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Home , Alcohol flush reaction, Pantetheine

(19) TZZ __T

(11) EP 2 869 717 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/122 (2006.01) A61P 43/00 (2006.01) 13.06.2018 Bulletin 2018/24 (86) International application number: (21) Application number: 13816903.2 PCT/US2013/049783

(22) Date of filing: 09.07.2013 (87) International publication number: WO 2014/011676 (16.01.2014 Gazette 2014/03)

(54) PREVENTION OF REACTION WITH DIETARY SUPPLEMENTS PRÄVENTION VON ALKOHOLREAKTIONEN MIT NAHRUNGSZUSÄTZEN PRÉVENTION D’UNE RÉACTION À L’ALCOOL AVEC DES COMPLÉMENTS DIÉTÉTIQUES

(84) Designated Contracting States: • Anonymous: "NoGlo Ingredients", Internet , 16 AL AT BE BG CH CY CZ DE DK EE ES FI FR GB November 2012 (2012-11-16), XP002752542, GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Retrieved from the Internet: PL PT RO RS SE SI SK SM TR URL:http://gonoglo.com/noglo-ingredients/ [retrieved on 2015-11-25] (30) Priority: 09.07.2012 US 201261669404 P • Anonymous:"Drinkwel Review - The 13.03.2013 US 201361780612 P Cure for ", Internet , 5 April 2012 (2012-04-05), XP002752543, Retrieved from the (43) Date of publication of application: Internet: 13.05.2015 Bulletin 2015/20 URL:http://www.chipchick.com/2011/09/drink wel-revie.html [retrieved on 2015-11-25] (73) Proprietor: Noglo LLC • Anonymous: "How to prevent the damaging San Francisco, CA 94103 (US) effects of smoking, alcohol consumption, and air pollution", Internet , 5 April 2012 (2012-04-05), (72) Inventors: XP002752544, Retrieved from the Internet: • Tolleth, Robert J. URL:http://coenzyme-a.com/effects_of_smoki Millbrae, CA 94030 (US) ng_alcohol_airpollution_article.html [retrieved • Gordon, Spencer A. on 2015-11-25] Ramona, CA 92065 (US) • Anonymous: "Mega antioxidant tablets", Internet , 15 April 2012 (2012-04-15), (74) Representative: Wytenburg, Wilhelmus Johannes XP002752545, Retrieved from the Internet: et al URL:http://www.drugs.com/drp/mega-antioxid Mewburn Ellis LLP ant-tablets.html [retrieved on 2015-11-25] City Tower • KANE ET AL.: ’ elevates physiological 40 Basinghall Street all-trans-retinoic acid levels in select loci through London EC2V 5DE (GB) altering retinoid metabolism in multiple loci: a potential mechanism of ethanol toxicity’ THE (56) References cited: FASEB JOURNAL vol. 24, no. 3, March 2010, WO-A1-2007/017139 WO-A1-2012/120036 pages 823 - 832, XP055185018 WO-A2-2012/027603 US-A1- 2001 033 881 US-A1- 2007 202 215 US-B1- 8 377 907 Remarks: Thefile contains technical information submitted after the application was filed and not included in this specification

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 869 717 B1

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Description mation and of the skin, can cause organ damage. There is evidence demonstrating that in- TECHNICAL FIELD dividuals with the variant ALDH2 are at a signif- icantly increased risk of gastric and esophageal cancers, [0001] The present invention relates to compositions 5 liver and failure, and even Alzheimer’s disease for use by a subject to prevent the flush and other un- if they consume alcohol with any regularity. This is shown pleasant symptoms that sometimes accompany the con- to be due to the accumulation of acetaldehyde. Individ- sumption of alcoholic beverages. uals that demonstrate the flush response to alcoholic beverages and drink moderately are at a much higher BACKGROUND 10 risk of than even heavy drinkers who do not experience the flush reaction. In addition, drinkers [0002] The alcohol reaction, also known as the alcohol that flush may also experience dizziness and af- flush reaction, is an unpleasant condition which occurs ter just one drink. in some individuals upon consumption of alcohol, even [0005] The health risks associated with drinking and in relatively small amounts. The reaction is characterized 15 flushing are not well understood by the general public. by flushing of the facial skin, and sometimes other areas The majority of research on the ALDH2 mutation and of the skin. The alcohol flush reaction may also include alcohol related diseases has been done in Japan, and dizziness, nausea, stupor, headache, light-headedness, theresults of this researchare not as widely disseminated increased heart rate, and other symptoms. in other countries, including the United States, which in [0003] The alcohol flush reaction occurs in individuals 20 2009 had an estimated 4 million residents of Chinese with lower rates of metabolism of acetaldehyde. Acetal- descent, 1.6 million residents of Korean descent, 1.3 mil- dehyde is metabolized by acetaldehyde dehydrogenase- lion residents of Japanese descent, and several million 2 (ALDH2; also known as mitochondrial aldehyde dehy- additional residents from other East Asian countries. drogenase; human precursor Swiss-Prot P05091), a liver While awareness of the health risks associated with the enzyme involved in the metabolism of ethanol, which ox- 25 alcohol flush reaction is increasing in Japan and China, idizes acetaldehyde to acetic acid. Approximately 1 bil- people continue to drink regularly despite these known lion people, including up to about 50% of people of Chi- long term risks. nese, Japanese and Korean ethnicity, have a point mu- [0006] Thus, there is a need for compositions and tation resulting in a less active version of ALDH2 methods for prevention or reduction of the alcohol flush (ALDH2*2, where a glutamic acid residue is mutated to 30 reaction, both for the short-term comfort of the alcohol lysine, i.e., ALDH2 E487K; the residue numbering is consumer, and for the potential to reduce the long-term based on the mature protein; see, e.g., Steinmetz et al., health risks associated with consumption of alcoholic Structure 5: 701-11, 1997), which functions at about 8% beverages by persons demonstrating the alcohol flush of the wild-type form. The enzyme is normally a homote- reaction. tramer. However, if an individual carries one mutated al- 35 [0007] WO 2012/120036 A1 (Gerdes Roman - 13 Sep- lele, then he or she will present the mutant phenotype tember 2012) describes a pharmaceutical composition due to the formation of heterotetramers. The mutation in for reducing and/or preventing the adverse effects of al- ALDH2 is at an amino acid residue located at the binding cohol consumption. site for adenine dinucleotide (NAD), an en- [0008] US 8377907 B1 (Halamicek III, William A - 19 zyme cofactor required for the conversion of acetalde- 40 February 2013) describes compositions for treating al- hyde to acetic acid; in the process, NAD is converted to cohol . NADH. The lowered activity of this enzyme results in an [0009] "NoGlo Ingredients" (16 November 2012 - re- accumulation of acetaldehyde in the blood when con- trieved from http://web.archive.org/ web/ suming alcohol. Certain individuals, especially those of 20121116062353/http://gonoglo.com/noglo-ingredients East Asian descent, may also have a highly active variant 45 on 25 November 2015) describes an anti-hangover, anti- of (ADH1B; also known as alco- flush supplement. hol dehydrogenase 1B; human precursor Swiss-Prot [0010] "Drinkwel Multivitamin Review - The Cure for P00325) caused by a R47H mutation (again, this residue Hangovers" (21 September 2011 - retrieved from ht- numbering is based on the mature protein), leading to tp://www.chipchick.com/2011/09/drinkwel-revie.html on more rapid accumulation of acetaldehyde (Peng et al., 50 25 November 2015) describes pills which "severely re- BMC Evolutionary Biology 2010, 10:15). Individuals with duce, or eliminate, the hangover". both the "fast" variant of alcohol dehydrogenase (which [0011] "How to prevent the damaging effects of smok- produces acetaldehyde from alcohol) and the "slow" var- ing, alcohol consumption, and air pollution" (5 April 2012 iant of acetaldehyde dehydrogenase (which eliminates - retrieved from http://coenzyme- acetaldehyde) can be strongly affected by the alcohol 55 a.com/effects_of_smoking_alcohol_ flush reaction. airpollution_article.html on 25 November 2015) de- [0004] Acetaldehyde is 30 times as toxic as ethanol scribes the common sources of acetaldehyde and its and is a known carcinogen. In addition to causing inflam- damaging effects on brain structure and function and pro-

2 3 EP 2 869 717 B1 4 vides a list of possible nutrient levels that may offer pro- [0020] In one embodiment, the composition further tection against chronic aldehyde toxicity, in an amount comprises alpha-lipoic acid. per day. [0021] In one embodiment, the composition further [0012] "Mega antioxidant tablets" (15 April 2012 - re- comprises an agent selected from beta-carotene and a trieved from http://www.drugs.com/ drp/mega-antioxi- 5 ester. dant-tablets.html on 25 November 2015) describes tab- [0022] In one embodiment, the agent is a retinol ester lets that contain essential and antioxidants at selected from retinyl arachidonate, retinyl stearate, reti- levels substantially higher than the recommended daily nyl oleate, retinyl linoleate, retinyl heptadecanoate, reti- allowance (RDA) amounts. nyl palmitate, retinyl myristate, retinyl laurate, retinyl [0013] WO 2007/017139 A1 (Tima Foundation -1510 caprylate, and retinyl acetate. February 2007) describes a composition for moderating [0023] In one embodiment, the agent is beta-carotene. alcohol metabolism and for reducing the risk of alcohol [0024] In one embodiment, the composition further induced diseases. comprises . [0014] WO 2012/027603 A2 (Clarity Products LLC - 1 [0025] In one embodiment, the composition compris- March 2012) describes a therapeutic consumable com- 15 es: position for the reduction of facial flush in response to consumption of alcohol in persons with deficient activity (i) between 300 mg and 1.5 g nicotinamide, of the gene ALDH2. (ii) between 10 mg and 500 mg or [0015] Kane et al., 2010, The FASEB Journal, Vol 24, a salt thereof, and No. 3, pp. 823-832, describes a study of the effects of 20 (iii) between 100 mg and 600 mg N-acetylcysteine, ethanol on all-trans-retinoic acid (atRA) concentration in different tissues (hippocampus, liver, etc.) in mice during and an excipient acceptable for daily oral administration. normal A nutriture and suggested that elevated [0026] In one embodiment, the composition further levels of atRA contribute to ethanol-induced disorders comprises in an amount between 100 mg and such as foetal alcohol syndrome (FAS). 25 500 mg. [0016] US 2007/202215 A1 (Lak, Z. S. - 30 August [0027] In one embodiment, the composition further 2007) describes a dietary nutritional supplement for hu- comprises alpha-lipoic acid in an amount between 50 mg mans who consume moderate to large amounts of alco- and 250 mg. hol. [0028] In one embodiment, the composition further [0017] US 2001/033881 A1 (Fuchs et al. - 25 October 30 comprises beta-carotene in an amount between 100 IU 2001) describes a fructose-containing refreshing drink and 15000 IU. composition for increasing the alcohol degradation ca- [0029] In one embodiment, the composition further pacity of the body. comprises thiamine. [0030] In one embodiment, the composition further SUMMARY OF THE INVENTION 35 comprises thiamine in an amount between 2.5 mg and 10 mg. [0018] The present invention relates to a composition [0031] In one embodiment, the composition further for use by a subject to prevent or reduce the alcohol flush comprises one or more of , vitamin C, thiamine, reaction, said composition comprising: and α-lipoic acid. 40 [0032] In one embodiment, the composition further (a) an agent selected from nicotinamide, nicotina- comprises one or more of: mide riboside, , and oxaloacetate; and (b) an agent selected from N-acetyl-cysteine, Vita- 1250 IU to 2500 IU vitamin A, min C, alpha lipoic acid, L-cysteine, glutathione, gly- 75 mg to 150 mg vitamin C, cine, L-glutamic acid, adenosylmethionine, and con- 45 2.5 to 10 mg thiamine, and jugated linoleic acid; and 62 to 125 mg α-lipoic acid. (c) an agent selected from pantothenic acid, panteth- ine, pantetheine, 4’-phosphopantothenate, and 4’- [0033] In one embodiment, the composition further phosphopantetheine; comprises each of vitamin A, vitamin C, thiamine, and α- 50 lipoic acid. wherein the composition is administered daily for at least [0034] Inone embodiment, the composition isprovided 30 days prior to consumption of alcohol by the subject; as a tablet or a capsule. wherein said agents are present in the composition in an [0035] Inone embodiment, the composition isprovided amount sufficient to prevent or reduce the alcohol flush in a food or in a beverage. reaction in the subject. 55 [0019] In one embodiment, the composition further DESCRIPTION comprises an agent which is selected from Vitamin C, , and alpha-lipoic acid. [0036] Described herein are compositions and meth-

