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Methods and compositions for treatment of ischemic conditions and conditions related to mitochondrial function

A technology of ischemia, compounds, compositions for use in the treatment of acute coronary syndromes, the treatment of ischemia or ischemia/reperfusion disorders in subjects, the prevention or restoration of chronic mitochondrial deficient or dysfunctional states , which can address frequent vitamin use and limited treatment options

Inactive Publication Date: 2012-05-30
CARDERO THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Although research continues, current treatment options are limited and vitamins are still frequently used

Method used

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  • Methods and compositions for treatment of ischemic conditions and conditions related to mitochondrial function
  • Methods and compositions for treatment of ischemic conditions and conditions related to mitochondrial function
  • Methods and compositions for treatment of ischemic conditions and conditions related to mitochondrial function

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0170] Methylation of epicatechin produces at least 4 different products, mainly due to the similar reactivity of its 4 phenolic groups.

[0171]

[0172] For general methylation reactions, refer to Donovan, L.R., etc. "Analysis of (+) catechin, (-) epicatechin and their 3'and 4'O-methylated analogs, A comparison of sensitive methods" Journal of Chomatography B, 726 (1999 ): 277-283. Anhydrous K 2 CO 3 (0.7g), (CH 3 ) 2 SO 4 (0.44mL) and epicatechin (1g) were stirred into H 2 A mixture of O (50 mL) and acetone (50 mL). The reaction was carried out in a sealed flask at room temperature for 3 hours. Acetone was removed by rotary evaporation under reduced pressure. The reaction product was extracted with ethyl acetate (50 mL X 2). The reaction product, including each of the -O-methylated derivatives at R1, R2, R3 and R4, was isolated and purified by preparative chromatography.

Embodiment 2

[0174] Prevention of mitochondrial pore opening when mitochondria are exposed to calcium overload is known to correlate with tissue protection from ischemic damage. The small size of the mitochondrial permeability transition pore (MPTP) can be assessed by measuring mitochondrial swelling induced by calcium addition. (Bernardi P, Krauskopf A., Basso E., et al. The mitochondrial permeability transition from in vitro artifact to disease target. FEBS Journal 273:2077-99, 2006). Mitochondrial swelling is the result of the influx of water and electrolytes into mitochondria through the open calcium-induced MPTP. This phenomenon induces light transmission at 535-540 nm (decrease in turbidity or decrease in absorbance at 535 nm) (Zoratti M and Szabo I. The mitochondrial permeability transition. Biochemic and Biophysic acta 1241:139-176, 1995).

[0175] Mitochondria were prepared from the hearts of male Sprague-Dawley rats (250-300 g body weight) and their protein content was determine...

Embodiment 3

[0182] Endothelial dysfunction has been proposed as one of the mechanisms promoting microvascular injury and hyporeperfusion following ischemia-reperfusion (I / R). The availability of L-arginine can be the rate-limiting factor for cellular nitric oxide (NO) production by nitric oxide synthase (NOS). Arginase shares L-arginine as a substrate with NOS and may compete for the preferred substrate, thereby regulating the activity of NOS in the vascular endothelium. Increased arginase activity has been associated with low NO levels, and inhibition of arginase activity has been reported to improve endothelium-dependent vasodilation. We have demonstrated that (-)-epicatechin (EPI) reduces ischemia-reperfusion (I / R) myocardial injury in rats and stimulates NO synthesis in human coronary artery endothelial cells in culture.

[0183] Others have shown that I / R inhibits NO-mediated coronary dilation by increasing arginase activity (1). Elevated levels of arginase activity in cardiac tiss...

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Abstract

The present invention relates to compositions and methods for prophylactic and / or therapeutic treatment of conditions related to mitochondrial function. In various aspects, the present invention comprises administering one or more compounds selected from the group consisting of epicatechin, an epicatechin derivative, catechin, a catechin derivative, nicorandil, and a nicorandil derivative in an amount effective to stimulate mitochondrial function in cells. The methods and compositions described herein provide for reducing infarct size in the heart following permanent ischemia or ischemia / reperfusion (IR) event or method for delaying, attenuating or preventing adverse cardiac remodeling, and can assist in prevention of impaired mitochondria biogenesis and thus prevention of the consequences of impaired mitochondrial biogenesis in various diseases and conditions, as well as provide for the active therapy of mitochondrial depletion that may have already occurred.

Description

[0001] This application claims priority to U.S. Provisional Patent Application 61 / 170,557, filed April 17, 2009, and U.S. Provisional Patent Application 61 / 243,501, filed September 17, 2009, each of which is hereby incorporated in its entirety, including all tables , drawings and claims. Background technique [0002] The following discussion of the background of the invention is provided solely to assist the reader in understanding the invention and is not an admission that the invention describes or constitutes prior art. [0003] This patent application relates to the treatment and prevention of acute injury, and the prevention or restoration of chronic states of mitochondrial deficiency or dysfunction. [0004] Ischemic organ injury and ischemia / reperfusion injury-related conditions are accompanied by alterations in signaling molecules and metabolic effectors that can independently or collectively trigger various forms of cell death. These include changes in intracellular ...

Claims

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Application Information

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IPC IPC(8): A01N43/16A61K31/35
CPCA61K31/4406A61K31/35A61K45/06A61P13/12A61P21/00A61P25/28A61P3/00A61P3/04A61P43/00A61P5/48A61P7/00A61P9/04A61P9/10A61P9/12A61K2300/00
Inventor F·維拉利P·R·桃博A·S·梅塞尔G·F·希莱纳A·墨菲K·山崎G·塞巴洛斯
Owner CARDERO THERAPEUTICS
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