反相高效液相色谱法测定马西替坦有关物质

目的 建立马西替坦有关物质的反相高效液相色谱(RP-HPLC)测定方法.方法 采用Agilent C18柱(250 mm×4.6 mm,5 μm),以乙腈-水-甲酸(50:50:0.1)为流动相A,以乙腈-水-甲酸(85:15:0.1)为流动相B,梯度洗脱,流速为1.0 mL·min-1,检测波长为260 nm.结果 在选定色谱条件下,马西替坦与各杂质之间分离良好,杂质A、杂质B、杂质C、杂质D浓度分别在0.042~10.445 mg·L-1(r=1.000 0)、0.024~9.880 mg·L-1(r=1.000 0)、0.060~9.380 mg·L-1(r=0.999 5)、0.051~9.736 mg·L-1(r=1.000 0)范围内与峰面积呈良好的线性关系,上述杂质的平均回收率分别为99.91%、98.15%、98.51%、98.59%,RSD分别为1.61%、2.45%、3.89%、2.87%(n=9).结论 该方法专属性好,可用于测定马西替坦中的有关物质.     

Comparison of the dissolution and pharmacokinetic profiles of two galenical formulations of the endothelin receptor antagonist macitentan

Macitentan (ACT-064992) is an orally active endothelin receptor antagonist. We first compared the in vitro dissolution characteristics of uncoated and film-coated tablets with hard gelatin capsules containing 10 mg ACT-064992. Subsequently, we compared the oral pharmacokinetics of ACT-064992 and its active metabolite ACT-132577 of the coated tablet and the gelatin capsule formulation in 11 male volunteers.The dissolution profile showed a rapid disintegration of all formulations with >90% dissolution of ACT-064992 within 45 min. The pharmacokinetics of ACT-064992 and its metabolite ACT-132577 were comparable for the two formulations. ACT-064992 revealed a slow absorption (median t_max 8 h) and a terminal half-life of approximately 13 h. Bioequivalence criteria were met for AUC_0−t and AUC_0−∞. Mean C_max was 19% lower after ingestion of the tablet compared to capsules with its lower 90% confidence limit below the accepted bioequivalence range. The pharmacokinetics of the metabolite ACT-132577, characterized by a t_max of approximately 48 h and a terminal half-life of approximately 45 h, was not different between the two formulations.We conclude that the absorption profile of the tablet differs from the capsule in peak but not in total exposure, which is not expected to be of clinical significance.     

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。     

内皮素受体拮抗剂在肺动脉高压治疗中的应用

内皮素是强的缩血管因子,肺动脉高压患者内皮素表达明显增加,内皮素受体拮抗剂已经作为靶向药物治疗肺动脉高压,其疗效及前景备受瞩目。波生坦、安立生坦分别为口服的双重和选择性内皮素受体拮抗剂(ERAs),均能显著降低肺动脉高压,改善患者的生存,Macitentan是一种新型的口服非肽类双重ERAs,现已完成Ⅲ期临床研究,疗效可观;西他生坦是选择性的内皮素受体拮抗剂,因其肝脏毒性已经退市。对于这些双重或选择性内皮素受体拮抗剂的选择问题至今仍存在分歧,长期疗效、联合用药及肝脏安全性等问题都需要更多循证医学证实。     

Macitentan treatment retards the progression of established pulmonary arterial hypertension in an animal model

Background

Macitentan is a new endothelin receptor antagonist that is used to treat pulmonary arterial hypertension in humans. Treatment of established pulmonary hypertension with macitentan was studied using the monocrotaline model of pulmonary hypertension.

Methods

Three groups of rats were created (n = 12): control (CON: macitentan only), monocrotaline (MCT: monocrotaline only) and macitentan (MACI: macitentan and monocrotaline). Monocrotaline (60 mg/kg) was injected in the MCT and MACI groups on day 0; volume matched saline was injected in the CON groups. Macitentan therapy (30 mg/kg/day) was commenced on day 11 in the CON and MACI groups. Serial echocardiography and ECGs were performed. The rats were sacrificed if they showed clinical deterioration.

