KR20070031146A - 4-methylpyrazole formulations for inhibiting ethanol intolerance - Google Patents

Abstract

Provided are methods, articles of manufacture, and compositions useful for preventing or alleviating the symptoms of acetaldehyde accumulation or ethanol resistance in a subject having reduced or absent aldehyde dehydrogenase subtype 2 (ALDH2) activity, wherein approximately 1 mg / kg to approximately 4 mg / kg 4-methylpyrazole (MP) or an equivalent amount of 4-MP salt is administered orally to the subject.

4-methylpyrazole

Description

4-methylpyrazole composition that inhibits ethanol resistance {4-METHYLPYRAZOLE FORMULATIONS FOR INHIBITING ETHANOL INTOLERANCE}

FIG. 1. 4-MP (mg) vs. kg of body weight administered to human subjects. Graph of% reduction in ethanol elimination rate. Lines were fitted to the data obtained from the sources mentioned in the examples using linear least squares regression.

Figure 2. Percent reduction in acetaldehyde levels in ethanol resistant subjects receiving 4-MP treatment. Graph of decrease in ethanol removal rate.

FIELD OF THE INVENTION

The present invention provides a composition comprising 4-methylpyrazole (4-MP) or a physiologically acceptable salt thereof and a physiologically acceptable excipient; It relates to their use to prevent or alleviate ethanol resistance in individuals with reduced or absent aldehyde dehydrogenase subtype 2 (ALDH2) activity.

Background of the Invention

Most of the ethanol consumed by humans is removed from the bloodstream in a two-stage pathway, where ethanol is oxidized to toxin acetaldehyde by alcohol dehydrogenase (ADH), and the acetaldehyde is an aldehyde dehydrogena, a mitochondrial liver enzyme. It is rapidly metabolized to acetic acid by azeotype 2 (ALDH2). Many of the human population are “ALDH2 deficient” and possess a variant ALDH2 allele that produces ALDH2 enzymes with a 40% -90% reduction in acetaldehyde removal due to reduced activity. Although various health conditions for these individuals in a large number of human populations, such as cirrhosis and hepatocellular carcinoma, can occur with long-term use of ethanol in ALDH2 deficient individuals, these diseases are relatively small in a shorter period of time. From ingestion of ethanol (Ohira (1996) Alcohol Clin. Exp. Res. 20: 378a-382a; Takeshita et al. (2000) Cancer Lett. 149: 69-76). The experience of ethanol consumption in ALDH2-deficient individuals is characterized by subjective pathological rather than hot flashes, accelerated heart rate, and euphoria and / or relaxation that typically occurs after ethanol consumption (Ward et al. (1994) Alcohol and Alcoholism 29: 433-438).

The recognized ADH inhibitor, 4-methylpyrazole (fomepizole or 4-MP), has been approved by the US Food and Drug Administration for the treatment of ethylene glycol or methanol poisoning. Scalley et al. (2002) American Family Physician 66: 807-812. In poisoning patients, ADH metabolizes ethylene glycol or methanol into toxic byproducts, such as oxalate and glycolide, which can be used to prevent severe damage to multiple organ systems by toxic byproducts produced by ADH. A dose that can completely inhibit 4-MP is prescribed. Administration of 4-MP as a therapeutic for ethylene glycol or methanol poisoning generally requires relatively large intravenous infusions under the supervision of a physician.

Although elevated acetaldehyde concentrations due to ADH activity on ethanol pose significant health risks, these risks are not as urgent or urgent as for ethylene glycol or methanol poisoning, where 4-MP is currently being administered. The persistence of 4-MP in the bloodstream of an individual during the several days of measurement currently practiced in the administration of 4-MP is very inadequate for ALDH2 deficient individuals who want to drink ethanol because they This is because they want a relatively temporarily elevated blood ethanol level that lasts from several hours to several hours. In addition, high doses of 4-MP inhibit ADH activity to the extent that individuals treated with 4-MP may have significantly higher blood ethanol levels than those without 4-MP. Because of this, the removal of ethanol from the blood stream in the 4-MP amount described in the existing literature proceeds too slowly to ensure the safe use of ethanol for diversion.

