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Claus G Roehrborn - One of the best experts on this subject based on the ideXlab platform.
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treatment satisfaction and clinically meaningful symptom improvement in men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia secondary results from a 6 month randomized double blind study comparing
2015Co-Authors: Claus G Roehrborn, Sidney Glina, Adolfo Casabe, Sebastian Sorsaburu, Carsten Henneges, Lars ViktrupAbstract:Objectives To report the secondary analyses of treatment satisfaction and clinically meaningful improvements in a randomized study comparing coadministration of tadalafil 5 mg with finasteride 5 mg versus finasteride alone in men with prostatic enlargement secondary to benign prostatic hyperplasia. Methods An international, randomized, double-blind, parallel study was carried out in men aged ≥45 years who were 5-alpha reductase Inhibitor naive, and had an International Prostate Symptom Score ≥13 and prostate volume ≥30 mL; 350 men received placebo/finasteride and 345 received tadalafil/finasteride over 26 weeks. Treatment satisfaction was assessed per protocol using the Treatment Satisfaction Scale-Benign Prostatic Hyperplasia. Responder cut-offs, analyzed post-hoc were total International Prostate Symptom Score improvement ≥3 points or ≥25% from randomization. Results Baseline patient characteristics were generally comparable between responders and non-responders. The proportion of patients with an International Prostate Symptom Score improvement ≥3 points with tadalafil/finasteride and placebo/finasteride, respectively, at week 4 was 57.0% and 47.9% (OR 1.45, 95% confidence interval 1.07–1.97), at week 12 was 68.8% and 60.7% (OR 1.48, 95% confidence interval 1.07–2.05) and at week 26 was 71.4% and 70.2% (OR 1.14, 95% confidence interval 0.81–1.61); for IPSS change ≥25%, the corresponding proportions were 44.8% and 32.9% (OR 1.66, 95% confidence interval 1.21–2.28), 55.5% and 51.9% (OR 1.18, 95% confidence interval 0.87–1.62), and 62.0% and 58.3% (OR 1.23, 95% confidence interval 0.89–1.70). Treatment satisfaction at week 26 was significantly greater with tadalafil/finasteride versus placebo/finasteride for total treatment satisfaction scale score (P=0.031) and satisfaction with efficacy subscore (P = 0.025); scores were not significantly different between treatments for satisfaction with dosing or side-effects (both P ≥ 0.371). Conclusions Tadalafil/finasteride results in significantly more patients achieving early clinical meaningful improvements in symptoms, and in greater treatment satisfaction versus placebo/finasteride.
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influence of baseline variables on changes in international prostate symptom score after combined therapy with dutasteride plus tamsulosin or either monotherapy in patients with benign prostatic hyperplasia and lower urinary tract symptoms 4 year res
2014Co-Authors: Claus G Roehrborn, Timothy Wilson, Jack Barkin, Mark Emberton, Andrea Tubaro, Betsy Brotherton, Ramiro CastroAbstract:Objective To examine, using post hoc analysis, the influence of baseline variables on changes in international prostate symptom score (IPSS), maximum urinary flow rate (Qmax) and IPSS quality of life (QoL) in patients with moderate-to-severe lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) treated with either the α-blocker tamsulosin or the dual 5-alpha reductase Inhibitor dutasteride, alone or in combination, as part of the 4-year Combination of Avodart and Tamsulosin (CombAT) study. Patients and Methods CombAT was a 4-year, multicentre, randomized, double-blind, parallel-group study in 4844 men ≥50 years of age with a clinical diagnosis of BPH by medical history and physical examination, an IPSS ≥12 points, prostate volume (PV) ≥30 mL, total serum PSA level ≥1.5 ng/mL, and Qmax >5 mL/s and ≤15 mL/s with a minimum voided volume ≥125 mL. Eligible subjects were randomized to receive oral daily tamsulosin, 0.4 mg; dutasteride, 0.5 mg; or a combination of both. Baseline variable subgroups analysed were as follows: PV (30 to <40; 40 to <60; 60 to <80; ≥80 mL), PSA level (1.5 to <2.5; 2.5 to <4; ≥4 ng/mL), age (median: <66, ≥66 years), IPSS (median: <16, ≥16; IPSS thresholds, <20, ≥20), IPSS