WO2014143192A1 - Réduction ou prévention de réaction à l'alcool avec des compléments alimentaires - Google Patents

Réduction ou prévention de réaction à l'alcool avec des compléments alimentaires Download PDF

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WO2014143192A1
WO2014143192A1 PCT/US2013/067345 US2013067345W WO2014143192A1 WO 2014143192 A1 WO2014143192 A1 WO 2014143192A1 US 2013067345 W US2013067345 W US 2013067345W WO 2014143192 A1 WO2014143192 A1 WO 2014143192A1
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composition
subject
alcohol
vitamin
acid
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Robert James TOLLETH
Spencer Adam GORDON
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NOGLO LLC
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NOGLO LLC
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Priority to US14/150,705 priority Critical patent/US20140256760A1/en
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Priority to US15/170,741 priority patent/US20160346266A1/en
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/175—Amino acids
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients

Definitions

  • the present invention relates to compositions and methods for reducing or preventing the flush and other unpleasant symptoms that sometimes accompany the consumption of alcoholic beverages.
  • the alcohol reaction also known as the alcohol flush reaction
  • the reaction is an unpleasant condition which occurs in some individuals upon consumption of alcohol, even in relatively small amounts.
  • the reaction is characterized by flushing of the facial skin, and sometimes other areas of the skin.
  • the alcohol reaction may also include dizziness, nausea, stupor, headache, light-headedness, increased heart rate, and other symptoms.
  • Acetaldehyde is metabolized by acetaldehyde dehydrogenase-2 (ALDH2; also known as mitochondrial aldehyde dehydrogenase; human precursor Swiss-Prot P05091), a liver enzyme involved in the metabolism of ethanol, which oxidizes acetaldehyde to acetic acid.
  • ADH2 acetaldehyde dehydrogenase-2
  • mitochondrial aldehyde dehydrogenase human precursor Swiss-Prot P05091
  • ALDH2*2 where a glutamic acid residue is mutated to lysine, i.e., ALDH2 E487K; the residue numbering is based on the mature protein; see, e.g., Steinmetz et al., Structure 5: 701-11, 1997, which is hereby incorporated by reference in its entirety
  • the enzyme is normally a homotetramer. However, if an individual carries one mutated allele, then he or she will present the mutant phenotype due to the formation of heterotetramers.
  • the mutation in ALDH2 is at an amino acid residue located at the binding site for nicotinamide adenine dinucleotide (NAD), an enzyme cofactor required for the conversion of acetaldehyde to acetic acid; in the process, NAD is converted to NADH.
  • NAD nicotinamide adenine dinucleotide
  • ADH1B also known as alcohol dehydrogenase IB; human precursor Swiss-Prot P00325
  • R47H mutation a highly active variant of alcohol dehydrogenase
  • an anti-oxidant and alpha-lipoic acid or a precursor to alpha-lipoic acid or
  • an agent capable of increasing the level of Coenzyme A in the subject, an anti-oxidant, and alpha-lipoic acid or a precursor to alpha-lipoic acid is not meant to be limiting.
  • the invention embraces a composition for use by a subject to prevent or reduce the alcohol reaction and/or to reduce acetaldehyde in tissues and body fluids, where the composition comprises an agent capable of increasing intracellular or
  • the invention embraces a composition for use by a subject to prevent or reduce the alcohol reaction, where the composition comprises an agent capable of increasing glutathione concentration in the subject. In some embodiments, the invention embraces a composition for use by a subject to prevent or reduce the alcohol reaction, where the composition comprises an agent capable of increasing intracellular Coenzyme A concentration in the subject. In these embodiments, the agent is present in the composition in an amount sufficient to prevent or reduce the alcohol reaction in the subject.
  • the agent can be administered to the subject in a daily dosage for at least one week prior to consumption of alcohol. The daily dosage can be administered in a single dosage per day, or in multiple divided dosages per day.
  • the invention embraces a composition for use by a subject to prevent or reduce the alcohol reaction and/or to reduce acetaldehyde in tissues and body fluids.
  • the composition can be described as an anti-alcohol reaction supplement.
  • the supplement or composition comprises an agent capable of increasing intracellular or intramitochondrial concentration of NAD in the subject; an agent capable of increasing glutathione concentration in the subject; an agent which is an anti-oxidant; an agent which is alpha-lipoic acid or a precursor to alpha-lipoic acid; and an agent capable of increasing the level of Coenzyme A in the subject
  • the agents are present in the supplement or composition in an amount or amounts effective to prevent or reduce the alcohol reaction in the subject.
  • the agents are present in the supplement or composition in an amount or amounts effective to prevent the alcohol reaction in the subject.
  • the agents are present in the supplement or composition in an amount or amounts effective to reduce the alcohol reaction in the subject.
  • the agent capable of increasing intracellular or intramitochondrial concentration of NAD in the subject can be nicotinamide, niacin, nicotinamide riboside, or oxaloacetate. If nicotinamide is used, the amount of nicotinamide in the supplement or composition can range from about 500 mg to about 1,500 mg, or from about 750 mg to about 1,250 mg. In another embodiment, the amount of nicotinamide in the supplement or composition is about 1000 mg. In another embodiment, the amount of nicotinamide in the supplement or composition is about 800 mg.
  • the amount of niacin in the supplement or composition can range from about 500 mg to about 1,500 mg, or from about 750 mg to about 1,250 mg. In another embodiment, the amount of niacin in the supplement or composition is about 1000 mg. In another embodiment, the amount of niacin in the supplement or composition is about 800 mg. If nicotinamide riboside is used, the amount of nicotinamide riboside in the supplement or composition can range from about 1,000 mg to about 3,200 mg, or from about 1,500 mg to about 2,600 mg. In another embodiment, the amount of nicotinamide riboside in the supplement or composition is about 2,100 mg. In another embodiment, the amount of nicotinamide riboside in the supplement or composition is about 1,700 mg.
  • the agent capable of increasing glutathione concentration in the subject can be N- acetyl cysteine, L-cysteine Vitamin C, alpha lipoic acid, glutathione, glycine, L-glutamic acid, adenosylmethionine, or conjugated linoleic acid.
  • N-acetyl cysteine is used, the amount in the supplement or composition can range from about 200 mg to about 600 mg, or from about 300 mg to about 500 mg. In another embodiment, the amount of N-acetyl cysteine in the supplement or composition is about 400 mg. In another embodiment, the amount of N-acetyl cysteine in the supplement or composition is about 300 mg.
