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WO2015071373A1 - Formulations comprenant de la s-adénosylméthionine, de la quercétine et de la glycyrrhizine pour la santé du foie - Google Patents

Formulations comprenant de la s-adénosylméthionine, de la quercétine et de la glycyrrhizine pour la santé du foie Download PDF

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WO2015071373A1
WO2015071373A1 PCT/EP2014/074521 EP2014074521W WO2015071373A1 WO 2015071373 A1 WO2015071373 A1 WO 2015071373A1 EP 2014074521 W EP2014074521 W EP 2014074521W WO 2015071373 A1 WO2015071373 A1 WO 2015071373A1
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composition
glycyrrhizin
liver
quercetin
anyone
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Caroline GREMILLET
Rosita GARCIA
Emmanuelle LEMAIRE
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Ceva Sante Animale
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof

Definitions

  • the present invention relates to the field of therapeutic compositions for the treatment, protection, and repair of hepatic tissue in humans and other animals. More specifically, the compositions of the invention comprise S-adenosylmethionine, quercetin; and glycyrrhizin.
  • the mammalian liver is comprised of four lobes. It is the both the largest endocrine gland in the body and the largest internal organ. There are two major types of cells present in the liver: (1) hepatocytes (parenchymal); and (2) non-parenchymal cells.
  • the l i v e r exhibits over five hundred essential physiological functions.
  • hepatocytes perform the majority of these tasks, with non-parenchymal cells contributing ancillary functions.
  • the liver has a dedicated vascular system, containing mainly of the hepatic artery and the portal vein.
  • the hepatic artery carries oxygenated blood to the liver from the heart.
  • the portal vein also supplies oxygenated blood, but additionally carries venous blood from the spleen and pancreas.
  • Both the hepatic artery and the portal vein form a large capillary matrix throughout the liver. This prodigious network ensures the effective oxygenation of cells and greater surface area for the exchange of various metabolites, nutrients, and hormones between the liver and the circulatory system.
  • the liver utilizes the portal vein system to process and distribute its various metabolic products, hormones, and digested nutrients from the gastrointestinal tract.
  • the portal vein and its circulatory elements are thus one of the primary points of entry into the general circulatory system of the body.
  • the liver is particularly susceptible to any ingested drugs or toxins.
  • drugs and toxins arrive in a completely undiluted form from the gastrointestinal tract, such that liver cells are maximally exposed.
  • Ethyl alcohol, a toxin is metabolized by hepatocytes, and can cause significant damage over time by inducing steatosis, alcoholic hepatitis, and cirrhosis. Even initially nontoxic compounds can cause devastating cytotoxicity in hepatocytes once they are activated by metabolic processes in the liver.
  • One such drug, acetaminophen is highly therapeutic as an analgesic and antipyretic.
  • liver tissue originates from blood-borne pathogens like bacteria or viruses, such as hepatitis A through E.
  • liver damage include necrosis, degeneration of functional activity, fibrosis, and inflammation. Because the l ive r is at significant risk of damage from its unshielded exposure to various cytotoxic elements, it has a high level of regenerative capacity. While the complete loss of a lobe is permanent, other lobes in the liver can compensate through enlargement. As little as 25% of a complete liver can regenerate and become fully functional. Nevertheless, progressive damage to the liver tissue beyond a certain threshold will be irreversible and life-threatening, leaving liver transplantation as the sole remedy.
  • Treatment options for most forms of liver damage are limited to symptomatic relief because the only permanent cure for such conditions is the regeneration of healthy hepatocytes.
  • diuretics are used to combat tissue edema
  • white anti-encephalopathic drugs are used to clear the build-up of toxins.
  • Such drugs can be used to mitigate the harmful effects of liver damage, though they generally produce unintended side effects and may become toxic to the liver itself if taken at high enough concentrations.
  • Treatments by antiviral compounds for hepatitis treat the cause of the liver damage, but are also highly cytotoxic. Drugs like interferon and ribavarin can cause anemia, hemolysis, and clinical depression.
  • the composition contains S-adenosylmethionine, quercetin, and glycyrrhizin (and/or salts thereof).
  • the preferred salt of glycyrrhizine is glycyrrhizinate ammonium.
  • the S-adenosylmethionine is preferably present at about 0.5% to about 53% by weight of the total composition, more preferably about 4% to about 25%.
