[Synthetic studies of salamander alkaloids, an animal venom].
Explore the source record for details and available documents.
Alkaloids↗
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.
Dutasteride: a dual 5-alpha reductase inhibitor for the treatment of symptomatic benign prostatic hyperplasia.
OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, safety, drug interactions, and dosing recommendations of dutasteride, a 5-alpha reductase inhibitor for benign prostatic hyperplasia (BPH). DATA SOURCES: A MEDLINE search (1966-February 2006) was conducted to extract human research data in the English language on dutasteride. Search terms included benign prostatic hyperplasia, dutasteride, and finasteride. The reference lists of articles identified through this search process, the manufacturer's Web site, and dutasteride prescribing information were also examined. STUDY SELECTION AND DATA EXTRACTION: All published studies and clinical data from the manufacturer were included, with emphasis placed on randomized, controlled trials. DATA SYNTHESIS: Dutasteride is approved for the treatment of symptomatic BPH in men with an enlarged prostate to improve urinary symptoms, reduce the risk of acute urinary retention, and reduce the need for BPH-related surgical interventions. Compared with placebo, dutasteride has been shown to significantly improve BPH symptoms, reduce the incidence of acute urinary retention and BPH-related surgery, and improve BPH-related quality of life. Few published data exist comparing dutasteride with finasteride. The most common adverse effects of dutasteride include ear, nose, and throat infection; malaise; headache; dizziness; and musculoskeletal pain. CONCLUSIONS: Clinical trials, sponsored primarily by the manufacturer, have shown dutasteride to be an effective treatment of BPH compared with placebo and to likely possess efficacy similar to that of finasteride. Further studies are needed to gain a more clear understanding of any clinically significant differences between dutasteride and finasteride.
Azasteroids↗
An update on the use of 5alpha-reductase inhibitors.
Twelve years ago, finasteride, the first 5alpha-reductase inhibitor, was introduced as drug therapy for benign prostatic hyperplasia, and more recently dutasteride has emerged as an alternative. The efficacy, safety and ability of these 5alpha-reductase inhibitors to reverse the natural progression of benign prostatic hyperplasia have been convincingly demonstrated and both drugs are now well established in the medical armamentarium against the disease. Given the multifactorial etiology of benign hyperplasia, the usefulness of 5alpha-reductase inhibitors in combination with alpha adrenergic blockers has also been investigated and justified in select patients. Wider applications of 5alpha-reductase inhibitors are also emerging, though their perhaps most important new role as chemopreventive agents remains unclear.
Adrenergic alpha-Antagonists↗
Dutasteride: a potent dual inhibitor of 5-alpha-reductase for benign prostatic hyperplasia.
Dutasteride is a 5alpha-reductase inhibitor that inhibits both types 1 and 2 isozymes of 5alpha-reductase, the enzyme responsible for converting testosterone to dihydrotestosterone in the prostate and other tissues. Dihydrotestosterone is the primary cause of prostate growth and has been proven to play a key role in the development and progression of benign prostatic hyperplasia. Dutasteride has been investigated in three multicenter studies involving 4325 men aged 50 years and above with benign prostatic hyperplasia. Data from these two-year, placebo-controlled studies demonstrated that dutasteride 0.5 mg once daily reduced the risk of both acute urinary retention and the need for benign prostatic hyperplasia-related surgical intervention, improved benign prostatic hyperplasia-related symptoms, decreased prostate volume and increased maximum urinary flow rates with a low incidence of generally mild to moderate adverse events.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
Noninvasive management of lower urinary tract symptoms and sexual dysfunction associated with benign prostatic hyperplasia in the primary care setting.
