Role of 5 alpha-reductase inhibitors in the management of prostate cancer

Prostate cancer is one of the most complex and enigmatic oncologic problems in medicine. It is highly prevalent, particularly in elderly males. Unfortunately, its generally protracted and variable clinical course and high association with treatment-related morbidity raise serious questions about the ideal treatment strategy for the individual patient. 5 alpha-reductase (5AR) inhibitors have a dramatic effect on benign prostatic disease with low toxicity. Thus, there is much interest in the potential role of 5AR inhibitors in the prevention and treatment of prostate cancer. Finasteride is the only agent that has been shown in a randomized clinical trial to decrease the risk of prostate cancer with a reduction of almost 25%. Additionally, a recent analysis of the Prostate Cancer Prevention Trial (PCPT) has found that finasteride improves the performance characteristics of prostate-specific antigen (PSA) blood test as a screening tool for prostate cancer, for both cancer detection as well as for detection of high risk disease. Finally, 5AR inhibitors have been studied as a component of multimodal therapy for all stages of prostate cancer, with the goal of improving oncologic outcomes while avoiding the toxicity of medical and surgical castration.     

Update on the use of dutasteride in the management of benign prostatic hypertrophy

Benign prostatic hyperplasia (BPH) is a frequent cause of lower urinary symptoms, with a prevalence of 50% by the sixth decade of life. Hyperplasia of stromal and epithelial prostatic elements that surround the urethra cause lower urinary tract symptoms (LUTS), urinary tract infection, and acute urinary retention. Medical treatments of symptomatic BPH include; 1) the 5α-reductase inhibitors, 2) the α1-adrenergic antagonists, and 3) the combination of a 5α-reductase inhibitor and a α1-adrenergic antagonist. Selective α1-adrenergic antagonists relax the smooth muscle of the prostate and bladder neck without affecting the detrussor muscle of the bladder wall, thus decreasing the resistance to urine flow without compromising bladder contractility. Clinical trials have shown that α1-adrenergic antagonists decrease LUTS and increase urinary flow rates in men with symptomatic BPH, but do not reduce the long-term risk of urinary retention or need for surgical intervention. Inhibitors of 5α-reductase decrease production of dihydrotestosterone within the prostate resulting in decreased prostate volumes, increased peak urinary flow rates, improvement of symptoms, and decreased risk of acute urinary retention and need for surgical intervention. The combination of a 5α-reductase inhibitor and a α1-adrenergic antagonist reduces the clinical progression of BPH over either class of drug alone.     

Metabolic Syndrome Enhances Prostate Contractility and In Vitro Phenylephrine‐induced α1‐Adrenoceptor Protein Expression in the Fructose‐fed Rat

Objectives: To study the effects of metabolic syndrome on prostate α‐adrenergic contractile function using fructose‐fed rats (FR). Methods: Age‐matched male Wistar rats were divided into two groups: group I, normal control rats; and group II, 9‐week FR. Animal body weight, blood pressure and serum metabolic parameters were monitored. The prostate was removed 9 weeks after induction of metabolic syndrome in the FR. The contractile responses of prostatic strips to phenylephrine (10^?7 to 10^?6 M) and KCl (50 mM) were tested. Prostate α₁‐adrenoceptor (α₁‐AR) protein expression was studied by Western blotting analysis with a polyclonal antiserum. Results: At week 9, the FR showed significant increases in body weight, blood pressure, plasma glucose, insulin and triglyceride levels. The FR prostate weight was significantly higher than that of the controls (610.5 ± 13.2 vs 422.3 ± 7.7 mg, P < 0.05 for n = 8). FR prostate contractile responses to phenylephrine and KCl were both significantly increased. Interestingly, prostate α₁‐AR protein expression level was lower in the FR. However, after in vitro 10^?6 M phenylephrine stimulation, FR prostate α₁‐AR protein expression was significantly increased. Conclusion: Metabolic syndrome in FR significantly increases prostate contractile responses to KCl and α‐adrenergic stimulation. Paradoxically, FR prostate α₁‐AR protein expression is decreased, but significantly enhanced after in vitro phenylephrine stimulation.     

