Document Detail

Liposomal fasudil, a rho-kinase inhibitor, for prolonged pulmonary preferential vasodilation in pulmonary arterial hypertension.
MedLine Citation:
PMID:  23353807     Owner:  NLM     Status:  MEDLINE    
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.
Vivek Gupta; Nilesh Gupta; Imam H Shaik; Reza Mehvar; Ivan F McMurtry; Masahiko Oka; Eva Nozik-Grayck; Masanobu Komatsu; Fakhrul Ahsan
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Publication Detail:
Type:  Journal Article; Research Support, American Recovery and Reinvestment Act; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-23
Journal Detail:
Title:  Journal of controlled release : official journal of the Controlled Release Society     Volume:  167     ISSN:  1873-4995     ISO Abbreviation:  J Control Release     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-28     Completed Date:  2013-09-30     Revised Date:  2014-05-07    
Medline Journal Info:
Nlm Unique ID:  8607908     Medline TA:  J Control Release     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  189-99     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 Elsevier B.V. All rights reserved.
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MeSH Terms
1,2-Dipalmitoylphosphatidylcholine / analogs & derivatives,  chemistry
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / administration & dosage,  analogs & derivatives*,  pharmacokinetics
Alkaline Phosphatase / metabolism
Bronchoalveolar Lavage Fluid / chemistry
Cell Line
Cell Survival / drug effects
Cholesterol / chemistry
Drug Stability
Hypertension, Pulmonary / drug therapy*,  metabolism,  physiopathology
L-Lactate Dehydrogenase / metabolism
Macrophages, Alveolar / drug effects,  metabolism
Myocytes, Smooth Muscle / drug effects,  metabolism
Protein Kinase Inhibitors / administration & dosage*,  pharmacokinetics
Pulmonary Artery / cytology
Rats, Sprague-Dawley
Vasodilation / drug effects
Vasodilator Agents / administration & dosage*,  pharmacokinetics
rho-Associated Kinases / antagonists & inhibitors*
Grant Support
Reg. No./Substance:
0/Aerosols; 0/Liposomes; 0/Protein Kinase Inhibitors; 0/Vasodilator Agents; 103745-39-7/fasudil; 2644-64-6/1,2-Dipalmitoylphosphatidylcholine; 319X2NFW0A/colfosceril palmitate; 84477-87-2/1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; 97C5T2UQ7J/Cholesterol; EC Dehydrogenase; EC Kinases; EC Phosphatase

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