Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – N-c doai
Reexamination Certificate
2000-07-10
2001-09-11
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
N-c doai
C514S599000, C514S707000, C514S866000, C514S913000, C514S929000
Reexamination Certificate
active
06288110
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of disulfiram as an angiogenesis inhibitor for the preparation of pharmaceutical compositions useful for the treatment of angiogenesis-dependent disorders and to a method of treatment of said disorders.
BACKGROUND OF THE INVENTION
Bis(diethylthiocarbamoyl) disulfide or tetraethylthiuram disulfide, hereinafter disulfiram, is an inhibitor of various enzymes and a chelator of heavy metals. Disulfiram is known as an alcohol deterrent and is the active ingredient of the drug Antabuse used in aversion therapy, an adjunctive treatment for chronic alcoholism (Haley, 1979). Disulfiram has an ampiphilic nature, is soluble in water but it solubilizes better in hydrophobic solutions such as methanol, acetone or chloroform.
Once ingested and absorbed through the intestinal tract or injected intraperitoneally as a colloidal suspension, disulfiram is extensively distributed throughout the body including the brain (Faiman, 1978). It is quickly converted into its main metabolite, diethyldithiocarbamate (DDC) (Eneanya, 1981), whereby the disulfide is reduced to a sulfhydryl group. The DDC produced is then further metabolized via different ways which include a non-enzymatic degradation to diethylamine (DEA) (Brien, 1983).
Both disulfiram and DDC are potent chelators of copper, iron and zinc. Chelation of the metal portion of an enzyme by disulfiram or DDC might lead to the inactivation of such enzyme. Thus disulfiram was shown to inhibit various zinc-containing dehydrogenases, such as aldehyde dehydrogenases as well as oxidases, dopamine-&bgr;-hydroxylases and aldolases (Eneanya, 1981). Inhibition of aldehyde dehydrogenases by disulfiram inhibits glycolysis, the tricarboxylic acid cycle and the pentose phosphate shunt.
Disulfiram was shown to interfere with induction of cancer by various carcinogens, often by inhibiting their metabolic activation, as shown for bladder cancer in rats exposed to N-butyl-N-(4-hydroxybutyl)nitrosamine (Irving, 1979) or to N-butyl-N-(3-carboxypropyl)nitrosamine (Irving, 1983), for liver tumors in rats induced by dimethyl- or diethylnitrosamine (Schmahl, 1976), for intestinal cancer induced by azoxymethane in rats (Nigro, 1978) (probably by blocking the metabolism of azoxymethane), for neoplasia of the large bowl induced by 1,2-dimethylhydrazine (Wattenberg, 1978), and in neoplasia of the forestomach induced by benzo(a)pyrene in mice (Borchert, 1976). Disulfiram inhibited the metabolism of the carcinogen azomethane thus offering protection from the oxymetabolite neoplasia (Fiala, 1977). Disulfiram was also shown to inhibit tumor progression—from papilloma to squamous cell carcinoma—in the murine skin multistage carcinogenesis model (Rotstein, 1988), to inhibit transmammary carcinogenesis induced in mice by 7,12-dimethylbenz(a)anthracene (Rao, 1989) and to reduce the incidence of mammary tumors induced in rats by N-2-fluorenylacetamide or N-hydroxy-N-2-fluorenylacetamide through inhibition of their metabolic activation (Malejka Giganti, 1980). Since a cytosolic aldehyde dehydrogenase is induced during rat hepatocarcinogenesis (Allen, 1982), the inhibitory effect of disulfiram on various carcinogens may be related to its inhibitory effect on aldehyde dehydrogenases.
Disulfiram was shown to protect mice against ifosfamide- and cyclophosphamide-induced urotoxicity when administered simultaneously with said drugs without compromising their anti-tumor activity against Sarcoma 180, EL-4 leukemia or L1210 murine leukemia (Hacker, 1982; Ishikawa, 1991; Ishikawa, 1994). On the other hand, disulfiram did not show any protection against cisplatin nephrotoxicity in humans (Verma, 1990). Disulfiram protected rats against the toxic side effects of 1-(2-hydroxyethyl)-3-(2-chloroethyl)-3-nitrosourea (HECNU), without inhibiting its anti-tumor potency (Habs, 1981). Disulfiram was also shown to potentiate the anti-cancer activity of some agents such as to nitrogen mustard (HN2) cytotoxicity against murine leukemia at 3 mg/mouse (Valeriote, 1989).
