CA2240002A1 - Method of decreasing atherosclerosis and its complications - Google Patents

Abstract

A method of decreasing atherosclerosis and its complications including but not limited to myocardialinfarction, stroke and peripheral vascular disease wherein the method involves administering to a human or an animal an amount of a substance sufficient to reduce atherosclerosis.

Description

BACKGROUND OF THE INVENTION
There are many steps in the biosynthesis and utilization by the tissues of testosfierone. Testosterone is made mostly in the testicles. A lesser amount is made in the adrenals. Production is stimulated by secretion of Gn RH or LHRH by the brain, which causes secretion of luteinizing hormone (LH) by the pituitary, which causes the testicles to make testosterone. Testosterone then flows into the blood stream and is absorbed by the target cells. Here it binds to a receptor and is transported into the cell and converted to dihydrotestosterone. This is bound and carried to the nucleus of the cell where it redirects cellular activity by turning on and off DNA. Hormonal manipulation is a term which refers to the reduction of testosterone or its effects by blocking any step in the above process in order to gain a desired effect. Until now the uses of hormonal manipulation include for example treating prostatic carcinoma, and treatment for baldness.
The present invention involves the use of hormonal manipulations in the prevention and treatment of atherosclerosis, coronary heart disease, stroke and peripheral vascular disease.
Leuprolide acetate is a synthetic nonapeptide of naturally occurring gonadotropin-releasing hormone (GnRH or LH-RH), the chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-Beryl-L-tyrosyl-D-leucyl-L-leucyl-L-orginyl-N-ethyl-L-prolinamide acetate salt sold under the trade name Lupron or Lupron Depot, as identified by US patent no. 4.897,256, the entire disclosure is incorporated by reference herein, is known for use in the treatment of prostatic carcinoma.
Leuproiide is a potent inhibitor of gonadotropin secretion known to decrease levels of LHRH, LH and Testosterone.
Goserelin Acetate, a synthetic decapeptide analogue of LHRH or GnRH, is chemically described as an acetate salt of [D-Ser(But)6 Azygly'°] LHRH.
Its chemical structure is pyro-Glu-His-Trp-Ser Tyr-D-Ser(Bu)-Leu-Arg-Pro-Azgly-NH2 acetate [C59H84N 18014 (C2H402) sold under the trade name Zoladex, as identified by the US patent no. 5,510,460, the entire disclosure is incorporated by reference herein, is known for the use in treatment of prostatic carcinoma. Goserelin acetate is a potent inhibitor of gonadotropin secretion known to reduce levels of GnRH or LHRH, LH and Testosterone.
Nilufiamide, a nonsteroidal, orally active, antiandrogen, having the chemical name 5,5-dimethyl3-[4-vitro-3-(trifluoromethyl)phenyl] 2,3-imidazolidinedlone, sold under the trade name Nilandron, as identified by US patent no. 5,023,088, the entire disclosure is incorporated by reference herein, is known for use in treatment of prostatic carcinoma.
Flutamide, an acetanilid, nonsteroidaf androgen having the chemical name, 2-methyl-N-[4-vitro-3-(firifluoromethy!)phenyl] propanamide sold under the trade name Eulexin, as identified by US patent nos. 3,995,060 and 4,474,813, the entire disclosure of which are incorporated by reference herein, Flutamide is known for use in treatment of prostatic carcinoma.

. CA 02240002 1998-06-08 Bicalutamide, a non-sfieroidal antiandrogen, chemical name is propanomide, N-{4cyano-3-(trifiuoromethyl}phenyl]-3-[(4-fluorophenyl)sulfonyl]-hydroxy-2-methyl-(+-) sold under the trade name Casodex, as identified by US
patent no. 4,636,505, the entire disclosure is incorporated by reference herein, is known for use in treatment of prostatic carcinoma.
A retrospective study was performed which compared the rates of patienfi reported heart attack in several groups: 1 - control group of males enfiering the urology office for any routine complaint. 2 - a group of prostate cancer patients treated with Leuprolide acetate. a LHRH inhibitor. 3 - a group of prostate cancer patients treated with Goserelin acetate (Zoladex), a LHRH inhibitor. 4 - a group of prostate cancer pafiients not treated with hormonal manipulation (neither Leuprolide or Goserelin}. 5 - a group of patients treated with I=inasteride (another form of hormonal manipulation}. 6 - all patients on LHRH inhibitors (group 2 +
group 3}.
the patients on either Leuprolide or Goserelin were treated with fihe recommended doses indicated for the treatment of prosfiatic carcinoma, at either one or three month intervals depending on the preparation used. Leuprolide was dosed of 7.5 mg monthly (single intromuscular injection) or at 22.5 mg at 3 month intervals {single intramuscular injection). Goserelin was dosed at 3.6 mg monthly (subcutaneous injection) or at a dose of 10.8 mg at 3 monfih intervals (subcutaneous injection).