3 5 EP 2 869 717 B1 6 ods for prevention or reduction of the alcohol flush reac- in the subject; an agent capable of increasing glutathione tion in a subject. concentration in the subject; an agent which is an anti- [0037] Also described herein is a composition for use oxidant; an agent which is alpha-lipoic acid or a precursor by a subject to prevent or reduce the alcohol flush reac- to alpha-lipoic acid; and an agent capable of increasing tion and/or to reduce acetaldehyde in tissues and body 5 the level of in the subject. The agents are fluids (e.g., liver, central nervous system, blood, saliva, present in the supplement or composition in an amount etc.). The composition comprises an agent capable of or amounts effective to prevent or reduce the alcohol increasing intracellular or intramitochondrial concentra- flush reaction in the subject. In other embodiments, the tion of NAD in the subject, and an agent capable of in- agents are present in the supplement or composition in creasing glutathione concentration in the subject, where 10 an amount or amounts effective to prevent the alcohol the agents are present in the composition in an amount flush reaction in the subject. In other embodiments, the sufficient to prevent or reduce the alcohol flush reaction agents are present in the supplement or composition in in the subject. Also as described herein, the composition an amount or amounts effective to reduce the alcohol can further comprise one or more of the following: reaction in the subject. [0038] an agent capable of increasing the level of15 [0047] As described herein, the agent capable of in- Coenzyme A in the subject; creasing intracellular or intramitochondrial concentration [0039] an agent which is an anti-oxidant; of NAD in the subject can be nicotinamide, niacin, nico- [0040] alpha-lipoic acid or a precursor to alpha-lipoic tinamide riboside, or oxaloacetate. If nicotinamide is acid; used, the amount of nicotinamide in the supplement or [0041] an agent capable of increasing the level of20 composition can range from about 500 mg to about 1,500 Coenzyme A in the subject and an anti-oxidant; mg, or from about 750 mg to about 1,250 mg. In another [0042] an agent capable of increasing the level of embodiment, the amount of nicotinamide in the supple- Coenzyme A in the subject and alpha-lipoic acid or a ment or composition is about 1000 mg. In another em- precursor to alpha-lipoic acid; bodiment, the amount of nicotinamide in the supplement [0043] an anti-oxidant and alpha-lipoic acid or a pre- 25 or composition is about 800 mg. If niacin is used, the cursor to alpha-lipoic acid; or amount of niacin in the supplement or composition can [0044] an agent capable of increasing the level of range from about 500 mg to about 1,500 mg, or from Coenzyme A in the subject, an anti-oxidant, and alpha- about 750 mg to about 1,250 mg. In another embodiment, lipoic acid or a precursor to alpha-lipoic acid. This list is the amount of niacin in the supplement or composition not meant to be limiting. 30 is about 1000 mg. In another embodiment, the amount [0045] Also described herein is a composition for use of niacin in the supplement or composition is about 800 by a subject to prevent or reduce the alcohol flush reac- mg. If nicotinamide riboside is used, the amount of nico- tion and/or to reduce acetaldehyde in tissues and body tinamide riboside in the supplement or composition can fluids, where the composition comprises an agent capa- range from about 1,000 mg to about 3,200 mg, or from ble of increasing intracellular or intramitochondrial con- 35 about 1,500 mg to about 2,600 mg. In another embodi- centration of NAD in the subject. Also described herein ment, the amount of nicotinamide riboside in the supple- is a composition for use by a subject to prevent or reduce ment or composition is about 2,100 mg. In another em- the alcohol flush reaction, where the composition com- bodiment, the amount of nicotinamide riboside in the sup- prises an agent capable of increasing glutathione con- plement or composition is about 1,700 mg. centration in the subject. Also described herein is a com- 40 [0048] As described herein, the agent capable of in- position for use by a subject to prevent or reduce the creasing glutathione concentration in the subject can be alcohol flush reaction, where the composition comprises N-acetyl cysteine, L-cysteine, Vitamin C, alpha lipoic ac- an agent capable of increasing intracellular Coenzyme id, glutathione, glycine, L-glutamic acid, adenosylmethio- A concentration in the subject. In these embodiments, nine, or conjugated linoleic acid. If N-acetyl cysteine is the agent is present in the composition in an amount suf- 45 used, the amount in the supplement or composition can ficient to prevent or reduce the alcohol flush reaction in range from about 200 mg to about 600 mg, or from about the subject. The agent can be administered to the subject 300 mg to about 500 mg. In another embodiment, the in a daily dosage for at least one week prior to consump- amount of N-acetyl cysteine in the supplement or com- tion of alcohol. The daily dosage can be administered in position is about 400 mg. In another embodiment, the a single dosage per day, or in multiple divided dosages 50 amount of N-acetyl cysteine in the supplement or com- per day. positionis about 300 mg. If L-cysteine is used, theamount [0046] Also described herein is a composition for use in the supplement or composition can range from about by a subject to prevent or reduce the alcohol flush reac- 200 mg to about 600 mg, or from about 300 mg to about tion and/or to reduce acetaldehyde in tissues and body 500 mg. In another embodiment, the amount of L- fluids. The composition can be described as an anti-al- 55 cysteine in the supplement or composition is about 400 cohol flush reaction supplement. The supplement or mg. In another embodiment, the amount of L-cysteine in composition comprises an agent capable of increasing the supplement or composition is about 300 mg. intracellular or intramitochondrial concentration of NAD [0049] As described herein, the agent used as the anti-

4 7 EP 2 869 717 B1 8 oxidant can be Vitamin C, Vitamin E, or alpha-lipoic acid. acetylcysteine.These compositions canfurther comprise If Vitamin C is used, the amount in the supplement or one or more of vitamin A, vitamin C, thiamine, andα - composition can range from about 100 mg to about 500 lipoic acid. By way of example only, the compositions mg, or from about 200 mg to about 400 mg. In another comprise one or more of, and preferably each of 1250 embodiment, the amount of Vitamin C in the supplement 5 IU to 2500 IU vitamin A, 75 mg to 150 mg vitamin C, 2.5 or composition is about 300 mg. In another embodiment, to 10 mg thiamine, and 62 to 125 mg α-lipoic acid. This theamount ofVitamin C in the supplement or composition list is not meant to be limiting. is about 150 mg. [0053] As noted herein, such daily dosages can be tak- [0050] As described herein, the amount of alpha lipoic en as a single administration, or in 2, 3, 4, 5 or more acid in the supplement or composition, when a separate 10 individual administrations. The skilled artisan will under- anti-oxidant is used in addition to alpha lipoic acid, can stand that the components of the composition may be range from about 50 mg to about 250 mg, or from about provided as various salt or prodrug forms. By way of ex- 100 mg to about 200 mg. In one embodiment, the amount ample only, pantothenic acid may be provided in the form of alpha-lipoic acid in the supplement or composition is of calcium pantothenate. about 150 mg. In one embodiment, the amount of alpha- 15 [0054] Preferredare compositions which comprise one lipoic acid in the supplement or composition is about 100 or more pharmaceutical excipients acceptable for oral or mg. If alpha lipoic acid is also used as the anti-oxidant, enteral administration. The compositions may be provid- the amount of alpha lipoic acid in the supplement or com- ed as a tablet or capsule; as a beverage; as a food; etc. position can range from about 100 mg to about 500 mg, [0055] As described herein is the establishment of a from about 200 mg to about 400 mg, or in another em- 20 daily dose over a period of time, e.g. 3 days, 5 days, 10 bodiment is about 300 mg, or in another embodiment is days, 14 days, 21 days, 30 days, or longer, and admin- about 200 mg. istering a supplemental dosage between 10 minutes and [0051] As described herein, the agent capable of in- 1 hour prior to consumption of ethanol by the human creasing the level of Coenzyme A in the subject can be adult. pantothenic acid, pantothenate, , , 25 [0056] As described herein, the levels of the composi- pantetheine, 4’-phosphopantothenate, 4’-phospho- tions described herein can reduce average peak blood pantetheine, N-acetyl-cysteine, or L-cysteine. If pan- levels of acetaldehyde in a population of human adults tothenic acid is used, the amount of pantothenic acid in having an E487K mutation in mitochondrial aldehyde de- the supplement or composition can range from about 50 hydrogenase and/or a R47H mutation in alcohol dehy- mg to about 250 mg, or from about 100 mg to about 200 30 drogenase 1B following ingestion of 0.5 g ethanol/kg mg. In another embodiment, the amount of pantothenic body wt by at least 5%, more preferably 10%, still more acid in the supplement or composition is about 150 mg. preferably 20%, yet more preferably 40%, and most pref- In another embodiment, the amount of pantothenic acid erably 50% or more relative to average peak blood levels in the supplement or composition is about 100 mg. If pan- in a corresponding untreated population. tothenate is used, the amount of pantothenate in the sup- 35 [0057] Also disclosed herein is a method of preventing plement or composition can range from about 50 mg to or reducing at least one symptom of the alcohol flush about 250 mg, or from about 100 mg to about 200 mg. reaction in a subject, by administering the supplement or In another embodiment, the amount of pantothenate in composition as described herein. The dosage of the sup- the supplement or composition is about 150 mg. In an- plement or composition can be administered to the sub- other embodiment, the amount of pantothenate in the 40 ject daily, either in a single dose per day, or in multiple supplement or composition is about 100 mg. If panthenol divided doses per day. The composition is administered is used, the amount of panthenol in the supplement or prior to the consumption of alcohol, and can be admin- composition can range from about 50 mg to about 250 istered daily for a period of time such as at least seven mg, or from about 100 mg to about 200 mg. In another days prior to consumption of alcohol by the subject, at embodiment, the amount of panthenol in the supplement 45 least 14 days prior to consumption of alcohol by the sub- or composition is about 150 mg. In another embodiment, ject, or at least 30 days prior to consumption of alcohol the amount of panthenol in the supplement or composi- by the subject. tion is about 100 mg. [0058] Also disclosed herein is a method of preventing [0052] As described herein are compositions which or reducing at least one symptom of the alcohol flush comprise (i) between 300 mg and 1.5 g nicotinamide, (ii) 50 reaction in a subject, by administering to the subject at between 10 mg and 500 mg pantothenic acid or a salt least one agent selected from the group consisting of an thereof, and between 100 mg and 600 mg N-acetyl- agent capable of increasing intracellular or intramito- cysteine; with preferred compositions comprising about chondrial concentration of NAD in the subject, an agent 700 mg nicotinamide, about 25 mg pantothenic acid, and capable of increasing glutathione concentration in the about 300 mg N-acetylcysteine, wherein the term "about" 55 subject, and an agent capable of increasing cellular refers to +/- 20% of each quantity. By way of example, Coenzyme A concentrations in the subject, where the at treatment can comprise a daily dosage of about 700 mg least one agent is administered in an amount sufficient nicotinamide, 25 mg pantothenic acid, and 300 mg N- to prevent or reduce the alcohol flush reaction in the sub-

5 9 EP 2 869 717 B1 10 ject. The dosage of the agent or agents can be adminis- would otherwise be reached without administration of the tered to the subject daily, either in a single dose per day, supplement or composition. As described herein is a or in multiple divided doses per day. The composition is method of reducing the accumulation of acetaldehyde in administered prior to the consumption of alcohol, and the blood after consumption of alcohol, by administering can be administered daily for a period of time such as at 5 the supplement or composition as described herein in an least seven days prior to consumption of alcohol by the amount and duration sufficient to reduce the accumula- subject, at least 14 days prior to consumption of alcohol tion of acetaldehyde by about 15%, up to about 15%, or by the subject, or at least 30 days prior to consumption by at least about 15% from the blood concentration that of alcohol by the subject. would otherwise be reached without administration of the [0059] As described herein, the symptom or symptoms 10 supplement or composition. As described herein is a to be prevented or reduced are selected from facial flush- method of reducing the accumulation of acetaldehyde in ing, hangover, headache, stupor, dizziness, nausea, ac- the blood after consumption of alcohol, by administering cumulation of acetaldehyde in the blood (i.e., increased the supplement or composition as described herein in an levels of blood acetaldehyde), or increased heart rate. In amount and duration sufficient to reduce the accumula- some embodiments, the symptom to be reduced is facial 15 tion of acetaldehyde by about 20%, up to about 20%, or flushing. In another embodiment, the symptom to be re- by at least about 20% from the blood concentration that duced is hangover. In another embodiment, the symptom would otherwise be reached without administration of the to be reduced is headache. In another embodiment, the supplement or composition. As described herein is a symptom to be reduced is stupor. In another embodi- method of reducing the accumulation of acetaldehyde in ment, the symptom to be reduced is dizziness. In another 20 the blood after consumption of alcohol, by administering embodiment, the symptom to be reduced is nausea. In the supplement or composition as described herein in an another embodiment, the symptom to be reduced is ac- amount and duration sufficient to reduce the accumula- cumulation of acetaldehyde in the blood or increased lev- tion of acetaldehyde by about 25%, up to about 25%, or els of blood acetaldehyde. In another embodiment, the by at least about 25% from the blood concentration that symptomto be reducedis increased heart rate.In another 25 would otherwise be reached without administration of the embodiment, the symptoms to be reduced are any com- supplement or composition. As described herein is a bination of any or all of the foregoing symptoms. In some method of reducing the accumulation of acetaldehyde in embodiments, the symptom to be prevented is facial the blood after consumption of alcohol, by administering flushing. In another embodiment, the symptom to be pre- the supplement or composition as described herein in an vented is hangover. In another embodiment, the symp- 30 amount and duration sufficient to reduce the accumula- tom to be prevented is headache. In another embodi- tion of acetaldehyde by about 50%, up to about 50%, or ment, the symptom to be prevented is stupor. In another by at least about 50% from the blood concentration that embodiment, the symptom to be prevented is dizziness. would otherwise be reached without administration of the In another embodiment, the symptom to be prevented is supplement or composition. As described herein is meth- nausea. In another embodiment, the symptom to be pre- 35 od of reducing the accumulation of acetaldehyde in the vented is accumulation of acetaldehyde in the blood. In blood after consumption of alcohol, by administering the another embodiment, the symptom to be prevented is supplement or composition as described herein in an increased heart rate. In another embodiment, the symp- amount and duration sufficient to reduce the accumula- toms to be prevented are any combination of any or all tion of acetaldehyde by about 75%, up to about 75%, or of the foregoing symptoms. 40 by at least about 75% from the blood concentration that [0060] Also disclosed herein is a method of reducing would otherwise be reached without administration of the the accumulation of acetaldehyde in the blood after con- supplement or composition. As described herein is a sumption of alcohol, by administering the supplement or method of reducing the accumulation of acetaldehyde in composition as described herein. As described herein is the blood after consumption of alcohol, by administering a method of reducing the accumulation of acetaldehyde 45 the supplement or composition as described herein in an in the blood after consumption of alcohol, by administer- amount and duration sufficient to reduce the accumula- ing the supplement or composition as described herein tion of acetaldehyde by about 90%, up to about 90%, or in an amount and duration sufficient to reduce the accu- by at least about 90% from the blood concentration that mulation of acetaldehyde by about 5%, up to about 5%, would otherwise be reached without administration of the or by at least about 5% from the blood concentration that 50 supplement or composition. As described herein is a would otherwise be reached without administration of the method of reducing the accumulation of acetaldehyde in supplement or composition. As described herein is a the blood after consumption of alcohol, by administering method of reducing the accumulation of acetaldehyde in the supplement or composition as described herein in an the blood after consumption of alcohol, by administering amount and duration sufficient to reduce the accumula- the supplement or composition as described herein in an 55 tion of acetaldehyde by about 95%, up to about 95%, or amount and duration sufficient to reduce the accumula- by at least about 95% from the blood concentration that tion of acetaldehyde by about 10%, up to about 10%, or would otherwise be reached without administration of the by at least about 10% from the blood concentration that supplement or composition.

