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PubMed2006

Treatment and pharmacologic management of BPH in the context of common comorbidities.

Benign prostatic hyperplasia (BPH) is extremely common in the aging man and may cause significant lower urinary tract symptoms (LUTS) necessitating treatment. Drug treatment is the mainstay of treatment for symptomatic BPH and is directed at relaxing prostatic smooth muscle, reducing prostate volume, or a combination of these effects. The most commonly used drugs for this indication are alpha1-adrenergic receptor antagonists, which relax prostatic smooth muscle, and 5-alpha-reductase inhibitors, which reduce prostatic androgen levels and consequently prostate size. Invasive interventions include the gold standard, transurethral resection of the prostate (TURP), and several minimally invasive surgical options. Although effective in alleviating symptoms, TURP carries a higher risk of morbidity and complications, including sexual side effects (mainly ejaculatory dysfunction), than medical therapy or minimally invasive techniques. Treatment for BPH, whether medical or surgical, must take patients' comorbid conditions into consideration so that LUTS may be effectively relieved, with the smallest risk of exacerbating any concomitant conditions.

5-alpha Reductase Inhibitors↗
PubMed1990

Androgen ablation and blockade in the treatment of benign prostatic hyperplasia.

Antiandrogen therapy appears to produce a 30 to 40 per cent decrease in the volume of the hyperplastic prostate after 3 to 6 months of therapy (Table 5). Longer treatment may result in further prostatic regression, although this remains to be seen. Biopsy studies suggest that epithelial regression occurs to a much more significant degree than does stromal regression, but this finding may simply reflect the relatively longer turnover of the stromal cell population. The significant placebo effect of oral medication in patients with BPH makes interpretation of clinical symptomatology and uro-flow data difficult. Analysis of symptom improvement is further complicated by the relatively slow improvement of patients on antiandrogen therapy, in contrast to surgery, in which relief is immediate. In addition to limited stromal involution and inadequate treatment duration, other biologic factors may limit the clinical efficacy of antiandrogen therapy. Most importantly, prostatic involution may not necessarily decrease urethral resistance. In addition, obstruction-induced detrusor dysfunction may persist after relief of outflow obstruction in some patients, as it does after surgery. Incomplete antiandrogen action of the compounds, as well as compliance issues, may likewise limit efficacy. Although there are no data to suggest that the 5 alpha-reductase inhibitor finasteride will be more effective than other antiandrogen compounds in the treatment of BPH, preliminary studies suggest that it has less toxicity. If long-term studies validate a modest but significant clinical response rate and preservation of sexual function, then finasteride therapy may well be acceptable to a subgroup of men presenting with the symptoms of BPH.(ABSTRACT TRUNCATED AT 250 WORDS)

5-alpha Reductase Inhibitors↗
PubMedDate not supplied

One-year experience in the treatment of benign prostatic hyperplasia with finasteride. The MK-906 (Finasteride) Study Group.

Finasteride (MK-906) is a 5 alpha-reductase inhibitor that reduces circulating dihydrotestosterone (DHT) levels without lowering testosterone levels. The goal of this study was to evaluate the effects of long-term (12 months) treatment with finasteride in 67 men with benign prostatic hyperplasia to determine if previously reported short-term efficacy was maintained with chronic therapy. Treatment with 10 mg of finasteride resulted in a 78% to 80% reduction in DHT levels (P less than 0.001) levels, and a small but significant increase in testosterone levels (P less than 0.05) that were maintained over the 12-month period. Significant reduction in prostate volume was observed after 6 months of treatment and maintained at month 12 (P less than 0.05). In patients with baseline maximum flow rates less than or equal to 15 ml/second, maximum urinary flow significantly increased by a mean of 4 ml/second (P less than 0.01), with at least a 3 ml/second improvement observed in up to 70% of the patients at month 12. These results indicate that finasteride can reduce prostate size and improve maximum urinary flow with no loss of efficacy after 1 year of treatment. It is concluded that finasteride has the potential to be an effective chronic therapy for benign prostatic hyperplasia.

5-alpha Reductase Inhibitors↗
PubMedDate not supplied

4-MAPC, a 5 alpha-reductase inhibitor, reduces rat ventral prostate weight, DNA, and prostatein concentrations.