In addition, administration of high doses, eg, 50 mg / kg body weight or more of 4-MP, itself has been reported to cause side effects similar to those in ALDH2 deficiency, eg flushing, headache, nausea (see Jacobsen et. al . (1988) Alcoholism: Clinical and Experimental Research 12: 516-522. In addition, the doses taught in the literature lead to unwanted side effects profiles in chronic use. In acute care situations, preclinical data in mice indicate a risk of up to 30% contraction in testicular volume after weeks of use.

How to address the side effects of acetaldehyde accumulation as a result of ethanol consumption in human populations with defective variants of ALDH2 is still not determined. Appropriately, this solution minimizes the effect on ethanol removal rates, avoiding the relatively long duration of the subject being under the influence of ethanol, and avoiding the unwanted side effects associated with high doses of 4-MP.

Summary of the invention

In one aspect, the present invention provides methods and compositions effective for preventing or alleviating the symptoms of acetaldehyde accumulation or ethanol resistance in a subject with reduced or absent ALDH2 activity.

In certain aspects, there is provided a method of preventing or alleviating ethanol resistance in a subject with reduced or absent aldehyde dehydrogenase subtype 2 (ALDH2) activity, the method comprising administering 4-MP to the subject. .

Symptoms of acetaldehyde accumulation in a subject can be selected from, for example, flushing, elevated heart rate, palpitation, hypotension, nausea, dizziness, headache.

In certain aspects, methods are provided for preventing diseases associated with long-term use of ethanol in individuals with reduced or absent ALDH2 activity. Diseases associated with long-term use of ethanol can be selected from, for example, cirrhosis and cancers including hepatocellular carcinoma, oral cancer, gastric cancer, esophageal cancer.

In some embodiments, the method comprises administering to the subject about 1 mg to about 4 mg 4-methylpyrazole (4-MP), or an equivalent amount of physiologically acceptable salt form, per kg body weight of the subject. Steps.

In certain embodiments, MP-4 is administered orally.

In some embodiments, 4-MP is administered orally before the subject consumes ethanol.

In some embodiments, 4-MP is administered orally about 2 hours to about 15 minutes before the individual consumes ethanol.

In another embodiment, 4-MP is administered orally concurrently with the subject's ethanol consumption or after the subject consumes ethanol.

In certain embodiments, the percent reduction in ethanol removal rate of the individual is about 10% or less relative to the ethanol removal rate of the individual not administered 4-MP.

In some embodiments, the method may comprise administering an effective amount of 4-MP to reduce acetaldehyde accumulation by about 25% to about 60% compared to an individual not administered 4-MP.

In some embodiments, the method may comprise administering to the individual an effective amount of 4MP or 4-MP physiologically acceptable salt that reduces or inhibits the ethanol-oxidative activity of alcohol dehydrogenase. .

In certain embodiments, an effective amount of 4-MP hydrochloride is administered.

In another aspect, the present invention provides an article of manufacture. In certain embodiments, the article of manufacture may comprise a packaging material and a composition containing 4-MP or a physiologically acceptable salt thereof and a physiologically acceptable excipient, and are suitable for oral administration to a subject.

In some embodiments, the composition form is a liquid.

In another embodiment, the composition form is a tablet.

In certain embodiments, where the article of manufacture comprises a composition further containing 4-MP in tablet form, the tablet contains approximately 85 mg of 4-MP.

In some embodiments, the article of manufacture may include printed instructions for use or administration of the composition. In certain embodiments, printed instructions suggest a dosing regimen for the prevention or alleviation of acetaldehyde accumulation symptoms associated with ethanol consumption in a subject.

In another aspect, the present invention provides a composition containing 4-MP or a physiologically acceptable salt thereof and a physiologically acceptable excipient and suitable for oral administration to a subject.

In another aspect, the present invention provides a method of identifying potential therapeutic agents for the prevention or alleviation of symptoms associated with ALDH2 deficiency. The therapeutic agent is considered as a potential therapeutic agent when ADH enzyme inhibition is confirmed in vitro by the techniques described below.