  • the amount in the supplement or composition can range from about 200 mg to about 600 mg, or from about 300 mg to about 500 mg. In another embodiment, the amount of L-cysteine in the supplement or composition is about 400 mg. In another embodiment, the amount of L-cysteine in the supplement or composition is about 300 mg.
  • the agent used as the anti-oxidant can be Vitamin C, Vitamin E, or alpha-lipoic acid. If Vitamin C is used, the amount in the supplement or composition can range from about 100 mg to about 500 mg, or from about 200 mg to about 400 mg. In another embodiment, the amount of Vitamin C in the supplement or composition is about 300 mg. In another embodiment, the amount of Vitamin C in the supplement or composition is about 150 mg.
  • the amount of alpha lipoic acid in the supplement or composition when a separate anti-oxidant is used in addition to alpha lipoic acid, can range from about 50 mg to about 250 mg, or from about 100 mg to about 200 mg. In one embodiment, the amount of alpha-lipoic acid in the supplement or composition is about 150 mg. In one embodiment, the amount of alpha- lipoic acid in the supplement or composition is about 100 mg. If alpha lipoic acid is also used as the anti-oxidant, the amount of alpha lipoic acid in the supplement or composition can range from about 100 mg to about 500 mg, from about 200 mg to about 400 mg, or in another embodiment is about 300 mg, or in another embodiment is about 200 mg.
  • the agent capable of increasing the level of Coenzyme A in the subject can be pantothenic acid, pantothenate, panthenol, pantethine, pantetheine, 4'-phosphopantothenate, 4'- phosphopantetheine, N-acetyl-cysteine, or L-cysteine.
  • pantothenic acid is used, the amount of pantothenic acid in the supplement or composition can range from about 50 mg to about 250 mg, or from about 100 mg to about 200 mg. In another embodiment, the amount of pantothenic acid in the supplement or composition is about 150 mg. In another embodiment, the amount of pantothenic acid in the supplement or composition is about 100 mg.
  • the amount of pantothenate in the supplement or composition can range from about 50 mg to about 250 mg, or from about 100 mg to about 200 mg. In another embodiment, the amount of pantothenate in the supplement or composition is about 150 mg. In another embodiment, the amount of pantothenate in the supplement or composition is about 100 mg. If panthenol is used, the amount of panthenol in the supplement or composition can range from about 50 mg to about 250 mg, or from about 100 mg to about 200 mg. In another embodiment, the amount of panthenol in the supplement or composition is about 150 mg. In another embodiment, the amount of panthenol in the supplement or composition is about 100 mg.
  • compositions which comprise (i) between 300 mg and 1.5 g nicotinamide, (ii) between 10 mg and 500 mg pantothenic acid or a salt thereof, and (iii) between 100 mg and 600 mg N-acetylcysteine.
  • the present invention provides compositions which comprise (i) between 500 mg and 900 mg nicotinamide, (ii) between 25 mg and 75 mg pantothenic acid or a salt thereof, and (iii) between 200 mg and 400 mg N-acetylcysteine.
  • the compositions comprise about 700 mg nicotinamide, about 50 mg pantothenic acid, and about 300 mg N- acetylcysteine; or about 700 mg nicotinamide, about 25 mg pantothenic acid, and about 300 mg N-acetylcysteine; or about 700 mg nicotinamide, about 100 mg pantothenic acid, and about 300 mg N-acetylcysteine; wherein the term "about” refers to +/- 20% of each quantity.
  • the present invention can comprise a daily dosage of 700 mg nicotinamide, 50 mg pantothenic acid, and 300 mg N-acetylcysteine, or a daily dosage of 700 mg nicotinamide, 25 mg pantothenic acid, and 300 mg N-acetylcysteine, or a daily dosage of 700 mg nicotinamide, 100 mg pantothenic acid, and 300 mg N-acetylcysteine.
  • These compositions can further comprise one or more of vitamin A, vitamin C, thiamine, and a-lipoic acid, in addition to the nicotinamide, pantothenic acid (or salt thereof), and N-acetylcysteine.
  • compositions further comprise, in addition to the nicotinamide, pantothenic acid (or salt thereof), and N- acetylcysteine, one or more of, and preferably each of, 1250 IU to 37500 IU vitamin A, 75 mg to 250 mg vitamin C, 2.5 to 100 mg thiamine, and 50 to 125 mg a-lipoic acid.
  • a supplement or composition of the invention comprising the combined ingredients can be taken once a day, or in multiple divided dosages over a day, or can be taken as individual components over the course of a day.
  • the supplements or compositions comprise vitamins, amino acids, anti-oxidants, and other dietary supplements. While not wishing to be limited by theory, it is hypothesized that use of the supplements or compositions of the invention results in a protective buildup of compounds which reduces the reactivity of acetaldehyde and which enhances enzyme kinetics, causing an increased rate of breakdown of acetaldehyde.
  • the ALDH2 E487K enzyme variant binds NAD less strongly than the variant with glutamic acid at position 487. Thus, it is hypothesized that increasing NAD concentration will enhance the binding of NAD to aldehyde dehydrogenase, increasing the rate of acetaldehyde
  • Acetaldehyde is oxidized to acetic acid by ALDH2. Acetic acid then binds to
  • Coenzyme A to form Acetyl-CoA and enters the Citric Acid Cycle. While not wishing to be limited by theory, it is hypothesized that during alcohol metabolism in subjects with the ALDH2 mutation, there is a build-up of acetic acid, and Coenzyme A is greatly reduced, as it is not regenerated quickly enough to keep up with the rate of production of acetic acid. With an accumulation of acetic acid, ALDH2 is inhibited based on known enzyme kinetics, as an increase in product concentration will decrease the favorability of the forward reaction.
  • the invention includes daily supplementation of any compound(s) to increase cellular Coenzyme A concentrations to increase the rate of formation of Acetyl-CoA, therefor clearing acetic acid more quickly and pushing the ALDH2 reaction towards the product. This reduces the accumulation and exposure to acetaldehyde, and as a result, reduces or prevents the alcohol reaction.
  • a subject, individual, or patient is a mammal, preferably a human.
  • Alcohol as used herein refers to ethanol (ethyl alcohol), unless another alcohol is explicitly indicated.
