Compositions and methods for treating and reducing alcohol-induced skin flushing

Abstract

The present application relates to a pharmaceutical composition for the prevention and treatment of alcohol-induced hypersensitivity reactions, including alcohol-induced skin flushing.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application number 202080052527.2, application date May 22, 2020, and invention name “Compositions and methods for treating and alleviating alcohol-induced skin flushing”.

[0002] CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 852,000, filed May 23, 2019, which is incorporated herein by reference in its entirety. SUMMARY OF THE INVENTION The present application relates to a pharmaceutical composition comprising a therapeutically effective amount of 4-methylpyrazole or a pharmaceutically acceptable salt, hydrate, polymorph or solvate thereof and a pharmaceutically acceptable carrier; wherein the pharmaceutical composition is configured for oral administration; and wherein the pharmaceutical composition further comprises at least one pharmaceutically inert coating that can be used to mask the smell of 4-methylpyrazole. In certain embodiments, the at least one pharmaceutically inert coating is selected from the group consisting of hydroxyalkyl cellulose, anti-adherent agents, plasticizers, sugars, methacrylate copolymers, hydroxyalkyl cellulose and water-soluble polymers. In certain embodiments, the pharmaceutical composition is configured as an oral dosage form selected from powders, tablets, lozenges, chewing gum, pills, capsules, microcapsules, caplets, orally disintegrating tablets, osmotic controlled release oral delivery systems or any combination thereof. Certain embodiments further comprise n-acetylcysteine, serpentine, Withania somifera / Ashwagandha, L-cystine, S-acetylglutathione, molybdenum, iron, zinc, iron chelator, L-ascorbic acid, L-threonine, or any combination thereof. In certain embodiments, the iron chelator comprises curcumin, quercetin, inositol hexaphosphate (IP6), or any combination thereof. In certain embodiments, the pharmaceutically acceptable carrier is water. In certain embodiments, the pharmaceutical composition further comprises a taste masking agent, an odor masking agent, or a combination thereof. In certain embodiments, the therapeutically effective amount of 4-methylpyrazole is an amount between about 10 and about 20 mg / kg. In certain embodiments, the therapeutically effective amount of 4-methylpyrazole is an amount that produces a plasma concentration of about 0.1 μmol / L.

[0004] Certain embodiments relate to a pharmaceutical composition comprising a therapeutically effective amount of 4-methylpyrazole or a pharmaceutically acceptable salt, hydrate, polymorph or solvate thereof and a pharmaceutically acceptable carrier; wherein the pharmaceutical composition is configured for transdermal administration. In certain embodiments, the pharmaceutical composition further comprises n-acetylcysteine, ampelopsis, Withania somifera / ashwagandha, L-cystine, S-acetyl glutathione, molybdenum, iron, zinc, iron chelator, L-ascorbic acid, L-threonine or any combination thereof. In certain embodiments, the iron chelator comprises curcumin, quercetin, inositol hexaphosphate or any combination thereof.

[0005] Certain embodiments relate to methods for treating and / or preventing alcohol-induced hypersensitivity in a subject, the method comprising administering a pharmaceutical composition disclosed herein. In certain embodiments, the alcohol-induced hypersensitivity is selected from flushing, increased heart rate, palpitations, hypotension, nausea, dizziness, headache, vomiting, diarrhea, stomach discomfort, ataxia, confusion, urticaria, systemic dermatitis, allergic rhinitis, bronchoconstriction, asthmatic bronchoconstriction aggravation, cardiovascular collapse, allergic conjunctivitis, atopic dermatitis, eosinophilic esophagitis, anaphylaxis, chronic bronchitis and chronic obstructive pulmonary disease (COPD) and any combination thereof. In certain embodiments, alcohol flush is characterized by facial flushing, increased skin temperature, increased heart rate, decreased diastolic blood pressure or any combination thereof. In certain embodiments, the pharmaceutical composition is administered before the subject ingests alcohol. In certain embodiments, the pharmaceutical composition is administered about 60 minutes to about 15 minutes before the subject ingests alcohol. In certain embodiments, the pharmaceutical composition is administered while the subject ingests ethanol or after the subject ingests ethanol.

[0006] Certain embodiments relate to methods of eliminating acetaldehyde formed from ethanol in a subject, the methods comprising administering a pharmaceutical composition described herein.

[0007] Certain embodiments relate to methods of reducing and / or eliminating acetaldehyde formed from ethanol in the oral cavity, esophagus, stomach, large intestine, and combinations thereof in a subject, the method comprising administering a pharmaceutical composition described herein.

[0008] Certain embodiments relate to methods of reducing and / or eliminating acetaldehyde levels in the blood of a subject, the methods comprising administering a pharmaceutical composition described herein.

[0009] Certain embodiments relate to methods of reducing and / or eliminating acetaldehyde from the digestive tract in a subject, the method comprising administering a pharmaceutical composition described herein.

[0010] Certain embodiments relate to methods of inhibiting mitochondrial aldehyde dehydrogenase 2 (ALDH2) in a subject, the methods comprising administering a pharmaceutical composition described herein.

[0011] Certain embodiments relate to methods of reducing the risk of a disease or disorder in a subject caused by the subject's ingestion of ethanol, the method comprising administering a pharmaceutical composition described herein.

[0012] In certain embodiments, the disease or disorder is selected from upper aerodigestive tract cancer, digestive tract cancer, or breast cancer. In certain embodiments, the upper aerodigestive tract cancer comprises esophageal cancer, oropharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, head or neck cancer. In certain embodiments, the digestive tract cancer comprises gastric cancer or colon cancer. In certain embodiments, the disease or disorder comprises late-onset Alzheimer's disease, hypertension, myocardial infarction, Parkinson's disease, amyotrophic lateral sclerosis, and cerebral ischemia.