Most men who live to middle age and beyond will ultimately develop lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH), and many will also experience sexual dysfunction. Clinical studies indicate that most patients will experience improvement in BPH-related LUTS with alpha-adrenergic blockade or 5alpha-reductase inhibition. Recent studies suggest that alpha-blockers and 5alpha-reductase inhibitors may help to slow the progression of LUTS; 5alpha-reductase inhibitors reduce the need for surgery and complications, such as acute urinary retention. Third-generation alpha-blockers (alfuzosin, tamsulosin) are infrequently associated with cardiovascular side effects, in contrast to their predecessors (doxazosin, terazosin, prazosin). This may provide an advantage for consideration as firstline therapy. alpha-Blocker therapy may also improve sexual functioning, with the exception of ejaculation disorders, predominantly associated with subtypeselective alpha-blockers. By contrast, 5alpha-reductase inhibition is not recommended for men without demonstrable prostatic enlargement, may be associated with a long delay between treatment initiation and LUTS improvement, and is clearly associated with sexual side effects, including decreased libido, ejaculatory dysfunction, and erectile dysfunction. When choosing appropriate pharmacotherapy, the clinician should consider not only the expeditious relief of the presenting symptoms but also the patient's quality of life, including sexual function and potential long-term outcomes, such as acute urinary retention and the need for surgical intervention.
Adrenergic alpha-Antagonists↗
Desmosterol accumulation in rats with experimental myotonia.
Desmosterol is found in various organs of rats that show signs of myotonia in their skeletal muscle as a result of treatment with 20.25-diazacholesterol. The amount of desmosterol depends on the time of treatment, and is different in different organs and different kinds of muscle. The increase in desmosterol is much lower and the rats do not show any signs of myotonia when fed a cholesterol rich diet in addition to treatment with 20.25-diazacholesterol. Treatment with triparanol also causes desmosterol accumulation but in these rats myotonia is rarely observed. Our results suggest that in the experimental animals myotonia becomes manifest when every second cholesterol molecule of the muscle cell membrane is replaced by desmosterol. This is easily achieved in animals fed with 20.25-diazacholesterol but rarely occurs with triparanol.
Animals↗
Dutasteride: a novel dual inhibitor of 5alpha-reductase for benign prostatic hyperplasia.
Dutasteride is a new dual 5alpha-reductase inhibitor for the treatment of benign prostatic hyperplasia. It differs from finasteride as it inhibits both isoenzymes of 5alpha-reductase and results in near-complete suppression of serum dihydro-testosterone. Similar to finasteride, it reduces serum prostatic specific antigen by approximately 50% at 6months and total prostate volume by 25% in 2years. Randomised, placebo-controlled trials conducted over 2years have shown the efficacy of dutasteride in symptomatic relief, improvements in quality of life and peak urinary flow rate, and reduction of acute urinary retention events and the need for surgery. The main side effects are erectile dysfunction, decreased libido, gynaecomastia and ejaculation disorders. However, long-term usage for > 4years did not reveal increased new onset of sexual side effects. In addition, the combination of dutasteride and tamsulosin is well-tolerated and has the added advantage of rapid symptomatic relief. Finally, dutasteride has been shown to possess tumour regression properties invitro and its role in chemoprevention of prostate cancer will be confirmed in the ongoing Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
5 alpha-reductase activity regulates testosterone accumulation in two bands of immature cultured Leydig cells isolated on Percoll density gradients.
The 5 alpha-reductase inhibitor, 4-methyl-4-aza-3-oxo-5 alpha-pregnan-20(s)-carboxylate was utilized to examine maturational changes in testosterone synthesizing capacity of Leydig cells localizing in Band 2 and Band 3 of Percoll density gradients. Immature Band 2 Leydig cells (from 25- to 39-day-old rats) cultured without the 5 alpha-reductase inhibitor, produced increased testosterone in response to hCG or 8-br-cAMP; however, basal, hCG- or 8-br-cAMP-stimulated testosterone accumulation was 4- to 12-fold higher when cells were cultured in the presence of inhibitor. Band 2 cells from older rats produced much less testosterone in response to hCG or 8-br-cAMP (less than 3.5 pmol/10(5], even when cultured with the inhibitor. Although immature Band 3 cells cultured in the absence of 5 alpha-reductase inhibitor produced increased testosterone in response to hCG or 8-br-cAMP, testosterone levels were relatively low, because elevated 5 alpha-reductase prevented appreciable androgen accumulation; however, Band 3 cells from older rats (over 39 days old) accumulated progressively more testosterone, because of the age-dependent decline in 5 alpha-reductase activity. Immature Band 3 cells cultured with the 5 alpha-reductase inhibitor accumulated 20- to 44-fold more testosterone in response to hCG of 8-br-cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
Differential regulation of steroidogenic enzymes metabolizing testosterone or dihydrotestosterone by human chorionic gonadotropin in cultured rat neonatal interstitial cells.