QoL score (question 8, Q8) (median: <4, ≥4), Qmax (median: <10.4, ≥10.4 mL/s), BPH impact index (BII) (median: <5, ≥5) and body mass index (BMI, median: <26.8, ≥26.8 kg/m2). Within each baseline variable subgroup, changes in IPSS, Qmax and IPSS QoL Q8 from baseline were evaluated using a generalized linear model with effects for baseline IPSS, Qmax or IPSS QoL Q8 and treatment group at each post-baseline assessment up to and including the month 48 visit using a last observation carried forward approach. The treatment comparisons of combination therapy vs dutasteride and combination therapy vs tamsulosin were performed from the general linear model with statistical significance defined as P ≤ 0.01. Results Combination therapy resulted in a significantly greater improvement from baseline IPSS at 48 months vs tamsulosin monotherapy across all baseline subgroups. The benefit of combination therapy over dutasteride was confined to groups with lower baseline PV (<60 mL) and PSA (<4 ng/mL). In groups with baseline PV ≥60 mL and PSA ≥4 ng/mL, dutasteride and combination therapy show similar improvements in symptoms. Combination therapy resulted in significantly improved Qmax compared with tamsulosin but not dutasteride monotherapy. Qmax improvement appeared to increase with PV and PSA level in combination therapy subjects. The proportion of subjects with an IPSS QoL ≤2 (at least mostly satisfied) at 48 months was significantly higher with combination therapy than with dutasteride for subgroups with PV 40–60 mL and PSA level <4 ng/mL and than with tamsulosin for all PSA subgroups and PV subgroups ≥40 mL. Conclusions CombAT data support the use of long-term combination therapy with dutasteride and tamsulosin in patients considered at risk for progression of BPH, as determined by high PV (≥30 mL) and high PSA (≥1.5 ng/mL). Combination therapy, dutasteride monotherapy and tamsulosin monotherapy all improved Qmax, but to different extents (combination therapy > dutasteride >> tamsulosin), suggesting that dutasteride contributes most to the Qmax benefit in combination therapy. Combination therapy provided consistent improvement over tamsulosin in LUTS across all analysed baseline variables at 48 months. Compared with dutasteride, the superiority of combination therapy at 48 months was shown in patients with PV <60 mL or PSA <4 ng/mL.
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efficacy and tolerability of doxazosin and finasteride alone or in combination in treatment of symptomatic benign prostatic hyperplasia the prospective european doxazosin and combination therapy predict trial
2003Co-Authors: R S Kirby, Georg Bartsch, Alain Jardin, Margaret M Cary, Michael O Sweeney, Peter Boyle, Claus G Roehrborn, Eric Ben GrossmanAbstract:Objectives To evaluate the efficacy and tolerability of the selective alpha1-adrenergic antagonist doxazosin and the 5-Alpha-Reductase Inhibitor finasteride, alone and in combination, for the symptomatic treatment of benign prostatic hyperplasia. Methods In a prospective, double-blind, placebo-controlled trial, 1095 men aged 50 to 80 years were randomized to treatment for 52 weeks with doxazosin, finasteride, the combination of doxazosin and finasteride, or placebo. The dose of finasteride (or its matched placebo) was 5 mg/day. Doxazosin (or its matched placebo) was initiated at 1 mg/day, and titrated up to a maximum of 8 mg/day over approximately 10 weeks according to the response of the maximal urinary flow rate (Qmax) and International Prostate Symptom Score (IPSS). The IPSS and Qmax were assessed at baseline and at weeks 10, 14, 26, 39, and 52 or at the endpoint. Results An intent-to-treat analysis of 1007 men showed doxazosin and doxazosin plus finasteride combination therapy produced statistically significant improvements in total IPSS and Qmax compared with placebo and finasteride alone (P <0.05). Finasteride alone was not significantly different statistically from placebo with respect to total IPSS and Qmax. All treatments were generally well tolerated. Conclusions Doxazosin was effective in improving urinary symptoms and urinary flow rate in men with benign prostatic hyperplasia, and was more effective than finasteride alone or placebo. The addition of finasteride did not provide further benefit to that achieved with doxazosin alone.