[0013] Certain embodiments relate to methods of blocking the histamine-releasing effects of acetaldehyde in a subject, the methods comprising administering a pharmaceutical composition described herein.

[0014] Certain embodiments relate to a method of blocking alcohol-induced acetaldehyde production in a subject, the method comprising administering a pharmaceutical composition described herein. In certain embodiments, the subject is heterozygous or homozygous for an aldehyde dehydrogenase 2 (ALDH2) allele designated as Glu487lys, ALDH2*2, ALDH2*487lys, Glu487lys, or rs671.

[0015] Certain embodiments further comprise testing the subject for the presence of an aldehyde dehydrogenase 2 (ALDH2) allele designated as Glu487lys, ALDH2*2, ALDH2*487lys, Glu504lys, or rs671. In certain embodiments, testing the subject for the presence of an aldehyde dehydrogenase 2 (ALDH2) allele referred to as Glu487lys, ALDH2*2, ALDH2*487lys, Glu504lys, or rs671 comprises: obtaining a breath sample from the subject; measuring ethanol and acetaldehyde levels in the breath sample; and determining the ratio of acetaldehyde levels to ethanol levels in the breath sample, wherein a ratio of acetaldehyde levels to ethanol levels of about 23.3 or greater indicates the presence of an aldehyde dehydrogenase 2 (ALDH2) allele referred to as Glu487lys, ALDH2*2, ALDH2*487lys, Glu504lys, or rs671; and if the subject has a ratio of acetaldehyde levels to ethanol levels of about 23.3 or greater, administering a pharmaceutical composition disclosed herein to the subject. In certain embodiments, measuring ethanol and acetaldehyde levels in a breath sample is performed by semiconductor gas chromatography. In certain embodiments, the breath sample is obtained after ingestion of alcohol. In certain embodiments, testing the subject for the presence of an aldehyde dehydrogenase 2 (ALDH2) allele called Glu487lys, ALDH2*2, ALDH2*487lys, Glu504lys, or rs671 comprises: obtaining a biological sample from the subject; isolating genomic DNA from the biological sample; identifying the presence of an aldehyde dehydrogenase 2 (ALDH2) allele called Glu487lys, ALDH2*2, ALDH2*487lys, Glu504lys, or rs671; and administering a drug described herein to the subject if the aldehyde dehydrogenase 2 (ALDH2) allele called Glu487lys, ALDH2*2, ALDH2*487lys, Glu504lys, or rs671 is present. In certain embodiments, the biological sample is a swab sample. In certain embodiments, the biological sample is a blood sample. Detailed Description The present application relates to a pharmaceutical composition for preventing and treating alcohol-induced hypersensitivity reactions including alcohol-induced skin flushing.

[0017] People consume alcohol, chemically known as ethanol, for a variety of social, recreational, and medicinal purposes. As used herein, the terms "alcohol" and "ethanol" are used interchangeably. Excessive alcohol intake causes damage to a variety of tissues, including the liver, brain, skeletal muscle, and cardiac muscle, and contributes to considerable public health morbidity and mortality. Many of these effects of alcohol are mediated by acetaldehyde produced during alcohol metabolism in a two-step pathway in which alcohol is oxidized to acetaldehyde by alcohol dehydrogenase (ADH), which in turn is rapidly metabolized to acetic acid by the liver mitochondrial enzyme aldehyde dehydrogenase (ALDH).

[0018] ADH and ALDH genes show polymorphisms, which modulate individual differences in alcohol oxidation capacity (Bosron et al., Hepatology 1986, 6, 502-510). East Asian populations carry a variant allele of alcohol dehydrogenase isoform 2 (ADH2*2), which encodes an ADH enzyme with an R47H amino acid substitution (Matsuo et al., Oncology 2006, 27(5), 1018-1023; Tamakoshi et al., Alcohol 2003, 38, 407-410). The H47 ADH enzyme is "hyperactive", showing a Vmax approximately 40-fold higher than the less active R47 ADH enzyme encoded by the "typical" allele (ADH2*1) (Bosron et al., Hepatology 1986, 6, 502-510; Yoshida et al., Prog. Nucleic Acid Res. Mol. Biol. 1991, 40, 255-287). The ADH2*2 allele is associated with the accumulation of acetaldehyde (Crabb et al., Proc. Nutr. Soc. 2004, 63(1), 49-63).

[0019] A variant allele of aldehyde dehydrogenase subtype 2 (ALDH2*2, also known as Glu487lys, ALDH2*487lys, Glu504lys or rs671) is also common in East Asian populations, encoding an ALDH enzyme with an E487K amino acid substitution (Chen et al., Am. J. Hum. Genet. 1999, 65(3), 795-807). The K487 ALDH enzyme exhibits reduced activity, resulting in a 40%-90% decrease in acetaldehyde removal rate compared to the more active E487 ALDH2 enzyme encoded by the "typical" allele (ALDH2*1), such that people expressing the variant allele exhibit reduced or absent ALDH2 activity.

