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.     

波生坦治疗先天性心脏病术后肺动脉高压的前瞻性随机对照研究

目的 评价应用波生坦治疗婴幼儿先天性心脏病术后肺动脉高压的疗效.方法 30例术前合并肺动脉高压且手术治疗后仍有肺动脉高压的先大性心脏病病儿入选.所有病儿均在低温体外循环辅助下完成心内畸形根治术,术后1周行超声心动图检查,估测肺动脉收缩压＞30mm Hg者随机分配到波生坦治疗组(15例)及对照组(15例)中.研究周期12周,波生坦组:传统治疗+波生坦,波生坦给药方案:10～20 kg病儿,31.25 mg,每日1次(qd)4周,31.25 mg,每日2次(bid)8周;5～10 kg病儿,15.6 mg,qd(4周),15.6 mg,bid(8周);对照组:传统治疗(地高辛、双氢克脲塞).两组病例于术后13周接受门诊随访、调查问卷、超声检查和血液检查.比较两组心功能及临床症状,超声心动图评价血流动力学和肺动脉高压变化,以及血浆内皮素(Endothelin-1,ET-1)变化.结果 两组病例年龄、平均体重、病种分布、基线肺动脉收缩压力、基线血浆ET-1浓度均无统计学差异.心功能改善方而,依据NYHA心功能分级(级数增高定义为心功能恶化,降低则为心功能改善).波生坦治疗组93%的病儿心功能较基线水平改善Ⅰ级,无心功能恶化;对照组只有73%病儿心功能较基线水平改善Ⅰ级,13%病儿心功能较基线水平恶化Ⅰ级.将术后因心肺功能不全再入院及死亡定义为临床恶化,波生坦治疗组无再入院及死亡发生;而对照组13%的病儿发生了临床恶化(1例病儿术后11大死亡,1例病儿术后60天再入院).波生坦治疗组:基线(术后1周)肺动脉收缩压(48.5±9)mm Hg,治疗12周后(29.0±8.0)mm Hg,治疗前后差异有统计学意义(P＜0.01,95%CI:12～27);对照组:基线(术后1周)肺动脉收缩压(45.4±16)mm Hg,12周后(35.1±15.0)mm Hg手术前后差异无统计学意义(P＞0.1).两组之间比较,波生坦治疗组较对照组能更好的降低肺动脉压力(P＜0.05,95%CI:0.1～1 8.3).应用波生坦治疗后血浆ET下降(2.01±0.03)fmol/ml(1 fmol/ml=10-15mol/ml,P=0.03),对照组血浆ET升高(0.15±0.10)fmol/ml(P=0.77).波生坦组有2例肝脏转氨酶升高,停药后自然恢复正常,后未继续服药;无其他明显副作用.结论 波生坦治疗左向右分流的先天性心脏病术后残留肺动脉高压疗效明显,有助于病儿术后心功能及临床症状的恢复.     

Bosentan对大鼠脊髓缺血再灌注损伤后一氧化氮及一氧化氮合酶表达的影响

目的观察非选择性内皮素受体阻断剂Bosentan对大鼠脊髓缺血再灌注损伤(SCIRI)后一氧化氮(NO)及一氧化氮合酶(NOS)表达的影响及其意义。方法健康雄性SD大鼠90只,建立SCIRI模型,分为正常组、假手术组、单纯缺血组(I)、生理盐水(NS)干预对照组、Bosentan干预组(Bos),NS和Bos组又以再灌注(IR)时间分为3、6、12、24、48、72h组,测定血清NO含量,免疫组织化学染色检测nNOS、iNOS和eNOS表达变化。结果①SCIRI后血清NO表达呈双峰样改变,峰值分别出现于IR3h及24h,Bosentan可显著降低第二个峰值(P<0.05)。②SCIRI后nNOS、iNOS、eNOS在脊髓中的表达均逐渐增加,并分别于IR后24、48、24h达峰值,Bosentan可显著下调nNOS、iNOS表达(P<0.05),上调eNOS表达(P<0.05)。③SCIRI后脊髓FADD蛋白、TrkA蛋白表达均逐渐增加,分别于IR后24、12h达峰值,Bosentan干预可下调FADD表达(P<0.05),上调TrkA含量(P<0.05)。结论 Bosentan可影响大鼠SCIRI病理过程中NO及nNOS、eNOS、iNOS的表达,其机制可能与调节FADD及TrkA表达有关。     