Jason S Reichenberg - One of the best experts on this subject based on the ideXlab platform.
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adverse effects and safety of 5 alpha reductase Inhibitors finasteride dutasteride a systematic review
2016Co-Authors: J M Hirshburg, P A Kelsey, C A Therrien, Alde Carlo P Gavino, Jason S ReichenbergAbstract:Finasteride and dutasteride, both 5-alpha reductase Inhibitors, are considered first-line treatment for androgenetic hair loss in men and used increasingly in women. In each case, patients are expected to take the medications indefinitely despite the lack of research regarding long-term adverse effects. Concerns regarding the adverse effects of these medications has led the United States National Institutes of Health to add a link for post-finasteride syndrome to its Genetic and Rare Disease Information Center. Herein, the authors report the results of a literature search reviewing adverse events of 5-alpha reductase Inhibitors as they relate to prostate cancer, psychological effects, sexual health, and use in women. Several large studies found no increase in incidence of prostate cancer, a possible increase of high-grade cancer when detected, and no change in survival rate with 5-alpha reductase Inhibitor use. Currently, there is no direct link between 5-alpha reductase Inhibitor use and depression; however, several small studies have led to depression being listed as a side effect on the medication packaging. Sexual effects including erectile dysfunction and decreased libido and ejaculate were reported in as many as 3.4 to 15.8 percent of men. To date, there are very few studies evaluating 5-alpha reductase Inhibitor use in women. Risks include birth defects in male fetuses if used in pregnancy, decreased libido, headache, gastrointestinal discomfort, and isolated reports of changes in menstruation, acne, and dizziness. Overall, 5-alpha reductase Inhibitors were well-tolerated in both men and women, but not without risk, highlighting the importance of patient education prior to treatment.
R S Kirby - One of the best experts on this subject based on the ideXlab platform.
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efficacy and tolerability of doxazosin and finasteride alone or in combination in treatment of symptomatic benign prostatic hyperplasia the prospective european doxazosin and combination therapy predict trial
2003Co-Authors: R S Kirby, Georg Bartsch, Alain Jardin, Margaret M Cary, Michael O Sweeney, Peter Boyle, Claus G Roehrborn, Eric Ben GrossmanAbstract:Objectives To evaluate the efficacy and tolerability of the selective alpha1-adrenergic antagonist doxazosin and the 5-Alpha-Reductase Inhibitor finasteride, alone and in combination, for the symptomatic treatment of benign prostatic hyperplasia. Methods In a prospective, double-blind, placebo-controlled trial, 1095 men aged 50 to 80 years were randomized to treatment for 52 weeks with doxazosin, finasteride, the combination of doxazosin and finasteride, or placebo. The dose of finasteride (or its matched placebo) was 5 mg/day. Doxazosin (or its matched placebo) was initiated at 1 mg/day, and titrated up to a maximum of 8 mg/day over approximately 10 weeks according to the response of the maximal urinary flow rate (Qmax) and International Prostate Symptom Score (IPSS). The IPSS and Qmax were assessed at baseline and at weeks 10, 14, 26, 39, and 52 or at the endpoint. Results An intent-to-treat analysis of 1007 men showed doxazosin and doxazosin plus finasteride combination therapy produced statistically significant improvements in total IPSS and Qmax compared with placebo and finasteride alone (P <0.05). Finasteride alone was not significantly different statistically from placebo with respect to total IPSS and Qmax. All treatments were generally well tolerated. Conclusions Doxazosin was effective in improving urinary symptoms and urinary flow rate in men with benign prostatic hyperplasia, and was more effective than finasteride alone or placebo. The addition of finasteride did not provide further benefit to that achieved with doxazosin alone.
