O'Connell Caroline, Amar David, Boucly Athénaïs, Savale Laurent, Jaïs Xavier, Chaumais Marie-Camille, Montani David, Humbert Marc, Simonneau Gérald, Sitbon Olivier
Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
AP-HP, Hôpital Bicêtre, Service de Pneumologie et Soins Intensifs, Centre de Référence del'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Le Kremlin-Bicêtre, France.
Drug Saf. 2016 Apr;39(4):287-94. doi: 10.1007/s40264-015-0365-x.
Prostacyclin (PGI2) is a prostaglandin derived from arachidonic acid in the endothelium and smooth muscle which causes vasodilation, inhibits platelet aggregation, and has anti-inflammatory, anti-thrombotic and anti-proliferative effects. In pulmonary arterial hypertension (PAH), PGI2 levels and PGI2 synthase expression are reduced, contributing to the vasoconstriction and vascular smooth muscle cell proliferation seen in the disease. Based on these findings, PGI2 analogues were developed to target this pathway. Epoprostenol was the first targeted therapy available for treating PAH. Due to the short half-life of this drug, it requires administration via a continuous intravenous infusion, and therefore it carries the risks of central line infections and thrombosis. However, it remains the treatment of choice in patients with severe PAH as it has a proven survival benefit as well as improved functional class and exercise capacity. Subsequently, several other PGI2 analogues have been developed with differing modes of administration and varying degrees of efficacy. Beraprost is an oral PGI2 analogue for which a sustained efficacy has not been demonstrated. Iloprost is a nebulised PGI2 analogue that requires administration six to nine times a day and leads to improved functional class, exercise capacity and haemodynamics. There are inhaled, oral, subcutaneous and intravenous forms of treprostinil. Subcutaneous treprostinil avoids the risks of a continuous intravenous administration; however, this drug can cause intractable pain at the injection site. Selexipag is the new oral non-prostanoid IP prostacyclin receptor agonist that has shown improved haemodynamics and good tolerance in a phase II study. Initial results of the phase III trial are promising. Comparison of the different PGI2 agents is limited by a lack of head-to-head clinical trials. However, the development of PGI2 analogues has improved survival in patients with PAH and remains the main treatment option in advanced disease. While PGI2 analogues have good efficacy in PAH, they are not interchangeable, and their delivery systems have many limitations; in particular, they are associated with significant deleterious consequences. In the future, it is hoped that the elusive goal of developing an effective oral PGI2 analogue will be achieved. This would increase the number of people who could benefit from the treatment while reducing the associated adverse events, and as a result improve the survival and quality of life for these patients.
前列环素（PGI2）是一种在内皮细胞和平滑肌中由花生四烯酸衍生而来的前列腺素，可引起血管舒张，抑制血小板聚集，并具有抗炎、抗血栓形成和抗增殖作用。在肺动脉高压（PAH）中，PGI2水平和PGI2合酶表达降低，导致该病出现血管收缩和血管平滑肌细胞增殖。基于这些发现，开发了PGI2类似物来针对这一途径。依前列醇是第一种可用于治疗PAH的靶向治疗药物。由于该药半衰期短，需要通过持续静脉输注给药，因此存在中心静脉导管感染和血栓形成的风险。然而，它仍然是重度PAH患者的首选治疗方法，因为它已被证明具有生存获益，同时能改善功能分级和运动能力。随后，又开发了其他几种PGI2类似物，其给药方式不同，疗效也有所不同。贝拉前列素是一种口服PGI2类似物，尚未证明其具有持续疗效。伊洛前列素是一种雾化吸入的PGI2类似物，需要每天给药6至9次，可改善功能分级、运动能力和血流动力学。曲前列尼尔有吸入、口服、皮下和静脉注射等剂型。皮下注射曲前列尼尔可避免持续静脉给药的风险；然而，这种药物可能会在注射部位引起难以忍受的疼痛。司来帕格是一种新型口服非前列腺素IP前列环素受体激动剂，在一项II期研究中显示出改善的血流动力学和良好的耐受性。III期试验的初步结果很有前景。由于缺乏直接比较的临床试验，不同PGI2药物之间的比较受到限制。然而，PGI2类似物的开发提高了PAH患者的生存率，仍然是晚期疾病的主要治疗选择。虽然PGI2类似物在PAH中疗效良好，但它们不可互换，并且其给药系统有许多局限性；特别是，它们会带来严重的有害后果。未来，希望能够实现开发一种有效的口服PGI2类似物这一难以实现的目标。这将增加能够从治疗中获益的人数，同时减少相关不良事件，从而提高这些患者的生存率和生活质量。
