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PubMed2001

Separation of finasteride and analogues.

This review is focused on the different chromatographic strategies for determination of finasteride and its analogues in biological fluids. These compounds are used for the treatment of benign prostatic hyperplasia. Particular attention is paid to high-performance liquid chromatography with spectrophotometric and mass spectrometric detection, the clean-up procedures are also included. The relationships between pharmacokinetics of finasteride, dose administered and required limit of quantitation of the chromatographic assays are discussed. Tandem mass spectrometry is recommended as the detection method for measuring concentrations <1 ng/ml, while cheaper spectrophotometric detection may be selected for determination of higher concentrations.

Chromatography, Liquid↗
PubMed1993

Finasteride: a slow-binding 5 alpha-reductase inhibitor.

A microsomal preparation of human prostatic tissue was used to study the kinetics of interaction of steroid 5 alpha-reductase with finasteride, a known 5 alpha-reductase inhibitor. This molecule has been reported to reversibly bind 5 alpha-reductase in a competitive manner to testosterone with a Ki value in the 10 nM range. The results presented in this paper show that enzyme-inhibitor complex formation does not take place instantaneously as assumed in previous studies. At neutral pH and 37 degrees C, the association of enzyme with inhibitor is governed by a rate constant, kon, of 2.7 x 10(5) M-1 s-1. This low kon value, in combination with the high energy of activation of the association reaction (150 kJ mol-1), indicates that the association process is not diffusion controlled and may proceed through intermediate steps. However, such an intermediate was not detected kinetically under the inhibitor concentrations investigated. We therefore conclude that the equilibrium dissociation constant, Ki*, for the initial binding of the enzyme to the inhibitor is higher than 1.5 x 10(7) M. Even at inhibitor concentrations as low as 1 nM, the reaction was completely displaced to the EI complex and no residual activity detected once the equilibrium was reached. Hence, the interaction between finasteride and 5 alpha-reductase can also be characterized by a very low overall equilibrium dissociation constant (Ki << 10(-9) M), at least 1 order of magnitude lower than previously reported values.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2000

A pilot study of a bioabsorbable self-reinforced poly L-lactic acid urethral stent combined with finasteride in the treatment of acute urinary retention from benign prostatic enlargement.

OBJECTIVE: To assess whether patients with acute urinary retention from benign prostatic enlargement can be treated with a combined therapy comprising a bioabsorbable self-reinforced poly L-lactic acid (SR-PLLA) urethral stent and finasteride. PATIENTS AND METHODS: Eleven men in acute urinary retention were treated as outpatients; they had a suprapubic catheter inserted and the SR-PLLA stent placed cystoscopically. The patients were allowed to attempt to void spontaneously after 2 days. RESULTS: All patients started to void spontaneously within 2 weeks. There was a steady improvement in urinary flow rates up to 9 months, followed by a slight impairment after the bioabsorption of the stent. During the mean (range) follow-up of 24 (23-26) months only three patients required surgical treatment. CONCLUSION: The bioabsorbable SR-PLLA stent combined with finasteride therapy provides a promising new alternative in the treatment of acute urinary retention, especially in patients unfit for surgical therapy. Larger, placebo-controlled studies are needed to establish the efficacy of this combined therapy.

Acute Disease↗
PubMed1996

The concentrations of the endogenous C19-steroids in hyperplastic prostatic tissue and the effect of finasteride treatment.

The concentrations of the antiandrogenic endogenous steroid epitestosterone (epiT) and of testosterone, dihydrotestosterone (DHT) and androstenedione in the prostate were determined in tissue samples obtained from 21 patients who underwent suprapubic prostatectomy for benign prostatic hyperplasia. Fifteen patients received no hormonal treatment before surgery and the other 6 patients were pretreated for 8 weeks before surgery with an oral dose of 5 mg/day finasteride. The steroids were extracted and separated by high pressure liquid chromatography and determined by specific radioimmunoassays. The concentration of epiT (mean 58.4 +/- 40.4 S.D., range 14.0-144.0 fmol/mg protein) exceeded that of testosterone and was nearly as high as that of DHT. The prostatic tissue from the patients treated with finasteride for 8 weeks showed a significant decrease not only in DHT but also in androstenedione and epiT, whereas the concentration of testosterone increased significantly.

5-alpha Reductase Inhibitors↗
PubMed1996

Human prostate tumor growth in athymic mice: inhibition by androgens and stimulation by finasteride.