Terms

As used herein, “approximately” indicates a range of +/− 10%. For example, “approximately 4 mg 4-MP” means 4-MP in the range of 3.6 mg to 4.4 mg.

As used herein, "dose" refers to the amount of 4-MP a subject takes once or is administered to a subject once. “Unit dosage form” means a physically discrete unit suitable for a single dose of a human subject, eg, a capsule, tablet, or liquid volume. Each unit contains, as a result of the present invention, a predetermined amount of 4-MP, which has been found to induce the desired pharmacodynamic profile that yields the desired therapeutic effect. Dosage units consist of 4-MP in combination with at least one pharmaceutically acceptable carrier, salt, excipient or combination thereof. By way of example, a 170 mg 4-MP dose means an amount of 4-MP that an individual can take once, where the dose is divided into two 85 mg dosage units, eg, two 85 mg 4MP tablets. Can be.

As used herein, “acetaldehyde accumulation symptoms associated with ethanol consumption” refers to any symptom experienced when an individual with reduced or absent ALDH2 activity consumes ethanol. Symptoms may include flushing, elevated heart rate, palpitations, hypotension, nausea, dizziness, and headaches.

"Subjects with reduced or absent aldehyde dehydrogenase subtype 2 (ALDH2) activity" are described in Goedde et al. (1992) Hum. Genet. 88: 344-346 and Xiao et al . (1995) J. Clin. Invest . A variant of the ALDH2 gene, as described in 96: 2180-2186, is a homozygous or heterozygous holder of the ALDH2 * 2 allele, or Xiao et al . (1995) J. Clin. Invest . By an aldehyde dehydrogenase activity described in 96: 2180-2186 is meant an individual expressing any variant ALDH2 enzyme that exhibits lower activity than a normal ALDH2 enzyme.

As used herein, “ethanol resistance” refers to a condition in which an individual experiences acetaldehyde accumulation symptoms associated with ethanol consumption.

As used herein, "ethanol removal rate" refers to a decrease in ethanol concentration in a subject's blood stream over time after the subject has consumed ethanol. Typically, the ethanol removal rate may be expressed in ethanol millimoles per kg body weight. Techniques for blood sampling and ethanol levels analysis in blood are well known to those skilled in the art (see Inoue et al . (1984) Alcoholism: Clincical and Experimental Research 8: 319-322). The “% reduction in ethanol removal” can be calculated as follows:

% Change in EtOH removal = [1- (EtOH removal rate of subject after taking 4-MP / 4 / EtOH removal rate of subject before taking 4-MP)] x 100

Where EtOH stands for ethanol and the% change in ethanol removal below 100 is the decrease in% change in ethanol removal. Blood ethanol levels may also be estimated based on algorithms using the amount of ethanol consumed by the individual, the weight of the individual, the post-consumption period of ethanol, or alternatively estimated from analysis of the subject's breathing, as known to those skilled in the art. Can be.

As used herein, "acetaldehyde accumulation" refers to the production of acetaldehyde in individuals who have consumed ethanol. Techniques for blood sampling and ethanol levels analysis in blood are well known to those skilled in the art (see Inoue et al . (1984) Alcoholism: Clincical and Experimental Research 8: 319-322; Stowell (1979) Clin. Chim. Acta . 98: 201-5). Typically, maximum concentrations of acetaldehyde accumulation appear within 15 minutes to 1 hour after ethanol consumption in individuals with reduced or absent ALDH2 activity.

As used herein, “% change in acetaldehyde accumulation” refers to the change in maximum concentration of acetaldehyde in an individual with reduced or absent ALDH2 activity, which can be estimated as follows:

% Change in aldehyde accumulation = [1- (maximum acetaldehyde concentration after taking 4-MP / 4 acetaldehyde concentration before taking 4-MP)] x 100

Here, the% change in acetaldehyde accumulation less than 100 is a decrease in% change in acetaldehyde accumulation. Acetaldehyde concentrations in blood can also be estimated from respiratory analysis of an individual, as known to those skilled in the art, or from other parameters such as physiological changes measurable in heart rate or flushing.

By “physiologically acceptable salts” is meant herein the relatively nontoxic, inorganic and organic acid addition salts of the compounds according to the invention.

