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PubMed2003

The extract of Thujae occidentalis semen inhibited 5alpha-reductase and androchronogenetic alopecia of B6CBAF1/j hybrid mouse.

BACKGROUND: The conversion of testosterone to dihydrotestosterone; 5alpha-androstan-17beta-ol-3-one by 5alpha-reductase plays a crucial role in hair baldness and prostatomegaly. Recent approach showed specific inhibitors for 5alpha-reductase type 2 such as finasteride promoted hair growth in male pattern alopecia. OBJECTIVE: In order to search for effective medicinal plant extracts applied topically for androgenetic alopecia, we screened natural plant extracts having inhibitory activities of 5alpha-reductase type 2 and demonstrated its biological function in androgen-related animal models. METHODS: We evaluated the inhibition activities of numerous plant extracts by contact cell based metabolic method using a stable HEK 293 cell line expressing human 5alpha-reductase (type 2). To elucidate the biological activity in vivo, the Thujae occidentalis semen (TOS) extract was topically applied to fuzzy rat and androchronogenetic alopecia (AGA) mouse, respectively. The secreted sebum and the size of sebaceous glands of fuzzy rat were measured after 6 weeks. Also, after the topical treatment with TOS extract and androgen receptor antagonist (cyproterone acetate) simultaneously with subcutaneous injection of testosterone (1 mg/mice/day), hair loss patterns of female B6CBAF1/j hybrid mouse were observed. RESULTS: TOS extract showed higher inhibition activity of 5alpha-reductase type 2(IC(50) value=2.6 microg/ml) than that of gamma-linolenic acid, but lower than that of finasteride. When applied to fuzzy rat, the amount of sebum and sebaceous gland size decreased remarkably. In AGA model, alopecia degrees of two groups, treated with TOS extract (P<0.015) or cyproterone acetate (P<0.01), were lower than that of vehicle (propylene glycol:ethanol=7:3) and there was no difference between above two groups. CONCLUSION: We have demonstrated the inhibitory activity of TOS extract for 5alpha-reductase type 2 and its biological action in two animal models, suggesting that TOS extract would be used as an effective agent for male pattern baldness by modifying androgen conversion.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1998

Synthesis and in vitro activity of some epimeric 20 alpha-hydroxy, 20-oxime and aziridine pregnene derivatives as inhibitors of human 17 alpha-hydroxylase/C17,20-lyase and 5 alpha-reductase.

Some epimeric 20-hydroxy, 20-oxime, 16 alpha, 17 alpha-, 17,20- and 20,21-aziridine derivatives of progesterone were synthesized and evaluated as inhibitors of human 17 alpha-hydroxylase/C17,20-lyase (P450(17) alpha) and 5 alpha-reductase (5 alpha-R). The reduction of 16-dehydropregenolone acetate (3a) was reinvestigated. NaBH4 in the presence of CeCl3 gave better stereo-selectivity for 20 beta-ol [20 alpha/20 beta-OH (4 alpha/4 beta) = 1/2.7] than LTBAH or the Meerwein-Pondroff method reported; reduction with Zn in HOAc formed exclusively 20 alpha-ol (4 alpha b). The 20 alpha- and 20 beta-hydroxy-4,16-pregnadien-3-one (9 alpha) and (9 beta) were synthesized from the alcohols 4 alpha b and 4 beta b. Several 20-oxime pregnadienes and 16 alpha, 17 alpha-, 17,20- and 20,21-aziridinyl-5-pregnene derivatives were also synthesized. LiAlH4 reduction of the 16-en-20-oxime (12b) yielded 20 (R)-(13a) and 20(S)-17 alpha,20-aziridine (13b) and 20(R)-17 beta,20-aziridine (14a). Several compounds inhibited the human P450(17) alpha with greater potency than ketoconzole. The 5 alpha-R enzyme assay showed that while (9 alpha) did not have any activity, (9 beta) and (3b) were potent 5 alpha-reductase (IC50 = 21 and 31 nM) inhibitors with activities similar to finasteride. The 20-oximes (17a) and (17b) were potent dual inhibitors for both 5 alpha-R (IC50 = 63 and 115 nM, compared to 33 nM for finasteride) and P450(17) alpha (IC50 = 43 and 25 nM, compared to 78 nM for ketoconazole).