When the human prostate cancer cell line, LNCaP 104-S, the growth of which is stimulated by physiological levels of androgen, is cultured in androgen-depleted medium for > 100 passages, the cells, now called LNCaP 104-R2, are proliferatively repressed by low concentrations of androgens. LNCaP 104-R2 cells formed tumors in castrated male athymic nude mice. Testosterone propionate (TP) treatment prevented LNCaP 104-R2 tumor growth and caused regression of established tumors in these mice. Such a tumor-suppressive effect was not observed with tumors derived from LNCaP 104-S cells or androgen receptor-negative human prostate cancer PC-3 cells. 5 alpha-Dihydrotestosterone, but not 5 beta-dihydrotestosterone, 17 beta-estradiol, or medroxyprogesterone acetate, also inhibited LNCaP 104-R2 tumor growth. Removal of TP or implantation of finasteride, a 5 alpha-reductase inhibitor, in nude mice bearing TP implants resulted in the regrowth of LNCaP 104-R2 tumors. Within 1 week after TP implantation, LNCaP 104-R2 tumors exhibited massive necrosis with severe hemorrhage. Three weeks later, these tumors showed fibrosis with infiltration of chronic inflammatory cells and scattered carcinoma cells exhibiting degeneration. TP treatment of mice with LNCaP 104-R2 tumors reduced tumor androgen receptor and c-myc mRNA levels but increased prostate-specific antigen in serum- and prostate-specific antigen mRNA in tumors. Although androgen ablation has been the standard treatment for metastatic prostate cancer for > 50 years, our study shows that androgen supplementation therapy may be beneficial for treatment of certain types of human prostate cancer and that the use of 5 alpha-reductase inhibitors, such as finasteride or anti-androgens, in the general treatment of metastatic prostate cancer may require careful assessment.

Androgen-Binding Protein↗
PubMed1991

5 alpha-metabolism in finasteride-treated subjects and male pseudohermaphrodites with inherited 5 alpha-reductase deficiency. A review.

Male pseudohermaphrodites (MPHs) with inherited 5 alpha-reductase deficiency and decreased dihydrotestosterone production have a global defect in 5 alpha-metabolism affecting both C19 androgen metabolism and C21 steroid metabolism. However, the decreased 5 alpha-reduction of testosterone to dihydrotestosterone is the only impaired steroid conversion to have clinical consequences, e.g., ambiguous genitalia, impaired prostate differentiation and development, and decreased facial and body hair. The 5 alpha-steroid metabolite profile in the MPHs was compared with that of men with benign prostatic hyperplasia who were administered varying doses of the 5 alpha-reductase inhibitor finasteride. Finasteride was found to be a potent inhibitor of both C19 androgen and C21 5 alpha-steroid metabolism affecting both hepatic and peripheral 5 alpha-metabolism. The 5 alpha-steroid metabolite profile was strikingly similar to that of MPHs with inherited 5 alpha-reductase deficiency. The data suggest that a 5 alpha-reductase gene codes for an enzyme with affinity for multiple steroid substrates.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1993

Treatment of advanced prostate cancer with the combination of finasteride plus flutamide: early results.

In an attempt to maximize the quality of life of advanced prostate cancer patients on prolonged total androgen ablation and to minimize side effects, we have devised a strategy of 'sequential androgen blockade'. Animal studies have demonstrated that the combination of the 5 alpha-reductase inhibitor finasteride and the antiandrogen flutamide was as effective as a luteinizing hormone-releasing hormone analog and flutamide in inhibiting the growth of the prostate. In a pilot trial, 10 potent patients with clinical stage C and D1 prostate cancer were given the combination of finasteride (5 mg b.i.d.) and flutamide (125-250 mg t.i.d.). Eight of ten men remained potent. At 3 months the mean prostate-specific antigen level of all patients was 3.8 ng/ml (34 ng/ml prior to therapy). In all patients serum testosterone increased and those with the highest increase demonstrated gynecomastia. The combination was easily tolerable and side effects were few. This treatment regime appears to offer the benefits of total androgen blockade, is less expensive and has fewer side effects. Further trials are warranted.

Aged↗
PubMed1995

Five-year follow-up of patients with benign prostatic hyperplasia treated with finasteride.

In 18 of 55 original patients who completed 5 years of treatment with finasteride, significant reductions in prostate size were noted at 1 year and sustained thereafter. Symptom scores in these same patients were significantly improved or stable over the 5 years while maximal urinary flow rates were unchanged. Data from 15 of 18 other patients who dropped out of the study before 5 years showed changes in prostate size, symptom score and flow rates that were similar to those noted in patients treated for 5 years. No side effects were noted in this study except for sexual dysfunction, which occurred in less than 5% of the patients. With few exceptions, finasteride appears to arrest the process of BPH over a 5 year period as indicated by sustained reductions in prostate size accompanied by either symptomatic improvement or stability in all other patients.

