他达拉非治疗勃起功能障碍的安全性研究

环磷酸鸟苷(cGMP)信号通路介导的一氧化氮平滑肌舒张效应是正常勃起功能的必要条件。这个信号通路的下调能引起勃起功能障碍(erectile dysfunction,ED)的许多病理生理状况,并导致一些慢性疾病的发生,比如高血压和2型糖尿病。因此,选择性抑制cGMP降解酶能够促进性刺激的勃起反应。最近,一种新型的5-磷酸二酯酶(PDE-5)抑制剂他达拉非问世,该药有很长的半衰期。本文对其治疗ED的安全性研究进行了综述。     

勃起功能障碍（ED）的联合疗法

二十世纪九十年代末二十一世纪初,口服PDE5抑制剂（PDE5Is）的引入在很大程度上革新了性医学领域。目前PDE5I已经成为勃起功能障碍（ED）的首选单一疗法。然而,对一些复杂型ED患者来说,PDE5I单一疗法的疗效还不尽人意。目前越来越多不易治疗的ED病例开始采用联合疗法治疗,但还缺少对当前使用的联合疗法的严格评估。基于此,本综述在Pubmed和Cochrane Library数据库中进行了全面的文献检索．主要检索对象是1990年1月到2010年12月间研究PDE5I单一治疗失败后接受联合疗法的所有相关综述、随机对照试验、队列研究和回顾性研究。同时还对检索所得文献的参考文献进行了人工筛选,获得了其它一些相关的文献资料。目前发表的联合疗法主要包括PDE5I加真空吸引器（VED）、尿道给药、阴茎注射（ICI）、雄激素补充疗法、α-阻断剂,还有其它一些联合疗法。本综述发现,有些联合疗法的初步试验结果是有效的。然而,进行治疗时还是要谨慎,因为近十年来发表的大部分联合疗法相关文章的研究方法有很多问题,比如研究偏见和样本量小等。尽管如此,目前的研究结果还是在为将来复杂型ED的治疗研究方面奠定了坚实的基础。     

Comparison of efficacy and safety of daily oral L-arginine and PDE5Is alone or combination in treating erectile dysfunction: A systematic review and meta-analysis of randomised controlled trials

The meta-analysis was performed to assess the efficacy and safety of daily oral L-arginine and phosphodiesterase type 5 inhibitors (PDE5Is) alone or combination in treating patients with erectile dysfunction (ED). We performed a search of randomised controlled trials in the following databases: PubMed, EMBASE and Cochrane Library databases. Four articles including 373 patients were studied. Erectile functions were significantly improved in three therapy groups compared with baseline. Patients who received the combination of L-arginine and PDE5Is showed significant improvement compared to those treated with L-arginine and PDE5Is alone, as assessed by sexual function index (p <0.00001 and p =0.005, respectively) and total testosterone (p <0.00001 and p =0.0007, respectively). Furthermore, patients who treated with PDE5Is alone exhibited the better efficacy than those treated with L-arginine alone in respects of sexual function index (p <0.00001) and total testosterone (p =0.0001). However, the combination of L-arginine and PDE5Is had no obvious difference relative to PDE5Is alone in terms of various adverse events (AEs). Conclusively, compared with monotherapy, the combination of L-arginine and PDE5Is showed a greater improvement of sexual function and total testosterone, and did not significantly increase the AEs. Besides, PDE5Is alone revealed a better effect than those treated with L-arginine alone for patients with ED.     

Sildenafil citrate, a selective phosphodiesterase type 5 inhibitor: urologic and cardiovascular implications

Erectile dysfunction (ED) occurs in varying degrees in an estimated 20 to 30 million American men and is associated with adverse effects on quality of life; particularly personal well-being, family and social interrelationships. Research into ED has focused primarily on the physiologic mechanisms of corpus cavernosum smooth muscle relaxation, and penile erection as the end result of smooth muscle relaxation. These processes are mediated by cholinergic, nonadrenergic, noncholinergic (NANC, e.g., nitric oxide), vasoactive intestinal peptide (VIP), and potentially calcitonin gene-related peptide (CGRP) containing nerves. Release of nitric oxide following sexual stimulation from non-adrenergic, non cholinergic nerves and vascular endothelium activates guanylyl cyclase and induces intracellular cGMP synthesis. In turn, cGMP results in lowering intracellular concentrations, inhibits contractility of the penile smooth muscle, and induces an erectile response. Phosphodiesterase type 5 (PDE 5) is the predominant enzyme responsible for cGMP hydrolysis in trabecular smooth muscle. Activation of PDE 5 terminates NO-induced, cGMP-mediated smooth muscle relaxation, and subsequent penile flaccidity. Sildenafil citrate is a potent PDE type 5 reversible and selective inhibitor which blocks cGMP hydrolysis effectively. FDA approval of sildenafil citrate as the first oral agent for ED in males has resulted in significant interest. We discuss the clinical and pharmacologic properties of sildenafil citrate as well as the urologic and cardiac implications.     