[0020] Acetaldehyde is associated with acute symptoms such as facial flushing, tachycardia, shortness of breath, dizziness, nausea, vomiting and headache, and is also associated with increased long-term health risks for upper gastrointestinal cancers, breast cancer, liver disease, Alzheimer's disease, hypertension and myocardial infarction (see Visapää et al., Gut 2004, 53, 871-876; Yokoyama et al., Jpn. J. Clin. Oncol. 2003, 33(3), 111-121; Ohsawa et al., J. Hum. Genet. 2003, 48, 404-409; and references cited therein). People who express the ALDH2*2 allele with reduced or absent ALDH2 activity show alcohol-related sensitivity such as facial flushing, tachycardia, etc. when drinking small amounts of ethanol (Goedde et al., Hum. Genet. 1992, 88, 344-346; Xiao et al., J. Clin. Invest. 1995, 96, 2180-2186). Therefore, reducing acetaldehyde levels in people with reduced or absent ALDH2 activity may help reduce the acute systemic and long-term health risks these people experience when consuming ethanol.

[0021] 4-Methylpyrazole (also known as fomepizole or 4-MP) inhibits alcohol dehydrogenase (ADH), an enzyme that oxidizes alcohol as part of a two-step metabolic elimination pathway in which ethanol is oxidized by ADH to acetaldehyde, which in turn is oxidized by aldehyde dehydrogenase (ALDH) to acetic acid.

[0022] In certain embodiments, the compounds used in the methods described herein can be formulated into pharmaceutical compositions. The pharmaceutical compositions of the present invention can include a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Such compositions can optionally include at least one additional therapeutic agent useful for preventing and treating alcohol-induced hypersensitivity reactions, including alcohol-induced skin flushing.

[0023] The compounds of the present invention can be used in a conventional manner to control the diseases described herein, including but not limited to alcohol-induced hypersensitivity reactions, including alcohol-induced skin flushing, and to treat the disease or reduce the progression or severity of the effects. Such treatment methods, their dosage levels and requirements can be selected by those of ordinary skill in the art from available methods and techniques. For example, the compounds of the present invention can be combined with a pharmaceutically acceptable adjuvant in a pharmaceutically acceptable manner and in an amount that effectively reduces the incidence and severity of the disease, for administration to patients with alcohol-induced hypersensitivity reactions, including alcohol-induced skin flushing, or susceptible to it.

[0024] In each of the embodiments disclosed herein, the compounds and methods can be used for or on a subject in need of such treatment, also referred to as "in need thereof." As used herein, the phrase "in need thereof" means that the subject has been identified as having a need for the particular method or treatment and that the treatment has been provided to the subject for that particular purpose.

[0025] The terms "patient" and "subject" are interchangeable and can be considered to refer to any living organism that can be treated with the compounds of the present invention. Therefore, the terms "patient" and "subject" can include, but are not limited to, any non-human mammal, primate, or human. In certain embodiments, the "patient" or "subject" is a mammal, such as a mouse, rat, other rodent, rabbit, dog, cat, pig, cattle, sheep, horse, primate, or human. In certain embodiments, the patient or subject is an adult, child, or infant. In certain embodiments, the patient or subject is a human.

[0026] When used herein, the terms "combination", "combined" and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, the described compound can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or administered together in a single unit dosage form. Therefore, the present invention provides a single unit dosage form, which comprises the described compound, an additional therapeutic agent and a pharmaceutically acceptable carrier, adjuvant or vehicle. When a patient or individual is exposed to two agents at the same time, the two or more agents are generally considered to be "combined" for administration. In many embodiments, when a patient or individual simultaneously shows therapeutically relevant levels of two or more agents in a specific target tissue or sample (e.g., in the brain, serum, etc.), the agents are considered to be "combined" for administration.

[0027] The term "pharmaceutically acceptable excipient" refers to a non-toxic excipient that can be administered to a patient with the compounds of the present invention and does not destroy its pharmacological activity. Pharmaceutically acceptable excipients that can be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin. Pharmaceutically acceptable excipients that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, lanolin, and self-emulsifying drug delivery systems (SEDDS) such as alpha-tocopherol, polyethylene glycol 1000 succinate or other similar polymer delivery matrices.

[0028] As used herein, the term "therapeutically effective amount" refers to the amount of an active compound or agent that elicits a biological or medical response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, physician, or other clinician, including one or more of the following: (1) prevention of the disease; e.g., prevention of the disease, condition, or disorder in an individual who may be susceptible to the disease, condition, or disorder but does not yet experience or exhibit the pathology or symptoms of the disease, (2) inhibition of the disease; e.g., inhibition of the disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder (i.e., stopping further development of the pathology and / or symptoms), and (3) amelioration of the disease; e.g., amelioration of the disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder (i.e., reversing the pathology and / or symptoms). In certain embodiments, a therapeutically effective amount of a compound represents a daily dose of a particular compound. In certain embodiments, a daily dose of a particular compound may be administered as a single daily dose or divided into two or more equal or unequal doses administered over the course of a day.

[0029] The compounds described herein can form acid addition salts thereof. It should be understood that for use in medicine, the salts of the compounds described herein should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts are obvious to those skilled in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, for example, with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; and acid addition salts formed with organic acids such as succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid or naphthalenesulfonic acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms. Pharmaceutically acceptable salts of the compounds described herein include conventional non-toxic salts or quaternary ammonium salts of the compounds, such as salts from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothiocarboxylic acid, etc. In other cases, the compounds described may contain one or more acidic functional groups and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. These salts can also be prepared in situ during the manufacture of the administration medium or dosage form, or by reacting the purified compound in the form of a free acid with a suitable base such as a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, ammonia, or with a pharmaceutically acceptable organic primary amine, secondary amine or tertiary amine separately. Representative alkali metal or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts, etc. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.

