Alpha-Blocker Therapy Can Be Withdrawn in the Majority of Men Following Initial Combination Therapy with the Dual 5α-Reductase Inhibitor Dutasteride

Barkin, Jack; Guimarães, Marcelo; Jacobi, G. H.; Pushkar, Dmitry; Taylor, Stephen; Trip, Oncko B. van Vierssen

doi:10.1016/s0302-2838(03)00367-1

Cited by 173 publications

(145 citation statements)

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“…Treatment with either drug significantly reduced BPH symptoms compared with placebo, but the combination therapy performed signifi-cantly better in alleviation of LUTS compared with monotherapy. The SMART-1 study showed that ␣-adrenergic receptor blockers used initially could be discontinued after 6 months without any loss of improvement from the combination therapy (21). However, treatment-resistant disease is still a considerable problem, and many men still fail medical therapy and go on to require invasive surgical intervention for symptomatic relief.…”

Section: Benign Prostatic Hyperplasia (Bph)mentioning

confidence: 99%

Opposing Effects of Cyclooxygenase-2 (COX-2) on Estrogen Receptor β (ERβ) Response to 5α-Reductase Inhibition in Prostate Epithelial Cells

Liu

Grubisha

Frahm

et al. 2016

Journal of Biological Chemistry

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Current pharmacotherapies for symptomatic benign prostatic hyperplasia (BPH), an androgen receptor-driven, inflammatory disorder affecting elderly men, include 5␣-reductase (5AR) inhibitors (i.e. dutasteride and finasteride) to block the conversion of testosterone to the more potent androgen receptor ligand dihydrotestosterone. Because dihydrotestosterone is the precursor for estrogen receptor ␤ (ER␤) ligands, 5AR inhibitors could potentially limit ER␤ activation, which maintains prostate tissue homeostasis. We have uncovered signaling pathways in BPH-derived prostate epithelial cells (BPH-1) that are impacted by 5AR inhibition. The induction of apoptosis and repression of the cell adhesion protein E-cadherin by the 5AR inhibitor dutasteride requires both ER␤ and TGF␤. Dutasteride also induces cyclooxygenase type 2 (COX-2), which functions in a negative feedback loop in TGF␤ and ER␤ signaling pathways as evidenced by the potentiation of apoptosis induced by dutasteride or finasteride upon pharmacological inhibition or shRNA-mediated ablation of COX-2. Concurrently, COX-2 positively impacts ER␤ action through its effect on the expression of a number of steroidogenic enzymes in the ER␤ ligand metabolic pathway. Therefore, effective combination pharmacotherapies, which have included non-steroidal anti-inflammatory drugs, must take into account biochemical pathways affected by 5AR inhibition and opposing effects of COX-2 on the tissue-protective action of ER␤. Benign prostatic hyperplasia (BPH)3 is a common disorder affecting elderly men. Although 50% of men over the age of 50 will develop histological BPH (1, 2), less than half will go on to develop lower urinary tract symptoms (LUTS) (3, 4) such as urinary frequency, urgency, and retention (5, 6). Multiple factors including altered steroid hormone signaling and chronic inflammation contribute to the pathogenesis of BPH, ultimately leading to an increase in prostate size through tissue remodeling (4, 7-9).The prostate epithelium is responsive to multiple sex steroids and expresses both androgen receptor (AR) and the ␤ isoform of estrogen receptor (ER␤) (9, 10). The prostate, which is mainly an androgen-dependent organ, can convert testosterone to not only the potent AR ligand dihydrotestosterone (DHT) but also to ER␤ ligands, the most abundant of which is 5␣-androstane-3␤,17␤-diol (3␤-diol) (11, 12). Although androgens regulate differentiation functions of the prostate and enhance proliferation of prostate cancer cells, these actions are opposed by estrogenic ligands, which limit proliferation and epithelial cell differentiation (12-15).The main pharmacotherapies for treating symptomatic BPH include ␣-adrenergic receptor blockers and 5␣-reductase (5AR) inhibitors, which limit conversion of testosterone to DHT (16,17). ␣-Adrenergic blockers alleviate LUTS, whereas 5AR inhibitors reduce prostate size. Several clinical trials (Medical Therapy of Prostatic Symptoms, Reduction by Dutasteride of Prostate Cancer Events, and Prostate Cancer Prevention Trial) have examined ...

