Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1999-09-09
2001-03-27
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
active
06207659
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a method of using 17&agr;-dihydroequilenin and metabolic conjugates thereof to reduce and prevent ischemic heart disease in males and females without causing endometrial proliferation in females and without producing feminizing changes in males. More particularly, the present invention relates to the use of 17&agr;-dihydroequilenin in atherosclerotic mammals and to evaluate its effects on plasma apolipoprotein, glucose, insulin concentrations, coronary artery vasomotor function, and reproductive organ and mammary gland proliferation.
Postmenopausal estrogen replacement therapy has gained wide recognition as a lifelong preventive regimen for the reduction of osteoporotic fracture and ischemic heart disease. Unfortunately, good scientific evidence has failed to persuade the majority of menopausal women that the benefits of long-term estrogen replacement therapy are worth the inconvenience or anxiety resulting from its side effects, especially vaginal bleeding and the putative increase in breast cancer risk. Additionally, part of the evidence of estrogen effects in preventing ischemic heart disease in the United States is from studies that used unopposed conjugated equine estrogens. The current evidence is unclear as to whether the addition of progestins, necessary to prevent iatrogenically induced endometrial carcinoma, may either partially or completely negate the cardioprotective effect of unopposed estrogens. Several of the inventors have described a component of Premarin® (Wyeth-Ayerst, Princeton, N.J.), 17&agr;-dihydroequilenin (DHEN), that caused no uterine hypertrophy in ovariectomized rats compared with ovariectomized controls and compared with a doubling of uterine weight in Premarin treated ovariectomized rats. [Washburn S A et al., A conjugated equine estrogen with differential effects on uterine weight and plasma cholesterol in the rat.
Am J Obstet Gynecol
1993;169:251-6]. It was determined that DHEN caused a 70% reduction in total plasma cholesterol concentrations compared with ovariectomized controls and compared with a 15% reduction of total plasma cholesterol in ovariectomized rats treated with oral Premarin®.
Currently, there are no hormone replacement therapies that deliver established benefits to menopausal females and males such as the prevention and/or reduction of atherosclerotic heart disease without causing endometrial proliferation or other side effects of the type previously mentioned. Thus, there remains a need for an alternative hormone replacement therapy for menopausal women and men without side effects or the need to take concomitant progestin therapy.
SUMMARY OF THE INVENTION
The present invention is directed to a method of using 17&agr;-dihydroequilenin (DHEN), a constituent of conjugated equine estrogens, to reduce and prevent atherogenesis by 1) preventing endothelium-dependent vasoconstriction in both males and menopausal females; 2) increasing apolipoprotein A-1; 3) improving insulin sensitivity (while decreasing plasma insulin concentrations without reducing glucose concentrations); 4) reducing LDL accumulation; and 5) reducing arterial peroxidation. Further, DHEN does not appear to have any proliferation or trophic effects on the female macaque reproductive or mammary organs, thus, making DHEN an attractive single-agent hormone replacement therapy that may be used without the need for a concomitant progestin. Additionally, DHEN does not appear to have any feminizing effects on the male genitourinary system or mammary gland, making DHEN a potential treatment for men in the prevention of ischemic heart disease without the feminizing side effects of the traditional estrogen regimen and may prevent prostate hyperplasia and neoplasia.
The present invention further provides a method of using DHEN for the treatment of the above conditions and/or diseases by administering a therapeutically effective amount of DHEN or a mammalian metabolic conjugate thereof and an appropriate pharmaceutical carrier.
In preventing and/or reducing atherosclerosis, DHEN or a metabolic conjugate thereof is administered in therapeutically effective amounts to mammals with atherosclerosis or to those susceptible to atherosclerosis or conditions related thereto. Other groups of mammals that are susceptible to the risk of atherosclerosis will be apparent to those skilled in the art.
The term “therapeutically effective amount” as used in the present invention is defined as the dose which provides effective treatment or prevention of the above described conditions and/or diseases to mammals, in particular humans.
The mammalian metabolic conjugates used in the present invention are sulfates and glucuronides of 17&agr;-dihydroequilenin. 17&agr;-dihydroequilenin can be used either in the form of a mono- or di-conjugate. It is further contemplated that any derivative of 17&agr;-dihydroequilenin that forms 17&agr;-dihydroequilenin or conjugate thereof in vivo may be used in treating or preventing the conditions and/or diseases described hereinabove.
In another aspect of the present invention, mammals susceptible to atherosclerotic heart disease include men and women.
In yet another aspect of the present invention, the mammal susceptible to atherosclerotic heart disease is a menopausal woman.
The route of administration for DHEN is selected from the group consisting of oral, intravenous, parental, transdermal, rectal, intravaginal, intranasal, and intrabronchial administration. However, oral dosing is the preferred route of administration.
The preceding and further objects of the present invention will be appreciated by those of ordinary skill in the art from a reading of the detailed description of the preferred embodiments which follow, such description being merely illustrative of the present invention.
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Washburn S.A. et al., A Conjugated Equine Estrogen With Differential Effects on Uterine Weight and Plasma Cholesterol in the Rat. Am J Obstet Gynecol 1993; 169:251-6.
Wagner J.D. et al., A Non-Feminizing Conjugated Equine Estrogen Decreases Artenal LDL Degradation and Improves Vascular Reactivity in Male Rhesus Monkeys (abstract). Circulation 1995; 92:1-627.
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Cefalu W.T. et al., The Effects of Hormone Replacement Therapy on Insulin Sensitivity in Surgically Postmenopausal Cynomolgus Monkeys (Macaca fascicularis). Am J Obstet Gynecol 1994;171:440-5.
Wagner J.D. et al., Estrogen and Progesterone Replacement Therapy Reduces Lipoprotein Accumulation in the Coronary Arteries of Surgically Postmenopausal Cynomolgus Macaques. J Clin Invest 1991;88:1995-2002.
Goodman A.L. et al., Composite Pattern of Circulating LH, FSH, Estradiol, and Progesterone During the Menstrual Cycle in Cynomolgus Monkeys. Pro Soc Exp Biol Med 1977;155:479-81.
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Cline J.M. et al., Effects of Hormone Replacement Therapy on the Mammary Gland of Surgically Postmenopausal Cynomolgus Macaques. Am J Obstet Gynecol 1996;174:93-100.
Cline J.M. et al., Divergent Effects of Hormone Replacement in Mammary and Endometrial Tissues of Macaques (abstract). Menopause 1995;2:255.
Cattoretti G. et al., Monoclonal Antibodies Against Recombinant Parts of the Ki-67 Antigen (MIB1 and MIB3) Detect Proliferating Cells in Microwave-Processed Formalin-Fixed Paraffin Sections. J. Pathol 1992;168:357-63.
Lindholm J. et al., A Morphometric Filter Improves the Diagnostic Value of Morphometric Analyses of Frozen Histophathologic Sections From Mammary Tumors. Anal Cell Phatho1992;4:443-9.
Williams J. K. et al., Determinantsio
Adams Michael R.
Adelman Steven J.
Clarkson Thomas B.
Cline J. Mark
Register Thomas C.
Henley III Raymond
Kennedy Pat Winston
Kilpatrick & Stockton LLP
Wake Forest University
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