finasteride, Propecia
Interaction of chronic ethanol exposure and finasteride: sex and strain differences.

Finn DA, Long SL, Tanchuck MA, Crabbe JC.

Portland Alcohol Research Center, Department of Veterans Affairs Medical Center, VAMC Research (R&D-49), 3710 SW U.S. Veterans Hospital Road, Portland, OR 97239, USA. finnd ohsu.edu

The neurosteroid allopregnanolone (ALLOP) is a very potent positive modulator of gamma-aminobutyric acidA (GABAA) receptors that can modulate ethanol (EtOH) withdrawal. The 5alpha-reductase inhibitor finasteride blocks the formation of ALLOP from progesterone and was recently found to reduce some effects of EtOH. Thus, the present studies were conducted to determine the effect of finasteride on chronic EtOH withdrawal severity in male and female C57BL/6 (B6) and DBA/2 (D2) mice. The animals were exposed to 72 h EtOH vapor or air and received four injections of finasteride (50 mg/kg ip) 24 h prior to, and each day of, the EtOH vapor exposure. Upon removal from the inhalation chambers, handling-induced convulsions (HICs) were measured hourly for the first 12 h and then again at 24 h. EtOH withdrawal severity was significantly greater in D2 than in B6 mice. Pretreatment with finasteride significantly decreased EtOH withdrawal severity only in the female D2 mice, produced a nonselective suppressive effect on HIC in male B6 and D2 mice, and did not significantly alter HIC in female B6 mice. Finasteride pretreatment significantly decreased blood EtOH concentration (BEC) upon initiation of withdrawal, suggesting that finasteride may affect withdrawal severity via an alteration in EtOH pharmacokinetics.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15251252&dopt=Abstract finasteride Propecia



finasteride, Propecia
Pharmacokinetic parameters and mechanisms of inhibition of rat type 1 and 2 steroid 5alpha-reductases: determinants for different in vivo activities of GI198745 and finasteride in the rat.

Stuart JD, Lee FW, Simpson Noel D, Kadwell SH, Overton LK, Hoffman CR, Kost TA, Tippin TK, Yeager RL, Batchelor KW, Bramson HN.

Division of Biochemistry, Glaxo Wellcome Inc., 5 Moore Drive, Research Triangle Park, NC 27709, USA. jds14989 gsk.com

The interaction of baculovirus expressed rat steroid 5alpha-reductase types 1 and 2 (r5AR1 and r5AR2) with 17beta-N-(2,5-bis(trifluoromethyl)phenyl)carbamoyl-4-aza-5alpha-androst-1-en-3-one (GI198745) was investigated at pH 7 and 37 degrees. This 5alpha-reductase inhibitor was found previously to be a time-dependent inhibitor of the two human 5alpha-reductase isozymes. In contrast, we demonstrate in the present study that although GI198745 is a potent time-dependent inhibitor of r5AR2, it is a classical rapid-equilibrium inhibitor of r5AR1. This type of behavior with human and rat 5alpha-reductases has been shown for the inhibitor 17beta-(N-tert-butylcarbamoyl)-4-aza-5alpha-androst-1-en-3-one (finasteride), a current therapy for benign prostatic hyperplasia. Inhibition of r5AR1 by GI198745 was competitive with testosterone and followed Michaelis-Menten kinetics with a K(i) value of 0.3 +/- 0.02 nM. Data for the inhibition of r5AR2 by GI198745 were consistent with a two-step mechanism, where K(i) is the dissociation constant for an initial enzyme-inhibitor complex and k(3) is the rate constant for the second slow step. The pseudo-bimolecular rate constant (k(3)/K(i)) for the association of GI198745 with r5AR2 was (2.0 +/- 0.4) x 10(7) M(-1) sec(-1). The high affinity of this inhibitor for r5AR2 was further demonstrated by the inability of the enzyme-inhibitor complex to dissociate after approximately 7 days of dialysis at 4 degrees. Both GI198745 and finasteride appear to inactivate r5AR2 by apparent irreversible modification, but are classical, reversible inhibitors of r5AR1. Therefore, we hypothesize that because of its pharmacokinetic parameters and increased potency against r5AR1, GI198745 is more effective than finasteride in preventing the growth of the rat prostate.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11543729&dopt=Abstract finasteride Propecia



finasteride, Propecia
The person-years saved model and other methodologies for assessing the population impact of cancer-prevention strategies.

Unger JM, LeBlanc M, Thompson IM, Coltman CA Jr.

Southwest Oncology Group Statistical Center, Seattle, WA, USA. junger fhcrc.org

The results of the Prostate Cancer Prevention Trial spurred debate because finasteride was found to reduce the period prevalence of prostate cancer by about 25% while also increasing the rate of high-grade prostate cancers. Assessing how finasteride would impact mortality at the population level is key to evaluating the public health implications of these results. Any model for evaluating the impact of chemoprevention at the population level will involve methods for assigning weights to competing outcomes of the chemoprevention. The person-years saved model, which uses survival to weigh outcomes, assesses the impact on population mortality and has particular strengths. The person-years saved model shows that more than 300,000 person-years would be saved during a period of 10 years with the widespread use of finasteride, assuming no change in the rate of high-grade prostate cancers. The rate of high-grade prostate cancers in the population, about 20% in any given year, would have to nearly triple to 60% for the net positive impact of finasteride to be zero. The person-years saved model shows that the administration of finasteride is likely to result in a net positive impact of finasteride on population mortality, even with an increase in the rate of high-grade prostate cancers. Future models may use other outcomes to assess population impact, including economic, quality-of-life, or various combinations of outcomes. Copyright 2004 Elsevier Inc.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15283898&dopt=Abstract finasteride Propecia



finasteride, Propecia
Comparison of the pharmacological effects of a novel selective androgen receptor modulator, the 5alpha-reductase inhibitor finasteride, and the antiandrogen hydroxyflutamide in intact rats: new approach for benign prostate hyperplasia.