  • Preventing the alcohol reaction is defined as preventing at least one symptom of the alcohol reaction, such as facial flushing, dizziness, nausea, increased heart rate, or other symptoms in a subject who would ordinarily experience such a reaction absent the use of the compositions and methods of the invention, or of preventing the buildup of acetaldehyde in the blood subsequent to alcohol consumption, that would occur absent the use of the compositions and methods of the invention.
  • at least one symptom of the alcohol reaction such as facial flushing, dizziness, nausea, increased heart rate, or other symptoms in a subject who would ordinarily experience such a reaction absent the use of the compositions and methods of the invention, or of preventing the buildup of acetaldehyde in the blood subsequent to alcohol consumption, that would occur absent the use of the compositions and methods of the invention.
  • hydrochloric acid hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.
  • organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acids, and salicylic acid.
  • Salts of basic compounds with amino acids, such as aspartate salts and glutamate salts can also be prepared.
  • the desired salt of an acidic compound can be prepared by methods known to those of skill in the art by treating the compound with a base.
  • supply is meant a composition that is taken in addition to the ordinary diet of an individual, subject, or patient.
  • the supplement can be taken with or without food, at any time of day (including divided dosages over the course of a day).
  • Measurements of skin and facial flushing can be quantitated using a chromameter (see, for example, the studies done in Muizzuddin et al., J. Soc. Cosmet. Chem. 41:369-378 (1990) and Alaluf et al., J. Nutr. 132:399-403 (2002)).
  • Chromameters are commercially available from vendors such as Konica Minolta (CR-400 or CR-410 Chroma Meter) or Gigahertz-Optik (HCT- 99D color meter).
  • baseline readings at one or more wavelengths are taken, and the baseline values are subtracted from subsequent readings. Flushing of the skin, especially facial flushing, is a very common symptom of the alcohol reaction, and can be measured non- invasively and in a time-dependent manner.
  • Blood (plasma or serum) concentrations of acetaldehyde can be readily measured using techniques known in the art (see, for example, McCarver-May, D. et al., Journal of Analytical Toxicology, 21: 134 (1997) and Badawy et al., Alcohol and Alcoholism 46:651-660 (2011), which discusses issues in measurement of total whole blood acetaldehyde). This provides an objective measurement of acetaldehyde blood levels and can also be determined in a time- dependent manner.
  • the concentration of acetaldehyde can be measured 10 minutes after the consumption of alcohol, 20 minutes after the consumption of alcohol, or 40 minutes after the consumption of alcohol, preferably 20 minutes after the consumption of alcohol.
  • the concentration of acetaldehyde can also be measured 1 hour after the consumption of alcohol, 2 hours after the consumption of alcohol, or 4 hours after the consumption of alcohol.
  • NAD concentration can be measured by extraction from blood samples
  • Nicotinamide Treatment of a Patient with the MELAS Syndrome Life Sciences, volume 58(8): (1996).
  • All-trans-retinoic acid concentration can be measured by High Performance Liquid Chromatography (HPLC) after blood collection by various methods, such as those described in De Leenheer et al., "All-trans-retinoic acid: measurement of reference values in human serum by high performance liquid chromatography," Journal of Lipid Research, 23(9): 1362-1367 (1982).
  • HPLC High Performance Liquid Chromatography
  • the invention raises measurable blood NAD concentration, which is reflective of the intracellular NAD concentration of erythrocytes, or red blood cells (RBCs).
  • the NAD concentration is measured by extraction from blood samples, and measured by enzymatic spectrophotometric methods (Majamaa et al).
  • the invention includes a method of raising RBC NAD concentration, through daily supplementation to prevent or reduce the alcohol reaction, by at least about 20 umol/L. In some embodiments, the invention includes a method of raising RBC NAD concentration, through daily supplementation to prevent or reduce the alcohol reaction, by at least about 10 umol/L. In some embodiments, the invention includes a method of raising RBC NAD concentration, through daily supplementation to prevent or reduce the alcohol reaction, by at least about 4 umol/L. Increases are measured relative to the levels of NAD prior to the start of supplementation.
  • the invention includes a method of raising RBC NAD concentration, through daily supplementation to prevent or reduce the alcohol reaction, by at least 500%. In some embodiments, the invention includes a method of raising RBC NAD concentration, through daily supplementation to prevent or reduce the alcohol reaction, by at least about 300%. In some embodiments, the invention includes a method of raising RBC NAD concentration, through daily supplementation to prevent or reduce the alcohol reaction, by at least about 100%. In some embodiments, the invention includes a method of raising RBC NAD concentration, through daily supplementation to prevent or reduce the alcohol reaction, by at least about 50%. Increases are measured relative to the levels of NAD prior to the start of supplementation .
  • the invention includes a method of raising blood glutathione concentration, through daily supplementation to prevent or reduce the alcohol reaction, by at least about 50%. In some embodiments, the invention includes a method of raising blood glutathione concentration, through daily supplementation to prevent or reduce the alcohol reaction, by at least about 25%. In some embodiments, the invention includes a method of raising blood glutathione concentration, through daily supplementation to prevent or reduce the alcohol reaction, by at least about 10%. In some embodiments, the invention includes a method of raising blood glutathione concentration, through daily supplementation to prevent or reduce the alcohol reaction, by at least about 5%. Increases are measured relative to the levels of glutathione prior to the start of supplementation.
  • the invention includes a method of raising blood all-trans retinoic acid concentration, through daily supplementation to prevent or reduce the alcohol reaction, by at least about 2 ng/mL. In some embodiments, the invention includes a method of raising blood all-trans retinoic acid concentration, through daily supplementation to prevent or reduce the alcohol reaction, by at least about 1 ng/mL. In some embodiments, the invention includes a method of raising blood all-trans retinoic acid concentration, through daily
  • the invention includes a method of raising blood all-trans retinoic acid
  • the invention includes a method of raising blood all-trans retinoic acid concentration, through daily supplementation to prevent or reduce the alcohol reaction, by at least about 75%. In some embodiments, the invention includes a method of raising blood all-trans retinoic acid concentration, through daily supplementation to prevent or reduce the alcohol reaction, by at least about 50%. In some embodiments, the invention includes a method of raising blood all-trans retinoic acid concentration, through daily supplementation to prevent or reduce the alcohol reaction, by at least about 25%. In some embodiments, the invention includes a method of raising blood all-trans retinoic acid concentration, through daily supplementation to prevent or reduce the alcohol reaction, by at least about 10%. Increases are measured relative to the levels of all-trans retinoic acid prior to the start of supplementation.