The present studies examined the effects of hCG on steroidogenic enzyme activities involved in the metabolism of testosterone or dihydrostestosterone in cultured rat neonatal interstitial cells. 5 alpha-reductase and 17 beta-hydroxysteroid dehydrogenase activities, which are involved in the conversion of testosterone to dihydrotestosterone and androstenedione, respectively, were low in cultured neonatal interstitial cells, were unresponsive to hCG and declined to undetectable levels during 14 days of culture. However, delta 5-3 beta-hydroxysteroid dehydrogenase-isomerase activity, which is involved in the biosynthesis of testosterone, and 5 alpha-androstane-3 alpha-hydroxysteroid dehydrogenase and 5 alpha-androstane-3 beta-hydroxysteroid dehydrogenase activities, which are involved in the conversion of dihydrotestosterone to 5 alpha-androstan-3 alpha, 17 beta-diol and 5 alpha-androstan-3 beta, 17 beta-diol, respectively, were maintained or increased by hCG during the same culture period. These results demonstrate that 5 alpha-reductase and 17 beta-hydroxysteroid dehydrogenase activities do not play a significant role in regulating testosterone accumulation in fetal/neonatal Leydig cells, and they suggest that these cells are adapted to maintain high testosterone but low dihydrotestosterone levels. The present results demonstrate also that fetal/neonatal Leydig cells differ from immature or adult Leydig cells with respect to the sensitivity of 5 alpha-reductase activity to LH/hCG.
17-Hydroxysteroid Dehydrogenases↗
Neonatal hormone manipulations and the maintenance of perineal muscles and their motor neurones in Albino Swiss rats.
Newborn female Albino Swiss rats received testosterone propionate, dihydrotestosterone benzoate or oestradiol benzoate for 4 days after birth. The neonatal administration of all three hormones maintained neurones of the spinal nucleus of bulbocavernosus (SNB) complex in adulthood at levels intermediate between those found in normal females (approximately 40 neurones) and those found in normal males (approximately 220 neurones). Dihydrotestosterone benzoate was the most effective treatment. Oestradiol benzoate, while as potent as testosterone propionate in maintaining SNB neurone numbers, could not maintain the perineal muscles which are their normal target. Dihydrotestosterone benzoate and testosterone propionate maintained both neurones and muscles. Newborn male Albino Swiss rats received either the aromatase inhibitor 4-OH-androstenedione, or the 5 alpha-reductase inhibitor aza-steroid 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one(4-MA). Only neonatal treatment with 4-MA led to reduced SNB neurone numbers in adulthood, but the reduction was modest (-16%). The results of the two experiments suggest that several hormones can maintain SNB neurone numbers in Albino Swiss rats, but that 5 alpha-reduced metabolites of testosterone may be particularly effective.
Androgen Antagonists↗
Update on prostate cancer chemoprevention.
