Erektile Dysfunktion

Erectile dysfunction (ED) tends to be associated with other diseases, the common basis of which is endothelial dysfunction. ED is also frequently combined with LUTS and the common basis for both conditions seems to be elevation of Rho-kinase activity and decrease of NO concentration. Because all three PDE 5 inhibitors sildenafil, tadalafil, and vardenafil have a common mode of action, i.e., inhibition of PDE 5, they are not different in terms of their efficacy and safety profile except for color vision disturbances which are more common after sildenafil and back pain/myalgia more often observed after tadalafil. The main differentiating characteristics among the three PDE 5 inhibitors are their pharmacokinetics. These are ultimately responsible for the observation that in head-to-head comparative trials depending on the respective study design the overwhelming majority of the patients opted either for tadalafil as the longest acting PDE 5 inhibitor (36 h) or for vardenafil as a relatively rapidly acting drug.All published studies so far have shown that in terms of the cardiovascular risk profile (myocardial infarction rate) all three PDE 5 inhibitors performed better than placebo although the results were not statistically significant. Without any exception it applies to all three PDE 5 inhibitors that they are absolutely contraindicated in patients taking nitrate- or molsidomine-containing medications and that they may interact in particular with non-uroselective alpha-adrenoceptor blockers. This is why their simultaneous application with PDE 5 inhibitors has to be avoided.In the near future chronic (daily) application of a PDE 5 inhibitor may show advantages, at least in those 50-60% of all patients in whom there is a high likelihood of endothelial dysfunction due to the diagnostic (penile duplex Doppler) outcome. Possible new developments in the management of ED with a time frame of 5-8 years until their market approval are guanylate cyclase activators, Rho-kinase inhibitors, melanocortin receptor agonists, gene therapy, and tissue engineering.     

Combining testosterone and PDE5 inhibitors in erectile dysfunction: basic rationale and clinical evidences

INTRODUCTION: Erectile dysfunction (ED) and decline of testosterone levels are frequently observed with age and also in illnesses with a common basis of endothelial damage. OBJECTIVES: To review molecular mechanisms underlying androgen action upon its receptor and phosphodiesterase type 5 (PDE5) expression and regulation by testosterone in cavernous tissue and their clinical implication in the treatment of ED refractory to PDE5 inhibitors (PDE5-Is). METHODS: From January 2003 to May 2006 [corrected] we performed an extensive, unsystematic MEDLINE literature search reviewing relevant data on basic and clinical studies regarding the efficacy of combination therapies. RESULTS: Most trials using testosterone alone for treatment of ED in hypogonadal men suffer from methodologic problems and report inconsistent results, but overall the trials suggest that testosterone is superior to placebo. Orally effective PDE5-Is, such as sildenafil, tadalafil, or vardenafil, may be ineffective depending on the demonstration of testosterone regulation of PDE5 expression in human corpus cavernous, and their efficacy may be enhanced by testosterone adjunction whenever necessary. CONCLUSIONS: Screening for hypogonadism in all men with ED is necessary to identify men with severe hypogonadism and some cases of mild to moderate hypogonadism, who may benefit from testosterone treatment. Identification of threshold values for testosterone supplementation to appropriately benefit from PDE5-Is failure may improve clinical management of unresponsive patients with minimization of unwanted effects.     