5-alpha Reductase Inhibitors↗
PubMed1997

19-nor-10-azasteroids: a novel class of inhibitors for human steroid 5alpha-reductases 1 and 2.

Steroid 5alpha-reductase is a system of two isozymes (5alphaR-1 and 5alphaR-2) which catalyzes the NADPH-dependent reduction of testosterone to dihydrotestosterone in many androgen sensitive tissues and which is related to several human endocrine diseases such as benign prostatic hyperplasia (BPH), prostatic cancer, acne, alopecia, pattern baldness in men and hirsutism in women. The discovery of new potent and selective 5alphaR inhibitors is thus of great interest for pharmaceutical treatment of these diseases. The synthesis of a novel class of inhibitors for human 5alphaR-1 and 5alphaR-2, having the 19-nor-10-azasteroid skeleton, is described. The inhibitory potency of the 19-nor-10-azasteroids was determined in homogenates of human hypertrophic prostates toward 5alphaR-2 and in DU-145 human prostatic adenocarcinoma cells toward 5alphaR-1, in comparison with finasteride (IC50 = 3 nM for 5alphaR-2 and approximately 42 nM for 5alphaR-1), a drug which is currently used for BPH treatment. The inhibition potency was dependent on the type of substituent at position 17 and on the presence and position of the unsaturation in the A and C rings. delta9(11)-19-Nor-10-azaandrost-4-ene-3,17-dione (or 10-azaestra-4,9(11)-diene-3,17-dione) (4a) and 19-nor-10-azaandrost-4-ene-3,17-dione (5) were weak inhibitors of 5alphaR-2 (IC50 = 4.6 and 4.4 microM, respectively) but more potent inhibitors of 5alphaR-1 (IC50 = 263 and 299 nM, respectively), whereas 19-nor-10-aza-5alpha-androstane-3,17-dione (7) was inactive for both the isoenzymes. The best result was achieved with the 9:1 mixture of delta9(11)- and delta8(9)-17beta-(N-tert-butylcarbamoyl)-19-nor-10-aza-4- androsten-3-one (10a,b) which was a good inhibitor of 5alphaR-1 and 5alphaR-2 (IC50 = 127 and 122 nM, respectively), with a potency very close to that of finasteride. The results of ab initio calculations suggest that the inhibition potency of 19-nor-10-azasteroids could be directly related to the nucleophilicity of the carbonyl group in the 3-position.

5-alpha Reductase Inhibitors↗
PubMed2003

Comparison of Saw Palmetto (extract and whole berry) and Cernitin on prostate growth in rats.

Pharmaceuticals such as finasteride and alpha blockers are used to treat symptoms of benign prostatic hyperplasia (BPH) and are known to cause severe adverse reactions. Accordingly, a search for safer, natural products has been undertaken. Two natural agents (nutraceuticals) have come under recent scrutiny; because natural products, in general, often have evidence of long-term safety. The present study compares the in vivo effects on androgen-induced prostatic enlargement in rats of two nutraceuticals--the widely recognized Saw Palmetto (Serenoa repens) and the less well-known Cernitin (defined pollen extract). Non-castrated rats, had a mean prostate weight of 124 mg +/- 8.8 (S.E.M.) compared to the 24.5 mg +/- 1.9 (S.E.M.) of the castrated rat followed under the same regimen (p < 0.01). When castrated rats were given testosterone, the mass increased significantly to 250.0 mg +/- 31.7 (S.E.M.) (p < 0.01). In the five remaining groups, castrated rats receiving testosterone were given finasteride, an extract of Saw Palmetto, crushed whole berry derived from Saw Palmetto fruit, a water soluble and fat soluble extract of Cernitin or a combination of the Saw Palmetto extract and Cernitin. All treatments decreased the size of the prostate to roughly the same size as in the non-castrated rats, a size that was significantly smaller than castrated rats treated with testosterone in the same manner (p < 0.01). A second study examining non-castrated rats treated with very high doses of testosterone showed similar results. In both studies, the nutraceuticals generally decreased body weight. In conclusion, these studies show the ability of Saw Palmetto (whole berry and extract) and Cernitin to influence prostatic hyperplasia via effects on androgen metabolism.

Androgens↗
PubMed1998

Predominance of type I 5alpha-reductase in apocrine sweat glands of patients with excessive or abnormal odour derived from apocrine sweat (osmidrosis).

