Dutasteride for the treatment of prostate-related conditions

Introduction: A variety of pharmaceuticals have been developed directed at mitigating the symptoms associated with benign prostatic hypertrophy (BPH) and have also been evaluated for their potential role in prevention and treatment of prostate cancer. One such agent is dutasteride, a non-selective inhibitor of 5α-reductase, an enzyme responsible for conversion of testosterone to a more potent androgen dihydrotestosterone (DHT).

Areas covered: This review will cover the safety profile of dutasteride when it is used in the treatment of prostate-related conditions, specifically looking at the pivotal clinical trials on this drug.

Expert opinion: Dutasteride has proved to be a safe and efficacious treatment for symptoms related to BPH. The primary safety concern relates to the increased incidence of high-grade prostate cancer seen in men treated with dutasteride in the setting of prostate cancer prevention. Dutasteride has a role as an adjunct in the treatment of prostate cancer; however, this is an area still under active investigation. It is not recommended for use in prostate cancer prevention given the increased risk of high-grade cancers.     

Dutasteride: a review of its use in the management of prostate disorders

Dutasteride (Avodart), an oral synthetic 4-azasteroid, is a potent, selective, irreversible inhibitor of type 1 and type 2 5alpha-reductase (5AR), the enzyme that converts testosterone to dihydrotestosterone (DHT) intracellularly. Although type 2 5AR predominates, both isoenzymes are overexpressed in prostate tissue in benign prostatic hyperplasia (BPH) and at all stages in some prostate cancers. Oral dutasteride 0.5 mg once daily is approved for the treatment of moderate to severe symptomatic BPH in men with an enlarged prostate to improve symptoms, and to reduce the risk of acute urinary retention (AUR) and the need for BPH-related surgery.In pivotal 2-year phase III trials, oral dutasteride 0.5 mg once daily improved urinary symptoms, decreased total prostate volume (TPV), and reduced the risk of AUR and BPH-related surgery in men with moderate to severe symptoms of BPH and prostate enlargement. The good efficacy and tolerability of dutasteride was maintained for up to 4 years in open-label extension studies. Results of the pre-planned, 2-year interim analysis of the CombAT trial showed that the combination of dutasteride and tamsulosin was superior to either drug as monotherapy in improving BPH-related symptoms, peak urinary flow and BPH-related health status. The overall adverse event profile for combination therapy was consistent with those reported for both monotherapies. Although drug-related adverse events were more frequent with combination therapy versus both monotherapies, most did not result in treatment cessation. Dutasteride is being investigated for its efficacy in reducing the risk of prostate cancer in at-risk men in the 4-year REDUCE study and as treatment to extend the time to progression in men with low-risk localized prostate cancer who would otherwise undergo watchful waiting in the 3-year REDEEM study. Thus, dutasteride is an effective treatment option in patients with moderate to severe symptomatic BPH and demonstrable prostatic enlargement, and may have potential to reduce the risk of developing biopsy-detectable prostate cancer in at-risk individuals or extending the time to progression in low-risk localized prostate cancer.     

Dutasteride: an evidence-based review of its clinical impact in the treatment of benign prostatic hyperplasia

INTRODUCTION: Benign prostatic hyperplasia (BPH) is a common condition affecting older men. Bothersome symptoms can progress to serious complications such as acute urinary retention (AUR) requiring surgical intervention. Dutasteride, a dual 5-alfa-reductase (5AR) inhibitor (5ARI), is a recently introduced therapy for the treatment of BPH. AIMS: The objective of this article is to review the evidence for the treatment of BPH with dutasteride. EVIDENCE REVIEW: Evidence from large clinical studies shows that men with an enlarged prostate achieve a measurable decrease in prostate volume by up to 26% after 4 years of treatment with dutasteride and urinary symptoms improve after 6 months of treatment. This is achieved by rapid suppression (through inhibition of 5AR) of the principal androgen (dihydrotestosterone or DHT) responsible for stimulating prostatic growth. Evidence suggests that dutasteride treatment results in a reduction in risk (rather than delay) of the most serious complications including episodes of AUR and the need for BPH-related surgery. Early symptom relief has been achieved with the combination of an alfa blocker and dutasteride. There is good evidence that dutasteride is well tolerated; side effects limited to sexual dysfunction (reduced libido, impotence, and gynecomastia) are more common compared with placebo but occur with a similar incidence to finasteride, another 5ARI. No pharmacoeconomic evidence from studies with dutasteride has so far been published. CLINICAL VALUE: In conclusion, dutasteride is a valuable treatment option in men with moderate to severe BPH. Reductions in prostate volume lead to symptom relief and serious complications appear to be reduced.     