6 11 EP 2 869 717 B1 12

[0061] Also disclosed herein is the use of any of the which substantially affect the condition being treated oth- compositions described herein for prevention or reduc- er than those steps expressly listed. tion of at least one symptom of the alcohol flush reaction [0066] Thecompositions and methods described here- in a subject. Also disclosed herein is the use of any of in, including any embodiment as described herein, may the compositions described herein for the manufacture 5 be used alone or may be used in combination with other of a medicament for use in preventing or reducing at least compositions and methods. one symptom of the alcohol flush reaction in a subject. [0062] As described herein, in any of the embodiments DETAILED DESCRIPTION of the compositions, supplements, methods, or uses de- scribed herein, the composition or supplement can fur- 10 [0067] Described herein are compositions which are ther comprise an agent capable of raising the blood level combinations of dietary supplements or compositions of all-trans retinoic acid. useful for prevention or reduction of the alcohol flush re- [0063] The features and embodiments disclosed here- action. Also disclosed herein are methods for use, includ- in can be combined and permuted in any desired manner. ing dosage regimens, of the compositions to prevent or These and other features and embodiments will become 15 reduce the alcohol flush reaction. As described herein, evident upon reference to the remainder of this applica- the supplement or composition may reduce the accumu- tion, including the following detailed description. lation of acetaldehyde in the blood after consumption of [0064] Some embodiments described herein are recit- alcoholic beverages. ed as "comprising" or "comprises" with respect to their [0068] A supplement or composition, as described various elements. In alternative embodiments, those el- 20 herein, comprising the combined ingredients can be tak- ements can be recited with the transitional phrase "con- en once a day, or in multiple divided dosages over a day, sisting essentially of" or "consists essentially of" as ap- or can be taken as individual components over the course plied to those elements. In further alternative embodi- of a day. The supplements or compositions comprise vi- ments, those elements can be recited with the transitional tamins, aminoacids, anti-oxidants,and other dietary sup- phrase "consisting of" or "consists of" as applied to those 25 plements. While not wishing to be limited by theory, it is elements. Thus, for example, if a composition or method hypothesized that use of the supplements or composi- is disclosed herein as comprising A and B, the alternative tions described herein results in a protective buildup of embodiment for that composition or method of "consist- compounds which reduces the reactivity of acetaldehyde ing essentially of A and B" and the alternative embodi- and which enhances enzyme kinetics, causing an in- ment for that composition or method of "consisting of A 30 creased rate of breakdown of acetaldehyde. The ALDH2 and B" are also considered to have been disclosed here- E487K enzyme variant binds NAD less strongly than the in. Likewise, embodiments recited as "consisting essen- variant with glutamic acid at position 487. Thus, it is hy- tially of" or "consisting of" with respect to their various pothesized that increasing NAD concentration will en- elements can also be recited as "comprising" as applied hance the binding of NAD to aldehyde dehydrogenase, to those elements. Finally, embodiments recited as "con- 35 increasing the rate of acetaldehyde dehydrogenation. sisting essentially of" with respect to their various ele- [0069] Acetaldehyde is oxidized to acetic acid by ments can also be recited as "consisting of" as applied ALDH2. Acetic acid then binds to Coenzyme A to form to those elements, and embodiments recited as "consist- Acetyl-CoA and enters the Citric Acid Cycle. While not ing of" with respect to their various elements can also be wishing to be limited by theory, it is hypothesized that recited as "consisting essentially of" as applied to those 40 during alcohol metabolism in subjects with the ALDH2 elements. mutation, there is a build-up of acetic acid, and Coen- [0065] When a composition is described as "consisting zyme A is greatly reduced, as it is not regenerated quickly essentially of" the listed components, the composition enough to keep up with the rate of production of acetic contains the components expressly listed, and may con- acid. With an accumulation of acetic acid, ALDH2 is in- tain other components which do not substantially affect 45 hibited based on known enzyme kinetics, as an increase condition being treated. However, the composition either in product concentration will decrease the favorability of does not contain any other components which do sub- the forward reaction. Also described herein is daily sup- stantially affect the condition being treated other than plementation of any compound(s) to increase cellular those components expressly listed; or, if the composition Coenzyme A concentrations to increase the rate of for- does contain extra components other than those listed 50 mation of Acetyl-CoA, therefore clearing acetic acid more which substantially affect the condition being treated, the quickly and pushing the ALDH2 reaction towards the composition does not contain a sufficient concentration product. This reduces the accumulation and exposure to or amount of those extra components to substantially af- acetaldehyde, and as a result, reduces or prevents the fect the condition being treated. When a method is de- alcohol flush reaction. scribed as "consisting essentially of" the listed steps, the 55 method contains the steps listed, and may contain other Definitions steps that do not substantially affect the condition being treated, but the method does not contain any other steps [0070] A subject, individual, or patient is a mammal,

7 13 EP 2 869 717 B1 14 preferably a human. ediamine, and triethylamine salts. Salts of acidic com- [0071] Alcohol as used herein refers to ethanol (ethyl pounds with amino acids, such as lysine salts, can also alcohol), unless another alcohol is explicitly indicated. be prepared. When salts of compounds are used, the [0072] Preventing the alcohol flush reaction is defined weight of the compound(s) used in the compositions and as preventing at least one symptom of the alcohol flush 5 supplements described herein can be adjusted to take reaction, such as facial flushing, dizziness, nausea, in- into account the additional weight contributed due to the creased heart rate, or other symptoms in a subject who salt form. would ordinarily experience such a reaction absent the [0074] By "supplement" is meant a composition that is use of the compositions and methods as described here- taken in addition to the ordinary diet of an individual, sub- in, or of preventing the buildup of acetaldehyde in the 10 ject, or patient. blood subsequent to alcohol consumption, that would oc- cur absent the use of the compositions and methods as Measurement and quantitation of symptoms described herein. Reducing the alcohol flush reaction is defined as reducing the intensity of at least one symptom [0075] The various symptoms of the alcohol flush re- of the alcohol flush reaction, such as facial flushing, diz- 15 action can be self-reported by the subject either qualita- ziness, nausea, increased heart rate, or other symptoms tively (for example, flushing or not flushing) or quantita- in a subject, or of reducing the buildup of acetaldehyde tively (for example, on a scale of one to ten for any of the in the blood subsequent to alcohol consumption, as com- symptoms; hangovers can be measured using standard pared to the intensity of said symptoms in the subject scales used to describe pain in clinical settings, such as absent the use of the compositions and methods de-20 the Wong-Baker FACES Pain Rating Scale or the 0-10 scribed herein. Prevention or reduction of the symptoms Numeric Pain Rating Scale described by McCaffery M. of the alcohol flush reaction can be self-reported by the and Casero, C. in Pain: Clinical Manual, St. Louis: Mosby, subject (that is, subjective), or reported or measured in 1999 at p. 16). The symptoms can also be reported or the subject for symptoms amenable to observation by measured by others, again either qualitatively or quanti- others (that is, objective). 25 tatively. [0073] The compounds described herein can occur [0076] Measurements of skin and facial flushing can and can be used as the neutral (non-salt) compounds; be quantitated using a chromameter (see, for example, however, the description is intended to embrace all salts the studies done in Muizzuddin et al., J. Soc. Cosmet. of the compounds described herein, as well as methods Chem. 41:369-378 (1990) and Alaluf et al., J. Nutr. of using such salts of the compounds. In one embodi- 30 132:399-403 (2002)). Chromameters are commercially ment, the salts of the compounds comprise pharmaceu- available from vendors such as Konica Minolta (CR-400 tically acceptable salts. Pharmaceutically acceptable or CR-410 Chroma Meter) or Gigahertz-Optik (HCT-99D salts are those salts which can be administered as drugs color meter). Typically, baseline readings at one or more or pharmaceuticals to humans and/or animals and which, wavelengths are taken, and the baseline values are sub- upon administration, retain at least some of the biological 35 tracted from subsequent readings. Flushing of the skin, activity of the free compound (neutral compound or non- especially facial flushing, is a very common symptom of salt compound). The desired salt of a basic compound the alcohol flush reaction, and can be measured non- may be prepared by methods known to those of skill in invasively and in a time-dependent manner. the art by treating the compound with an acid. Examples [0077] Blood (plasma or serum) concentrations of of inorganic acids include, but are not limited to, hydro- 40 acetaldehyde can be readily measured using techniques chloric acid, hydrobromic acid, sulfuric acid, nitric acid, known in the art (see, for example, McCarver-May, D. et and phosphoric acid. Examples of organic acids include, al., Journal of Analytical , 21:134 (1997) and but are not limited to, formic acid, acetic acid, propionic Badawy et al., Alcohol and 46:651-660 acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, (2011), which discusses issues in measurement of total malonic acid, succinic acid, fumaric acid, tartaric acid, 45 whole blood acetaldehyde). This provides an objective citric acid, benzoic acid, cinnamic acid, mandelic acid, measurement of acetaldehyde blood levels and can also sulfonic acids, and salicylic acid. Salts of basic com- be determined in a time-dependent manner. pounds with amino acids, such as aspartate salts and glutamate salts, can also be prepared. The desired salt Increase of biomarkers and measurement and quantita- of an acidic compound can be prepared by methods50 tion of biomarkers known to those of skill in the art by treating the compound with a base. Examples of inorganic salts of acid com- [0078] The effects of various agents on the levels of pounds include, but are not limited to, alkali metal and various biomarkers, such as Coenzyme A, glutathione, alkaline earth salts, such as sodium salts, potassium and NAD, can be measured by a variety of techniques. salts, magnesium salts, and calcium salts; ammonium 55 Measurement of biomarker levels can provide an indirect salts; and aluminum salts. Examples of organic salts of measurement of the degree of protection provided by a acid compounds include, but are not limited to, procaine, particular dosage regimen, and/or can guide a subject in dibenzylamine, N-ethylpiperidine, N,N-dibenzylethylen- choice of, or modification of, a dosage regimen. Blood

8 15 EP 2 869 717 B1 16 levels of biomarkers can be measured in whole blood, in prevent or reduce the alcohol flush reaction, by at least plasma, in serum, or in extracts thereof. about 300%. As described herein is a method of raising [0079] NAD concentration can be measured by extrac- RBC NAD concentration, through daily supplementation tion from blood samples, and quantitated by enzymatic to prevent or reduce the alcohol flush reaction, by at least spectrophotometric methods, such as the procedure de- 5 about 100%. As described herein is a method of raising scribed in Majamaa et al., "Increase of Blood NAD+ and RBC NAD concentration, through daily supplementation Attenuation of Lacticacidemia During Nicotinamide to prevent or reduce the alcohol flush reaction, by at least Treatment of a Patient with the MELAS Syndrome," Life about 50%. Increases are measured relative to the levels Sciences, volume 58(8): (1996). of NAD prior to the start of supplementation. [0080] Coenzyme A concentrations can be measured 10 [0087] As described herein is a method of raising blood by Cayman Coenzyme A Assay Kit f (Cayman Chemical glutathione concentration, through daily supplementa- Company, Ann Arbor, Michigan, USA; Item Number tion to prevent or reduce the alcohol flush reaction, by at 700440). Coenzyme A concentrations can be measured least about 1 mmol/L. As described herein is a method in plasma, serum, urine, cell lysates, or tissue homoge- of raising blood glutathione concentration, through daily nates. The compositions described herein may raise15 supplementation to prevent or reduce the alcohol flush measurable blood Coenzyme A concentrations which reaction, by at least about 0.5 mmol/L. As described here- are reflective of intracellular concentrations in erythro- in is a method of raising blood glutathione concentration, cytes, or red blood cells (RBCs). through daily supplementation to prevent or reduce the [0081] Glutathione concentrations can measured by alcohol flush reaction, by at least about 0.25 mmol/L. As High-Performance Liquid Chromatography (HPLC) after 20 described herein is a method of raising blood glutathione blood collection, or by colorimetric methods, such as the concentration, through daily supplementation to prevent 5,5’-dithiobis-2-nitrobenzoic acid assay described in or reduce the alcohol flush reaction, by at least about 0.1 Johnston et al., "Vitamin C Elevates Red Blood Cell Glu- mmol/L. Increases are measured relative to the levels of tathione in Healthy Adults," American Journal of Clinical glutathione prior to the start of supplementation. Nutrition, volume 58(1):103 (1993) and in Beutler et al., 25 [0088] As described herein is a method of raising blood "Improved method for the determination of blood glutath- glutathione concentration, through daily supplementa- ione," J. Lab. Clin. Med. 61:882-888 (1963). tion to prevent or reduce the alcohol flush reaction, by at [0082] All-trans-retinoic acid concentration can be least about 50%. As described herein is a method of rais- measured by High Performance Liquid Chromatography ing blood glutathione concentration, through daily sup- (HPLC) after blood collection by various methods, such 30 plementation to prevent or reduce the alcohol flush re- as those described in De Leenheer et al., "All-trans-retin- action, by at least about 25%. As described herein is a oic acid: measurement of reference values in human se- method of raising blood glutathione concentration, rum by high performance liquid chromatography," Jour- through daily supplementation to prevent or reduce the nal of Lipid Research, 23(9): 1362-1367 (1982). alcohol flush reaction, by at least about 10%. As de- [0083] The compositions described herein may raise 35 scribed herein is a method of raising blood glutathione measurable blood NAD concentration, which is reflective concentration, through daily supplementation to prevent of the intracellular NAD concentration of erythrocytes, or or reduce the alcohol flush reaction, by at least about red blood cells (RBCs). 5%. Increases are measured relative to the levels of glu- [0084] The NAD concentration may be measured by tathione prior to the start of supplementation. extraction from blood samples, and measured by enzy- 40 [0089] As described herein is a method of raising blood matic spectrophotometric methods (Majamaa et al). all-trans retinoic acid concentration, through daily sup- [0085] As described herein is a method of raising RBC plementation to prevent or reduce the alcohol flush re- NAD concentration, through daily supplementation to action, by at least about 2 ng/mL. As described herein is prevent or reduce the alcohol flush reaction, by at least a method of raising blood all-trans retinoic acid concen- about 20 umol/L. As described herein is a method of rais- 45 tration, through daily supplementation to prevent or re- ing RBC NAD concentration, through daily supplemen- duce the alcohol flush reaction, by at least about 1 ng/mL. tation to prevent or reduce the alcohol flush reaction, by As described herein is a method of raising blood all-trans at least about 10 umol/L. As described herein is a method retinoic acid concentration, through daily supplementa- of raising RBC NAD concentration, through daily supple- tion to prevent or reduce the alcohol flush reaction, by at mentation to prevent or reduce the alcohol flush reaction, 50 least about 0.5 ng/mL. As described herein is a method by at least about 4 umol/L. Increases are measured rel- of raising blood all-trans retinoic acid concentration, ative to the levels of NAD prior to the start of supplemen- through daily supplementation to prevent or reduce the tation. alcohol flush reaction, by at least about 0.25 ng/mL. In- [0086] Also described herein is a method of raising creases are measured relative to the levels of all-trans RBC NAD concentration, through daily supplementation 55 retinoic acid prior to the start of supplementation. to prevent or reduce the alcohol flush reaction, by at least [0090] As described herein is a method of raising blood 500%. As described herein is a method of raising RBC all-trans retinoic acid concentration, through daily sup- NAD concentration, through daily supplementation to plementation to prevent or reduce the alcohol flush re-

