finasteride, Propecia
[Effects of androgen regulation system on bladder carcinogenesis in male mice]

[Article in Japanese]

Imada S, Akaza H, Otani M, Koiso K.

Department of Urology, University of Tsukuba.

PURPOSE: In several previous reports, it has been suggested that the androgen system is related to bladder carcinogenesis. In this study, to understand the mechanism underlying this relationship, we administered a LH-RH agonist depot (Leuprolide depot), a pure-antiandrogen (flutamide) or a 5 alpha-reductase inhibitor (finasteride) to the mice in the promotion state of bladder carcinogenesis by N-butul-N-(4-hydroxybutyl) nitrosamine (BBN). MATERIALS AND METHODS: 177 C3H/He male mice were divided into 7 groups. All mice were treated with 0.05% BBN for 10 weeks and were maintained over the subsequent 12 weeks with the following treatments. Group 1 was a control group; in group 2, castration was performed at the 11th week; in group 3, finasteride was administered starting the 11th week; in group 4, a LH-RH agonist depot was administered starting the 11th week; in group 5, flutamide was administered starting the 11th week; in group 6, both finasteride and a LH-RH agonist depot were administered simultaneously starting the 11th week; and in group 7, both flutamide and a LH-RH agonist depot were administered simultaneously starting the 11th week. RESULTS AND CONCLUSIONS: (1) We confirmed that castration significantly suppressed bladder carcinogenesis. (2) Finasteride or flutamide administration as monotherapy had no effect on the results; however, the dosages of these drugs may have been too low, so we are planning a study with higher doses. (3) Conversely, the LH-RH agonist depot significantly promoted bladder carcinogenesis, we believe that the high levels of testosterone immediately after the administration were responsible for this promotion. (4) Simultaneous administration of flutamide suppressed this LH-RH induced promotion of carcinogenesis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8551710&dopt=Abstract finasteride Propecia



finasteride, Propecia
The American Urological Association symptom score in the evaluation of men with lower urinary tract symptoms: at 2 years of followup, does it work?

Kaplan SA, Olsson CA, Te AE.

Department of Urology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.

PURPOSE: The American Urological Association (AUA) benign prostatic hyperplasia (BPH) guidelines committee established criteria for the diagnosis and treatment of patients with BPH. In a prospective study we determined the usefulness of these guidelines in 145 previously untreated patients with BPH symptoms. MATERIALS AND METHODS: Patients were evaluated initially by AUA symptom score, digital rectal examination, urinalysis, serum creatinine and prostate specific antigen. Based on symptom score, patients with mild symptoms were treated with watchful waiting, while those with moderate and severe symptoms were offered watchful waiting, finasteride alpha-blockers, or laser or transurethral prostatectomy. Minimum followup was 2 years. Patients were offered a change in therapy if they had an intolerable adverse event or no improvement. Analysis included maintenance of therapy at 1 and 2 years, number of office visits and diagnostic tests performed. In addition, all patients were queried regarding which factors influenced their therapeutic choice. RESULTS: Of 37 patients with mild symptoms 31 (81%) remained on watchful waiting at 2 years and 6 advanced to medical therapy. Among 71 patients with moderate symptoms 9 of 15 (60%) remained on watchful waiting, 27 of 36 (75%) remained on alpha-blockers and 12 of 20 (60%) remained on finasteride at 2 years. Of the 37 patients with severe symptoms 1 of 5 (20%) remained on watchful waiting, 1 of 6 (17%) remained on finasteride and 9 of 15 (60%) remained on alpha-blockers, while 3 of 5 (60%) who underwent laser prostatectomy and all 6 (100%) who underwent transurethral prostatectomy received no further treatment. At 2 years 83% of the men who selected either finasteride or alpha-blockers as either the primary or secondary therapeutic choice were still on medications. Most patients with mild (61%) or moderate (51%) symptoms cited adverse events as the predominant concern when selecting therapeutic options. In contrast, efficacy was the overriding concern (70%) in patients with more severe symptoms. CONCLUSIONS: Overall, with these guidelines and the AUA symptom score 110 men (76%) were still on original therapy at 1 year and 99 (68%) at 2 years. Additionally, 31 patients (21%) changed to an alternative, nonoperative therapy. These results suggest that the AUA BPH guidelines provide a rational and balanced approach for evaluation and management of patients with symptomatic BPH. Patients can reasonably expect to remain on the initial therapeutic option for at least 2 years.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8618299&dopt=Abstract finasteride Propecia



finasteride, Propecia
Inhibition of human steroid 5alpha reductases type I and II by 6-aza-steroids: structural determinants of one-step vs two-step mechanism.

Moss ML, Kuzmic P, Stuart JD, Tian G, Peranteau AG, Frye SV, Kadwell SH, Kost TA, Overton LK, Patel IR.

Department of Enzymology, Glaxo Wellcome, Research Triangle Park, North Carolina 27709, USA.