As used herein, a weight of 4-MP, eg, “2 mg 4MP” means an equivalent amount of 4-MP in free base form. Thus, for example, when 2 mg 4-MP in the form of a constant salt is administered in the manner described herein, those skilled in the art will perform the necessary conversion using the molecular weight of the salt form 4-MP and the molecular weight of the free base form 4-MP to free The actual weight of salt form 4-MP necessary to achieve an equivalent amount of 2 mg 4-MP in base form can be determined. As another example, when 2 mg 4MP in free base form is administered by the methods described herein, no conversion is necessary.

Detailed description of the invention

The present invention provides compositions and methods effective for alleviating or preventing the severity of physiological side effects associated with acetaldehyde accumulation associated with ethanol consumption in individuals with reduced or absent aldehyde dehydrogenase subtype 2 (ALDH2) activity. present.

Reduced or absent aldehyde dehydrogenase subtype 2 (ALDH2) activity is evident in individuals who consume small or medium amounts of ethanol and is typically identified by skin flushing. ALDH2 deficiency can be caused, for example, by genetic mutations in the ALDH2 gene (Xiao et al . (1995) J. Clin. Invest . 96: 2180-2186). In general, acetaldehydemia, or acetaldehyde accumulation, is believed to be responsible for symptoms that occur in ALDH2 deficient individuals after ethanol consumption. Side effects associated with acetaldehyde accumulation may include flushing, elevated heart rate, nausea, dizziness, and headaches.

As described below, the methods of the present invention comprise the administration of 4-MP or physiologically acceptable salts of 4-MP. Without wishing to be bound by any particular theory, 4-MP is believed to play a role in inhibiting alcohol dehydrogenase (ADH), reducing acetaldehyde accumulation resulting from the consumption of ethanol. As disclosed herein, a relatively small amount administered to an individual with reduced or absent ALDH2 activity, eg, 4-MP of approximately 1 mg / kg to approximately 4 mg / kg, has a minimal effect on the ethanol removal rate of the individual. By preventing or alleviating the symptoms of acetaldehyde accumulation, the level of satisfaction of an individual can be significantly increased.

How to prevent or alleviate acetaldehyde accumulation symptoms

In certain aspects, The present invention provides methods for preventing or alleviating the symptoms of acetaldehyde accumulation or ethanol resistance in individuals with reduced or absent ALDH2 activity. In some embodiments, the method may comprise administering to the subject about 1 mg to about 4 mg 4-methylpyrazole (4-MP) per kg of body weight of the subject.

In certain embodiments, the compound used in the method is a free base of 4-MP. In other embodiments, physiologically acceptable salts of 4-MP may be used in the method. In some embodiments, 4-MP hydrochloride can be used in the methods described herein.

4-methylpyrazole (4-MP, pomepisol) is commercially available from a chemical supplier, for example Sigma Aldrich (St. Louis, MO), and is also available in pharmaceutical grade commercially viable amounts. It can also synthesize | combine easily.

4-MP may be administered alone or in combination with other substances or actives. In some embodiments, a composition containing 4-MP and other ingredients is administered as described below.

4-MP may be administered according to any technique known to those skilled in the art. In certain embodiments, 4-MPs can be delivered transdermally. In a preferred embodiment, the individual can self-administer 4-MP. In a preferred embodiment, 4-MP can be administered orally. When administered orally, 4-MP may be in solid form, such as a powder, tablet, capsule, or the like, or a liquid form.

In certain embodiments, the dosage of 4-MP is from about 0.1 mg / kg to about 4 mg / kg. In some embodiments, 4-MP of approximately 1 mg / kg to approximately 4 mg / kg may be administered. As will be appreciated by those skilled in the art, the dosage of 4-MP described herein is based on the weight of the subject in kilograms. In some embodiments, about 0.1 mg / kg, about 0.5 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, to an individual with reduced or absent ALDH2 activity, Approximately 3.5 mg / kg, or approximately 4 mg / kg of 4-MP is administered. In certain embodiments, the dosage of 4-MP is approximately 0.1 mg / kg to approximately 3 mg / kg, 0.5 mg / kg to 2 mg / kg, or 2 mg / kg to 4 mg / kg.