Safety and efficacy of vardenafil in patients with erectile dysfunction: Result of a bridging study in Japan

AIM: Vardenafil is a selective and highly potent phosphodiesterase type 5 (PDE5) inhibitor for the treatment of erectile dysfunction (ED), with improved selectivity for PDE5 and demonstrated efficacy for improving sexual function in men with ED. The current study investigated the safety and efficacy of this new PDE5 inhibitor in Japanese men with ED. METHODS: This was a prospective, double blind, randomized clinical trial designed to evaluate the efficacy and safety of vardenafil. Following a 4-week treatment-free observation period, 283 eligible patients were randomized to 12 weeks treatment with vardenafil 5 mg, 10 mg, 20 mg, or placebo. Primary efficacy responses were assessed using the scores of Q3 and Q4 of the international index of erectile function (IIEF). RESULTS: All three vardenafil doses showed significantly better improvement than the placebo group in Q3 and Q4 scores of the IIEF questionnaire, either at 12 weeks or at the 'last observation carried forward' (LOCF, P < 0.0001). Q3 scores were improved to 4.06 with vardenafil 5 mg, 4.53 with vardenafil 10 mg, and 4.64 with vardenafil 20 mg, versus 3.17 with placebo. Comparable scores for Q4 were 3.47, 4.15 and 4.31 versus 2.31 for placebo. Up to 86% of patients achieved improved erections as assessed by the global assessment question (GAQ). Reported adverse event rates were 35.3%, 45.3% and 54.5% with vardenafil 5 mg, 10 mg and 20 mg, respectively, versus 21.1% in the placebo group. No serious adverse drug reactions were reported. The most common treatment-emergent adverse events were transient headache, flushing and rhinitis, which were mostly mild. CONCLUSION: Vardenafil is an effective and well-tolerated treatment for ED and provides improvement in key indices of erectile function among Japanese men with ED. The results of our trial show that up to nearly 90% of patients achieve improved erections with the administration of vardenafil.     

Erectile dysfunction, discrepancy between high prevalence and low utilization of treatment options: results from the 'Cottbus Survey' with 10 000 men

OBJECTIVE: To investigate the age-stratified prevalence of erectile dysfunction (ED) and its comorbidities, and to assess the population's knowledge, utilization, and general attitude towards the treatment for ED. SUBJECTS AND METHODS: In all, 10 000 men received a 35-item questionnaire including the International Index of Erectile Function (IIEF) and sociodemographic questions regarding life style, comorbidities, quality of sexual life and knowledge or experience of ED therapy. In all, 3124 responses were included (31.2%), 2499 men lived in well established partnerships and were assessed as the basic study group. RESULTS: In the entire population the prevalence rate of ED was 40.1%. However, although known, medical treatment for ED is used only by a minority of affected men. The prevalence of ED was independently associated with age, peripheral arterial occlusive disease, hypertension, ischaemic heart disease, diabetes mellitus, and liver diseases. Correlations between sexual quality of life (QoL) and ED were statistically significant (P < 0.01) and moderate to strong (absolute values: Spearman's rho 0.35-0.76). Although 96% of the study population knew at least one phosphodiesterase type 5 (PDE5) inhibitor by name, only 53% considered taking the medication and only 9% of the men with ED had had experience with available PDE5 inhibitors. CONCLUSIONS: The sexual QoL was significantly reduced by ED. Despite high levels of awareness and general acceptance of oral medication for ED, experience with PDE5 inhibitors was low. Further investigation is required to evaluate the general impact of ED on sexual QoL and the need or wish for treatment.     

