Liposomal fasudil, a rho-kinase inhibitor, for prolonged pulmonary preferential vasodilation in pulmonary arterial hypertension.
Liposomal fasudil, a rho-kinase inhibitor, for prolonged pulmonary preferential vasodilation in pulmonary arterial hypertension.
复制标题
DOI：
10.1016/j.jconrel.2013.01.011
复制
发表时间：
2013-04-28
期刊：
影响因子：
--
通讯作者：
Ahsan F
中科院分区：
文献类型：
--
作者：
Gupta V;Gupta N;Shaik IH;Mehvar R;McMurtry IF;Oka M;Nozik-Grayck E;Komatsu M;Ahsan F
目前对肺动脉高压(PAH)的药物干预需要持续输液、多次吸入或口服药物，这些药物作用于参与PAH发病机制的各种途径。然而，侵入性给药方法、作用持续时间短以及缺乏肺选择性会导致不依从性和患者预后不良。在这项研究中，我们测试了一种假说，即将研究中的抗PAH分子法舒地尔(HA-1077)包裹到脂质体中会导致远端肺小动脉的血管扩张延长。采用水合挤压法制备脂质体，硫酸铵诱导的跨膜电化学梯度负载法舒地尔。然后对脂质体进行了各种物理化学性质的表征。在野百合碱(MCT)诱导的大鼠PAH模型上，对优化的处方进行了肺吸收和药理作用的测试。优化后的法舒地尔脂质体包封率为68.1±0.8%~73.6±2.3%，37℃时5d累积释放率为98~99%。与静脉注射法舒地尔相比，脂质体雾化吸入法舒地尔的终末血药浓度半衰期延长约10倍。静脉注射法舒地尔的t1/2为0.39±0.12h，经肺给药后t1/2延长至4.71±0.72h，给药后1h，平均肺动脉压(MPAP)下降37.6±5.7%，并持续下降约3h，提示脂质体对MCT诱导的PAH大鼠有优先的肺血管扩张作用。总体而言，这项研究确立了雾化脂质体法舒地尔是非侵入性、控释和肺优先治疗PAH的可行选择的原则。
Current pharmacological interventions for pulmonary arterial hypertension (PAH) require continuous infusions, multiple inhalations, or oral administration of drugs that act on various pathways involved in the pathogenesis of PAH. However, invasive methods of administration, short duration of action, and lack of pulmonary selectivity result in noncompliance and poor patient outcomes. In this study, we tested the hypothesis that encapsulation of an investigational anti-PAH molecule fasudil (HA-1077), a Rho-kinase inhibitor, into liposomal vesicles results in prolonged vasodilation in distal pulmonary arterioles. Liposomes were prepared by hydration and extrusion method and fasudil was loaded by ammonium sulfate-induced transmembrane electrochemical gradient. Liposomes were then characterized for various physicochemical properties. Optimized formulations were tested for pulmonary absorption and their pharmacological efficacy in a monocrotaline (MCT) induced rat model of PAH. The entrapment efficiency of optimized liposomal fasudil formulations was between 68.1±0.8% and 73.6±2.3%, and the cumulative release at 37°C was 98–99% over a period of 5 days. Compared to intravenous (IV) fasudil, a ~10 fold increase in the terminal plasma half-life was observed when liposomal fasudil was administered as aerosols. The t1/2 of IV fasudil was 0.39±0.12 h. and when given as liposomes via pulmonary route, the t1/2 extended to 4.71±0.72 h. One h after intratracheal instillation of liposomal fasudil, mean pulmonary arterial pressure (MPAP) was reduced by 37.6±5.7% and continued to decrease for about 3 h, suggesting that liposomal formulations produced pulmonary preferential vasodilation in MCT induced PAH rats. Overall, this study established the proof-of-principle that aerosolized liposomal fasudil is a feasible option for a non-invasive, controlled release and pulmonary preferential treatment of PAH.
登录
查看更多内容
DOI：
10.1152/ajplung.00258.2006
发表时间：
2007-04-01
影响因子：
4.9
作者：
Crossno, Joseph T.;Garat, Chrystelle V.;Klemm, Dwight J.
通讯作者：
Klemm, Dwight J.
影响因子：
13.3
作者：
Bailey, Mark M.;Berkland, Cory J.
通讯作者：
Berkland, Cory J.
影响因子：
5.8
作者：
Ishida, T;Takanashi, Y;Kiwada, H
通讯作者：
Kiwada, H
影响因子：
3.7
作者：
Gupta, Vivek;Davis, Marauo;Ahsan, Fakhrul
通讯作者：
Ahsan, Fakhrul
DOI：
10.1164/ajrccm.150.4.7921463
发表时间：
1994-10-01
影响因子：
24.7
作者：
DIZONCO, L;IKEGAMI, M;RIDER, ED
通讯作者：
RIDER, ED