Adult↗
PubMed1991

Effects of flutamide and finasteride on rat testicular descent.

The endocrine control of descent of the testis in mammalian species is poorly understood. The androgen dependency of testicular descent was studied in the rat using an antiandrogen (flutamide) and an inhibitor of the enzyme 5 alpha-reductase (finasteride). Androgen receptor blockade inhibited testicular descent more effectively than inhibition of 5 alpha-reductase activity. Moreover, its inhibitory effect was limited to the outgrowth phase of the gubernaculum testis, particularly the earliest stages of outgrowth. Gubernacular size was also significantly reduced in fetuses exposed to flutamide during the outgrowth period. In contrast, androgen receptor blockade or 5 alpha-reductase inhibition applied after the initiation of gubernacular outgrowth or during the regression phase did not affect testicular descent. Successful inhibition of the development of epididymis and vas by prenatal flutamide did not correlate with ipsilateral testicular maldescent, suggesting that an intact epididymis is not required for descent of the testis. Plasma androgen assays confirmed significant inhibition of dihydrotestosterone formation in finasteride-treated rats. These data suggest that androgens, primarily testosterone, are required during the early phases of gubernacular outgrowth for subsequent successful completion of testicular descent.

5-alpha Reductase Inhibitors↗
PubMed1990

C19 and C21 5 beta/5 alpha metabolite ratios in subjects treated with the 5 alpha-reductase inhibitor finasteride: comparison of male pseudohermaphrodites with inherited 5 alpha-reductase deficiency.

Male subjects administered the 5 alpha-reductase inhibitor finasteride were studied to determine its effect on C19 and C21 5 alpha-metabolism. Plasma testosterone (T) and 5 alpha-dihydrotestosterone (DHT) were measured and T/DHT ratios determined at doses of 0.2-80 mg. Urinary etiocholanolone (5 beta)/androsterone (5 alpha) ratios and 5 beta/5 alpha metabolite ratios of cortisol, 11 beta-hydroxyandrostenedione, and corticosterone were also measured. The steroid profile was compared to male pseudohermaphrodites with inherited 5 alpha-reductase deficiency who have a global defect in C19 and C21 5 alpha-metabolism. The mean plasma DHT levels were decreased at all doses, resulting in elevated T/DHT ratios. The mean urinary etiocholanolone/androsterone, 11 beta-hydroxyetiocholanolone/11 beta-hydroxyandrosterone, tetrahydrocortisol/allotetrahydrocortisol, and tetrahydrocorticosterone/allotetrahydrocorticosterone ratios were elevated compared to pretreatment levels and placebo control values. The mean ratios appeared to be dose dependent for plasma T/DHT, urinary etiocholanolone/androsterone tetrahydrocorticosterone/allotetrahydrocorticosterone ratios. The mean 11 beta-hydroxyetiocholanolone-hydroxyandrosterone ratio was maximally elevated at the lowest doses. The results indicate that finasteride has a broad steroid spectrum inhibiting C19 and C21 5 alpha-steroid metabolism and affecting hepatic and peripheral 5 alpha-metabolism. These results suggest that a single gene codes for a single 5 alpha-reductase enzyme with affinity for multiple steroid substrates. The steroid profile is strikingly similar to that of male pseudohermaphrodites with inherited 5 alpha-reductase deficiency.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1990

Effects of finasteride (MK-906), a 5 alpha-reductase inhibitor, on circulating androgens in male volunteers.

Finasteride, a 5 alpha-reductase inhibitor, was administered to normal male volunteers in a blinded placebo-controlled study at daily oral doses of 25, 50, and 100 mg for 11 days (part 1) and daily oral doses of 0.04, 0.12, 0.2, and 1.0 mg for 14 days (part 2). Results from part 1 showed a significant reduction in dihydrotestosterone (DHT) at all doses and a significant increase in both testosterone (T) and delta 4-androstenedione at the 50- and 100-mg doses. No change was seen in LH, FSH, cortisol, or estradiol levels. Serum lipids, including total cholesterol, low density lipoprotein, high density lipoprotein, and triglycerides were not affected by treatment. Results from part 2 again showed significant reduction in DHT at all doses. DHT levels returned to pretreatment values within 14 days of discontinuing treatment. Significant increases in T were observed only in the 1.0 mg group and only during the first 8 days of treatment. The T/DHT ratio increased with all doses and returned to baseline when drug was discontinued. The DHT metabolites and androstanediol glucuronide and androsterone glucuronide were significantly reduced at all doses. There were no significant adverse experiences reported during part 1 or 2. In conclusion, finasteride is well tolerated by normal volunteers and results in significant suppression of serum DHT at all doses tested.