Molecular pharmacotherapeutic targeting of PDE5 for preservation of penile health

The molecular science of erection physiology has established that phosphodiesterase 5 (PDE5) serves an important biological role in the penis. Current research in the field has revealed this molecular effector to be relevant for penile erection, controlling the erectile response by degrading the second messenger product of the erection mediatory nitric oxide (NO) signaling pathway, 3', 5'-cyclic guanosine monophosphate. Accordingly, PDE5 has been targeted for sexual medicine purposes, and orally administered PDE5 inhibitors such as sildenafil, tadalafil, and vardenafil comprise a foremost intervention for erectile dysfunction (ED). New investigation of PDE5 regulation in the penis has suggested alternative roles for the enzyme and new therapeutic opportunities involving its molecular interactions. In particular, PDE5 function is altered under derangements of androgen deficiency, decreased NO bioactivity, and oxidative stress-associated inflammatory changes, thus contributing to an assortment of erectile disorders including hypogonadism-associated ED, recurrent ischemic priapism, penile vasculopathy, and penile fibrosis. This review provides a critical examination of the multifaceted role of the PDE5 regulatory system in the penis and its relevance for applying existing and emerging therapeutic strategies for erectile disorders.     

西地那非的起效时间和维持时间的研究进展

西地那非是一种特异性环磷酸鸟苷(cGMP)磷酸二酯酶5(PDE5)抑制剂,通过抑制第二信使cGMP的代谢,促进海绵体动脉平滑肌舒张,进而改善勃起功能障碍(ED)症状的口服药物。本文对西地那非的药代动力学、起效时间和作用维持时间等不同方面的研究进展作一综述。     

伐地那非在难治性ED人群中的应用

本文回顾了高选择性口服磷酸二酯酶5(PDE5)抑制剂伐地那非在各种难治性ED人群的疗效和安全性。结果表明,伐地那非对于合并糖尿病、抑郁症、前列腺切除术后、外伤性脊髓损伤性、以及西地那非治疗无效的ED患者安全有效,为这些难治性ED人群提供了一种合理的治疗选择。     

Tadalafil and vardenafil vs sildenafil: a review of patient‐preference studies

The immediate objective of phosphodiesterase type 5 (PDE5) inhibitor treatment is to restore the ability of a man to achieve and/or maintain an erection adequate for sexual intercourse. As erectile dysfunction (ED) generally develops in the second half of life, the ultimate objective generally is not procreation, but quality of sexual life. Indeed, ED is known to impair quality of life considerably; two‐thirds of men report that ED has impaired their self‐esteem and nearly a third claim that it has damaged the relationship with their partner. It follows that the therapeutic success of PDE5 inhibition has an important subjective component, which is compounded by the subjective nature and complexity of sexual life in humans. This makes it very difficult for physicians to be certain that they have selected the optimal therapy for a couple, even after a thorough evaluation. The 2007 European Association of Urology Guidelines stress the importance of educating the patient and claim that ‘the patient will choose the final drug after his own experience’. However, PDE5 inhibitors are typically used twice a week, so a patient would have to spend ≈3 months trying the various compounds and dosages to achieve adequate exposure to all three PDE5 inhibitors; this would seem an unrealistic strategy in normal clinical practice. The acknowledgement that the patient has an important role in therapeutic decisions for ED has fuelled interest in the concept of patient preference. It has been established that patient preference depends on three factors, i.e. personal characteristics, e.g. age, duration of ED, frequency and dynamics of sexual relations, and the characteristics of their partners, e.g. age, menopausal status and level of interest in sexual activity and medication profile. Medication features of interest include efficacy in terms of quality of erection, consistency of effects, rapid onset of action, long duration of action, side‐effect profile and route of administration; drug costs must also be considered if the medicinal product is not reimbursed.     

Recent insights into androgen action on the anatomical and physiological substrate of penile erection

Erectile response is centrally and peripherally regulated by androgens.The original insights into the mechanismsof action of androgens were that androgens particularly exert effects on libido and that erections in response to eroticstimuli were relatively androgen-independent.It was shown that sexual functions in men required androgen levels atthe low end of reference values of testosterone.So it seemed that testosterone was not useful treatment for men witherectile difficulties,particularly following the advent of the phosphodiesterase type 5(PDE5)inhibitors.However,approximately 50% of those treated with PDE5 inhibitors discontinue their treatment.A number of recent develop-ments shed new light on testosterone treatment of erectile dysfunction(ED)in aging men.(1)A recent insight is that,in contrast to younger men,elderly men might require higher levels of testosterone for normal sexual functioning.(2)Several studies have indicated that PDE5 inhibitors are not always sufficient to restore erectile potency in men,andthat testosterone improves the therapeutical response to PDE5 inhibitors considerably.(3)There is growing insightthat testosterone has profound effects on tissues of the penis involved in the mechanism of erection and that testoster-one deficiency impairs the anatomical and physiological substrate of erectile capacity,reversible upon androgenreplacement.The synthesis of PDE5 is upregulated by androgens,and the arterial inflow into the penis is improved bygiving androgen.The above invites a re-examination of the merits of giving testosterone to aging men with ED.Thebeneficial effects of PDE5 inhibitors may only be optimally expressed in a eugonadal environment.(Asian J Androl2006 Jan;8:3-9)     

