title: Anti-anginal effect of fasudil, a Rho-kinase inhibitor, in patients with stable effort angina: a multicenter study.
abstract: Rho-kinase plays an important role in calcium sensitization for vascular smooth muscle (VSMC) contraction and may be involved in the inappropriate coronary vasoconstriction during exercise-induced myocardial ischemia. In this multicenter phase II study, the anti-anginal effect of fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil after oral administration, was examined in patients with stable effort angina. In the phase IIa trial, after a 2-week washout period of anti-anginal drugs, 45 patients received increasing doses of fasudil (5, 10, and 20 mg TID for every 2 weeks). The fasudil treatment significantly prolonged the maximum exercise time and the time to the onset of 1-mm ST segment depression on treadmill exercise test (both p < 0.01), whereas blood pressure and heart rate during exercise were unchanged before and after the treatment. Higher doses of fasudil (20 and 40 mg TID) were subsequently tested in 22 patients in the same manner with similar positive results. In the phase IIb trial, after a 2-week washout period of anti-anginal drugs, 125 patients were assigned, in a double-blind manner, to a 4-week oral treatment with a different dose of fasudil (5, 10, 20, or 40 mg TID) and treadmill exercise test was performed before and after the treatment. Again, both maximum exercise time and time to the onset of 1-mm ST segment depression were prolonged in all groups. A significant dose-response relation was noted across the treatment groups for the exercise tolerance index that was determined by the combined effect of exercise time and ST segment depression (p = 0.006). Fasudil was well tolerated in both trials without any serious adverse reactions. These results suggest the efficacy and adequate safety profile of fasudil, the first drug in a novel class of vasodilators, for the treatment of stable effort angina.
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. shimo@cardiol.med.kyushu-u.ac.jp
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Hiramori
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Iinuma
authors.forename: Saichi
authors.initials: S
authors.lastname: Hosoda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kishida
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Osada
authors.forename: Takashi
authors.initials: T
authors.lastname: Katagiri
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Yamauchi
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Yui
authors.forename: Takazo
authors.initials: T
authors.lastname: Minamino
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Nakashima
authors.forename: Kazuzo
authors.initials: K
authors.lastname: Kato
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000787:Angina Pectoris / Q000188:drug therapy* / Q000209:etiology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D015444:Exercise; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007564:Japan; D008297:Male; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D054460:rho-Associated Kinases
chemical_list: D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; C049347:fasudil