finasteride, Propecia
Unique preclinical characteristics of GG745, a potent dual inhibitor of 5AR.

Bramson HN, Hermann D, Batchelor KW, Lee FW, James MK, Frye SV.

Division of Biochemistry, Glaxo Wellcome Research Institute, Research Triangle Park, North Carolina 27709, USA.

Selective inhibition of type 2 5alpha-reductase has been shown to be efficacious in the treatment of benign prostatic hyperplasia. Pharmacokinetic and pharmacodynamic results are reported of treatment with a potent inhibitor of both 5alpha-reductase isozymes, GG745, in rats, dogs and men. In the rat, GG745 has a similar effect on DHT-driven prostatic growth as finasteride, another dual 5alpha-reductase inhibitor in this species. However, GG745 appears to be more potent in the rat, a result that likely reflects the greater inherent potency and terminal half-life of GG745 (14 hr) compared with that of finasteride (1 hr). These pharmacokinetic differences are also maintained in the dog (65 and 4 hr for GG745 and finasteride, respectively). From these results, the literature, and in vitro studies, we estimated doses of GG745 likely to prove efficacious in reducing DHT levels in man. These estimated values were predictive of single-dose effects of GG745 in man. Results from single-dose evaluations in man indicate that GG745 has a terminal half-life of approximately 240 hr, and single doses of >10 mg decreased DHT levels significantly more than did single 5-mg doses of finasteride. These data support the hypothesis that a molecule (GG745) that effectively inhibits both 5alpha-reductases will lower serum DHT levels significantly more than a molecule that inhibits only a single 5alpha-reductase isozyme (e.g., finasteride, a selective inhibitor of the type 2 enzyme in man).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9316864&dopt=Abstract finasteride Propecia



finasteride, Propecia
Inhibition of rat alpha-reductases by finasteride: evidence for isozyme differences in the mechanism of inhibition.

Azzolina B, Ellsworth K, Andersson S, Geissler W, Bull HG, Harris GS.

Department of Enzymology, Merck Research Laboratories, Rahway, NJ 07065, U.S.A.

The mechanism of inhibition of the rat types 1 and 2 5alpha-reductase by finasteride was investigated using recombinantly expressed enzymes. These studies revealed that finasteride is a potent, reversible inhibitor of the rat type 1 5alpha-reductase with Ki=10.2+/-1.3 nM. Finasteride is a potent inhibitor of the rat type 2; however, in this case the compound binds to the type 2 isozyme-NADPH complex to form a ternary complex with Ki=1.19+/-0.10 nM, which then rearranges to a high affinity complex (E:I) with a pseudo first order rate constant of 1.62+/-0.22 x 10(-3)/s. The second order rate constant is k3/Ki=1.37+/-0.31 x 10(6) M/s. Heat denaturation of the (type 2 enzyme:inhibitor) complex releases dihydrofinasteride and presumably the NADP+-adduct previously identified with the human 5alpha-reductases. The effects of finasteride were also studied in intact COS cells transiently expressing the rat types 1 and 2 5alpha-reductase. Results with whole cell assays confirm differences in mechanism of inhibition of rat types 1 and 2 5alpha-reductase by finasteride.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9328210&dopt=Abstract finasteride Propecia



finasteride, Propecia
Prevalent decrease of the EGF content in the periurethral zone of BPH tissue induced by treatment with finasteride or flutamide.

Monti S, Sciarra F, Adamo MV, Toscano V, Trotta MC, Martini C, Lanzara S, Silverio FD.

Department of Fisiopatologia Medica, III Endocrinologia, University of Rome La Sapienza, Italy.

The aim of the present investigation is to verify whether treatment with Finasteride or Flutamide influences the regional distribution of testosterone (T), dihydrotestosterone (DHT), and epidermal growth factor (EGF) in benign prostatic hyperplasia (BPH) tissue. Thirty seven BPH patients were studied: 15 untreated, 9 treated with Flutamide (750 mg/day for 2 months), and 13 treated with Finasteride (5 mg/day for 3 months). Testosterone and DHT were evaluated by radioimmunoassay (RIA) after purification of the extracts on celite columns, and EGF was evaluated by RIA after purification on Sep-pak C18 cartridges in total tissue and in periurethral, subcapsular, and intermediate zone. In the untreated group, T, DHT, and EGF of the periurethral region are higher than those of the subcapsular zone (P < 0.01 for T and P < 0.001 for DHT and EGF). In the Flutamide group, DHT is not modified, T is increased (P = 0.045), and EGF is decreased in total tissue (P < 0.02) and in the periurethral zone (P < 0.01). In the Finasteride group, T is increased (P < 0.001), and DHT and EGF are decreased (P < 0.001), particularly in the periurethral zone. A positive linear correlation between DHT and EGF is observed in the Finasteride and in the untreated groups. In conclusion, in BPH the production of EGF is a DHT-dependent receptor-mediated function. The reduction of this growth factor during both treatments, associated with a fall of DHT in only the Finasteride group, is particularly evident in the periurethral zone. Since Finasteride reduces prostatic volume, mainly of the periurethral zone, we can speculate that DHT is responsible, either directly or indirectly through growth factors such as EGF for the enlargement of this region and thus responsible for urinary obstruction.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9349746&dopt=Abstract finasteride Propecia



finasteride, Propecia
Synthesis and pharmacological evaluation of new 16-methyl pregnane derivatives.