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Section: Benign Prostatic Hyperplasia (Bph)mentioning

confidence: 99%

Opposing Effects of Cyclooxygenase-2 (COX-2) on Estrogen Receptor β (ERβ) Response to 5α-Reductase Inhibition in Prostate Epithelial Cells

Liu

Grubisha

Frahm

et al. 2016

Journal of Biological Chemistry

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“…Se puede concluir que 3 estudios 5-7 plantean objetivos clásicos basados en variables ampliamente aceptadas, mientras que los otros dos nacen de unos objetivos originales y por ello más novedosos pero basados en unas variables definidas por primera vez en dichos estudios [8][9] .…”

Section: Análisis De La Hipótesis Y Las Variablesunclassified

“…En primer lugar, se considera que un ensayo clínico de una patología como la HBP, que presenta una progresión lenta con altibajos en su sintomatología, ha de tener una duración mínima de un año y en dos de los estudios ésta es sólo de 6 meses 6,8 . Además, en uno de ellos, el estudio ALFIN 6 , no existe grupo control con placebo.…”

Section: Análisis De La Validez Internaunclassified

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Análisis de la evidencia científica de los estudios publicados sobre terapia combinada en hiperplasia prostática benigna

Rodríguez

2005

Actas Urol Esp

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PROSTÁTICA BENIGNA Objetivo: El análisis de la evidencia científica de los estudios publicados sobre terapia combinada en Hiperplasia Prostática Benigna (HBP).Material y métodos: Se han analizado y comparado desde el punto de vista de la Medicina Basada en la Evidencia (MBE) los 5 ensayos clínicos publicados sobre terapia combinada en HBP. Se han analizado las hipóte-sis y las variables de cada estudio, la validez interna, la relevancia de los resultados, y la validez externa.Resultados: Cuatro estudios evaluaron los cambios en la sintomatología y en el flujo máximo (Qmax) y sólo uno la progresión de la enfermedad. Los criterios de inclusión y exclusión fueron similares en los 5 estudios. La corta duración, el porcentaje de abandonos, la ausencia de grupo placebo y el sesgo en la dosificación en un brazo de tratamiento fueron las principales causas de escasa o leve validez interna en 3 estudios. La validez externa está afectada en los 5 estudios por la rigidez de los criterios de exclusión y en 3 de ellos por alcanzar el efecto terapéutico con dosis altas del alfabloqueante. Sólo el estudio que tiene un mayor nivel de evidencia científica (MTOPS) proporciona los intervalos de confianza y el número de pacientes a tratar.Conclusiones: En todos los estudios el incremento del Qmax y la mejora de la sintomatología presentan respectivamente una nula y una moderada relevancia clínica. El estudio MTOPS demuestra que la progresión de la HBP tiene una incidencia baja pero se puede reducir de forma importante con el tratamiento combinado.Palabras clave: Hiperplasia Prostática Benigna. Tratamiento combinado. Medicina Basada en la Evidencia. ABSTRACT ANÁLISIS OF THE SCIENTIFIC EVIDENCE OF THE COMBINATION THERAPY IN BENIGN PROSTATICHYPERPLASIA Objective: The analysis of the scientific evidence of the combination therapy in Benign Prostatic Hyperplasia (BPH).Methods: 5 published studies about combination therapy in BPH were analysed following the criteria of the Evidence Based Medicine (EBM). Hypothesis, variables, internal validity, results relevance, and the external validity of every study were analysed.Results: Symptoms changes and maximal flow rate (Qmax) improvement were evaluated in four studies and only one analysed the BPH progression. Inclusion and exclusion criteria were similar in the 5 studies. The main reasons of a poor internal validity in 3 studies were the short follow-up, the missing percentage, the absence of a placebo group and a dosage bias. External validity were decreased in the 5 studies by the exclusion criteria and in 3 of them because high doses of alpha-blocker were given to achieve a therapeutic effect. The study with the highest scientific evidence (MTOPS) is the only that offers confidence intervals and number needed to treat.Conclusions: The Qmax and the symptoms improvement found in all the studies has a moderate clinical relevance. MTOPS study shows that BPH progression has a low incidence that can be highly reduced by means of combination therapy.