The various groups of office patients were given a questionnaire. In groups 2, 3 and 5 only those on drug for at least one year were considered. Cardiac event is defined as either the history of o heart attack or occurrence of coronary artery bypass or angioplasty. In control groups only events occurring in the 3 years prior to the questionnaire are charted. The results were as follows:
No Patients Cardiac EventsSubject YearsEvents/Year Group i (control247 26 741 .0351 no cancer) Group 4 (control69 6 207 .0290 cancer patients) Total Control 316 32 948 .0338 (Groups 1 + 4) Group 2 (i_upron)28 1 118 .00847 Group 3 25 1 62 .0161 (Zoladex) Group 5 - 91 4 242 .0165 (Finasteride) Group 6 50 2 180 .O1 11 (antiLHRH) groups 2 + 3 The observed difference between the proportions of Total Control vs Group 6 (LHRH) is .0226. 95% Confidence )nterval for the difference between the proportions is .00350 to .0418. Patients treated with LHRH inhibitors had fewer heart attacks than controls.

r The observed difference between the proportions of Group 2 (Lupron) and Total Control is .0253. 9S% Confidence Interval for the difference between the proportions is .00514 and .0454. Pafients treated with Leuprolide acetate had fewer heart attacks than controls.
The observed difference between the proportions of Group 3 and Total Control is .0177. Patients treated with Goserelin (Zoladex) had fewer heart attacks than controls.
The observed difference between the proportions of Group 1 (Control) and Group 5 (Finasteride) is .0186. 90% Confidence Interval for the difference between the proportions is .00103 to .0361. Patients treated with Finasteride had fewer heart attacks than control.
Without further elaboration the foregoing will so fully illustrate our invention that others may, by applying current and future knowledge, adopt the same for use under various conditions of service.

Claims (14)

1. A method of decreasing atherosclerosis and its complications including but not limited to myocardial infarction, stroke and peripheral vascular disease comprising administering to an animal or human an amount of a substance which acts to decrease the levels of testosterone or which inhibits the actions of testosterone.

2. A method of decreasing atherosclerosis and its complications including but not limited to myocardial infarction, stroke and peripheral vascular disease comprising administering to a human or an animal an amount of a substance which is an inhibitor of the release of LHRH or GnRH, or any substance which inhibits the action or effects of LHRH, resulting in decreased levels of LH
(luteinizing hormone).

3. A method of decreasing atherosclerosis and its complications including but not limited to myocardial infarction, stroke and peripheral vascular disease comprising administering to an animal or human an amount of Finasteride or other inhibitor of 5 alpha reductase inhibitor or an inhibitor of any subtype of that enzyme resulting in decreased levels of dihydrotestosterone (DHT), in an amount sufficient to reduce atherosclerosis.

4. A method of decreasing atherosclerosis and its complications including but not limited to myocardial infarction, stroke and peripheral vascular disease comprising administering to an animal or human an amount of non-steroidal antiandrogen sufficient to reduce atherosclerosis.

5. The method of Claim 4 comprising administering to a human or an animal an amount of Bicalutamide sufficient to reduce atherosclerosis.

6. The method of Claim 5 wherein the effective amount of Bicalutamide is 50 mg as an oral tablet taken daily.

7. The method of Claim 5 wherein Bicalutamide is administered as a tablet, or as part of a liquid solution or dispersion, or patch, or subcutaneous pellet, or intramuscular injection, or any other method with the intent of accomplishing systemic absorption of the drug sufficient to reduce atherosclerosis.

8. The method of Claim 4 comprising administering to a human or an animal an amount of Flutamide sufficient to reduce atherosclerosis.

9. The method of Claim 8 wherein the effective amount of Flutamide is 250 mg orally three times a day.

10. The method of Claim 5 wherein Flutamide is administered as a tablet, or as part of a liquid solution or dispersion, or patch, or subcutaneous pellet, or intramuscular injection, or any other method with the intent of accomplishing systemic absorption of the drug sufficient to reduce atherosclerosis.

11. The method of Claim 4 comprising administering to a human or an animal an amount of Nilutamide sufficient to reduce atherosclerosis.

12. The method of Claim 11 wherein the effective amount of Nilutamide is 50 mg orally three times a day.

13. The method of Claim 11 wherein Nilutamide is administered as a tablet, or as part of a liquid solution or dispersion, or patch, or subcutaneous pellet, or intramuscular injection, or any other method with the intent of accomplishing systemic absorption of the drug sufficient to reduce atherosclerosis.

14. A method of decreasing atherosclerosis and its complications including but not limited to myocardial infarction, stroke and peripheral vascular disease comprising administering to an animal or human an amount of a substance sufficient to decrease or inhibit synthesis of testosterone.