Clinical Efficacy of α1‐Adrenargic Receptor Antagonist Naftopidil 75 mg/day in Patients with Benign Prostatic Hyperplasia

Objectives: The clinical efficacy and safety of 75 mg/day of naftopidil, an α1‐adrenargic receptor antagonist, was assessed in patients with benign prostatic hyperplasia (BPH). Methods: A total of 28 patients (mean age, 71.1 years; range, 46–86 years) with BPH were studied. Inclusion criteria were: (i) International Prostate Symptom Score (IPSS) ≥8; and (ii) quality of life (QOL) index ≥3. IPSS, QOL index, Overactive Bladder Symptom Score (OABSS), and bladder diary (urinary frequency in daytime and nighttime, frequency of urinary incontinence and urgency) were evaluated before and 4 weeks after treatment with naftopidil at 75 mg/day. Results: Total IPSS and QOL index were significantly decreased after treatment. Total OABSS tended to decrease after treatment, with significant improvements in the “urgency” parameter. From the bladder diary, urinary frequency in daytime and nighttime and frequency of urgency were significantly decreased after treatment. Total IPSS and QOL index in patients with previous treatment were significantly improved after treatment, with significant improvements in the “incomplete emptying,”“poor flow” and “nocturia” parameters of IPSS. One case with a mild adverse effect of dizziness was encountered. Conclusion: These results suggest that administration of naftopidil at 75 mg/day was safe and effective for patients with BPH, regardless of the presence of previous treatment. This study indicates the feasibility of naftopidil at 75 mg/day as a first‐line treatment for men with BPH, or a second‐line treatment in cases with symptoms of incomplete emptying, poor flow and nocturia.     

Effects of α1‐Blockers for Lower Urinary Tract Symptoms and Sleep Disorders in Patients with Benign Prostatic Hyperplasia

Objectives: We evaluated the association of lower urinary tract symptoms (LUTS) and sleep disorders (SD) in patients with benign prostatic hyperplasia (BPH). We also examined improvement of SD following the α1‐blocker therapy for LUTS. Methods: Sixty‐eight male patients were enrolled in the study, consisting of 38 cases with LUTS and BPH (BPH group), and 30 men without significant LUTS or BPH (non‐BPH group). The degree of LUTS and SD was evaluated by the International Prostate Symptom Score and the Pittsburg Sleep Quality Index (PSQI), respectively. The patients of BPH group then were treated with α1‐blocker for 4 weeks, and were re‐examined by all the questionnaires to evaluate the therapeutic efficacies. Results: The correlation analyses showed a significant association of LUTS with SD in BPH group (r = 0.4995, P = 0.0068). Twenty cases (52.6%) in BPH group showed 5.5 or more PSQI scores. Following 4 weeks of α1‐blocker administration, the average PSQI decreased significantly from 6.3 to 4.8 points (P < 0.001). Significant improvement was observed in domains of “sleep quality” and “sleep disturbances” among PSQI (P = 0.0215 and 0.0391, respectively). Moreover, significant association between α1‐blocker induced improvements of nocturia and SD was identified in patients with 5.5 or more PSQI score at baseline (r = 0.445, P = 0.0334). Conclusion: These results suggested that SD is associated with LUTS among BPH patients and therapeutic effects of α1‐blockers on LUTS lead to improvements of SD.     

