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| 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. |
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