同期内使用3种PDE5抑制剂治疗ED的经验

目的:观察与比较同期内使用3种PDE5抑制剂治疗ED患者的疗效,满意情况和不良反应。分析影响患者疗效、接受度、倾向性的因素。方法:11个月在门诊应用3种PDE5抑制剂治疗ED患者331例。使用西地那非134例,他达拉非88例,及伐地那非109例。医师详细指导药物的应用,注意事项,观察的内容等,并互留电话,列表登记、随访。结果:复诊或电话随访时间,结果为:①获得良好的疗效及满意率为西地那非72例(79.12%),他达拉非52例(78.78%),伐地那非63例(81.81%)。②PDE5抑制剂单纯或交叉应用的资料分析显示:青年患者或新婚者,偏好伐地那非;③中青年患者倾向于他达拉非;中老年及较长期应用PDE5抑制剂的患者多选用西地那非。3种PDE5抑制剂用于早泄均有一定疗效。④对不能继续用此类药治疗ED的原因进行了分析,分别为:价高,不治本,效果差,耽心不良反应。结论:①同期3种PDE5抑制剂治疗ED的疗效基本相近。亦各有一些优势和特点。②3种PDE5抑制剂的安全性均好,一般、轻度不良反应相近,中度、特殊的不良反应少,严重不良反应均无发生。③PDE5抑制剂的疗效观察,目前众多的问卷、量表实际均仍以主观的感受为主。对同一个人以相同形式、相同问题、繁简一致阐述,获得的有关疗效满意情况、感受等简易回答是有可比性、可信度和实用性的。     

他达拉非治疗勃起功能障碍:卓越的36小时疗效

磷酸二酯酶5(PDE5)抑制剂是治疗勃起功能障碍(ED)的一线口服药物,与其他两种PDE5抑制剂(西地那非和伐地那非)相比,他达拉非有着起效快、服用方便和疗效显著的特点,但更为突出的是其较长的血浆清除半衰期带来的36h的持续药效,可以使患者和伴侣能更加自由地安排用药时间。患者和伴侣对他达拉非治疗的高满意度可能主要源于对用药时间顾虑的减少和对性生活时程关注度下降等社会心理收益。同时,他达拉非的安全性和耐受性良好,符合安全、有效、方便的用药原则,使其成为大多数ED患者及其伴侣偏爱的首选用药。     

Do vardenafil and tadalafil have advantages over sildenafil in the treatment of erectile dysfunction?

Erectile dysfunction (ED) affects up to 50% of men between the ages of 40 and 70 years of age. Sildenafil, vardenafil and tadalafil have all been shown to be similarly effective in the treatment of men with ED of vary etiologies, to have similar adverse effects profiles, and to improve quality-of-life by similar amounts. As these phosphodiesterase 5 (PDE5) inhibitors all increase the hypotensive effects of nitrates, they are not suitable for use in patients taking nitrates for the treatment of ischaemic heart disease. All three inhibitors must be used with caution in patients taking alpha(1)-adrenoceptors antagonists for benign prostatic hyperplasia. Although nonarteritic anterior ischaemic neuropathy has been reported in some users of the PDE5 inhibitors, there is no conclusive evidence that PDE5 inhibitors cause this rare effect. Tadalafil has a longer half-life than sildenafil or vardenafil, and a longer duration of action than sildenafil and vardenafil. Most preference studies have shown tadalafil to be preferred, but there are serious limitations to some of these studies. One approach to treatment is to give each patient a short- and long-acting agent, and for individuals to decide their preference.     

Comparative Effectiveness and Safety of Oral Phosphodiesterase Type 5 Inhibitors for Erectile Dysfunction: A Systematic Review and Network Meta-analysis

Context

Phosphodiesterase type 5 inhibitors (PDE5-Is) are currently the first-line therapy for erectile dysfunction (ED), but available studies investigating the comparative effects of different PDE5-Is are limited.

Objective

To compare the efficacy and safety of different classes of oral PDE5-Is for ED.

Evidence acquisition

A systematic search was performed in PubMed, Cochrane Library, and Embase to identify randomized controlled trials that compared different PDE5-Is or PDE5-Is with a placebo for ED. The methodological quality of included studies was appraised with the Cochrane Collaboration bias appraisal tool, and the quality of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation system.

Evidence synthesis

A total of 118 trials (31 195 individuals) were included. There was no major difference in the results between the traditional meta-analysis and the network meta-analysis. Network meta-analysis demonstrated that PDE5-Is were superior to placebo to improve erectile function. Compared with tadalafil (relative risk [RR]: 0.61; 95% confidence interval [CI], 0.33–0.90) and vardenafil (RR: 0.63; 95% CI, 0.35–0.92), avanafil was less effective on Global Assessment Questionnaire question 1. Tadalafil was more effective than vardenafil (mean difference [MD]: 1.49; 95% CI, 0.50–2.50) and udenafil (MD: −1.84; 95% CI, −3.31 to −0.33) as measured by the erectile function domain of the International Index of Erectile Function. For all efficacy outcomes, the absolute effects and the rank tests indicated that tadalafil and vardenafil were the most effective agents. After adjusting for dosage, the conclusion remained the same. Safety analysis showed there was no major difference among different agents.

