finasteride, Propecia
Finasteride, a 5alpha-reductase inhibitor, blocks the anticonvulsant activity of progesterone in mice.

Kokate TG, Banks MK, Magee T, Yamaguchi S, Rogawski MA.

Neuronal Excitability Section, Epilepsy Research Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1408, USA.

Progesterone is an effective anticonvulsant against pentylenetetrazol (PTZ) seizures. This action is hypothesized to require the metabolic conversion of progesterone to the gamma-aminobutyric acidA receptor potentiating neuroactive steroid allopregnanolone by 5alpha-reductase isoenzymes followed by 3alpha-hydroxy oxidoreduction. We evaluated this possibility using the competitive 5alpha-reductase inhibitor finasteride. Progesterone (50-200 mg/kg, i.p.) protected mice against PTZ-induced seizures in a dose-dependent manner (ED50, 94 mg/kg). Pretreatment with finasteride (50-300 mg/kg, i.p.) produced a dose-dependent (ED50, 146 mg/kg) reversal of the protective effects of progesterone (2 x ED50 dose = 188 mg/kg). In contrast, finasteride (up to 300 mg/kg) failed to affect the anticonvulsant activity of allopregnanolone (10-30 mg/kg, i.p.; ED50, 12 mg/kg). Finasteride (up to 300 mg/kg) did not block the protective effect of high doses of progesterone (250-350 mg/kg) on tonic hindlimb extension in the maximal electroshock seizure test (progesterone ED50, 235 mg/kg). The anticonvulsant activity of progesterone against PTZ-induced seizures can be blocked by 5alpha-reductase inhibition, providing strong evidence that the anticonvulsant effect of the steroid in this model is mediated by its active metabolite allopregnanolone.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9918575&dopt=Abstract finasteride Propecia



finasteride, Propecia
Finasteride: a review of its use in male pattern hair loss.

McClellan KJ, Markham A.

Adis International Limited, Mairangi Bay, Auckland, New Zealand. demail adis.co.nz

The 5alpha-reductase inhibitor finasteride blocks the conversion of testosterone to dihydrotestosterone (DHT), the androgen responsible for male pattern hair loss (androgenetic alopecia) in genetically predisposed men. Results of phase III clinical studies in 1879 men have shown that oral finasteride 1 mg/day promotes hair growth and prevents further hair loss in a significant proportion of men with male pattern hair loss. Evidence suggests that the improvement in hair count reported after 1 year is maintained during 2 years' treatment. In men with vertex hair loss, global photographs showed improvement in hair growth in 48% of finasteride recipients at 1 year and in 66% at 2 years compared with 7% of placebo recipients at each time point. Furthermore, hair counts in these men showed that 83% of finasteride versus 28% of placebo recipients had no further hair loss compared with baseline after 2 years. The clinical efficacy of oral finasteride has not yet been compared with that of topical minoxidil, the only other drug used clinically in patients with male pattern hair loss. Therapeutic dosages of finasteride are generally well tolerated. In phase III studies, 7.7% of patients receiving finasteride 1 mg/day compared with 7.0% of those receiving placebo reported treatment-related adverse events. The overall incidence of sexual function disorders, comprising decreased libido, ejaculation disorder and erectile dysfunction, was significantly greater in finasteride than placebo recipients (3.8 vs 2.1%). All sexual adverse events were reversed on discontinuation of therapy and many resolved in patients who continued therapy. No other drug-related events were reported with an incidence > or =1% in patients receiving finasteride. Most events were of mild to moderate severity. Oral finasteride is contraindicated in pregnant women because of the risk of hypospadias in male fetuses. CONCLUSIONS: Oral finasteride promotes scalp hair growth and prevents further hair loss in a significant proportion of men with male pattern hair loss. With its generally good tolerability profile, finasteride is a new approach to the management of this condition, for which treatment options are few. Its role relative to topical minoxidil has yet to be determined.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9951956&dopt=Abstract finasteride Propecia



finasteride, Propecia
An economic evaluation of finasteride for treatment of benign prostatic hyperplasia.

Baladi JF, Menon D, Otten N.

Canadian Coordinating Office for Health Technology Assessment, Ottawa, Ontario, Canada.

This evaluation was conducted at the request of a Canadian provincial government considering finasteride for formulary inclusion. The comparator therapies, in accordance with Canadian pharmacoeconomic guidelines, were the most prevalent treatment [transurethral resection of the prostate (TURP)] and the lowest cost treatment (watchful waiting). All costs were measured in 1994 Canadian dollars ($Can), and both costs and outcomes were discounted at 5% per annum. Cost-effectiveness and cost-utility ratios were calculated, and were found to be dependent on initial symptom severity and the anticipated duration of treatment with finasteride. The drug was shown to be the dominant alternative compared with both TURP and watchful waiting for patients with moderate symptoms, when the duration of drug therapy is 3 years or less. However, finasteride is a weak alternative for patients with severe symptoms who are treated for 4 years or more. For other groups of patients (i.e. moderate symptoms and on finasteride for 4 years or more; severe symptoms and on treatment for 3 years or less), the drug can improve health-related quality of life, but at a cost of between $Can3000 and $Can97,000 per incremental quality-adjusted life year (1994 dollars). Our study also indicated that it would cost between $Can2.7 million and $Can5.6 million, depending on the severity mix of the patients, to treat cohort of 10,000 men aged 60 years or older with finasteride.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10160256&dopt=Abstract finasteride Propecia



finasteride, Propecia
The impact of 5-alpha-reductase inhibitors on the number of prostatectomies for benign prostatic hyperplasia.