High levels of 5alpha-reductase activity have been detected in human apocrine glands, and the concentration of dihydrotestosterone has been found to be higher than that of testosterone in the nuclear fraction of the skin of patients who suffer from excessive or abnormal odour derived from apocrine sweat (osmidrosis). Although these results suggest that 5alpha-reductase may play a central role in the action of androgens in the apocrine gland, the isozyme responsible is not known. We therefore assayed 5alpha-reductase type I and type II activity and mRNA expression in isolated apocrine glands from four patients with osmidrosis. When we incubated gland homogenates with [3H]testosterone, we found that the biochemical properties of the apocrine gland enzyme were consistent with those of type I 5alpha-reductase: at substrate concentrations of both 50 nmol/L and 1 micromol/L, the optimum pH was in the range 6.0-7.5, and the apparent Km was 21.1 micromol/L. The apocrine gland enzyme was inhibited by MK386, a specific inhibitor of type I 5alpha-reductase, in a dose-dependent manner, but it was hardly affected by finasteride, a specific inhibitor of type II isozyme, in that a nanomolar concentration of finasteride produced only a slight inhibition. Reverse transcriptase-polymerase chain reaction showed that the apocrine gland expressed type I 5alpha-reductase mRNA exclusively, except for a faint band of type II isozyme in a few preparations. These data indicate that the type I isozyme is the predominant form of 5alpha-reductase in the apocrine gland and may play a central role in the anabolic activity of androgens, as reported for the sebaceous gland. In addition, a small amount of type II isozyme may be expressed by mesenchymal cells that surround the apocrine glands and also contribute to their development.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1999

Immunohistochemical localization of types 1 and 2 5alpha-reductase in human scalp.

The predominant form of 5alpha-reductase (5aR) in human scalp is 5aR1. None the less, clinical studies have shown that finasteride, a selective inhibitor of 5aR2, decreases scalp dihydrotestosterone and promotes hair growth in men with androgenetic alopecia. Immunolocalization studies were thus carried out to examine 5aR isozyme distribution within scalp and, in particular, to determine whether 5aR2 might be associated with hair follicles. 5aR2 was localized using both a rabbit polyclonal and a mouse monoclonal antibody. 5aR1 was detected with a mouse monoclonal antibody. The specificity of these reagents was demonstrated both by immunofluorescence and Western blot analyses of COS cells overexpressing human 5aR1 or 5aR2. When cryosections of scalp from men with androgenetic alopecia were stained with antibody against 5aR2, using immunoperoxidase avidin-biotin complex methodology, immunostaining was observed in the inner layer of the outer root sheath and, in more proximal regions of the follicle, in the inner root sheath. Staining was also prominent in the infundibular region of the follicle, with less intense staining extending throughout the granular layer of the epidermis. Some staining was also seen in sebaceous ducts. Similar results were obtained with both the polyclonal and monoclonal 5aR2 antibodies. In contrast, in scalp cryosections stained with antibody to 5aR1, no immunostaining was observed within hair follicles. Intense staining for the type 1 isozyme was, however, detected within sebaceous glands. Our immunolocalization data suggest that the results seen in clinical trials of men with male pattern hair loss treated with finasteride may be due, at least in part, to local inhibition of 5aR2 within the hair follicle.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1999

Effects of androgens on the expression of nitric oxide synthase mRNAs in rat corpus cavernosum.

OBJECTIVE: To examine the effects of androgens on erectile response and the expression of nitric oxide synthase (NOS) isoform mRNAs in the penile corpus cavernosum of castrated rats. MATERIALS AND METHODS: The study comprised 50 adult male Sprague-Dawley rats in five groups: sham controls; castrated; castrated and receiving testosterone; castrated and receiving dihydrotestosterone (DHT); castrated and receiving testosterone and 5alpha-reductase inhibitor (finasteride). Androgen replacements were administered via implants of silicone tubing. After 7 days, some animals underwent electrical stimulation of the cavernosal nerves and the remainder were used for further analysis. NOS activity was measured in the soluble fraction of the corpus cavernosum, using the Griess reaction. Total RNA was isolated and nNOS and eNOS mRNA expression examined using semiquantitative reverse-transcriptase polymerase chain reaction. RESULTS: Castration caused a marked decrease in erectile response and the ratio of maximal intracavernosal pressure (ICPmax) to systemic blood pressure (SBP), although both testosterone and DHT effectively restored the response to normal. NOS activity and the amount of nNOS mRNA were reduced in castrated rats but restored by androgen replacement. Although there was no significant difference in NOS activity between the androgens, nNOS mRNA expression was higher in rats treated with DHT. There were no effects of androgen in rats treated with finasteride, as the ICPmax/SBP ratio, NOS activity and amount of nNOS mRNA decreased. eNOS mRNA expression was independent of androgen. CONCLUSIONS: Androgens enhance nNOS gene expression in the penile corpus cavernosum of rats, suggesting that they play an important role in maintaining NOS activity. Of the two androgens, DHT was more potent.

