Clinical application of 5α-reductase inhibitors (original) (raw)
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An overview on 5α-reductase inhibitors
Steroids, 2010
Benign prostatic hyperplasia (BPH) is the noncancerous proliferation of the prostate gland associated with benign prostatic obstruction and lower urinary tract symptoms (LUTS) such as frequency, hesitancy, urgency, etc. Its prevalence increases with age affecting around 70% by the age of 70 years. High activity of 5␣-reductase enzyme in humans results in excessive dihydrotestosterone levels in peripheral tissues and hence suppression of androgen action by 5␣-reductase inhibitors is a logical treatment for BPH as they inhibit the conversion of testosterone to dihydrotestosterone. Finasteride (13) was the first steroidal 5␣reductase inhibitor approved by U.S. Food and Drug Administration (USFDA). In human it decreases the prostatic DHT level by 70-90% and reduces the prostatic size. Dutasteride (27) another related analogue has been approved in 2002. Unlike Finasteride, Dutasteride is a competitive inhibitor of both 5␣-reductase type I and type II isozymes, reduced DHT levels >90% following 1 year of oral administration. A number of classes of non-steroidal inhibitors of 5␣-reductase have also been synthesized generally by removing one or more rings from the azasteroidal structure or by an early non-steroidal lead (ONO-3805) (261). In this review all categories of inhibitors of 5␣-reductase have been covered.
A New Look at the 5?Reductase Inhibitor Finasteride
Cns Drug Reviews, 2006
Finasteride is the first 5α-reductase inhibitor that received clinical approval for the treatment of human benign prostatic hyperplasia (BPH) and androgenetic alopecia (male pattern hair loss). These clinical applications are based on the ability of finasteride to inhibit the Type II isoform of the 5α-reductase enzyme, which is the predominant form in human prostate and hair follicles, and the concomitant reduction of testosterone to dihydrotestosterone (DHT). In addition to catalyzing the rate-limiting step in the reduction of testosterone, both isoforms of the 5α-reductase enzyme are responsible for the reduction of progesterone and deoxycorticosterone to dihydroprogesterone (DHP) and dihydrodeoxycorticosterone (DHDOC), respectively. Recent preclinical data indicate that the subsequent 3α-reduction of DHT, DHP and DHDOC produces steroid metabolites with rapid non-genomic effects on brain function and behavior, primarily via an enhancement of γ-aminobutyric acid (GABA)ergic inhibitory neurotransmission. Consistent with their ability to enhance the action of GABA at GABAA receptors, these steroid derivatives (termed neuroactive steroids) possess anticonvulsant, antidepressant and anxiolytic effects in addition to altering aspects of sexual- and alcohol-related behaviors. Thus, finasteride, which inhibits both isoforms of 5α-reductase in rodents, has been used as a tool to manipulate neuroactive steroid levels and determine the impact on behavior. Results of some preclinical studies and clinical observations with finasteride are described in this review article. The data suggest that endogenous neuroactive steroid levels may be inversely related to symptoms of premenstrual and postpartum dysphoric disorder, catamenial epilepsy, depression, and alcohol withdrawal.
Life Sciences, 2002
Steroid 5a-reductase (5-AR) catalyses the reduction of testosterone (T) to dihydrotestosterone (DHT). The 5areductase found in human benign prostatic hyperplasia (BPH) has been compared with that found in human breast skin tissue in respect of sensitivity to inhibition by Finasteride and Epristeride. Kinetic studies showed the presence of two isoforms of 5a-reductase in benign prostatic hyperplasia indicated by low and high Km isoforms for testosterone, while female breast skin tissue contained only one isoform. The isoforms differ in their affinity for the inhibitors Finasteride and Epristeride, both compounds being more effective for the low Km 5a-reductase isoform than the high Km 5a-reductase of prostatic tissue, with Finasteride displaying competitive inhibition and Epristeride uncompetitive. Finasteride and Epristeride are also inhibitors of skin 5a-reductase, which possesses a comparable Ki for Finasteride to that of the low Km prostatic enzyme, but Epristeride was a less potent inhibitor of the skin enzyme relative to the prostate isoform. These results suggest that the inhibitors have therapeutic potential, other than for treatment of benign prostatic hyperplasia, for treating skin disorders influenced by the action of dihydrotestosterone and warrant further investigation. D
The Role of Finasteride in the Management of Androgenetic Alopecia in Male: A Narrative Review
Indian Journal of Pharmacy Practice, 2019
The purpose of this review was to evaluate the role of finasteride, a type-II 5α-reductase inhibitor in the prevention and treatment of androgenetic alopecia (AGA) in males. Finasteride inhibits 5α-reductase and reduce the biosynthesis of dihydrotestosterone (DHT). This inhibition marks a decrease in concentration of DHT and provides a novel and selective approach to androgen deprivation. Clinical trials have proven the safety and efficacy of tablet finasteride 1 mg for AGA. In this review, we discuss all aspects of finasteride, including dosing and indication, pharmacology, pharmacokinetics to its role in the treatment of AGA.