[0030] The compounds described herein can be prepared in crystalline or amorphous form, and if crystalline, can be optionally solvated, for example as a hydrate. The present invention includes within its scope stoichiometric solvates (e.g., hydrates) as well as compounds containing variable amounts of solvents (e.g., water). Certain compounds described herein can exist in stereoisomeric forms (e.g., diastereomers and enantiomers), and the present invention extends to each of these stereoisomeric forms and mixtures thereof, including racemates. Different stereoisomeric forms can be separated from each other by conventional methods, or any given isomer can be obtained by stereospecific or asymmetric synthesis. The present invention also extends to any tautomeric forms and mixtures thereof.

[0031] Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, the preferred methods, devices, and materials are now described.

[0032] Alternatively, the compounds of the present invention can be used in compositions and methods for treating or protecting individuals against conditions described herein over an extended period of time, including but not limited to neurodegenerative diseases. The compounds can be used in such compositions alone or together with other compounds of the present invention in a manner consistent with the conventional use of such compounds in pharmaceutical compositions. For example, the compounds of the present invention can be combined with pharmaceutically acceptable adjuvants conventionally used in vaccines and administered in a preventive effective amount to protect individuals against diseases described herein over an extended period of time, including but not limited to neurodegenerative diseases.

[0033] The present application relates to a pharmaceutical composition comprising a therapeutically effective amount of 4-methylpyrazole or a pharmaceutically acceptable salt, hydrate, polymorph or solvate thereof and a pharmaceutically acceptable carrier; wherein the pharmaceutical composition is configured for oral administration.

[0034] In certain embodiments, the pharmaceutical composition further comprises at least one pharmaceutically inert coating that can be used to mask the odor of 4-methylpyrazole. In other embodiments, the pharmaceutical composition described herein can be encapsulated. In certain embodiments, the encapsulation medium includes but is not limited to capsules, soft gel sleeves, gel sleeves, coatings, or any combination thereof. In certain embodiments, coatings can include but are not limited to films, waxes, varnishes, glazes, polymer coatings, sugar coatings, polysaccharide-based coatings, enteric coatings, or combinations thereof.

[0035] In certain embodiments, the at least one pharmaceutically inert coating is selected from the group consisting of hydroxyalkyl cellulose, hydroxypropyl cellulose, anti-adherents, plasticizers, sugars, methacrylate copolymers, hydroxyalkyl cellulose, and water-soluble polymers. Examples of anti-adherents include, but are not limited to, talc (Alphafil 500), silicon dioxide, silicon dioxide hydrogel, microcrystalline cellulose, alkali metal stearates, starch, and combinations thereof. Examples of plasticizers include, but are not limited to, propylene glycol, glycerol, trimethylolpropane, polyethylene glycol, dibutyl sebacate, acetylated monoglycerides, diethyl phthalate, triacetin, triacetin, triethyl acetyl citrate, triethyl citrate, and combinations thereof. Examples of water-soluble polymers include, but are not limited to, hydroxypropyl cellulose, hydroxypropyl methylcellulose, gum arabic, sodium carboxymethyl cellulose, dextrin, alginic acid, ethyl cellulose resin, gelatin, guar gum, liquid glucose, methyl cellulose, pregelatinized starch, sodium alginate, starch, zein, polyvinyl pyrrolidone, vinyl pyrrolidone-vinyl acetate copolymer, vinyl acetate-crotonic acid copolymer, ethyl acrylate-methacrylic acid copolymer, and combinations thereof.

[0036] In certain embodiments, the pharmaceutical composition is formulated into an oral dosage form selected from powders, tablets, lozenges, chewing gums, pills, capsules, microcapsules, caplets, orally disintegrating tablets, osmotic controlled release oral delivery systems, or any combination thereof.

[0037] Formulations suitable for oral administration as described herein can take the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a lozenge (using an inert base such as gelatin and glycerin or sucrose and acacia) and / or as a mouthwash, etc., each containing a predetermined amount of a compound of the invention as the active ingredient. The compounds described herein can also be administered as boluses, electuaries, or pastes.

[0038] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate and / or any of the following: fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; binders such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or gum arabic; humectants such as glycerol; disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; dissolution retardants such as paraffin; absorption accelerators such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glyceryl monostearate and nonionic surfactants; adsorbents such as kaolin and bentonite; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical composition may also contain a buffer. Solid compositions of a similar type may also be employed as fillers in soft and hard shell gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0039] Tablets can be optionally manufactured by compression or molding together with one or more auxiliary ingredients (excipients). Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), a surfactant, or a dispersant. Molded tablets can be prepared in a suitable machine, wherein a mixture of powdered compounds is moistened with an inert liquid diluent. If a solid carrier is used, the preparation can be in the form of a tablet, placed in a hard gelatin capsule in the form of a powder or granules, or in the form of a lozenge or a tablet. The amount of the solid carrier will be variable, e.g., about 0.01 to 800 mg, preferably about 0.01 mg to 400 mg or about 3 mg to about 400 mg. When a liquid carrier is used, the preparation can be in the form of, for example, a syrup, an emulsion, a soft gelatin capsule, a sterile injectable liquid such as an ampoule, or a non-aqueous liquid suspension. When the composition takes the form of a capsule, any conventional encapsulation is suitable, for example using the above-mentioned carriers in a hard gelatin capsule shell.

[0040] Tablets and other solid dosage forms such as dragees, capsules, pills and granules can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings known in the field of drug formulation. Alternatively or in addition, they can be prepared using, for example, different proportions of hydroxypropyl methylcellulose to provide the required release characteristics, other polymer matrices, liposomes and / or microspheres to provide a slow or controlled release of the active ingredient therein. They can be formulated for rapid release, such as freeze-dried. They can be sterilized by, for example, filtering through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition, which can be dissolved in sterile water or some other sterile injectable medium before use. These compositions can also optionally include an opacifier, and can be a composition that releases the active ingredient only or preferably in a specific part of the gastrointestinal tract, preferably in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. If appropriate, the active ingredient can also take the form of a microencapsulation containing one or more of the above-mentioned excipients.