In certain embodiments, the dosage of 4-MP, or a physiologically acceptable salt thereof, is effective to reduce or inhibit the ethanol-oxidative activity of alcohol dehydrogenase in a subject.

In certain embodiments, 4-MP may be administered before the individual consumes ethanol. In some embodiments, 4-MP can be administered about 1 minute, about 15 minutes, or about 1 hour before the individual consumes ethanol. In some embodiments, 4-MP may be administered orally between about 2 hours and about 15 minutes before the individual consumes ethanol.

In certain embodiments, 4-MP may be administered simultaneously with ethanol consumption. In certain embodiments, 4-MP may be administered immediately before or after consumption of ethanol. In some embodiments, 4-MP may be administered to a subject after the subject has consumed ethanol.

As noted above, 4-MP is particularly useful for reducing the peak concentration of acetaldehyde that occurs during ethanol consumption without reducing the ethanol removal rate in the blood of individuals with reduced or absent ALDH2 activity. At the 4-MP dose contemplated in the process of the present invention, ie from about 1 mg / kg to about 4 mg / kg, the% reduction in ethanol removal rate is negligible as described below.

In certain embodiments, a method comprising administering 4-MP is provided wherein the percent reduction in ethanol removal rate is about 0%, about 1%, about 2%, about 3%, about 4%, about 5%, or about 6% to about 10% or less. For example, if the subject shows a removal rate of 2.50 mmol / kg / hr when not receiving 4-MP treatment and a 2.30 mmol / kg / hr removal rate when 4-MP is administered, the percent reduction in ethanol removal is 8%.

In some embodiments, a method wherein the percent reduction in ethanol removal rate of the individual ranges from no removal or 1-2% reduction in ethanol removal rate to approximately 7%, approximately 8%, approximately 9% or approximately 10% reduction in the ethanol removal rate of the subject. present. In some embodiments, the methods of the present invention induce about 5% to about 10% ethanol removal. In some embodiments, the percent reduction in ethanol removal rate of the individual is about 10% or less compared to the ethanol removal rate of the individual not receiving 4-MP treatment.

At the 4-MP dose contemplated by the methods of the present invention, the percent reduction in peak blood acetaldehyde concentration may be reduced in individuals with or without ALDH2 activity.

In certain embodiments, the methods of the present invention can reduce acetaldehyde accumulation from about 50% to about 60% in a subject with reduced or absent ALDH2 activity as long as 4-MP is not administered to the subject. In certain embodiments, peak acetaldehyde accumulation is effectively removed or approximately 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40 %, 35%, 30%, 25%, 20%, 15%, 10% or about 5%.

In a population of individuals with reduced or absent ALDH2 activity, the methods of the present invention, although not completely eliminating one or more symptoms of acetaldehyde accumulation, substantially reduce the severity of one or more symptoms in a substantial portion of the patient population, thereby providing a broad spectrum of such individuals. It is an effective treatment in the population.

In certain embodiments, the methods of the present invention prevent or treat acetaldehyde accumulation symptoms selected from flushing, elevated heart rate, palpitations, hypotension, nausea, dizziness, headache.

Although any individual with reduced or absent ALDH2 activity can be treated with 4-MP as described herein, it is possible to identify certain subsets that can benefit particularly. For example, the present invention is a subject having a significant facial flushing of the face when consuming alcohol, or having a variant ALDH2 allele encoding a substitution of glutamate to lysine at position 487 of the mitochondrial aldehyde dehydrogenase enzyme. It covers how to use 4-MP.

In certain aspects, the present invention provides methods for preventing diseases associated with long-term use of ethanol in individuals with reduced or absent ALDH2 activity. In general, diseases associated with long-term use of ethanol are for example cirrhosis and cancers including hepatocellular carcinoma, oral cancer, gastric cancer, esophageal cancer. In some embodiments, the methods of the present invention can comprise administering to the individual 1 mg to 4 mg 4-MP per kg body weight of the individual. In certain embodiments, 4-MP may be administered before, during or after the individual consumes ethanol. In some embodiments, 4-MP is administered orally. In some embodiments, physiologically acceptable salts of 4-MP are administered.

