Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Conjugate or complex
Reexamination Certificate
2000-02-02
2001-04-24
Lilling, Herbert J. (Department: 1651)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Conjugate or complex
C514S783000
Reexamination Certificate
active
06221358
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method for lowering blood alcohol concentration by administering an extract of
Rhus verniciflua
to human, thereby resolving hangover, and preventing or treating alcoholic gastritis and alcohol-induced liver damage.
BACKGROUND OF THE INVENTION
Pharmaceutically useful compounds may be obtained from
Rhus verniciflua
which has been traditionally used in Korea, Japan and China in making a lacquer paint. For example, fisetin, fustin and other compounds have been found in the aqueous extract of the xylem of
Rhus verniciflua
(Hasegawa, M. and T. Shirato,
J. Chem. Soc
., 72, 223 (1951)). Fisetin and fustin have pharmacological activity in: protecting blood vessel and capillary (Beretz, A. and Cazenave, J. P., “The Effect of Flavonoids on Blood Vessel Wall Interactions” in
Plant Flavonoids in Biology and Medicine: Biochemical, Pharmacological and Structure-Activity Relationships
, E. Middleton Jr. and J. B. Harborne, Eds., A. R. Liss, New York, pp 187-200 (1988)); suppressing the formation of peroxidized lipids (Kappus, H. et al.,
Pharmacol
., 300, 179-187 (1977); Baumann, J. et al.,
Prostaglandins
, 20, 627-639 (1980); and Yoshimoto, T. et al.,
Biochem. Biophys. Res. Commun
., 116, 612-618 (1983)); and inhibiting allergy and dermatopathies (Loggia, R. D. et al., in Cody, V. et al.(eds),
Plant Flavonoids in Biology and Medicine
, A. R. Liss, New York, 481-484 (1986)).
Besides fisetin and fustin, various other flavonoids such as agathisflavone, butein, corilagin, 3′,4′-dihydroxy flavone, eicosanedioic acid, europetin, sulfuretin and quercetin have also been found in the plants of genus Rhus(Bukkingham,
J. Dictionary of Natural Products
, 7, 761 (1994)). However, none of these compounds has been tested for their alcohol-decomposing activity.
Ethanol, the intoxicating component of various liquors, gives rise to various undesirable physiological and mental influences in the body, and therefore, there have been carried out a number of studies regarding its metabolic and toxicological characteristics. When imbibed, ethanol is absorbed through the gastrointestinal tract and its concentration in the blood reaches the highest level at 20 to 120 minutes after ingestion. The imbibed ethanol is then metabolized at various organs including the liver, while a small amount thereof is excreted through exhalation, urine and perspiration.
When a small amount of ethanol is ingested, it is decomposed in the liver into an acetate form by the action of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in cytosol and the acetate is excreted from the liver cell (Lieber, C. S.,
Hepatology
, 4, 1234-1256 (1984)). A large amount of ingested ethanol, on the other hand, causes temporary accumulation of fat as well as acetaldehyde in the liver (Weiner, F. R. et al., “
Ethanol and the Liver in the Liver Biology and Pathology
”, Arias, M. et al. Ed., Raven Press, New York, 1988, p1169). Acetaldehyde is a reactive, toxic substance that interferes with the metabolic process of mitochondria and inhibits the oxidative phosphorylation reaction. It also binds with membrane proteins and collagen to generate antigens (Koskinas, J. et al.,
Gastroenterology
, 103, 1860 (1992)); exhibits cytotoxicity (Zetterman, R. K., “
Autoimmune Manifestation of Alcoholic Liver Diseases
”, ed. Kravitt, K. I. and Wiesner, R. H., Raven Press, New York, p. 247, 1991; Takase, S. et al.
Hepatology
, 17, 9 (1993); Yokoyama, H. et al.,
Hepatology
, 17, 14 (1993)); suppresses the release of proteins from the liver cell (Xu, D. S. et al.,
Alcohol Alcohol
, 24, 281 (1989)); stimulates collagen biosynthesis (Pawlica, E., et al.,
Arch. Toxicol
., 65, 678 (1991)); promotes alcoholic fibrogenesis (Friedman, S. L. et al.,
Hepatology
, 12, 609 (1990); and causes liver damage through the formation of macromolecular adducts (Barry, R. E.,
G. I. Futures Clin. Practice
, 4, 4 (1989); Lieber, C. S.,
Biochem. Soc. Trans
., 16, 241 (1988)).
