Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Azasteroids”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 289 records · Page 16Linked to original sources
PubMed2006

Clinical usefulness of serum prostate specific antigen for the detection of prostate cancer is preserved in men receiving the dual 5alpha-reductase inhibitor dutasteride.

PURPOSE: We determined whether the decrease in serum PSA seen with 5alpha-reductase inhibitors affects the clinical usefulness of PSA for prostate cancer screening using data from 2 dutasteride benign prostatic hyperplasia studies. MATERIALS AND METHODS: A total of 2,802 men 50 years or older with a clinical diagnosis of benign prostatic hyperplasia, no history of prostate cancer, PSA 1.5 to 10 ng/ml, prostate volume 30 cc or greater, an American Urological Association symptom score of 12 or greater and peak urinary flow rate 15 ml per second or less were randomized to 0.5 mg dutasteride daily or matching placebo for 24 months. Increases in PSA from baseline and the maximum increase from nadir to month 24 were compared between the groups and analyzed by prostate cancer status, as determined by PSA driven biopsy and an advised cutoff of more than 4 ng/ml after doubling to correct for dutasteride treatment with sensitivity and specificity calculated for each. RESULTS: In placebo treated men without prostate cancer there was an 8.3% median increase in PSA at month 24 compared with -59.5% in those who received dutasteride, using doubled values to correct for dutasteride treatment. In those with prostate cancer these changes were 23.8% and -37.2%, respectively. Using the upper PSA limit of 4 ng/ml sensitivity for prostate cancer in men receiving dutasteride vs placebo was 0.737 vs 0.804, while specificity was 0.671 vs 0.578. Using a PSA increase from nadir of 0.8 ng/ml the sensitivity of dutasteride was 0.548 and its specificity was 0.795. CONCLUSIONS: A doubling factor is effective for maintaining the sensitivity and specificity of PSA for prostate cancer detection in men on dutasteride. Increases in serum PSA in men receiving dutasteride should be considered suspicious and serial PSA measurements should be used to evaluate changes from nadir.

Aged↗
PubMed1993

Maximum urinary flow rate by uroflowmetry: automatic or visual interpretation.

We measured the maximum urinary flow rate monthly for 1 year by uroflowmetry in 1,645 patients in a double-blind, placebo-controlled study of finasteride therapy for benign prostatic hyperplasia. Patients were randomized to receive placebo (555) or finasteride (1,090). A total of 23,857 flow measurements was obtained. Because of the presence of artifacts on many uroflow curves, we read the maximum urinary flow rate values manually and compared them to the values provided electronically by the uroflowmeter. On average, the manually read values were 1.5 ml. per second lower than the machine read values. Artifacts causing a difference of 2 ml. per second or more between the 2 methods were found in 20% and of more than 3 ml. per second in 9% of the tracings. The difference between treatment groups in mean maximum urinary flow rate change at the end of the study was the same with both reading methods. However, confidence intervals were 15 to 25% larger for the machine read compared to the manually read values. This larger variability in machine read maximum urinary flow rate has a marked negative impact on the power of statistical tests to assess any given difference in maximum urinary flow rate between treatment groups. Furthermore, it increases sample size requirements by 50% to achieve any given statistical power. We conclude that maximum urinary flow rate artifacts contribute significantly to the variability of maximum urinary flow rate measurement by uroflowmetry. Manual reading of the maximum urinary flow rate eliminates an important fraction of such variability.

5-alpha Reductase Inhibitors↗
PubMed1993

Urodynamic effects of finasteride in the treatment of bladder outlet obstruction due to benign prostatic hyperplasia.

Urodynamic effects of the 5-alpha-reductase inhibitor, finasteride, were studied in the treatment of patients with bladder outlet obstruction due to benign prostatic hyperplasia (BPH). A total of 36 patients was randomly assigned in a double-bind manner to receive either 5 mg. finasteride daily (19) or placebo (17) for 6 months. The possible relief of bladder outlet obstruction was monitored with uroflowmetry and repeated urodynamics. The mean flow rate, detrusor opening pressure, detrusor pressure at maximum flow and maximum detrusor pressure improved significantly in the patients treated with finasteride. There were no significant differences in the improvement of symptom score or peak flow rate, or in the reduction of residual urine between the finasteride and placebo groups. The treatment resulted in 30% average decrease in prostatic size and 46% decrease in prostate specific antigen concentration. The efficacy of finasteride in relief of bladder outlet obstruction caused by BPH seems to be of the same degree as that achieved by chemical castration therapy but without any significant side effects. There were wide variations among BPH patient response to finasteride treatment. Further studies are needed to define the responders who benefit from this treatment.

