4-METHYLPYRAZOLE FORMULATIONS FOR INHIBITING ETHANOL INTOLERANCE
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.
1 . A method for ameliorating a symptom of ethanol intolerance in a subject with reduced or absent aldehyde dehydrogenase subtype 2 (ALDH2) activity comprising orally administering to the subject about 0.1 mg to about 1.0 mg 4-methylpyrazole (4-MP) per kilogram of the subject's body mass.
2 . The method of claim 1 wherein 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).
3 . The method of claim 1 , wherein the symptom of ethanol intolerance is selected from the group consisting of flushing, elevated heart rate, palpitations, hypotension, nausea, dizziness, headache, vomiting, diarrhea, upset stomach, ataxia, and confused consciousness.
4 . The method of claim 1 , wherein 4-MP is administered in a free base form.
5 . The method of claim 1 , wherein 4-MP is administered in a physiologically acceptable salt form.
6 . The method of claim 1 , wherein 4-MP is orally administered before the subject consumes ethanol.
7 . The method of claim 6 , wherein 4-MP is orally administered about one hour to about fifteen minutes before the subject consumes ethanol.
8 . The method of claim 1 , wherein 4-MP is orally administered concurrently with the subject's consumption of ethanol or after the subject has consumed ethanol.
9 . The method of claim 1 , wherein the percent reduction in the subject's ethanol elimination rate is no more than about 10% in comparison to the ethanol elimination rate of a subject not administered 4-MP.
10 . A method of reducing a symptom associated with acetaldehyde accumulation accompanying ethanol consumption in a subject with reduced or absent aldehyde dehydrogenase subtype 2 (ALDH2) activity comprising administering an effective amount of 4-MP that reduces acetaldehyde accumulation by about 50% to about 60% as compared to a subject not administered 4-MP, wherein about 0.1 mg to about 1.0 mg 4-MP per kilogram of the subject's body mass is administered.
11 . The method of claim 10 wherein 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).
12 . A method of ameliorating a symptom of acetaldehyde accumulation accompanying ethanol consumption in a subject with reduced or absent aldehyde dehydrogenase subtype 2 (ALDH2) activity comprising administering an amount of 4-MP or a physiologically acceptable salt of 4-MP effective to reduce or inhibit ethanol-oxidizing activity of alcohol dehydrogenase in the subject, wherein about 0.1 mg to about 1.0 mg 4-MP per kilogram of the subject's body mass is administered.
13 . The method of claim 12 wherein 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).
14 . The method of claim 10 or 12 , wherein a symptom of acetaldehyde accumulation is selected from the group consisting of flushing, elevated heart rate, palpitations, hypotension, nausea, dizziness, headache, vomiting, diarrhea, upset stomach, ataxia, and confused consciousness.
15 . The method of claim 10 or 12 , wherein the percent reduction in ethanol elimination rate that is no more than about 10% in comparison to the ethanol elimination rate of a subject not administered 4-MP.
16 . The method of claim 10 or 12 wherein an effective amount of a hydrochloride salt of 4-MP is administered.
17 . A method for reducing a risk in a subject for a disease or disorder caused by exposure to acetaldehyde in a subject with reduced or absent aldehyde dehydrogenase subtype 2 (ALDH2) activity comprising administering an amount of 4-MP or a physiologically acceptable salt of 4-MP effective to increase catabolism of acetaldehyde in the subject, wherein increasing catabolism of acetaldehyde reduces the risk for the disease or disorder.
18 . The method of claim 17 wherein 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).
19 . The method of claim 17 wherein the acetaldehyde is a product of ethanol consumption by the subject.
20 . The method of claim 17 , wherein the disease or disorder comprises upper aerodigestive tract cancers, digestive tract cancers or breast cancer.
21 . The method of claim 20 wherein the upper aerodigestive tract cancer comprises esophageal, oropharynx, hypopharynx, larynx, head or neck cancer.
22 . The method of claim 20 , wherein the digestive cancer comprises stomach or colon cancer.
23 . The method of claim 17 , wherein the disease or disorder comprises late-onset Alzheimers disease, hypertension, myocardial infarction, Parkinson's disease, amyotropic lateral sclerosis, or cerebral ischemia.
24 . The method of claim 1 , 10 , 12 or 17 , wherein about 1.0 mg 4-MP per kilogram of the subject's body mass is administered.
25 . The method of claim 1 , 10 , 12 or 17 , wherein about 0.5 mg 4-MP per kilogram of the subject's body mass is administered.
26 . The method of claim 1 , 10 , 12 or 17 , wherein the subject is a human.