BACKGROUND: Prostate cancer is the most common type of cancer and the second leading cause of cancer-related deaths in American men. Its high rate of occurrence and long lead time to clinically significant disease make prostate cancer an ideal disease for pharmacologic or nutritional chemoprevention. METHODS: To identify the various chemoprevention strategies for prostate cancer, a MEDLINE search (from 1967-2005) and bibliographic search of the English-language literature were conducted. RESULTS: Epidemiologic and retrospective studies have assessed the effect of carotenoids (e.g., lycopene), vitamins, selenium, and nonsteroidal antiinflammatory drugs (NSAIDs) on the rate of occurrence of prostate cancer. The few published prospective trials evaluated prostate cancer as a secondary end point. Lycopene (as beta-carotene) and selenium supplementation have been associated with a reduced risk of prostate cancer in nested case-control studies, but only in subgroups of men with low baseline plasma lycopene (or beta-carotene) and selenium levels respectively. The Prostate Cancer Prevention Trial prospectively evaluated finasteride, a 5-alpha-reductase inhibitor, as chemoprevention. The results showed a 25% relative risk reduction in prostate cancer, albeit at an increased risk of invasive tumors. CONCLUSION: Data regarding lycopene, vitamin E, and selenium as chemoprevention for prostate cancer appear promising. Prospective trials such as the Selenium and Vitamin E Cancer Prevention Trial (SELECT) will clarify the role of these agents in prostate cancer prevention. The role of NSAIDs is unclear, and the long-term toxicity associated with NSAIDs may limit their usefulness. Although finasteride has decreased overall prostate cancer occurrence, the risk of invasive tumors may outweigh the benefit of this agent. The continuing Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial may help define a role for the 5-alpha-reductase inhibitors in cancer chemoprevention. At this time, nothing has been proven effective as chemoprevention against clinically significant prostate cancer.
5-alpha Reductase Inhibitors↗
Pharmacogenetic analysis of human steroid 5 alpha reductase type II: comparison of finasteride and dutasteride.
Human steroid 5 alpha-reductase type II is a prostate-specific, membrane-associated enzyme that catalyzes the conversion of testosterone to dihydrotestosterone, the most potent androgen in the prostate gland. Genetic variants of this enzyme have been associated with both the development and the progression of prostate cancer. Both finasteride and dutasteride are competitive inhibitors of the type II steroid 5 alpha-reductase that have been effectively used for the treatment of benign prostatic hyperplasia. Finasteride has also been successfully utilized for prostate cancer chemoprevention. We here investigate 5 alpha-reductase inhibition assays in vitro to measure the effect of incubation time on the apparent inhibition constant (Ki) for both constitutional and somatic (prostate cancer) enzyme variants. Our systematic pharmacogenetic analysis shows that both finasteride and dutasteride are slow, time-dependent inhibitors of steroid 5 alpha-reductase type II, and that the inhibition kinetics depend on the 5 alpha-reductase genotype. We also show that, overall, dutasteride is a more efficient steroid 5 alpha-reductase inhibitor than finasteride. Based on our data, we are able to map areas of the enzyme that are responsible for this time-dependent inhibition for either (or both) enzyme inhibitor(s). This comprehensive pharmacogenetic analysis of steroid 5 alpha-reductase variants unveiled significant pharmacogenetic variation for both finasteride and dutasteride and thus should be taken into account when designing protocols for treatment and/or chemoprevention of prostatic diseases with either one of these 5 alpha-reductase inhibitors since there is considerable pharmacogenetic variation for both drugs.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
Activation of sexual behaviour in castrated rats: the role of oestradiol.
Sexual behaviour was induced in castrated male rats with oestradiol-17 beta- or testosterone-filled constant-release implants. Testosterone-induced sexual behaviour was unaffected by treatment with the 5 alpha-reductase inhibitor 17 beta-N,N-diethylcarbamoyl-4-aza-5 alpha-androstan-3-one (4-MA; 16.7 mg/day) but treatment with the aromatization inhibitor 1,4,6-androstatriene-3,17-dione (ATD; 10 mg/day) prevented testosterone from inducing the behaviour. Sexual behaviour could be activated in castrated rats treated with testosterone plus ATD by treatment with 4-MA or with implants filled with a low dose of oestradiol. Lordosis behaviour induced in ovariectomized rats with testosterone-filled implants and progesterone was blocked by ATD treatment and could not be activated with 4-MA but oestradiol implants restored the display of lordosis in the testosterone plus ATD-treated females. 4-MA inhibited the in-vitro formation of [14C]5 alpha-dihydrotestosterone from [14C]testosterone by combined preoptic and hypothalamic tissue at all doses tested and a high dose of oestradiol exerted a similar effect. The results suggest that androgen aromatization is required for testosterone-activated female sexual behaviour but not for testosterone-activated male sexual behaviour. It is suggested that oestradiol normally acts to control the sexual behaviour of male rats by modifying neural androgen metabolism.