Gao W, Kearbey JD, Nair VA, Chung K, Parlow AF, Miller DD, Dalton JT.

Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, Ohio State University, Columbus, Ohio 43210, USA.

Tissue-selective androgen receptor modulators (SARMs) demonstrate tissue selectivity in both castrated and intact male rats, behaving as partial agonists in androgenic tissues (i.e. prostate and seminal vesicle), but full agonists in anabolic tissues (i.e. levator ani muscle). The partial agonist activity of SARMs (compounds S-1 and S-4) in the prostate of intact rats suggested that SARM could be used for androgen suppression in the treatment of benign prostate hyperplasia (BPH). This study was designed to explore the mechanisms of action of SARM and to characterize the tissue selectivity of S-1 in intact male rats compared with that of hydroxyflutamide (antiandrogen) and finasteride (5alpha-reductase inhibitor), two major drugs used for androgen suppression treatment of BPH. In intact male rats, S-1 (5, 10, and 25 mg/kg) selectively decreased the prostate weight with similar efficacy to finasteride (5 mg/kg), without affecting the levator ani muscle or increasing the plasma levels of testosterone, LH, and FSH. Hydroxyflutamide (0.5, 1, 5, 10, and 25 mg/kg), however, decreased both the prostate and levator ani muscle weights without any selectivity and increased plasma hormone levels in a dose-dependent manner. Furthermore, S-1 and S-4 showed very weak inhibitory effects toward transiently expressed type I and II human 5alpha-reductase (Ki, >20 microm) during in vitro assays. Therefore, although S-1 and finasteride showed very similar suppressive effects in the prostate of intact male rats, they decreased prostate size via different mechanisms of action. S-1 simply worked as androgen receptor partial agonist, whereas finasteride inhibited prostatic 5alpha-reductase. These studies indicate that SARMs may demonstrate clinical utility as single agent or combination therapy for BPH.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15308613&dopt=Abstract finasteride Propecia



finasteride, Propecia
Finasteride-associated male infertility.

Glina S, Neves PA, Saade R, Netto NR Jr, Soares JB, Galuppo AG.

Human Reproduction Unit, Albert Einstein Jewich Hospital, Sao Paulo, SP, Brazil. glinas terra.com.br

Finasteride is a potent and specific inhibitor of the 5alpha-reductase enzyme in men. Clinical studies have shown that finasteride 1mg/day is effective for promoting hair growth in men with male pattern hair loss. However, there is a concern about the use of finasteride, especially in young fertile patients, because of its action on testosterone metabolism. This paper describes 3 cases of young patients who had very poor seminal quality during finasteride treatment (1 mg/day), and their seminal quality greatly improved after cessation of finasteride treatment. Two of them presented with a left varicocele and the other was obese. We hypothesize that finasteride may not dramatically change the spermatogenesis process in healthy men, but in patients with conditions related to infertility, an amplification of the negative influence of finasteride could occur. Future studies should be done to clarify the extent of the effect of finasteride in patients fertility problems.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15361986&dopt=Abstract finasteride Propecia



finasteride, Propecia
An economic evaluation of doxazosin, finasteride and combination therapy in the treatment of benign prostatic hyperplasia.

McDonald H, Hux M, Brisson M, Bernard L, Nickel JC.

Innovus Research Inc., Burlington, Ontario, Canada.

OBJECTIVE: The Proscar Long-Term Efficacy and Safety Study (PLESS) and the Medical Therapy of Prostatic Symptoms (MTOPS) study provide new evidence regarding the benefits of finasteride in the treatment of benign prostatic hyperplasia (BPH). The objective of this study was to utilize data from the PLESS and MTOPS studies to assess the cost-utility of finasteride and finasteride in combination with doxazosin, compared to doxazosin alone in men with moderate to severe BPH symptoms. METHODS: A semi-Markov decision analytic model was constructed to estimate the clinical consequences, costs and cost-utility of doxazosin, finasteride, and combination therapy. Analyses were conducted for a 15-year time frame from the perspective of the Ontario Ministry of Health and Long Term Care (MOHLTC). Results are reported stratified by baseline serum prostate-specific antigen (PSA) level according to all baseline serum PSA levels, patients with baseline serum PSA > 1.3 ng/ml, and patients with baseline serum PSA > 3.2 ng/ml. RESULTS: Compared to doxazosin alone, combination therapy was more expensive but more effective. Cost-utility ratios ranged from 27,823 dollars/QALY for patients with PSA > 3.2 ng/ml to 34,085 dollars/QALY for all patients. Finasteride, although dominated by doxazosin, may be cost-effective compared to watchful waiting in patients who fail doxazosin and do not choose to proceed to surgery. Compared to watchful waiting, cost-utility ratios for finasteride ranged from 35016 dollars/QALY for patients with PSA > 3.2 ng/ml to 44,336 dollars/QALY for all patients. Results were robust across a wide range of sensitivity analyses. CONCLUSIONS: Combination therapy is cost-effective compared to doxazosin with cost-utility ratios under 40,000 dollars/QALY across a wide range of scenarios. The cost-effectiveness of combination therapy increases as serum PSA level increases.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15380054&dopt=Abstract finasteride Propecia