9 17 EP 2 869 717 B1 18 action, by at least about 75%. As described herein is a ment is about 150 mg. In another embodiment the method of raising blood all-trans retinoic acid concentra- amount of oxaloacetate in the supplement is about 200 tion, through daily supplementation to prevent or reduce mg. the alcohol flush reaction, by at least about 50%. As de- [0097] Agents enhancing glutathione concentration, scribed herein is a method of raising blood all-trans retin- 5 such as N-Acetyl Cysteine: N-Acetyl Cysteine (NAC) is oic acid concentration, through daily supplementation to a preferred agent used to enhance the level of the anti- prevent or reduce the alcohol flush reaction, by at least oxidant glutathione. Other agents that can be used for about 25%. As described herein is a method of raising this purpose include Vitamin C, alpha lipoic acid, L- blood all-trans retinoic acid concentration, through daily cysteine, glutathione, glycine, L-glutamic acid, adenosyl- supplementation to prevent or reduce the alcohol flush 10 methionine, or conjugated linoleic acid. Cysteine is a pre- reaction, by at least about 10%. Increases are measured cursor to glutathione, which can help protect against cel- relative to the levels of all-trans retinoic acid prior to the lular damage. NAC is more bioavailable than L-cysteine start of supplementation. itself and serves multiple purposes. Both NAC as well as glutathione contain sulfur groups that can react directly Ingredients of the anti-alcohol flush reaction supplement 15 with acetaldehyde, clearing it from the cell. Glutathione is an activator of the enzyme ALDH2, increasing the [0091] The combination anti-alcohol flush reaction breakdown of acetaldehyde, as well as an inhibitor of supplementcomprises various ingredients, which arede- ADH, reducing acetaldehyde build-up. Finally, NAC is scribed herein. also a necessary precursor for the compound Coenzyme [0092] Agents enhancing intracellular or intramito-20 A. When acetaldehyde is converted to acetic acid by chondrial concentration of NAD, such as nicotinamide: ALDH2, the acetic acid produced is bound to Coenzyme As mutant ALDH2 has a Michaelis constant K M for NAD A and enters the Citric Acid Cycle to produce energy for about 150 times higher than wild-type, a much higher the cell. Thus, enhancement of Coenzyme A levels is concentration of NAD is required for optimal enzyme ac- advantageous in clearing the acetic acid. Together with tivity. Thus, elevation of the concentration of NAD pro- 25 pantothenic acid, NAC can raise Coenzyme A levels and vides more cofactor for ALDH2, increasing the break- enhance the enzyme kinetics of the ALDH2 reaction. down of acetaldehyde at a corresponding rate, reducing Coenzyme A is also a slight inhibitor of ADH, reducing the level of accumulation. acetaldehyde build-up. [0093] Nicotinamide (niacinamide) is a preferred agent [0098] If N-acetyl cysteine is used, the amount of N- for enhancing intracellular and intramitochondrial NAD 30 acetyl cysteine in the supplement can range from about concentrations. Nicotinamide, or Vitamin B3, is a precur- 10 mg to about 2,000 mg, or from about 50 mg to about sor for NAD. One study indicated that nicotinamide sup- 1000 mg, or from about 100 mg to about 500 mg, or from plementation was responsible for raising NAD concen- about 200mg to about 500 mg, or from about 500mg, to trations 24 fold. The amount of nicotinamide in the sup- about 1000mg. In another embodiment the amount of N- plement can range from about 10 mg to about 2,500 mg, 35 Acetyl Cysteine in the supplement is about 500 mg. In from 500 mg to about 1,500 mg, preferably about 750 another embodiment the amount of N-Acetyl Cysteine in mg to about 1,250 mg, more preferably about 1000 mg the supplement is about 300 mg. In other embodiments, or about 750 mg. the amount of N-acetyl cysteine in the supplement can [0094] If niacin is used as the agent for enhancing NAD range from about 200 mg to about 600 mg, or about 300 concentrations, the amount of niacin in the supplement 40 mg to about 500 mg, or about 400 mg. can range from about 10 mg to 2,500 mg, or from about [0099] If Vitamin C is used, the amount of Vitamin C in 500 mg to 1,500 mg. In another embodiment the amount the supplement can range from about 10 mg to about of niacin in the supplement is about 1000 mg. In another 3,000 mg, or from about 50 mg to about 1000 mg, or from embodiment the amount of niacin in the supplement is about 100 mg to about 500 mg, or from about 200 mg to about 750 mg. 45 about 500 mg, or from about 500 mg to about 2,000 mg. [0095] If nicotinamide riboside is used as the agent for In another embodiment the amount of Vitamin C in the enhancing NAD concentrations, the amount of nicotina- supplement is about 1000 mg. In another embodiment mide riboside in the supplement can range from about the amount of Vitamin C in the supplement is about 150 10 mg to 2,500 mg, or from about 500 mg to 1,500 mg. mg. In another embodiment the amount of Vitamin C in In another embodiment the amount of nicotinamide ribo- 50 the supplement is about 500 mg. side in the supplement is about 1000 mg. In another em- [0100] If alpha lipoic acid is used, the amount of alpha bodiment the amount of nicotinamide riboside in the sup- lipoic acid in the supplement can range from about 10 plement is about 750 mg. mg to about 500 mg, or from about 50 mg to about 300 [0096] If oxaloacetate is used is used as the agent for mg, or from about 100 mg to about 300 mg. In another enhancing NAD concentrations, the amount of oxaloac- 55 embodiment the amount of alpha lipoic acid in the sup- etate in the supplement can range from about 10 mg to plement is about 150 mg. In another embodiment the 1000 mg, or from about 50 mg to 250 mg. In another amount of alpha lipoic acid in the supplement is about embodiment the amount of oxaloacetate in the supple- 250 mg.

10 19 EP 2 869 717 B1 20

[0101] If glutathione is used, the amount of glutathione alpha-lipoic acid, another agent used in the supplement in the supplement can range from about 10 mg to about as a separate ingredient, can also be employed as an 1,500 mg, or from about 100 mg to about 1000 mg, or anti-oxidant. from about 100 mg to about 500 mg. In another embod- [0110] Alpha Lipoic Acid: Alpha Lipoic Acid is an anti- iment the amount of glutathione in the supplement is 5 oxidant, and its use in the supplement helps to maintain about 500 mg. high concentrations of glutathione. This occurs due to [0102] If L-cysteine is used, the amount of L-cysteine regeneration of reduced glutathione. The R-enantiomer in the supplement can range from about 10 mg to about of alpha lipoic acid is used in the supplement 2,000 mg, or from about 50 mg to about 1000 mg, or from (5-[(3R)-dithiolan-3-yl]pentanoic acid). about 100 mg to about 500 mg, or from about 200 mg to 10 [0111] The amount of alpha lipoic acid in the supple- about 500 mg, or from about 500 mg to about 1000 mg. ment can range from about 50 mg to about 250 mg, pref- In another embodiment the amount of L-cysteine in the erably about 100 mg to about 200 mg, more preferably supplement is about 500 mg. In another embodiment the about 150 mg. If alpha lipoic acid is also used as the anti- amount of L-cysteine in the supplement is about 300 mg. oxidant, approximately double this amount is used, that [0103] If glycine is used, the amount of glycine in the 15 is, from about 100 mg to about 500 mg, preferably about supplement can range from about 10 mg to about 2000 200 mg to about 400 mg, more preferably about 300 mg. mg, or from about 50 mg to about 1000 mg, or from about If racemic alpha lipoic acid is used in the supplement, 100 mg to about 500 mg, or from about 200 mg to about the foregoing amounts are doubled, so as to provide the 500 mg, or from about 500 mg to about 1000 mg. In an- specified amount of the R-isomer in the supplement. That other embodiment the amount of glycine in the supple- 20 is, if 300 mg of R-alpha lipoic acid is desired in the sup- ment is about 500 mg. In another embodiment the plement, and the racemic mixture is used to make the amount of glycine in the supplement is about 300 mg. supplement, 600 mg of the racemic mixture is used in [0104] If L-glutamic acid is used, the amount of L- order to provide 300 mg of the R-enantiomer. glutamic acid in the supplement can range from about [0112] Agents enhancing the level of Coenzyme A, 10 mg to about 2,000 mg, or from about 50 mg to about 25 such as pantothenic acid: As described previously, in- 1000 mg, or from about 100 mg to about 500 mg, or from creased Coenzyme A has two functions in lowering blood about 200 mg to about 500 mg, or from about 500 mg to acetaldehyde. Pantothenic acid is a precursor to Coen- about 1000 mg. In another embodiment the amount of zyme A and is a preferred agent for use in the supplement L-glutamic acid in the supplement is about 500mg. In to enhance the levels of Coenzyme A. another embodiment the amount of L-glutamic acid in 30 [0113] The agent capable of raising intracellular Coen- the supplement is about 300mg. zyme A glutathione concentration in the subject can be [0105] If adenosylmethionine (SAMe) is used, the pantothenic acid, pantethine, pantetheine, 4’-phospho- amount of SAMe in the supplement can range from about pantothenate, 4’-phosphopantetheine, N-acetyl- 10 mg to about 500 mg, or from about 50 mg to about cysteine, or L-cysteine. 250 mg. In another embodiment the amount of SAMe in 35 [0114] If pantothenic acid is used (also known as pan- the supplement is about 150 mg. In another embodiment tothenate), the amount of pantothenic acid in the supple- the amount of SAMe in the supplement is about 250 mg. ment can range from about 10 mg to 1000 mg, or from [0106] If conjugated linoleic acid is used, the amount about 100 mg to 500 mg, or from about 50 mg to about of conjugated linoleic acid in the supplement can range 250 mg, or from about 100 mg to about 200 mg, or about from about 10 mg to about 500 mg, or from about 50 mg 40 150 mg. In another embodiment the amount of pan- to about 300 mg, or from about 100 mg to about 300 mg. tothenic acid in the supplement is about 50 mg. In another In another embodiment the amount of conjugated linoleic embodiment the amount of pantothenic acid in the sup- acid in the supplement is about 150 mg. In another em- plement is about 250 mg. bodiment the amount of conjugated linoleic acid in the [0115] If pantethine is used, the amount of pantethine supplement is about 250 mg. 45 in the supplement can range from about 10 mg to about [0107] Anti-oxidants, such as Vitamin C: The supple- 1000 mg, or from about 100 mg to about 500 mg. In an- ment also includes at least one anti-oxidant. Vitamin C other embodiment the amount of pantethine in the sup- is a well-documented anti-oxidant. Supplementation with plement is about 50 mg. In another embodiment the Vitamin C can increase levels of glutathione by 50% in amount of pantethine in the supplement is about 250 mg. only two weeks. In addition, Vitamin C has general pro- 50 [0116] If 4’-phosphopantetheine is used, the amount tective properties as an anti-oxidant, and is relatively safe of 4’-phosphopantetheine in the supplement can range at high doses. from about 10 mg to about 1000 mg, or from about 100 [0108] The amount of Vitamin C in the supplement can mg to about 500 mg. In another embodiment the amount range from about 100 mg to about 500 mg, preferably of 4’-phosphopantetheine in the supplement is about 50 about 200 mg to about 400 mg, more preferably about 55 mg. In another embodiment the amount of 4’-phospho- 300 mg. pantetheine in the supplement is about 250 mg. [0109] Vitamin E or other anti-oxidants can be em- [0117] If 4’-phosphopantothenate is used, the amount ployed instead of or in addition to Vitamin C. Alternatively, of 4’-phosphopantothenate in the supplement can range

