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At least 469 records · Page 26Linked to original sources
PubMed2006

Discovery and clinical development of dutasteride, a potent dual 5alpha-reductase inhibitor.

In this review the preclinical medicinal chemistry, biochemistry and clinical results achieved in the treatment of prostatic disease with dutasteride, a dual inhibitor of type 1 and type 2,5alpha-reductase are described. During the discovery phase, dutasteride was optimized to inhibit both forms of human 5 alpha-reductase (5AR) via extensive structure activity relationship studies versus the cloned human isozymes. Dutasteride has subsequently been shown to improve disease measures in patients with symptomatic benign prostatic hyperplasia (BPH) in three randomized, placebo-controlled, Phase III clinical studies lasting for 2 years. Additionally, dutasteride is now under study for the ability to reduce the incidence of prostate cancer in men at high risk of the disease--an indication where the unique dual inhibitor nature, half-life and tolerability of dutasteride may be especially significant factors in determining treatment success. The connections between preclinical drug design and clinical outcomes during the discovery and development of dutasteride are exemplified.

Animals↗
PubMed1988

Alpha-L-fucosidase in rat testis during sexual maturity.

alpha-L-fucosidase (EC 3.2.1.51) activity, concentration of testosterone (T), and its metabolite dihydrotestosterone (DHT) were tested in rat testis during the onset of puberty. This study was also carried out in testes of rats treated with 17-beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5-alpha-androstane-3-one (DMAA), an inhibitor of the 5-alpha-reductase-mediated conversion of T into DHT. alpha-L-fucosidase activity in seminiferous tubules of control and DMAA-treated rats was found to be relatively high on the 25th day after birth (approximately 24 units) but decreased and remained relatively constant the following days (approximately 10 units). In contrast, alpha-L-fucosidase activity was nearly undetectable in the immature interstitium of the control rats but sharply increased the following days. A maximum was reached at the 55th day, followed by a rapid decrease. alpha-L-fucosidase activity evolved in parallel with an increase and decrease of DHT concentration. In DMAA-treated rats with DHT levels and an alpha-L-fucosidase activity significantly lower than in the control rats between the 55th and the 65th days, this parallelism existed as well.

Aging↗
PubMed1991

Lysosomal glycosidase activities in rat testis during sexual maturation.

Concentrations of testosterone and its metabolite dihydrotestosterone were determined in whole rat testis during the transition from the prepuberal to the mature status. The activities of five glycosidases (beta-N-acetylhexosaminidase, alpha-L-fucosidase, beta-D-galactosidase, alpha-D-glucosidase and alpha-D-mannosidase) were also investigated in the seminiferous tubules and interstitial tissues. The same androgens and enzyme activities were measured in testis of rats treated with 17-beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5-alpha-androstan-3-on e, a potent inhibitor of the 5-alpha-reductase-mediated conversion of testosterone into dihydrotestosterone. Lysosomal glycosidic activities in seminiferous tubules were found to vary slightly with the age of the animals, and thus seemed not to depend on the hormonal status of the tested animals. In contrast, the enzyme activities were low in the immarure interstitium but increased sharply during the onset of sexual maturity. The activity of each glycosidase reached a maximum between the 45th and the 65th day, except for beta-N-acetylhexosaminidase which did not decrease significantly following the 55th day. The five lysosomal enzyme activities decreased in the interstitial compartment of rat testis treated with DMAA, suggesting a relationship between these glycosidic enzyme activities and dihydrotestosterone.

Aging↗
PubMed1992

Testosterone regulation of sex differences in fetal lung development.

