and the fibrotic process in SSc. Bosentan is a dual endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension. In patients with pulmonary hypertension secondary to SSc, bosentan therapy prevents deterioration in exercise capacity and may improve survival. No beneficial effect was found in one study in patients with interstitial lung disease and SSc. Bosentan is able to reduce the number of new digital ulcers in patients with either a history of previous ulcers or an active ulcer, without expediting the healing of existing ulcers. Bosentan therapy is contraindicated in pregnancy and causes elevated liver transaminases in up to 14% of patients. Hence, monthly pregnancy tests should be performed and hepatic function should be monitored.     

Bosentan for idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a debilitating, fatal, chronic fibrosing lung disease with no known effective therapy. Endothelin-1 may underlie the pathogenesis of lung fibrosis, therefore it was hypothesized that the oral dual endothelin receptor antagonist bosentan may have efficacy for the treatment of IPF. The BUILD-1 study evaluated the efficacy, safety and tolerability of bosentan in patients with IPF. Bosentan was associated with a trend toward delayed time to disease progression or death and improvement in quality-of-life, both of which were more pronounced in patients with a biopsy-confirmed IPF diagnosis. These observations are being investigated in the ongoing BUILD-3 trial.     

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.     

Bosentan预防大鼠低氧性肺动脉高压形成的作用

目的研究Bosentan预防低氧诱导的肺动脉高压发生的药效作用,探讨内皮素-1(ET-1)在慢性高原病发病中的作用。方法30只Wistar大鼠随机均分为常氧对照组、低氧对照组和Bosentan组,将低氧对照组和Bosentan组放入模拟海拔为5.5 km的低氧、低压环境中。常氧对照组和低氧对照组ig 0.9%生理盐水,Bosentan组ig 100 mg.ml-1Bosentan水剂,每天2次。饲养15 d后,测量大鼠平均肺动脉高压(PAP)、左右心室比重[RV/(LV S)]比值。结果Bosentan组大鼠血红蛋白(Hb)、红细胞压积(Hct),ET-1与低氧对照组相比无差异,而PAP、RV/(LV S)均显著低于低氧对照组(P<0.01)。结论Bosentan可显著预防低氧性肺动脉压的升高,缓解低氧对心肌细胞和血管平滑肌细胞的损伤,但不能抑制红细胞的过度增生。     

双重内皮素受体阻滞剂波生坦

波生坦是一种相对分子质量低的竞争性双重内皮素受体阻滞剂,通过与ETA和ETB的结合来阻止ET-1的作用.它能降低血管压力,阻止心脏和血管增生,减轻肺纤维化和炎症,用于治疗WHO功能组Ⅲ和Ⅳ型肺动脉高压.现综述波生坦的药理学、药动学和临床应用方面的进展.     

Bosentan: a dual endothelin receptor antagonist

The peptide endothelin plays a significant role in a wide array of pathological conditions, including primary pulmonary hypertension and pulmonary arterial hypertension associated with collagen vascular disease. These are life-threatening conditions that can severely compromise the function of the lungs and heart. Inhibiting the actions of endothelin by blockade of its receptors provides a new and effective approach to therapy for patients with these conditions. Bosentan (Tracleer ) is the first orally-active dual endothelin receptor antagonist and has recently been approved in the US, Canada, Switzerland and the EU for the treatment of pulmonary arterial hypertension. Bosentan significantly improves exercise capacity, symptoms and functional status in patients with this disease and also slows clinical deterioration, which may be indicative of a delay of disease progression. Results from large-scale studies of bosentan in patients with pulmonary arterial hypertension and chronic heart failure have established its long-term safety and tolerability profiles. The introduction of the dual endothelin receptor antagonist bosentan has provided an essential treatment for pulmonary arterial hypertension and ongoing trials are evaluating its potential role in the management of other endothelin-mediated disease states.     