Conversion to Silodosin in Men on Conventional α1‐Blockers for Symptomatic Benign Prostatic Hyperplasia

Objectives: α₁‐blockers have commonly been used as first‐line medical therapy for symptomatic benign prostatic hyperplasia (BPH). Recently, a highly selective α_1A‐adrenoceptor antagonist, silodosin, was developed in Japan. We examined the efficacy and safety of conversion from conventional α₁‐blockers to silodosin in men with BPH. Methods: Conversion to silodosin was proposed to consecutive patients on conventional α₁‐blockers for symptomatic BPH for at least 6 months. The effects of conversion were examined by the International Prostate Symptom Score, quality of life index, overactive bladder symptom score, peak flow rate, residual urine volume, and adverse events at 12 weeks. The efficacy of silodosin was also evaluated by patients' impression. Results: Eighty‐one men underwent conversion, for the most part because of dissatisfaction with the efficacy of their current treatment in improving nocturia or weak stream. The International Prostate Symptom Score total score significantly improved from 12.7 ± 5.9 at baseline to 10.6 ± 5.4 at 4 weeks (P < 0.001) and 10.9 ± 5.8 at 12 weeks (P < 0.01). The progress was mostly due to improvement in voiding symptoms, although reduction of storage symptoms was also significant. The quality of life index also significantly decreased with conversion to silodosin. Efficacy as judged by patients' impression was 76% (37/49) at 12 weeks of treatment. None of the overactive bladder symptom score, peak flow rate, and residual urine volume exhibited significant change. No serious adverse events were observed during the study period. Conclusion: Conversion to silodosin may be beneficial in men who are dissatisfied with conventional α₁‐blockers for BPH, and be particularly useful in improving voiding symptoms.     

Clinical Efficacy of α 1‐blocker Naftopidil in Patients with Overactive Bladder Associated with Benign Prostatic Hyperplasia

Objectives: We evaluated the clinical efficacy of α1‐blocker naftopidil in patients with overactive bladder associated with benign prostatic hyperplasia (BPH). Methods: A total of 29 patients (range 50–83 years of age, mean 66.7 years) who had severe storage symptoms associated with BPH were studied. The inclusion criteria were (i) a total of seven or more points in storage symptom scores (frequency, urgency and nocturia) of the International Prostate Symptom Score (I‐PSS) and (ii) a quality of life (QOL) index of two or more. Subjective (I‐PSS and QOL index) and objective (uroflowmetry, post‐void residual and filling cystometry) parameters were evaluated before and 3 months after treatment with naftopidil. Results: Total I‐PSS significantly decreased after treatment, with significant improvement of both storage and voiding symptoms scores and QOL index. Improvement of QOL index was most correlated with the reduction of storage symptoms scores. In nine patients who had involuntary detrusor contractions during filling cystometry before treatment, bladder volume at first desire to void significantly increased (from a mean of 174 to 260 mL), and involuntary detrusor contractions disappeared in three patients after treatment. Conclusion: Naftopidil improves not only voiding symptoms, but also storage symptoms associated with BPH, and is effective for improving bladder storage function in patients with detrusor overactivity.     

经尿道柱状水囊前列腺扩开术治疗高危老年前列腺增生患者的分析

目的研究经尿道柱状水囊前列腺扩开术(TUDP)治疗老年良性前列腺增生(BPH)高危患者的临床疗效及安全性。方法入选2015年1月至2016年10月在眉山市中医医院外三科拟实施手术治疗的老年BPH高危患者100例,随机数字表法分为经尿道前列腺等离子双极电切术(BP-TURP)组和TUDP组,每组50例,研究两种术式用于老年BPH高危患者的临床疗效和安全性。结果相比BP-TURP组,TUDP组患者的手术时间、手术出血量、尿管留置时间、术后住院时间缩短,差异有统计学意义(P0.05)。两组患者治疗前、治疗3个月后的国际前列腺症状评分(IPSS)、残余尿量(RUV)、生活质量评分(QOL)和最大尿流率(Qmax)差异无统计学意义(P0.05)。两组患者的血尿、尿道狭窄、暂时性尿失禁等并发症的发生差异无统计学意义(P0.05)。结论 TUDP具有手术创伤小、术后恢复快的优势,可用于老年BPH高危患者。     