Controlling the digital ulcerative disease in systemic sclerosis is associated with improved hand function

ObjectivesIschemic digital ulcers (DU) represent a major complication of systemic sclerosis (SSc). We investigated the impact of controlling the ulcerative disease on disability, pain, and quality of life in SSc patients receiving bosentan.MethodsECLIPSE (Study AC-052-517) is a 2-year prospective, multicenter, and observational study. Patients with SSc who experienced at least 1 DU in the previous year and received bosentan were included between October 2009 and March 2011. Disability scores [Cochin Hand Function Scale (CHFS) and Health Assessment Questionnaire Disability Index (HAQ-DI)], pain scores (visual analog scale), and quality-of-life scores (SF-36) were collected at inclusion and 1 year later (primary endpoint). A controlled ulcerative disease was defined by the absence of ongoing/new DU episode between inclusion and 1-year follow-up.ResultsData were available at 1 year for 120 patients out of 190 included. During follow-up, 46 (38.3%) patients experienced a new DU episode. The number of DU per patient decreased from 1.4 ± 1.8 at inclusion to 0.6 ± 1.6 (p < 0.0001) at 1 year. Disability scores decreased from 1.0 ± 0.7 to 0.9 ± 0.7 (p = 0.04) for the HAQ-DI and from 29 ± 20 to 25 ± 20 (p = 0.005) for the CHFS; the pain score decreased from 4.3 ± 3.1 to 2.9 ± 2.8 (p < 0.0001).This improvement was attributed to patients with a controlled ulcerative disease (48.3%), who significantly improved HAQ-DI (p = 0.04), CHFS (p = 0.04), and pain score (p = 0.046).ConclusionsIn patients with SSc, control of the ulcerative disease for 1 year was associated with significant attenuation of hand disability.     

Effects of bosentan on the skin lesions: an observational study from a single center in Japan

Effects of a dual endothelin receptor antagonist, bosentan on peripheral circulatioin and skin lesions as well as pulmonary arterial hypertension (PAH) were investigated in Japanese patients with connective tissue diseases (CTD). Fifteen patients with PAH associated with CTD [systemic sclerosis (SSc) 13, mixed connective tissue disease (MCTD) 2] were treated with bosentan for 40–96 weeks, and changes of exercise capacity (6-min walk distance and Borg’s dyspnea scale), cardio-pulmonary hemodynamics (right ventricular pressure, specific activity scale and cardiac index), Raynaud’s phenomenon, digital ulcers and dermal sclerosis were observed. Bosentan improved exercise capacity, had a positive effect on hemodynamic parameters, and was well tolerated as previously reported. After a median 8 weeks of treatment, 13 out of 15 patients had improved Raynaud’s phenomenon. Digital ulcers also improved after a median 12 weeks’ treatment in all of 8 patients. Modified Rodnan total skin score decreased from 21.0 ± 5.9 to 11.5 ± 3.9 in diffuse cutaneous SSc and from 17.0 ± 6.5 to 9.5 ± 4.5 in limited cutaneous SSc after 24 months’ treatment, reaching significance after 6 months in both groups. These data suggest that bosentan is effective for both PAH and peripheral vascular diseases in Japanese patients with CTD. The pathological background to the improvement in dermal sclerosis observed in this study should be further investigated.     

Systemic lupus erythematosus, complicated with refractory skin ulcers, treated successfully with bosentan

A 20-year-old woman was admitted to our hospital because of bilateral pretibial edema. Administration of prednisolone was started after she was diagnosed with systemic lupus erythematosus (SLE). However, skin ulcers on her extremities developed; they subsequently worsened with tapering of prednisolone. She also developed pulmonary hypertension (PH). Her skin ulcers improved considerably after administration of bosentan, an endothelin receptor antagonist. Bosentan may be efficacious not only for PH but also for refractory skin ulcers.     

Drug eruption due to bosentan in a patient with systemic sclerosis

Abstract

We present the case of a 60-year-old female patient with systemic sclerosis complicated by pulmonary hypertension. Ten days after the initiation of treatment with bosentan, high fever and skin eruptions were noted. In the previous reports, the frequency of drug-induced skin eruptions has not been well documented. Since the use of bosentan is expected to increase, we should be aware of the previously unknown adverse effects as well as skin eruptions.