Conclusions

In recommended doses, oral PDE5-Is are more effective than placebo for ED, and tadalafil seems to be the most effective agent, followed by vardenafil. PDE5-Is are generally safe and well tolerated, and there is no major difference on the safety profile.     

勃起功能障碍患者及其伴侣偏好他达拉非治疗

5型磷酸二酯酶(phosphodiesterase type 5,PDE5)抑制剂———西地那非、他达拉非和伐地那非是治疗勃起功能障碍(erectile dysfunction,ED)的一线药物。给予患者尝试所有三种药物的机会可以大大提高患者的治疗依从性,同时大多数患者会偏好使用其中一种药物。ED患者普遍偏好使用他达拉非,而且不受ED病情、病因、给药顺序、患者年龄以及剂量的影响。女性伴侣与ED患者的药物选择偏好基本一致,并影响男性伴侣的药物选择。他达拉非起效时间长达36 h,患者可以在较为自由的治疗时间窗内达到勃起,无需刻意安排服药与性活动尝试,性活动时压力明显下降,有助于改善患者的心理状态以及与伴侣的关系。女性伴侣感到回归轻松、自然的性活动,性生活质量得到了整体改善。临床医师开具PDE5抑制剂处方时应考虑患者及其伴侣的药物选择偏好。     

意大利临床实践中的PDE5抑制剂治疗模式：“勃起功能障碍观测研究”的纵向数据

“勃起功能障碍观测研究”（Erectile Dysfunction Observational Study,EDOS）是一项为期6个月的多中心前瞻性研究,研究对象包括被要求开始接受治疗或改变治疗方式的ED病人。本研究旨在分析ED的治疗模式,并比较不同治疗模式的疗效。研究对象为到医院看病并诊断需要进行ED治疗的患者。他们接受ED治疗,并在治疗开始时、治疗3个月、6个月时回答来自IIEF（International Index of Erectile Function）,EDITS（Erectile Dysfunction Inventory of Treatment Satisfaction）,SF-PAIRS（Short Form of the Psychological and Interpersonal Relationship Scale）／nq卷的问题。医生可以给病人开出市场上现有的任何疗法,并可以在治疗过程中任何时间改变疗法。在完成为期6个月的分析的1338名病人中,有624人（47％）改变了疗法,714人（53％）一直接受最初诊断的疗法,其中接受治疗的病人持续接受一种疗法的比率显著高于接受西地那非或伐地那非治疗的病人。其它影响这一比率的变量包括性欲低下和ED。各种PDE-5抑制剂在效力、病人满意度、自信心、自发性等方面无显著差异。接受他达拉非治疗的病人的SF—PAIRS“时间相关”项的分数显著优于接受其它治疗的病人。结果显示现有的三种PDE-5抑制剂的临床实践和临床实验结果相似,但病人如果要终止或改变用药,他达拉非的风险较低。     

他达拉非:ED患者及其配偶的选择偏爱?

勃起功能障碍(erectile dysfunction,ED)是男性常见疾病,直接影响患者及其配偶的生活质量。PDE5抑制剂是治疗ED的首选药物。尽管临床主要有3种PDE5抑制剂(西地那非、伐地那非和他达拉非)可供选择,但是患者及其配偶在选择PDE5抑制剂上是否有偏好,以及影响其选择的因素又有哪些本文简要地综述了最近的研究进展。     

Evaluating preference trials of oral phosphodiesterase 5 inhibitors for erectile dysfunction