  • the combination anti-alcohol reaction supplement comprises various ingredients, which are described herein.
  • Nicotinamide (niacinamide) is a preferred agent for enhancing intracellular and intramitochondrial NAD concentrations. Nicotinamide, or Vitamin B3, is a precursor for NAD.
  • nicotinamide supplementation was responsible for raising NAD concentrations 24 fold.
  • the amount of nicotinamide in the supplement can range from about 10 mg to about 2,500 mg, from 500 mg to about 1,500 mg, preferably about 750 mg to about 1,250 mg, more preferably about 1000 mg or about 750 mg.
  • the amount of niacin in the supplement can range from about 10 mg to 2,500 mg, or from about 500 mg to 1,500 mg. In another embodiment the amount of niacin in the supplement is about 1000 mg. In another embodiment the amount of niacin in the supplement is about 750 mg.
  • the amount of nicotinamide riboside in the supplement can range from about 10 mg to 2,500 mg, or from about 500 mg to 1,500 mg. In another embodiment the amount of nicotinamide riboside in the supplement is about 1000 mg. In another embodiment the amount of nicotinamide riboside in the supplement is about 750 mg.
  • the amount of oxaloacetate in the supplement can range from about 10 mg to 1000 mg, or from about 50 mg to 250 mg. In another embodiment the amount of oxaloacetate in the supplement is about 150 mg. In another embodiment the amount of oxaloacetate in the supplement is about 200 mg.
  • Agents enhancing glutathione concentration such as N-Acetyl Cysteine: N- Acetyl Cysteine (NAC) is a preferred agent used to enhance the level of the anti-oxidant glutathione.
  • agents that can be used for this purpose include Vitamin C, alpha lipoic acid, L-cysteine, glutathione, glycine, L-glutamic acid, adenosylmethionine, or conjugated linoleic acid.
  • Cysteine is a precursor to glutathione, which can help protect against cellular damage.
  • NAC is more bioavailable than L-cysteine itself and serves multiple purposes. Both NAC as well as glutathione contain sulfur groups that can react directly with acetaldehyde, clearing it from the cell.
  • Glutathione is an activator of the enzyme ALDH2, increasing the breakdown of acetaldehyde, as well as an inhibitor of ADH, reducing acetaldehyde build-up.
  • NAC is also a necessary precursor for the compound Coenzyme A.
  • acetaldehyde is converted to acetic acid by ALDH2
  • the acetic acid produced is bound to Coenzyme A and enters the Citric Acid Cycle to produce energy for the cell.
  • enhancement of Coenzyme A levels is advantageous in clearing the acetic acid.
  • NAC can raise Coenzyme A levels and enhance the enzyme kinetics of the ALDH2 reaction.
  • Coenzyme A is also a slight inhibitor of ADH, reducing acetaldehyde build-up.
  • the amount of N-acetyl cysteine in the supplement can range from about 10 mg to about 2,000 mg, or from about 50 mg to about 1000 mg, or from about 100 mg to about 500 mg, or from about 200mg to about 500 mg, or from about 500mg to about lOOOmg. In another embodiment the amount of N- Acetyl Cysteine in the supplement is about 500 mg. In another embodiment the amount of N- Acetyl Cysteine in the supplement is about 300 mg. In other embodiments, the amount of N-acetyl cysteine in the supplement can range from about 200 mg to about 600 mg, or about 300 mg to about 500 mg, or about 400 mg.
  • Vitamin C is used, the amount of Vitamin C in the supplement can range from about 10 mg to about 3,000 mg, or from about 50 mg to about 1000 mg, or from about 100 mg to about 500 mg, or from about 200 mg to about 500 mg, or from about 500 mg to about 2,000 mg. In another embodiment the amount of Vitamin C in the supplement is about 1000 mg. In another embodiment the amount of Vitamin C in the supplement is about 150 mg. In another
  • the amount of Vitamin C in the supplement is about 500 mg.
  • the amount of alpha lipoic acid in the supplement can range from about 10 mg to about 500 mg, or from about 50 mg to about 300 mg, or from about 100 mg to about 300 mg. In another embodiment the amount of alpha lipoic acid in the supplement is about 150 mg. In another embodiment the amount of alpha lipoic acid in the supplement is about 250 mg.
  • the amount of glutathione in the supplement can range from about 10 mg to about 1,500 mg, or from about 100 mg to about 1000 mg, or from about 100 mg to about 500 mg. In another embodiment the amount of glutathione in the supplement is about 500 mg.
  • the amount of L-cysteine in the supplement can range from about 10 mg to about 2,000 mg, or from about 50 mg to about 1000 mg, or from about 100 mg to about 500 mg, or from about 200 mg to about 500 mg, or from about 500 mg to about 1000 mg. In another embodiment the amount of L-cysteine in the supplement is about 500 mg. In another embodiment the amount of L-cysteine in the supplement is about 300 mg.
  • the amount of glycine in the supplement can range from about 10 mg to about 2000 mg, or from about 50 mg to about 1000 mg, or from about 100 mg to about 500 mg, or from about 200 mg to about 500 mg, or from about 500 mg to about 1000 mg. In another embodiment the amount of glycine in the supplement is about 500 mg. In another embodiment the amount of glycine in the supplement is about 300 mg.
  • the amount of L-glutamic acid in the supplement can range from about 10 mg to about 2,000 mg, or from about 50 mg to about 1000 mg, or from about 100 mg to about 500 mg, or from about 200 mg to about 500 mg, or from about 500 mg to about 1000 mg. In another embodiment the amount of L-glutamic acid in the supplement is about 500mg. In another embodiment the amount of L-glutamic acid in the supplement is about 300mg.
  • the amount of SAMe in the supplement can range from about 10 mg to about 500 mg, or from about 50 mg to about 250 mg. In another embodiment the amount of SAMe in the supplement is about 150 mg. In another embodiment the amount of SAMe in the supplement is about 250 mg.
  • Alpha Lipoic Acid is an anti-oxidant, and its use in the supplement helps to maintain high concentrations of glutathione. This occurs due to regeneration of reduced glutathione.
  • the R-enantiomer of alpha lipoic acid is used in the supplement (5-[(3R)-dithiolan- 3-yl]pentanoic acid).
