Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-25
2003-08-12
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06605622
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the treatment of fungal infections with estrogenic derivatives.
BACKGROUND OF THE INVENTION
Candidiasis is a fungal infection of mucosal membranes and other tissues. The infection is caused by the yeast-like organism Candida. Numerous species of Candida exist, including
C. albicans.
The recent increase in candidiasis is most likely caused by the rising incidence of AIDS, more intensive regimens of cancer therapy, complications of abdominal or cardio-thoracic surgery, organ transplantations, burns and trauma. Immunocompromised individuals and women of childbearing age, especially pregnant women or women with one or more child births, are known to be more susceptible to microbial pathogenesis. Alteration of the fungi microenvironment is currently considered to be accountable for the initiation of
C. albicans
infection symptoms (1). Changes in pH, temperature, osmotic pressure, and hormonal concentrations are some of the environmental factors that induce virulence expression.
While most candidiasis patients are infected with
C. albicans,
the number of non-
C. albicans
infections has been growing steadily and may reflect the increased use of azole drug prophylaxis and therapy since some non-
C. albicans
species are innately resistant to these drugs. Additional risk factors commonly associated with the onset of candidiasis include protracted, broad-spectrum antibiotic therapies, invasive devices, and prolonged hospital stays. Under these conditions, an antibiotic resistant replacement flora, including one or more fungal species, can proliferate in the gastrointestinal tract and invade from mucosal foci to deep tissues, especially when mucosal integrity has been disrupted as a result of chemotherapy or surgery.
2-Methoxyestradiol (2ME2), an end product of 17&bgr;-estradiol metabolism, is a well-known anti-mitogen that suppresses the growth of rapidly dividing mammalian cells by interfering with the progression of their cell cycle. Although a number of studies have been published regarding the effects of 2ME2 and related derivatives on the proliferation of endothelial and tumor cells, nothing is known about the effects of this metabolite on the replication of non-mammalian cells.
Recently, 17&bgr;-estradiol has emerged as one of the agents that support
C. albicans
germination and growth (1, 2). Specifically, growth of yeast cells in serum stripped of any steroid compound (by means of activated charcoal) results in reduction of the percentage of germinating cells, and thus, in reduction in virulence. Supplementation of the stripped media with exogenous estradiol in nanomolar concentrations restores germination. This property is specific to 17&bgr;-estradiol, since cholesterol and the &agr;-isomer of estradiol do not induce morphogenic changes in
C. albicans.
In addition, certain strains of
C. albicans
require the presence of 17&agr;- or 17&bgr;-estradiol for rapid growth.
The importance of estrogen as a virulence factor is also reinforced by in vivo studies in which estrogen treatment is required to induce susceptibility of oophorectomized to vaginal colonization of
C. albicans
(3, 4), and the presence of an estrogen-binding protein (EBP) in
C. albicans
that binds to estrogen with high affinity and specificity (5, 6).
SUMMARY OF THE INVENTION
The present invention provides compounds that are useful for inhibiting the growth of fungi. The compounds are estrogenic derivatives, such as 2ME2, and analogs thereof. The compounds may be used for treating infections of fungi in humans and animals, or to prevent or inhibit the growth of fungi on any surface. Furthermore, the invention contemplates the use of anti-estrogenic compounds, such as tamoxifen and raloxifene, as anti-fungal treatments.
REFERENCES:
patent: 2584271 (1952-02-01), Huffman
patent: 2846453 (1958-08-01), Hoehn
patent: 3410879 (1968-11-01), Smith et al.
patent: 3470218 (1969-09-01), Farah
patent: 3492321 (1970-01-01), Crabbe
patent: 3496272 (1970-02-01), Kruger
patent: 3956348 (1976-05-01), Hilscher
patent: 4172132 (1979-10-01), Draper et al.
patent: 4212864 (1980-07-01), Tax
patent: 4307086 (1981-12-01), Tax
patent: 4522758 (1985-06-01), Ward et al.
patent: 4743597 (1988-05-01), Javitt et al.
patent: 4994443 (1991-02-01), Folkman et al.
patent: 5001116 (1991-03-01), Folkman et al.
patent: 5135919 (1992-08-01), Folkman et al.
patent: 5504074 (1996-04-01), D'Amato et al.
patent: 5521168 (1996-05-01), Clark
patent: 5621124 (1997-04-01), Seilz et al.
patent: 5643900 (1997-07-01), Fotsis et al.
patent: 5661143 (1997-08-01), D'Amato et al.
patent: 5892069 (1999-04-01), D'Amato et al.
patent: 6011023 (2000-01-01), Clark et al.
patent: 6136992 (2000-10-01), Ram et al.