Adult↗
PubMed1999

[Medical treatment of benign prostatic hyperplasia. The efficacy of finasteride depends on prostatic volume].

OBJECTIVE: To demonstrate that the efficacy of finasteride in benign prostatic hyperplasia (BPH) depends on the prostate volume. METHODS: 75 patients with BPH were classified according to the prostate volume: 20-40 Gm (group I), 40-80 Gm (group II) and more than 80 Gm (group III). The average duration of treatment for all three groups was 16.2 months. Patients were evaluated for symptom score (I-PSS), quality of life, prostate volume by ultrasound, maximum urinary flow rate, residual urine, plasma PSA and testosterone levels. RESULTS: Ultrasound demonstrated a reduction in prostatic volume of 6.8-14.8 Gm. Symptom score was reduced by 9.2-15.5 points and quality of life 2-2.7 points. Maximum urinary flow rate increased 3.4-4.4 ml/sec and residual urine decreased in all three groups. Testosterone values showed no significant changes. PSA values showed a reduction of 1.3-1.7 ng/ml. CONCLUSIONS: The efficacy of finasteride depends on the prostatic volume. Medical treatment is a temporary alternative to surgery due to its cost and because patients are unaccustomed to having to take a tablet daily.

Enzyme Inhibitors↗
PubMedDate not supplied

Suppression of spermatogenesis with desogestrel and testosterone pellets is not enhanced by addition of finasteride.

Conversion of testosterone to dihydrotestosterone (DHT) by the action of 5alpha-reductase can amplify androgen action. This may be of particular importance in the presence of low testosterone concentrations and may contribute to maintenance of spermatogenesis in a proportion of men receiving male contraceptive regimens. We therefore investigated whether the addition of finasteride, a 5alpha-reductase inhibitor, to a prototype male hormonal contraceptive regimen consisting of desogestrel (150 microg orally daily) and repeated administration of testosterone pellets (2 x 200 mg per 12 weeks) would enhance suppression of spermatogenesis. Sixteen normal men were randomized to receive either the standard androgen/progestogen treatment alone (control group) or with finasteride (5 mg orally daily-FIN group) for 24 weeks. Both groups showed profound suppression of spermatogenesis with azoospermia being obtained in 6 of 8 subjects in the control group and in 5 of 7 in the FIN group. There were no significant differences between the groups with respect to sperm concentrations. Significant suppression of luteinizing hormone and follicle-stimulating hormone was achieved within 2 weeks of treatment in both groups, while testosterone concentrations were maintained in the normal physiological range. DHT concentrations fell in both groups but were significantly lower in the FIN group. Gonadotropin and testosterone concentrations were similar for both regimens throughout the study. This study demonstrates the potential for long-term suppression of spermatogenesis using a combination of an oral progestogen with repeated administration of a depot preparation of testosterone. However, these data do not support the involvement of 5alpha-reductase in maintaining residual spermatogenesis during gonadotropin suppression for hormonal male contraception.

5-alpha Reductase Inhibitors↗
PubMed2001

[Photographic documentation of the effectiveness of 1 mg. oral finasteride in treatment of androgenic alopecia in the man in routine general practice in Switzerland].

A 6-month, prospective, open, multicenter cohort study in 265 men with male pattern hair loss treated with oral finasteride 1 mg/day (Propecia) was conducted in the office of 52 Swiss dermatologists. The patient's head was placed in a stereotactic device, and Polaroid photographs were taken of the vertex and frontal areas. Endpoints used to determine treatment efficacy were patient self-assessment, investigator clinical assessment, and blinded assessment of the serial Polaroid photographs by a panel of 2 experienced dermatologists. Significant improvements were stated on the photographs by both clinical investigators and the blinded expert panel: 54% of patients showed improvement of hair growth at 6 months of treatment in the vertex region, and 48.7% in the frontal area. No progression of hair loss was found in an additional 38% (vertex) and 47% (frontal region), respectively. Clinical investigator and expert assessment yielded comparable results. Independently, patient self-assessment and investigator clinical assessment confirmed the progress. Propecia was well-tolerated, and no significant safety concerns were identified during the study. The photographic method was well accepted by the physicians. The office-based Polaroid photographic system allowed reliable assessment of change during treatment of male pattern hair loss with Propecia. The data generated in this manner corresponded to the antecedent results of the multicenter, placebo-controlled studies with oral finasteride.

