Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1984-04-06
1985-05-28
Friedman, Stanley J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
564223, A61Y 31165, C07C10338
Patent
active
045201340
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel pharmaceutical compositions of matter comprising N-alkyl-4'-hydroxyacetanilide, which have analgesic, antipyretic, antiinflammatory and sedative activity, but lack the nephrotoxicity and hepatotoxicity of acetaminophen. This invention further relates to a method of ameliorating pain through the administration of these compounds.
2. Description of the Related Art
Acetaminophen (paracetamol) has become increasingly popular as an analgesic, despite the fact that its heptatoxicity has been documented since 1966. D. G. Davidson and W. N. Eastham, British Medical Journal 2:497-499 (1966). It has recently been shown that chronic ingestion of therpeutically recommended doses of acetaminophen in humans for extended periods of time can cause massive hepatic necrosis. A. J. Ware, et al., Annals of Internal Medicine 88:267-268 (1978); D. M. Rosenberg and F. A. Neelon, Annals of Internal Medicine 88:129 (1978); J. D. Barker, Jr., Annals of Internal Medicine 87:299-301 (1977) and G. K. Johnson and K. G. Tolman, Annals of Internal Medicine 87:302-303 (1977). Individuals with underlying liver injury or disease have been found to be particularly susceptible to acetaminophen-mediated hepatotoxicity. D. M. Rosenberg, et al., Southern Medical Journal 70:600-601 (1977); H. L. Bonkowsky, et al., Lancet 2:1016-1018 (1978); V. Schoenfeld, et al., New England Journal of Medicine 303:47 (1980 ); and D. P. Golden et al., Oral Surgery 51:385-389 (1981). Additionally, conditions which induce the liver enzymes responsible for the metabolization of acetaminophen, such as consumption of alcohol or barbituates, will markedly potentiate the heptatoxicity of this compound.
Studies by Nebert with inbred mice have suggested that acetaminophen can cause cataracts in humans. Science, 200:539-541 (1978). Acetaminophen has also recently been implicated as a possible human carcinogen. M. I. Mihatasch, et al., Schweizerische Medizonische Wochenschrift 110:255-264 (1980). Thus, acetaminophen, which is an ubiquitious component of over-the-counter and prescription drugs, may present a serious risk to general users and sensitive user subpopulations in terms of its hepatic and other toxic effects.
The mechanism of acetaminophen toxicity is not fully understood in the prior art. Editorial, Lancet 2:1189 (1975); B. E. Walker, et al., Clinical Science & Molecular Medicine 47:449-459 (1974). However, recent studies, which are discussed infra, suggest the involvement of certain hepatic enzyme systems which convert acetaminophen into a toxic metabolite or produce a toxic by-product.
Because such diverse compounds as cysteamine, methionine, cysteine, dimethlymercaptol, selenium and vitamin E have afforded varying degrees of protection in man and experimental animals against the hepatotoxicity of acetaminophen, and because these compounds under certain circumstances can act as antioxidants, it has been suggested that other antioxidants would also provide protection. J. Kelleher, et al., Journal of Internal Medical Research 4, Supplement (4):138-144 (1976). Compounds such as 2-methylthiazolidine-4-carboxylic acid which form cysteine in the liver can also protect against heptotoxins. Chemical & Engineering News, Aug. 2, 1982 at p. 18.
Animal studies indicate that antioxidants can provide limited protection against the hepatotoxic effects of acetaminophen. For example, .alpha.-tocopherol protects vitamin E deficient rats. B. E. Walker, et al., supra; J. Kelleher, et al., supra. It has been reported that vitamin C may also provide such protection. T. C. Raghuram, et al., Toxicology Letters 2:175-178 (1978).
U.K. patent application No. 2,040,164 and U.S. Pat. No. 4,292,298 (assigned to Beecham Group Ltd.), both claim compositions and methods for reducing the acute liver toxicity effects of acetaminophen by the oral administration of a co-formulation with ascorbic acid. The U.S. patent discloses that 300 mg/kg of ascorbic acid in nonsustained release form had no protective effect a
REFERENCES:
Hinsberg et al., Arch. Exp. Pathol. Pharm., 33: 216-250 (1894).
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