More treatment options are available now for the treatment of erectile dysfunction (ED) than ever. Treatments include oral phosphodiesterase 5 (PDE5) inhibitors, intracavernosal injections, vacuum constriction devices, and penile implants. Clinicians, researchers, and patients are interested in making direct comparisons between the response of newer treatments and that of established and more developed therapies. Of the currently available treatment options for ED, the most commonly prescribed therapies are oral PDE5 inhibitors, which include sildenafil citrate (Viagra, Pfizer Inc), tadalafil (Cialis, Lilly ICOS), and vardenafil (Levitra, Bayer). However, most patient preference studies of these drugs conducted to date have serious design flaws that hinder interpretation of the data, and thus limit the utility of the results. To make an informed decision on the most appropriate treatment option available, physicians and their patients require a thorough understanding of the methodology of these studies. Clinical comparison or preference trials must establish internal and external validity if the data are to be used in a generalized patient population. We review preference studies that compared sildenafil, tadalafil, and vardenafil, and highlight study designs that can introduce bias. We propose that, like safety and efficacy trials, randomized controlled trials (RCTs) should be the gold standard for evaluating patient preference treatments for ED. We do not wish to discourage individual investigators from performing preference studies, but rather to highlight the features of current preference trials to help patients and clinicians alike become aware of potential biases from independent or industry-sponsored patient preference trials so that they can interpret the results accordingly. Key components of patient preference RCTs are reviewed: period and carryover effects, preference assessments, eligibility criteria, and data analysis. We discuss why these components of patient-preference RCTs are important for evaluating the validity and relevance of patient preference studies. The preference studies discussed in this brief review are summarized in , and the methodological problems with each study are indicated. We provide a recommendation for the design of such trials that can minimize bias and provide better data for physicians and their patients.     

Drug Insight: oral phosphodiesterase type 5 inhibitors for erectile dysfunction

Erectile dysfunction (ED) is a common medical condition that affects the sexual life of millions of men. At present, first-line oral pharmacotherapy for most patients with ED is a phosphodiesterase type 5 (PDE-5) inhibitor, of which three are currently available worldwide. Sildenafil (Viagra, Pfizer) has a very satisfactory efficacy-safety profile in all patient categories. The first PDE-5 inhibitor to reach the market, it is now the most widely prescribed oral agent for ED. Tadalafil (Cialis, Lilly ICOS) and vardenafil (Levitra, Bayer/GlaxoSmithKline) were introduced to the European Union and the US in 2003 and 2004, respectively. These three PDE-5 inhibitors share many characteristics, but each has unique features. This review describes the chemical, pharmacologic and clinical features of sildenafil, vardenafil and tadalafil as oral first-line treatments for ED. First, we describe the physiology of penile erection and PDE-5 inhibitor pharmacology, including chemistry, PDE selectivity, pharmacokinetics, and possible drug interactions. We then summarize data on the efficacy and safety profiles of the three PDE-5 inhibitors for the treatment of ED in the general population, in patients with diabetes mellitus and in men that have undergone bilateral nerve-sparing retropubic radical prostatectomy.     

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.     

Medikamentöse Therapie des benignen Prostatasyndroms mit Phosphodiesterase-5-Inhibitoren

Phosphodiesterase-5 (PDE5) inhibitors, such as sildenafil, tadalafil and vardenafil are first line treatment for erectile dysfunction (ED). These PDE5 inhibitors are known to increase cyclic guanosine monophosphate (cGMP) concentrations in the smooth muscle cells of the corpora cavernosa penis by inhibiting PDE5, leading to smooth muscle relaxation. This mode of action is also believed to result in prostatic smooth muscle relaxation and to improve lower urinary tract symptoms (LUTS). Randomized controlled trials have shown beneficial effects on LUTS and on objective parameters such as maximum urinary flow rate (tadalafil). Based on these data tadalafil was recently approved for treatment of patients with male LUTS; however, the mechanisms leading to improvement of symptoms are still under debate.     

Efficacy and satisfaction rates of oral PDE5is in the treatment of erectile dysfunction secondary to spinal cord injury: a review of literature

Concept

Decreased sexual function is a major concern of men with spinal cord injuries (SCIs). Treatment of erectile dysfunction (ED) through oral pharmacotherapies has been proven to be an effective way to address and treat this concern.

