Hairloss Study Abstract: Effect of MK-386, a novel inhibitor of type 1 5 alpha-reductase, alone and in

Title: Effect of MK-386, a novel inhibitor of type 1 5 alpha-reductase, alone and in combination with finasteride, on serum dihydrotestosterone concentrations in men.
Title Abreviation: J Clin Endocrinol Metab		Date of Pub: 1996 Aug
Author: Schwartz JI; Van Hecken A; De Schepper PJ; De Lepeleire I; Lasseter KC; Shamblen EC; Winchell GA; Constanzer ML; Chavez CM; Wang DZ; Ebel DL; Justice SJ; Gertz BJ;
Issue/Part/Supplement: 8	Volume Issue: 81		Pagination: 2942-7
MESH Headings: Adult; Azasteroids (AE/PD); Double-Blind Method; Drug Synergism; Finasteride (PD); Human; Male; Osmolar Concentration; Oxidoreductases (AI); Stanolone (BL); Support, Non-U.S. Gov't; -RN-;
Journal Title Code: HRB	Publication Type: CLINICAL TRIAL
Date of Entry: 961223N	Entry Month: 9702
Country: UNITED STATES	Index Priority: 1
Language: Eng	Unique Identifier: 96320086
Unique Identifier: 96320086	ISSN: 0021-972X
Abstract: Two isozymes (types 1 and 2) of 5 alpha-reductase (5 alpha R; EC 1.3.99.5), with differential tissue distribution, have been identified in humans. These enzymes catalyze the reduction of testosterone (T) to dihydrotestosterone (DHT). The contributions of each of these isozymes to serum and tissue concentrations of DHT remain to be fully defined. Finasteride, a selective inhibitor of type 2 5 alpha R, lowers circulating DHT levels by approximately 70% in men after treatment with 5 mg daily. MK-386 (4,7 beta-dimethyl-4-aza-5 alpha-cholestan-3-one) is a new selective inhibitor of type 1 5 alpha R. A single rising dose, alternating panel, trial in 16 healthy males (age range, 21-25 yr) studied the effect of 0.1-100 mg MK-386. DHT was maximally reduced by 20-30% relative to placebo at MK-386 doses of 10 mg or more, orally, by 24 h posttreatment (P < 0.01 vs. placebo). No consistent effect on T concentrations was evident. In a second trial, finasteride (5 mg) was given for 19 days to 10 healthy young men (age range, 24-47 yr); a 25-mg dose of MK-386 was added for 2 days of combination therapy after at least 10 days of finasteride treatment. Withdrawal of MK-386 was followed by 5-6 days of finasteride follow-up treatment. Finasteride alone reduced DHT, on the average, by 68.7% (SE = 3.4%). Addition of MK-386 suppressed DHT by 89.5% (SE = 1.4%) relative to baseline (P < 0.01 vs. effect of finasteride alone). Small increases in serum T were observed with finasteride alone and in combination with MK-386 (approximately 10% and 19%, respectively). These data are consistent with selective 5 alpha R type 1 inhibition in man by MK-386 and the prediction that types 1 and 2 5 alpha R account for all, or nearly all, of circulating DHT. Further clinical trials are needed to assess the therapeutic utility of type 1 5 alpha R inhibition as well as that of combined inhibition of types 1 and 2 5 alpha R.
Abstract By: Author
Address: Merck Research Laboratories, Rahway, New Jersey 07065, USA.