We have discovered that 17beta-[N,N-(diethyl)carbamoyl]-6-azaandrost-4-en-3-one is a time-dependent inhibitor of type II 5alpha-reductase, as is the drug finasteride. Unlike finasteride, the 6-aza-steroid is not a time-dependent inhibitor of type I 5 alpha-reductase. Finasteride inhibition of type II enzyme proceeds in a two-step mechanism. At pH 6 and 37 degrees C, an initial finasteride-reductase complex is formed with a K(i)(app) of 11.9 +/- 4.1 nM. In a second step, an irreversible complex is formed with a rate constant of inactivation of 0.09 +/- 0.01 s(-1). In contrast, the 6-aza-steroid is a reversible inhibitor. From the results of a simplified mathematical analysis, based on the rapid equilibrium approximation, the inhibitor and the enzyme form an initial complex with a K(i) of 6.8 +/- 0.2 nM. The reversible formation of a final complex, with an overall K(i) of 0.07 +/- 0.02 nM, is characterized by a first-order isomerization rate constant 0.0035 +/- 0.0001 s(-1) for the forward step and 0.00025 +/- 0.00006 s(-1) for the backward step. All rate constants for the two-step mechanism were obtained by using a general numerical integration method. The best fit values for the association and dissociation rate constants were 5.0 microM(-1) s(-1) and 0.033 +/- 0.008 s(-1), respectively, and the isomerization rate constants were 0.0035 +/- 0.007 s(-1) and 0.000076 +/- 0.000019 s(-1). These values correspond to an initial K(i) of 6.5 nM and an overall dissociation constant of 0.14 nM. The data presented here show that both finasteride and the 6-aza-steroid analogs are potent against type II 5alpha-reductase, although their mechanisms of inhibition are different.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8639496&dopt=Abstract finasteride Propecia



finasteride, Propecia
CGP 53153: a new potent inhibitor of 5alpha-reductase.

Hausler A, Allegrini PR, Biollaz M, Batzl C, Scheidegger E, Bhatnagar AS.

Research Department, Pharmaceuticals Division, CIBA-GEIGY Ltd, Basel, Switzerland.

CGP 53153 (N-2-(cyano-2-propyl)-3-oxo-4-aza-5alpha-androst-1-ene-17beta-carb oxamide) is a steroidal inhibitor of 5alpha-reductase, the enzyme which effects the conversion of testosterone (T) to 5alpha-dihydrotestosterone (DHT). In vitro, CGP 53153 competitively inhibited rat microsomal 5alpha-reductase from prostate by 50% (IC50) at a concentration of 36nM compared to the reference compound finasteride which inhibited 5alpha-reductase with an IC50 of 11 nM in the same system. In vivo, inhibition of 5alpha-reductase activity was characterized in three different test systems. Inhibition of 5alpha-reductase activity was first assessed in a standard test designed to compare directly the potency of different 5alpha-reductase inhibitors. This test assesses potency through the inhibition of prostate growth in juvenile castrate male rats treated with a standard dose of T-propionate (1 mg/kg, s.c.) and a 5alpha-reductase inhibitor administered orally at various doses for 4 days. CGP 53153 and finasteride significantly reduced T-propionate-mediated prostate growth by about 25% (ED25) compared to T-propionate-treated controls at oral doses of 0.01 and 0.1 mg/kg, respectively. Second, the effects on prostate weight were studied in normal adult male rats treated orally once daily for 14 days with 1, 3 and 10 mg/kg CGP 53153 and with 10 mg/kg finasteride. CGP 53153 significantly reduced prostate weight at 3 and 10 mg/kg by 31% and 37%, respectively, compared to vehicle-treated controls, whereas the dose of 10 mg/kg finasteride did not significantly reduce prostate weight. Third, the effects on prostate volume were studied in normal 6-9-year-old male dogs treated orally once daily with 5 mg/kg CGP 53153 and with 5 mg/kg finasteride for 12 weeks. Prostate volume was monitored with magnetic resonance imaging every 2 weeks beginning 6 weeks before start of the treatment with 5alpha-reductase inhibitors and ending after a recovery period of 8 weeks after termination of treatment. Treatment for 12 weeks with both CGP 53153 and finasteride was equally effective in reducing prostate volume by more than 70% in individual dogs. Anti-androgenic potency of CGP 53153 and finasteride was assessed in juvenile castrate male rats treated with DHT-propionate (1 mg/kg, s.c.) and a 5alpha-reductase inhibitor (p.o.) for 4 days. Neither CGP 53153 nor finasteride given at a dose of 10 mg/kg had any significant effect on DHT-propionate-mediated prostate growth, whereas the reference anti-androgen flutamide given at a dose of 10 mg/kg reduced prostate weight to levels comparable to those seen in untreated castrate animals. For CGP 53153, the dose of 10 mg/kg is 1000-fold higher than the ED25 for 5alpha-reductase inhibition in vivo. In conclusion, both CGP 53153 and finasteride are potent inhibitors of the rat 5alpha-reductase enzyme system in vitro without showing any anti-androgenic effects in vivo. Both CGP 53153 and finasteride were equally potent in reducing prostate volume in aged male dogs, whereas in rats, CGP 53153 is up to 10 times more potent than finasteride in reducing prostate weight as shown in two different rat models.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8645628&dopt=Abstract finasteride Propecia



finasteride, Propecia
Identification of human cytochrome P450 isozymes responsible for the in vitro oxidative metabolism of finasteride.

