Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-09-30
1998-02-17
Cooney, Jr., John M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548420, C07D20994, C07D20970
Patent
active
057191743
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to the use of hydrophobic antioxidants having an indenoindole structure in medical therapy for preservation of organs in vitro as well as in vivo. Such compounds are already known to be highly efficient in reducing, i.e. quenching, free radicals in lipids or lipid biphases, thereby terminating the lipid peroxidation process and preventing conditions and diseases initiated by this or related processes. In particular the present invention is based on the use of at least one of two specific compounds or a salt thereof, preferably a therapeutically acceptable salt thereof, as an additive in a preservation solution for organs, especially a cardioplegia solution. Such a preservation solution may be used both for in situ organ treatment in the donor and for organ storage after the organ is harvested. Furthermore the invention relates to an improved preservation solution for organs.
BACKGROUND OF THE INVENTION
Some biological processes generate more or less stable intermediates that contain an unpaired electron, which can either be donated, or paired with an additional electron from the surroundings. Such intermediates are called free radicals, and they may be the products of various enzymatic and nonenzymatic reactions, some of which are vital for body functions, e.g. reduction of ribonucleoside diphosphates for DNA synthesis and the generation of prostaglandins in the prostaglandin synthetase reaction. The latter is essential for inflammatory response following cell injury, and a number of other functions. Other radical reactions include the myeloperoxidase reaction in neutrophils and macrophages which destroy bacteria and other invading particles, and the electron transport in the mitochondrial respiratory chain. Most organisms contain chemical antioxidants such as .alpha.-tocopherol (vitamin E), ascorbic acid and different radical and peroxide-inactivating enzymes, e.g. superoxide dismutase, catalase and glutathione peroxidase.
Free radicals of various types are becoming increasingly associated with a broad range of conditions and diseases such as ischemic and reperfusion injury, atherosclerosis, thrombosis and embolism, allergic/inflammatory conditions such as bronchial asthma, rheumatoid arthritis, conditions related to Alzheimer's disease, Parkinson's disease and ageing, cataract, diabetes, neoplasms and toxicity of anti-neoplastic or immunosuppresive agents and chemicals. One possible explanation for these conditions and diseases is that, for unknown reasons, the endogeneous protecting agents against radical damage are not sufficiently active to protect the tissue against radical damage. Lipid peroxidation caused by excess generation of radicals may constitute one significant damaging pathway in the above conditions. Inhibition of this lipid peroxidation would thus provide a way of preventing or curing the above conditions and diseases.
The general idea of using antioxidants for alleviating ischemia/reperfusion injuries have been described in several papers, for example Drugs 42(4): 569-605, 1991, and J Lab Clin Med, Vol. 119 (6): 598-620, June 1992. The possible use of indenoindoles for alleviating ischemia and reperfusion injuries as well as other conditions and diseases mention above has been proposed by M. Sainsbury and H. G. Shertzer in the patent specifications EP-A 409 410 and GB 9022453.6-A. In practice, however, it is very difficult to show any correlation between antioxidant potency and organ protecting ability. The two specific compounds which now have been found useful for preservation of organs in accordance with the present invention are prior disclosed in EP-A 409 410 and GB 9022453.6-A as well as processes for their preparation.
SUMMARY OF THE INVENTION
The present invention describes a novel use of two known specific antioxidants of the indenoindole type, which compounds fulfill both the requirement of being sufficiently hydrophobic, thus possibly accumulating in membranes, and to be potent inhibitors of lipid peroxidation. These
REFERENCES:
patent: 5185360 (1993-02-01), Sainsbury et al.
patent: 5407793 (1995-04-01), Del Nido et al.
Halliwell et al., Drugs vol. 42, No. 4, pp.569-605 Dec. 1991).
Halliwell et al., J. Lab. Clin. Med. vol. 119, No. 6, pp.598-620 Dec. 1992).
Swanson et al., J. Heart Transplantation vol. 7, No. 6, pp.456-467 Dec. 1988).
Sainsbury Malcolm
Shertzer Howard G.
Sjoqvist Per-Ove
Astra Aktiebolag
Cincinnati
Cooney Jr. John M.
Univ. of Bath
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