11 21 EP 2 869 717 B1 22 from about 10 mg to about 1000 mg, or from about 100 garding this extract is available from the World Health mg to about 500 mg. In another embodiment the amount Organization at URL apps.who.int/medicine- of 4’-phosphopantothenate in the supplement is about docs/pdf/s4927e/s4927e.pdf, pages 300-316. 50 mg. In another embodiment the amount of 4’-phos- [0124] Hovenia dulcis fruit extract. Hovenia dulcis (ori- phopantothenate in the supplement is about 250 mg. 5 ental raisin tree) is a tree found in Asia, over Eastern [0118] If N-acetyl cysteine is used, the amount of N- China, Korea, and in the Himalayan mountains (found at acetyl cysteine in the supplement can range from about altitudes up to 2,000 m). There is evidence that extracts 10mg to about 2,000 mg, or from about 50 mg to about of the Hovenia dulcis fruit are hepatoprotective and can 1000 mg, or from about 100 mg to about 500 mg, or from reduce blood alcohol levels (see Hyun et al., Planta Med- about 200 mg to about 500 mg, or from about 500 mg to 10 ica 76:943-949 (2010) and references therein). The main about 1000 mg. In another embodiment the amount of chemical for this effect inHovenia dulcis is quercetin, N-acetyl cysteine in the supplement is about 500 mg. In which is believed to act as an anti-inflammatory and anti- another embodiment the amount of N-acetyl cysteine in oxidant. Another component ofHovenia dulcis, am- the supplement is about 300 mg. pelopsin (dihydromyricetin), also affects alcohol metab- [0119] If L-cysteine is used, the amount of L-cysteine 15 olism and is discussed in Shen et al., The Journal of in the supplement can range from about 10 mg to about Neuroscience, 32(1): 390-401 (2012). For treating a hu- 2,000 mg, or from about 50 mg to about 1000 mg, or from man patient, a typical daily dose of the above-mentioned about 100 mg to about 500 mg, or from about 200 mg to extract may range from about 0.01 to 10 g/kg body about 500 mg, or from about 500 mg to about 1000 mg. weight, preferably 1 to 5 g/kg body weight. A lower alco- In another embodiment the amount of L-cysteine in the 20 hol-insoluble fraction and the polysaccharide isolated supplement is about 500 mg. In another embodiment the therefrom can be used in tablet or capsule form, or may amount of L-cysteine in the supplement is about 300 mg. be added to food or beverage. The amount of the fraction [0120] Agents enhancing the level of All-Trans Retin- and/or polysaccharide may generally range from about oic Acid: beta-carotene or a retinol ester can be used to 0.1 to 15 w/w %, preferably 1 to 10 w/w % based on the raise concentrations of all-trans retinoic acid in a subject. 25 total weight of food, and 0.1 to 15 g, preferably 1 to 10 g. Examples of esters of retinol that can be used are retinyl arachidonate, retinyl stearate, retinyl oleate, retinyl li- Dosing/administration noleate, retinyl heptadecanoate, retinyl palmitate, retinyl myristate, retinyl laurate, retinyl caprylate, or retinyl ac- [0125] The compositions described herein comprising etate. 30 thesupplement can be administered invarious regimens. [0121] If beta-carotene is used, the amount of beta- The compositions can be administered to a subject prior carotene in the supplement can range from about 100 IU to consumption of alcohol by the subject. The composi- to about 15,000 IU, or from about 1000 IU to about 10,000 tions can be administered to the subject for at least three IU. In another embodiment the amount of beta-carotene days prior to consumption of alcohol by the subject, such in the supplement is about 2.500IU. In another embodi- 35 as periods of at least about seven days, at least about ment the amount of beta-carotene in the supplement is 14 days, at least about a month, or at least about three about 5000 IU. months. [0122] If a retinol ester is used, the amount of retinol [0126] The compositions can be administered in a sin- ester in the supplement can range from about 100 IU to gle daily dose, where the dose contains the entire amount about 15,000 IU, or from about 1000 IU to about 10,000 40 of the composition to be administered on that day. Alter- IU. In another embodiment the amount of retinol ester in natively, the compositions can be administered in multi- the supplement is about 2500 IU. In another embodiment ple divided doses over the course of one day, such that the amount of retinol ester in the supplement is about the multiple doses administered add up to the entire 5000 IU. amount of the composition to be administered on that [0123] Silybum marianum extract. Silybum marianum 45 day. Thus, one-half of the daily dosage can be adminis- (milk thistle) is an annual or biannual plant of the Aster- tered twice a day, one-third of the daily dosage can be aceae family. It has been used as a medicinal plant for administered three times a day, one-fourth of the daily centuries, and its extract is used in medicine under the dosage can be administered four times a day, one-fifth namesilymarin. Milk thistle istypically extracted with 95% of the daily dosage can be administered five times a day, ethanol, which may then be filtered and dried by solvent 50 etcetera. The individual components of the supplement evaporation. The resulting extract typically contains may be administered separately, or in any sub-combina- 1.5-3% flavonolignans (referred to collectively as sily- tion, over the course of the day; for example, the amount marin; the principal components are silybin and isosily- of anti-oxidant and the amount of alpha-lipoic acid can bin), 20-30% fatty acids (including linoleic, oleic, and pal- be administered in the morning, and the amount of the mitic acids), 25-30% proteins, and small amounts of vi- 55 agents capable of increasing intracellular or intramito- tamin E and various sterols. It may be included in the any chondrial concentration of NAD, of increasing glutathione of the compositions as disclosed herein at concentrations concentration, and of increasing Coenzyme A can be ad- between 100-5000 mg/day. Additional information re- ministered in the evening.

12 23 EP 2 869 717 B1 24

Formulations and Routes of Administration (e.g., lecithin), a condensation product of an alkylene ox- ide with a fatty acid (e.g., polyoxyethylene stearate), a [0127] For the purposes of this disclosure, the com- condensation product of ethylene oxide with a long chain pounds may be administered by a variety of means in- aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a cluding orally, parenterally, by inhalation spray, topically, 5 condensation product of ethylene oxide with a partial es- or rectally in formulations containing pharmaceutically ter derived from a fatty acid and a hexitol anhydride (e.g., acceptable carriers, adjuvants and vehicles. The term polyoxyethylene sorbitan monooleate). The aqueous oral as used herein includes, but is not limited to sublin- suspension may also contain one or more preservatives gual and buccal. Oral administration includes fluid drinks, such as ethyl or n-propyl p-hydroxy-benzoate, one or energy bars, as well as pill formulations. Oral adminis- 10 more coloring agents, one or more flavoring agents and tration isadvantageous due to its convenience.However, one or more sweetening agents, such as sucrose or sac- a patient who has consumed a great deal of alcohol may charin. have difficulty in swallowing, or may be unconscious, in [0131] Oil suspensions may be formulated by sus- which case introduction of the supplements by other pending the active ingredient in a vegetable oil, such as means (feeding tube, intravenously, etc.) may be desir- 15 arachis oil, olive oil, sesame oil or coconut oil, or a mineral able. oil such as liquid paraffin. The oral suspensions may con- [0128] Pharmaceutical compositions containing the tain a thickening agent, such as beeswax, hard paraffin active ingredient may be in any form suitable for the in- or cetyl alcohol. Sweetening agents, such as those set tended method of administration. When used for oral use forth above, and flavoring agents may be added to pro- for example, tablets, troches, lozenges, aqueous or oil 20 vide a palatable oral preparation. These compositions suspensions, dispersible powders or granules, emul- may be preserved by the addition of an anti-oxidant such sions, hard or soft capsules, syrups or elixirs may be as ascorbic acid. prepared. Compositions intended for oral use may be [0132] Dispersible powders and granules of the disclo- prepared according to any method known to the art for sure suitable for preparation of an aqueous suspension the manufacture of pharmaceutical compositions and 25 by the addition of water provide the active ingredient in such compositions may contain one or more agents in- admixture with a dispersing or wetting agent, a suspend- cluding sweetening agents, flavoring agents, coloring ing agent, and one or more preservatives. Suitable dis- agents and preserving agents, in order to provide a pal- persing or wetting agents and suspending agents are atable preparation. Tablets containing the active ingre- exemplified by those disclosed above. Additional excip- dient in admixture with non-toxic pharmaceutically ac- 30 ients, for example sweetening, flavoring and coloring ceptable excipient which are suitable for manufacture of agents, may also be present. tablets are acceptable. These excipients may be, for ex- [0133] The pharmaceutical compositions of the disclo- ample, inert diluents, such as calcium or sodium carbon- sure may also be in the form of oil-in-water emulsions. ate, lactose, calcium or sodium phosphate; granulating The oily phase may be a vegetable oil, such as olive oil and disintegrating agents, such as maize starch, or al- 35 or arachis oil, a mineral oil, such as liquid paraffin, or a ginic acid; binding agents, such as starch, gelatin or aca- mixture of these. Suitable emulsifying agents include nat- cia; and lubricating agents; such as magnesium stearate, urally-occurring gums, such as gum acacia and gum tra- stearic acid or talc. Tablets may be uncoated or may be gacanth, naturally occurring phosphatides, such as soy- coated by known techniques including microencapsula- bean lecithin, esters or partial esters derived from fatty tion to delay disintegration and adsorption in the gastroin- 40 acids and hexitol anhydrides, such as sorbitan mo- testinal tract and thereby provide a sustained action over nooleate, and condensation products of these partial es- a longer period. For example, a time delay material such ters with ethylene oxide, such as polyoxyethylene sorb- as glyceryl monostearate or glyceryl distearate alone or itan monooleate. The emulsion may also contain sweet- with a wax may be employed. ening and flavoring agents. [0129] Formulations for oral use may be also present- 45 [0134] Syrups and elixirs may be formulated with ed as hard gelatin capsules where the active ingredient sweetening agents, such as glycerol, sorbitol or sucrose. is mixed with an inert solid diluent, for example calcium Such formulations may also contain a demulcent, a pre- phosphate or kaolin, or as soft gelatin capsules wherein servative, a flavoring or a coloring agent. the active ingredient is mixed with water or an oil medium, [0135] As noted above, formulations of the disclosure such as peanut oil, liquid paraffin or olive oil. 50 suitable for oral administration may be presented as dis- [0130] Aqueous suspensions of the disclosure contain crete units such as capsules, cachets or tablets each the active materials in admixture with excipients suitable containing a predetermined amount of the active ingre- for the manufacture of aqueous-suspensions. Such ex- dient, as a powder or granules; as a solution or a sus- cipients include a suspending agent, such as sodium car- pension in an aqueous or non-aqueous liquid, or as an boxymethylcellulose, methylcellulose, hydroxypropyl55 oil-in-water liquid emulsion or a water-in-oil liquid emul- methylcellulose, sodium alginate, polyvinylpyrrolidone, sion. The active ingredient may also be administered as gum tragacanth and gum acacia, and dispersing or wet- a bolus, electuary or paste. ting agents such as a naturally occurring phosphatide [0136] A tablet may be made by compression or mold-

13 25 EP 2 869 717 B1 26 ing, optionally with one or more accessory ingredients. animal consumption. Compressed tablets may be prepared by compressing [0142] Food products or foodstuffs are for example in a suitable machine the active ingredient in a free flow- beverages such as non-alcoholic drinks as well as liquid ing form such as a powder or granules, optionally mixed preparation to be added to drinking water and liquid food, with a binder (e.g., povidone, gelatin, hydroxypropyl ethyl 5 non-alcoholic drinks are for instance soft drinks, sport cellulose), lubricant, inert diluent, preservative, disinte- drinks, fruit juices, such as for example orange juice, ap- grant (e.g., sodium starch glycolate, cross-linked povi- ple juice and grapefruit juice; lemonades, teas, near-wa- done, cross-linked sodium carboxymethyl cellulose) sur- ter drinks and milk and other dairy drinks such as for face active or dispersing agent. Molded tablets may be example yoghurt drinks, and diet drinks. In another em- made by molding in a suitable machine a mixture of the 10 bodiment food products or foodstuffs refer to solid or powdered compound moistened with an inert liquid dilu- semi-solid foods comprising the composition describd ent. The tablets may optionally be coated or scored and herein. These forms can include, but are not limited to may be formulated so as to provide. slow or controlled baked goods such as cakes and cookies, puddings, dairy release of the active ingredient therein using, for exam- products, confections, snack foods, or frozen confections ple, hydroxypropyl methylcellulose in varying proportions 15 or novelties (e.g., ice cream, milk shakes), prepared fro- to provide the desired release profile. Tablets may op- zen meals, candy, snack products (e.g., chips), liquid tionally be provided with an enteric coating, to provide food such as soups, spreads, sauces, salad dressings, release in parts of the gut other than the stomach. This prepared meat products, cheese, yogurt and any other is particularly advantageous with the compounds of for- fat or oil containing foods, and food ingredients (e.g., mula 1 when such compounds are susceptible to acid 20 wheat flour). hydrolysis. [0143] Animal feed including pet food compositions ad- [0137] Formulations suitable for topical administration vantageously include food intended to supply necessary in the mouth include lozenges comprising the active in- dietary requirements, as well as treats (e.g., dog biscuits) gredient in a flavored base, usually sucrose and acacia or other food supplements. The animal feed comprising or tragacanth; pastilles comprising the active ingredient 25 the composition described herein may be in the form of in an inert base such as gelatin and glycerin, or sucrose a dry composition (for example, kibble), semi-moist com- and acacia; and mouthwashes comprising the active in- position, wet composition, or any mixture thereof. Alter- gredient in a suitable liquid carrier. natively or additionally, the animal feed is a supplement, [0138] Formulations for rectal administration may be such as a gravy, drinking water, yogurt, powder, suspen- presented as a suppository with a suitable base compris- 30 sion,chew, treat (e.g., biscuits) or any otherdelivery form. ing for example cocoa butter or a salicylate. [0144] The term dietary supplement refers to a small [0139] Formulations suitable for vaginal administration amount of a compound for supplementation of a human may be presented as pessaries, tampons, creams, gels, or animal diet packaged in single or multiple dose units. pastes, foams or spray formulations containing in addi- Dietary supplements do not generally provide significant tion to the active ingredient such carriers as are known 35 amounts of calories but may contain other micronutrients in the art to be appropriate. (e.g., vitamins or minerals). The term food products or [0140] As used herein, pharmaceutically acceptable foodstuffs also includes functional foods and prepared salts include, but are not limited to: acetate, pyridine, am- food products pre-packaged for human consumption. monium, piperazine, diethylamine, nicotinamide, formic, [0145] The term nutritional supplement refers to a com- urea, sodium, potassium, calcium, magnesium, zinc, lith- 40 position comprising a dietary supplement in combination ium,cinnamic, methylamino, methanesulfonic,picric, tar- with a source of calories. In some embodiments, nutri- taric, triethylamino, dimethylamino, and tris(hydoxyme- tional supplements are meal replacements or supple- thyl)aminomethane. Additional pharmaceutically accept- ments (e.g., nutrient or energy bars or nutrient beverages able salts are known to those skilled in the art. or concentrates). [0141] The compositions described herein may also 45 [0146] Dietary supplements described herein may be be formulated as nutraceutical compositions. The term delivered in any suitable format. In preferred embodi- "nutraceutical composition" as used herein refers to a ments, dietary supplements are formulated for oral de- food product, foodstuff, dietary supplement, nutritional livery. The ingredients of the dietary supplement de- supplement or a supplement composition for a food prod- scribed herein are contained in acceptable excipients uct or a foodstuff comprising the compositions described 50 and/or carriers for oral consumption. The actual form of herein added exogenously. As used herein, the term food the carrier, and thus, the dietary supplement itself, is not product refers to any food or feed suitable for consump- critical. The carrier may be a liquid, gel, gelcap, capsule, tion by humans or animals. The food product may be a powder, solid tablet (coated or non- coated), tea, or the prepared and packaged food (e.g., mayonnaise, salad like. The dietary supplement is preferably in the form of dressing, bread, grain bar, beverage, etc.) or an animal 55 a tablet or capsule and most preferably in the form of a feed (e.g., extruded and pelleted animal feed, coarse hard (shell) capsule. Suitable excipient and/or carriers mixed feed or pet food composition). As used herein, the include maltodextrin, calcium carbonate, dicalcium phos- term foodstuff refers to any substance fit for human or phate, tricalcium phosphate, microcrystalline cellulose,

