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Fasudil in combination therapies for the treatment of pulmonary arterial hypertension

a combination therapy and pulmonary arterial hypertension technology, applied in the field of therapeutic formulations, can solve the problems of unsatisfactory current therapies for pulmonary arterial hypertension, imbalance of vasodilators, and impaired endothelial function, and achieve the effect of preventing pah and/or stable angina

Inactive Publication Date: 2011-07-14
ASAHI KASEI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, impairment of endothelial functions leading to an imbalance of vasodilator and vasoconstrictor influences is likely to play a central role in the initiation and progression of PH.
Current therapies for pulmonary hypertension are unsatisfactory.
However, each treatment has limitations and side effects.

Method used

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  • Fasudil in combination therapies for the treatment of pulmonary arterial hypertension
  • Fasudil in combination therapies for the treatment of pulmonary arterial hypertension
  • Fasudil in combination therapies for the treatment of pulmonary arterial hypertension

Examples

Experimental program
Comparison scheme
Effect test

example 1

Isolated PA Rings

[0074]Small (4th or 5th branch) pulmonary arteries (SPA, 200-300 μm ID) were isolated from rats exposed to chronic hypoxia (˜10% oxygen) for 3 to 4 weeks. Briefly, after anesthesia with pentobarbital sodium (30 mg ip) and heparinization (100 IU), the heart and lungs were removed en bloc, and the SPA were isolated under a dissecting microscope. Care was taken to avoid damage to the endothelium. The SPA rings were, placed on steel wires attached to a force transducer and suspended in baths containing 10 ml of physiological salt solution (PSS) at 37° C. Resting passive force was adjusted to a previously determined optimal tension (determined by maximum response to 80 mM KCl: 400 mg for SPA from normotensive lungs (NL), and 750 mg for SPA from hypoxic hypertensive lungs (HL). Rings were gassed with 21% O2-5% CO2-74% N2 and allowed to equilibrate for 60 mM. The artery rings were then constricted with a combination of endothelin-1 (ET-1) (3 nM) plus thromboxane analogue U...

example 2

Isolated PA Rings

[0075]The experiments are performed essentially as described above, but the rings are constricted with each of the vasoconstrictors individually. The dose response curves of fasudil with iloprost, fasudil with bosentan, fasudil with sildenafil show synergistic effects on the relaxation of the PA rings.

example 3

Conscious Catheterized Rats

[0076]Experiments are performed with a chronically hypoxic, pulmonary-hypertensive group of rats which have been exposed to hypobaric hypoxia (410 mmHg barometric pressure, 76 mmHg inspired O2 tension) for 3-4 wk in a chamber flushed continuously with room air to prevent accumulation of CO2, NH3, and H2O. Hypobaric exposure has been 24 h / day, except when the chamber has been opened for 10-15 min every 2 days to remove rats or clean cages and replenish food and water. All rats are exposed to a 12:12-h light-dark cycle and allowed free access to standard rat food and water.

[0077]The chronically hypoxic rats are anesthetized with ketamine (100 mg / kg) and xylazine (15 mg / kg) for placement of catheters in the right jugular vein and pulmonary and right carotid arteries (Oka M. 2001 Am J Physiol Lung Cell Mol Physiol 280: L432-L435). The rats are allowed to recover for 48 h in room air. After recovery, conscious rats are placed in a ventilated plastic box, and pu...

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PUM

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Abstract

Preferred embodiments of the present invention are related to novel therapeutic drug combinations and methods for treating and / or preventing pulmonary arterial hypertension and / or stable angina. More particularly, aspects of the present invention are related to therapeutic combinations comprising a Rho-kinase inhibitor, such as fasudil, and one or more additional compounds selected from the group consisting of prostacyclins, such as iloprost, endothelin receptor antagonists, PDE inhibitors, calcium channel blockers, 5-HT2A antagonists, such as sarpogrelate, selective serotonin reuptake inhibitors, such as fluoxetine, statins, and vascular remodeling modulators, such as Gleevec.

Description

RELATED APPLICATIONS[0001]The present application is a continuation of pending U.S. patent application Ser. No. 11 / 588,185, filed on Oct. 25, 2006, which claims the benefit of U.S. Provisional Patent Application No. 60 / 730,273, filed on Oct. 26, 2005. The disclosures of application Ser. Nos. 11 / 588,185 and 60 / 730,273 are incorporated by reference herein in their entireties.FIELD OF THE INVENTION[0002]Embodiments of this invention are related to therapeutic formulations and methods of using Rho-kinase inhibitors, such as fasudil, in combination with a prostacyclin or prostacyclin agonist, such as iloprost for treating and / or preventing pulmonary arterial hypertension (“PAH”). In other preferred embodiments, the Rho-kinase inhibitor may be used in therapeutic combinations with other agents, such as for example, endothelin receptor antagonists, PDE inhibitors, calcium channel blockers, 5-HT2A antagonists (such as sarpogrelate), selective serotonin reuptake inhibitors (such as fluoxetin...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/5513A61K9/12A61P11/00
CPCA61K31/137A61K31/192A61K45/06A61K31/5578A61K31/554A61K31/551A61K31/519A61K31/22A61K31/343A61K31/353A61K31/366A61K31/401A61K31/4409A61K31/455A61K31/506A61K2300/00A61P11/00A61P43/00A61P9/08A61P9/10A61P9/12
Inventor FONG, BENSON M.
Owner ASAHI KASEI PHARMA
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