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.     

Persistent pulmonary hypertension of the newborn with transposition of the great arteries: successful treatment with bosentan

Persistent pulmonary hypertension of the newborn (PPHN) occurs in 1–4% of neonates with transposition of the great arteries with intact ventricular septum (TGA/IVS). This association is often lethal. To our knowledge, only eight survivors have been described in the literature, two of whom benefited from extracorporeal membrane oxygenation (ECMO). We report two cases of PPHN complicating a TGA/IVS that were refractory to multiple therapies and resolved 48 hours after initiation of bosentan therapy. Bosentan, an oral dual endothelin-1 receptor antagonist, is a new treatment for pulmonary arterial hypertension that was both effective and safe in these two cases of TGA/IVS with PPHN. To our knowledge, it is the first use of bosentan in newborns.     

波生坦治疗儿童先天性心脏病相关肺动脉高压的疗效观察

目的 评价非选择性内皮素受体拮抗剂波生坦用于儿童先天性心脏病(CHD)相关肺动脉高压(PAH)治疗的临床效果.方法 32例具备用药指征的CHD患儿接受口服波生坦治疗,其中18例为左向右分流,男10例,女8例,年龄2个月至15岁;14例为功能性单心室(FSV),男8例,女6例,年龄5个月至15岁.术前90 d至术后8年开始口服波生坦治疗,用药后定期随访,评估临床效果和药物不良反应.结果 左向右分流患儿口服波生坦后1、2、3个月肺动脉压(mm Hg,1 m Hg=0.133 kPa)分别为57±26、52±31、46±22,均明显低于用药前(74±15,均P<0.05);用药后3个月心功能分级明显改善(Ⅳ、Ⅲ、Ⅱ级构成比分别为55.6%、33.3%、11.1%比0、16.7%、83.3%,P<0.01).其中7例8～15岁患儿用药后3个月6 min步行距离较用药前明显增加[(497±56)比(424±31)m,P<0.01)].FSV组患儿末次随访(用药2～5个月)经皮血氧饱和度比用药前明显提高[(86±5)%比(78±6)%,P<0.01];心功能分级明显改善(Ⅳ、Ⅲ、Ⅱ级构成比分别为0、21.4%、71.5%比35.7%、42.9%、21.4%,P<0.01);颜面部水肿和胸腔积液发生率明显降低(均为7.1%比57.1%,均P<0.05),未发现因服用波生坦而发生的明显不良反应.结论 波生坦用于治疗儿童CHD相关PAH是安全的.对左向右分流患儿可有效降低术后肺动脉压,改善心功能分级和活动耐量;对FSV患儿可改善血氧饱和度和心功能,降低肺血管阻力增高所致并发症的发生率.     

REVIEW: Endothelin Receptor Antagonists for Pulmonary Arterial Hypertension: An Overview

The last decade has seen major advances in the pharmacotherapy of pulmonary arterial hypertension (PAH). One of these advances has been the discovery of endothelin receptor antagonists (ERAs). ERAs are a class of potent vasodilators and antimitotic substances, which could specifically dilate and remodel pulmonary arterial system, and have been proposed as an alternative to traditional therapies for PAH. Current available evidence suggests that ERAs improve exercise capacity, functional status, pulmonary hemodynamics, and delay the time to clinical worsening for patients with PAH. This review attempts to provide an overview of the pharmacology, therapeutic benefits, and safety profile of ERAs in patients with PAH.     

Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil

Objective

The aim of this study was to systematically investigate the mutual pharmacokinetic interactions in healthy volunteers between sildenafil, a phosphodiesterase-5 inhibitor, and bosentan, a dual endothelin receptor antagonist, both approved for treating pulmonary arterial hypertension (PAH).

Methods

A randomised, double-blind, placebo-controlled, parallel-group study with three treatment arms (sildenafil plus placebo, bosentan plus placebo and sildenafil plus bosentan) was conducted in 55 healthy male volunteers (51 completers). Study duration was 18 days per treatment group. Sildenafil was administered three times daily on Days 1–6 and 11–16 (20 mg initially, increased to 80 mg after 3 days), and bosentan (125 mg) was administered twice daily on Days 7–17.

Results

On Day 16, bosentan decreased the maximum plasma concentration of sildenafil ©_max) by 55.4% [90% confidence interval (CI) 40.3–66.6%] and the area under the plasma concentration versus time curve over a dosing interval $ {\left( {{\text{AUC}}_{\tau } } \right)} Objective The aim of this study was to systematically investigate the mutual pharmacokinetic interactions in healthy volunteers between sildenafil, a phosphodiesterase-5 inhibitor, and bosentan, a dual endothelin receptor antagonist, both approved for treating pulmonary arterial hypertension (PAH). Methods A randomised, double-blind, placebo-controlled, parallel-group study with three treatment arms (sildenafil plus placebo, bosentan plus placebo and sildenafil plus bosentan) was conducted in 55 healthy male volunteers (51 completers). Study duration was 18 days per treatment group. Sildenafil was administered three times daily on Days 1–6 and 11–16 (20 mg initially, increased to 80 mg after 3 days), and bosentan (125 mg) was administered twice daily on Days 7–17. Results On Day 16, bosentan decreased the maximum plasma concentration of sildenafil ?_max) by 55.4% [90% confidence interval (CI) 40.3–66.6%] and the area under the plasma concentration versus time curve over a dosing interval by 62.6% (90% CI 56.8–67.7%). Sildenafil increased bosentan C_max by 42.0% (90% CI 15.4–74.8%) and by 49.8% (90% CI 28.7–74.5%). Bosentan and sildenafil in combination were well tolerated, with no serious adverse events reported. All adverse events were of mild or moderate intensity. Conclusions In healthy volunteers, there is a mutual pharmacokinetic interaction between bosentan and sildenafil that may influence the dosage of each drug in a combination treatment. The clinical implications of combination therapy with bosentan and sildenafil are as yet unknown, and further trials in patients with PAH are needed.