finasteride, Propecia
Anaemia in men receiving combined finasteride and flutamide therapy for advanced prostate cancer.

Ornstein DK, Beiser JA, Andriole GL.

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

OBJECTIVE: To determine the effect of combined finasteride and flutamide therapy on haemoglobin and haematocrit values in men with advanced prostate cancer. PATIENTS AND METHODS : Nineteen men, previously untreated by hormone therapy, with histologically confirmed adenocarcinoma of the prostate and clinical evidence of advanced disease, were treated with combined finasteride (5 mg/day) and flutamide (750 mg/day) for at least 6 months. Complete blood counts were performed before initiation and after 6 months of therapy. RESULTS: After 6 months of finasteride and flutamide therapy both haemoglobin levels and haematocrit decreased in all men, with a mean (sd, range) decrease of 16 (10, 3-42) g/L and 4.6 (2.7, 0.8-9.9)%, respectively. CONCLUSION: Combined finasteride and flutamide therapy significantly lowers haemoglobin and haematocrit levels in men with advanced prostate cancer, and further study of this effect is warranted.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10233450&dopt=Abstract finasteride Propecia



finasteride, Propecia
Modulation of steroidal levels by adrenalectomy/castration and inhibition of neurosteroid synthesis enzymes affect sigma1 receptor-mediated behaviour in mice.

Phan VL, Su TP, Privat A, Maurice T.

INSERM U. 336, Developpement, Plasticite et Vieillissement du Systeme Nerveux, ENSCM, 8. rue de lEcole Normale, 34296 Montpellier Cedex 5, France.

The interaction between neurosteroids and sigma1 (sigma1) receptors may be of therapeutic interest during physiological or pathological ageing, particularly concerning their neuromodulatory role on cognitive functions. Neurosteroids modulate memory processes through a mechanism involving interactions with GABAA, N-methyl-D-aspartate and/or sigma1 receptors. To measure the contribution of endogenous neurosteroid levels to the antiamnesic effects of sigma1 agonists, we investigated the effects of inhibitors of key enzymes involved in neurosteroid synthesis, in adrenalectomized/castrated (AdX/CX) mice to avoid the effect of circulating steroids. Trilostane, a 3beta-hydroxysteroid-deshydrogenase inhibitor, blocks the pregnenolone to progesterone conversion and leads to a decrease of progesterone. Finasteride, a 5alpha-reductase inhibitor, blocks the progesterone to 5alpha-pregnane-3,20-dione conversion and leads to an accumulation of progesterone. The in vivo binding of (+)-[3H]SKF-10 047 to sigma1 sites was measured in the mouse hippocampus and cortex. The attenuating effect of the selective sigma1 agonist PRE-084 (0.1-3 mg/kg) against dizocilpine (0.15 mg/kg)-induced learning impairment was examined using spontaneous alternation behaviour, step-down passive avoidance and place learning in the elevated plus-maze. The in vivo (+)-[3H]SKF-10 047 binding appeared significantly increased in AdX/CX mice and after trilostane treatment (10 mg/kg twice a day, 7 days), compared with sham-operated animals. The finasteride treatment (25 mg/kg, 7 days) significantly decreased binding levels. The learning deficits induced by dizocilpine were not affected by the treatments. The antiamnesic effect of PRE-084 was facilitated in AdX/CX mice and even more after trilostane treatment, as several parameters for animals treated with both PRE-084 and dizocilpine returned to control values. The PRE-084 effect was blocked after finasteride. These results confirmed that endogenous neurosteroidal levels modulate sigma1 receptor-mediated behaviour directly, and revealed that, among neurosteroids, progesterone may be the main modulator of sigma1 receptors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10383628&dopt=Abstract finasteride Propecia



finasteride, Propecia
Expression of basic fibroblast growth factor and its receptors FGFR1 and FGFR2 in human benign prostatic hyperplasia treated with finasteride.

Saez C, Gonzalez-Baena AC, Japon MA, Giraldez J, Segura DI, Rodriguez-Vallejo JM, Gonzalez-Esteban J, Miranda G, Torrubia F.

Department of Pathology, Hospital Universitario Virgen del Rocio, Seville, Spain.