  • the amount of alpha lipoic acid in the supplement can range from about 50 mg to about 250 mg, preferably about 100 mg to about 200 mg, more preferably about 150 mg. If alpha lipoic acid is also used as the anti-oxidant, approximately double this amount is used, that is, from about 100 mg to about 500 mg, preferably about 200 mg to about 400 mg, more preferably about 300 mg. If racemic alpha lipoic acid is used in the supplement, the foregoing amounts are doubled, so as to provide the specified amount of the R-isomer in the supplement. That is, if 300 mg of R-alpha lipoic acid is desired in the supplement, and the racemic mixture is used to make the supplement, 600 mg of the racemic mixture is used in order to provide 300 mg of the R-enantiomer.
  • Agents enhancing the level of Coenzyme A such as pantothenic acid: As described previously, increased Coenzyme A has two functions in lowering blood acetaldehyde.
  • Pantothenic acid is a precursor to Coenzyme A and is a preferred agent for use in the supplement to enhance the levels of Coenzyme A.
  • the agent capable of raising intracellular Coenzyme A concentration in the subject can be pantothenic acid, pantethine, pantetheine, 4'-phosphopantothenate, 4'-phosphopantetheine, N- acetyl cysteine, or L-cysteine.
  • the amount of pantethine in the supplement can range from about 10 mg to about 1000 mg, or from about 100 mg to about 500 mg. In another embodiment the amount of pantethine in the supplement is about 50 mg. In another embodiment the amount of pantethine in the supplement is about 250 mg.
  • the amount of N-acetyl cysteine used in the supplement for this purpose can range from about lOmg to about 2,000 mg, or from about 50 mg to about 1000 mg, or from about 100 mg to about 500 mg, or from about 200 mg to about 500 mg, or from about 500 mg to about 1000 mg. In another embodiment the amount of N-acetyl cysteine in the supplement is about 500 mg. In another embodiment the amount of N-acetyl cysteine in the supplement is about 300 mg.
  • the amount of N-acetylcysteine added for use as the agent capable of raising intracellular Coenzyme A concentration is in addition to the amount used if N-acetylcysteine is used as the agent capable of increasing glutathione concentration.
  • the amount of L-cysteine used in the supplement for this purpose can range from about 10 mg to about 2,000 mg, or from about 50 mg to about 1000 mg, or from about 100 mg to about 500 mg, or from about 200 mg to about 500 mg, or from about 500 mg to about 1000 mg. In another embodiment the amount of L-cysteine in the supplement is about 500 mg. In another embodiment the amount of L-cysteine in the supplement is about 300 mg.
  • the amount of L-cysteine added for use as the agent capable of raising intracellular Coenzyme A concentration is in addition to the amount used if L-cysteine is used as the agent capable of increasing glutathione concentration.
  • the amount of retinol ester in the supplement can range from about 100 IU to about 15,000 IU, or from about 1000 IU to about 10,000 IU. In another embodiment the amount of retinol ester in the supplement is about 2500 IU. In another embodiment the amount of retinol ester in the supplement is about 5000 IU.
  • Silybum marianum extract Silybum marianum (milk thistle) is an annual or biannual plant of the Asteraceae family. It has been used as a medicinal plant for centuries, and its extract is used in medicine under the name silymarin. Milk thistle is typically extracted with 95% ethanol, which may then be filtered and dried by solvent evaporation. The resulting extract typically contains 1.5-3% flavonolignans (referred to collectively as silymarin; the principal components are silybin and isosilybin), 20-30% fatty acids (including linoleic, oleic, and palmitic acids), 25-30% proteins, and small amounts of vitamin E and various sterols. It may be included in the any of the compositions of the present invention as disclosed herein at concentrations between 100-5000 mg/day. Additional information regarding this extract is available from the World Health Organization at URL
  • Hovenia dulcis fruit extract is a tree found in Asia, over Eastern China, Korea, and in the Himalayan mountains (found at altitudes up to 2,000 m). There is evidence that extracts of the Hovenia dulcis fruit are hepatoprotective and can reduce blood alcohol levels (see Hyun et al., Planta Medica 76:943-949 (2010) and references therein). The main chemical for this effect in Hovenia dulcis is quercetin, which is believed to act as an anti-inflammatory and anti-oxidant.
  • a typical daily dose of the above-mentioned extract may range from about 0.01 to 10 g/kg body weight, preferably 1 to 5 g/kg body weight.
  • a lower alcohol-insoluble fraction and the polysaccharide isolated therefrom can be used in tablet or capsule form, or may be added to food or beverage.
  • the amount of the fraction and/or polysaccharide may generally range from about 0.1 to 15 w/w , preferably 1 to 10 w/w % based on the total weight of food, and 0.1 to 15 g, preferably 1 to 10 g.
  • compositions of the invention comprising the supplement can be administered in various regimens.
  • the compositions can be administered to a subject prior to consumption of alcohol by the subject.
  • the compositions are administered to the subject for at least three days prior to consumption of alcohol by the subject, such as periods of at least about seven days, at least about 14 days, at least about a month, or at least about three months.
  • compositions can be administered in a single daily dose, where the dose contains the entire amount of the composition to be administered on that day.
  • the compositions can be administered in multiple divided doses over the course of one day, such that the multiple doses administered add up to the entire amount of the composition to be
  • the individual components of the supplement can be administered separately, or in any sub-combination, over the course of the day; for example, the amount of anti-oxidant and the amount of alpha-lipoic acid can be administered in the morning, and the amount of the agents capable of increasing intracellular or intramitochondrial concentration of NAD, of increasing glutathione concentration, and of increasing Coenzyme A can be administered in the evening.
  • the compounds may be administered by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles.
  • oral as used herein includes, but is not limited to, sublingual and buccal.
  • Oral administration includes fluid drinks, energy bars, as well as pill formulations.
  • Oral administration by swallowing the compounds is advantageous due to its convenience. However, a patient who has consumed a great deal of alcohol may have difficulty in swallowing, or may be unconscious, in which case introduction of the supplements by other means (feeding tube, intravenously, etc.) may be desirable.
  • compositions containing the active ingredient may be in any form suitable for the intended method of administration.
  • tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • excipients which are suitable for manufacture of tablets are acceptable.
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents; such as magnesium stearate, stearic acid or talc.
  • Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example calcium phosphate or kaolin
  • an oil medium such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions of the disclosure contain the active materials in admixture with excipients suitable for the manufacture of aqueous-suspensions.
  • excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g.,
  • Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin.
  • the oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules of the disclosure suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.