Treating erectile dysfunction by endothelial rehabilitation with phosphodiesterase 5 inhibitors

A large body of evidence has accumulated demonstrating that a common pathway in conditions such as hypertension, atherosclerosis, hypercholesterolemia, diabetes mellitus, and erectile dysfunction (ED) is endothelial dysfunction. Although a complete pharmacological cure for ED is currently unavailable, the phosphodiesterase 5 (PDE5) inhibitors sildenafil, vardenafil, and tadalafil are efficacious oral therapy for ED. Results from recent studies suggest that regular treatment with a PDE5 inhibitor may lead to enhanced erectile function (EF) beyond that observed with on-demand usage, possibly through improvement of endothelial function. Such an effect may be viewed as rehabilitation of damaged erectile tissue. The present review focuses on several recent studies which provide evidence for the beneficial effect of regular PDE5 inhibitor administration on the improvement of EF by rehabilitation of vascular endothelium.     

Critical analysis of the relationship between sexual dysfunctions and lower urinary tract symptoms due to benign prostatic hyperplasia

Context

This review focuses on the relationship among sexual dysfunction (SD), lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH), and related therapies.

Objective

We reviewed the current literature to provide an overview of current data regarding epidemiology and pathophysiology of SD and LUTS. Moreover, we analysed the impact of currently available therapies of LUTS/BPH on both erectile dysfunction (ED) and ejaculatory dysfunction and the effect of phosphodiesterase type 5 inhibitors (PDE5-Is) in patients with ED and LUTS.

Evidence acquisition

We conducted a Medline search to identify original articles, reviews, editorials, and international scientific congress abstracts by combining the following terms: benign prostatic hyperplasia, lower urinary tract symptoms, sexual dysfunction, erectile dysfunction, and ejaculatory dysfunction.

Evidence synthesis

We conducted a comprehensive analysis of more relevant general population-based and BPH/LUTS or SD clinic-based trials and evaluated the common pathophysiologic mechanisms related to both conditions. In a further step, the overall impact of current BPH/LUTS therapies on sexual life, including phytotherapies, novel drugs, and surgical procedures, was scrutinized. Finally, the usefulness of PDE5-Is in LUTS/BPH was critically analysed, including preclinical and clinical research data as well as possible mechanisms of action that may contribute to the efficacy of PDE5-Is with LUTS/BPH.

Conclusions

Community-based and clinical data demonstrate a strong and consistent association between LUTS and ED, suggesting that elderly men with LUTS should be evaluated for SD and vice versa. Pathophysiologic hypotheses regarding common basics of LUTS and SD as discussed in the literature are (1) alteration of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway, (2) enhancement of RhoA-Rho-kinase (ROCK) contractile signalling, (3) autonomic adrenergic hyperactivity, and (4) pelvic atherosclerosis. The most important sexual adverse effects of medical therapies are ejaculation disorders after the use of some α-blockers and sexual desire impairment, ED, and ejaculatory disorders after the use of α-reductase inhibitors. Minimally invasive, conventional, and innovative surgical treatments for BPH may induce both retrograde ejaculation and ED. PDE5-Is have demonstrated significant improvements in both LUTS and ED in men with BPH; combination therapy with PDE5-Is and α1-adrenergic blockers seems superior to PDE5-I monotherapy.     