Androgens↗
PubMed2000

Effects of androgen and ageing on gene expression of vasoactive intestinal polypeptide in rat corpus cavernosum.

OBJECTIVE: To clarify the effects of androgens (testosterone and dihydrotestosterone, DHT) and ageing on gene expression of vasoactive intestinal polypeptide (VIP), assessed as the expression of VIP mRNA, in rat corpus cavernosum. Materials and methods The study comprised 160 male Sprague Dawley rats divided into group A (56 rats, 5 weeks old), group B (50 rats, 10 weeks old) and group C (54 rats, 58 weeks old). Groups A-C were subdivided, respectively, into subgroups 1 (intact controls), 2 (castrated), 3 (castrated but given testosterone undecanoate 25 mg/kg per month by intramuscular injection), 4 (castrated with testosterone undecanoate 50 mg/kg per month) and 5 (treated with finasteride 4.5 mg/kg per day, orally). At 4 and 10 weeks after these treatments half the rats were killed. Serum samples were taken for the measurement of total and free testosterone and DHT, using a radioimmunoassay. Penile samples (corpus cavernosum) were frozen in liquid nitrogen and stored at -80 degrees C. VIP mRNA was estimated using a semi-quantitative reverse-transcription polymerase chain reaction. RESULTS: There was no significant difference in VIP mRNA in rat corpus cavernosum between intact control and castrated subgroups, or subgroups treated with finasteride, in groups A-C, including both the 4- and 10-week old animals (P > 0.05). Penile VIP mRNA was unchanged at any dose of testosterone in the castrated subgroups in all groups (P > 0.05). There was no significant relationship between penile VIP mRNA and ageing (P > 0.05). CONCLUSIONS: The gene expression of VIP in rat corpus cavernosum is independent of androgens (testosterone and DHT) and ageing. Androgens probably induce penile erection by pathways other than VIP; ageing may have little effect on penile VIP mRNA.

Aging↗
PubMed2003

Heat versus drugs in the treatment of benign prostatic hyperplasia.

The improvement in symptoms and voiding function is greater with transurethral microwave thermotherapy than with drug therapy, and the associated morbidity is low. Transient urinary retention necessitating catheterization is of short duration after targeted microwave thermotherapy. The short-term effect of microwave thermotherapy can be improved by neoadjuvant and adjuvant alpha-blockade. Microwave treatment offers greater versatility than drug therapy, allowing patients with severe baseline symptoms and small prostates to be treated successfully. Medical management improves symptoms to a more modest extent than does microwave treatment. Finasteride gives comparatively small symptom and flow rate improvements and requires several months for the maximum responses. With alpha-blockers the onset of action is fast and side-effects reversible, although they limit their utility. Finasteride or alpha-blockers must be continued indefinitely to maintain improvements in patients with BPH, but they have a favourable safety and tolerability profile.

5-alpha Reductase Inhibitors↗
PubMed2001

Contribution of androgens to chronic allograft nephropathy is mediated by dihydrotestosterone.