  • a dispersing or wetting agent and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the disclosure may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these.
  • Suitable emulsifying agents include naturally- occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweetening and flavoring agents.
  • formulations of the disclosure suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in- water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be administered as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropyl ethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross- linked sodium carboxymethyl cellulose) surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide, slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach. This is particularly advantageous with the compounds of formula 1 when such compounds are susceptible to acid hydrolysis.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • compositions of the present invention may also be formulated as nutraceutical compositions.
  • the term "nutraceutical composition” as used herein refers to a food product, foodstuff, dietary supplement, nutritional supplement or a supplement composition for a food product or a foodstuff comprising the compositions of the present invention added exogenously.
  • the term food product refers to any food or feed suitable for consumption by humans or animals.
  • the food product may be a prepared and packaged food (e.g., mayonnaise, salad dressing, bread, grain bar, beverage, etc.) or an animal feed (e.g., extruded and pelleted animal feed, coarse mixed feed or pet food composition).
  • the term foodstuff refers to any substance fit for human or animal consumption.
  • Food products or foodstuffs are for example beverages such as non-alcoholic drinks as well as liquid preparation to be added to drinking water and liquid food
  • non-alcoholic drinks are for instance soft drinks, sport drinks, fruit juices, such as for example orange juice, apple juice and grapefruit juice; lemonades, teas, near- water drinks and milk and other dairy drinks such as for example yoghurt drinks, and diet drinks.
  • food products or foodstuffs refer to solid or semi-solid foods comprising the composition according to the invention.
  • These forms can include, but are not limited to baked goods such as cakes and cookies, puddings, dairy products, confections, snack foods, or frozen confections or novelties (e.g., ice cream, milk shakes), prepared frozen meals, candy, snack products (e.g., chips), liquid food such as soups, spreads, sauces, salad dressings, prepared meat products, cheese, yogurt and any other fat or oil containing foods, and food ingredients (e.g., wheat flour).
  • baked goods such as cakes and cookies, puddings, dairy products, confections, snack foods, or frozen confections or novelties (e.g., ice cream, milk shakes), prepared frozen meals, candy, snack products (e.g., chips), liquid food such as soups, spreads, sauces, salad dressings, prepared meat products, cheese, yogurt and any other fat or oil containing foods, and food ingredients (e.g., wheat flour).
  • Animal feed including pet food compositions advantageously include food intended to supply necessary dietary requirements, as well as treats (e.g., dog biscuits) or other food supplements.
  • the animal feed comprising the composition according to the invention may be in the form of a dry composition (for example, kibble), semi-moist composition, wet composition, or any mixture thereof.
  • the animal feed is a supplement, such as a gravy, drinking water, yogurt, powder, suspension, chew, treat (e.g., biscuits) or any other delivery form.
  • dietary supplement refers to a small amount of a compound for centuries.
  • diets packaged in single or multiple dose units. Dietary supplements do not generally provide significant amounts of calories but may contain other micronutrients (e.g., vitamins or minerals).
  • food products or foodstuffs also includes functional foods and prepared food products pre-packaged for human consumption.
  • Dietary supplements of the present invention may be delivered in any suitable format.
  • dietary supplements are formulated for oral delivery.
  • the ingredients of the dietary supplement of this invention are contained in acceptable excipients and/or carriers for oral consumption.
  • the actual form of the carrier, and thus, the dietary supplement itself, is not critical.
  • the carrier may be a liquid, gel, gelcap, capsule, powder, solid tablet (coated or non- coated), tea, or the like.
  • the dietary supplement is preferably in the form of a tablet or capsule and most preferably in the form of a hard (shell) capsule.
  • methylcellulose, povidone, carboxymethylcellulose, corn starch, and the like include mixtures thereof.
  • Preferred carriers include calcium carbonate, magnesium stearate, maltodextrin, and mixtures thereof.
  • the various ingredients and the excipient and/or carrier are mixed and formed into the desired form using conventional techniques.
  • the tablet or capsule of the present invention may be coated with an enteric coating that dissolves at a pH of about 6.0 to 7.0.
  • a suitable enteric coating that dissolves in the small intestine but not in the stomach is cellulose acetate phthalate.
  • the present invention provides nutritional supplements (e.g., energy bars or meal replacement bars or beverages) comprising the composition according to the invention.
  • the nutritional supplement may serve as meal or snack replacement and generally provide nutrient calories.
  • the nutritional supplements provide carbohydrates, proteins, and fats in balanced amounts.
  • the nutritional supplement can further comprise carbohydrate, simple, medium chain length, or polysaccharides, or a combination thereof.
  • a simple sugar can be chosen for desirable organoleptic properties.
  • Uncooked cornstarch is one example of a complex carbohydrate.
  • Sources of protein to be incorporated into the nutritional supplement of the invention can be any suitable protein utilized in nutritional formulations and can include whey protein, whey protein concentrate, whey powder, egg, soy flour, soy milk soy protein, soy protein isolate, caseinate (e.g., sodium caseinate, sodium calcium caseinate, calcium caseinate, potassium caseinate), animal and vegetable protein and hydrolysates or mixtures thereof.
  • caseinate e.g., sodium caseinate, sodium calcium caseinate, calcium caseinate, potassium caseinate
  • caseinate e.g., sodium caseinate, sodium calcium caseinate, calcium caseinate, potassium caseinate
  • the protein is a combination of whey protein concentrate and calcium caseinate.
  • the nutritional supplement can also contain other ingredients, such as one or a combination of other vitamins, minerals, anti-oxidants, fiber and other dietary supplements (e.g., protein, amino acids, choline, lecithin). Selection of one or several of these ingredients is a matter of formulation, design, consumer preferences and end- user.
  • the amounts of these ingredients added to the dietary supplements of this invention are readily known to the skilled artisan. Guidance to such amounts can be provided by the U.S. RDA doses for children and adults.