Chronic low dosing of phosphodiesterase type 5 inhibitor for erectile dysfunction

Oral phosphodiesterase type 5 (PDE5) inhibitors have provided non-invasive, effective, and well-tolerated treatments for patients with erectile dysfunction (ED). However, many patients with ED are unresponsive to 'on-demand' PDE5 inhibitors. In addition, the lack of spontaneity and naturalness of the on-demand regimen could be a reason for decreased compliance with PDE5 inhibitors. Recently, tadalafil and udenafil were approved for low-dose daily administration for the treatment of ED. Since the introduction of the concept of daily administration of PDE5 inhibitors, several reports have supported the potential benefits of this therapy for disease modification, improvement of the treatment response in difficult-to-treat populations, spontaneity, and safety, although further research is needed to better address these hypotheses. In this article, we reviewed the daily administration of PDE5 inhibitors in terms of pharmacokinetics, safety, efficacy, and distinct features.     

Effect of phosphodiesterase type 5 inhibitors on prostate cancer risk and biochemical recurrence after prostate cancer treatment: A systematic review and meta‐analysis

Recent studies have examined the impact of phosphodiesterase type 5 inhibitors (PDE5‐Is) use on the risk of prostate cancer, and biochemical recurrence (BCR) in prostate cancer patients, but the results were inconsistent. A meta‐analysis was conducted to assess the associations with all published studies. Databases (PubMed, Web of Science and MEDLINE) were retrieved to identify relevant studies which explored the impact of PDE5‐Is use on the risk of prostate cancer, and BCR in prostate cancer patients. The summary results along with 95% confidence intervals (CIs) were calculated. Nine articles were eligible for the inclusion criteria. The pooled analysis showed that PDE5‐Is use was not related to the increased risk of prostate cancer (odds ratio (OR), 0.71; 95% CI, 0.40–1.29). Moreover, PDE5‐Is use was not linked to BCR risk in prostate cancer patients with erectile dysfunction (ED) following radical prostatectomy or radiation therapy (relative risk (RR), 1.09; 95% CI, 0.89–1.34). The heterogeneity test suggested moderate heterogeneity across studies. PDE5‐Is use does not influence the risk of prostate cancer, and BCR in prostate cancer patients. More well‐designed studies are warranted to confirm the findings of our analyses.     

伐地那非治疗勃起功能障碍的有效性和安全性

伐地那非是一种有效的、高选择性的口服磷酸二酯酶 (PDE5 )抑制剂。它对各种病因、各种程度、各年龄段的男性勃起功能障碍 (ED)患者均有良好疗效 ,可显著改善勃起功能。该药口服后最快 10min即可起效 ,长期使用仍能保持疗效 ,不良反应少 ,耐受性好。因此 ,伐地那非是治疗男性ED患者的有效、安全的药物。     

Centrally acting mechanisms for the treatment of male sexual dysfunction

The development of pharmacologic therapy for erectile dysfunction (ED) has been possible because of incremental growth in our understanding of the physiology of normal erections and the complex pathophysiology of ED. Although the oral phosphodiesterase type 5 (PDE5) inhibitors have provided safe, effective treatment of ED for some men, a large proportion of men who have ED do not respond to PDE5 inhibitors or become less responsive or less satisfied as the duration of therapy increases. Also, men who are receiving organic nitrates and nitrates, such as amyl nitrate, cannot take PDE5 inhibitors because of nitrate interactions. The current options for treatment beyond PDE5 inhibitors are invasive, unappealing to some patients, and sometimes ineffective. The search for other options by which ED can be treated has branched out and now encompasses centrally acting mechanisms that control erectile function. Drugs available in Europe include apomorphine. This article focuses on the mechanism of centrally acting agents and reviews clinical data on potential new centrally acting drugs for men who have ED.     

全面康复:勃起功能障碍治疗的新目标

5型磷酸二酯酶(PDE5)抑制剂有效改善勃起功能障碍(ED)患者的勃起功能。枸橼酸西地那非的应用范围不断扩展,肺动脉高压已成为新的适应证。临床研究发现,西地那非能改善多种血管性疾病患者的内皮功能。在ED领域的研究进展包括:动物实验发现,西地那非可以改善海绵体内皮功能,增强磷酸化内皮型一氧化氮合酶(eNOS)蛋白表达,逆转缺血或缺氧导致的海绵体内压(ICP)降低。临床研究证实,西地那非可以使50%以上ED患者阴茎勃起恢复到最充分的硬度(4级勃起);使50%以上保留神经的根治性前列腺切除术后患者勃起功能康复,自发产生足以性交的勃起;使ED患者的自尊心、自信心和性关系满意度等社会心理功能恢复正常。从勃起功能到社会心理功能的全面恢复可能成为今后ED治疗的新目标。