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“…According to this illustrative cost analysis the secondary-care costs associated with managing AUR and BPH-related surgery, common complications of BPH, stands at £111 568 793. This is almost 60% more than the amount spent on drugs to treat BPH (£69 228 637) and more than 3.5 times the expenditure on the 5ARI class of drugs (£29 170 450), which have been shown in several studies to not only improve LUTS but also to reduce the risks of both AUR and BPHrelated surgery by about half [3][4][5][6].The time and cost burden associated with primary-care consultations should also be considered when evaluating the effect of treating BPH within the NHS. In this cost analysis it is estimated that 1 648 830 GP consultations are for BPH at a total cost to the NHS of £44 518 410 per year.…”

mentioning

confidence: 99%

Benign Prostatic Hyperplasia: Counting the Cost of Its Management

Kirby

Fitzpatrick

2010

BJU International

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9 0 1 INTRODUCTION BPH is estimated to affect around 3.2 million men of middle age and beyond in the UK. BPH not only has a serious effect on the quality of life of patients and their families; the condition is also expensive for the NHS, both in terms of costs both for GP practices in primary care, and for urology services in secondary care. Moreover, BPH, especially if acute urinary retention (AUR) develops, can have a very deleterious effect on an individual's quality of life [1]. In the future the social and economic burden is only likely to increase with the rising numbers of men with bothersome LUTS resulting from the increasing prevalence of BPH in the ageing population. From Hospital Episode Statistics (HES) data [2](2007/2008) urology currently represents the fifth most expensive disease area for the UK NHS, accounting for an expenditure of £1.16 billion each year. Surgery for BPH represents the 10th most common operation across the NHS, and AUR is amongst the top 5% of causes of acute admissions to NHS hospitals.Although there are published estimates for the number of men affected by BPH symptoms in the UK, accurate, up-to-date data on the number of men who visit their GP to discuss these symptoms are limited to local, practice-based surveys. The latest published national data are from the Third National Morbidity Survey (1983) which reported that 0.51% of all GP consultations were for BPH. If we adopt the assumption that the proportion of consultations for BPH has remained the same (0.51%), we can combine these data with current all-cause consultation rates and population data to estimate the average number and cost of primary-care consultations related to BPH each year. Using an all-cause consultation rate of 5. Using HES data for 2007/2008, which are based on all hospital treatments in England, an estimate of the volume of hospital treatment for BPH can be made for the UK as a whole. HES data for England show that 28 499 men were admitted to hospital with AUR at a total tariff cost of £29 702 780, and 26 618 were admitted to hospital for BPHrelated surgery (e.g. TURP) at a cost of £55 357 650. Adding these costs together and applying an increase factor of 19% to reflect the whole UK population gives a total cost for treating these major complications of BPH in secondary care of £101 221 912.It seems reasonable to assume that additional costs are incurred as a result of patients requiring review in the urology clinic, either before their admission for surgery or after their discharge from either elective surgery or procedures related to AUR. It is standard practice and therefore assumed that all patients admitted for BPH-related surgery will have a preoperative consultation at a tariff of £161, followed by one postoperative followup at a tariff of £80. Similarly, it is assumed that all men admitted with AUR have a follow-up review at a tariff of £80. This equates to an additional cost of £10 346 881 directly attributable to the costs of treating key BPH complications in the UK.Using these costs, base...

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Alpha-Blocker Therapy Can Be Withdrawn in the Majority of Men Following Initial Combination Therapy with the Dual 5α-Reductase Inhibitor Dutasteride

Cited by 173 publications

References 9 publications

Opposing Effects of Cyclooxygenase-2 (COX-2) on Estrogen Receptor β (ERβ) Response to 5α-Reductase Inhibition in Prostate Epithelial Cells

Opposing Effects of Cyclooxygenase-2 (COX-2) on Estrogen Receptor β (ERβ) Response to 5α-Reductase Inhibition in Prostate Epithelial Cells

Análisis de la evidencia científica de los estudios publicados sobre terapia combinada en hiperplasia prostática benigna

Benign Prostatic Hyperplasia: Counting the Cost of Its Management

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