In certain preferred embodiments of the method for preventing a disease associated with long term use of ethanol in a subject, 4-MP is administered prior to consumption of ethanol by the subject. In some embodiments, 4-MP may be administered approximately 2 hours before the subject consumes ethanol.

Manufactured goods

In certain aspects, the present invention provides articles of manufacture effective for preventing or alleviating the symptoms of acetaldehyde accumulation or ethanol resistance in individuals with reduced or absent ALDH2 activity.

In certain embodiments, the article of manufacture comprises a packaging material and a composition containing 4-MP or a physiologically acceptable salt thereof and a physiologically acceptable excipient, and are suitable for oral administration to a subject.

In certain embodiments, the form of the composition is a liquid.

In some embodiments, the form of the composition is a solid selected from powders, tablets, capsules.

In certain embodiments, the composition in the article of manufacture contains 4-MP or a physiologically acceptable salt thereof in unit dosage form. In some embodiments, the unit dosage form contains approximately 85 mg of 4-MP or equivalent amounts of salt form.

In some embodiments, the article of manufacture comprises a label or printed instructions relating to the use or administration of the composition. Typically, printed instructions may suggest a dosing regimen for the prevention or alleviation of acetaldehyde accumulation symptoms associated with ethanol consumption in a subject.

In certain embodiments, the printed instructions direct the subject to orally take a predetermined number of tablets according to the table below:

Weight of the object The number of tablets you take

36-46 kg 1

46-66 kg 2

66-86 kg 3

86-106 kg 4

106-126 kg 5.

In certain embodiments, printed instructions provide a dosing regimen for the prevention or alleviation of acetaldehyde accumulation symptoms in a subject, eg, flushing, elevated heart rate, palpitations, hypotension, nausea, dizziness, headache. I can suggest.

Composition

In certain aspects, the present invention provides compositions that are effective for preventing or alleviating the symptoms of acetaldehyde accumulation or ethanol resistance in individuals with reduced or absent ALDH2 activity. The compositions of the present invention can be used in the manufacture of drugs or formulations for preventing or alleviating the symptoms of acetaldehyde accumulation or ethanol resistance in individuals with reduced or absent ALDH2 activity.

In certain aspects, the present invention provides compositions that are effective for preventing diseases associated with long-term use of ethanol in individuals with reduced or absent ALDH2 activity. The compositions of the present invention can be used in the manufacture of drugs or formulations for the prevention of diseases associated with long-term use of ethanol in individuals with reduced or absent ALDH2 activity. In certain embodiments, the disease associated with long term use of ethanol is selected from cirrhosis and cancers including hepatocellular carcinoma, oral cancer, gastric cancer, esophageal cancer.

In certain embodiments, compositions containing 4-MP or physiologically acceptable salts thereof and physiologically acceptable excipients or diluents are provided.

The composition can be administered orally or transdermally. The composition takes the form of a powder, tablet, lozenge tablet, granule, capsule, pill, ampoule, syrup or fluid.

In certain embodiments, the composition may contain 4-MP or a salt thereof, with one or more other active agents. Additional active agents include, for example, vitamins, antioxidants, anti-inflammatory agents (eg, aspirin), non-steroidal anti-inflammatory agents, antihistamines, ibuprofen and the like.

In general, the compositions are formulated to allow for convenient administration of 4-MP or salts of 4-MP or salts thereof from approximately 1 mg / kg to approximately 4 mg / kg of a diseased individual. In one embodiment, the unit dosage form is in the form of approximately 85 mg 4-MP or an equivalent amount of salt. Unless otherwise specified, all weights of active agent are calculated on the basis of 4-MP and increase in proportion to salt.

A physiologically acceptable excipient should be "acceptable" in the sense of being compatible with the other ingredients of the composition and not harmful to the patient.

Compositions of the invention suitable for oral administration are provided in individual units such as capsules, cachets or tablets, each unit being as a powder or granules; As a solution or suspension in an aqueous or non-aqueous fluid; A water-in-oil liquid emulsion or a water-in-oil liquid emulsion contains a predetermined amount of the active ingredient. The active ingredient may be provided in the form of a cyclic, soft or paste.