[0041] Liquid dosage forms for oral administration of the compounds of the present invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage form may contain an inert diluent commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuran methanol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof.

[0042] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0043] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0044] The amount of the active ingredient or its active salt or derivative required for treatment varies not only with the specific salt selected, but also with the route of administration, the nature of the condition to be treated, and the age and condition of the patient, and will ultimately be determined at the discretion of the attending physician or clinician. In general, those skilled in the art understand how to extrapolate the in vivo data obtained in a model system, usually an animal model, to another system such as humans. In some cases, these extrapolations may be based only on the comparison of the weight of an animal model with another animal such as a mammal, preferably a human, but more generally, these extrapolations are not based only on weight, but include various factors. Representative factors include the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicological characteristics of the specific compound used, whether a drug delivery system is used, whether an acute or chronic disease state is being treated or prevented, or whether other active compounds are administered in addition to the compounds of the present invention and as part of a drug combination. The dosage regimen for treating disease conditions using the compounds and / or compositions of the present invention is selected according to the various factors mentioned above. Thus, the actual dosage regimen employed may vary widely and therefore may deviate from the preferred dosage regimen, and those skilled in the art will recognize that doses and dosage regimens outside of these typical ranges can be tested and, where appropriate, used in the methods of the present invention.

[0045] The desired dose can be conveniently present as a single dose or as a sub-dose administered at appropriate intervals, for example as two, three, four or more sub-doses per day. The sub-dose itself can be further divided into, for example, multiple discrete loosely spaced administrations. The daily dose can be divided into several, for example, 2,3 or 4 partial administrations, especially when a relatively large amount is administered when it is considered appropriate. Depending on individual behavior, if suitable, it may be necessary to deviate upward or downward from the indicated daily dose.

[0046] In certain embodiments, the pharmaceutical composition disclosed herein may further comprise n-acetylcysteine, ampelopsis, Withania somifera / Ashwagandha, L-cystine, S-acetyl glutathione, molybdenum, iron, zinc, iron chelator (curcumin / quercetin / IP6), L-ascorbic acid, L-threonine, or any combination thereof. In certain embodiments, the iron chelator comprises curcumin, quercetin, inositol hexaphosphate (IP6), or any combination thereof. In certain embodiments, the pharmaceutically acceptable carrier is water. In certain embodiments, the pharmaceutical composition further comprises a taste masking agent, an odor masking agent, or a combination thereof.

[0047] In certain embodiments, the therapeutically effective amount of the 4-methylpyrazole is an amount between about 0.1 to about 200 mg / kg. In certain embodiments, the therapeutically effective amount of the 4-methylpyrazole is an amount between about 10 to about 20 mg / kg. In other embodiments, the therapeutically effective amount of the 4-methylpyrazole is an amount that produces a plasma concentration of about 0.01 μmol / L to about 10 μmol / L. In other embodiments, the therapeutically effective amount of the 4-methylpyrazole is an amount that produces a plasma concentration of about 0.1 μmol / L.

[0048] Embodiments herein also relate to a pharmaceutical composition comprising a therapeutically effective amount of 4-methylpyrazole or a pharmaceutically acceptable salt, hydrate, polymorph or solvate thereof and a pharmaceutically acceptable carrier; wherein the pharmaceutical composition is formulated for transdermal administration.

[0049] In certain embodiments, the pharmaceutical composition may further comprise n-acetylcysteine, ampelopsis, Withania somifera / Ashwagandha, L-cystine, S-acetyl glutathione, molybdenum, iron, zinc, iron chelator (curcumin / quercetin / IP6), L-ascorbic acid, L-threonine, or any combination thereof. In certain embodiments, the iron chelator comprises curcumin, quercetin, inositol hexaphosphate, or any combination thereof.

[0050] Also described herein are methods for treating and / or preventing alcohol-induced hypersensitivity in a subject, the method comprising administering a pharmaceutical composition described herein. In certain embodiments, the alcohol-induced hypersensitivity is selected from flushing, increased heart rate, palpitations, hypotension, nausea, dizziness, headache, vomiting, diarrhea, stomach discomfort, ataxia, confusion, urticaria, systemic dermatitis, allergic rhinitis, bronchoconstriction, asthmatic bronchoconstriction aggravation, cardiovascular collapse, allergic conjunctivitis, atopic dermatitis, eosinophilic esophagitis, anaphylaxis, chronic bronchitis, and chronic obstructive pulmonary disease (COPD), and any combination thereof. In certain embodiments, alcohol flushing is characterized by facial flushing, increased skin temperature, increased heart rate, decreased diastolic blood pressure, or any combination thereof. In certain embodiments, the pharmaceutical composition is administered before the subject ingests alcohol.

[0051] In certain embodiments, the pharmaceutical composition is administered about 60 minutes to about 15 minutes before the subject ingests alcohol. In certain embodiments, the pharmaceutical composition is administered at the same time as the subject ingests alcohol or after the subject ingests alcohol.

[0052] Also disclosed are methods of eliminating acetaldehyde produced from alcohol in a subject, the methods comprising administering the pharmaceutical compositions described herein.

[0053] Also described herein are methods of reducing and / or eliminating acetaldehyde formed from alcohol in the oral cavity, esophagus, stomach, large intestine, or a combination thereof in a subject, the methods comprising administering a pharmaceutical composition described herein. Studies have shown that acetaldehyde is most abundant in these compartments, rather than in the bloodstream, immediately after ingestion (Salaspuro MP, Acetaldehyde, microbes and cancer of the digestive tract, Crit Rev ClinLab Sci 2003; 40:183-208; Salaspuro M., Acetaldehyde as a common denominator and cumulative carcinogen indigestive tract cancers, Scand J Gastroenterol 2009; 44:912-25; Salaspuro M., Acetaldehyde and gastric cancer, J Dig Dis 2011; 12:51-9).