  • Further vitamins and minerals that can be added include, but are not limited to, calcium phosphate or acetate, tribasic; potassium phosphate, dibasic;
  • magnesium sulfate or oxide ; salt (sodium chloride); potassium chloride or acetate; ascorbic acid; ferric orthophosphate; niacinamide; zinc sulfate or oxide; calcium pantothenate; copper gluconate; riboflavin; beta-carotene; pyridoxine hydrochloride; thiamin mononitrate; folic acid; biotin; chromium chloride or picolinate; potassium iodide; sodium selenate; sodium molybdate; phylloquinone; vitamin D3 ; cyanocobalamin; sodium selenite; copper sulfate; vitamin A;
  • useful flavoring include, but are not limited to, pure anise extract, imitation banana extract, imitation cherry extract, chocolate extract, pure lemon extract, pure orange extract, pure peppermint extract, imitation pineapple extract, imitation rum extract, imitation strawberry extract, or pure vanilla extract; or volatile oils, such as balm oil, bay oil, bergamot oil, cedarwood oil, walnut oil, cherry oil, cinnamon oil, clove oil, or peppermint oil; peanut butter, chocolate flavoring, vanilla cookie crumb, butterscotch or toffee.
  • the dietary supplement contains cocoa or chocolate.
  • the article of manufacture comprises a container with a label.
  • Suitable containers include, for example, bottles, vials, and test tubes.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the containers can hold one or more of the individual ingredients.
  • the label on the container indicates that the kit is used for prevention or reduction of one or more symptoms associated with the alcohol reaction.
  • Pantothenic Acid 150 mg
  • Alpha- Lipoic Acid 100 mg
  • Pantothenic Acid 100 mg
  • Vitamin C 150 mg
  • Pantothenic Acid 100 mg
  • Vitamin A 2500 IU
  • Three more blood tests for acetaldehyde after alcoholic beverage consumption are conducted at time points of 15 minutes, 45 minutes and 90 minutes after finishing the drinks.
  • Each patient must have suitable transportation to and from the research facility in order to avoid driving while under the influence of alcohol.
  • Patient privacy and confidentiality is maintained according to law and regulation.
  • Patients can also fill out questionnaires indicating the degree to which they experience facial flushing, dizziness, nausea, headache, stupor, or increased heart rate at the same time points at which the blood tests are conducted.
  • the degree of facial flushing can also be reported by the staff (either by visual observation or by measurement with a chromameter), and heart rate can be monitored.
  • Patient privacy and confidentiality is maintained according to law and regulation. Patients can also fill out questionnaires indicating the degree to which they experience facial flushing, dizziness, nausea, headache, stupor, or increased heart rate at the same time points at which the blood tests are conducted. The degree of facial flushing can also be reported by the staff (either by visual observation or by measurement with a chromameter), as well as self-reported by the subject.
  • Patients can also fill out questionnaires indicating the degree to which they experience facial flushing, dizziness, nausea, or increased heart rate at the same time points at which the blood tests are conducted.
  • the degree of facial flushing can also be reported by the staff (using the same method— either by visual observation or by measurement with a chromameter— as used previously), and can also be self -reported by the subject.
  • the data is compared between visits two and three to demonstrate the effects of the supplement in preventing accumulation of acetaldehyde, relevant to the placebo group.
  • Formulation C, or Formulation D of Example 1 is used with all subjects. Other than the twice- daily administration of supplement (or placebo), the trial is carried out as described in Example 2.
  • Subject 1 (male) took a supplement containing 500 mg of N- Acetyl Cysteine, 500 mg Vitamin C and 1000 mg nicotinamide. After the supplementation period, upon consumption of alcohol, subject 1 experienced immediately noticeable reduction in facial redness, headache, and body temperature from what the subject typically previously experienced in response to the same amount of alcohol consumption.
  • Subject 2 (female) and Subject 3 (male) took a supplement containing 500 mg of N- Acetyl Cysteine, 100 mg pantothenic acid, 500 mg Vitamin C, and 1000 mg nicotinamide.
  • Subject 2 displayed a significant reduction in both physical discomfort and headache.
  • Subject 3 displayed mild reductions in all assessments for the alcohol reaction.
  • Subject 5 (female), Subject 6 (female), and Subject 7 (male) took a supplement containing 500 mg N- Acetyl Cysteine, 100 mg Pantothenic acid, 500 mg Vitamin C, 1000 mg nicotinamide and 150 mg Alpha Lipoic Acid.
  • Subject 5 displayed mild reductions in all alcohol reaction assessments, with a significant reduction in heart rate.
  • Subject 6 displayed a significant reduction in heart rate and headache, and a reduction in physical discomfort and facial flushing.
  • Subject 7 displayed dramatic decreases in heart rate, nausea, physical discomfort, and body temperature, and a mild reduction in facial redness.
  • Subject 8 (female) took a supplement containing 2500 IU Vitamin A, 700 mg
  • Nicotinamide 25 mg pantothenic acid, 150 mg Vitamin C, 125 mg Alpha Lipoic Acid, 300 mg N- Acetyl Cysteine, and 10 mg Thiamine. Subject 8 displayed dramatic reductions in all assessments for the alcohol reaction, with zero displayed facial redness.
  • Alcohol The alcohol product for use in the study is Absolut® Vodka (40% alcohol/80 proof) in 280 ml (9.5 oz.) of Tropicana® Pure Premium Orange juice.
  • ABSOLUT is a registered trademark of The Absolut Company, Sweden.
  • TROPICANA is a registered trademark of Tropicana Products, Inc., East Bradenton, Florida, United States.
  • Inclusion Criteria are: 1) healthy adult volunteers of either gender who are 21-55 years of age; 2) cooperative, able to read, understand and give informed consent, and able to adhere to the study visit schedule and protocol requirements; 3) have body weight greater than 100 pounds with a calculated Body Mass Index (BMI) greater than 19 at study entry; 4) altered alcohol metabolism due to genetic polymorphisms with known symptoms of acetaldehyde toxicity (by ALDH2*2 allele test); 5) not naive to alcohol consumption and have consumed alcohol previously; 6) willing to consume 0.25 g of ethanol per Kg body weight (2 standard drinks for a 70 Kg individual), during two separate study visits as part of the study; 7) agree to not operate any motor vehicles after the consumption of alcohol, for at least 4 hours; 8) self-reported to be of at least 50% Chinese, Japanese, or Korean ethnicity; 9) if a woman of childbearing potential, have a negative serum pregnancy test at screening and be willing to follow adequate contraceptive measures during the
  • a genetic test for ALDH2 *2 allele will be carried out, which will involve having a blood spot sample collected from the fingertip for genotyping (Visit 1). This is done by making a small finger prick with a lancet and spotting blood drops onto a piece of paper.
  • Randomization of the Subjects There will be 12, 4 and 4 subjects in each of the 3 groups, respectively.