5-alpha Reductase Inhibitors↗
PubMed1993

Benign prostatic hyperplasia in a transgenic mouse: a new hormonally sensitive investigatory model.

Recent advances in molecular biology have enabled incorporation of proto-oncogenes into the mouse germline. In this study we use a transgenic mouse line that overexpresses the fibroblastic growth factor (FGF) family member, int-2, under the control of mouse mammary tumor virus (MMTV) regulatory elements. One of the tissues targeted by MMTV is the mouse prostate. Expression of the MMTV-int-2 transgene in male transgenic mouse carriers results in a dramatic enlargement of the prostate gland which on histologic examination closely resembles the epithelial/glandular BPH observed in human and canine models. Pre- and postpubertal transgenic (NR) and wild-type (WT) FVB/N male mice were evaluated for the effects of hormonal manipulation by orchiectomy and orchiectomy followed by androgen replacement. Orchiectomy results in a significant decrease in size of the prostate in both NR and WT mice (p < 0.05), regardless of sexual maturity. Exogenous hormonal replacement with testosterone or dihydrotestosterone following orchiectomy results in significant regrowth of the prostate in both NR and WT mice. Flutamide, a potent nonsteroidal anti-androgen, resulted in a 55% reduction in size of the NR prostate (p < 0.002) and a similar 44% reduction in size of the WT prostate. Similarly, treatment of both NR and WT mice with leuprolide, a GnRH agonist, resulted in a significant decrease in prostate size (p < 0.05). Treatment of both NR and WT mice with finasteride (MK-906), a 5-alpha reductase inhibitor, failed to produce any significant regression in prostatic tissue. Based upon these data, we conclude that this transgenic mouse model, expressing int-2, produces an epithelial BPH histologically similar to other animal models. This transgenic model is hormonally sensitive and appears to represent a unique model for the investigation of BPH and growth factor induced epithelial cell hyperplasia.

5-alpha Reductase Inhibitors↗
PubMed1992

Multicenter, randomized, double-blind, placebo controlled study to investigate the effect of finasteride (MK-906) on stage D prostate cancer.

A total of 28 untreated patients with asymptomatic, stage D prostate cancer was randomized in a double-blinded fashion to receive finasteride (10 mg. per day), a 5 alpha-reductase inhibitor or placebo. Patients were evaluated at 3-week intervals by rectal examination, and serum prostate specific antigen (PSA) and prostatic acid phosphatase (PAP) levels, and at 6-week intervals by bone scan and transrectal ultrasound determinations of prostatic volume. Patients stopped the medication at week 6 at the discretion of the investigator when PSA levels increased from baseline. After 12 weeks all patients were reevaluated. Of the patients 13 received finasteride and 15 received placebo. The 2 groups did not differ statistically with respect to patient age, initial PSA and PAP level, or the extent of metastases on initial bone scan. A statistically significant decrease in the median percentage change from baseline in PSA at weeks 3 and 6 occurred in the finasteride group compared to the placebo group (-22.9% versus -2.9% and -15.1% versus +11.7%, respectively, p less than 0.05). Finasteride had no effect upon PAP, serum testosterone, prostatic volume or appearance of bone scans. A decrease in serum PSA in the finasteride treatment group suggests that finasteride exerts a minor effect in patients with prostate cancer. This effect does not approach that seen with medical or surgical castration yet because of the potency preserving feature and the lack of toxicity finasteride may warrant further study in the treatment of prostate cancer.

5-alpha Reductase Inhibitors↗
PubMed1992

Sequential androgen blockade: a biological study in the inhibition of prostatic growth.