  • Quercetin is preferably present at about 1% to 50% by weight of the total composition, more preferably about 1% to about 5%.
  • Glycyrrhizinine is preferably present at about 0.05% to 10% by weight of the total composition, more preferably about 0.40% to about 1.60%.
  • FIG. 1 shows the molecular structure of S-adenosylmethionine.
  • FIG. 2 shows the S-adenosylmethionine cycle in the body.
  • FIG. 3 shows the major metabolic pathways of S-adenosylmethionine in the body.
  • FIG. 4 shows the molecular structure of quercetin.
  • FIG. 5 shows the molecular structure of glycyrrhizinate ammonium.
  • the invention contemplated relates to novel compositions containing of S- adenosylmethionine, quercetin, and glycyrrhizin (and/or salts thereof), and to the use of that composition for the maintenance of health in a subject, more specifically maintenance, protection, treatment, and regeneration of liver tissue.
  • the invention relates to a composition for use in the treatment of a liver disorder or condition.
  • Active compounds may include other biologically active substances, such as vitamins, minerals, amino acids, and combinations thereof.
  • Inactive compounds may be, for example, excipients that are commonly used in pharmaceuticals and nutraceuticals, as well as physiologically inert additives that make the embodiment more palatable for oral administration, improving its taste or smell.
  • SAMe S-adenosylmethionine
  • FIG.l S-adenosylmethionine
  • SAMe Upon donation of its methyl group in a number of enzymatic processes, SAMe is converted to S-adenosyl homocysteine ("SAH"). SAH is then hydrolyzed into homocysteine and adenosine by SAH hydrolase.
  • SAH S-adenosyl homocysteine
  • SAMe participates as a cosubstrate in a number of biochemical reactions, functioning primarily in the transfer of methyl groups.
  • the chemically reactive region of SAMe is found at the methyl group attached to the sulfur atom of methionine. This methyl group can be donated in a transmethylation reaction to a variety of substrates, as discussed above.
  • SAMe is also responsible for the glutathione pathway, in that one of the products of the SAMe cycle, homocysteine may be co-opted by cystathionine ⁇ -synthase and cystathionine ⁇ -lyase to form cysteine.
  • the cysteine is converted to glutathione through the actions of glutamate cysteine ligase and glutathionine synthetase.
  • Glutathione acts as an endogenous antioxidant, quenching reactive oxygen species produced during enzymatic reactions, such as ethanol oxidation in the liver.
  • liver conditions include, but are not limited to, cholestatic disorders, hepatic steatosis, viral hepatitis, chronic active hepatitis, primary or secondary cirrhosis, and chronic or acute liver toxicity linked to ingestion or medicinal side effects.
  • cholestatic disorders While there are a myriad of agents and pathogens responsible for liver damage, ethanol is the best understood, and is therefore used as a representative example. Ethanol is able to affect the liver in a variety of ways. Other toxins and pathogens modulate similar oxidative damage pathways. Thus, an examination of the effects of ethanol on liver function is highly instructive in providing background on common pathogenic pathways for liver damage.
  • Ethanol absorbed into the circulatory system is cleared from the body by the liver.
  • Hepatocytes in the liver use a number of enzymatic reactions to convert ethanol into carbon dioxide and water.
  • the primary system for ethanol clearance operates in the cytoplasm of hepatocytes.
  • the enzyme alcohol dehydrogenase
  • Acetalaldehyde is a highly reactive oxygen species that must be quenched by an antioxidant, like glutathione. Prolonged exposure to reactive oxygen species can cause injury to DNA and mitochondria in surrounding tissue, leading to liver damage.
  • glutathione and other antioxidants are essential in limiting damage prior to acetalaldehyde's oxidation.
  • the enzyme aldehyde dehydrogenase, is responsible for converting acetalaldehyde into acetic acid.
  • the next step in ethanol oxidation is the conversion of acetic acid into acetyl-CoA, a core element of the citric acid cycle.
  • the enzyme responsible is known as acetyl-coenzyme A synthetase.
  • acetyl-CoA Once acetyl-CoA enters the citric acid cycle, it is facile ly converted into inert carbon dioxide and water. Ethanol can also be processed in the liver via the microsomal ethanol oxidizing system (hereinafter, the "MEO system"). This system utilizes the cytochrome P450 enzyme, CYP2E 1, and related enzymes.