内皮素受体拮抗剂波生坦与其他药物的相互作用

内皮素受体拮抗剂波生坦是治疗肺动脉高压的有效药物之一。综述波生坦的药动学、药效学特点,以及与其他药物相互作用的机制和临床应用注意事项,并展望了波生坦等内皮素受体拮抗剂的临床应用前景。     

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。     

波生坦治疗新生儿缺氧性肺动脉高压的临床观察

目的:观察波生坦治疗新生儿缺氧性肺动脉高压(HPH)的有效性和安全性。方法:选择2014年1月-2019年3月于我院新生儿科住院治疗的82例HPH新生儿为研究对象,按是否加用波生坦治疗分为波生坦组(50例)和非波生坦组(32例);另选取25例血清标本留取时间、出生胎龄、日龄等一般资料与波生坦组匹配的非HPH新生儿为对照组。所有HPH新生儿均给予持续静脉滴注盐酸多巴胺注射液5 mg/(kg·min),直到肺动脉收缩压(PASP)正常;在此基础上,波生坦组患儿加用波生坦片1 mg/kg(用适量注射用水溶解后喂服),q12 h,连用72 h。分析HPH患儿血清内皮素1(ET-1)水平与PASP的关系,并比较治疗前后波生坦组和非波生坦组HPH患儿的PASP和疗效以及3组患儿的动脉血气指标变化及不良反应发生情况。结果:治疗前,波生坦组患儿血清ET-1水平为(164.3±115.3)pg/mL,显著高于对照组的(41.9±3.7)pg/mL,且与PASP呈正相关(r=0.864,P<0.001)。波生坦组患儿的治疗总有效率为90.00%,显著高于非波生坦组的71.88%(P<0.05)...     

Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension

AIMS: To determine whether bosentan decreases the plasma concentration of sildenafil in patients with pulmonary arterial hypertension. METHODS: Ten patients (aged 39-77 years) with pulmonary arterial hypertension in WHO functional class III received bosentan 62.5 mg twice daily for 1 month, then 125 mg twice daily for a second month. Sildenafil 100 mg was given as a single dose before starting bosentan (visit 1) and at the end of each month of bosentan treatment (visits 2 and 3). Sildenafil and its primary metabolite, desmethylsildenafil, were measured in plasma at 0 h and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18 and 24 h using liquid chromatography-tandem mass spectrometry. Statistical analysis was by repeated measures anova, using log transformed data where appropriate. RESULTS: Treatment with bosentan 62.5 mg twice daily for 4 weeks was associated with a two-fold increase in sildenafil clearance/F and a 50% decrease in the AUC (P < 0.001). Increasing the dose of bosentan to 125 mg twice daily led to a further increase in sildenafil oral clearance and decrease in the AUC (P < 0.001 vs. 62.5 mg bosentan). The ratio of AUC on bosentan treatment relative to that of visit 1 was 0.47 [95% confidence interval (CI) 0.36, 0.61] for visit 2 and 0.31 (95% CI 0.23, 0.41) for visit 3 (P < 0.001). Sildenafil C(max) fell from 759 ng ml(-1) on visit 1 to 333 ng ml(-1) on visit 3 (P < 0.01) and there was a significant decrease in the plasma half-life of sildenafil on the higher bosentan dose (P < 0.05). The AUC and plasma half-life of desmethylsildenafil was also decreased by bosentan in a dose-dependent manner (P < 0.01). CONCLUSIONS: Bosentan significantly decreases the plasma concentration of sildenafil when coadministered to patients with pulmonary hypertension.     

Bosentan improves renal regional blood flow in rats with experimental congestive heart failure

The effects of the mixed endothelin receptor antagonist bosentan on renal regional haemodynamics were investigated in rats with aorto-caval fistula, an experimental model of congestive heart failure. A matched group of normal rats served as control. Injection of bosentan (10 mg/kg i.v.) to the rats with decompensated congestive heart failure produced an increase in cortical (+20%) and medullary (+12%) blood flow, and a decrease in vascular resistance in the cortex (−30%) and medula (−23%), while reducing mean arterial pressure by approximately 10 mm Hg. In rats with compensated congestive heart failure and in normal animals, infusion of bosentan did not affect blood pressure and cortical perfusion. These findings indicate that 1) endothelin receptor blockade produces beneficial effects on renal haemodynamics in rats with experimental congestive heart failure and 2) endothelin-1 may be involved in the pathogenesis of renal hypoperfusion only in decompensated congestive heart failure.