Ramirez E, Cabeza M, Heuze I, Gutierrez E, Bratoeff E, Membrillo M, Lira A.

Department of Pharmacy, Faculty of Chemistry, UNAM Ciudad Universitaria, Mexico DF, Mexico.

The pharmacological activity of several new pregnane derivatives 15-19 were determined on gonadectomized male hamster flank organs, seminal vesicles and in vitro conversion of testosterone (T) to dihydrotestosterone (DHT) as 5alpha-reductase inhibitors. Steroids 15-19 decreased the diameter of the pigmented spot in the flank organs as compared to the T treated animals; in this model, steroids 16 and 19 showed a higher activity than the commercially available finasteride 3. Injection of T increased the weight of the seminal vesicles. Compounds 15-19 when injected together with T decreased the weight of the seminal vesicles thus showing an antiandrogenic effect. The trienone 19 exhibited a considerably higher activity than finasteride. Steroids 15-19 inhibited the in vitro metabolism of [3H]T to [3H]DHT in seminal vesicles homogenates of gonadectomized male hamsters. Compounds 18 and 19 showed a much higher antiandrogenic effect than finasteride. This enhancement of the biological activity could probably be attributed to the coplanarity of the steroidal skeleton as previously observed by our group. The high antiandrogenic activity of the epoxy compound 16 is probably the result of the ring opening of the oxiran ring with the nucleophilic part of the enzyme 5alpha-reductase thus leading to a stable adduct with concomitant deactivation of this enzyme.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11824579&dopt=Abstract finasteride Propecia



finasteride, Propecia
Effect of finasteride (Proscar MSD) on seminal composition, prostate function and fertility in male dogs.

Iguer-Ouada M, Verstegen JP.

Department of Small Animal Reproduction, College of Veterinary Medicine, University of Liege, Belgium.

This study reports the long-term effects and reversibility of the administration of Finasteride, a 5 alpha-reductase inhibitor, on the prostate, prostatic fluid composition and volume, sperm output and characteristic, and fertility of adult beagle dogs treated for 21 weeks at a dose of 1 mg kg-1 body weight. Finasteride was not associated with any side effects. After 5 to 15 weeks of treatment, it induced a marked decrease in the size of the prostate and a fall in its secretions and in the production of spermatozoa. Sperm concentration increased and was inversely correlated with the decrease in the volume of prostatic secretions. At maximum effect, the calculated prostate volume was reduced to 30% of the initial value, and together with the reduced prostatic secretion, no ejaculate could be collected despite normal behaviour. These effects were reversible in 6 to 8 weeks after the cessation of treatment. Matings at 20 to 22 weeks after the start of treatment were fertile, demonstrating the absence of long-term effects of this treatment on male fertility. As fertility was not impaired and prostatic benign hyperplasia successfully regressed. Finasteride treatment in this preliminary study appears to be an interesting alternative therapy in valuable breeding dogs with benign prostatic hyperplasia.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9404280&dopt=Abstract finasteride Propecia



finasteride, Propecia
Comparison of percent free prostate-specific antigen levels in men with benign prostatic hyperplasia treated with finasteride, terazosin, or watchful waiting.

Keetch DW, Andriole GL, Ratliff TL, Catalona WJ.

Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri 63141, USA.

OBJECTIVES: Finasteride is known to lower total serum prostate-specific antigen (PSA) levels by approximately 50%. Terazosin is thought to have little or no effect on serum PSA concentration. The objective of our study was to determine the effect of finasteride and terazosin on serum total and serum free PSA levels and the ratio of free to total PSA. METHODS: We identified 69 men with symptomatic benign prostatic hyperplasia (BPH) who had been receiving 5 mg/day (n = 33) of finasteride or 2 to 5 mg/day (n = 14) of terazosin or no therapy ("watchful waiting") (n = 22). The three groups were compared with respect to pretreatment total serum PSA levels and post-treatment total, free, and percent free serum PSA levels. RESULTS: Median (+/- semi-interquartile range [SIR]) pretreatment total serum PSA levels (ng/mL) were not significantly different in men taking finasteride (2.8 +/- 1.9), terazosin (2.2 +/- 2.5), or undergoing watchful waiting (5.5 +/- 1.4) (P = 0.12). The median (+/- SIR) post-treatment total serum PSA levels (ng/mL) were significantly lower in the finasteride group (1.1 +/- 1) when compared with the terazosin (2.5 +/- 1.5) or watchful waiting (4.3 +/- 2.8) groups (P = 0.016). Only the finasteride group had significantly lower post-treatment total serum PSA levels compared with pretreatment levels. The median (+/- SIR) post-treatment free PSA levels were significantly lower in the finasteride group (0.26 +/- 0.16) compared with the terazosin (0.54 +/- 0.5) and watchful waiting (0.85 +/- 0.5) groups (P = 0.0015). However, the median (+/- SIR) percent free PSA was not significantly different in the finasteride (23 +/- 6), terazosin (22 +/- 4), and watchful waiting (25 +/- 5) groups (P = 0.66). CONCLUSIONS: Finasteride appears to lower total and free PSA levels equally in men with BPH and does not appear to change the ratio of free to total serum PSA. Terazosin does not appear to alter total or free serum PSA levels in men with BPH. The percent free PSA could potentially be used to screen for prostate cancer in men taking finasteride. Prospective studies are needed to further evaluate this issue.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9426721&dopt=Abstract finasteride Propecia