14 27 EP 2 869 717 B1 28 dextrose, rice flour, magnesium stearate, stearic acid, is one example of a complex carbohydrate. If it is desired croscarmellose sodium, sodium starch glycolate, that it should maintain its high molecular weight structure, crospovidone, sucrose, vegetable gums, lactose, meth- it should be included only in food formulations or portions ylcellulose, povidone, carboxymethylcellulose, corn thereof which are not cooked or heat processed since starch, and the like (including mixtures thereof). Pre- 5 the heat will break down the complex carbohydrate into ferred carriers include calcium carbonate, magnesium simple carbohydrates, wherein simple carbohydrates are stearate, maltodextrin, and mixtures thereof. The various mono- or disaccharides. The nutritional supplement con- ingredients and the excipient and/or carrier are mixed tains, in one embodiment, combinations of sources of and formed into the desired form using conventional tech- carbohydrate of three levels of chain length (simple, me- niques. The tablet or capsule described herein may be 10 dium and complex; e.g., sucrose, maltodextrins, and un- coated with an enteric coating that dissolves at a pH of cooked cornstarch). about 6.0 to 7.0. A suitable enteric coating that dissolves [0150] Sources of protein to be incorporated into the in the but not in the stomach is cellulose nutritional supplement described herein can be any suit- acetate phthalate. able protein utilized in nutritional formulations and can [0147] In other embodiments, the dietary supplement 15 include whey protein, whey protein concentrate, whey is provided as a powder or liquid suitable for adding by powder, egg, soy flour, soy milk soy protein, soy protein the consumer to a food or beverage. For example, in isolate, caseinate (e.g., sodium caseinate, sodium calci- some embodiments, the dietary supplement can be ad- um caseinate, calcium caseinate, potassium caseinate), ministered to an individual in the form of a powder, for animal and vegetable protein and hydrolysates or mix- instance to be used by mixing into a beverage, or by20 tures thereof. When choosing a protein source, the bio- stirring into a semi-solid food such as a pudding, topping, logical value of the protein should be considered first, sauce, puree, cooked cereal, or salad dressing, for in- with the highest biological values being found in casein- stance, or by otherwise adding to a food or the dietary ate, whey, lactalbumin, egg albumin and whole egg pro- supplement e.g. enclosed in caps of food or beverage teins. In a preferred embodiment, the protein is a com- container for release immediately before consumption. 25 bination of whey protein concentrate and calcium casein- The dietary supplement may comprise one or more inert ate. These proteins have high biological value; that is, ingredients, especially if it is desirable to limit the number they have a high proportion of the essential amino acids. of calories added to the diet by the dietary supplement. See Modern Nutrition in Health and Disease, 8th ed., Lea For example, the dietary supplement described herein & Febiger, 1986, especially Volume 1, pages 30-32. The may also contain optional ingredients including, for ex- 30 nutritional supplement can also contain other ingredi- ample, herbs, vitamins, minerals, enhancers, colorants, ents, such as one or a combination of other vitamins, sweeteners, flavorants, inert ingredients, and the like. minerals, anti-oxidants, fiber and other dietary supple- [0148] In some embodiments, the dietary supplements ments (e.g., protein, amino acids, choline, lecithin). Se- further comprise additional vitamins and minerals includ- lection of one or several of these ingredients is a matter ing, but not limited to, calcium phosphate or acetate, tri- 35 of formulation, design, consumer preferences and end- basic; potassium phosphate, dibasic; magnesium sulfate user. The amounts of these ingredients added to the di- or oxide; salt (sodium chloride); potassium chloride or etary supplements described herein are readily known acetate; ascorbic acid; ferric orthophosphate; zinc sulfate to the skilled artisan. Guidance to such amounts can be or oxide; copper gluconate; ; beta-carotene; py- provided by the U.S. RDA doses for children and adults. ridoxine hydrochloride; thiamin mononitrate; folic acid; 40 Further vitamins and minerals that can be added include, ; chromium chloride or picolonate; potassium io- but are not limited to, calcium phosphate or acetate, tri- dide; sodium selenate; sodium molybdate; phylloqui- basic; potassium phosphate, dibasic; magnesium sulfate none; vitamin D3; ; sodium selenite; or oxide; salt (sodium chloride); potassium chloride or copper sulfate; vitamin A; vitamin C; inositol; potassium acetate; ascorbic acid; ferric orthophosphate; niacina- iodide. Suitable dosages for vitamins and minerals may 45 mide; zinc sulfate or oxide; calcium pantothenate; copper be obtained, for example, by consulting the U.S. RDA gluconate; riboflavin; beta-carotene; hydro- guidelines and the disclosure herein. chloride; thiamin mononitrate; folic acid; biotin; chromium [0149] Asdescribed hereinare nutritional supplements chloride or picolonate; potassium iodide; sodium selena- (e.g., energy bars or meal replacement bars or beverag- te; sodium molybdate; phylloquinone; vitamin D3 ; cy- es) comprising the composition as described herein. The 50 anocobalamin; sodium selenite; copper sulfate; vitamin nutritional supplement may serve as meal or snack re- A; vitamin C; inositol; potassium iodide. placement and generally provide nutrient calories. Pref- [0151] The nutritional supplement can be provided in erably, the nutritional supplements provide carbohy- a variety of forms, and by a variety of production methods. drates, proteins, and fats in balanced amounts. The nu- For example, to manufacture a food bar, the liquid ingre- tritional supplement can further comprise carbohydrate, 55 dients are cooked; the dry ingredients are added with the simple, medium chain length, or polysaccharides, or a liquid ingredients in a mixer and mixed until the dough combination thereof. A simple sugar can be chosen for phase is reached; the dough is put into an extruder, and desirable organoleptic properties. Uncooked cornstarch extruded; the extruded dough is cut into appropriate

15 29 EP 2 869 717 B1 30 lengths; and the product is cooled. The bars may contain a variety of materials such as glass or plastic. The con- other nutrients and fillers to enhance taste, in addition to tainers can hold one or more of the individual ingredients. the ingredients specifically listed herein. The label on the container indicates that the kit is used [0152] It is understood by those of skill in the art that for prevention or reduction of one or more symptoms as- other ingredients can be added to those described here- 5 sociated with the alcohol flush reaction. in, for example, fillers, emulsifiers, preservatives, etc. for the processing or manufacture of a nutritional supple- EXAMPLES ment. [0153] Additionally, flavors, coloring agents, spices, Example 1 nuts and the like may be incorporated into the nutraceu- 10 tical composition. Flavorings can be in the form of fla- Supplement Formulations vored extracts, volatile oils, chocolate flavorings, peanut butter flavoring, cookie crumbs, crisp rice, vanilla or any [0158] The supplement can be prepared with the fol- commercially available flavoring. Examples of useful fla- lowing amounts of individual components: voring include, but are not limited to, pure anise extract, 15 imitation banana extract, imitation cherry extract, choc- Formulation A: olate extract, pure lemon extract, pure orange extract, pure peppermint extract, imitation pineapple extract, im- Nicotinamide: 1000 mg itation rum extract, imitation strawberry extract, or pure N Acetyl Cysteine: 400 mg vanilla extract; or volatile oils, such as balm oil, bay oil, 20 Vitamin C: 300 mg bergamot oil, cedarwood oil, walnut oil, cherry oil, cinna- Alpha-Lipoic Acid: 150 mg mon oil, clove oil, or peppermint oil; peanut butter, choc- Pantothenic Acid: 150 mg olate flavoring, vanilla cookie crumb, butterscotch or tof- fee. In one embodiment, the dietary supplement contains Formulation B: cocoa or chocolate. 25 [0154] Emulsifiers may be added for stability of the nu- Nicotinamide: 800 mg traceutical compositions. Examples of suitable emulsifi- N Acetyl Cysteine: 300 mg ers include, but are not limited to, lecithin (e.g., from egg Vitamin C: 150 mg or soy), and/or mono- and di- glycerides. Other emulsi- Alpha-Lipoic Acid: 100 mg fiers are readily apparent to the skilled artisan and selec- 30 Pantothenic Acid: 100 mg tion of suitable emulsifier(s) will depend, in part, upon the formulation and final product. Preservatives may also be Formulation C: added to the nutritional supplement to extend product shelf life. Preferably, preservatives such as potassium Nicotinamide: 700 mg sorbate, sodium sorbate, potassium benzoate, sodium 35 N Acetyl Cysteine: 300 mg benzoate or calcium disodium EDTA are used. Vitamin C: 150 mg [0155] In addition to the carbohydrates described Pantothenic Acid: 100 mg above, the nutraceutical composition can contain natural Vitamin A: 2500 IU or artificial (preferably low calorie) sweeteners, e.g., sac- Thiamine: 50mg charides, cyclamates, aspartamine, aspartame, acesul- 40 fame K, and/or sorbitol. Such artificial sweeteners can Formulation D: be desirable if the nutritional supplement is intended to be consumed by an overweight or obese individual, or N Acetyl Cysteine: 300 mg an individual with type II diabetes who is prone to hyper- Nicotinamide: 700 mg glycemia. 45 Pantothenic Acid: 100 mg [0156] In addition to the preparations described above, standardpharmaceutical preparations, suchas those de- Reference Example 2 scribed in Remington: The Science and Practice of Phar- macy (22nd Edition, Pharmaceutical Press, 2012 and Demonstration of Efficacy of Combination Anti-Alcohol 21st Edition, Pharmaceutical Press, 2011), can be used. 50 Flush Reaction Supplement Therapy

Kits [0159] The efficacy of the combination anti-alcohol flush reaction supplement (hereafter "supplement") is [0157] Also described herein are articles of manufac- demonstrated in the following manner. A double blind ture and kits containing the compositions described here- 55 supplement trial is conducted where subjects take the in. The article of manufacture comprises a container with supplement (or placebo) once daily for three weeks. Ei- a label. Suitable containers include, for example, bottles, ther Formulation A or Formulation B of Example 1 is used vials, and test tubes. The containers may be formed from with all subjects. Subjects provide informed consent for

16 31 EP 2 869 717 B1 32 participation in accordance with all laws and regulations, Example 3 and all policies of the institution where the study is con- ducted. The age of subjects is verified to ensure that they Demonstration of Efficacy of Combination Anti-Alcohol are of legal age to consume alcohol in the jurisdiction Flush Reaction Supplement Therapy where the study takes place (typically, age 21 years or 5 older in the United States). Subjects that qualify under [0162] The efficacy of the combination anti-alcohol the inclusion criteria of the study come in for a first visit, flush reaction supplement (hereafter "supplement") is where their health and ability to participate in the study demonstrated in the following manner. A double blind are assessed by the staff. At this initial visit, subjects first supplement trial is conducted where subjects take the have their blood acetaldehyde level measured before 10 supplement (or placebo) once daily for 30 days. One drinking any alcohol. Subjects then consume two stand- group will not supplement for 30 days and will take a ard alcoholic drinks. Three more blood tests for acetal- single dose prior to consuming alcohol. Either Formula- dehyde after alcoholic beverage consumption are con- tion C or Formulation D of Example 1 is used with all ducted at time points of 15 minutes, 45 minutes and 90 subjects. Subjects provide informed consent for partici- minutes after finishing the drinks. Each patient must have 15 pation in accordance with all laws and regulations, and suitable transportation to and from the research facility all policies of the institution where the study is conducted. in order to avoid driving while under the influence of al- The age of subjects is verified to ensure that they are of cohol. Patient privacy and confidentiality is maintained legal age to consume alcohol in the jurisdiction where according to law and regulation. Patients can also fill out the study takes place (typically, age 21 years or older in questionnaires indicating the degree to which they expe- 20 the United States). Subjects that qualify under the inclu- rience facial flushing, dizziness, nausea, headache, stu- sion criteria of the study come in for a first visit, where por, or increased heart rate at the same time points at their health and ability to participate in the study are as- which the blood tests are conducted. The degree of facial sessed by the staff. At this initial visit there will be samples flushing can also be reported by the staff (either by visual taken for a PCR genotyping to confirm that all subjects observation or by measurement with a chromameter), 25 with self-reported facial flushing when drinking, are het- and heart rate can be monitored. erozygous for the ALDH2 mutation. If they do possess [0160] Subjects commence taking supplement (or pla- this mutation and pass the inclusion criteria, they will visit cebo) daily for three weeks, starting the day after the the facility for a 2nd visit. At this 2nd visit, subjects first initial visit. The double-blind trial utilizes three groups: have their blood acetaldehyde level measured before one group consisting of individuals with ALDH2 deficien- 30 drinking any alcohol. Subjects then consume 0.3g/Kg cy who take the supplement, one group of individuals bodyweight of ethanol. Three more bloodtests for acetal- without the deficiency (that is, they do not demonstrate dehyde after ethanol consumption are conducted imme- the alcohol flush reaction) who take the supplement, and diately after drinking, and at two more time points, each a third group of individuals who do have ALDH2 deficien- with 20 minutes of separation. At each of these time cy, but who take a placebo. 35 points there will be measurements for heart rate and skin [0161] The subjects visit the research facility again temperature. Each patient must have suitable transpor- three weeks later.The same steps are performed as were tation to and from the research facility in order to avoid conducted during the initial visit of the subjects. Again, driving while under the influence of alcohol. Patient pri- subjects have a blood test to determine acetaldehyde vacy and confidentiality is maintained according to law levels, consume two alcoholic drinks, and have three 40 and regulation. Patients can also fill out questionnaires more blood tests at time points of 15 minutes, 45 minutes indicating the degree to which they experience facial and 90 minutes after finishing the drinks in order to meas- flushing, dizziness, nausea, headache, stupor, or in- ure the levels of acetaldehyde in the blood. Patients can creased heart rate at the same time points at which the also fill out questionnaires indicating the degree to which blood tests are conducted. The degree of facial flushing they experience facial flushing, dizziness, nausea, or in- 45 can also be reported by the staff (either by visual obser- creased heart rate at the same time points at which the vation or by measurement with a chromameter), as well blood tests are conducted. The degree of facial flushing as self-reported by the subject. can also be reported by the staff (using the same method- [0163] Subjects commence taking supplement (or pla- either by visual observation or by measurement with a cebo) daily for 30 days, starting the day after the initial chromameter-as used previously), and heart rate can be 50 visit. The double-blind trial utilizes 4 groups: one group monitored. The data is compared between visits one and consisting of individuals with ALDH2 deficiency who take two to demonstrate the effects of the supplement in pre- the supplement for 30 days (formulation C), one group venting accumulation of acetaldehyde. of individuals with the ALDH2 deficiency who take a sub- set of the supplement for 30 days (formulation D), one 55 group of individuals with the ALDH2 deficiency, but who take a placebo for 30 days, and one group of individuals with the ALDH2 deficiency who do NOT supplement for 30 days, but take a single dose of the supplement (for-