  • the MEO system generally functions as a back-up to the alcohol dehydrogenase, and is usually triggered by the chronic use of alcohol that overwhelms it.
  • the MEO system is localized to microsomes formed from the smooth endoplasmic reticulum of hepatocytes. Similar to the alcohol dehydrogenase pathway, the MEO system produces acetalaldehyde, which is then introduced into the original metabolic pathway. Unlike the primary alcohol dehydrogenase system, the MEO system is a redox reaction that requires cofactor NADPH. As a redox reaction, the MEO system utilizes oxygen to oxidize ethanol, resulting in the production of free radicals and reactive oxygen species like superoxide, in addition to acetalaldehyde.
  • the CYP2E1 enzyme is involved in the gluconeogenesis, fatty acid oxidation, and detoxification of xenobiotics. Activation of its expression in response to excess ethanol results in an up- regulation of all of these processes. Overproduction of glucose and fatty acid oxidation leads to fatty acid disease and steatohepatitis in the liver. Leiber, Drug Metab. Rev. 36(3-4):51 1-529, (Oct. 2004). Thus, it is clear that ethanol has numerous pathways by which to damage liver tissue.
  • SAMe deficiency has been shown to cause a wide variety of diseases, including colon cancer, breast cancer, coronary disease, pathologic brain function, and liver disease. Loenen et al., Biochem. Society Transactions 34(2):330-333, 332 (2006).
  • SAMe is necessary to ensure that there is sufficient glutathione to quench any free radicals present in the liver tissue.
  • the primary reactive oxygen species formed during ethanol oxidation is acetalaldehyde.
  • the MEO system is activated as well, resulting in a proliferation of free radicals like superoxide, hydrogen peroxide, and hydroxyl, as well as overly active fatty acid synthesis.
  • SAMe has a number of beneficial effects in hepatocytes that combat these acute negative effects of ethanol and other toxins.
  • Studies in rats have shown that administration of SAMe has a restorative effect on hepatic levels of the antioxidant, glutathione.
  • cirrhosis was artificially induced in the rats. Some were administered SAMe for an extended period of time, while others received no treatment.
  • the study determined that administration of SAMe in the rats reduced liver injury, attenuated fibrosis and fibrogenesis in the liver. Further, rats that were administered SAMe concurrently with the cirrhosis-inducing agent were less likely to develop cirrhosis.
  • SAMe produced both a preventative as well as a restorative effect on fibrosis and cirrhosis of the liver.
  • SAMe which was converted to glutathione in vivo, acted to prevent lipid peroxidation, one of leading causes of fibrosis and eventual cirrhosis in the liver.
  • SAMe prevents apoptosis and can provide time for hepatocytes to regenerate and prevent more serious liver problems. Gasso et al, J. Hepatology 25:200-205, 203-204 (1996).
  • SAMe also has the additional benefit of preventing the build-up of reactive oxygen species and free radicals from bath alcohol dehydrogenase and the MEO system from damaging mitochondria in hepatocytes.
  • SAMe was shown to attenuate damage from superoxides to the mitochondrial electron chain as well as to mitochondrial DNA.
  • Quercetin (FIG. 4) is a naturally occurring flavonoid (polyphenol) that is also biosynthesized in humans and other animals. It is found in a number of dietary sources, including tomatoes, red onions, kale, and cranberries.
  • Quercetin is synthesized from the commonly ingested amino acid, phenylalanine, through a series of enzymatic reactions. As a polyphenol, quercetin operates as an antioxidant, neutralizing free radicals and reactive oxygen species that can harm cellular membranes and DNA. Quercetin has also been shown to inhibit the release of cytokines by cells in vitro, thereby mitigating inflammation. Other beneficial effects of quercetin include induction of apoptotic pathways in cancerous cells and the prevention of 1 ipid peroxidation in cell membranes. The antioxidant properties of quercetin are meditated through its ability to quench superoxide and nitric oxide reactive oxygen species in the liver.