Results

The MCT and MACI rats showed signs of pulmonary hypertension by day 7 (maximum pulmonary velocity, CON 1.15 ± 0.15 m/s vs MCT 1.04 ± 0.10 m/s vs MACI 0.99 ± 0.18 m/s; p < 0.05). Both the MCT and MACI groups developed pulmonary hypertension, but this was less severe in the MACI group (day 21 pulmonary artery acceleration time, MCT 17.55 ± 1.56 ms vs MACI 22.55 ± 1.00 ms; pulmonary artery deceleration, MCT 34.72 ± 3.72 m/s² vs MACI 17.30 ± 1.89 m/s²; p < 0.05). Right ventricular hypertrophy and QT interval increases were more pronounced in MCT than MACI (right ventricle wall thickness, MCT 0.13 ± 0.1 cm vs MACI 0.10 ± 0.1 cm; QT interval, MCT 85 ± 13 ms vs MACI 71 ± 14 ms; p < 0.05). Survival benefit was not seen in the MACI group (p = 0.50).

Conclusions

Macitentan treatment improves haemodynamic parameters in established pulmonary hypertension. Further research is required to see if earlier introduction of macitentan has greater effects.     

HPLC测定马西替坦中的有关物质

目的 采用HPLC法测定马西替坦中有关物质的含量.方法 色谱柱为AgelaVenusil XBP C18柱(250 mm×4.6 mm,5μm),流动相为乙腈-水(1L水中加入1.0 mL三乙胺,用磷酸调pH3),梯度洗脱,流速1 mL· min-1,柱温35℃,检测波长220nm,进样量10 μL.结果 马西替坦与11种杂质均可达到基线分离,马西替坦和各杂质的线性范围均为0.05～1.5 μg·mL-1,重复性试验的RSD＜ 2.0％,平均回收率的RSD＜ 10％.结论 所用方法专属性强、准确度高,可用于马西替坦中有关物质的检查.     

内皮素受体拮抗剂治疗肺动脉高压疗效和耐受性的网状Meta分析

目的采用网状Meta分析的方法比较安贝生坦、波生坦、西他生坦和马西替坦四种内皮素受体拮抗剂治疗肺动脉高压的疗效和耐受性。方法计算机检索Pub Med、EMBASE、Cochrane Library和中国生物医学文献数据库、中国知网、万方数据库,检索时间截至2014年1月31日,纳入比较四种内皮素受体拮抗剂治疗肺动脉高压的随机对照试验,主要结局指标为疗效和耐受性,次要结局指标为病死率和临床恶化率。研究筛选、数据提取及方法学质量评价均由两人独立完成。分别使用Rev Man 5.2和GEMTC软件进行直接比较和网状Meta分析。结果纳入12篇文献,包含13个随机对照试验,总计2191例患者。直接Meta分析结果显示,4种内皮素受体拮抗剂疗效均优于安慰剂,在耐受性方面,只有安贝生坦的效果优于安慰剂,其余药物与安慰剂的比较差异无统计学意义。网状Meta分析结果显示:在疗效方面,安贝生坦和波生坦的疗效优于安慰剂,西他生坦及马西替坦与安慰剂比较以及各种药物的互相比较差异均无统计学意义。等级概率图显示:安贝生坦效果最佳,其次为波生坦、西他生坦,马西替坦疗效最差。在耐受性方面,安贝生坦与西他生坦优于安慰剂,其余药物与安慰剂的比较以及各类药物之间的比较差异均无统计学意义。等级概率图显示:耐受性最好的药物为安贝生坦,其余依次为西他生坦、马西替坦,最差为波生坦。结论在治疗肺动脉高压的4种内皮素受体拮抗剂中,安贝生坦在疗效和耐受性方面均优于其他3种药物。在未来的研究中,应该更多关注安贝生坦及其他药物在病死率和临床恶化率方面的效果,此外,应注重探讨不同药物剂量、不同类型肺动脉高压患者的具体疗效。