Dutasteride/tamsulosin: in benign prostatic hyperplasia

The 5α-reductase inhibitor dutasteride and the α(1)-adrenergic receptor antagonist tamsulosin are available as a fixed-dose combination for use in men with symptomatic benign prostatic hyperplasia (BPH) and an enlarged prostate. Dutasteride 0.5?mg/day plus tamsulosin 0.4?mg/day improved lower urinary tract symptoms (LUTS) to a significantly greater extent than dutasteride or tamsulosin alone in men with BPH, moderate to severe LUTS and an increased risk of disease progression, according to the results of the randomized, double-blind, multinational CombAT trial. The mean change from baseline in the total International Prostate Symptom Score was significantly greater with dutasteride plus tamsulosin than with dutasteride or tamsulosin alone after 2 years (primary endpoint) and 4 years of therapy. After 4 years' therapy in the CombAT trial, the time to first acute urinary retention or BPH-related surgery (primary endpoint) significantly favoured men with symptomatic BPH who were receiving dutasteride plus tamsulosin versus those receiving tamsulosin alone, with no significant difference between recipients of dutasteride plus tamsulosin and recipients of dutasteride alone. In the CombAT trial, health-related quality of life and treatment satisfaction were improved to a significantly greater extent with dutasteride plus tamsulosin than with dutasteride or tamsulosin alone. Combination therapy with oral dutasteride plus tamsulosin was generally well tolerated in patients with symptomatic BPH in the CombAT trial.     

Dutasteride

Dutasteride, a potent inhibitor of type 1 and 2 5alpha-reductase, reduced dihydrotestosterone levels by >90% in 85% of patients following 1 years' administration of oral dutasteride 0.5 mg/day. A combined analysis of three placebo-controlled clinical studies conducted in patients with benign prostatic hyperplasia (BPH) found sustained improvements in American Urological Association- Symptom Index scores and urinary flow rate and a 57% decrease in the risk of acute urinary retention throughout the 2-year treatment period (all p < 0.001 vs placebo). Total prostate and transition zone volume were also reduced (both p < 0.001), as was the risk of BPH-related surgery (by 48%). A nonblind extension study found that dutasteride maintains efficacy for up to 4 years. Dutasteride monotherapy maintained symptom relief following combination treatment with dutasteride and tamsulosin in all patients but those with severe symptoms. Dutasteride was generally well tolerated. Impotence, reduced libido, gynaecomastia and ejaculation disorder occurred significantly more often in dutasteride than placebo recipients, but incidence was generally low. With the exception of gynaecomastia, incidence consistently decreased over time.     

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.     

Dutasteride: a novel dual inhibitor of 5alpha-reductase for benign prostatic hyperplasia

Dutasteride is a new dual 5alpha-reductase inhibitor for the treatment of benign prostatic hyperplasia. It differs from finasteride as it inhibits both isoenzymes of 5alpha-reductase and results in near-complete suppression of serum dihydro-testosterone. Similar to finasteride, it reduces serum prostatic specific antigen by approximately 50% at 6months and total prostate volume by 25% in 2years. Randomised, placebo-controlled trials conducted over 2years have shown the efficacy of dutasteride in symptomatic relief, improvements in quality of life and peak urinary flow rate, and reduction of acute urinary retention events and the need for surgery. The main side effects are erectile dysfunction, decreased libido, gynaecomastia and ejaculation disorders. However, long-term usage for > 4years did not reveal increased new onset of sexual side effects. In addition, the combination of dutasteride and tamsulosin is well-tolerated and has the added advantage of rapid symptomatic relief. Finally, dutasteride has been shown to possess tumour regression properties invitro and its role in chemoprevention of prostate cancer will be confirmed in the ongoing Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial.     

Dutasteride: a potent dual inhibitor of 5-alpha-reductase for benign prostatic hyperplasia

Dutasteride is a 5alpha-reductase inhibitor that inhibits both types 1 and 2 isozymes of 5alpha-reductase, the enzyme responsible for converting testosterone to dihydrotestosterone in the prostate and other tissues. Dihydrotestosterone is the primary cause of prostate growth and has been proven to play a key role in the development and progression of benign prostatic hyperplasia. Dutasteride has been investigated in three multicenter studies involving 4325 men aged 50 years and above with benign prostatic hyperplasia. Data from these two-year, placebo-controlled studies demonstrated that dutasteride 0.5 mg once daily reduced the risk of both acute urinary retention and the need for benign prostatic hyperplasia-related surgical intervention, improved benign prostatic hyperplasia-related symptoms, decreased prostate volume and increased maximum urinary flow rates with a low incidence of generally mild to moderate adverse events.     