  • quercetin In addition to directly neutralizing reactive oxygen species in rats, quercetin is demonstrated to inhibit nuclear transcription factor NF- ⁇ activation. By preventing this nuclear factor from initiating gene activation, quercertin is responsible for limiting the production of downstream nitric oxide gene products that form reactive oxygen species. Thus, quercetin operates by two independent pathways. It actively quenches reactive oxygen species and free radicals, while also preventing the expression of genes that would result in the production of additional free radicals. Dias et al, J. Nutr. 135:2299-2304, 2303 (2005). Quercetin has also been demonstrated to have protective and ameliorative effects on liver cells exposed to ethanol.
  • quercetin treatment prior to ethanol ingestion was found to increase the endogenous production of the antioxidant, glutathione, in liver tissue, as well as operating directly as an antioxidant on the lipid peroxides produced through the normal ethanol metabolism.
  • the quercetin administered thus reduced cellular damage by removing reactive oxygen species via two separate mechanisms.
  • Mouse hepatic cells treated with quercetin prior to the introduction of ethanol also maintained higher levels of intracellular glutathione, such that these hepatocytes could withstand greater oxidative stress from toxins. Molina et al., Biol. Pharm. Bull. 26(10), 1398-1402, 1399- 1401 (2003). Quercetin's anti-inflammatory properties are also well documented.
  • adducts As discussed above, the breakdown of toxins like ethanol results in the formation of reactive oxygen species like acetal aldehyde. In addition to direct intracellular damage, failure to quench these species can result in their binding to intracellular proteins, forming adducts. These adducts, when released into plasma, are not recognized by immune cells. The immune cells initiate the release of cytokines and other pro-inflammatory compounds in a misguided attempt to instigate an immune response to the area. This immune response results in pervasive damage to liver tissue and the eventual fibrosis. A major trigger of inflammation is nuclear factor NF-KB, which starts a downstream cascade that releases pro-inflammatory cytokines and reactive nitric oxide species.
  • nuclear factor NF-KB nuclear factor NF-KB
  • nitric oxide synthase NOS
  • NOS nitric oxide synthase
  • quercetin can reduce the inflammatory response in liver tissue, even after it has been initiated.
  • Yet another documented pharmacologic effect of quercetin is the ability of its 3-O-galactoside, hyperoside, to inhibit key viral proteins, HBeAg and HBsAg, associated with hepatitis B. In this manner, quercetin's metabolites have the potential to act against viral infections in the liver. Acta Pharmacol. Sin. 28(3):404-409, 408 (Mar. 2007).
  • Glycyrrhizinate ammonium (FIG. 5) is the water-soluble salt of glycyrrhizin (glycyrrhizinic acid) which is primarily found in licorice root.
  • glycyrrhizinate ammonium, glycyrrhizin, and glycyrrhizinic acid are used interchangeably, except for dosage guidelines, which are specific to glycyrrhizinate ammonium.
  • Glycyrrhizin or any other salt thereof can be provided in an amount equivalent to the amount glycyrrhizinate ammonium.
  • Glycyrrhizin can be found in licorice products worldwide.
  • glycyrrhizin is typically extracted from licorice root, for example by solvent extraction. Tian et al, Int. J. Mol. Sci. 9:571-577 (2008). A typical licorice root extract contains about 3% to about 5% glycyrrhizin by weight. Isbrucker et al, Regul Toxicol Pharmacol. 46(3): 167-92 (2006). Glycyrrhizin is also used as an artificial sweetener internationally, because it is many times sweeter than sucrose. The compound contemplated in this composition could also include artificially synthesized glycyrrhizin.
  • glycyrrhizin is found to operate as an anti-inflammatory agent, an antioxidant, and an anti-viral agent.
  • mice hepatocytes in vivo it has been shown to be more effective than the widely used silymarin in protecting hepatocytes from oxidative injury which generally occurs from exposure to toxins like ethanol.
  • glycyrrhizin attenuated the release of alanine aminotransferase and aspartate aminotransferase, two clinically significant enzymes released by hepatocytes in response to acute injury. This reduction in the release of these enzymes is indicative of the protective effects of glycyrrhizin on hepatocytes.
  • the glycyrrhizin treatment increased IFN- ⁇ and decreased the IL-4 cytokine, which is responsible for the production of naive CD4 T-cells that are responsible for inflammation. Rather, by inducing production of IFN- ⁇ , glycyrrhizin increased the T-cell differentiation and maturation, stimulating the adaptive immune system while heading off its innate inflammatory response. Li et al., Int. J. Mol. Sci. 12:905-916, 912 (201 1). Glycyrrhizin's anti-inflammatory effects are mediated through a number of pathways. One of these pathways is directed through the selectin receptors found on lymphocytes and endothelial cells.
