Plasma concentrations and effect on testosterone metabolism after single doses of MK-0434, a steroid 5 alpha-reductase inhibitor, in healthy subjects

Hecken, Anne Van; Depré, M.; Schwartz, Jules I.; Tjandramaga, T. B.; Winchell, Gregory A.; Lepeleire, Inge De; Ng, Jennifer; Schepper, P. J. De

doi:10.1007/bf00199874

Cited by 9 publications

(7 citation statements)

References 12 publications

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“…However, there was no reduction in T levels with tamsulosin treatment in this study. This finding is inconsistent with some prior reports in which T levels were shown either to remain unchanged subsequent to 5α-RI therapy [62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77] or relative increase in T levels were reported with 5α-RI therapy [56,[78][79][80][81][82][83][84][85][86][87]. Kacker et al [88] did not find any changes in T levels in men receiving dutasteride treatment; however, there was a clear tendency for a decline in T which did not reach statistical significance.…”

Section: Discussioncontrasting

confidence: 63%

“…Several studies have shown that treatment with 5α-RIs resulted in either no significant changes in T levels [62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77] or in increased T levels [78][79][80][81][82][83][84][85][86][87]. It should be noted that Hong et al [83] and Roehrborn et al [82] noted marked increase in T levels in patients with low baseline T and reduced increase in T levels in patients with high baseline T levels.…”

Section: Discussionmentioning

confidence: 96%

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Finasteride, not tamsulosin, increases severity of erectile dysfunction and decreases testosterone levels in men with benign prostatic hyperplasia

Traish

Haider²,

Doros

et al. 2015

Hormone Molecular Biology and Clinical Investigation

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Section: Discussioncontrasting

confidence: 63%

Section: Discussionmentioning

confidence: 96%

Finasteride, not tamsulosin, increases severity of erectile dysfunction and decreases testosterone levels in men with benign prostatic hyperplasia

Traish

Haider²,

Doros

et al. 2015

Hormone Molecular Biology and Clinical Investigation

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“…Significant reduction in DHT levels observed following administration of this azosteroid [50]. This 4-azosteroid decreased DHT levels up to 80% with no apparent increase in serum testosterone levels [51].…”

Section: Commentsmentioning

confidence: 78%

Treatment options for benign prostatic hyperplasia

Thurlow

1998

Emerging Drugs

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Benign prostatic hyperplasia (BPH) is a disease of the prostate in which benign enlargement leads to partial constriction of the urethra and reduced urinary flow rates during micturition are observed. BPH is prevalent in men over 60 with about 50% of all males in this age group developing symptomatic BPH. Symptomatic BPH is characterised by symptoms that include increased frequency of urination, especially at night (nocturia), difficulty or delay in initiating urination (hesitancy), reduced force of the urinary stream and post-void dribbling. Current therapy options fall into two categories: surgery and pharmacotherapy. Significant morbidity is associated with surgery but this currently remains the gold-standard treatment option for many sufferers of the disease. Current pharmacotherapy is not curative and treatment with pharmaceuticals has mainly targeted the alleviation of the symptomatic manifestation of the disease. The most effective treatment option is the use of non-selective alpha-adrenergic antagonists. These block the smooth muscle contraction of the prostate that is associated with the obstructive symptoms described above. Other existing treatments have been targeted at the irritative, static or proliferative component of the disease. These agents, 5α-reductase (5αR) inhibitors, despite wide prescription initially, have yielded disappointing results in the clinic with limited symptomatic relief and reduction in prostate size mainly confined to those individuals with an exceptionally enlarged prostate. The proliferative (or static) component is observed in discrete regions of the prostate, predominantly in the stromal cell layer. Future drug therapies are being developed to treat both the dynamic and static components of BPH. Firstly, through pharmacological characterisation of the prostate, it is now possible to target α 1 -adrenoceptor antagonists that are selective for the prostate rather than acting in both the prostate and the cardiovascular system. It has been hypothesised that these agents will have fewer cardiovascular side-effects, and several of these are currently in early to late phase clinical trials. Secondly, companies are continuing to developing new generations of 5αR inhibitors that target both isoforms of this enzyme (5αR1 and 5αR2), despite poor clinical symptomatic relief observed with the first generation 5αR inhibitor, finasteride (Proscar, Merck), which is selective for the 5αR2 over the 5αR1 isoform. Through extensive research it has become evident that the proliferative component of BPH involves a complex relationship between androgens and growth factors. 5αR inhibitors lower dihydrotestosterone (DHT) levels, the main mediator of androgen action in the 225 1998

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“…Cilazapril and benazepril, for instance, have biexponential kinetics and are metabolized to active compounds, 30 , 47 benazepril being a prodrug 41 . The 5 α‐reductase inhibitor MK‐0434 and SQ 28,668, a structural analogue of thromboxane A 2 , both have nonlinear kinetics 21 , 24 . Methadone not only induces its own metabolism 48 but also is subject to tolerance, as is buprenorphine 22 .…”

Section: Discussionmentioning

confidence: 99%

A Systematic Review and Empirical Analysis of the Relation Between Dose and Duration of Drug Action

Hughes

Aronson

2010

The Journal of Clinical Pharma

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There is a log-linear relation between the dose and duration of action of drugs with single-compartment pharmacokinetics and direct, reversible mechanisms of action. However, it has been suggested that this relation does not extend to drugs whose metabolites are active or slowly eliminated, drugs with saturable kinetics, and drugs with hit-and-run effects. The purpose of this study is to test this hypothesis and to quantify the relationship by way of a systematic review coupled to an empirical analysis. All issues of 4 clinical pharmacology journals from 1980 to 2005 are hand-searched for articles that present pharmacodynamic response versus time curves for 4 or more different doses. Data on duration of action, dose, and area under the plasma concentration versus time curve from zero to infinity (AUC) are abstracted and analyzed by panel data regression modeling, with within-study fixed effects. Duration of drug action is defined as the time during which a pharmacodynamic effect (or response) exceeds a nominal threshold. The generalized models of all observations from 33 publications, with duration of action as the dependent variable and the logarithm of the dose (or AUC) as the explanatory variable, yield significant log-linear relationships. The regressions for individual studies are correctly specified in 27 cases; there are insufficient data for analysis in 10 studies, and a log-linear specification is deemed inappropriate in 6. Analysis of published dose-ranging studies shows that the duration of action of a drug is directly proportional to the logarithm of dose across a wide range of different drugs, extending a result that was previously documented for very few compounds.

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Plasma concentrations and effect on testosterone metabolism after single doses of MK-0434, a steroid 5 alpha-reductase inhibitor, in healthy subjects

Cited by 9 publications

References 12 publications

Finasteride, not tamsulosin, increases severity of erectile dysfunction and decreases testosterone levels in men with benign prostatic hyperplasia

Finasteride, not tamsulosin, increases severity of erectile dysfunction and decreases testosterone levels in men with benign prostatic hyperplasia

Treatment options for benign prostatic hyperplasia

A Systematic Review and Empirical Analysis of the Relation Between Dose and Duration of Drug Action

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