Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing – Multienzyme complexes or mixtures of enzymes
Patent
1992-03-02
1994-08-09
Wax, Robert A.
Drug, bio-affecting and body treating compositions
Enzyme or coenzyme containing
Multienzyme complexes or mixtures of enzymes
424 943, 424 944, 435188, 435189, 435192, 5303911, A61K 3762, A61K 3750, C12N 908, C12N 996
Patent
active
053364937
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to novel superoxide dismutase-catalase conjugates and to novel therapeutic agents utilising said conjugates.
BACKGROUND OF THE INVENTION
The human and animal body produces highly reactive free radicals by a variety of normal metabolic processes. The action of xanthine oxidase on xanthine, for example, results in the single-electron reduction of oxygen and produces both superoxide and hydroxyl free radicals (Kuppusamy & Zweier (1989) J. Biol. Chem. 264, 9880-9884). Free radicals have been implicated in the causation of a wide range of clinical conditions including atherosclerosis, rheumatoid arthritis, cancer, pulmonary diseases of the newborn and the normal ageing process, and have been reported to be associated with reperfusion injuries following ischemic episodes associated with myocardial infarct, cerebral ischemia and vasospasm and surgical intervention.
Superoxide and hydroxyl free radicals and hydrogen peroxide can result in peroxidation of membrane phospholipids and oxidation of cellular proteins and nucleic acids. These species are thought to be involved in various pathological conditions including tissue injury, inflammatory conditions and radiation damage.
A variety of endogenous defence mechanisms are thought to protect the organism from the deleterious effects of these reactive oxygen species under normal physiological conditions. One of these is the enzyme, superoxide dismutase (SOD), which occurs widely in prokaryotes and eukaryotes. SOD catalyses the dismutation of the superoxide free radical (O.sub.2.), in the presence of hydrogen, to produce hydrogen peroxide.
Hydrogen peroxide, which is itself a potentially deleterious reactive species, is reduced to oxygen and water by the enzyme, catalase. Catalase also destroys the hydroxyl free radical (OH.) by removing H.sub.2 O.sub.2 and hence decreasing the reaction of H.sub.2 O.sub.2 with O.sub..sub.2. to produce OH.
The effect of exogenously administered SOD as a therapeutic agent to protect against superoxide free radical damage has been studied in mammals with mixed results. The variability of the effect produced by SOD makes it somewhat unsatisfactory as a therapeutic agent.
One factor contributing to the variability of effect found with exogenous SOD administration is the very short half-life of SOD in the mammalian circulation, of the order of 4 to 5 minutes.
Previous work has shown that the half-life of SOD in the circulation can be increased by conjugation of the enzyme with a larger molecule, for example, albumin or polyethylene glycol (PEG). SOD-albumin conjugates have circulation half-lives of 4-6 hours and show reduced immunogenicity compared to SOD alone (Mao & Poznansky (1989), Biomat. Art. Cells & Art. Org., v. 17 (3) , p. 229-244).
Another factor which likely plays a role in the variable results found with exogenous SOD administration is the strong inhibition of SOD by hydrogen peroxide, one of the products of its own catalytic activity.
A further limitation on the usefulness of SOD, and also of SOD-albumin conjugates, is that SOD is not able to remove hydroxyl free radicals. At high levels of exogenous SOD administration, SOD actually increases hydroxyl free radical production and a similar effect is seen with high levels of SOD-albumin conjugate.
The SOD-careless conjugates of the invention are advantageous as novel free radical scavengers capable of removing both oxygen and hydroxyl free radicals.
DISCLOSURE OF THE INVENTION
According to one aspect of the invention, a multi-component conjugate having at least two components is provided, wherein said at least two components are superoxide dismutase and catalase.
According to a further aspect of the invention, a pharmaceutical composition is provided comprising a multi-component conjugate having at least two components, wherein the at least two components are superoxide dismutase and catalase, in an amount effective to reduce harmful levels of superoxide and hydroxyl free radicals in body tissues.
According to a further aspect of the i
REFERENCES:
Mao & Poznansky, 1989, Biomat. Art. Cells & Art. Org., vol. 17:3, pp. 229-244.
Chemical Abstracts, vol. 107, No. 3, Abstract 17857k, Jul. 20, 1987.
Chemical Abstracts, vol. 108, No. 25, Abstract 216322c, Jun. 20, 1988.
Chemical Abstracts, vol. 107, No. 8, Abstract 64752g, Aug. 24, 1987.
Chemical Abstracts, vol. 110, No. 15, Abstract 128364d, Apr. 10, 1989.
Mao Guo D.
Poznansky Mark J.
Hendricks Keith D.
Wax Robert A.
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