5alpha-reductase inhibitors in benign prostatic hyperplasia and prostate cancer risk reduction

Androgens play an essential role in prostatic development and function, but are also involved in prostate disease pathogenesis. The primary prostatic androgen, dihydrotestosterone (DHT), is synthesized from testosterone by 5alpha-reductase types 1 and 2. Inhibition of the 5alpha-reductase isoenzymes therefore has potential therapeutic benefit in prostate disease. The two currently approved 5alpha-reductase inhibitors (5ARIs), finasteride and dutasteride, have demonstrated long-term efficacy and safety in the treatment of benign prostatic hyperplasia. Finasteride, a type-2 5ARI, has also been studied for its ability to reduce the incidence of biopsy-detectable prostate cancer in the Prostate Cancer Prevention Trial. Treatment with dutasteride, a dual 5ARI, has been shown to result in a greater degree and consistency of DHT suppression compared with finasteride. Two large-scale studies of dutasteride are currently investigating the role of near-maximal DHT suppression in the settings of prostate cancer risk reduction and expectant management of localized prostate cancer.     

Clinical symptoms and pedigree analysis in two families with benign familial persistently elevated α‐fetoprotein

OBJECTIVE : To evaluate the nature of persistently elevated α‐fetoprotein (AFP) in a family and the importance of correct recognition and diagnosis of familial AFP elevation. METHODS : In 1984 and 1997, a series of AFP radio‐immunoassays from two families with persistently elevated AFP were investigated and the family pedigrees were subanalyzed. RESULTS : Of the 29 members in the two families, 15 were examined. The AFP level of 10 people was persistently elevated, two of these had been misdiagnosed with primary hepatocellular carcinoma. CONCLUSIONS : Familial elevation of AFP is benign in nature. It should be kept in mind during mass surveys of AFP.     

A1蛋白与前列腺特异性抗原在前列腺癌与前列腺增生疾病中联合检测的意义

目的选取50~70岁之间的前列腺增生、前列腺癌患者和健康对照者,对其血液中A1蛋白的表达与PSA的表达水平进行比较分析,为前列腺增生和前列腺癌的临床鉴别诊断提供依据。方法采用电化学发光仪检测PSA浓度,采用反转录酶-聚合酶链锁反应(RT-PCR)技术和蛋白免疫印迹法(western-blot)检测20例前列腺癌患者、20例前列腺增生患者和20例正常者新鲜前列腺组织中A1 mRNA和蛋白的表达情况,探讨A1蛋白表达与前列腺增生和前列腺癌中PSA表达水平的关系。结果 RT-PCR与westem-blot检测结果一致,A1蛋白在前列腺增生组织和前列腺癌组织中均有阳性表达,前列腺癌组织中A1蛋白阳性表达明显高于前列腺增生组织,有显著性差异(P0.01)。A1蛋白表达的阳性率与PSA的浓度相关。结论 A1蛋白阳性表达程度与前列腺病变程度相关,A1蛋白在细胞凋亡调节中起着重要的作用,其过度表达在前列腺癌的发生、发展中扮演着重要的角色。联合检测A1和PSA的表达变化对判断前列腺癌的生物学行为有参考价值。     

Peripheral T cell receptors αβ and γδ in patients with Hodgkin's lymphoma

Antigen recognition by T cells is determined by an antigen specific T cell receptor (TCR). Two heterodimeric TCR structures associated with CD3 have been defined: TCR αβ and TCR γδ. TCR αβ and its function are well described but the role of TCR γδ in normal and lymphoproliferative disorders is not well established. In newly diagnosed or relapsed/refractory Hodgkin's disease (HD), a disease associated with defective T cell functions and increased sIL-2R, We determined levels of seven TCR αβ variable regions [βV5(a), βV5(b), βV6(a), βV12(a), αβV(a), αV2(a)] and TCR γδ by using monoclonal antibodies (MCA). TCR γδ levels did not show any difference, but several variable regions of the TCR αβ differed when groups are compared with each other and the control group.     