Fatty liver, promoted by excessive ethanol intake, usually results from the inhibition of the oxidative metabolism of fatty acids (Lieber, C. S.,
Acta Med. Scan. Suppl
., 703, 11 (1985); Kim, M-H. and Kwon, O-H.,
Korean Biochem. J
., 25, 499 (1992)). The increase in the blood lipid level found in animals fed with ethanol is believed to be due to the increase in VLDL (very low density lipoprotein) in the liver (Baraona, E. and Lieber, C. S.,
J. Clin. Invest
., 49, 769 (1970)) and it has also been confirmed that an oral or intravenous administration of ethanol to a human subject induces an acute increase in the level of the VLDL-containing plasma lipids (Jones, D. P. et al.,
J. Lab. Clin. Med
., 62, 675 (1963)). A high plasma lipid level was also observed in chronic alcohol abuse patients, the degree being dependent on the duration and the amount of ethanol ingested (Schapiro, R. H., et al.,
J. Clin. Invest
., 43, 1338 (1964)). The accumulation of fat in the liver interferes with the liver's metabolic function and leads to fibrogenesis and damaged liver cells.
Carbon tetrachloride (CCl
14
) induces liver damage and is used in various animal and cultured cell tests to evaluate agents for treating hepatic disorders. CCl
4
converts to a radical species, CCl
3
, by the action of such a metabolic enzyme as cytochrome P450 and the radical induces oxidation of the fat in the liver or the fatty acids present in the phospholipid membrane. This oxidative process is participated by oxygen to form lipid peroxides. This peroxidation process, in turn, brings about fat accumulation, lowering of protein secretion, degradation of glycogen, destruction of enzymes, and eventually, the death of liver cells. Accordingly, CCl
4
-induced liver damage is used as a model in tests to evaluated liver disorders caused by ethanol (Recknagel, R. O.,
Pharmacol. Rev
., 19, 145-208 (1967); Alpers et al.,
Mol. Pharmacol
., 4, 566-573 (1968); Slater,
Free Radicals, Lipid Peroxidation and Cancer
, Academic Press, London, p 243 (1982); Chang, I. M. et al.,
Drug and Chemical Toxicology
, 6(5), 443-453 (1989)).
Stomach lesion, ulcer, or cancer usually progresses from gastric mucosal injuries caused by such factors as psychological stress, excessive intake of ethanol,
Helicobacter pyloris
(Suzuki, M. and S. Miura,
Nippon Rinsho
, 15(12), 3154-3158 (1993)), and thyrotropin-releasing hormone (TRH). Nicotine also damages the gastric mucous membrane and smokers are known to have a 55% higher risk of getting stomach cancer than non-smokers (Kneller, R. W. et al.,
J. Natl. Cancer Inst
., 84(16), 1261-1266 (1992)).
It has been reported that the administration of adenosine to rats having ethanol-induced gastric mucous membrane damage at a dosage of 7.5 mg/kg is effective in restoring the damaged membrane through increased blood circulation therethrough (Cho, C. H.,
Acta Physiol. Hung
, 80(1-4): 175-180 (1992)). Also, polysaccharides extracted from ginseng leaves and roots have been described to exhibit dosage-dependent therapeutic effects in treating HCl- or ethanol-induced gastric mucous membrane injuries (Sun, X. B. et al.,
Planta Med
., 58(5), 445-448 (1992)). There have been conducted many animal tests to evaluate cures for gastric lesions of two types; stress-induced and ethanol-induced. Although these two types are of similar nature, there exists a significant difference in terms of therapeutic method. For example, prostaglandin is more effective in treating the ethanol-induced gastric injury, while in the stress-induced case, cimetidine is.
The present inventors have unexpectedly found that an acetone extract of
Rhus verniciflua
is a potent agent for lowering the blood alcohol level and it is capable of treating or preventing alcohol-induced damage of the liver or stomach.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide a method for lowering blood alcohol concentration by administering an extract of
Rhus verniciflua
to human.
Another object of the present invention is to provide a method for resolving
Jung Nam-Chul
Na Chun-Soo
Forestry Research Institute
Lilling Herbert J.
Rosenman & Colin LLP
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