Fetal lung development, in particular surfactant synthesis, exhibits a sexual dimorphism. Dihydrotestosterone (DHT) has been shown to delay fetal pulmonary surfactant production, but the potential role for testosterone is unknown. Both testosterone and DHT are potent masculinizing hormones, yet in some instances, an end organ specificity for DHT is present. We hypothesized that the delay in fetal lung surfactant production is dependent upon DHT such that inhibition of the synthesis of DHT from the precursor hormone testosterone would eliminate the sex difference by allowing the male fetus to produce surfactant at the female level. We tested this hypothesis using 17 beta-N,N-diethylcarbamoyl-4-aza-4-methyl-5-alpha-androstane-3-one (4-MA), a potent inhibitor of the enzyme 5 alpha-reductase, which converts testosterone into DHT. First, studies were performed in vivo. 4-MA (20 mg/kg/day) or an equivalent volume of vehicle was injected into pregnant rabbits from Day 12 through Day 26 of gestation. On Day 26, the fetuses were delivered, the lungs were lavaged, and fetal sex was noted. Treatment with 4-MA resulted in a lack of any male-female difference in the anogenital distance and no DHT was detected in the serum of any treated fetus. Phosphatidylcholine (PC), saturated phosphatidylcholine (SPC), and sphingomyelin (S) were measured in the lung lavage, and were expressed as the ratios of PC to sphingomyelin (PC:S) and SPC to sphingomyelin (SPC:S). Sex differences in the PC to sphingomyelin ratio of 4-MA-treated fetuses (female PC:S ratio, 1.43 +/- 0.14; male PC:S ratio, 1.00 +/- 0.13 [mean +/- SE]; P = 0.04) and in the SPC:S ratio of the 4-MA-treated group (female SPC:S ratio, 0.68 +/- 0.10; male SPC:S ratio, 0.35 +/- 0.10; P = 0.03) were present after treatment with 4-MA. The effect of testosterone and of 4-MA on fibroblast pneumonocyte factor (FPF) production was studied in vitro. Fetal rat lung fibroblasts were cultured to confluence with either no added androgen, DHT, testosterone, or testosterone plus 4-MA, and conditioned media for FPF were prepared. Conditioned media were added to fetal Type II cell cultures and FPF activity was measured as the degree of stimulation of the incorporation of [3H] choline into SPC. The conversion of radiolabeled testosterone to DHT by the fibroblasts was inhibited by 4-MA (10(-5) M). Conditioned media from untreated female fibroblasts stimulated with cortisol exhibited significant FPF activity ([3H]choline incorporation into SPC, 140 +/- 17% of control).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1976

The cholesterol problem, the egg and lipid metabolism in the laying hen.

There is little doubt that high blood serum lipid levels are related to a higher incidence of atherosclerotic disease in humans. Experimental evidence to date suggests that dietary intervention can reduce blood lipid levels in most cases and that some small reduction in occurrence of cardiovascular disease will probably result. On the other hand no reduction in total mortality has been demonstrated in the well constructed dietary studies. It appears that there is considerable variation in the human population with regard to their patterns of lipid metabolism. Some apparently regulate body production of cholesterol in response to dietary changes, others do not. Some seem to excrete excess sterols efficiently, while some do not. It seems likely, therefore, that dietary manipulation would be useful for those disposed by heredity and other conditions to accumulation of excessive sterols in the body. On the other hand drug control of cholesterol biosynthesis and/or sterol excretion may be more effective solutions to the problem of sterol accumulation. Irrespective of whether diet or drugs prove to be the best answer to control of sterol balance, these should be applied only to that segment of the population known to require such treatment. The egg is an important dietary source of cholesterol and as a result is used sparingly in low cholesterol diets. On the other hand normal egg consumption of two eggs per day does not appear to overload cholesterol balance in the healthy human adult since depression in cholesterol biosynthesis and increased sterol excretion will result. Investigation of the lipid metabolism of the laying hen has shown that most of the cholesterol found in the egg is synthesized in the liver where it is under both dietary and drug control. Most of the cholesterol deposited in egg yolk may be essential for embryonic development. Drugs that severely limit cholesterol biosynthesis probably also limit synthesis of adrenal and sex hormones and hence limit reproduction. Moderate depressions in lipogenesis achieved without feeding of large amounts of dietary fat may offer a means for moderating cholesterol deposition in eggs. On the other hand, it also seems clear that genetic selection could be used to moderate egg cholesterol concentration. In any event, a great deal more evidence from well constructed human diet studies will be needed before low cholesterol diets can be recommended to the general population as an aid to control of cholesterol balance and heart disease.