Tablets are prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be, in suitable machines, binders (eg povidone, gelatin, hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrants (eg sodium starch glycolate, cross-linked povidone, cross-linked Sodium carboxymethyl cellulose), a surface-active or free-flowing form optionally mixed with a dispersant, for example, in powder or granule form. Molded tablets are prepared by molding, in a suitable machine, a mixture of powdered compounds moistened with an inert liquid diluent. Tablets are optionally coated or engraved, and are formulated to provide controlled release of the active ingredient, for example using hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile.

 In certain embodiments, the unit dose is provided as a tablet composition consisting of 4-MP, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate.

Formulations suitable for topical administration in the mouth include lozenge tablets containing the active ingredient in seasoned bases, usually sucrose and acacia or tragacanth; Pastilles containing the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; Mouthwashes containing the active ingredient in a suitable liquid carrier and the like.

Pharmaceutical compositions for topical administration according to the invention may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. Alternatively, the formulation may comprise a patch or dressing, such as a bandage or sticky plaster, impregnated with the active ingredient and optionally one or more excipients or diluents.

In addition to the ingredients mentioned above, the formulations of the present invention may contain other ingredients conventional in the art with respect to the type of formulation desired, for example, formulations suitable for oral administration may contain ingredients such as sweeteners, thickeners and flavoring agents. It may further contain.

Example

Without being limited to a particular theory of work, when 4-MP is administered to a human subject at a dose of approximately 4 mg / kg or less, the reduction in the removal of ethanol consumed by the subject is less than approximately 10%. 1 shows the amount of 4-MPs per kilogram body weight administered to human subjects vs. A graph of the data is shown showing the percentage reduction observed in ethanol removal. Data was obtained from the following sources and the mean was determined as indicated in parentheses: Lindros et al . (1981) Alcoholism: Clinical and Experimental Research 5: 528-530 (6 mg 4-MP; 20% in EtOH removal) decrease); Inoue et al . (1984) Alcoholism: Clinical and Experimental Research 8: 319-322 (10 mg 4-MP; 20% reduction in EtOH clearance); Inoue et al . (1985) Japan. J. Pharmacol. 38: 43-48 (8.5 mg 4-MP; 12% decrease in EtOH removal); Sarkola et al . (2002) Alcoholism: Clinical and Experimental Research 26: 239-245 (12.5 mg 4-MP; 34% reduction in EtOH removal). Data was written in the figures and a line was fitted to the data using linear least squares regression. 1 suggests that at 4-MP doses up to 4 mg / kg, ethanol removal rates are minimally affected. In other words, it indicates that the reduction in ethanol removal is approximately 10% or less.

Without being limited to a particular theory of work, when 4-MP is administered to a human individual at a dose of approximately 4 mg / kg or less, the reduction in the removal of ethanol consumed by the individual reaches 25% up to 60%. Figure 2 shows the percent reduction in acetaldehyde levels observed in ethanol resistant subjects treated with 4-MP. The graph of% reduction in ethanol levels is shown. Data points are shown in Inoue et al . (1984) Alcoholism: Clinical and Experimental Research 8: Ethanol observed in subjects KM, KI, YF, AM, MF, YI before and after administration of 10 mg 4-MP in Table I of 319-322. Levels of clearance and acetaldehyde levels and ALDH2-deficient after 10-15 mg 4-MP administration as presented in Vakevainen et al . (2001) Alcoholism: Clinical and Experimental Research 25: 829-834 (page 831, left column). It was estimated from the average ethanol removal rate and the average acetaldehyde level in volunteers. Data was written in the figures and a line was fitted to the data using linear least squares regression. In the range of 5% -10% ethanol reduction expected to occur in ethanol resistant individuals treated with approximately 2 mg to approximately 4 mg 4-MP in FIG. 2 (see FIG. 1), acetaldehyde levels are up to 50% to 60%. Can be reduced.