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selectivity of finasteride as an in vivo Inhibitor of 5 alpha reductase isozyme enzymatic activity in the human prostate
1999Co-Authors: Paul N Span, M Voller, Anthony G H Smals, F Sweep, Jack A Schalken, Mark Feneley, R S KirbyAbstract:AbstractThe type II 5 alpha-reductase Inhibitor finasteride is used in the treatment of benign prostatic hyperplasia (BPH), reducing local production of the growth promoting androgen dihydrotestosterone (DHT). The effect of prolonged treatment with this time-dependent irreversible Inhibitor on the recently described prostatic type I 5 alpha-reductase, however, is not clear. Therefore, we assessed the effects of 5 mg. finasteride per day for 6 months on prostatic 5 alpha-reductase isozymes, and prostatic tissue composition and androgen content of patients suffering from BPH. In prostatic tissue from these patients, the type II enzymatic activity is inhibited 100-fold compared with tissues obtained from placebo treated patients. The type II immunoreactivity is up regulated 2-fold. The type I isozyme is inhibited 3-fold and potentially still contributes to DHT production. In conclusion, finasteride is a selective type II Inhibitor in vivo. Further research is warranted to assess the possibly distinct roles o...
Marisa Cabeza - One of the best experts on this subject based on the ideXlab platform.
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recent advances in the chemistry and pharmacological activity of new steroidal antiandrogens and 5α reductase Inhibitors
2005Co-Authors: Eugene Bratoeff, Marisa Cabeza, Elena Ramirez, Yvonne Heuze, Eugenio FloresAbstract:The object of this paper is to summarize for the past two years the most recent development in the field of prostate cancer and 5 alpha-reductase Inhibitors. In addition we are also including some results on the synthesis and pharmacological evaluation of new steroidal compounds developed in our laboratory. Most of the new steroidal derivatives are based on the progesterone skeleton and showed a high Inhibitory activity for the enzyme 5 alpha-reductase. Presently, similar compounds are used for the treatment of androgen dependent diseases such as: hirsutism, androgenic alopecia, benign prostatic hyperplasia and prostate cancer. Dihydrotestosterone 2 (Fig. 1) a 5 alpha-reduced metabolite of testosterone 1 has been implicated as a causative factor for the progression of these diseases, largely through the clinical evaluation of males who are genetically deficient of the enzyme steroid 5 alpha-reductase. As a result of this study, the inhibition of this enzyme has become a pharmacological strategy for the design and synthesis of new antiandrogenic drugs. The advent of finasteride 7 (Fig. 3) a 5 alpha-reductase Inhibitor has greatly alleviated the symptoms associated with benign prostatic hyperplasia. In our laboratory, we recently synthesized several new 16 beta-methylpregnadiene-3,20-diones: 40, 41 (Fig. 8), 16 beta-phenylpregnadiene-3,17a-dione derivatives 46 and 47 (Fig. 9) and 49 (C-4 bromoderivative) (Fig. 11), 52-56 (Fig. 13). The analogue pregnatriene derivatives were also prepared: 44, 45 (Fig. 9) 50, 51 (Fig. 11) and 57-60 (Fig. 13) These compounds were evaluated as 5 alpha-reductase Inhibitors in the following biological models: Penicillium crustosum broths, the flank organs of gonadectomized male hamsters, the incorporation of radiolabeled sodium acetate into lipids, the effect of the new steroids on the reduction of the weight of the seminal vesicles and on the in vitro metabolism of [3H]T to [3H]DHT in seminal vesicles of homogenates of gonadectomized male hamsters. All trienones 44, 45, 50, 51 and 57-60 in all biological models showed consistently a higher 5 alpha-reductase Inhibitory activity than the corresponding dienones: 40, 41, 46, 47, 49 and 52-56. We believe that with these compounds the 5 alpha-reductase enzyme is inactivated by an irreversible Michael type addition of the nucleophilic portion of the enzyme to the conjugated double bond of the steroid. The trienones having a more coplanar structure react faster with the enzyme thus showing a higher Inhibitory activity.