Combined medical treatment using dutasteride and tamsulosin for lower urinary tract symptoms suggestive of benign prostatic hyperplasia

Importance of the field: Benign prostatic hyperplasia (BPH) is the fourth most commonly diagnosed medical condition in the elderly. Selective α-blockers (tamsulosin) and dual 5α-reductase inhibitors (dutasteride) have an important role in the medical treatment of symptomatic BPH. Safety and efficacy of combination therapy with dutasteride and tamsulosin as well as long-term benefit on prevention of disease progression have been widely studied in recent trials.

Areas covered in this review: The present article summarizes the pharmacologic properties of both dutasteride and tamsulosin. Clinical efficacy of combination therapy in different trials has also been reported. Major randomized trials on this concept published between 2000 and 2010 have been covered in this article.

What the reader will gain: Long-term efficacy and safety of combination therapy and its beneficial effect on quality of life and risk reduction of need for BPH-related surgeries have been discussed.

Take home message: Combination therapy with dutasteride and tamsulosin is a highly efficacious medical treatment in patients with moderate-to-severe lower urinary tract symptoms due to benign prostatic enlargement, which could be safely tolerated and administrated for ≥ 4 years.     

Dutasteride/tamsulosin fixed-dose combination for the treatment of benign prostatic enlargement

Fixed-dose dutasteride/tamsulosin is a combination therapy for lower urinary tract symptoms secondary to benign prostatic enlargement (LUTS/BPE), which is composed of two active ingredients, tamsulosin and dutasteride. Tamsulosin is an α-adrenoceptor blocker that is relatively selective for the α(1A)-adrenoceptor subtype within the prostatic smooth muscles. The inhibition of α(1A)-adrenoceptors results in smooth muscle relaxation. Dutasteride is an inhibitor of 5α-reductase, an enzyme that is responsible for the conversion of testosterone to its active form dihydrotestosterone. This occurs in the prostate, liver and skin. 5α-Reductase results in the shrinkage of the prostatic epithelium and reduction in the size of the prostate. No clinical studies have been performed on the fixed-dose dutasteride/tamsulosin combination, although several clinical trials have been conducted on the combination therapy of 5α-reductase and α-adrenoceptor blockers for LUTS/BPE. The CombAT study is a multicenter, randomized, double-blind trial in men with a clinical diagnosis of LUTS/BPE that is comparing tamsulosin or dutasteride as a monotherapy to tamsulosin and dutasteride as combination therapy (as separate tablets). The combination therapy was associated with significant improvements in the symptom score compared to tamsulosin or dutasteride as monotherapy. It is therefore logical to combine the two medications into one tablet.     

Combination pharmacological therapies for the management of benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is a highly prevalent condition of older men caused by unregulated growth of the prostate gland. Clinical trials of medical therapy for BPH have consistently demonstrated that combined therapy with an α(1)-adrenergic receptor (AR) antagonist and a 5α-reductase inhibitor is superior to either agent alone. The addition of anticholinergic therapy to a treatment regimen could effectively improve symptoms in men with persistent storage lower urinary tract symptoms (LUTS) who have not seen a benefit with an α(1)-AR antagonist or 5α-reductase inhibitor. Among α(1)-AR antagonists, doxazosin, terazosin, tamsulosin, and alfuzosin, although with slight differences in adverse event profiles, are equivalent in effectiveness and efficacy. No data in the form of direct comparator trials exist to suggest a difference in clinical efficacy of finasteride and dutasteride, the two 5α-reductase inhibitors currently available. Current American Urological Association guidelines do not recommend phytotherapy or dietary supplements in any combination for the medical management of BPH. The current literature supports the safety and efficacy of the combination of an α(1)-AR antagonist and a 5α-reductase inhibitor in the treatment of symptomatic BPH and, in select patients, the use of an α(1)-AR antagonist and anticholinergic medication in the treatment of LUTS suggestive of BPH.     