Selective non-steroidal inhibitors of 5α-reductase type 1
Journal of Steroid Biochemistry and Molecular Biology, 2004
The enzyme 5␣-reductase (5␣R) catalyses the reduction of testosterone (T) into the more potent androgen dihydrotestosterone (DHT). The abnormal production of DHT is associated to pathologies of the main target organs of this hormone: the prostate and the skin. Benign prostatic hyperplasia (BPH), prostate cancer, acne, androgenetic alopecia in men, and hirsutism in women appear related to the DHT production. Two isozymes of 5␣-reductase have been cloned, expressed and characterized (5␣R-1 and 5␣R-2). They share a poor homology, have different chromosomal localization, enzyme kinetic parameters, and tissue expression patterns. Since 5␣R-1 and 5␣R-2 are differently distributed in the androgen target organs, a different involvement of the two isozymes in the pathogenesis of prostate and skin disorders can be hypothesized. High interest has been paid to the synthesis of inhibitors of 5␣-reductase for the treatment of DHT related pathologies, and the selective inhibition of any single isozyme represents a great challenge for medical and pharmaceutical research in order to have more specific drugs. At present, no 5␣R-1 inhibitor is marketed for the treatment of 5␣R-1 related pathologies but pharmaceutical research is very active in this field. This paper will review the major classes of 5␣R inhibitors focusing in particular on non-steroidal inhibitors and on structural features that enhance the selectivity versus the type 1 isozyme. Biological tests to assess the inhibitory activity towards the two 5␣R isozymes will be also discussed. (G. Danza). marily responsible for the effect of androgens in the endorgans.
FCE 28260, a new 5α-reductase inhibitor: In vitro and in vivo effects
Journal of Steroid Biochemistry and Molecular Biology, 1996
FCE 28260 is a novel inhibitor of 5α-reductase (5αR), the enzyme responsible for the conversion of testosterone (T) to 5α-dihydrotestosterone (DHT). The compound caused inhibition of rat and human prostatic enzymes, with IC50 values of 15 and 16 nM, respectively, compared to the values of 30 and 52 nM shown by finasteride. Furthermore, FCE 28260 was highly potent in inhibiting human recombinant 5αR type 2 and 1 isozymes, showing IC50 values of 3.3 and 36 nM, and therefore it was more potent than finasteride (IC50 values of 8.5 and 470 nM) on both isozymes. In prepubertal, T-implanted castrated rats, FCE 28260, given orally for 7 days, reduced ventral prostate growth with an ED50 of 0.8 mg/kg, i.e. five times lower than that shown by finasteride. No anti-androgenic activity in DHT-implanted castrated rats was found up to 10 mg/kg/day. In adult male rats, FCE 28260 reduced prostatic DHT concentrations 6 h after oral dosing with a potency similar to that of finasteride (65% reduction at 1 mg/kg) but was found to be markedly more potent than the reference compound at 24 h (74% reduction in prostate DHT at 10 mg/kg, compared to 26% reduction induced by finasteride). These results indicate that FCE 28260 represents a marked improvement over finasteride.
5-α-REDUCTASE INHIBITORS -A REVIEW
5-alpha reductase is an important enzyme in metabolic pathway of testosterone. Its three subtypes SRD5A1, SRD5A2 andSRD5A3 are responsible for conversion of testosterone to its more potent derivative dihydrotestosterone (DHT). Excess production of DHT leads to prostate cancer and alopecia. The production of DTH can be reduced by inhibiting the 5-alpha reductase enzyme. Several 5-alpha reductase inhibitors were synthesized in the past and are marketed and used for the treatment of prostate cancer and baldness. The dosing of these drugs is between 1 to 5 mg/day. The low dosing of these drugs need special attention on quality control and quantitative estimation of drug in formulation and biological fluids. The details of 5-alpha reductase inhibitors and the recent developments in their quantitative estimation have been compiled in the presented review.