17 33 EP 2 869 717 B1 34 mulation C) at the third visit. redness, heart rate, self-evaluated body temperature, [0164] The subjects visit the research facility again for headache, nausea, and general physical discomfort. a 3rd visit 30 days later. The same steps are performed These are symptoms of the alcohol flush reaction that as were conducted during the 2 nd visit, with one addition. have all been directly linked with an increase in blood Again, subjects have a blood test to determine acetalde- 5 acetaldehyde. hyde levels. All subjects (except placebo) will then con- [0168] Subject 1 (male) took a supplement containing sume one dosage, 20 minutes prior to consuming alco- 500 mg of N-Acetyl Cysteine, 500 mg Vitamin C and 1000 hol. Subjects will then consume 0.3g/Kg body weight of mg nicotinamide. After the supplementation period, upon ethanol. Three more blood tests for acetaldehyde after consumption of alcohol, subject 1 experienced immedi- ethanol consumption are conducted immediately after 10 ately noticeable reduction in facial redness, headache, drinking, and at two more time points, each with 20 min- and body temperature from what the subject typically pre- utes of separation. At each of these time points there will viously experienced in response to the same amount of be measurements for heart rate and skin temperature. alcohol consumption. Patients can also fill out questionnaires indicating the de- [0169] Subject 2 (female) and Subject 3 (male) took a gree to which they experience facial flushing, dizziness, 15 supplement containing 500 mg of N-Acetyl Cysteine, 100 nausea, or increased heart rate at the same time points mg pantothenic acid, 500 mg Vitamin C, and 1000 mg at which the blood tests are conducted. The degree of nicotinamide. Upon consumption of alcohol, Subject 2 facial flushing can also be reported by the staff (using displayed a significant reduction in both physical discom- the same method-either by visual observation or by fort and headache. Subject 3 displayed mild reductions measurement with a chromameter-as used previously), 20 in all assessments for the alcohol flush reaction. and can also be self-reported by the subject. The data is [0170] Subject 4 (male) took a supplement containing compared between visits two and three to demonstrate only with 1500 mg nicotinamide. The subject reported the effects of the supplement in preventing accumulation reductions in facial redness and heart rate. of acetaldehyde, relevant to the placebo group. [0171] Subject 5 (female), Subject6 (female), and Sub- 25 ject 7 (male) took a supplement containing 500 mg N- Reference Example 4 Acetyl Cysteine, 100 mg Pantothenic acid, 500 mg Vita- min C, 1000 mg nicotinamide and 150 mg Alpha Lipoic Additional Demonstration of Efficacy of Combination An- Acid. Subject 5 displayed mild reductions in all alcohol ti-Alcohol Flush Reaction Supplement Therapy flush reaction assessments, with a significant reduction 30 in heart rate. Subject 6 displayed a significant reduction [0165] The efficacy of the combination anti-alcohol in heart rate and headache, and a reduction in physical flush reaction supplement (hereafter "supplement") can discomfort and facial flushing. Subject 7 displayed dra- also be demonstrated in a double blind trial, where sub- matic decreases in heart rate, nausea, physical discom- jects take the supplement (or placebo) twice daily for fort, and body temperature, and a mild reduction in facial three weeks. Formulation A, Formulation B, Formulation 35 redness. C, or Formulation D of Example 1 is used with all subjects. [0172] Subject 8 (female) took a supplement contain- Other than the twice-daily administration of supplement ing 2500 IU Vitamin A, 700 mg Nicotinamide, 25 mg pan- (or placebo), the trial is carried out as described in Ref- tothenic acid, 150 mg Vitamin C, 125 mg Alpha Lipoic erence Example 2. Acid, 300 mg N-Acetyl Cysteine, and 10 mg Thiamine. 40 Subject 8 displayed dramatic reductions in all assess- Reference Example 5 ments for the alcohol flush reaction, with zero displayed facial redness. Studies in Individuals of Efficacy of Combination Anti- [0173] Subject 9 (female), Subject 10 (female), and Alcohol Flush Reaction Supplement Therapy Subject 11 (male) took a supplement containing 2500 IU 45 Vitamin A, 700mg Nicotinamide, 50 mg Pantothenic acid, [0166] In order to evaluate the efficacy of certain sup- 150 mg Vitamin C, 80 mg Alpha Lipoic Acid, 300 mg N- plements, as described herein, subjects took various Acetyl Cysteine, and 50 mg Thiamine. Subject 11 did not forms of the supplements daily for two weeks. The sub- display reductions in any assessments. Subject 9 dis- jects then consumed two standard alcohol beverages played a dramatic reduction in heart rate, and mild re- and their symptoms were evaluated. One hour prior to 50 ductions in facial redness, body temperature, headache, drinking the alcohol beverages, the subjects also con- nausea, and physical discomfort. Subject 10 displayed sumed another dose of the formulation. Overt physical significant reductions in all assessments. symptoms and self-reported physical symptoms were [0174] Different individuals display varying degrees of used as assessments for the alcohol flush reaction. severity for the symptoms of the alcohol flush reaction. These experimental tests include eleven subjects. All ex- 55 This suggests that at a given concentration of acetalde- perimental subjects were unpaid volunteers who experi- hyde in the blood, individuals experience varying inten- ence all symptoms of the alcohol flush reaction. sities of the alcohol flush reaction symptoms assessed [0167] The following symptoms were assessed: facial in these experiments. This is confirmed by the experi-

18 35 EP 2 869 717 B1 36 mental results, in that 10 out of 11 individuals displayed comprising the step of administering to the subject reductions in at least one symptom, although the symp- a dosage of a composition according to any one of toms varied. The results suggest that various supple- (1)-(11), or use of any composition according to ments, as described herein, reduce acetaldehyde in the (1)-(11) for preventing or reducing at least one symp- blood, and individuals respond differently to that reduc- 5 tom of the alcohol flush reaction in a subject. tion. The most consistently reduced symptom was heart (13). The method or use of (12), wherein the dosage rate. is administered to the subject daily, either in a single [0175] Also described herein are: dose per day, or in multiple divided doses per day. (14). The method or use of (12) or (13), wherein the (1). A composition for use by a subject to prevent or 10 composition is administered to the subject for at least reduce the alcohol flush reaction, said composition seven days prior to consumption of alcohol by the comprising: subject. (15). The method or use of any of (12)-(14), wherein a) an agent capable of increasing intracellular the at least one symptom is selected from the group or intramitochondrial concentration of NAD in 15 consisting of facial flushing, hangover, dizziness, the subject; nausea, increased blood acetaldehyde concentra- b) an agent capable of increasing glutathione tion, and increased heart rate. concentration in the subject; (16). The method or use of any of (12)-(15), wherein c) an agent which is an anti-oxidant; the at least one symptom is facial flushing. d) an agent which is alpha-lipoic acid or a pre- 20 (17). The method or use of any of (12)-(15), wherein cursor to alpha-lipoic acid; and the at least one symptom is hangover. e) an agent capable of increasing the level of (18). The method or use of any of (12)-(15), wherein Coenzyme A in the subject; the at least one symptom is increased blood acetal- dehyde concentration. wherein said agents are present in the composition 25 (19). The method or use of any of (12)-(15), wherein in an amount effective to prevent or reduce the al- the at least one symptom is increased heart rate. cohol flush reaction in the subject. (20). The method or use of any of (12)-(15), wherein (2). The composition of (1), wherein the agent capa- the at least one symptom is nausea. ble of increasing intracellular or intramitochondrial (21). The method or use of any of (12)-(15), wherein concentration of NAD in the subject is nicotinamide. 30 the at least one symptom is dizziness. (3). The composition of (2), wherein the amount of (22). The composition of any of (1)-(11) for use in nicotinamide in the dosage is between about 500 mg preventing or reducing at least one symptom of the to about 1,500 mg. alcohol flush reaction in a subject. (4). The composition of any of (1)-(3), wherein the (23). Use of a composition of any of (1)-(11) for the agent capable of increasing glutathione concentra- 35 manufacture of a supplement or medicament for use tion in the subject is N-acetyl cysteine. in preventing or reducing at least one symptom of (5). The composition of (4), wherein the amount of the alcohol flush reaction in a subject. N-acetyl cysteine in the dosage is between about (24). A composition comprising: 200 mg to about 600 mg. (6). The composition of any of (1)-(5), wherein the 40 a) an agent capable of increasing intracellular anti-oxidant is Vitamin C. or intramitochondrial concentration of NAD in a (7). The composition of (6), wherein the amount of subject; and Vitamin C in the dosage is between about 100 mg b) an agent capable of increasing glutathione to about 500 mg. concentration in the subject. (8). The composition of any of (1)-(7), wherein the 45 amount of alpha lipoic acid in the dosage is between (25). The composition of (24), wherein said agents about 50 mg to about 250 mg. are present in the composition in an amount effective (9). The composition of any of (1)-(8), wherein the to prevent or reduce the alcohol flush reaction in the agent capable of increasing the level of Coenzyme subject. A in the subject is pantothenic acid. 50 (26). The composition of (24) or (25), further com- (10). The composition of (9), wherein the amount of prising at least one additional agent selected from pantothenic acid in the dosage is about 50 mg to the group comprising: an agent which is an anti-ox- about 250 mg. idant; an agent which is alpha-lipoic acid or a pre- (11). The composition of any of (1)-(9), further com- cursor to alpha-lipoic acid; and an agent capable of prising an agent capable of raising the blood con- 55 increasing the level of Coenzyme A in the subject. centration of all-trans retinoic acid in a subject. (27). A composition comprising: (12). A method of preventing or reducing at least one symptom of the alcohol flush reaction in a subject, a) an agent capable of increasing intracellular

19 37 EP 2 869 717 B1 38

or intramitochondrial concentration of NAD in a Coenzyme A in the subject. subject; b) an agent capable of increasing glutathione (33). The composition of any of (24)-(32), wherein concentration in the subject; and said agents are present in the composition in an c) an anti-oxidant. 5 amount effective to prevent or reduce the alcohol flush reaction in the subject. (28). A composition comprising: (34). A composition for use by a subject to prevent or reduce the alcohol flush reaction, said composi- a) an agent capable of increasing intracellular tion comprising: or intramitochondrial concentration of NAD in a 10 subject; a) an agent capable of increasing intracellular b) an agent capable of increasing glutathione or intramitochondrial concentration of NAD in concentration in the subject; and the subject; c) alpha-lipoic acid or a precursor to alpha-lipoic b) an agent capable of increasing glutathione acid. 15 concentration in the subject; c) an agent which is an anti-oxidant; and (29). A composition comprising: d) an agent which is alpha-lipoic acid or a pre- cursor to alpha-lipoic acid; and a) an agent capable of increasing intracellular e) an agent capable of increasing the level of or intramitochondrial concentration of NAD in a 20 Coenzyme A in the subject. subject; b) an agent capable of increasing glutathione (35). The composition of any of (24)-(33) or the com- concentration in the subject; and position for use of (34), wherein said agents are c) an agent capable of increasing the level of present in the composition in an amount effective to Coenzyme A in the subject. 25 prevent or reduce the alcohol flush reaction in a sub- ject. (30). A composition comprising: (36). The composition for use of any of (1)-(11) or (34), further comprising an agent capable of raising a) an agent capable of increasing intracellular the blood level of all-trans retinoic acid. or intramitochondrial concentration of NAD in a 30 (37). The composition of any of (24)-(33), further subject; comprising an agent capable of raising the blood lev- b) an agent capable of increasing glutathione el of all-trans retinoic acid. concentration in the subject; (38). The method or use of any of (12)-(23), wherein c) an anti-oxidant; and the composition, supplement, or medicament further d) alpha-lipoic acid or a precursor to alpha-lipoic 35 comprises an agent capable of raising the blood level acid. of all-trans retinoic acid. (39). A composition comprising: a) an agent selected (31). A composition comprising: from the group consisting of nicotinamide, nicotina- mide riboside, niacin, and oxaloacetate; and b) an a) an agent capable of increasing intracellular 40 agent selected from the group consisting of N-acetyl- or intramitochondrial concentration of NAD in a cysteine, Vitamin C, alpha lipoic acid, L-cysteine, subject; glutathione, glycine, L-glutamic acid, adenosylme- b) an agent capable of increasing glutathione thionine, and conjugated linoleic acid; wherein said concentration in the subject; agents are present in the composition in an amount c) an anti-oxidant; and 45 sufficient to prevent or reduce the alcohol flush re- d) an agent capable of increasing the level of action in the subject. Coenzyme A in the subject. (40). The composition of (39), further comprising an agent selected from the group consisting of pan- (32). A composition comprising: tothenic acid, pantethine, pantetheine, 4’-phospho- 50 pantothenate, and 4’-phosphopantetheine. a) an agent capable of increasing intracellular (41). The composition of (39) or (40), further com- or intramitochondrial concentration of NAD in a prising an agent which is selected from the group subject; consisting of Vitamin C, Vitamin E, and alpha-lipoic b) an agent capable of increasing glutathione acid. concentration in the subject; 55 (42). The composition of (39) or (40), further com- c) alpha-lipoic acid or a precursor to alpha-lipoic prising alpha-lipoic acid or a precursor to alpha-lipoic acid; and acid. d) an agent capable of increasing the level of (43). The composition of any one of (39)-(42), further