Androgens↗
Inhibition of testosterone metabolism in the brain and cloacal gland of the quail by specific inhibitors and antihormones.
The effects of antioestrogens, antiandrogens and of various inhibitors of testosterone metabolism on testosterone metabolism in the quail hypothalamus and cloacal gland were studied by an in-vitro radioenzymatic assay. It was found that antioestrogens and antiandrogens generally had little or no effect on aromatase and 5 alpha- and 5 beta-reductases of testosterone, except when used at very high doses. The 5 alpha-reductase inhibitor, 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one, inhibited both 5 alpha- and 5 beta-dihydrotestosterone production without markedly affecting aromatase activity. Surprisingly, the aromatase inhibitor, 1,4,6-androstatriene-3,17-dione, inhibited not only the production of oestradiol but also that of 5 beta-dihydrotestosterone and, to a lesser extent, 5 alpha-dihydrotestosterone. These unexpected properties should be taken into account when interpreting the results of in-vivo experiments using these compounds.
Androgen Antagonists↗
Precopulatory behaviour in the male hamster: effect of the 5 alpha-reductase inhibitor 17 beta-N,N-diethylcarbamoyl-4-aza-5 alpha-androstan-3-one.
Three independent components of hamster masculine behaviour (approaching, leaving and sniffing the female) have been shown to depend on both androgenic and oestrogenic action. The behavioural role of 5 alpha-reduced androgens was assessed by blocking 5 alpha-reduction of testosterone by means of 17 beta-N,N-diethylcarbamoyl-4-aza-5 alpha-androstan-3-one (4-MA) through slow-release silicone elastomer implants. Three dose levels of 4-MA were given to intact, sexually active males. The probability of approaching the female and the amount of sniffing directed to her were both decreased, while the probability of leaving the female was increased. Sniffing and the tendency to approach were affected at lower dose levels than was the tendency to leave. The higher dosage of 4-MA also abolished odour-based discrimination between females shown by normal males. These effects of 4-MA on behaviour were confirmed in castrated hamsters maintained on testosterone. The suppressive effects of 4-MA on behaviour were reversed by treatment with 5 alpha-dihydrotestosterone (DHT). We conclude that testosterone maintains sociosexual behaviour in part by conversion to its 5 alpha-reduced metabolites; components of this behaviour differ in their relative dependence on DHT. In this species, DHT is likely to be a behaviourally active metabolite of testosterone involved in the fine control of behaviour.
Androgen Antagonists↗
Role of reductase and aromatase in sex determination in the red-eared slider (Trachemys scripta), a turtle with temperature-dependent sex determination.