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steroidal antiandrogens and 5alpha reductase Inhibitors
1999Co-Authors: Eugene Bratoeff, Elena Ramirez, G Flores, E Murillo, Marisa CabezaAbstract:The purpose of this work is to synthesize a pregnane derivative with a high antiandrogenic effect or a high Inhibitory activity for the enzyme 5 alpha-reductase type 2. Benign prostatic hyperplasia and prostate cancer are androgen dependent diseases which afflict a large percentage of the male population. Dihydrotestosterone 3, a 5 alpha-reductase metabolite of testosterone 2 has been implicated as a causative factor in the progression of these diseases, largely through the clinical evaluation of males who are genetically deficient of steroid 5 alpha-reductase enzyme. As a result of this study, the inhibition of this enzyme has become a pharmacological strategy for the design and synthesis of new drugs. The advent of finasteride 22 "figure 5" a 5 alpha-reductase Inhibitor, has greatly alleviated the symptoms associated with benign prostatic hyperplasia. On the other hand, the discovery of cyproterone acetate 4 "figure 2" alone or in combination with the antiandrogens flutamide 14 "figure 3" or bicalutamide 21 has greatly reduced the misery of prostate cancer. Prostate cancer kills about 40,000 men in the USA and approximately 400,000 prostatectomies are performed each year. In our laboratory we have recently synthesized ten new progesterone derivatives 17 alpha-acyloyloxy-6-halo (chloro, bromo) 16 beta-methyl-4, 6-pregnadiene-3, 20-diones (54a-54e and 55a-55e), "figure 10". These steroids were evaluated as antiandrogens and exhibited a much higher activity than the commercially available cyproterone acetate 4. The same compounds were also evaluated as 5 alpha-reductase Inhibitors and showed a slightly higher Inhibitory activity than that of finasteride 22, the drug of choice today for the treatment of benign prostatic hyperplasia In another study we synthesized several new 4-halo (bromo and chloro) 17 alpha-benzoyloxy and also 4-halo-17 alpha-acetoxy progesterone derivatives (58-63) "figure 13". These compounds were prepared from the commercially available 17 alpha-acetoxy progesterone 56. The pharmacological evaluation of these steroids "figure 14" indicated that the 17 alpha-benzoyloxy derivatives (4-chloro and bromo) 62 and 63 were very potent antiandrogens. On the other hand, the 4-halo (bromo and chloro) 17 alpha-acetoxy (58, 59) and the 17 alpha-benzoyloxy-4-chloro analog 63 showed a very high Inhibitory activity for the enzyme 5 alpha-reductase type 2 "figure 15".
Eugene Bratoeff - One of the best experts on this subject based on the ideXlab platform.
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recent advances in the chemistry and pharmacological activity of new steroidal antiandrogens and 5α reductase Inhibitors
2005Co-Authors: Eugene Bratoeff, Marisa Cabeza, Elena Ramirez, Yvonne Heuze, Eugenio FloresAbstract:The object of this paper is to summarize for the past two years the most recent development in the field of prostate cancer and 5 alpha-reductase Inhibitors. In addition we are also including some results on the synthesis and pharmacological evaluation of new steroidal compounds developed in our laboratory. Most of the new steroidal derivatives are based on the progesterone skeleton and showed a high Inhibitory activity for the enzyme 5 alpha-reductase. Presently, similar compounds are used for the treatment of androgen dependent diseases such as: hirsutism, androgenic alopecia, benign prostatic hyperplasia and prostate cancer. Dihydrotestosterone 2 (Fig. 1) a 5 alpha-reduced metabolite of testosterone 1 has been implicated as a causative factor for the progression of these diseases, largely through the clinical evaluation of males who are genetically deficient of the enzyme steroid 5 alpha-reductase. As a result of this study, the inhibition of this enzyme has become a pharmacological strategy for the design and synthesis of new antiandrogenic drugs. The advent of