We attempted to determine the effects of the combination of a 5-alpha reductase inhibitor and an antiandrogen on rat ventral prostate and seminal vesicle weight. We also attempted to determine whether the prostatic cell death gene TRPM-2 would be expressed using this combination of drugs. Adult male Sprague-Dawley rats were randomly assigned to 7 groups of 15 animals. Four groups served as controls: an intact group sacrificed at the initiation of the trial (group 1), a castrate control group (group 2), an intact control group (group 3), and a group treated with the combination of an LHRH agonist plus antiandrogen (group 7). Three other groups were treated with daily subcutaneous injections of 5 alpha reductase inhibitor (group 5), a nonsteroidal pure antiandrogen (group 4) or both (group 6). After 5 days of treatment 5 animals in each group were sacrificed and prostatic tissue was assayed for the androgen repressed prostatic cell death gene TRPM-2. At 30 days (35 days for group 7) the remaining animals were sacrificed and their ventral prostates, seminal vesicles, and testes (except group 3) were weighed. The combination group (group 6) had a significantly lower prostate weight than either of the monotherapy groups (4, 5), or intact control groups, was equivalent to group 7 but was significantly heavier than the castrate group 2. The seminal vesicle weights of the combination group 6 were significantly lower than the monotherapy groups (4, 5), intact control group, castrate group (3) and was equivalent to group 7. Only castration was able to induce expression of the cell death gene TRPM-2. In this model, the combination of 5 alpha reductase inhibitor and an antiandrogen is as effective a mode of androgen ablation as combination therapy of LHRH agonist plus antiandrogen. Clinically, this combination may translate into adequate androgen blockade without impotence or other side effects of testosterone deprivation. Clinical trials appear warranted to assess this hypothesis.

5-alpha Reductase Inhibitors↗
PubMed1992

The clinical effects of a 5 alpha-reductase inhibitor, finasteride, on benign prostatic hyperplasia. The Finasteride Study Group.

Finasteride (Proscar--an orally active 5 alpha-reductase enzyme inhibitor) blocks the conversion of testosterone to dihydrotestosterone. The effects of finasteride in patients with benign prostatic hyperplasia were investigated in 2 double-blind, placebo-controlled studies. In study 1, 86 patients were treated with placebo or finasteride (5 to 80 mg. per day) for 12 weeks, followed by a 12-week drug-free period. After 12 weeks of treatment all doses of finasteride showed significant decreases in prostate volume. However, 12 weeks after discontinuation of finasteride prostate volume returned to near baseline values. In study 2, 104 patients were treated with placebo or finasteride (0.2 to 40 mg. per day) for 24 weeks. After 24 weeks of finasteride treatment prostate volume showed a mean decrease of 24% and 28% (p less than 0.01) in the 1 and 5 mg. groups, respectively. Lower doses had a lesser effect on prostate shrinkage. Maximum urinary flow showed a mean increase of 3.7 cc per second when the 1 and 5 mg. groups were combined. Symptom improvement was observed in the 1 and 5 mg. groups, although this was not statistically different from the placebo group due to the small sample size.

5-alpha Reductase Inhibitors↗
PubMed1991

Effect of 5-alpha-reductase inhibitor, 4-MAPC, on testicular descent in male rat.

Testicular descent has been reported to be a dihydrotestosterone (DHT) dependent event. To further elucidate the role of DHT in the process of testicular descent, a group of rats were treated with the 5-alpha reductase inhibitor, 4-MAPC, from birth to day 28 of age and the incidence of testicular descent as well as ventral prostate weight was noted at day 29 of age. It was determined that in the doses used, 4-MAPC failed to prevent testicular descent. Because 4-MAPC inhibited ventral prostate weight by only 53% (as compared to a 75% inhibition by castration), the failure of the 4-MAPC to prevent testicular descent could be due to its inability to completely inhibit tissue 5-alpha reductase activity. The results of this study do not mitigate against the role of other nonhormonal factors working in tandem with DHT in the induction of testicular descent in this animal model.

5-alpha Reductase Inhibitors↗
PubMed1993

Medical treatment of benign prostatic hyperplasia: 5 alpha-reductase inhibitors and alpha-adrenergic antagonists.

Benign prostatic hyperplasia (BPH), a nonmalignant neoplasm of the prostatic epithelial and stromal tissue, occurs commonly in elderly men. The "gold standard" of care for symptomatic BPH has been and remains transurethral resection of the prostate. This operation, however, like any surgical procedure, has associated morbidity and imposes an appreciable expense on the health-care system; therefore, enthusiasm for the development of medical therapies for the management of symptomatic BPH has been substantial. Currently, practicing physicians have two types of medications for the treatment of symptomatic BPH: 5 alpha-reductase inhibitors and alpha-adrenergic antagonists. The former drugs inhibit the conversion of testosterone to the potent prostatic androgen dihydrotestosterone. As a result, the androgenic stimulation to the prostate gland is suppressed, and the size of the prostate is decreased by approximately 25%. In some patients, this outcome decreases the mechanical obstruction of the prostatic urethra and improves micturition. alpha-Adrenergic antagonists decrease the smooth muscle tone of the bladder neck, prostatic adenoma, and prostatic capsule. After these structures have been relaxed, resistance to urine flow through the prostatic urethra can be decreased, and obstructive voiding symptoms can be resolved. Although two distinctly different mechanisms are involved, both types of medications are effective for treating BPH. Thus, in 1993, transurethral resection of the prostate is no longer the only available therapeutic option. With the advent of medical therapies, internists and primary-care physicians will have more involvement in the care of patients with BPH than previously. Therefore, urologists and nonurologists must work together to serve the needs of patients with prostatism.

