Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine.
Circ J. 2013;77(10):2619-25. doi: 10.1253/circj.cj-13-0443. Epub 2013 Aug 3.
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.
23 PAH patients were treated with either placebo (10/2 females/males, 51 ± 16 years, idiopathic 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 hydroxyfasudil, an active metabolite of AT-877ER tended to correlate with improvements in the cardiac index and mean pulmonary artery pressure.
Mid-term treatment with oral AT-877ER showed additional improvement in pulmonary hemodynamics in patients with PAH.
我们之前已经证明，长期抑制 Rho-激酶可改善动物模型中的肺动脉高压（PAH）。在本研究中，我们研究了 Rho-激酶抑制剂（AT-877）的一种延长释放制剂（盐酸法舒地尔，AT-877ER）在 PAH 中的中期口服治疗对临床的影响。
23 名 PAH 患者接受安慰剂（10/2 名女性/男性，51 ± 16 岁，特发性 PAH（IPAH）6 例，结缔组织疾病相关 PAH（CTD-PAH）3 例，先天性心脏病相关 PAH（CHD-PAH）2 例，门静脉高压性 PAH 1 例）或 AT-877ER（6/5 名女性/男性，47 ± 14 岁，IPAH 2 例，CTD-PAH 5 例，CHD-PAH 4 例）治疗；3 名患者被排除在外。我们对其余 20 名患者进行了 6 分钟步行测试和右心导管检查，在治疗前（安慰剂组 11 名，AT-877ER 组 9 名）和 3 个月后。尽管两组间 6 分钟步行距离无显著差异，但 AT-877ER 组的肺血流动力学倾向于改善，尤其是心脏指数改善的发生率明显高于安慰剂组。在 AT-877ER 组中，活性代谢物羟基法舒地尔的血清水平与心脏指数和肺动脉平均压的改善呈正相关。
口服 AT-877ER 的中期治疗在 PAH 患者中显示出肺血流动力学的额外改善。