20 39 EP 2 869 717 B1 40 comprising an agent selected from the group con- (54). Any of the compositions, compositions for use, sisting of beta-carotene and a retinol ester. or methods of (1)-(50), wherein the composition, (44). The composition of (43), wherein the agent is supplement, dosage, or medicament is provided in a retinol ester selected from the group consisiting of a food. retinyl arachidonate, retinyl stearate, retinyl oleate, 5 retinyl linoleate, retinyl heptadecanoate, retinyl [0176] Although the foregoing invention has been de- palmitate, retinyl myristate, retinyl laurate, retinyl scribed in some detail by way of illustration and example caprylate, and retinyl acetate. for purposes of clarity of understanding, it is apparent to (45). A composition comprising an agent capable of those skilled in the art that certain changes and modifi- increasing intracellular or intramitochondrial con- 10 cations will be practiced. centration of NAD in a subject; and Hovenia dulcis fruit extract. (46). A composition comprising an agent capable of Claims increasing intracellular or intramitochondrial con- centration of NAD in a subject; andSilybum mari- 15 1. A composition for use by a subject to prevent or re- anum extract. duce the alcohol flush reaction, said composition (47). A composition comprising an agent capable of comprising: increasing intracellular or intramitochondrial con- centration of NAD in a subject; Hovenia dulcis fruit (a) an agent selected from nicotinamide, nicoti- extract; and Silybum marianum extract. 20 namide riboside, niacin, and oxaloacetate; and (48). A composition comprising: a) an agent selected (b) an agent selected from N-acetyl-cysteine, Vi- from the group consisting of nicotinamide, nicotina- tamin C, alpha lipoic acid, L-cysteine, glutath- mide riboside, niacin, and oxaloacetate; and b) one ione, glycine, L-glutamic acid, adenosylmethio- or more, and preferably, 3, 4, 5 or more, agents se- nine, and conjugated linoleic acid; and lected from the group consisting of Hovenia dulcis 25 (c) an agent selected from pantothenic acid, fruit extract, Silybum marianum extract, N-acetyl- pantethine, pantetheine, 4’-phosphopantothen- cysteine, Vitamin C, alpha lipoic acid, L-cysteine, ate, and 4’-phosphopantetheine; glutathione, glycine, L-glutamic acid, adenosylme- thionine, and conjugated linoleic acid; wherein said wherein the composition is administered daily for at agents are present in the composition in an amount 30 least 30 days prior to consumption of alcohol by the sufficient to prevent or reduce the alcohol flush re- subject; action in the subject. wherein said agents are present in the composition (49). A composition comprising: a) an agent selected in an amount sufficient to prevent or reduce the al- from the group consisting of nicotinamide, nicotina- cohol flush reaction in the subject. mide riboside, niacin, and oxaloacetate; b) Hovenia 35 dulcis fruit extract; c) Silybum marianum extract; and 2. A composition for use according to claim 1, further d) α-lipoic acid; wherein said agents are present in comprising an agent which is selected from Vitamin the composition in an amount sufficient to prevent C, Vitamin E, and alpha-lipoic acid. or reduce the alcohol flush reaction in the subject. (50). A composition comprising: a) an agent selected 40 3. A composition for use according to claim 1 or 2, fur- from the group consisting of nicotinamide, nicotina- ther comprising alpha-lipoic acid. mide riboside, niacin, and oxaloacetate; b) Hovenia dulcis fruit extract; c) Silybum marianum extract; d) 4. A composition for use according to any one of claims vitamin A; e) vitamin B5; f) vitamin c; g) N-acetyl 1 to 3, further comprising an agent selected from cysteine; h) thiamine; and i) α-lipoic acid; wherein 45 beta-carotene and a retinol ester. said agents are present in the composition in an amount sufficient to prevent or reduce the alcohol 5. A composition for use according to claim 4, wherein flush reaction in the subject. the agent is a retinol ester selected from retinyl ara- (51). A composition as described herein in (45)-(50), chidonate, retinyl stearate, retinyl oleate, retinyl li- comprising at least 500 mg niacinamide. 50 noleate, retinyl heptadecanoate, retinyl palmitate, (52). Any of the compositions, compositions for use, retinyl myristate, retinyl laurate, retinyl caprylate, and or methods of (1)-(50), wherein the composition, retinyl acetate. supplement, dosage, or medicament is in tablet or capsule form. 6. A composition for use according to claim 4, wherein (53). Any of the compositions, compositions for use, 55 the agent is beta-carotene. or methods of (1)-(50), wherein the composition, supplement, dosage, or medicament is in liquid or 7. A composition for use according to any one of claims beverage form. 1 to 6, further comprising thiamine.

21 41 EP 2 869 717 B1 42

8. A composition for use according to claim 1, compris- Patentansprüche ing: 1. Zusammensetzung zur Verwendung von einem In- (i) between 300 mg and 1.5 g nicotinamide, dividuum zur Vorbeugung oder Verringerung von Al- (ii) between 10 mg and 500 mg pantothenic acid 5 koholintoleranz, wobei die Zusammensetzung Fol- or a salt thereof, and gendes umfasst: (iii) between 100 mg and 600 mg N-acetyl- cysteine, (a) ein Mittel, das aus Nicotinamid, Nicotinami- dribosid, Niacin und Oxaloacetat ausgewählt ist; and an excipient acceptable for daily oral adminis- 10 und tration. (b) ein Mittel, das aus N-Acetylcystein, Vitamin C, α-Liponsäure, L-Cystein, Glutathion, Glycin, 9. A composition for use according to claim 8, further L-Glutaminsäure, Adenosylmethionin und kon- comprising vitamin C in an amount between 100 mg jugierter Linolsäure ausgewählt ist; und and 500 mg. 15 (c) ein Mittel, das aus Pantothensäure, Pante- thin, Pantethein, 4’-Phosphopantothenat und 4’- 10. A composition for use according to claim 8 or 9, fur- Phosphopantethein ausgewählt ist; ther comprising alpha-lipoic acid in an amount be- tween 50 mg and 250 mg. wobei die Zusammensetzung täglich für zumindest 20 30 Tage vor der Konsumation von Alkohol durch das 11. A composition for use according to any one of claims Individuum verabreicht wird; 8 to 10, further comprising beta-carotene in an wobei die Mittel in der Zusammensetzung in einer amount between 100 IU and 15000 IU. Menge vorhanden sind, die ausreicht, um die Alko- holintoleranzreaktion beim Individuum zu verhin- 12. A composition for use according to any one of claims 25 dern oder zu verringern. 8 to 11, further comprising thiamine. 2. Zusammensetzung zur Verwendung nach Anspruch 13. A composition for use according to any one of claims 1, die weiters ein Mittel umfasst, das aus Vitamin C, 8 to 11, further comprising thiamine in an amount Vitamin E und α-Liponsäure ausgewählt ist. between 2.5 mg and 10 mg. 30 3. Zusammensetzung zur Verwendung nach Anspruch 14. A composition for use according to claim 8, further 1 oder 2, das weiters α-Liponsäure umfasst. comprising one or more of vitamin A, vitamin C, thi- amine, and α-lipoic acid. 4. Zusammensetzungzur Verwendung nach einemder 35 Ansprüche 1 bis 3, das weiters ein Mittel umfasst, 15. A composition for use according to claim 8, further das aus β-Carotin und einem Retinolester ausge- comprising one or more of: wählt ist.

1250 IU to 2500 IU vitamin A, 5. Zusammensetzung zur Verwendung nach Anspruch 75 mg to 150 mg vitamin C, 40 4, wobei das Mittel ein Retinolester ist, der aus Re- 2.5 to 10 mg thiamine, and tinylarachidonat, Retinylstearat, Retinyloleat, Reti- 62 to 125 mg α-lipoic acid. nyllinoleat, Retinylheptadecanoat, Retinylpalmitat, Retinylmyristat, Retinyllaurat, Retinylcaprylat und 16. A composition for use according to claim 14 or 15, Retinylacetat ausgewählt ist. comprising each of vitamin A, vitamin C, thiamine, 45 and α-lipoic acid. 6. Zusammensetzung zur Verwendung nach Anspruch 4, wobei das Mittel β-Carotin ist. 17. A composition for use of any one of claims 1 to 16, wherein the composition is provided as a tablet or a 7. Zusammensetzungzur Verwendung nach einemder capsule. 50 Ansprüche 1 bis 6, das weiters Thiamin umfasst.

18. A composition for use of any one of claims 1 to 16, 8. Zusammensetzung zur Verwendung nach Anspruch wherein the composition is provided in a food or in 1, die Folgendes umfasst: a beverage. 55 (i) zwischen 300 mg und 1,5 g Nicotinamid, (ii) zwischen 10 mg und 500 mg Pantothensäure oder ein Salz davon und (iii) zwischen 100 mg und 600 mg N-Acetylcy-

22 43 EP 2 869 717 B1 44

stein (a) un agent choisi parmi le nicotinamide, le ni- cotinamide riboside, la niacine et und einen zur täglichen oralen Verabreichung ge- l’oxaloacétate ; et eigneten Exzipienten. (b) un agent choisi parmi la N-acétyl-cystéine, 5 la vitamine C, l’acide alpha lipoïque, la L-cystéi- 9. Zusammensetzung zur Verwendung nach Anspruch ne, la glutathione, la glycine, l’acide L-glutami- 8, die weiters Vitamin C in einer Menge zwischen que, l’adénosylméthionine et l’acide linoléique 100 mg und 500 mg umfasst. conjugué ; et (c) un agent choisi parmi l’acide pantothénique, 10. Zusammensetzung zur Verwendung nach Anspruch 10 la pantéthine, la pantéthéine, le 4’-phosphopan- 8 oder 9, die weiters α-Liponsäure in einer Menge tothénate et la 4’-phosphopantéthéine ; zwischen 50 mg und 250 mg umfasst dans laquelle la composition est administrée quoti- 11. Zusammensetzung zurVerwendung nacheinem der diennement pendant au moins 30 jours avant la con- Ansprüche 8 bis 10, die weitersβ -Carotin in einer 15 sommation d’alcool par le sujet ; Menge zwischen 100 IU und 15000 IU umfasst. dans laquelle lesdits agents sont présents dans la composition en une quantité suffisante pour prévenir 12. Zusammensetzung zurVerwendung nacheinem der ou réduire les bouffées associées à la consomma- Ansprüche 8 bis 11, die weiters Thiamin umfasst. tion d’alcool chez le sujet. 20 13. Zusammensetzung zurVerwendung nacheinem der 2. Composition pour une utilisation selon la revendica- Ansprüche 8 bis 11, die weiters Thiamin in einer tion 1, comprenant en outre un agent qui est choisi Menge zwischen 2,5 mg und 10 mg umfasst. parmi la vitamine C, la vitamine E et l’acide alpha- lipoïque. 14. Zusammensetzung zur Verwendung nach Anspruch 25 8, die weiters eines oder mehrere aus Vitamin A, 3. Composition pour une utilisation selon la revendica- Vitamin C, Thiamin und a-Liponsäure umfasst. tion 1 ou 2, comprenant en outre de l’acide alpha- lipoïque. 15. Zusammensetzung zur Verwendung nach Anspruch 8, die weiters eines oder mehrere aus Folgenden 30 4. Composition pour une utilisation selon l’une quel- umfasst: conque des revendications 1 à 3, comprenant en outre un agent choisi parmi le bêta-carotène et un 1250 IU bis 2500 IU Vitamin A, ester de rétinol. 75 mg bis 150 mg Vitamin C, 2,5 bis 10 mg Thiamin und 35 5. Composition pour une utilisation selon la revendica- 62 bis 125 mg α-Liponsäure. tion 4, dans laquelle l’agent est un ester de rétinol choisi parmi l’arachidonate de rétinyle, le stéarate 16. Zusammensetzung zur Verwendung nach Anspruch de rétinyle, l’oléate de rétinyle, le linoléate de rétiny- 14 oder 15, die jedes aus Vitamin A, Vitamin C, Thi- le, l’heptadécanoate de rétinyle, le palmitate de ré- amin und a-Liponsäure umfasst. 40 tinyle, le myristate de rétinyle, le laurate de rétinyle, le caprylate de rétinyle et l’acétate de rétinyle. 17. Zusammensetzung zurVerwendung nacheinem der Ansprüche 1 bis 16, wobei die Zusammensetzung 6. Composition pour une utilisation selon la revendica- als Tablette oder Kapsel bereitgestellt ist. tion 4, dans laquelle l’agent est le bêta-carotène. 45 18. Zusammensetzung zurVerwendung nacheinem der 7. Composition pour une utilisation selon l’une quel- Ansprüche 1 bis 16, wobei die Zusammensetzung conque des revendications 1 à 6, comprenant en in einem Nahrungsmittel oder Getränk bereitgestellt outre de la thiamine. ist. 50 8. Composition pour une utilisation selon la revendica- tion 1, comprenant : Revendications (i) entre 300 mg et 1,5 g de nicotinamide, 1. Composition pour une utilisation par un sujet pour (ii) entre 10 mg et 500 mg d’acide pantothénique prévenir ou réduire les bouffées associées à la con- 55 ou d’un sel de celui-ci, et sommation d’alcool, ladite composition (iii) entre 100 mg et 600 mg de N-acétylcystéine, comprenant : et un excipient acceptable pour une administration

23 45 EP 2 869 717 B1 46

orale quotidienne.

9. Composition pour une utilisation selon la revendica- tion 8, comprenant en outre de la vitamine C en une quantité entre 100 mg et 500 mg. 5

10. Composition pour une utilisation selon la revendica- tion 8 ou 9, comprenant en outre de l’acide alpha- lipoïque en une quantité entre 50 mg et 250 mg. 10 11. Composition pour une utilisation selon l’une quel- conque des revendications 8 à 10, comprenant en outre du bêta-carotène en une quantité entre 100 UI et 15 000 UI. 15 12. Composition pour une utilisation selon l’une quel- conque des revendications 8 à 11, comprenant en outre de la thiamine.

13. Composition pour une utilisation selon l’une quel- 20 conque des revendications 8 à 11, comprenant en outre de la thiamine en une quantité entre 2,5 mg et 10 mg.

14. Composition pour une utilisation selon la revendica- 25 tion 8, comprenant en outre un ou plusieurs de la vitamine A, de la vitamine C, de la thiamine et d’un acide α-lipoïque.

15. Composition pour une utilisation selon la revendica- 30 tion 8, comprenant en outre un ou plusieurs de :

1 250 UI à 2 500 UI de vitamine A, 75 mg à 150 mg de vitamine C, 2,5 à 10 mg de thiamine, et 35 62 à 125 mg d’acide α-lipoïque.

16. Composition pour une utilisation selon la revendica- tion 14 ou 15, comprenant chacune de la vitamine A, de la vitamine C, de la thiamine et un acideα - 40 lipoïque.

17. Composition pour une utilisation selon l’une quel- conque des revendications 1 à 16, dans laquelle la composition se présente sous la forme d’un compri- 45 mé ou d’une capsule.

18. Composition pour une utilisation selon l’une quel- conque des revendications 1 à 16, dans laquelle la composition se présente dans un aliment ou dans 50 une boisson.

55

24 EP 2 869 717 B1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• WO 2012120036 A1, Gerdes Roman [0007] • WO 2012027603 A2 [0014] • US 8377907 B1, Halamicek III, William A [0008] • US 2007202215 A1, Lak, Z. S. [0016] • WO 2007017139 A1 [0013] • US 2001033881 A1, Fuchs [0017]

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