Administration, Oral↗
PubMed2001

Determination of concentrations of sex steroids in blood plasma and semen of male dogs treated with delmadinone acetate or finasteride.

The concentrations of testosterone, 5 alpha-dihydrotestosterone, oestradiol and oestrone were determined in peripheral blood plasma and semen of male dogs. In an experimental study, three Beagles were treated once with delmadinone acetate (1 mg kg-1 body weight, i.m.) and three were submitted to oral applications of finasteride (1 mg kg-1 body weight) once a day for 3 weeks. In a clinical study, 51 dogs of different breeds were divided into four groups according to the total number of spermatozoa in ejaculates (normospermia, slight oligozoospermia, severe oligozoospermia and azoospermia). The testosterone concentrations were significantly lower in sperm-rich ejaculate fractions and prostatic secretions compared with blood plasma (P < 0.05). The lowest concentration of testosterone was found in prostatic fluid. Concentrations of 5 alpha-dihydrotestosterone were similar in blood plasma and sperm-rich fractions, and significantly lower in prostatic secretions (P < 0.05). The concentrations of oestradiol and oestrone did not differ between blood plasma and either ejaculate fraction. Significantly higher 5 alpha-dihydrotestosterone concentrations and significantly lower concentrations of oestradiol and oestrone were found in prostatic secretions from azoospermic ejaculates compared with prostatic secretions of normospermic and oligozoospermic ejaculates. Delmadinone acetate and finasteride caused reversible suppression of the secretory activity of the prostate gland. The application of delmadinone acetate led to a temporary alteration of maturation of epididymal spermatozoa.

5-alpha Reductase Inhibitors↗
PubMed1992

Finasteride for benign prostatic hyperplasia.

The pathogenesis of benign prostatic hyperplasia is related to the action of 5 alpha-dihydrotestosterone (DHT), the physiologically active form of testosterone. The conversion of testosterone to DHT is catalyzed intracellularly in prostatic tissue by the enzyme 5 alpha-reductase. Finasteride blocks the action of 5 alpha-reductase by competitively inhibiting the binding of testosterone to 5 alpha-reductase. The maximum effect of finasteride on reducing prostatic volume occurs after three months of oral therapy. Most patients experience improvement in urine flow rates, and side effects are minimal. However, following discontinuation of treatment, serum DHT levels return to baseline within two weeks.

5-alpha Reductase Inhibitors↗
PubMed2005

[Is tumour grade applicable to finasteride-treated prostate cancer?].

The treatment of prostate cancer by endocrine therapy induces histological changes of benign or malignant prostate glands. Treated cancers often have a more suspicious architecture, resulting in a higher Gleason score, while their nuclear grade (WHO) appears to be more reliable due to a reduction of the size of nuclei. Most authors appear to agree that cancers discovered by biopsy in patients treated with endocrine therapy should not be graded. A review of the literature appears to indicate that finasteride has less marked histomorphological consequences than other hormone-suppressor treatments and could have a lesser effect on the Gleason score. This paper, based on a review of the literature on this subject, emphasizes: (1) the extent of histological changes after androgen deprivation endocrine therapy; (2) histological changes after Finasteride and the difficulties of histological interpretation, particularly the risk of overestimating the Gleason histoprognostic score; (3) the need for urologists to indicate any treatment by 5-alpha-reductase inhibitors or androgen deprivation when requesting histological examination; (4) the value of collecting and documenting cases observed in the Uropathology Club in collaboration with the Oncology committee of the Association Française d'Urologie.

5-alpha Reductase Inhibitors↗
PubMed1993

[Finasteride (Proscar) for benign prostatic hypertrophy].

Several alternatives to surgery for benign prostatic hypertrophy (BPH) were studied during the past few years. Finasteride (Proscar), a 4-azosteroid, is an inhibitor of the enzyme 5-alpha reductase, which is responsible for the conversion of testosterone to the biologically more active dihydrotestosterone (DHT). We report 3 years of experience with the drug in 23 men. Persistent significant decreases in serum DHT and prostate-specific antigen (PSA) were documented. Prostatic volume decreased by about 25% after 1 year, and remained fairly constant thereafter. Urination improved, as evidenced by increased maximal flow rate and decreased volume of residual urine. Symptoms were affected favorably, but only mildly. One of the main advantages of the drug is its lack of side-effects. More data on a larger number of patients with a longer follow-up are needed before finasteride can be established as having a role as an alternative treatment for BPH.

Aged↗