Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-12-22
1997-04-08
Goldberg, Jerome D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514449, 514562, A61K 3144, A61K 31335, A61K 31195
Patent
active
056188234
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 PCT/EP 93/01494 filed Jun. 14, 1992.
The present invention relates to the use of reduced glutathione (GSH) as protecting agent towards neurotoxicity induced by antitumor drugs active on the mitotic fuse.
Examples of such drugs include Vinca alkaloids, such as vincristine and vinblastine, and cyclotaxan derivatives, whose parent compound, i.e. taxol, is presently under advanced clinical trial (Anti-Cancer Drugs, 2, 1991, page. 519-530).
The most serious limitation to the success of antineoplastic chemotherapy resides in the severe toxicity annexed to the use of antitumor drugs: toxic symptoms limit administrable doses, they affect treatment cycles and seriously jeopardize the life quality of the oncologic patient.
The high toxicity of the antitumor drugs is due to the lack of selective activity of the drugs themselves, which, besides hitting the tumor cells, interact with other organs or cell populations in the human body.
Toxic symptoms deriving from the treatment with antitumor compounds are there fore strictly connected with the chemical structure of the compounds and with their mechanism of action. For example, anthracycline induced cardiotoxicity was strictly related to the quinone substructure typical of anthracyclines. In fact, this structure undergoes in vivo a single-electron reduction, thus forming the emiquinone radical. This last compound is capable of promoting the avalanche formation of free oxygen radicals, which, in their turn, are responsible for the cardiac tissue damage. Not by chance several radical scavengers are able to perform a protective effect lowering the anthracycline cardiotoxicity.
As another example, cis-platin is an antitumor agent which is endowed with heavy organo-specific toxicities, particularly relevant especially towards kidney. In fact, cis-platin, when absorbed by kidney, forms the diaquo species by loss of two chlorine ions This happens since in the renal tubule the concentration of chlorine ions is lower than in blood. So activated cis-platin is capable of damaging the tubules with resulting nephropathy. Several thiol compounds, among which diethyldithiocarbamate and glutathione are able to protect kidney from the cis-platin effect, since they accumulate at kidney level and probably interact with the compound.
Cis-platin is known to cause neurotoxic effects too (Eur. J. Cancer Vol. 27(3), 1991, 372-376), which several protective agents have been evaluated towards. among these, nimodipine (Eur. J. Pharmacol. 1990, 183, 1710-1711) and ACTH (4-9) neuropeptide (Eur. J. Cancer Clin. Oncol. 1988, 89, 81-87) turned out to be the most. effective.
Also glutathione and other sulphur compounds (thiosulfate, ethiofos, diethyldithiocarbamate) resulted effective to different extents in the prevention of cis-platin neurotoxicity (Tumori, 1987, 73, 337-340, EP-A-0265719 Cancer Res., 1993, 53, 544-549), presumably as an effect coming from the nephrotoxicity protection, which is widely described especially for glutathione. An uncompromised kidney functional capacity would assure an effective and ready elimination of cis-platin, thus avoiding the accumulation and the resulting toxicity towards other tissues or target cells.
From the whole of the data reported in clinical and pharmacological literature, it comes out that a single agent capable of protecting indiscriminately from the toxic effects of any antitumor compound does not exist. It is neither foreseen that a compound capable of limiting or nullifying the toxicity of a certain antitumor drug can also exert a protecting effect from the toxicity of another antitumor drug belonging to a different chemical class and having a different activity mechanism.
On the other hand, vinca alkaloids and cyclotaxans derivatives, such as taxotere and taxol, characterized by the same cytotoxic mechanisms at microtubule level, share, as unwished side effect, neurotoxicity against peripheral nerve (Neurology, 39, 1980, 368-37; Neuroscience 10(2), 1983, 491-509; J. Neurocytol. 15, 1986, 483 J. Clin. Oncol. 9, 1991, 1261-7)
REFERENCES:
Seminars in Oncology, vol. 18, No. 1, Feb. 1991, pp. 1-4.
Neroreport, vol. 2, No. 6, Jun. 1991, pp. 345-347.
The Merck Index, 11th Ed, 1989, Merck & Co., Inc., Rahway, N.J., U.S.A.
WO,A,8 602 353, Apr. 24, 1986.
WO,A,9, 102 810, Mar. 7, 1991.
Cavalletti Ennio
Tognella Sergio
Boehringer Mannheim Italia S.p.A.
Goldberg Jerome D.
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