Update on prostate cancer chemoprevention

BACKGROUND: Prostate cancer is the most common type of cancer and the second leading cause of cancer-related deaths in American men. Its high rate of occurrence and long lead time to clinically significant disease make prostate cancer an ideal disease for pharmacologic or nutritional chemoprevention. METHODS: To identify the various chemoprevention strategies for prostate cancer, a MEDLINE search (from 1967-2005) and bibliographic search of the English-language literature were conducted. RESULTS: Epidemiologic and retrospective studies have assessed the effect of carotenoids (e.g., lycopene), vitamins, selenium, and nonsteroidal antiinflammatory drugs (NSAIDs) on the rate of occurrence of prostate cancer. The few published prospective trials evaluated prostate cancer as a secondary end point. Lycopene (as beta-carotene) and selenium supplementation have been associated with a reduced risk of prostate cancer in nested case-control studies, but only in subgroups of men with low baseline plasma lycopene (or beta-carotene) and selenium levels respectively. The Prostate Cancer Prevention Trial prospectively evaluated finasteride, a 5-alpha-reductase inhibitor, as chemoprevention. The results showed a 25% relative risk reduction in prostate cancer, albeit at an increased risk of invasive tumors. CONCLUSION: Data regarding lycopene, vitamin E, and selenium as chemoprevention for prostate cancer appear promising. Prospective trials such as the Selenium and Vitamin E Cancer Prevention Trial (SELECT) will clarify the role of these agents in prostate cancer prevention. The role of NSAIDs is unclear, and the long-term toxicity associated with NSAIDs may limit their usefulness. Although finasteride has decreased overall prostate cancer occurrence, the risk of invasive tumors may outweigh the benefit of this agent. The continuing Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial may help define a role for the 5-alpha-reductase inhibitors in cancer chemoprevention. At this time, nothing has been proven effective as chemoprevention against clinically significant prostate cancer.     

NX-1207: a novel investigational drug for the treatment of benign prostatic hyperplasia

Importance of the field: Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) is a common affliction among older men that can have significant impact on health-related quality of life. BPH is a progressive condition that can lead to complications including acute urinary retention (AUR) and to surgical intervention. There is an ongoing need for new, safe and effective treatments for BPH. Currently available therapies have significant safety and efficacy limitations. NX-1207 is a promising first-in-class drug currently in Phase III trials for the treatment of BPH.

Areas covered in this review: This review provides an overview of BPH and currently approved medical treatments and drugs as described in the literature and treatment practice guidelines in the past 10 years, an outline of the results of the Phase II trials of NX-1207 and an expert opinion on the role NX-1207 may play in the treatment of men with clinical BPH.

What the reader will gain: This review aims to introduce readers to NX-1207, a new treatment for BPH that is administered in an office-based procedure by transrectal intraprostatic injection under ultrasound guidance. NX-1207 has selective pro-apoptotic properties, which induces focal cell loss in prostate leading to prostate volume reduction with both short- and long-term symptomatic improvement.

Take home message: In four US clinical trials to date, NX-1207 has shown evidence of symptomatic improvement substantially better than currently approved BPH medications with no significant safety issues. Larger Phase III trials are ongoing to further confirm the efficacy, safety and tolerability for this minimally invasive, anesthetic free, clinic-based treatment for BPH.     

Expression of vascular endothelial growth factor (VEGF) and association with microvessel density in benign prostatic hyperplasia and prostate cancer

BACKGROUND: Tumor angiogenesis is an absolute requirement for tumor growth and a prognostic factor for various malignant neoplasms. Recent reports in the literature have addressed the importance of the VEGF system in benign prostatic hyperplasia (BPH) and adenocarcinoma, however the results are controversial. The aim of the present study was to determine and compare the levels of VEGF expression and vascularity in BPH and prostate carcinoma. MATERIALS AND METHODS: We examined 60 prostate adenocarcinomas and 64 benign prostatic hyperplasias. Angiogenesis was estimated by determining microvessel counts (MVC), with the use of anti-CD31 and anti-CD34 antibodies. Expression of VEGF was also evaluated immunohistochemically. RESULTS AND CONCLUSION: Our data showed that angiogenesis was more prominent in carcinomas than in BPH. Furthermore, increased MVC was significantly associated with high-grade carcinomas. Angiogenesis was correlated with VEGF expression and it was, at least in part, mediated by the latter. Thus, prostate adenocarcinoma may represent a suitable neoplasm for antiangiogenic treatment in combination with conventional therapies.     

前列腺增生症合并慢性肾功能不全手术治疗体会

目的:探讨前列腺增生症合并肾后性肾功能不全手术治疗的安全性及临床疗效。方法:43例合并慢性肾功能不全的前列腺增生症患者,通过留置尿管或耻骨上膀胱造瘘尿液引流,在肾功能改善后行耻骨后经膀胱前列腺摘除术。结果:本组持续尿液引流后,肾功能均有显著的恢复。43例行开放性前列腺摘除术,顺利完成手术,康复顺利。术后随访6~24个月,残余尿0~30mL;血Cr38例在正常范围,5例在250~450μmol/L。结论:尿液引流为手术创造条件,术前尽可能纠正肾功能不全、改善机体状况是手术成功的关键。行前列腺摘除术可有效改善临床症状及肾功能。     

