4-methylpyrazole formulations for inhibiting ethanol intolerance

Abstract

Provided herein are methods, compositions and formulations to prevent or ameliorate ethanol intolerance, reduce or ameliorate symptoms associated with acetaldehyde accumulation accompanying ethanol consumption, or reduce the risk of diseases or disorders caused by acetaldehyde accumulation, comprising administering 4-MP, or physiologically acceptable salts thereof, to subjects with reduced or absent aldehyde dehydrogenase subtype 2 (ALDH2) activity.

Description

1. RELATED APPLICATIONS[0001]This application is a continuation of U.S. patent application Ser. No. 12 / 797,594, filed Jun. 9, 2010, which is a continuation-in-part of U.S. patent application Ser. No. 10 / 591,735, filed Jul. 23, 2007, which is a 35 U.S.C. §371 U.S. National Stage Entry of International Patent Application No. PCT / US05 / 07273, filed Mar. 3, 2005, which claims the benefit of U.S. Provisional Application No. 60 / 642,007, filed Jan. 6, 2005, and U.S. Provisional Application No. 60 / 550,261, filed Mar. 3, 2004, all of which applications are herein incorporated by reference in their entireties. This application also claims the benefit of U.S. Provisional Application No. 61 / 185,884, filed Jun. 10, 2009, which application is herein incorporated by reference in its entirety.2. TECHNICAL FIELD[0002]Provided herein are methods, compositions and formulations to prevent or ameliorate ethanol intolerance, reduce or ameliorate symptoms associated with acetaldehyde accumulation, for exam...

AI Technical Summary

Benefits of technology

[0013]In another aspect, methods are provided for reducing a likelihood or risk in a subject with reduced or absent aldehyde dehydrogenase subtype 2 (ALDH2) for a disease or disorder caused by exposure to acetaldehyde. In certain embodiments, the acetaldehyde is a product of ethanol consumption by the subject. In certain embodiments, the subject with reduced or absent ALDH2 activity is homozygous for alcohol dehydrogenase subtype 2*1 (ADH2*1 / ADH2*1) or is heterozygous for alcohol dehydrogenase subtypes 2*1 and 2*2 (ADH2*1 / ADH2*2). In certain embodiments, the subject with reduced or absent ALDH2 activity is homozygous for alcohol dehydrogenase subtype 2*2 (ADH2*2 / ADH2*2).

[0015]In yet other aspects, methods are provided for reducing a likelihood or risk in a subject for a disease or disorder caused by exposure to acetaldehyde comprising administering to a subject in need thereof an amount of a 4-MP, or a physiologically acceptable salt of 4-MP, effective to increase catabolism of acetaldehyde in the subject, thereby reducing the likelihood or risk for the disease or disorder. In certain embodiments, the acetaldehyde is a product of ethanol consumption.

Problems solved by technology

Moreover, people who express the ALDH2*2 allele also exhibit increased long-term health risks for cancers of the upper digestive tract, breast cancer, liver disease, Alzheimer's disease, hypertension and myocardial infarction (Yokoyama et al., Carcinogenesis.

However, administration of such large doses of 4-MP itself has been reported to cause side effects similar to ALDH2 deficiency including flushing, headache and nausea.

Further, high doses of 4-MP inhibit ADH activity to an extent that human subjects treated with 4-MP can have much higher blood ethanol concentrations than when not treated with 4-MP, leading to relatively lengthy periods of time during which the subject is under the influence of ethanol.

However, such administration has not been shown to be consistently helpful for all alcohol intolerant persons.

Accordingly, a dose of 4-MP found to be helpful to treat one genetic subpopulation of alcohol intolerance persons may not be equally helpful, or may even be ineffective, to treat another genetic subpopulation of alcohol intolerance persons.

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