5-alpha Reductase Inhibitors↗
PubMedDate not supplied

The role of 5alpha-reductase activity in sexual behaviors of the green anole lizard.

Both testosterone (T) and its metabolite, 5alpha-dihydrotestosterone (DHT), can facilitate male sexual behavior in the lizard Anolis carolinensis. The present study addresses the role of DHT synthesis in regulating male sexual behavior by inhibiting 5alpha-reductase, the enzyme that converts T into DHT. In two separate experiments (one replacement and one maintenance paradigm), breeding adult males were castrated and implanted with capsules of T, DHT, or a control capsule (blank, BL). The animals were then injected with the 5alpha-reductase inhibitor, FCE, or with steroid suspending vehicle (SSV) as a control. Both experiments produced similar results. Overall, T was most effective in eliciting courtship and copulatory behaviors above control levels. In both experiments, treatment with FCE attenuated the T-induced effects on courtship behavior, whereas the inhibition of 5alpha-reductase activity resulted in modest and inconsistent effects on the latency to intromission and the proportion of copulating males. DHT treatment did not significantly increase courtship or copulatory behaviors above control levels. These results suggest that (a) 5alpha-reductase activity is necessary but that DHT alone is not sufficient for stimulating courtship in male A. carolinensis; and (b) courtship behavior is more sensitive than copulatory behavior to the activity of the androgen metabolizing enzyme.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1997

Expression of rat steroid 5 alpha-reductase (isozyme-1) in Spodoptera frugiperda, SF21, insect cells: expression of rat steroid 5 alpha-reductase.

The enzyme steroid 5 alpha-reductase (5 alpha R) catalyzes the reduction of testosterone (T) to 5 alpha-dihydrotestosterone (DHT). In this study, the baculovirus expression system was used to overexpress rat 5 alpha R type I isozyme (r5 alpha R 1). The full length of r5 alpha R1 cDNA was inserted into the Autographa californica nuclear polyhedrosis virus (Ac-MNPV) genome and expressed in Spodoptera frugiperda, Sf 21, insect cells. The expressed recombinant r5 alpha-R1 showed maximal enzymatic activity when the infected cells were harvested on day 3 of post-transfection. The K(m) values for NADPH and T were 17 microM and 2.7 microM, respectively. Inhibition of the recombinant r5 alpha R1 by N,N diethyl-4-aza-4-methyl-3-oxo-5 alpha-androstane-17 beta-carboxamide (4MA) was competitive with respect to the substrate (T), and a Ki of 3 nM was obtained. The enzyme was located primarily in the nuclear fraction, and the maximum velocity for the recombinant r5 alpha R1 in this fraction was 60 nmoles DHT/min/mg. Immunoblot analysis indicated a single immunoreactive band at 26 kDa, which corresponds to the molecular weight of r5 alpha R1. Photoaffinity labeling by [2'-32P]-2-azido-NAD P+ ([2'-32P]2N3-NAD P+) and [1,2(3)H] N-(benzylbenzoyl)-3-oxo-4-aza-4-methyl-5 alpha androstane-17 beta-carboxamide ([3H]-4MABP) also showed a labeled protein band at 26 kDa.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1997

A practical route for the synthesis of 17 substituted steroidal 3-thioxamides.

A facile method for the synthesis of a series of new steroidal 3-thioxamides from the 3-oxo compound, variously substituted at the 17 position, is described. The "one pot" reaction, using Lawesson's reagent (4-methoxyphenylthionophosphine sulphide dimer) in dichloromethane solution, gives the desired compounds with a high degree of chemoselectivity, in good yields (> 80%).

5-alpha Reductase Inhibitors↗
PubMedDate not supplied

Synthesis and stereochemistry of 8,13-diaza-2,3-dimethoxygona-1,3,5(10),9(11)-tetraen-12-one and D-homo derivatives.

