Institute of Biomedicine, Pharmacology, Aarhus University, Aarhus, Denmark.
Clinic for Plastic, Aesthetic and Hand Surgery, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
Curr Pharm Des. 2017;23(34):5191-5199. doi: 10.2174/1381612823666170908114227.
This review focuses on the treatment of pulmonary arterial hypertension (PAH) with selexipag and compares its drug-related therapeutic effects with those of prostacyclin analogues.
We searched the relevant literature and summarized the current clinical trials concerning selexipag and PAH.
With only few cases per million, PAH is a rare disease, but when untreated it can be life-threatening. PAH is linked to elevated levels of endothelin (ET-1) and decreased levels of nitric oxide (NO) and prostacyclin (PGI2). PAH-specific therapeutic approaches concentrate on these characteristics with drugs targeting the endothelin- receptor (e.g. bosentan), phosphodiesterase-5 (e.g. sildenafil) or the prostacyclin-receptor (e.g. treprostinil). Recently, the new drug selexipag acting as a non-prostanoid IP2-receptor agonist has been approved for PAH therapy. The active form of selexipag (ACT-333679) was designed by the help of a medicinal chemistry program and it was further modified by replacing the terminal carboxyl group with an N-acylsulfonamide group to form the more stable oral drug, selexipag. Selexipag has a high selectivity for the IP2-receptor and differs from conventional prostacyclin analogues in its chemical structure. In the GRIPHON trial selexipag was demonstrated to significantly improve the primary composite endpoint of death or complications related to PAH (hazard ratio 0.6, 99% confidence interval, 0.46 to 0.78; P < 0.001) as well as exercise capacity in the form of the 6-minute walk distance (12.0 m treatment effect, 99% confidence interval, 1 to 24; P = 0.003). However, no significant reduction in all-cause mortality was achieved. Selexipag has also shown promising results in combination therapy with phosphodiesterase-5 inhibitors (PDE-5i) and/or endothelin receptor antagonists (ERA). The most common adverse effects (AEs), associated with selexipag, are headache, diarrhea, jaw pain, and nausea. Nevertheless, Selexipag was generally well tolerated during the GRIPHON trial.
Selexipag is a valuable addition to PAH therapeutics especially by reducing the PAH-related hospitalizations and thus improving quality of life in PAH patients.
本综述重点介绍了用于治疗肺动脉高压（PAH）的塞来昔帕，并将其与前列环素类似物的药物相关治疗效果进行了比较。
我们检索了相关文献，并对塞来昔帕与 PAH 相关的临床试验进行了总结。
PAH 是一种罕见疾病，每百万人中仅有少数病例，但如果不进行治疗，可能会危及生命。PAH 与内皮素（ET-1）水平升高和一氧化氮（NO）和前列环素（PGI2）水平降低有关。针对 PAH 的特定治疗方法集中在这些特征上，药物靶向内皮素受体（例如，波生坦）、磷酸二酯酶-5（例如，西地那非）或前列环素受体（例如，曲前列尼尔）。最近，作为非前列腺素 IP2 受体激动剂的新药塞来昔帕已被批准用于 PAH 治疗。塞来昔帕的活性形式（ACT-333679）是通过药物化学程序设计的，进一步通过用 N-酰基磺酰胺基团取代末端羧基来形成更稳定的口服药物塞来昔帕来修饰。塞来昔帕对 IP2 受体具有高选择性，并且在化学结构上与传统的前列环素类似物不同。在 GRIPHON 试验中，塞来昔帕显著改善了主要复合终点（死亡或与 PAH 相关的并发症；风险比 0.6，99%置信区间为 0.46 至 0.78；P<0.001），以及 6 分钟步行距离的运动能力（12.0 m 治疗效果，99%置信区间为 1 至 24；P=0.003）。然而，并未实现全因死亡率的显著降低。塞来昔帕与磷酸二酯酶-5 抑制剂（PDE-5i）和/或内皮素受体拮抗剂（ERA）联合治疗也显示出有前景的结果。与塞来昔帕相关的最常见不良事件（AE）为头痛、腹泻、颌痛和恶心。尽管如此，在 GRIPHON 试验中，塞来昔帕总体上耐受性良好。
塞来昔帕是 PAH 治疗的一种有价值的补充，特别是通过降低 PAH 相关住院率，从而提高 PAH 患者的生活质量。
