TY - JOUR
T1 - Double-blind, placebo-controlled clinical trial with a rho-kinase inhibitor in pulmonary arterial hypertension; a pilot efficacy trial
AU - Fukumoto, Yoshihiro
AU - Yamada, Norikazu
AU - Matsubara, Hiromi
AU - Mizoguchi, Minori
AU - Uchino, Kazuaki
AU - Yao, Atsushi
AU - Kihara, Yasuki
AU - Kawano, Mitsuhiro
AU - Watanabe, Hiroshi
AU - Takeda, Yutaka
AU - Adachi, Takeshi
AU - Osanai, Shinobu
AU - Tanabe, Nobuhiro
AU - Inoue, Teruo
AU - Kubo, Akihiro
AU - Ota, Yuri
AU - Fukuda, Koichiro
AU - Nakano, Takeshi
AU - Shimokawa, Hiroaki
PY - 2013
Y1 - 2013
N2 - Background: We have previously demonstrated that long-term inhibition of Rho-kinase ameliorates pulmonary arterial hypertension (PAH) in animal models. In the present study, we examined the clinical effects of mid-term oral treatment with an extended release formulation of AT-877 (fasudil hydrochloride), a specific Rho-kinase inhibitor (AT-877ER) on PAH. Methods and Results: 23 PAH patients were treated with either placebo (10/2 females/males, 51±16 years, idio-pathic PAH (IPAH) in 6, PAH associated with connective tissue disease (CTD-PAH) in 3, PAH with congenital heart disease (CHD-PAH) in 2, and portal PAH in 1) or AT-877ER (6/5 females/males, 47±14 years, IPAH in 2, CTD-PAH in 5, and CHD-PAH in 4); 3 patients were excluded. We performed a 6-min walk test and right heart catheterization in the remaining 20 patients, before and 3 months after the treatment (placebo n=11, AT-877ER n=9). Although there were no significant differences between the 2 groups for the 6-min walk distance, pulmonary hemodynamics tended to be improved in the AT-877ER group, especially the prevalence of improved cardiac index from baseline, which was significantly higher in the AT-877ER than in the placebo group. In the AT-877ER group, serum levels of hy-droxyfasudil, an active metabolite of AT-877ER tended to correlate with improvements in the cardiac index and mean pulmonary artery pressure. Conclusions: Mid-term treatment with oral AT-877ER showed additional improvement in pulmonary hemodynam-ics in patients with PAH.
AB - Background: We have previously demonstrated that long-term inhibition of Rho-kinase ameliorates pulmonary arterial hypertension (PAH) in animal models. In the present study, we examined the clinical effects of mid-term oral treatment with an extended release formulation of AT-877 (fasudil hydrochloride), a specific Rho-kinase inhibitor (AT-877ER) on PAH. Methods and Results: 23 PAH patients were treated with either placebo (10/2 females/males, 51±16 years, idio-pathic PAH (IPAH) in 6, PAH associated with connective tissue disease (CTD-PAH) in 3, PAH with congenital heart disease (CHD-PAH) in 2, and portal PAH in 1) or AT-877ER (6/5 females/males, 47±14 years, IPAH in 2, CTD-PAH in 5, and CHD-PAH in 4); 3 patients were excluded. We performed a 6-min walk test and right heart catheterization in the remaining 20 patients, before and 3 months after the treatment (placebo n=11, AT-877ER n=9). Although there were no significant differences between the 2 groups for the 6-min walk distance, pulmonary hemodynamics tended to be improved in the AT-877ER group, especially the prevalence of improved cardiac index from baseline, which was significantly higher in the AT-877ER than in the placebo group. In the AT-877ER group, serum levels of hy-droxyfasudil, an active metabolite of AT-877ER tended to correlate with improvements in the cardiac index and mean pulmonary artery pressure. Conclusions: Mid-term treatment with oral AT-877ER showed additional improvement in pulmonary hemodynam-ics in patients with PAH.
KW - Pulmonary arterial hypertension
KW - Rho-kinase inhibitor
KW - Signal transduction
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U2 - 10.1253/circj.CJ-13-0443
DO - 10.1253/circj.CJ-13-0443
M3 - Article
C2 - 23912836
AN - SCOPUS:84884603855
VL - 77
SP - 2619
EP - 2625
JO - Circulation Journal
JF - Circulation Journal
SN - 1346-9843
IS - 10
ER -