BACKGROUND: Donor and recipient gender influence long-term allograft outcome after kidney transplantation. Sex hormones are likely to contribute to these gender-related differences. The present study investigated the role of androgens and their inhibition on the development of chronic allograft nephropathy. METHODS: Male or female Fisher (F344) kidneys were orthotopically transplanted into intact male Lewis recipients. Animals were treated either with testosterone, the antiandrogen flutamide, the 5alpha-reductase inhibitor finasteride, or vehicle. Twenty weeks after transplantation animals were harvested for histology, immunohistology, and molecular analysis. RESULTS: Testosterone treatment resulted in an increased proteinuria as well as profound glomerulosclerosis, tubulointerstitial fibrosis, and mononuclear cell infiltration that paralleled enhanced intragraft mRNA levels of transforming growth factor-beta (TGF-beta) and platelet-derived growth factor-A and -B chain (PDGF-A and -B). In contrast, flutamide and finasteride reduced glomerulosclerosis as well as the inflammatory cell infiltration associated with decreased TGF-beta, PDGF-A, and -B chain mRNA expression. No gender-related donor differences were noted between the groups. CONCLUSIONS: Our data suggest that dihydrotestosterone mediates the adverse effects of androgens on chronic allograft nephropathy. The inhibition of androgens improves long-term allograft outcome after kidney transplantation.

Androgen Antagonists↗
PubMed2001

Is there a place for combination medical therapy?

Medical therapy for lower urinary tract symptoms and benign prostatic hyperplasia with either alpha adrenergic receptor blockers or 5alpha-reductase inhibitors has become the most common treatment choice over the past 10 years, replacing transurethral resection of the prostate as the standard intervention. Both classes of drugs have demonstrated efficacy and safety in numerous randomized, placebo-controlled clinical trials. Because of the two different mechanisms of action proposed for these two classes of drugs, the idea of utilizing both to enhance efficacy appears logical and promising. However, few well-conducted trials are available to address the issue of combination medical therapy for lower urinary tract symptoms and benign prostatic hyperplasia, the majority of the data available coming from trials with significant design flaws. Two prospective, randomized, placebo-controlled studies have been conducted comparing the safety and efficacy of an alpha blocker-finasteride combination versus placebo in large numbers of patients. Neither one of the two trials suggests superior efficacy of the combination therapy, whereas some of the less well-controlled studies do. Recent evidence suggests superior efficacy of finasteride in men with large glands and higher serum prostate-specific antigen levels in terms of symptoms and outcome prevention. A trial addressing this specific patient population, in whom theoretically the most benefit might be gained from combining both classes of drugs to address symptoms and prevent outcomes, would be a welcome addition to our knowledge base.

Combined Modality Therapy↗
PubMed2004

Who will benefit from combination therapy? The role of 5 alpha reductase inhibitors and alpha blockade: a reflection from MTOPS.

PURPOSE OF REVIEW: The purpose of this review is to revisit the medical treatment of benign prostatic hyperplasia in the light of the most recent data concerning the association of alpha-blockers and 5alpha-reductase inhibitors. Combining these two drugs is not a new concept in treating benign prostatic hyperplasia patients. Alpha blockers are believed to improve symptoms and flow rate by inducing relaxation of the smooth muscle neck and prostate area (dynamic component), while 5alpha-reductase inhibitors are believed to improve symptoms and flow rate by shrinking the transition zone of the prostate through hormonal mechanisms (static component). The proof of this concept, however, could not be clinically demonstrated up until now. The design of previous studies investigating combination therapy with the 5alpha-reductase inhibitor finasteride has been questionable. RECENT FINDINGS: Extrapolated from the Medical Therapy of Prostatic Symptoms (MTOPS) study, not yet fully published, again raises the question of the effectiveness of such a combination. There is now some evidence to suggest that combining alpha-blockers and finasteride may be more effective in relieving and preventing the progression of symptoms than either of the two drugs alone. SUMMARY: Patients most likely to benefit from combination therapy are those in whom baseline risk of progression is significantly higher, generally patients with larger glands and higher prostatic specific antigen values.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2004

Benign prostatic hyperplasia progression and its impact on treatment.

