Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-04-20
2001-02-06
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S386000
Reexamination Certificate
active
06184227
ABSTRACT:
1. INTRODUCTION
The present invention is directed to methods and compositions for the prevention and/or inhibition of tissue injury caused by alcohol, therapeutically useful drugs as well as by industrial, dietary and environmental toxins, by administration of salts of aminoimidazole carboxamide (AICA). Use of the entire group of organic acid salts and inorganic acid salts of 5-aminoimidazole carboxamide rather than only those obtained from orotic acid are encompassed by the methods of the invention. For example, AICA may also be reacted with aliphatic acids including, but not limited to, lactic, succinic, maleic, citric, and tartaric or with sugar acids such as gluconic, galactonic, etc., particularly penta and poly hydroxycarboxylic acids to form organic acid salts, or AICA may be reacted with inorganic acids including, but not limited to, hydrohloric and phosphoric acids, to form inorganic salts suitable for use according to the methods of the present invention.
The methods involve administering to an individual consuming alcohol, therapeutic drugs and/or exposed to xenobiotic agents, an effective dose of a salt of aminoimidazole carboxamide with or without antioxidants, including, but not limited to vitamin E, vitamin C, vitamin A and its derivatives, glutathione, N-acetylcysteine or magnesium gluconate. In the practice of the invention, compositions containing salts of AICA are used to detoxify harmful and noxious agents or toxins, to inhibit bioactivation of agents to harmful electrophiles or free radicals, to inhibit suppression of cell-mediated or humoral immune mechanisms, to stimulate the regeneration of target cells of the damaged issue and to inhibit the failure of energy supply. Preferred compositions of the invention are those which specifically or preferentially inhibit tissue injury involving , but not limited to, hepatocytes, nonparenclymal cells, endothelial cells, pit cells and other cells lining the hepatic sinusoids and bile duets.
2. BACKGROUND OF THE INVENTION
2.1 Salts of Aminoimidazole Carboxamide
AICA orotate, also referred to as “Orazamide Orotate” is incorporated into animal nucleic acids and possesses the ability to prevent necrosis of liver induced by acute and chronic hepatic damage in animals. Miller, C. S. et al., 1950, Science 112: 654.
2.1.1 Chemical Nature and Properties of Salts of Aminoimidazole Carboxamide
Orazamide is available in different forms as: 5-aminoimidazole-4-carboxamide orotate, 4-amino-5-imidazole carboxamide orotate or a combination of 1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidine carboxylic acid with 5-amino-1H-imidazole-4-carboxamide (1:1) or a combination of orotic acid with 5(or 4)-aminoimidazole-4(or 5)-carboxamide (1:1). The C5 amine group on the imidazole ring can be attached to the C4 carboxyl group of orotic acid or any other organic acid which is chemically compatible to the body:
2.1.2 Metabolic Effect of Orotic Acid
Any kind of organic or inorganic acid which is clinically compatible with the body may be selected to be reacted with AICA, an intermediate in the purine pathway. Especially desirable are orotic, lactic, succinic, maleic, citric, tartaric, gluconic, galactonic, hydrochloric, phosphoric and penta or poly hydroxycarboxylic acids.
Orotic acid is an intermediate in the pyrimidine pathway and its main source in human and animal diet is bovine milk and its products.
2.2 Alcohol and Liver Disease
An association of alcohol with damage to the liver rests primarily on the clinical observation that cirrhosis occurs in-patients consuming large amounts of ethanol. Ethanol has been shown to have a variety of toxic effects on livers in otherwise normal animals, including normal men and women.
Alcohol abuse costs the U.S. more than one hundred and sixteen billion dollars per year, of which about twelve percent is for direct costs of medical care. Advertising, counter advertising and depiction in the public media, 1986, JAMA 256: 1485. The basic reason for the large epidemic of alcohol-related disease is that ethanol is an effective drug in relieving anxiety, depression and the pressures of modern society. The easy availability of ethanol and the social acceptability of ethanol consumption are advertised widely and aggressively. The public seems unaware that chronic use of ethanol in the absence of addiction can lead to serious medical illness and/or the development of social consequences. About three quarters of the population of the United States uses ethanol. The incidence of alcoholism in the United States is approximately seven percent, being higher for men (11 percent) than for women (4.08 percent). Alcohol Health and Research World, 1995, 18: 243-8.
Prevention and/or treatment of alcoholism is a problem for which there are no certain answers. Therefore, an understanding of the biochemical basis for the hepatotoxicity of ethanol and its eventual control may provide an effective means to reduce and manage alcohol related liver diseases and medical complications.
2.3 Therapeutic Drugs and Liver Disease
Drug-induced liver disease is encountered rarely in general practice but accounts for between two to three percent of all admissions due to adverse drug reactions. Lewis, J. H., et al., 1989, Med. Clin. North Am. 73: 775. Published compilations of drug-related liver pathology list between 500 and 1000 therapeutic agents that have been implicated in the etiology of various liver diseases. Zimmerman, H. J., 1990, Semin. Liver. Dis. 10: 322.
Drugs with the potential for producing liver injury are divided into the “direct” or “predictable” hepatotoxins and “unpredictable” hepatotoxins. Direct hepatotoxins produce liver damage in a predictable, dose-dependent fashion, and they produce liver cell necrosis that affects predominantly a particular region of the liver lobule. Unpredictable hepatotoxins produce liver injury that is diffuse, consisting of necrosis and/or cholestasis, usually associated with a significant inflammatory reaction. Despite significant advances in the understanding of hepatotoxicity, the mechanisms by which certain drugs injure or kill the liver cell, or alter its function remain largely unknown and uncontrolled.
2.4 Industrial and Environmental Toxins and Liver Disease
The liver's potential for injury by environmental or occupational/industrial toxins is very high because it is the first organ after the gastrointestinal tract that is exposed to these agents, also known as xenobiotics. Hepatic metabolism usually detoxifies these agents. However, hepatic metabolism of xenobiotics can result in metabolites that are considerably more hepatotoxic than the parent chemicals. The hepatotoxic effects that result in humans from accidental or intentional exposures to xenobiotics or toxins range from mild liver dysfunction to necrosis. Xenobiotics may react with nutrients, destroy them or make them unavailable because of altered absorption or changes in detoxification or metabolic rates. Nutritional deficiencies in turn may enhance the toxic effects of xenobiotics. The realization that commonly used chemical compounds present health hazards has stirred considerable apprehension not only for industrial workers exposed directly to these agents but also for the general public who unwittingly get exposed to these ubiquitous noxious agents in the environment, in the food they eat or in their homes.
3. SUMMARY OF THE INVENTION
The present invention is directed to a method for the prevention and treatment of tissue damage caused by alcohol which involves administering a salt of AICA to an individual in need thereof.
The present invention is also directed to a method for the prevention and treatment of drug-induced liver disease which involves administering a salt of AICA to an individual in need thereof.
The present invention further involves a method for the prevention and treatment of hepatotoxic effects of exposure to xenobiotics and/or toxins, which involves administering a salt of AICA to an individual in need thereof.
The present invention is also directed to a method of inhibiting the oxidation of ethanol an
Raymond Richard L.
SavviPharm Inc.
LandOfFree
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