Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heavy metal containing doai
Patent
1996-02-29
1997-04-08
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heavy metal containing doai
556 1, A61K 3128, C07F 724
Patent
active
056188382
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/US 94/06878 filed Jun. 17, 1994.
The present invention relates to a pharmaceutical composition containing a gallium complex (Ga) as active ingredient therein, or a combination of Ga complex with zinc (Zn) and/or manganese (Mn) complexes, therein.
More particularly, the present invention relates to pharmaceutical preparations which are effective against iron-mediated and copper-mediated damage, said preparations being based on Gallium complexes with desferrioxamine B (desferrioxamine=DFO) or with penicillamine and preparations based on combinations of Ga, Zn and Mn complexes with DFO or with penicillamine.
Redox-active iron and copper have been demonstrated to be responsible for tissue damage in ischemia and reperfusion injury, ionizing irradiation, thaltesemia, hemochromatosis and Wilson disease. Furthermore, in a wide variety of pathologic states, the causative role of free radicals has been proposed. These metals can readily serve as effective mediators enhancing free radical-induced damage and thus have been incriminated as a major responsible species for tissue injury (M. Chevion, "A Site-Specific Mechanism for Free Radical-Induced Biological Damage: The Essential Role of Redox Active Transition Metals", Free Radicals for Biology and Medicine, Vol. 5, No. 1, pp. 27-37, 1988).
The present inventors have shown that the use of desferrioxamine, and better still, the combination of DFO and nitrilotriacetate (NTA) resulted in a dramatic increase in the rate of survivors in paraquat toxicity. While in control group there were no survivors, following treatment with either chelators, 25-30% survivors were monitored. The administration of a combination of these specific chelators led to 60-90% survivors (average 70%) (R. Kohen and M. Chevion, "Paraquat Toxicity Is Enhanced by Iron and Inhibited by DFO in Laboratory Mice", Biochemical Pharmacology, Vol. 34, pp. 1841-1843, 1985).
Similarly, the present inventors have shown that neocuproine, a chelator that effectively binds iron and copper and easily penetrates into cells, provides marked protection against ischemic-induced arrhythmias and against loss of cardiac function in the isolated rat heart using the Langendorff configuration (Y. J. Appelbaum, G. Uretzky, and M. Chevion, "The Protective Effect of Neocuproine on Cardiac Injury Induced by Oxygen Active Species in the Presence of Copper Sulfate", Journal of Molecular and Cellular Cardiology, Vol. 19 (Supp. III), Abstract No. 8, 1987; J. Kuvin, Y. J. Appelbaum, M. Chevion, J. B. Borman and G. Uretzky, "Role of Oxygen-Free Radicals in Reperfusion-Induced Arrhythmias: Protection by Neocuproine", Journal of Molecular and Cellular Cardiology, Vol. 19 (Supp. III), Abstract No. 150, 1987; Y. J. Appelbaum, J. Kuvin, J. B. Borman, G. Uretzky, and M. Chevion, "Role of Oxygen-Free Radicals in Reperfusion-Induced Arrhythmias: Protection by Neocuproine", Free Radicals in Biology and Medicine, Vol. 8, pp. 133-143, 1990).
The protective effect of another chelator, TPEN, has also been demonstrated by the inventors (Y. J. Appelbaum, J. Kuvin, M. Chevion and G. Uretzky, "TPEN, A Heavy Metal Chelator, Protects the Isolated Perfused Rat Heart from Reperfusion-Induced Arrhythmias", Journal of Molecular and Cellular Cardiology, Vol. 20 (Supp. V), Abstract No. 32, 1988; Y. J. Appelbaum, M. Bublil, J. B. Borman, G. Uretzky and M. Chevion, "Role of the Metal Chelator TPEN against Ischemic and Reperfusion Injury in the Isolated Perfused Rat Heart", Proceedings of the SOD V Conference, Jerusalem, Israel, p. 135, Sep. 17-22, 1989; M. Karck, Y. Appelbaum, H. Schwalb, A. Haverich, M. Chevion and G. Uretzky, "TPEN, A Transition Metal Chelator, Improves Myocardial Protection during Ischemia", Journal of Heart and Lung Transplantation, Vol. 11, pp. 979-985, 1992).
It has now been found by the applicant that the complex Ga-DFO possesses the characteristics which could markedly improve the pharmaceutical efficacy of Desferal.RTM..
This will be achieved by markedly enhancing its permeability into cells, and by th
REFERENCES:
patent: 5328992 (1994-07-01), Peter et al.
Berenshtein Edward
Chevion Mordechai
Henley III Raymond
Yissum Research Development Company of the Hebrew University of
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