  • Selectin receptors are translocated to the cell membrane in response to inflammatory cytokines. Glycyrrhizin is shown to block binding to selectin receptors, resulting in anti-inflammatory activity. Narasinga et al., J. Biol. Chem. 269(31): 19663- 19666, 19665 (1994). Glycyrrhizin has also been demonstrated to act as an antiinflammatory agent via other pro-inflammatory surface receptors. By blocking the NF-KB pathway as well as the pro-inflammatory Toll-Like Receptors TLR3 and TLR4 on the cell surface, glycyrrhizin has broad anti-inflammatory activity through its interaction with the membranes of affected cells. Schrofelbauer et al., Biochem. J. 421 :473-482, 480 (2009).
  • glycyrrhizin can act as an antiviral agent against hepatitis C.
  • the study was based on past findings of glycyrrhizin's antiviral abilities. In previous studies, it had been shown to stimulate production of antiviral interferon in vivo, as well as inhibiting NF- ⁇ and inducing IL-8 secretion. This study demonstrated the glycyrrhizin's ability to directly inhibit expression of the viral core protein, leading to a viral inhibition rates as high as 85%. Ashfaq et al, J. Trans. Med. 9: 112 (2011).
  • the compounds in the presently claimed invention demonstrate antioxidant properties, anti-inflammatory properties, anti-fatty acid properties, and antiviral properties.
  • S-adenosylmethionine acts an antioxidant, quenching free radicals and reactive species in hepatocytes. It has also been shown to prevent lipid peroxidation, which can lead to excessive build-ups of fatty acids in liver cells, resulting in the fatty acid disease that accompanies many liver conditions.
  • S-adenosylmethionine acts indirectly to increase intracellular glutathione, providing an additional antioxidant supply to combat future oxidative damage.
  • Quercetin is demonstrated ta increase the endogenous production of the antioxidant, glutathione, in liver tissue, as well as operating directly as an antioxidant on the lipid peroxides produced through the normal ethanol metabolism. Further, quercetin is shown to act as an anti-inflammatory agent, attenuating the release of pro-inflammatory cytokines and nitric oxide species through its inhibition of transcriptional factor, NF- ⁇ . Quercetin is also shown to act as an antiviral agent, inhibiting key proteins associated with hepatitis B. In combination, S-adenosylmethionine and quercetin thus produce beneficial effects for a number of liver conditions. Adding glycyrrhizin to the combination treats an even broader range of liver diseases.
  • glycyrrhizin has a number of beneficial properties. It is an antioxidant, an anti-inflammatory, a stimulant of adaptive immunity, and has been shown to exhibit antiviral properties against key viral proteins in hepatitis C. Similarly to the other compounds in the composition, glycyrrhizin mediates these actions through a variety of pathways. Thus, the combination of all three compounds in the composition acts synergistically to treat, protect, and repair the liver. This synergistic effect is further enhanced because the complementary actions of the compounds allow for a lower effective dose of the composition. Administration of a lower effective dose is economically favorable while also minimizing any possible side effects.
  • composition claimed contemplates a composition containing of S- adenosylmethionine, quercetin, and glycyrrhizinate ammonium, with additional compounds including (1) n-acetyl cysteine; (2) 1-taurine; (3) zinc ascorbate; (4) vitamin E; (5) vitamin B6; and (6) any other B vitamins.
  • additional compounds including (1) n-acetyl cysteine; (2) 1-taurine; (3) zinc ascorbate; (4) vitamin E; (5) vitamin B6; and (6) any other B vitamins.
  • Other embodiments of the invention can include any combination of the foregoing compounds in a composition containing of S- adenosylmethionine, quercetin, and glycyrrhizinate ammonium.
  • compositions of the present invention can be administered orally, parenterally, transdermally, sublingually, intravenously, intramuscularly, rectally, and subcutaneously.
  • the foregoing methods are by no means the only vehicles for administration of the invention. Other conventionally accepted methods of administration will occur to those skilled in the art, and these may be used as well.