Early Efficacy of an α1 Adrenoceptor Antagonist,Naftopidil, against Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia

Objectives: The present study investigated the early efficacy of naftopidil against lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). Methods: Subjects comprised patients with LUTS suggestive of BPH who were followed prospectively for 8 weeks. Inclusion criteria were: (i) international prostate symptom score (IPSS) ≥8; (ii) no previous treatment for BPH; and (iii) eligibility for naftopidil monotherapy. IPSS and quality of life index were evaluated, and uroflowmetry and residual urine volume were determined optionally. In the previous study, patients who demonstrated a decrease in total American Urological Association symptom score of 25% or more from baseline were considered responders. The ratio of onset of efficacy of naftopidil was calculated by the ratio of the number of responder in each group with the starting dose. Results: Naftopidil efficacy was analyzed for 243 patients. Significant improvement of IPSS was achieved within 1–3 days after medication. Starting dosage and average dosage were identified as factors associated with the period until onset of naftopidil efficacy. Onset of efficacy was significantly quicker with a starting dosage of 50 mg/day as compared with 25 mg/day (P = 0.0047). However, ratios of onset of efficacy with starting dosages of 25, 50 and 75 mg/day were 77.9, 76.7 and 85.7%, respectively, showing no significant difference between groups (P = 0.7463). Duration to onset of efficacy with naftopidil dosage ≥50 mg/day was 11.2 days, significantly early compared to dosage <50 mg/day. Incidence of adverse effect was 3.8%. Conclusion: Naftopidil showed early effects against LUTS suggestive of BPH within a few days.     

经尿道等离子前列腺剜除术治疗前列腺增生症的疗效分析

目的探讨经尿道前列腺等离子剜除术(TUPK-EP)治疗巨大良性前列腺增生(BPH)的疗效。方法入选2013年1月至2015年12月广州市增城区新塘医院泌尿外科收治的巨大BPH患者65例,依据治疗方法分为两组:经尿道前列腺等离子电切术(TUPK-RP)组(n=32)和TUPK-EP组(n=33)。对比两组患者的疗效、最大尿流量(Q_(max))及残余尿量(PVR)等临床指标。结果与TUPK-RP组相比,TUPK-EP组患者的手术时间显著缩短、冲洗液用量和术中出血量显著减少、Hb下降值亦显著降低,而腺体切除量显著增加,差异均具有统计学意义(P0.05)。术后3个月的复查结果显示,与TUPK-RP组相比,TUPK-EP组的Q_(max)显著增高、PVR显著降低,差异均具有统计学意义(P0.05)。结论在治疗巨大BPH时,与TUPK-RP比较,TUPK-EP的优势更明显,能更完全地切除腺体,缩短手术时间,降低术中出血量,值得临床推广应用。     

Role of α1‐blockers in the current management of hypertension

There is emerging evidence that α1‐blockers can be safely used in the treatment of hypertension. These drugs can be used in almost all hypertensive patients for blood pressure control. However, there are several special indications. Benign prostatic hyperplasia is a compelling indication of α1‐blockers, because of the dual treatment effect on both high blood pressure and lower urinary tract symptoms. Many patients with resistant hypertension would require α1‐blockers as add‐on therapy. Primary aldosteronism screen is a rapidly increasing clinical demand in the management of hypertension, where α1‐blockers are useful for blood pressure control in the preparation for the measurement of plasma aldosterone and renin. Nonetheless, α1‐blockers have to be used under several considerations. Among the currently available agents, only long‐acting α1‐blockers, such as doxazosin gastrointestinal therapeutic system 4–8 mg daily and terazosin 2–4 mg daily, should be chosen. Orthostatic hypotension is a concern with the use of α1‐blockers especially in the elderly, and requires careful initial bedtime dosing and avoiding overdosing. Fluid retention is potentially also a concern, which may be overcome by combining an α1‐blocker with a diuretic.