Several compounds, such as 4-MAPC (4-methyl-3-oxo-4-aza-5 alpha-pregnane-20- carboxylate), that inhibit conversion of testosterone (T) to dihydrotestosterone (DHT) by 5 alpha-reductase have been demonstrated to reduce prostate size in rats and dogs. The current studies were undertaken to determine if this effect is due to a reduction in cell number, in epithelial cell synthetic activity, or both. Eight-week-old intact rats were treated daily for 14 days with sesame seed oil, 4-MAPC (10 mg/kg), 4-MAPC + testosterone propionate (TP, 1 mg/kg), or 4-MAPC + TP (3 mg/kg). Rats were killed 24 hours after the last injection. In the animals treated only with 4-MAPC, ventral prostate weight was reduced 37%, but the 14% reduction in total DNA was not significant. The mean intraprostatic concentration of prostatein, a major secretory protein, was reduced 45% (P less than 0.05). The 3 mg/kg dose of TP increased ventral prostate weight, prostatein concentrations, and acid phosphatase activity, even though DNA/ventral prostate was similar to that in control animals. These observations indicate that the reduction in ventral prostate weight in adult rats is due in part to a reduction in cell number, but the primary effect was due to a reduction in synthetic activity, and possibly atrophy of the epithelial cells. Furthermore, TP in pharmacologic doses increased ventral prostate weight and synthetic activity without increasing DNA.

5-alpha Reductase Inhibitors↗
PubMed1991

Role of 5 alpha-reductase inhibitors in the treatment of advanced prostatic carcinoma.

Everything we know about the biology of the prostate supports the concept that DHT is the obligate androgen responsible for normal and hyperplastic growth. Whether this selectivity is maintained during malignant transformation is unknown. The consistent emergence of androgen-insensitive disease highlights the spectrum of biologic evolution this cancer is capable of. If the tumor is dependent only on DHT for neoplastic growth, the unique characteristics of a 5 alpha-reductase inhibitor offer several potential actions that warrant a systematic evaluation.

5-alpha Reductase Inhibitors↗
PubMedDate not supplied

Progesterone metabolism in hepatic microsomes. Effect of the cytochrome P-450 inhibitor, ketoconazole, and the NADPH 5 alpha-reductase inhibitor, 4-MA, upon the metabolic profile in human, monkey, dog, and rat.

Progesterone was incubated in the presence of NADPH with hepatic microsomes isolated from male and female human, monkey, dog, and rat and the effect of 17 beta-NN-diethylcarbamoyl-4-methyl-4-aza-5 alpha- androstan-3-one (4-MA), an NADPH 5 alpha-reductase inhibitor, and ketoconazole, a cytochrome P-450 inhibitor, upon oxidative metabolism was evaluated. 4-MA caused an increase in detectable oxidative products only with microsomes isolated from rat. An increase in 2 alpha- and 16 alpha-hydroxylation was observed in male rat, and an increase in the formation rate of nine products was observed in female rat. delta 6-Progesterone, 6 beta-, 15 alpha-, 16 alpha-, and 21-hydroxyprogesterone (6 beta-, 15 alpha-, 16 alpha-, and 21-OHP) were common products in both sexes of all species studied. Differences were observed in the formation rate of 2 alpha-, 2 beta-, 6 alpha-, 7 alpha-, and 17 alpha-OHPs. At the 2-carbon, microsomes isolated from both sexes of primates hydroxylated progesterone exclusively at the 2 beta-position. Microsomes from both dog sexes and female rat formed 2 alpha- and 2 beta-OHP, while microsomes isolated from male rat formed exclusively 2 alpha-OHP. 7 alpha-Hydroxylation was detected exclusively in rat, and 6 alpha-hydroxylation was detected in both dog and rat. 17 alpha-Hydroxylase activity in primates was detected only in microsomes from male human. IC50 values associated with ketoconazole inhibition of progesterone metabolism differed among species.(ABSTRACT TRUNCATED AT 250 WORDS)

5-alpha Reductase Inhibitors↗
PubMed1991

Combination of an antiandrogen and a 5 alpha-reductase inhibitor: a further step towards total androgen blockade?

While the elimination of androgens of testicular origin can be easily achieved by orchiectomy or medical castration with LHRH agonists, the action of adrenal androgen precursors which are converted into the active androgen 5 alpha-dihydrotestosterone (DHT) in the prostatic tissue itself can be partially neutralized by antiandrogens which compete with DHT for binding to the androgen receptor. In order to increase the efficiency of androgen blockade, we have used 4-MA, an inhibitor of 5 alpha-reductase, the enzyme which converts testosterone into DHT, to reduce intracellular DHT concentrations and thus facilitate the action of the antiandrogen Flutamide. The present data show that the inhibitory effects of 4-MA (17 beta, N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one) and of the antiandrogen Flutamide are additive on prostatic growth and on androgen-sensitive prostatic binding protein mRNA levels in the rat, thus clearly suggesting that such a combination could provide the basis for a further improvement in the therapy of prostate cancer.

