急性期脳梗塞に対する蛋白リン酸化酵素阻害剤:塩酸ファスジル(エリル)の効果
二重盲検試験の結果
2004 年 26 巻 4 号 p. 607-612
詳細
2004 年 26 巻 4 号 p. 607-612
Fasudil (hexahydro-1-(5-isoquinolinesulfonyl)-1H-1, 4-diazepine hydrochloride or AT877, HA1077, Eril) is a unique vasodilating and brain protecting drug. It has been used in Japan since 1995 in patients with aneurysmal subarachnoid hemorrhage (SAH) to prevent vasospasm. It showed more brain protective effect than vasodilating effect itself, which suggested its efficacy in the treatment of cerebral infarction. A recent double blind trial of fasudil (60mg, iv/60 min, bid for 14 days) on patients with acute cerebral infarction showed that it significantly improved both motor dysfunction (p=0.0013) on day 14 and ADL (P=0.0015) on 30 days. In experimental animal models of stroke, fasudil prevented decrease in number of hippocampal CA1 neurons, migration of white blood cells (WBCs) to the infarction area, inhibited free radical production by WBCs and normalized increased blood viscosity.
Mechanism of action of fasudil has gradually been elucidated, now inhibition of protein kinases, especially rho kinase (Ki=0.3 uM), and protein kinase C (Ki=3uM) are considered to be important. In both cerebral vasospasm and infarction, upregulation of Rho kinase is considered to be important in the pathogenesis of brain damage. Rho kinase inhibits myosin phosphatase, leading to increased phosphorylation of myosin light chain. Rho kinase also inhibits NO synthase in the vascular endothelium. Upregulated Rho and C kinases are considered to be involved in migration of WBCs, production of free radicals by NADPH oxidase in WBCs and decreased NO synthesis in the endothelium. Thus, inhibition of these protein kinases by fasudil can explain its clinical effects.
Hydroxylated metabolite of fasudil (M3) similarly inhibits both Rho and C kinases with longer biological half-life of about 5 hours compared with that of fasudil (45 min) after intravenous infusion. Effectiveness of fasudil by intermittent infusion (two or three times a day) may, at least partly, depend on its hydroxylated metabolite.