  • the preferred route of administration is oral.
  • Preferred daily doses of the compounds in the composition are as follows:
  • More preferable daily per kilogram dosage range for all species 2mg/kg- 30mg/kg
  • Preferred small domestic animal dose range 1 mg/kg- 60mg/kg
  • Preferred human dose range 3mg/kg- 30mg/kg
  • Preferred livestock dose range 1 mg/kg- 30mglkg
  • More preferable daily per kilogram dosage range for all species 0.5 mg/kg- 50 mg/kg
  • Preferred small animal dose range 2 mg/kg- 25 mg/kg
  • Preferred human dose range 2 mg/kg- 25 mg/kg
  • Preferred livestock dose range 2 mg/kg- 25 mg/kg Glycyrrhizinate ammonium:
  • Preferred small animal dose range 0.5 mg/kg- 4.0 mg/kg
  • Preferred human dose range 0.2 mg/kg-2.0 mg/kg
  • Preferred livestock dose range 0.1 mg/kg- 4.0 mg/kg
  • the dosages for glycyrrhizin or its other salts can be provided in amounts equivalent to the dosages for glycyrrhizinate ammonium given above.
  • composition of the present invention can be formulated into a dosage form convenient for administration.
  • Dosage forms appropriate for the present invention include, but are not limited to: tablets, capsules (swallowed and chewable), powders, granulate, solutions, and suspensions.
  • the composition may also be provided as a kit or blister pack, in which the various components are separately provided for coadministration.
  • the invention provides a kit comprising a composition as defined in the present invention and a package leaflet or user instructions including the information that said composition is to be used for maintaining liver health in a mammal, preferably in a dog or a cat.
  • the components are mixed together prior to administration or are co-administered at the time of use.
  • the dosage of the composition may be administered in various combinations in which the components may be present in a single dosage form or in more than one dosage form. Accordingly, the doses may be administered in combinations of more than one dosage form, such that each dosage form contains at least one component or in which two or more components are combined into a single dosage form.
  • the kit or composition of the invention can more specifically allow a single dose or more of S- adenosylmethionine that provides from 1 mg/kg to about 1 00 mg/kg, a single dose or more of quercetin provides from about 0.5 mg/kg to about 100 mg/kg, and/or a single dose or more of glycyrrhizin and/or salts thereof provides an amount equivalent to about 0.1 mg/kg to about 5 mg/kg of glycyrrhizinate ammonium.
  • Oral dosage forms are preferred.
  • each dose preferably contains about 0.5 to about 53%, more preferably about 4 to about 24% S-adenosylmethionine; about 1% to about 50%, more preferably about 1% to about 5% mg quercetin; and about 0.05% to about 10%, more preferably about 0.40% to about 1.60% glycyrrhizinate ammonium.
  • the daily dose of the composition can vary in a large extent depending on the condition of the subject to be treated. According to specific embodiments, the daily dose of the composition is about 1.6 mg/kg to about 205 mg/kg.
  • compositions and treatment methods of the invention are useful in fields of veterinary medicine and human medicine.
  • the subject for administration is a mammal, such as a human or other mammalian animal.
  • subjects include for example, livestock (farm animals) including cows, sheep, pigs, horses and goats; companion animals such as dogs and cats, exotic and/or zoo animals; laboratory animals including mice rats, rabbits, guinea pigs and hamsters; and poultry such as chickens, turkeys, ducks and geese, which may also be considered livestock.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne le domaine de compositions thérapeutiques destinées au traitement, à la protection et à la réparation d'un tissu hépatique chez l'homme ou d'autres animaux. Plus particulièrement, les compositions de l'invention comprennent de la S-adénosylméthionine, de la quercétine, et de la glycyrrhizine.
PCT/EP2014/074521 2013-11-13 2014-11-13 Formulations comprenant de la s-adénosylméthionine, de la quercétine et de la glycyrrhizine pour la santé du foie WO2015071373A1 (fr)

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WO2023212233A1 (fr) * 2022-04-27 2023-11-02 Mars, Incorporated Composition d'aliment pour animaux comprenant une source de glycyrrhizine

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WO2023212233A1 (fr) * 2022-04-27 2023-11-02 Mars, Incorporated Composition d'aliment pour animaux comprenant une source de glycyrrhizine

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