[0054] Also described herein are methods of reducing and / or eliminating acetaldehyde levels in the blood of a subject comprising administering a pharmaceutical composition described herein.

[0055] Also described herein are methods of reducing and / or eliminating acetaldehyde from the digestive tract in a subject, the methods comprising administering a pharmaceutical composition described herein.

[0056] Also described herein are methods of inhibiting mitochondrial aldehyde dehydrogenase 2 (ALDH2) in a subject comprising administering a pharmaceutical composition described herein.

[0057] Also described herein are methods of reducing the risk of a disease or disorder caused by alcohol ingestion in a subject, the methods comprising administering a pharmaceutical composition described herein. In certain embodiments, the disease or disorder is selected from upper aerodigestive tract cancer, digestive tract cancer, or breast cancer. In certain embodiments, the upper aerodigestive tract cancer comprises esophageal cancer, oropharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, head or neck cancer. In certain embodiments, the digestive tract cancer comprises gastric cancer or colon cancer. In certain embodiments, the disease or disorder comprises late-onset Alzheimer's disease, hypertension, myocardial infarction, Parkinson's disease, amyotrophic lateral sclerosis, and cerebral ischemia.

[0058] Certain embodiments relate to methods of blocking the histamine-releasing effects of acetaldehyde in a subject, the methods comprising administering a pharmaceutical composition disclosed herein.

[0059] Certain embodiments relate to methods of blocking alcohol-induced acetaldehyde production in a subject, the method comprising administering a pharmaceutical composition disclosed herein.

[0060] In certain embodiments, the subject is heterozygous or homozygous for an aldehyde dehydrogenase 2 (ALDH2) allele designated as Glu487lys, ALDH2*2, ALDH2*487lys, Glu504lys, or rs671.

[0061] Certain embodiments further comprise testing the subject for the presence of an aldehyde dehydrogenase 2 (ALDH2) allele designated as Glu487lys, ALDH2*2, ALDH2*487lys, Glu504lys, or rs671.

[0062] In certain embodiments, testing the subject for the presence of an aldehyde dehydrogenase 2 (ALDH2) allele designated as Glu487lys, ALDH2*2, ALDH2*487lys, Glu504lys, or rs671 comprises: obtaining a breath sample from the subject; measuring alcohol and acetaldehyde levels in the breath sample; and determining a ratio of acetaldehyde level to alcohol level in the breath sample, wherein a ratio of acetaldehyde level to alcohol level of about 23.3 or greater indicates the presence of an aldehyde dehydrogenase 2 (ALDH2) allele designated as Glu487lys, ALDH2*2, ALDH2*487lys, Glu504lys, or rs671; and administering the pharmaceutical composition of claim 1 or claim 12 to the subject if the subject has a ratio of acetaldehyde level to alcohol level of about 23.3 or greater.

[0063] In certain embodiments, measuring the alcohol and acetaldehyde levels in the breath sample is performed by semiconductor gas chromatography.

[0064] In certain embodiments, the breath sample is obtained after ingestion of alcohol.

[0065] In certain embodiments, testing the subject for the presence of an aldehyde dehydrogenase 2 (ALDH2) allele designated as Glu487lys, ALDH2*2, ALDH2*487lys, Glu504lys, or rs671 comprises: obtaining a biological sample from the subject; isolating genomic DNA from the biological sample; identifying the presence of an aldehyde dehydrogenase 2 (ALDH2) allele designated as Glu487lys, ALDH2*2, ALDH2*487lys, Glu504lys, or rs671; and administering to the subject the pharmaceutical composition of claim 1 or claim 12 if the aldehyde dehydrogenase 2 (ALDH2) allele designated as Glu487lys, ALDH2*2, ALDH2*487lys, Glu504lys, or rs671 is present. In certain embodiments, the biological sample is a swab sample. In certain embodiments, the biological sample is a blood sample.

[0066] Although the above invention has been described in some detail by way of illustration and example for the purpose of clear understanding, it will be apparent to those skilled in the art that certain changes and modifications will be implemented. Therefore, the description and examples should not be construed as limiting the scope of the invention, which is defined by the appended claims. Although the present disclosure has been described in considerable detail with reference to certain preferred versions thereof, other versions are possible. Therefore, the spirit and scope of the present application should not be limited to the description of the preferred versions described herein.

[0067] Although compositions, materials and methods similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable formulations, methods and materials are described herein. All publications mentioned herein are incorporated by reference in their entirety. In the event of a conflict, the present specification including definitions shall prevail. In addition, the specific embodiments discussed below are merely illustrative and are not intended to be limiting.

[0068] All features disclosed in this specification, including the abstract and the drawings, and all steps in any disclosed method or process, may be combined in any combination, except where at least some of these features and / or steps are mutually exclusive combinations. Unless otherwise expressly stated, each feature disclosed in this specification, including the abstract and the drawings, may be replaced by an optional feature for the same, equivalent or similar purpose. Therefore, unless otherwise expressly stated, each feature disclosed is merely an example in a series of general equivalent or similar features. In addition to those described herein, various other modifications of the present application are also apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.