  • SAS SAS Institute, Cary NC
  • inclusion/exclusion criteria including a positive screen for the ALDH2 mutation, will receive one of the two products or placebo daily for 28 days. These products will be distributed to subjects on Visit 2 (see also product administration section for more details on dosing and below). There will be three visits to the site (see Schedule of events, Table la and Table lb).
  • Study Visit 2 is the Baseline day. During this visit, baseline blood for acetaldehyde levels will be drawn (about 1 to 2 teaspoons per draw). Sixty minutes prior to alcohol consumption, subjects in group 1 and 2 will receive placebo in order to mimic the protocol for day 28, in the presence of the study staff. Two out of the four subjects in group 3 will receive active (NoGlo) and two will receive placebo. Group 3 will be in a cross over design and subjects will be reversed on Day 28.
  • Study Visit 3 will occur on study day 28. The subject will have taken a dose of the study supplements or placebo the morning of the 3 rd visit. During this visit, baseline
  • acetaldehyde levels will be drawn (about 1 to 2 teaspoons per draw). Sixty minutes prior to alcohol consumption, subjects in group 1 and 2 will take an additional dose of the study supplements, in the presence of the study staff, according to their study group. Two out of the four subjects in group 3 will receive active (NoGlo) and two will receive placebo, in reverse order from baseline. Subsequently, subjects will consume 0.25 g of ethanol per kilogram of body weight. Additional blood samples for determination of acetaldehyde will be obtained at 10, 20 and 40 minutes following completion of alcohol consumption. At each of these time points, vital sign, skin temperature of both cheeks, flushing and questionnaire measurements will also be made. A breathalyzer test will be administered prior to alcohol intake and at two and four hours following alcohol. Subjects will not be released from the site until the breathalyzer reads zero or four hour time point reached.
  • the primary efficacy endpoint is the change in blood acetaldehyde concentration following alcohol ingestion after 28-days' administration of study supplements compared to the concentration following alcohol ingestion at Baseline.
  • Secondary endpoints include: Changes in heart rate and skin temperature of both cheeks following alcohol consumption comparing Day 28 to Baseline and changes in symptomatic responses following alcohol consumption comparing Day 28 to Baseline.
  • Compliance Compliance will be enforced and monitored using the following methods: proper subject selection; subject education, management, and encouragement;
  • an agent which is an anti-oxidant and d) an agent which is alpha-lipoic acid or a precursor to alpha-lipoic acid; and e) an agent capable of increasing the level of Coenzyme A in the subject.
  • Embodiment 44 A composition comprising an agent capable of increasing
  • Embodiment 46 A composition comprising: a) an agent selected from the group consisting of nicotinamide, nicotinamide riboside, niacin, and oxaloacetate; b) Hovenia dulcis fruit extract; c) Silybum marianum extract; and d) a-lipoic acid; wherein said agents are present in the composition in an amount sufficient to prevent or reduce the alcohol reaction in the subject.
  • Embodiment 47 A composition comprising: a) an agent selected from the group consisting of nicotinamide, nicotinamide riboside, niacin, and oxaloacetate; b) Hovenia dulcis fruit extract; c) Silybum marianum extract; d) vitamin A; e) vitamin B5; f) vitamin c; g) N-acetyl cysteine; h) thiamine; and i) a-lipoic acid; wherein said agents are present in the composition in an amount sufficient to prevent or reduce the alcohol reaction in the subject.
  • an agent selected from the group consisting of nicotinamide, nicotinamide riboside, niacin, and oxaloacetate
  • b) Hovenia dulcis fruit extract c) Silybum marianum extract
  • Embodiment 48 A composition as described herein in Embodiments 42-47, comprising at least 500 mg niacinamide.
  • Embodiment 49 Any of the compositions, compositions for use, or methods of Embodiments 1-47, wherein the composition, supplement, dosage, or medicament is in tablet or capsule form.
  • Embodiment 50 Any of the compositions, compositions for use, or methods of Embodiments 1-47, wherein the composition, supplement, dosage, or medicament is in liquid or beverage form.
  • Embodiment 51 Any of the compositions, compositions for use, or methods of Embodiments 1-47, wherein the composition, supplement, dosage, or medicament is provided in a food.

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Abstract

La présente invention concerne des compositions pour empêcher ou réduire les bouffées vasomotrices et d'autres symptômes déplaisants qui accompagnent parfois la consommation de boissons alcoolisées, et des procédés en vue d'une utilisation desdites compositions. Les compositions comprennent un agent, ou des combinaisons de divers agents, tels qu'un agent apte à augmenter la concentration intracellulaire ou intramitochrondriale de NAD dans le sujet ; un agent apte à augmenter la concentration de glutathione dans le sujet ; un agent anti-oxydant ; un acide alpha-lipoïque ou un précurseur d'acide alpha-lipoïque ; et/ou un agent apte à augmenter le taux de coenzyme A dans le sujet ; où l'agent ou les agents sont présents ou administrés dans des quantités efficaces pour empêcher ou réduire la réaction à l'alcool chez un sujet qui a consommé une ou plusieurs boissons alcoolisées.
PCT/US2013/067345 2012-07-09 2013-10-29 Réduction ou prévention de réaction à l'alcool avec des compléments alimentaires Ceased WO2014143192A1 (fr)

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WO2016042205A1 (fr) * 2014-09-15 2016-03-24 Biohit Oyj Préparations pour le traitement et la prévention de la réaction d'intolérance à l'alcool ("alcohol flushing") et de réactions d'hypersensibilité induites par l'alcool
CN110004119A (zh) * 2019-04-18 2019-07-12 华东理工大学 ε-酮酯还原酶突变体及其催化合成(R)-α-硫辛酸前体的应用

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WO2013009997A1 (fr) * 2011-07-12 2013-01-17 Burn-Off, Llc Composition et procédé d'utilisation de la composition, efficace pour minimiser les effets nocifs associés aux individus souffrant d'une intoxication alcoolique

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* Cited by examiner, † Cited by third party
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WO2016042205A1 (fr) * 2014-09-15 2016-03-24 Biohit Oyj Préparations pour le traitement et la prévention de la réaction d'intolérance à l'alcool ("alcohol flushing") et de réactions d'hypersensibilité induites par l'alcool
CN110004119A (zh) * 2019-04-18 2019-07-12 华东理工大学 ε-酮酯还原酶突变体及其催化合成(R)-α-硫辛酸前体的应用

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