In many turtles the temperature during the middle of incubation determines the gonadal sex of the hatchling. In the red-eared slider turtle (Trachemys scripta), an incubation temperature of 26 degrees C results in all male offspring, whereas an incubation temperature of 31 degrees C results in all female offspring; at temperatures intermediate to these (e.g. 29, 29.2, 29.4 degrees C) a mixed sex ratio is obtained. Administration of exogenous oestrogens will overcome the effects of an all-male producing incubation temperature to cause female sex determination, whereas administration of exogenous dihydrotestosterone (DHT) or testosterone to eggs incubating at an all-female temperature will have no discernible effect. Administration of DHT will cause male sex determination only if administered at intermediate incubation temperatures whereas administration of testosterone to eggs incubating at all male-producing and male-biased intermediate temperatures results in a significant number of female offspring, an effect presumably due to aromatization of testosterone to oestradiol (OE2). Since testosterone serves as the precursor to both DHT and OE2, being metabolized by reductase and aromatase respectively, three experiments were conducted to determine whether various putative reductase and aromatase inhibitors would overcome the effect of incubation temperature. First, while administration of testosterone to eggs incubating at all male-producing and male-biased intermediate temperatures produced females in a dose- and temperature-dependent manner, significant numbers of intersex individuals resulted from high dosage testosterone treatment to eggs incubating at a female-biased intermediate temperature. The reductase inhibitors 4MA and MK906 were capable of producing female offspring if administered at intermediate temperatures, but not in a dose-dependent fashion. Administration of the aromatase inhibitors CGS16949A and CGS20267 resulted in male offspring at both female-biased intermediate and at all female-producing temperatures in a dose-dependent fashion. Second, similar findings were obtained with combined doses of testosterone and reductase or aromatase inhibitors. Combined treatment of eggs at male-biased intermediate incubation temperatures with testosterone and reductase inhibitor resulted in female hatchlings, whereas combined treatment of testosterone and aromatase inhibitor at both female-biased intermediate and at all female-producing temperatures resulted in male hatchlings.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Oral testosterone in oil: pharmacokinetic effects of 5alpha reduction by finasteride or dutasteride and food intake in men.
Oral administration of 400 mg of testosterone (T) in oil, when combined with the 5alpha reductase inhibitor dutasteride (D), elevates serum T in medically castrated men to the normal range. In this study, we sought to determine the impact of 1) finasteride (F) and 2) food intake on the serum T and dihydrotestosterone (DHT) levels observed after the oral administration of T in oil. Therefore, we conducted a pharmacokinetic study of oral T in oil, alone or with D or F, in the fasting and fed states in normal men whose endogenous T production was suppressed by the GnRH antagonist acyline. After acyline administration, 7 healthy men (mean age 31 +/- 8 years) were sequentially administered five 400-mg doses of oral T in sesame oil once daily. The first dose of oral T (T-alone) in oil was given while fasting without F or D. The second (fasting) and third (fed) doses were administered after pretreatment with F (T + F). Four days later, the fourth (fasting) and fifth (fed) doses were administered after pretreatment with D (T + D). Blood samples for measurement of serum T and DHT were obtained before T dosing and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours after each administration. In the fasting state, 24-hour area-under-the-curve of serum T after oral T administration was significantly greater with coadministration of either D or F compared with T-alone (126 +/- 36 nmol-h/L [T-alone] vs 287 +/- 98 nmol-h/L [T + F] vs 236 +/- 82 nmol-h/L [T + D]; P < .05 for T + F and T + D vs T-alone). Administration of the T with food nonsignificantly decreased serum T levels compared with fasting administration. The administration of oral T in oil combined with either F or D results in serum T levels adequate to treat men with testicular failure. Additional studies of the combination of oral T in oil with 5alpha-reductase inhibitors as a novel form of oral T therapy are warranted.
5-alpha Reductase Inhibitors↗
Dutasteride.
Dutasteride, a potent inhibitor of type 1 and 2 5alpha-reductase, reduced dihydrotestosterone levels by >90% in 85% of patients following 1 years' administration of oral dutasteride 0.5 mg/day. A combined analysis of three placebo-controlled clinical studies conducted in patients with benign prostatic hyperplasia (BPH) found sustained improvements in American Urological Association- Symptom Index scores and urinary flow rate and a 57% decrease in the risk of acute urinary retention throughout the 2-year treatment period (all p < 0.001 vs placebo). Total prostate and transition zone volume were also reduced (both p < 0.001), as was the risk of BPH-related surgery (by 48%). A nonblind extension study found that dutasteride maintains efficacy for up to 4 years. Dutasteride monotherapy maintained symptom relief following combination treatment with dutasteride and tamsulosin in all patients but those with severe symptoms. Dutasteride was generally well tolerated. Impotence, reduced libido, gynaecomastia and ejaculation disorder occurred significantly more often in dutasteride than placebo recipients, but incidence was generally low. With the exception of gynaecomastia, incidence consistently decreased over time.
5-alpha Reductase Inhibitors↗