[0069] Unless otherwise indicated, all the numbers representing the quantity, properties such as molecular weight, reaction conditions, etc. of the components used in this specification and claims should be understood to be modified by the term "about" in all cases. When used in this article, the term "about" means plus or minus 10% of a given value. For example, "about 50%" means in the range of 45%-55%. Therefore, unless otherwise indicated, the numerical parameters set forth in this specification and the accompanying claims are approximate values, which can be changed according to the desired characteristics that the present invention attempts to obtain. At least, and without attempting to limit the application of the principle of equivalence to the scope of the claims, each numerical parameter should at least be interpreted according to the number of significant figures reported and by applying common rounding techniques. Although the numerical range and parameters setting forth the wide range of the present invention are approximate values, the numerical values ​​set forth in the specific examples are reported as accurately as possible. However, any numerical value inherently contains certain errors that are inevitably produced by the standard deviation present in their corresponding experimental measurements.

[0070] The description of the range of values ​​herein is intended only to be used as a shorthand method for individually referring to each individual value falling within the range. Unless otherwise specified herein, each individual value is incorporated into this specification as if it were individually narrated herein. Unless otherwise specified herein or clearly contradictory to the context, all methods described herein can be performed in any suitable order. The use of any and all examples or exemplary language (such as "for example") provided herein is intended only to better illustrate the present invention and is not intended to limit the scope of the present invention to which protection is otherwise claimed. Any language in this specification should not be interpreted as indicating that any unclaimed element is essential to the practice of the present invention.

[0071] The grouping of optional elements or embodiments of the present invention disclosed herein should not be construed as limiting. Each group member can be mentioned and claimed individually or in any combination with other members of the group or other elements present herein. It is expected that one or more members of a group may be included in a group, or deleted from a group, for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, this specification is deemed to include the modified group, thereby satisfying the written description of all Markush groups used in the accompanying claims.

[0072] Certain embodiments of the present invention are described herein, including the best mode known to the inventor for implementing the present invention. Of course, for those of ordinary skill in the art, after reading the above description, the changes in the embodiments of these descriptions will become apparent. The inventor expects that professional and technical personnel will appropriately adopt such changes, and the inventor intends to practice the present invention in a manner different from that specifically described herein. Therefore, the present invention includes all modifications and equivalents allowed by applicable law of the subject matter narrated in the claims attached hereto. In addition, unless otherwise stated herein or clearly contradictory to the context, the present invention covers any combination of the above elements in all possible variations.

[0073] Specific embodiments disclosed herein may be further limited in the claims using language such as "consisting of" or "consisting essentially of" rather than "comprising." When used in the claims, whether as filed or added by amendment, the transitional term "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional term "consisting essentially of" limits the scope of a claim to the specified materials or steps, and those that do not materially affect the basic and novel characteristics. Embodiments of the invention so claimed are inherently or expressly described and enabled herein.

[0074] Finally, it should be understood that the embodiments of the present invention disclosed herein are illustrations of the principles of the present invention. Other modifications that may be employed are within the scope of the present invention. Therefore, by way of example and not limitation, alternative configurations of the present invention may be used in accordance with the teachings herein. Therefore, the present invention is not limited to those contents that are fully as shown and described.

Claims

1. A pharmaceutical composition comprising a therapeutically effective amount of 4-methylpyrazole or a pharmaceutically acceptable salt, hydrate, polymorph or solvate thereof and a pharmaceutically acceptable carrier; wherein the pharmaceutical composition is configured for oral administration; and wherein the pharmaceutical composition further comprises at least one pharmaceutically inert coating that can be used to mask the odor of 4-methylpyrazole.

2. The pharmaceutical composition of claim 1, wherein the at least one pharmaceutically inert coating is selected from the group consisting of hydroxyalkyl cellulose, anti-adherent agents, plasticizers, sugars, methacrylate copolymers, hydroxyalkyl cellulose, and water soluble polymers.

3. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is configured into an oral dosage form selected from powders, tablets, lozenges, chewing gum, pills, capsules, microcapsules, caplets, orally disintegrating tablets, osmotic controlled release oral delivery systems, or any combination thereof.

4. The pharmaceutical composition according to claim 1, further comprising n-acetylcysteine, ampelopsis, Withania somifera / ashwagandha, L-cystine, S-acetyl glutathione, molybdenum, iron, zinc, iron chelators, L-ascorbic acid, L-threonine, or any combination thereof.

5. The pharmaceutical composition of claim 4, wherein the iron chelator comprises curcumin, quercetin, inositol hexaphosphate (IP6), or any combination thereof.

6. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable carrier is water.

7. The pharmaceutical composition of claim 1, further comprising a taste masking agent, an odor masking agent, or a combination thereof.

8. The pharmaceutical composition of claim 1, wherein the therapeutically effective amount of 4-methylpyrazole is an amount between about 10 mg / kg to about 20 mg / kg.

9. The pharmaceutical composition of claim 1, wherein the therapeutically effective amount of 4-methylpyrazole is an amount that produces a plasma concentration of about 0.1 μmol / L.

10. A pharmaceutical composition comprising a therapeutically effective amount of 4-methylpyrazole or a pharmaceutically acceptable salt, hydrate, polymorph or solvate thereof and a pharmaceutically acceptable carrier; wherein the pharmaceutical composition is formulated for transdermal administration.

11. The pharmaceutical composition according to claim 10, further comprising n-acetylcysteine, ampelopsis, Withania somifera / ashwagandha, L-cystine, S-acetyl glutathione, molybdenum, iron, zinc, iron chelators, L-ascorbic acid, L-threonine, or any combination thereof.

12. The pharmaceutical composition of claim 11, wherein the iron chelator comprises curcumin, quercetin, inositol hexaphosphate, or any combination thereof.