finasteride 7 (Fig. 3) a 5 alpha-reductase Inhibitor has greatly alleviated the symptoms associated with benign prostatic hyperplasia. In our laboratory, we recently synthesized several new 16 beta-methylpregnadiene-3,20-diones: 40, 41 (Fig. 8), 16 beta-phenylpregnadiene-3,17a-dione derivatives 46 and 47 (Fig. 9) and 49 (C-4 bromoderivative) (Fig. 11), 52-56 (Fig. 13). The analogue pregnatriene derivatives were also prepared: 44, 45 (Fig. 9) 50, 51 (Fig. 11) and 57-60 (Fig. 13) These compounds were evaluated as 5 alpha-reductase Inhibitors in the following biological models: Penicillium crustosum broths, the flank organs of gonadectomized male hamsters, the incorporation of radiolabeled sodium acetate into lipids, the effect of the new steroids on the reduction of the weight of the seminal vesicles and on the in vitro metabolism of [3H]T to [3H]DHT in seminal vesicles of homogenates of gonadectomized male hamsters. All trienones 44, 45, 50, 51 and 57-60 in all biological models showed consistently a higher 5 alpha-reductase Inhibitory activity than the corresponding dienones: 40, 41, 46, 47, 49 and 52-56. We believe that with these compounds the 5 alpha-reductase enzyme is inactivated by an irreversible Michael type addition of the nucleophilic portion of the enzyme to the conjugated double bond of the steroid. The trienones having a more coplanar structure react faster with the enzyme thus showing a higher Inhibitory activity.
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steroidal antiandrogens and 5alpha reductase Inhibitors
1999Co-Authors: Eugene Bratoeff, Elena Ramirez, G Flores, E Murillo, Marisa CabezaAbstract:The purpose of this work is to synthesize a pregnane derivative with a high antiandrogenic effect or a high Inhibitory activity for the enzyme 5 alpha-reductase type 2. Benign prostatic hyperplasia and prostate cancer are androgen dependent diseases which afflict a large percentage of the male population. Dihydrotestosterone 3, a 5 alpha-reductase metabolite of testosterone 2 has been implicated as a causative factor in the progression of these diseases, largely through the clinical evaluation of males who are genetically deficient of steroid 5 alpha-reductase enzyme. As a result of this study, the inhibition of this enzyme has become a pharmacological strategy for the design and synthesis of new drugs. The advent of finasteride 22 "figure 5" a 5 alpha-reductase Inhibitor, has greatly alleviated the symptoms associated with benign prostatic hyperplasia. On the other hand, the discovery of cyproterone acetate 4 "figure 2" alone or in combination with the antiandrogens flutamide 14 "figure 3" or bicalutamide 21 has greatly reduced the misery of prostate cancer. Prostate cancer kills about 40,000 men in the USA and approximately 400,000 prostatectomies are performed each year. In our laboratory we have recently synthesized ten new progesterone derivatives 17 alpha-acyloyloxy-6-halo (chloro, bromo) 16 beta-methyl-4, 6-pregnadiene-3, 20-diones (54a-54e and 55a-55e), "figure 10". These steroids were evaluated as antiandrogens and exhibited a much higher activity than the commercially available cyproterone acetate 4. The same compounds were also evaluated as 5 alpha-reductase Inhibitors and showed a slightly higher Inhibitory activity than that of finasteride 22, the drug of choice today for the treatment of benign prostatic hyperplasia In another study we synthesized several new 4-halo (bromo and chloro) 17 alpha-benzoyloxy and also 4-halo-17 alpha-acetoxy progesterone derivatives (58-63) "figure 13". These compounds were prepared from the commercially available 17 alpha-acetoxy progesterone 56. The pharmacological evaluation of these steroids "figure 14" indicated that the 17 alpha-benzoyloxy derivatives (4-chloro and bromo) 62 and 63 were very potent antiandrogens. On the other hand, the 4-halo (bromo and chloro) 17 alpha-acetoxy (58, 59) and the 17 alpha-benzoyloxy-4-chloro analog 63 showed a very high Inhibitory activity for the enzyme 5 alpha-reductase type 2 "figure 15".