Huskey SW, Dean DC, Miller RR, Rasmusson GH, Chiu SH.

Department of Drug Metabolism, Merck Research Laboratories, Rahway 07065, USA.

Finasteride, a prescription drug for the treatment of benign prostatic hypertrophy and alleviation of symptoms associated with benign prostatic hypertrophy and alleviation of symptoms associated with benign prostatic hypertrophy, has been shown to be metabolized in rat hepatic microsomes by hydroxylation at the t-butyl group (omega-OH finasteride), followed by further oxidation to the corresponding acid (omega-oic acid finasteride), with omega-aldehyde finasteride as an intermediate. In this study, we identified specific human cytochrome P450 (CYP) isozyme(s) involved in the in vitro metabolism of [14C]finasteride using CYP isozyme-selective inhibitors and microsomes containing specific recombinant human CYP isozymes (expressed in human AHH-1 TK+/-cells). Each of the three steps of the oxidative pathway was examined separately by using [14C]finasteride and its consecutive metabolites (omega-OH finasteride and omega-aldehyde finasteride) as substrates, and human liver microsomes or expressed recombinant CYP isozymes as the enzyme source. Gestodene, a mechanism-based inhibitor of CYP3A isozymes, showed a concentration-dependent inhibition of the oxidative metabolism of [14C]finasteride. In addition, the respective omega-OH finasteride and omega-oic acid finasteride metabolites were generated only by microsomes containing recombinant CYP3A4, but not the other isozymes (CYP1A1, CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP2E1). Similar results were obtained for the oxidation of omega-OH finasteride to omega-aldehyde finasteride, suggesting that human CYP3A isozymes were involved in the oxidation of omega-OH finasteride. When omega-aldehyde finasteride was incubated with human liver microsomes in the presence of an NADPH regenerating system, both the omega-oic acid finasteride and the omega-OH finasteride were detected, suggesting that oxidative and reductive reactions were occurring simultaneously and that they were NADPH- or NADP-dependent. Inhibitors of CYP3A isozymes inhibited the oxidation of omega-aldehyde finasteride in a concentration-dependent manner; an increase in the reduction was also observed, presumably caused by inhibition of the competitive oxidative reaction. Other selective CYP inhibitors for CYP1A1/2 (alpha-naphthoflavone), CYP2C8-10 (sulfaphenazole), CYP2D6 (quinidine), and CYP2E1 (diallylsulfone) showed minor or no effects on both reactions. Consistent with these results, only microsomes containing human recombinant CYP3A4 catalyzed the oxidation of omega-aldehyde finasteride to omega-oic acid finasteride. These results indicate that the oxidation of omega-aldehyde finasteride was NADPH-dependent and was mediated at least in part by CYP3A4. In addition, NAD-dependent enzymes in cytosolic, microsomal, and mitochondrial fractions were capable of oxidizing omega-aldehyde finasteride to omega-oic acid finasteride. Other cellular fractions, particularly mitochondria, were shown to convert finasteride to omega-oic acid finasteride in a similar fashion.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8654202&dopt=Abstract finasteride Propecia



finasteride, Propecia
Treatment of benign prostatic hyperplasia with 5-alpha-reductase inhibitor: morphological changes in patients who fail to respond.

Montironi R, Valli M, Fabris G.

Institute of Pathological Anatomy and Histopathology, School of Medicine, University of Ancona, Italy.

AIMS: To describe the prostatic adenectomy specimens of six patients with symptomatic benign prostatic hyperplasia (BPH) who failed to respond to long term treatment with a 5-alpha-reductase inhibitor, finasteride. METHODS: Histological sections from six cases of BPH who had been treated with finasteride were investigated. Five patients were prescribed 5 mg finasteride daily for six months and one patient 5 mg daily for 12 months. The patients underwent adenectomy as their urethral obstruction failed to resolve. Twenty cases of untreated BPH served as controls. RESULTS: In patients taking finasteride for six months the prostatic adenectomy specimens showed a reduction in the size of the prostate and an increase in the stroma:epithelial and stroma:lumen ratios compared with controls. The size of the ducts and acini was not as uniform as in the controls. In particular, some ducts and acini were still lined by a bistratified epithelium similar to that found in controls but lacked undulations at the epithelial border; other ducts/acini were atrophic. Some scattered clusters of small acini with a focally fragmented basal cell layer were observed in two of the five treated cases. One prostatic adenectomy specimen, from the patient treated for one year, showed extensive lobular atrophy and diffuse squamous and transitional cell metaplasia. At the periphery of the transition zone, there was a complex intra-acinar papillary-cribriform proliferation of clear cells without nuclear atypia, similar to clear cell papillary hyperplasia. The periurethral region showed stromal nodules in both patients and controls. CONCLUSIONS: Morphological evaluation of finasteride treated BPH showed changes in the lobules of the transition zone, but not in the periurethral stroma.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8655710&dopt=Abstract finasteride Propecia