BACKGROUND: The development of benign prostatic hyperplasia (BPH) is an androgen-dependent process which may be mediated by a number of locally produced growth factors. One of these, the basic fibroblast growth factor (bFGF or FGF2), has a mitogenic effect on prostatic stroma. High expression levels of bFGF have been reported in BPH. FGFR1 and FGFR2 receptors, that exhibit affinity for bFGF, have been identified in normal and hyperplastic prostate. Finasteride, a 5alpha-reductase inhibitor, is an effective drug in the treatment of BPH, inducing regressive changes in the prostate of treated patients, even though its mechanisms of action are not yet completely elucidated. This study was designed to assess the effects of finasteride on the expression levels of bFGF, FGFR1, and FGFR2 in patients with BPH. METHODS: The expression levels of bFGF, FGFR1, and FGFR2 in 9 patients with prostatic hyperplasia treated with finasteride were assessed by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) analysis of mRNA expression and were compared with those of 9 control patients with untreated BPH. RESULTS: Immunohistochemistry showed strong bFGF immunoreactivity in the prostatic stroma of untreated patients, this being somewhat weaker in the epithelium. In treated patients, epithelial immunoreactivity was practically negative, and a considerable reduction in stromal immunoreactivity was seen. These findings were also confirmed by RT-PCR. FGFR1 showed a weak immunoreactivity in the stroma and in basal epithelial cells. FGFR1 showed a weak immunoreactivity in the stroma and in basal epithelial cells. FGFR2 exhibited strong stromal immunoreactivity, becoming weaker in the basal epithelium. No differences were seen in the expression of both receptors between the groups of treated and untreated patients. CONCLUSIONS: A marked reduction in bFGF levels is seen in BPH treated with finasteride in comparison to untreated BPH. In our opinion, finasteride may act as a negative regulator of bFGF expression, counteracting the role of bFGF in the development of BPH.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10386468&dopt=Abstract finasteride Propecia



finasteride, Propecia
Economic analysis of finasteride: a model-based approach using data from the Proscar Long-Term Efficacy and Safety Study.

Albertsen PC, Pellissier JM, Lowe FC, Girman CJ, Roehrborn CG.

University of Connecticut Health Center, Farmington, USA.

Benign prostatic hyperplasia (BPH) is one of the most common medical conditions in older men in the United States. BPH is often associated with a reduction in quality of life and may progress to acute urinary retention (AUR), the inability to pass any urine. Recently, a 4-year placebo-controlled clinical trial known as the Proscar Long-Term Efficacy and Safety Study (PLESS) demonstrated that finasteride use reduces the risk of developing AUR by 57% and the need for BPH-related surgery by 55%. The economic implications of these findings were investigated using a model-based decision-analytic approach to compare finasteride with both watchful waiting and alpha-blocker therapy. The modeling used the longest-term published controlled data concerning alpha-blockers, which were for the alpha-blocker terazosin. The base case considered a 64-year-old man (the mean age of a PLESS patient) with prostatic enlargement on digital rectal examination and moderate-to-severe symptoms of BPH. The model suggested savings in surgical and AUR costs with finasteride versus watchful waiting, with an estimated 25% of total finasteride costs recouped in savings on surgical events avoided in the first year. Over 2 years, the expected cost per patient starting finasteride therapy was $2304, whereas the expected cost per patient starting terazosin was $2334. Analyses also explored the variation in economic results by baseline levels of prostate-specific antigen (PSA), a proxy for prostate volume. For patients with PSA levels > or =1.4 ng/mL, expected 2-year costs with finasteride and terazosin were $2342 and $2479, respectively. For patients with PSA levels > or =3.3 ng/mL, expected 2-year costs with finasteride were $373 less than with terazosin ($2347 vs $2720). Results were robust over a range of model assumptions and cost estimates. The analyses illustrate that all medical interventions, including watchful waiting, have associated costs. Finasteride shows cost offsets compared with watchful waiting and cost savings compared with terazosin over 2 years. Finasteride appears to be more economical in men with higher PSA levels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10440624&dopt=Abstract finasteride Propecia



finasteride, Propecia
Androgen-induced regrowth in the castrated rat ventral prostate: role of 5alpha-reductase.

Wright AS, Douglas RC, Thomas LN, Lazier CB, Rittmaster RS.

Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada. aswright is2.dal.ca

Testosterone (T), the major circulating androgen, must be converted to dihydrotestosterone (DHT) by the enzyme 5alpha-reductase (5alpha-R) to be maximally active in the prostate. The present study was designed to determine the relative potency of T and DHT on regrowth of the involuted prostate and to elucidate the role of 5alpha-R in the growing prostate. To create dose-response curves for intraprostatic T or DHT, rats were castrated for 2 weeks to allow their prostates to fully regress and then given T implants of various sizes in the presence or absence of the 5alpha-R inhibitor, finasteride. Markers for androgen effects on regrowth of the prostate were prostate weight, duct mass (a measure of secretory activity) and DNA content (a measure of cell number). To assess the relative uptake of T and DHT by the prostate, a comparison was made of intraprostatic DHT levels resulting from T and DHT implants. In the prostate, 1.6-1.9 times more T than DHT was required to achieve a half-maximal response for each of the three markers of prostate regrowth. The dose-response curves revealed that thresholds for intraprostatic T and DHT had to be attained before significant growth was observed. The threshold for T was 2- to 3-fold greater than that for DHT. However, at high intraprostatic concentrations, the effects of T mimicked those of DHT. When the relationship between serum T levels and prostate regrowth was considered, 13 times more serum T was required for half-maximal prostate regrowth when its conversion to DHT was blocked by finasteride. This is partly due to decreased androgen accumulation in the prostate when T was the major intraprostatic androgen. Finally, T or DHT implants in the absence of finasteride resulted in similar intraprostatic DHT levels, indicating that uptake of each serum androgen into the prostate was similar. However, to achieve similar levels of DHT or T in serum, much larger DHT pellets were needed, suggesting more rapid metabolism of DHT in tissues other than the prostate. We conclude that the role of 5alpha-R is 2-fold: it converts testosterone into a modestly more potent androgen and enhances prostatic accumulation of androgen. DHT, in principle, could serve equally well as T as the circulating androgen, although the rate of DHT production would have to be considerably higher to counter the apparent rapid clearance from serum. In addition, we hypothesize that T has arisen as the major circulating androgen instead of DHT because it can be aromatized to estradiol, which itself has important roles in male reproductive function and bone physiology.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10499505&dopt=Abstract finasteride Propecia



finasteride, Propecia
Management of symptomatic BPH in the US: who is treated and how?

Bruskewitz R.

Department of Urology, University of Wisconsin Madison, Center of Health Services, Madison, WI 53792, USA. arentson surgadmin.surgery.wisc.edu

OBJECTIVE: To review the contemporary management of symptomatic benign prostatic hyperplasia (BPH) in North America. METHODS: Information was obtained from published scientific articles, lay press articles, Medicare outcomes data, IMS market analysis data and surveys among primary care practitioners and urologists. RESULTS: A survey in Olmsted County in the US identified the number of men with an I-PSS score >7 and maximum urinary flow rate <15 ml/s. This survey found that 17% of men in the 50-59 year old age bracket, 27% of men in the 60-69 bracket and 37% of men in the 70-79 bracket meet this minimum criterion for discussions about treatment. Currently in the US, there are approximately 5.6 million men that fall in this category, and the number is expected to double by the year 2025. Primary care physicians in 25% of cases and internal medicine in 24% of cases provide initial management of BPH. Urologists provide initial management in 37% of cases. Improvement in urinary symptoms and quality of life is the most important health outcome in the management of symptomatic BPH in the US, particularly because serious complications from BPH are distinctly uncommon. A survey among urologists determined that for men with mild symptoms, watchful waiting was employed 77% of the time, alpha(1)-adrenoceptor antagonists 21% and finasteride 1%. For those with moderate symptoms and prostate volume </=40 ml, alpha(1)-adrenoceptor antagonists are employed 88% of the time, finasteride 1% and TURP 1%. When the prostate is in excess of 40 ml, alpha(1)-adrenoceptor antagonists are used 69% of the time, finasteride 10% and TURP 9%. alpha(1)-Adrenoceptor antagonists are also employed most of the time for patients with severe symptoms: 58% of the time for small and 45% of the time for large prostates. The respective data for TURP are 31% and 38%. Primary care physicians utilize predominantly watchful waiting and long-acting alpha(1)-adrenoceptor antagonists. Laser use in the management of BPH has fallen from 40% of urologists in 1994 to 26% in 1997. TUMT and TUNA are each employed by 3% of urologists. The use of transurethral vaporisation of the prostate has increased to 62% of urologists. For those patients being treated with medication, 36% are treated with terazosin, 31% with doxazosin, 15% with finasteride and 18% with tamsulosin, which was introduced only recently and is growing. CONCLUSIONS: In the future, the number of older men in the US will increase dramatically. Likely the percentage of patients undergoing surgical treatment such as TURP will decrease but the absolute number having surgery will increase. It is also likely that alpha(1)-adrenoceptor antagonists will be used with greater frequency in the future and finasteride will be used less frequently. Copyrightz1999S.KargerAG,Basel

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10559625&dopt=Abstract finasteride Propecia