Disulfiram, together with ascorbic acid, augmented inhibition of Meth A tumor cell proliferation in vitro by increasing the intracellular oxygen free radicals (Mashiba, 1990). In addition, disulfiram inhibited superoxide dismutase in vivo (Forman, 1980; Ohman, 1986). All of these could result in an increase in oxygen species toxic to the cell thereby making the cell more sensitive to damage by a variety of chemotherapeutic agents or radiation that produce superoxide anions species (Goodman, 1977). Resistance to cyclophosphamide and oxazaphosphorines is related to aldehyde dehydrogenase activity (Magni, 1996; Rekha, 1994), and inhibition of this enzyme by disulfiram thus increase sensitivity to these chemotherapies.
U.S. Pat. No. 4,870,101 (Ku and Doherty, 1989) discloses a method for inhibiting the release of interleukin-1 in animals which comprises administering to said animals an amount of disulfiram effective to inhibit the release of interleukin-1, thus proposing disulfiram for the treatment of IL-1 mediated inflammations such as psoriasis, rheumatoid arthritis, diabetes and atherosclerosis.
Disulfiram, given 0.05% in diet for 2 years, did not increase any tumor type in rats (Cheever, 1990). The toxic dose for disulfiram in normal mice is about 6-10 mg/mouse/day. The LD
50
of disulfiram given orally in rats is 8.6 g/Kg.
None of the above publications describes or suggests the use of disulfiram as an inhibitor of angiogenesis.
SUMMARY OF THE INVENTION
It has now been found in accordance with the present invention that disulfiram inhibits angiogenesis and is able to block neovascularization induced subcutaneously in nude mice.
The present invention thus relates to the use of disulfiram for the preparation of a pharmaceutical composition useful for inhibition of angiogenesis.
The pharmaceutical composition of the invention is suitable for treatment of angiogenesis-dependent diseases including, but not being limited to, ophthalmologic disorders such as diabetic retinopathy, corneal graft neovascularization, neovascular glaucoma, trachoma and retinopathy of prematurity also known as retrolental fibroplasia, dermatologic disorders such as dermatitis and pyogenic granuloma, pediatric disorders such as hemangioma, angiofibroma, and hemophilic joints, orthopedic disorders such as nonunion fractures, neurologic cerebrovascular disorders such as arteriovenous malformation, neoplasms such as leukemia and solid tumors, connective tissue disorders such as scleroderma, and treatment of hypertrophic scars.
Examples of solid tumors that can be treated with disulfiram according to the invention include, but are not limited to, bladder, breast, cervix, ear, esophagus, kidney, larynx, liver, lung, ovary, pancreas, prostate, skin, stomach, thyroid, urethra and uterus carcinomas.
For the preparation of the pharmaceutical compositions of the invention, disulfiram is mixed with pharmaceutically acceptable carriers and conventional excipients to produce unit dosage formulations suitable for administration. Any suitable mode of administration is envisaged by the invention, but oral administration is preferred.
The dosage of disulfiram to be administered daily will depend on the disorder being treated and the age, weight and condition of the patient being treated, and can be determined without difficulty by skilled physicians. Based on the examples herein performed in animals, it can be deduced that dosages between 1-50 mg/person are suitable for humans.
In another aspect, the invention relates to a method for inhibiting angiogenesis in a mammal, particularly humans, which comprises administering to a mammal in need thereof an amount of disulfiram effective for inhibiting angiogenesis.
In still another aspect, the invention relates to the use of disulfiram to prevent cell hyperproliferation and formation of clots along or around medical devices such as stents, catheters, cannulas, electrodes, and the like. In one embodiment, disulfiram may be systemically administered to a patient in which such a device
Browdy and Neimark
Shah Mukund J.
Truong Tamthom N.
Yeda Research and Development Co Ltd.
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