Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-11-18
1999-06-15
Goldberg, Jerome D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514456, A61K 31335, A61K 3135
Patent
active
059122650
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to the use of flavanolignanes, alone or combined with known chemotherapeutic agents, for the preparation of medicaments for the therapy and prophylaxis of uterus, ovary and breast tumors.
BACKGROUND OF THE INVENTION
Recently, some flavonoids have been found to have antitumoral activity (Verna, Cancer Research 48, 5754, 1988) and chemoprophylactic activity in some tumors (Cassady, J. Nat. Prod. 53, 23, 1990). Particularly quercetin, a flavonoid which is almost ubiquitous in plants, has proved some inhibiting activity on the proliferation of human leukemia cells (Larocca, Br. J. of Haematology 75, 489, 1990) and on other cell lines (Scambia, Br. J. Cancer 62, 942, 1990--Int. J. Cancer 46, 1112, 1990--Cancer Chemother. Pharmacol. 28, 255, 1991--Gynecologic Oncology 45, 13, 1992) besides having a synergistic activity with the usual chemotherapeuticals. Though the mechanism of such an inhibiting action on proliferation is unknown, it seems to be connected with the interaction of this flavonoid with the estrogen receptors of type II (Markaverich, J. steroid Biochem. 30, 71, 1988). These receptors, first described by Clark (J. Biol. Chem. 253, 7630, 1978) in the rat uterus, are different from the real estrogen receptors (ER) since these are present in a higher concentration and have a dissociation affinity constant (K.sub.D : 10-20 nM) for estradiol lower than that of the estrogen receptors (K.sub.D : 0.2-1 nM).
SUMMARY OF THE INVENTION
The invention relates to methods for preventing, inhibiting, or suppressing tumors by administering to a person in need of such treatment a therapeutically effective amount of a flavanolignane selected from the group of silymarin,, silybin, silidianin, silicristin, dehydrosilybin, and mixtures thereof. The flavanolignane exhibits antagonistic activity on type II estrogen receptors and antiproliferative activity. In one embodiment, the flavanolignane is provided in a concentration from 0.01 .mu.M to 20 .mu.M. In a preferred embodiment, the flavanolignane is provided in an amount from 50 to 1,500 mg/day.
In a preferred embodiment, the method also includes administering a therapeutically amount of a different antitumor agent with the flavanolignane. In a more preferred embodiment, the different antitumor agent is administered concurrently or sequentially with the flavanolignane. In another preferred embodiment, the different antitumor agent includes cisplatin or adriamycin.
In one embodiment, the flavanolignane is administered together with a pharmaceutically acceptable carrier or excipient. In a preferred embodiment, the carrier or excipient includes a glyceride or a phospholipid. In a more preferred embodiment, the glyceride includes a liquid semi-synthetic glyceride of one or more medium-chain fatty acids. In a different embodiment, the administration is selected to be oral.
The invention also relates to antitumor pharmaceutical compositions including a therapeutically effective amount of a flavanolignane selected from the group of silymarin, silybin, silidianin, silicristin, dehydrosilybin, and mixtures thereof, in combination with a different antitumor agent. In one embodiment, the flavanolignane is present in a concentration from 0.01 .mu.M to 20 .mu.M. In a preferred embodiment, the composition includes an amount from 50 to 1,500 mg/day of the flavanolignane.
In a preferred embodiment, the different antitumor agent is concurrently administered with the flavanolignane. In a more preferred embodiment, the different antitumor agent includes cisplatin or adriamycin.
In another embodiment, the composition includes a pharmaceutically acceptable carrier or excipient. In a preferred embodiment, the carrier includes a phospholipid or a liquid semi-synthetic glyceride of one or more medium-chain fatty acids. In a different embodiment, the composition is suitable for oral administration.
The invention also relates to a pharmaceutical composition includes a therapeutically effective amount of a flavanolignane selected from the gr
REFERENCES:
Mai et al., Zhonghua Xinxueguanbing Zazhi, 15(1), 49-51, Abstract only, 1987.
Pietrangelo et al., Gastroenterology, 109(6), 1941-9 Abstract only, 1995.
V. Steele et al., "Preclinical Efficacy Evaluation of Potential Chemopreventive Agents in Animal Carcinogenesis Models: Methods and Results From the NCI Chemoprevention Drug Development Program," Journal of Cellular Biochemistry, Supplement 20:32-54 (1994).
Abstract No. 95-215777, "Capsule For Curing Hepatitis," Derwent Publications Ltd., p. 1, Apr. 27, 1994.
R. Invernizzi, et al., "Silymarine During Maintenance Therapy of Acute Promyelocytic Leukemia," Haematologica, Letters to the Editor, 78:340-341 (1993).
V. Steele et al., "Inhibition of Transformation in Cultured Rat Tracheal Epithelial Cells by Potential Chemopreventive Agents," Cancer Research, 50:2068-2074 (Apr. 1, 1990).
Bombardelli Ezio
Morazzoni Paolo
Goldberg Jerome D.
Indena S.p.A.
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