PURPOSE OF REVIEW: Management of men with benign prostatic hyperplasia should reduce the lifetime risk of acute urinary retention and the need for benign prostatic hyperplasia-related surgery. A number of recent studies demonstrate that 5alpha-reductase inhibitors are unique in providing a long-term combination of improvements in symptoms and flow, and reductions in the risks of acute urinary retention and surgical intervention. RECENT FINDINGS: The 5alpha-reductase inhibitor finasteride was shown to reduce the risk of retention and surgery in men with large prostate volumes and/or high PSA. Recent studies have examined the role of adding an alpha1-blocker to 5alpha-reductase inhibitor in short- or long-term combination. The Medical Therapy of Prostatic Symptoms study randomised 3,047 men with benign prostatic hyperplasia to treatment with a 5alpha-reductase inhibitor (finasteride), an alpha1 blocker (doxazosin), a combination of both, or placebo. Only treatment arms containing 5alpha-reductase inhibitor therapy were associated with longer-term significant reductions in the risk of acute urinary retention and invasive therapy for benign prostatic hyperplasia. Three randomised, two-year, placebo-controlled studies have assessed the clinical relevance of the >93% DHT suppression provided by dutasteride. Dutasteride was also associated with a reduction in the risk of acute urinary retention of 57%, and a reduction of 48% in the risk of surgical intervention compared with placebo after 2 years. SUMMARY: Short-term combination of 5alpha-reductase inhibitor and alpha-blockade are optimal in providing symptomatic improvement among patients who require symptom relief, while enabling the initiation of 5alpha-reductase inhibitor therapy to reduce the risk of subsequent acute urinary retention or benign prostatic hyperplasia-related surgery in men who are at greater risk of disease progression.

Adrenergic alpha-Antagonists↗
PubMed2005

Chemoprevention using dutasteride: the REDUCE trial.

PURPOSE OF REVIEW: This article will review the design and rationale of the dutasteride prostate cancer chemoprevention trial known as the REDUCE trial (Reduction by Dutasteride of Prostate Cancer Events) in the context of the recently completed Prostate Cancer Prevention Trial. RECENT FINDINGS: The Prostate Cancer Prevention Trial used the 5alpha-reductase inhibitor finasteride to prevent prostate cancer in a prospective randomized trial. The trial demonstrated a nearly 25% reduction in the prevalence of prostate cancer compared with placebo. Finasteride is a type 2-specific 5alpha-reductase inhibitor, whereas dutasteride is an inhibitor of both type 1 and type 2 5alpha-reductase. Recent evidence suggests that there may be increased expression of the type 1 5alpha-reductase in prostate cancer versus benign prostate tissue making dutasteride an attractive agent to study. SUMMARY: Proof of principle has been demonstrated by the Prostate Cancer Prevention Trial that a chemoprevention strategy using a hormonal agent such as a 5alpha-reductase inhibitor can be effective. The REDUCE trial will use the dual 5alpha-reductase inhibitor dutasteride in a group of men identified at increased risk of developing prostate cancer to determine if this will be an effective chemoprevention strategy.

5-alpha Reductase Inhibitors↗
PubMed2004

Ethanol-induced elevation of 3 alpha-hydroxy-5 alpha-pregnan-20-one does not modulate motor incoordination in rats.

BACKGROUND: Ethanol administration elevates the levels of GABAergic neuroactive steroids in brain and contributes to some of its behavioral actions. In the present study, we investigated whether such elevation of GABAergic neuroactive steroids contributes to the motor incoordinating effects of ethanol. METHODS: Sprague-Dawley rats were administered ethanol (2 g/kg intraperitoneally) or saline, and the level of 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) was measured across time in cerebral cortex and in various brain regions at the peak time by radioimmunoassay. To study whether increases in GABAergic neuroactive steroids are responsible for the motor incoordinating actions of ethanol, rats were subjected to chemical (5alpha-reductase inhibitor, finasteride) and surgical (adrenalectomy) manipulations before receiving ethanol (2 g/kg intraperitoneally) injections. The rats were then subjected to different paradigms to evaluate motor impairment including the Majchrowicz motor intoxication rating scale, Rotarod test, and aerial righting reflex task at different time points. RESULTS: The radioimmunoassay of 3alpha,5alpha-THP in different brain regions showed that ethanol increases 3alpha,5alpha-THP levels by 3- and 9-fold in cerebral cortex and hippocampus, respectively. There was no change in 3alpha,5alpha-THP levels in cerebellum and midbrain. The time course of 3alpha,5alpha-THP elevations in the cerebral cortex showed significant increases 20-min after ethanol injection with a peak at 60 min. In contrast, motor toxicity peaked between 5 and 10 min after ethanol injections and gradually decreased over time. Furthermore, adrenalectomy or pretreatment with finasteride (2 x 50 mg/kg, subcutaneously) did not reduce motor incoordinating effects of ethanol as assessed by the Majchrowicz intoxication rating score, Rotarod test, or aerial righting reflex task. CONCLUSIONS: Ethanol increases GABAergic neuroactive steroids in a time- and brain region-selective manner. The role of neuroactive steroids in alcohol action is specific for certain behaviors. Alcohol-induced deficits in motor coordination are not mediated by elevated neuroactive steroid biosynthesis.