patent: 6200966 (2001-03-01), Stewart
patent: 6239123 (2001-05-01), Green et al.
patent: 6399773 (2002-06-01), Liu et al.
patent: 1907330 (1969-10-01), None
patent: 3625315 (1998-01-01), None
patent: WO 90/15816 (1990-12-01), None
patent: WO 93/03729 (1993-03-01), None
patent: WO 93/19746 (1993-10-01), None
patent: WO 95/04535 (1995-02-01), None
patent: WO 98/40398 (1998-09-01), None
Beggs, William H. “Anti-candida activity of the anti-cancer drug tamoxifen.” Research Communications in Chemical Pathology and Pharmacology, (1993) Vol 80, No. 1, pp. 125-128 ISSN: 0034-5164.*
Title: Lilopristone/(1-[4-(Dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxy-1-propenyl) estra-4,9-diene-3-one; AK 98734 Publ:Dict. of Drugs (1990), Dict. of Steroids (1991), Dict. of Org. Cmpds (6th Ed) (1996), Dict. of Pharm. Agents (1997).
Title: (paragraphs 583-584) Publ:The Merck Index 11th Editionpp.: 88 Date: 1989.
Author: Adams, E.F. et al. Title: Steroidal regulation of oesteradiol-17B dehydrogenase activity of the human breast cancer cell line MCF-7 Publ:Journal of EndrocrinologyVol/Iss: 188 (1) pp.: 149-154 Date: Jul. 1988.
Author: Aizu-Yokota et al. Title: Natural Estrogens Induce Modulation of Microtubules in Chinese Hamster V79 Cells in Culture Publ:Cancer ResearchVol/Iss: 55 pp.: 1863-1868 Date: May 1, 1995.
Author: Attalia et al. Title: 2-Methoxyestradiol Arrests Cells in Mitosis without Depolarizing Tubulin Publ:Biochemical and Biophysical Research CommunicationsVol/Iss: 228 pp.: 467-473 Date: 1996.
Author: Ayala et al. Title: The Induction of Accelerated Thymic Programmed Cell Death During Polymicrobial Sepsis: Control by Corticosteroids but not Tumor Necrosis Factor (Abstract only) Publ:ShockVol/Iss: 3 (4) pp.: 259-267 Date: Apr. 1995.
Author Banik et al. Title: Orally Active Long-Acting Estrogen (3-(2-propynyloxy)-estra-1,3,5,(10)-triene-17. beta.-ol trimethylacetate) (Identifier only) Publ:SteroidsVol/Iss: 16 (3) pp.: 289-296 Date: 1970.
Author: Bardon et al. Title: Steroid Receptor-Mediated Cytotoxicity of an Antiestrogen and an Antiprogestin in Breast Cancer Cells (Abstract only) Publ:Cancer ResearchVol/Iss: 47 (5) pp.: 1441-1448 Date: Mar. 1, 1987.
Author: Bhat et al. Title: Estradiol-induced Mitotic Inhibition in the Bursa of Fabricius of Male Domestic Duckling Publ:MikroskopieVol/Iss: 39 pp.: 113-117 Date: May 1982.
Author: Blagosklonny et al. Title: Raf-1/bcl-2 Phosphorylation: A Step from Microtubule Damage to Cell Death Publ:Cancer ResearchVol/Iss: 57 pp.: 130-135 Date: Jan. 1, 1997.
Author: Blickenstaff et al. Title: Estrogen-Catharanthus (Vinca) Alkalid Conjugates Publ:Cytotoxic Estrogens in Hormone Receptive Tumorspp.:89-105 Date: 1980.
Author: Boye et al. Title: 185. Deaminocolchinyl Methyl Ether: Synthesis from 2,3,4,4′-Tetramethoxybiphenyl-2-carbaldehyde. Comparison of Antitubulin Effects of Publ:Helvetica Chimica ActaVol/Iss: 72 pp.: 1690-1696 Date: 1989.
Author Brodie, A.M. Title: Aromatase Inhibitors in the Treatment of Breast Cancer (Abstract only) Publ:Journal of Steroid Biochemistry and Molecular BiologyVol/Iss: 49 (4-6) pp.:281-287 Date: Jun. 1994.
Author: Brosens et al. Title: Comparative Study of the Estrogenic Effect of Ethinylestradiol and Mestranol on the Endometrium Publ:Laboratory for Gynecological PhysiopathologyVol/Iss: 14 (6) pp.: 679-685 Date: Dec. 1,
Green Shawn J.
Papathanassiu Adonia
Criares Theodore J.
EntreMed, Inc.
Kilpatrick & Stockton LLP
Kim Jennifer
LandOfFree
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