经尿道前列腺汽化电切除术治疗前列腺增生的临床观察

目的观察经尿道前列腺汽化电切除术（TUVP）治疗前列腺增生的效果。方法回顾性分析我院2000年4月至2006年6月期间用TUVP治疗前列腺增生患者的效果、并发症及预防治疗方法。结果600例前列腺增生患者TUVP治疗后，症状明显改善，患者国际前列腺症状评分明显下降，剩余尿量减少，最大尿流率增加，生活质量评分也明显升高。并发症有：暂时性尿失禁17例、迟发性出血18例，无经尿道电切综合征发生。结论TUVP是治疗前列腺增生的首选方法，为避免并发症的发生，应加强术前准备、术中监测和术后处理等工作。     

Combination therapy for the pharmacological management of benign prostatic hyperplasia: rationale and treatment options

The management of symptomatic benign prostatic hyperplasia (BPH) continues to evolve, with new techniques and forms of medical management being introduced and traditional surgical techniques being used less frequently. Medical management of BPH has evolved from nonspecific alpha-adrenoceptor antagonists to uroselective alpha-adrenoceptor antagonists and 5-alpha reductase inhibitors. Traditionally, alpha-adrenoceptor antagonists have been used for relief of lower urinary tract symptoms (LUTS) as a result of BPH and are known for their quick onset of action. 5-alpha Reductase inhibitors have proven useful for the prevention of BPH progression as measured by prostate volume, disease progression, incidence of acute urinary retention and the need for subsequent BPH-related surgery. Recent studies have shown that the combination of an alpha-adrenoceptor antagonist and a 5-alpha reductase inhibitor has significantly better efficacy than either drug alone or placebo. Currently, alpha-adrenoceptor antagonists are used in the acute setting or for short-term relief of LUTS. The combination of an alpha-adrenoceptor antagonist and a 5-alpha reductase inhibitor is used for the longer term management of BPH symptoms and to prevent progression of BPH and perhaps avoid surgical intervention.     

Atypical post-finasteride syndrome: A pharmacological riddle

Finasteride and dutasteride are commonly used 5-alpha reductase inhibitors. While finasteride is a selective inhibitor of 5-alpha reductase Type II, dutasteride inhibits 5- alpha reductase Type I and II. The United States Food and Drug Administration approved the use of finasteride for benign prostatic hypertrophy (BPH) as well as androgenic alopecia (AGA) while dutasteride is approved only for BPH. Off-label use of dutasteride is not uncommon in AGA as well. Although the postfinasteride syndrome (PFS) is a well-established entity, its symptomatology is quite variable. Here, we describe a case of an atypical PFS in a patient treated with dutasteride and finasteride for AGA. The multisystem involvement and irreversible nature of this case warrant its reporting.KEY WORDS: 5-alpha reductase inhibitors, dutasteride, finasteride, postfinasteride syndrome     

Trends in the development of new drugs for treatment of benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is a common condition in aging men that is characterized by nonmalignant enlargement of the prostate gland, and is frequently accompanied by urinary obstruction, and lower urinary tract symptoms (LUST). Currently pharmacotherapy of BPH is based on two classes of drugs: alpha(1)-adrenoceptor (alpha(1)-AR) antagonists and 5alpha-reductase inhibitors. It has been shown that alpha(1)-AR antagonists reduce symptom scores and increase peak urinary flow rates in BPH. Of particular importance for BPH therapy are uroselective alpha(1)-AR antagonists for which the hypotensive related side-effect caused by alpha(1)-AR blockade is reduced. 5alpha-Reductase inhibitors reduce prostate volume and symptom scores, while increasing peak urinary flow rates. This review describes new alpha(1)-AR antagonists and 5alpha-reductase inhibitors in the treatment of BPH. The new alpha(1)-AR antagonists represent various structures such as quinazolines, phenylethylamines, piperidines, and arylpiperazines. 5alpha-Reductase inhibitors are classified into two groups: steroidal and non-steroidal. The newer non-steroidal inhibitors include derivatives of benzo[c]quinolizinones, benzo[f]quinolonones, piperidones and carboxylic acids. Besides the development of new compounds belonging to the above mentioned groups, new agents for BPH treatment are sought among combined 5alpha-reductase/alpha(1)-AR inhibitors, endothelins, androgen receptors antagonists, growth factors, estrogens and phosphodiesterase isoenzymes as well as several phytomedicines, used for prevention and treatment of prostate disorders. These new agents can be used for the design of future targets and development of new drugs in the treatment of BPH. The discovery of a number of active leads may also ultimately help in developing new safe and effective drugs.