5-alpha Reductase Inhibitors↗
PubMed1990

Activity of 17 beta-hydroxy-3-aza-A-homo-4 alpha-androsten-4-one-p-N, N-bis(2-chloroethyl)aminophenoxyacetate (NSC-620480) in P388 leukemia. Activity of steroidal lactams in Ehrlich tumor.

A new homo-aza-steroidal ester, 17 beta-hydroxy-3-aza-A-homo-4 alpha-androsten-4-one-p-N,N-bis(2-chloroethyl)aminophenoxyaceta te gives a T/C greater than 125% in the treatment of P388 lymphoid leukemia. Modified and unmodified steroids without alkylating congener have been studied for activity in L1210 leukemia and EAT cells.

Animals↗
PubMed1990

A possible specific receptor for 3-beta-androstanediol in the human sebaceous gland.

Dihydrotestosterone (DHT) does not seem to be the active specific metabolite of testosterone in hypertrophic sebaceous glands of subjects affected by male pattern baldness (MPB) and several results indicate that probably 3-beta-androstanediol (beta DIOL) could be an active form of testosterone in those glands. Cytosol and serum from several patients affected by MPB and subjected to hair autotransplantation, was incubated with both beta DIOL and 3-alpha-androstanediol (alpha DIOL). Binding patterns indicate that alpha DIOL binds to cytosolic proteins probably due to the contaminating sex hormone binding globulin (SHBG), whereas beta DIOL exhibits an atypical binding process in cytosol in the presence of high concentrations of non radioactive beta DIOL. This binding increases progressively up to 2 pmol/mg protein at the limit solubility conditions for the non radioactive steroid. This pattern is not observed in serum from the same patients, where the binding of beta DIOL is typically restricted to the SHBG. These results strongly suggest the existence of a specific beta DIOL-binding protein in the hypertrophic sebaceous glands and explain the lack of specific receptor for DHT in these tissues.

Alopecia↗
PubMed1987

gamma-Aminobutyric acid receptor-regulated 36Cl- flux in mouse cortical slices.

An improved neurochemical assay for gamma-aminobutyric acid (GABA) function has been developed using tracer-radioactive chloride efflux in mouse cortical slices. Careful maintenance of the brain slice viability resulted in a 3-fold stimulation of 36Cl- efflux rate by the GABA agonist muscimol (EC50 = 3 microM), comparable to electrophysiologic and other chloride flux preparations. The shape of the muscimol dose-response curve was shallow, suggestive of negative cooperativity or heterogeneous receptors, but tissue uptake of agonist, possible diffusion barriers and apparent functional desensitization complicated these results. The response to muscimol was inhibited by GABAA receptor antagonists such as RU5135 and was enhanced by barbiturates and benzodiazepines. As observed previously, barbiturates stimulated 36Cl- efflux rate on their own and potentiated the response (potency and maximal effect) to muscimol in a stereospecific and picrotoxin-sensitive manner. Benzodiazepine receptor ligands alone did not alter 36Cl- flux, but agonists such as flunitrazepam enhanced the response to muscimol, an effect sensitive to the antagonist Ro15-1788. The inverse agonist methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate did not inhibit muscimol-activated 36Cl- flux. The anthelminthic-insecticide avermectin B1a stimulated 36Cl- flux by itself, and this response was apparently additive with that of muscimol. This brain slice chloride flux assay is therefore suitable for the assessment of activity including dose-response curves for GABAA agonists, antagonists and modulators including benzodiazepines.

Androstanes↗
PubMed1988

[Molecular and crystallographic structure of D-11-aza-19-nortestosterone].

Crystal and molecular structure of D-11-aza-19-nortestosterone monohydrate C17H25NO2.H2O (a 8,288(2), b 12,433(2), c 7,570(2) A, beta 90,25(1) degrees; space group P2(1), R 8.3%) has been determined by X-ray analysis. Its comparison with the molecular structure of D-19-nortestosterone showed that the decrease in the hormonal activity upon 11-aza-substitution may be due to difference in chemical properties of imino and methylene groups.

Azasteroids↗
PubMed1987

A new class of compounds for stroke and trauma: effects of 21-aminosteroids on lipid peroxidation.

The Lazaroids are the result of a blend of reasonable objectives which sprang from experience and hypothesis with a strong dose of serendipity. We believe that these compounds inhibit lipid peroxidation at a membrane level and, thus, blunt the damage from the secondary wave of injury which follows stroke, trauma and other insults to cell membranes. Certainly, these compounds are superior in animal models in potency and efficacy to older glucocorticoids. One compound, U74006F, has been selected for clinical development. Clinical trials in head injury will begin soon in selected centers in the United States.

Animals↗