Animals↗
PubMed2003

The evolution of detrusor overactivity after watchful waiting, medical therapy and surgery in patients with bladder outlet obstruction.

PURPOSE: We analyzed the evolution of detrusor overactivity in patients with bladder outlet obstruction treated with either medical or surgical therapy or watchful waiting. MATERIALS AND METHODS: Of 255 patients with symptomatic benign prostatic enlargement who completed the International Prostate Symptom Score and underwent full urodynamic investigation 161 presented with bladder outlet obstruction. Of the 161 men 101 were reevaluated with a second clinical evaluation and urodynamics 1 to 5 years (mean 2) after watchful waiting in 20, medical treatment (alfuzosin 20 and finasteride 16) in 36 and surgery (transurethral incision of the prostate 13 and prostatectomy 32) in 45. For statistical analysis Wilcoxon matched paired data and Kruskal Wallis tests were used as appropriate. RESULTS: Overall detrusor overactivity was present in 53 patients (52%) at baseline and 41 (40%) at followup. Detrusor overactivity was present in 9 patients (45%) at baseline and 11 (55%) at followup in the watchful waiting group (p = 0.17); 7 (35%) at baseline and 6 (30%) at followup in the alfuzosin group (p = 0.37); 10 (62.5%) at baseline and 10 at followup in the finasteride group (p = 1); 6 (46%) at baseline and 4 (30%) at followup in the transurethral prostate incision group (p = 0.48); and 21 (68%) at baseline and 10 (31%) at followup in the prostatectomy group (p = 0.02). CONCLUSIONS: Detrusor overactivity is highly prevalent (52%) in patients with bladder outlet obstruction, and appears to persist for long periods when obstruction is left untreated or treated only with medical therapy. However, surgical treatment of bladder outlet obstruction, prostatectomy in particular, significantly reduces the incidence of detrusor overactivity and lessens the chance of its de novo appearance for up to 5 years.

Humans↗
PubMed2006

An update on chemoprevention strategies in prostate cancer for 2006.

PURPOSE OF REVIEW: An increasing volume of research has been directed at the prevention of prostate cancer. This review proposes to summarize the large trials, novel approaches and molecular mechanisms of effect published in 2004 and 2005. RECENT FINDINGS: The impact of the Prostate Cancer Prevention Trial continues and subsequent articles have addressed the increase of high-grade prostate cancers detected in the finasteride arm of the trial, as well as the potential costs and benefits of extrapolating the findings to a public health campaign. Studies of risk have been published warning of excessive vitamin E and cyclooxygenase-2 inhibitor use in chemoprevention. Growing evidence supports the concept of chemopreventative agent combinations and further data on the roles of selenium, lycopene, soy, green tea, anti-inflammatories and statins in prostate-cancer prevention are presented. SUMMARY: Level one evidence exists for the preventative effects of finasteride in prostate cancer. The evidence for other agents is less conclusive but a number of large-scale, appropriately designed trials will hopefully address some of the relevant issues in prostate-cancer prevention over the next decade.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

Pharmacological therapy of benign prostatic hyperplasia/lower urinary tract symptoms: an overview for the practising clinician.

Less than 10 years ago surgery and watchful-waiting were the only widely accepted management options for lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) and benign prostatic obstruction (BPO). There has been an enormous decline in the popularity of surgery and it is now apparent that medication is the most frequently used treatment for BPH/LUTS; this has arguably therefore been the most major change in urological clinical practice in the last decade. Currently alpha(1)-adrenoceptor antagonists are the commonest medical therapy, and are thought to act by relaxing prostatic smooth muscle, the neural or so-called 'dynamic' component of BPO. 5alpha-reductase inhibitors (finasteride, dutasteride) are another option for BPH/LUTS, which reduce prostatic mass and therefore the mechanical or 'static' component of BPO. In the last 10 years there have been four direct comparative studies between alpha(1)-adrenoceptor antagonists and finasteride, including their combination, the results of which, and their implications for therapy, are discussed. Another group of agents are the phytotherapeutic extracts, which act via various mechanisms, many as yet poorly defined. This review critically assesses existing publications relating to the medical management of BPH/LUTS.

Adrenergic alpha-Antagonists↗