Agha AH, Roy JB, Culkin DJ, Lyon K.

Department of Urology, University of Oklahoma College of Medicine, Oklahoma City, USA.

To determine the impact of a 5-alpha-reductase inhibitor on the need for surgical treatment of symptomatic benign prostatic hyperplasia (BPH) in clinical urologic practice, we retrospectively reviewed records of 794 patients treated with pharmacotherapy or surgery (or both). The number of transurethral resections of the prostate (TURPs) performed during the 30 months since introduction of finasteride was compared with the number performed during the 30 months before finasteride became available. The alpha-blockers doxazosin and prazosin were used during both times for the treatment of BPH. Of the 619 patients treated with drugs, 88.5% received finasteride for a mean of 249.6 days. The alpha-blockers, either alone or combined with finasteride, were prescribed for 11.5% of patients for a mean of 179 days. In the 30 months after the introduction of finasteride, 65 patients underwent TURP: 28 of these men had initially received drug therapy. In contrast, 138 TURPs were performed in the 30 months prior to the availability of finasteride. The use of a 5-alpha-reductase inhibitor as primary medical therapy for symptomatic BPH decreased the number of prostatectomies by 52.9% (65 vs 138). This observation warrants corroboration through additional prospective studies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10163332&dopt=Abstract finasteride Propecia



finasteride, Propecia
Hair growth effects of oral administration of finasteride, a steroid 5 alpha-reductase inhibitor, alone and in combination with topical minoxidil in the balding stumptail macaque.

Diani AR, Mulholland MJ, Shull KL, Kubicek MF, Johnson GA, Schostarez HJ, Brunden MN, Buhl AE.

Upjohn Laboratories, Kalamazoo, Michigan 49001.

A 5 alpha-reductase inhibitor, finasteride, was administered orally at 0.5 mg/day, alone or in combination with topical 2% minoxidil, for 20 weeks to determine the effects on scalp hair growth in balding adult male stumptail macaque monkeys. A 7-day dose-finding study showed that both 0.5- and 2.0-mg doses of the drug produced a similar diminution in serum dihydrotestosterone (DHT) in male stumptails. Hair growth was evaluated by shaving and weighing scalp hair at baseline and at 4-week intervals during treatment to obtain cumulative delta hair weight (sum of the 4-week changes in hair weight from baseline) for the 20-week study. The activity of the 5 alpha-reductase enzyme was assessed by RIA of serum testosterone (T) and DHT at 4-week intervals. The combination of finasteride and minoxidil generated significant augmentation of hair weight (additive effect) compared to either drug alone. Finasteride increased hair weight in four of five monkeys. When the data of the one nonresponsive monkey were excluded, finasteride elicited a significant elevation in hair weight compared to topical vehicle alone. Minoxidil also evoked a significant increase in hair weight compared to vehicle alone. Serum T was unchanged, whereas serum DHT was significantly depressed in monkeys that received either finasteride or the combination of finasteride and minoxidil. These data suggest that inhibition of the conversion of T to DHT by this 5 alpha-reductase inhibitor reverses the balding process and enhances hair regrowth by topical minoxidil in the male balding stumptail macaque.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1309834&dopt=Abstract finasteride Propecia



finasteride, Propecia
Four-amino acid segment in steroid 5 alpha-reductase 1 confers sensitivity to finasteride, a competitive inhibitor.

Thigpen AE, Russell DW.

Department of Molecular Genetics, University of Texas, Southwestern Medical Center, Dallas 75235.

The 4-azasteroid 17 beta-(N-t-butyl)carbamoyl-4-aza-5 alpha-androst-1-en-3-one (finasteride) is 100-fold more potent as a competitive inhibitor of the rat NADPH:delta 4-3-oxosteroid-5-alpha- oxidoreductase (steroid 5 alpha-reductase) type 1 enzyme (Ki = 3-5 nM) than of the human type 1 enzyme (Ki greater than or equal to 300 nM). In this study, we exploit this differential sensitivity to map a major determinant of finasteride sensitivity in steroid 5 alpha-reductase. Chimeric steroid 5 alpha-reductase cDNAs composed of different combinations of rat and human exon sequences were created by genetic engineering, expressed in human embryonic kidney 293 cells, and assayed for their sensitivity to finasteride. Hybrid proteins containing sequences encoded by rat exon 1 were found to be as sensitive to finasteride as the parental enzyme. The exchange of progressively smaller protein segments encoded within exon 1 identified a tetrapeptide sequence (Val-Ser-Ile-Val) in the rat enzyme that conferred sensitivity to finasteride. The analogous sequence in the human enzyme (Ala-Val-Phe-Ala) conferred partial resistance to the drug. Finasteride was a competitive inhibitor of the native and all chimeric enzymes tested, suggesting that the tetrapeptide segments form a portion of the substrate-binding domain of steroid 5 alpha-reductase.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1314830&dopt=Abstract finasteride Propecia