Animal Feed↗
PubMed2005

Evaluation and medical management of benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is common among aging men. Untreated BPH may lead to complications including urinary tract infection, acute urinary retention, and obstructive nephropathy. Diagnosing BPH can be challenging because lower urinary tract symptoms are found in conditions other than BPH, and prostate size correlates poorly with symptoms of obstruction. Nonetheless, a careful medical history and physical examination, along with prudent use of diagnostic tests, can yield an accurate diagnosis. We review the evaluation of men with suspected BPH and indications for referral to a urologist for invasive therapy. We also review supporting evidence and treatment considerations for saw palmetto and the 2 major classes of prescription medications, alpha1-adrenergic antagonists and 5alpha-reductase inhibitors.

Adrenergic alpha-Antagonists↗
PubMed1975

Estimation of glycoalkaloids as solasodine in Solanum laciniatum.

Solasodine is isolated from Solanum laciniatum leaves by a rapid, one-step procedure which involves extraction and hydrolysis of the glycoalkaloids. The resulting steroidal aglycone is directly estimated by the formation of a colored complex with bromocresol green. The method is applicable to concentrations of 25-125 mug solasodine/7ml.

Alkaloids↗
PubMed2001

Comparative study of sister chromatid exchange induction and antitumor effects by homo-aza-steroidal esters of [p-[bis(2-chloroethyl)amino]phenyl]butyric acid.

The present work was undertaken in order to test the hypothesis that the Sister Chromatid Exchange (SCE) assay in vitro can be used for the prediction of in vivo tumor response to newly synthesized potential chemotherapeutics. The effect of three homo-aza-steroidal esters containing the -CONH- in the steroidal nucleus, 1, 2, and 3 on SCE rates and on cell kinetics in cultured human lymphocytes was studied. The antitumor activity of these compounds was tested on leukemia P388- and leukemia L1210-bearing mice. The three substances induced statistically significant enhancement of SCEs and of cell division delays. Compounds 1 and 3 were identified, on a molar basis, as more effective inducers of SCEs and of cell division delays compared with compound 2. Compounds 1 and 3 had upon both experimental tumors better therapeutic effects compared with compound 2 at equitoxic doses. Therefore, the order of the antitumor effectiveness of the three compounds coincided with the order of the cytogenetic effects they induced.

Animals↗
PubMed1992

Finasteride for benign prostatic hyperplasia.

The pathogenesis of benign prostatic hyperplasia is related to the action of 5 alpha-dihydrotestosterone (DHT), the physiologically active form of testosterone. The conversion of testosterone to DHT is catalyzed intracellularly in prostatic tissue by the enzyme 5 alpha-reductase. Finasteride blocks the action of 5 alpha-reductase by competitively inhibiting the binding of testosterone to 5 alpha-reductase. The maximum effect of finasteride on reducing prostatic volume occurs after three months of oral therapy. Most patients experience improvement in urine flow rates, and side effects are minimal. However, following discontinuation of treatment, serum DHT levels return to baseline within two weeks.

5-alpha Reductase Inhibitors↗
PubMed1992

Benign prostatic hyperplasia: drug and nondrug therapies.

Benign prostatic hyperplasia (BPH) is a frequent finding in older men. Patients with symptoms have traditionally been treated with transurethral resection of the prostate, a surgical technique that effectively reduces infravesical obstruction. Nonsurgical management of BPH also has the potential to play an important role in the treatment of patients with moderate or severe symptoms or in those who do not elect surgery. Data are being evaluated to determine the efficacy of treating symptomatic BPH with such modalities as balloon dilation, prostate hyperthermia, androgen suppression, the 5-alpha reductase inhibitor finasteride, and selective alpha blockers.

5-alpha Reductase Inhibitors↗