From the condensation reaction of O-methylbutyrolactim (2), O-methylvalerolactim (3), O-methylcaprolactim (4) and O-methyl-4-t-butylcaprolactim (5) with ethyl 6,7-dimethoxy-alpha-[1-(1,2,3,4-tetrahydro-isoquinolyl)] acetate (1), 8,13-diaza-2,3-dimethoxygona-1,3,5(10),9(11)-tetraen-1 2-one (6) D-homo-derivatives (7-9), and medium-sized ring cyclic diamides (10,11) were obtained. The stereoselective reduction of compounds 6-9 by Adam's platinum catalyst afforded 8,13-diaza-2,3-dimethoxygona-1,3,5(10)-trien-12-one (12) and its D-homo derivatives (13-15). The structures of the compounds obtained were established by NMR and X-ray crystallographic analyses.

Azasteroids↗
PubMed2002

Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia.

OBJECTIVES: To study the efficacy and safety of dutasteride, a dual inhibitor of the 5-alpha-reductase isoenzymes types I and II. METHODS: A total of 4325 men (2951 completed) with clinical benign prostatic hyperplasia, moderate to severe symptoms (American Urological Association-Symptom Index score of 12 points or greater), a peak flow rate of 15 mL/s or less, a prostate volume of 30 cm3 or greater (as measured by transrectal ultrasonography), and a serum prostate-specific antigen level of 1.5 to 10.0 ng/mL (inclusive) were enrolled into three identical clinical trials and randomized to 0.5 mg dutasteride daily or placebo. After a 1-month, single-blind, placebo lead-in, patients were followed up for 24 months in a double-blind trial with multiple interval assessments. RESULTS: At 24 months, serum dihydrotestosterone was reduced from baseline by a mean of 90.2% (median -93.7%; P <0.001), and the total prostate and transition zone volumes were reduced by a mean of 25.7% and 20.4%, respectively (P <0.001). The symptom score was improved by as early as 3 months, with pooled significance from 6 months onward (P <0.001) and a reduction of 4.5 points (21.4%) at 24 months (P <0.001). The maximal flow rate improved significantly from 1 month (P <0.01), with an increase of 2.2 mL/s reported at 24 months (P <0.001). Hence, the risk reduction of acute urinary retention was 57% and the risk reduction of benign prostatic hyperplasia-related surgical intervention was 48% compared with placebo. The drug was well tolerated. CONCLUSIONS: Dutasteride is a potent inhibitor of dihydrotestosterone production that is safe and effective in terms of the reduction of prostate volume and symptoms, flow rate improvement, and the reduction of the risk of acute urinary retention and surgery during a 24-month study period.

5-alpha Reductase Inhibitors↗
PubMed1996

Prenatal alcohol exposure influences the effects of neuroactive steroids on separation-induced ultrasonic vocalizations in rat pups.

Fetal alcohol exposure has been reported to be associated with hyper-responsiveness to stress. Using a maternal separation paradigm, this study examined whether prenatal alcohol exposure affected sensitivity to neurosteroid modulation of stress. We have shown that the neuroactive steroid allopregnanolone reduces ultrasonic vocalizations (USVs) after brief maternal separation in week-old rat pups. Prenatal alcohol exposure, however, resulted in reduced sensitivity to this neurosteroid. In this study's first experiment, the behavioral effects of pregnenolone sulfate, a neurosteroid with reportedly opposite modulatory effects on the GABAA receptor, were characterized. Pregnenolone sulfate had a triphasic effect on the production of ultrasonic vocalizations and on open field activity. Blockade of conversion of pregnenolone sulfate to allopregnanolone via the 5 alpha-reductase inhibitor 4-MA also blocked the drug-related reduction in USVs, but not the higher-dose augmentation. The enzyme inhibitor alone had no significant effects on USV production, nor did progesterone. These results suggest that the neuroactive steroid pregnenolone sulfate may play an independent role in the stress response after maternal separation as well as being a precursor for the anxiolytic neurosteroid allopregnanolone. In the second experiment, prenatal alcohol exposure was found to eliminate both the low dose USV-reducing effect and the higher dose USV-increasing effect. These results support previous results demonstrating that prenatal alcohol exposure may cause an altered sensitivity to the neuromodulatory effects of neurosteroids.

Androgen Antagonists↗