Typical Administration of 4-MP to Human Subjects : 4-MP in free base, liquid form is mixed with orange juice to prepare a 0.5% (w / v) 4-MP solution. 4-MP is stored in containers with associated preparation cups with labels indicating various amounts of solution used for different body weights of individuals to which 4-MP is administered. Individuals with reduced or absent ALDH2 activity consuming alcohol and weighing approximately 75 kg may pour approximately 60 ml of 4-MP into the preparation cup and drink the 4-MP solution from the cup minutes to hours before consuming alcohol. Can be.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, various modifications are possible as would be appreciated by those skilled in the art. For this reason, the foregoing description and examples are intended to be in the scope of the invention. It is not intended to be limited to, but only defined by the appended claims.

The present invention provides a composition comprising 4-methylpyrazole (4-MP) or a physiologically acceptable salt thereof and a physiologically acceptable excipient; It relates to their use to prevent or alleviate ethanol resistance in individuals with reduced or absent aldehyde dehydrogenase subtype 2 (ALDH2) activity.

Claims (20)

A method of preventing or alleviating symptoms of ethanol tolerance in a subject with reduced or absent aldehyde dehydrogenase subtype 2 (ALDH2) activity, the method comprising: about 1 mg to about 4 mg 4-methylpyrazole (4- Oral administration of MP). The method of claim 1, wherein 4-MP is administered in free base form. The method of claim 1, wherein the 4-MP is administered in the form of a physiologically acceptable salt. The method of claim 1, wherein the 4-MP is administered orally before the subject consumes ethanol. The method of claim 4, wherein the 4-MP is administered orally about 1 hour to about 15 minutes before the individual consumes ethanol. The method of claim 1, wherein the 4-MP is administered orally concurrently with the subject's ethanol consumption or after the subject consumes ethanol. The method of claim 1, wherein the percent reduction in the ethanol removal rate of the individual is about 10% or less compared to the ethanol removal rate of the individual not administered 4-MP. A method for preventing or reducing the symptoms associated with acetaldehyde accumulation associated with ethanol consumption in individuals with reduced or absent aldehyde dehydrogenase subtype 2 (ALDH2) activity, as compared to speakers not administered 4-MP. Administering an effective amount of 4-MP to reduce accumulation from approximately 50% to approximately 60%. 10. The method of claim 8, wherein the subject with reduced or absent ALDH2 activity shows a percent reduction in ethanol removal of less than about 10% compared to the ethanol removal rate of the subject not administered 4-MP. A method of alleviating the symptoms associated with acetaldehyde accumulation associated with ethanol consumption in a subject with reduced or absent aldehyde dehydrogenase subtype 2 (ALDH2) activity, the ethanol-oxidizing activity of alcohol dehydrogenase in the subject. Administering an effective amount of 4-MP or physiologically acceptable salt of 4-MP to inhibit or inhibit. The method of claim 8 or 10, wherein the symptoms of acetaldehyde accumulation in the subject with reduced or absent ALDH2 activity are selected from flushing, elevated heart rate, palpitations, hypotension, nausea, dizziness, headache. The method of claim 10, wherein an effective amount of 4-MP hydrochloride is administered. The method of claim 10, wherein about 1 mg to about 4 mg of 4-MP is administered per kg body weight of the subject. An article of manufacture comprising a packaging material and a composition containing 4-methylpyrazole (4-MP) or a physiologically acceptable salt thereof and a physiologically acceptable excipient, wherein the article of manufacture is suitable for oral administration to a subject. The article of manufacture of claim 14, wherein the form of the composition is a liquid. The article of manufacture of claim 14, wherein the form of the composition is a tablet. The article of manufacture of claim 16, wherein the tablet contains approximately 85 mg of 4-MP. The article of manufacture of claim 16, further comprising a printed instruction manual relating to the use or administration of the composition. 19. The article of manufacture of claim 18, wherein the printed instructions provide a dosing regimen for the prevention or alleviation of acetaldehyde accumulation symptoms associated with ethanol consumption in the subject. The article of manufacture of claim 19, wherein the printed instruction manual instructs the individual to orally take a predetermined number of tablets according to the table below: Weight of the object The number of tablets you take 36-46 kg 1 46-66 kg 2 66-86 kg 3 86-106 kg 4 106-126 kg 5.

Images