Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1995-01-03
1996-07-09
Nutter, Nathan M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 17, 514 18, 514 19, 514810, 514811, 514812, 514813, 2609982, A61K 3702
Patent
active
055344925
DESCRIPTION:
BRIEF SUMMARY
This invention relates to the treatment, prophylaxis and management of toxicity caused by a variety of toxic substances, including alcohol, anaesthetics and narcotics.
Human and other animal bodies have developed a number of approaches to detoxifying toxic substances. The range of toxic substances likely to be encountered is extremely broad, particularly for humans but also for animals, and so it would be impracticable for the organism to have enzymes in store to deal specifically with all the new compounds already produced and yet to be produced by the organic chemist; such enzymes as are already available must serve as effectively as possible.
In some ways any study of detoxification is hampered by the difficulty of deciding precisely what constitutes a toxic substance. Many compounds develop toxicity if the dose is sufficiently great and some species are quite resistant to substances which are extremely toxic in others. Also the time of exposure to the toxic substance is important, as is the route by which it enters the body. However, in spite of this diversity both in the nature of the compounds likely to be encountered and in the different effects which can be exhibited by a single compound, there is in practice little difficulty in determining whether a compound is toxic and needs to be detoxified by the body. Possibly related to this, there is a remarkably small number of types of reaction which the human or animal body uses to deal with many toxic substances: the most commonly encountered are hydroxylation, oxidation, reduction and conjugation. Many of these reactions take place in the liver.
A wide variety of compounds are detoxified by hydroxylation, frequently mediated by the cytochrome P.sub.450 system, which uses NADPH+H.sup.+ as a reductant; molecular oxygen is also required and the substance is hydroxylated in the process. This system appears to interact with many different chemical types of compounds, including aliphatic, aromatic and unsaturated compounds and those containing sulphur and nitrogen. Common drugs hydroxylated include: (a) barbiturates such as phenobarbitone (a sedative); (b) antipyrine (an analgesic and antipyretic); (c) amphetamine (a stimulant); (d) heroin (a narcotic); (e) meprobromate (a tranquilliser); and (f) acetanilide. Many toxic substances themselves stimulate the activity of hydroxylating systems in vivo. The consequence of hydroxylation is an easier elimination of unwanted foreign substances because of their conversion from lipid-soluble molecules into more polar substances.
Reduction is another method of detoxication and is a reaction used to detoxify aromatic nitro groups, for example. Nitrobenzene is reduced (and hydroxylated) to p-aminophenol.
Conjugation is one of the most versatile methods of detoxication. Glycine is frequently the conjugating substance. It reacts with carboxyl groups of organic acids to form a substituted amide: for example, hippuric acid is formed as a conjugate of benzoic acid and glycine. In fact, this conjugation proceeds through a benzoyl-CoA intermediate, which serves as another example of the role of coenzyme A in detoxication by conjugation. Other conjugations involve formation of sulphate esters (as in the metabolism of phenol and unwanted steroid hormones) and acetylated or methylated derivatives. Glucuronic acid is also involved in conjugate formation.
Oxidation is another way of metabolising unwanted material. Often the products are organic acids. For example, benzylamine is converted to benzoic acid by oxidation of the amino group, presumably by an amine oxidase and aldehyde dehydrogenase. The toxic effect of alcohol (that is to say, ethyl alcohol or ethanol) is mediated by its oxidised metabolite acetaldehyde (Cedarbaum and Rubin Federation Proc. 34 2045 (1975)). Ethanol is oxidised to acetaldehyde by the enzyme alcohol dehydrogenase (EC 1.1.1.1). Ethanol also has the effect of inducing the cytochrome P.sub.450 system. In the absence of the induction of the metabolism of acetaldehyde (for example by oxidation by aldehyde dehyd
REFERENCES:
Farghali et al "Muramyl Dipeptide and Carbon Tetrachloride Hepatotoxicity in Rats! Involvement of Plasma Membrane and Calcium Homeostasis in Protective Effect" Meth and Find Exptl Clin Pharmacology 1986; 8(8):469-477.
Farghali et al "The Protection from Hepatotoxicity of Some Compounds by the Synthetic Immunomodulator Muramyl Dipeptide (MDP) in Rat Hepatocytes and In Vivo" Meth and Find Exptl Clin Pharmacol. 1984; 6(8):449-454.
Aston Roger
Kovalev Igor E.
Nutter Nathan M.
Peptech (UK) Limited
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