13. A method for treating and / or preventing alcohol-induced hypersensitivity in a subject, the method comprising administering to the subject a pharmaceutical composition according to claim 1 or claim 12.

14. The method of claim 13, wherein the alcohol-induced hypersensitivity reaction is selected from the group consisting of flushing, increased heart rate, palpitations, hypotension, nausea, dizziness, headache, vomiting, diarrhea, stomach upset, ataxia, confusion, urticaria, systemic dermatitis, allergic rhinitis, bronchoconstriction, asthmatic bronchoconstriction exacerbated, cardiovascular collapse, allergic conjunctivitis, atopic dermatitis, eosinophilic esophagitis, anaphylaxis, chronic bronchitis, and chronic obstructive pulmonary disease (COPD), and any combination thereof.

15. The method of claim 14, wherein the alcohol flush is characterized by facial redness, increased skin temperature, increased heart rate, decreased diastolic blood pressure, or any combination thereof.

16. The method of claim 13, wherein the pharmaceutical composition is administered prior to the subject's ingestion of alcohol.

17. The method of claim 13, wherein the pharmaceutical composition is administered from about 60 minutes to about 15 minutes prior to the subject's ingestion of alcohol.

18. The method of claim 13, wherein the pharmaceutical composition is administered simultaneously with or after the subject ingests alcohol.

19. A method of eliminating acetaldehyde formed from alcohol in a subject, the method comprising administering to the subject the pharmaceutical composition of claim 1 or claim 12.

20. A method of reducing and / or eliminating acetaldehyde formed from alcohol in the oral cavity, esophagus, stomach, large intestine, or a combination thereof in a subject, the method comprising administering to the subject a pharmaceutical composition according to claim 1 or claim 12.

21. A method for reducing and / or eliminating acetaldehyde levels in blood in a subject, the method comprising administering to the subject the pharmaceutical composition according to claim 1 or claim 12.

22. A method for reducing and / or eliminating acetaldehyde from the digestive tract in a subject, the method comprising administering the pharmaceutical composition according to claim 1 or claim 12 to the subject.

23. A method of inhibiting mitochondrial aldehyde dehydrogenase 2 (ALDH2) in a subject, the method comprising administering to the subject the pharmaceutical composition of claim 1 or claim 12.

24. A method of reducing the risk of a disease or disorder in a subject caused by the subject's intake of alcohol, the method comprising administering to the subject a pharmaceutical composition according to claim 1 or claim 12.

25. The method of claim 24, wherein the disease or disorder is selected from upper aerodigestive tract cancer, digestive tract cancer, or breast cancer.

26. The method of claim 24, wherein the upper aerodigestive tract cancer comprises esophageal cancer, oropharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, head or neck cancer.

27. The method of claim 24, wherein the digestive tract cancer comprises gastric cancer or colon cancer.

28. The method of claim 24, wherein the disease or disorder comprises late-onset Alzheimer's disease, hypertension, myocardial infarction, Parkinson's disease, amyotrophic lateral sclerosis, and cerebral ischemia.

29. A method of blocking the histamine-releasing effect of acetaldehyde in a subject, the method comprising administering to the subject the pharmaceutical composition of claim 1 or claim 12.

30. A method of blocking alcohol-induced acetaldehyde production in a subject, the method comprising administering to the subject the pharmaceutical composition of claim 1 or claim 12.

31. The method of any one of claims 13-30, wherein the subject is heterozygous or homozygous for an aldehyde dehydrogenase 2 (ALDH2) allele designated as glu487lys, ALDH2*2, or ALDH2*487lys.

32. The method of any one of claims 13-30, further comprising testing the subject for the presence of an aldehyde dehydrogenase 2 (ALDH2) allele designated Glu487lys, ALDH2*2, ALDH2*487lys, Glu504lys, or rs671.

33. The method of claim 32, wherein testing the subject for the presence of an aldehyde dehydrogenase 2 (ALDH2) allele designated as Glu487lys, ALDH2*2, ALDH2*487lys, Glu504lys, or rs671 comprises: Obtaining a breath sample from the subject; measuring alcohol and acetaldehyde levels in the breath sample; and determining a ratio of acetaldehyde level to alcohol level in the breath sample, wherein a ratio of acetaldehyde level to alcohol level of about 23.3 or greater indicates the presence of an aldehyde dehydrogenase 2 (ALDH2) allele known as Glu487lys, ALDH2*2, ALDH2*487lys, Glu504lys, or rs671; and administering a pharmaceutical composition according to claim 1 or claim 12 to the subject if the subject has a ratio of acetaldehyde level to alcohol level of about 23.3 or greater.

34. The method of claim 33, wherein measuring the ethanol and acetaldehyde levels in the breath sample is performed by semiconductor gas chromatography.

35. The method of claim 33, wherein the breath sample is obtained after ingestion of alcohol.

36. The method of claim 32, wherein testing the subject for the presence of an aldehyde dehydrogenase 2 (ALDH2) allele designated as Glu487lys, ALDH2*2, ALDH2*487lys, Glu504lys, or rs671 comprises: Obtaining a biological sample from the subject; isolating genomic DNA from the biological sample; identifying the presence of an aldehyde dehydrogenase 2 (ALDH2) allele designated as Glu487lys, ALDH2*2, ALDH2*487lys, Glu504lys, or rs671; and administering to the subject a pharmaceutical composition according to claim 1 or claim 12 if the aldehyde dehydrogenase 2 (ALDH2) allele designated as Glu487lys, ALDH2*2, ALDH2*487lys, Glu504lys, or rs671 is present.

37. The method of claim 33, wherein the biological sample is a swab sample.

38. The method of claim 33, wherein the biological sample is a blood sample.