Objective

To find an efficacious and satisfactory treatment ED secondary to SCI through the compilation of studies that utilized the International Index of Erectile Function (IIEF) when testing phosphodiesterase V inhibitors (PDE5i).

Method

Ten articles, which used the IIEF to study satisfaction and/or efficacy of PDE5is sildenafil, tadalafil, and vardenafil in the treatment of ED were reviewed and analyzed. Through the use of a self-made grading scale the value of each article was determined for this research.

Results

Sildenafil, tadalafil, and vardenafil all have been proven to be effective in treating ED in men with SCI. While sildenafil is the most thoroughly studied ED treatment for patients with SCI, tadalafil has a longer time duration effectiveness, which allows for more spontaneity in the sexual experience. Minimal adverse effects have been noted in patients with SCI using these medications; headache, flushing, and mild hypotension are the most common. In articles that study satisfaction, patients show great improvement over baseline with the use of these medications.

Conclusion

Although there is a need for further research on the safety in long-term use of tadalafil and vardenafil, comparative studies done on all three medications show no statistically significant difference in effectiveness or satisfaction. New medications and treatment options, such as avanafil, are being studied in hope of continued improvement of sexual function in men with SCI.     

Efficacy and safety of phosphodiesterase type 5 (PDE5) inhibitors in treating erectile dysfunction after bilateral nerve‐sparing radical prostatectomy

We carried out a systematic review and meta‐analysis to assess the efficacy and safety of phosphodiesterase type 5 (PDE5) inhibitors for treating erectile dysfunction (ED) after bilateral nerve‐sparing radical prostatectomy (BNSRP). A literature review was performed to identify all published randomised double‐blind, placebo‐controlled trials of PDE5 inhibitors for the treatment of ED after BNSRP. The search included the following databases: MEDLINE, EMBASE and the Cochrane Controlled Trials Register. The reference lists of the retrieved studies were also investigated. Six publications involving a total of 1678 patients were used in the analysis, including six RCTs that compared PDE5 inhibitors (tadalafil, sildenafil, avanafil and vardenafil) with placebo. Co‐primary efficacy end points: International Index of Erectile Function‐Erectile Function (IIEF‐EF) domain score [the standardised mean difference (SMD) = 4.04, 95% confidence interval (CI) = 2.87–5.22, P < 0.00001]; successful vaginal penetration (SEP2) [the odds ratio (OR) = 14.87, 95%CI = 4.57–48.37, P < 0.00001]; and successful intercourse (SEP3) (OR = 47, 95%CI = 3–13.98, P < 0.00001) indicated that PDE5 inhibitors was more effective than the placebo. Specific adverse events with PDE5 inhibitors included headache (12.08%), dyspepsia (6.76%) and flushing (6.52%), which were significantly less likely to occur with placebo. This meta‐analysis indicates that PDE5 inhibitors to be an effective and well‐tolerated treatment for ED after BNSRP.     

The effects of phosphodiesterase type 5 inhibitors on penile rigidity variables during a period with no sexual stimulation: a laboratory setting double‐blind study

Study Type – Therapy (RCT)
Level of Evidence 1b What’s known on the subject? and What does the study add? There is a positive effect of PDE5 inhibitors on several aspects of the men’s sex lives, chiefly erectile function, personal self‐esteem, and satisfaction from their sex lives. To our knowledge, our study is the first study to evaluate the effects of PDE5 inhibitors on erectile variables simultaneously in a laboratory setting. In the present study, significant penile rigidities were obtained with PDE5 inhibitors in a short period, with no sexual stimulation, in laboratory conditions. Our findings might support the use of PDE5 inhibitors in the men who need penile rehabilitation.

OBJECTIVE

To investigate the effects of phosphodiesterase type 5 (PDE5) inhibitors on erectile variables during a period with no sexual stimulation in a laboratory setting double‐blind study.

PATIENTS AND METHODS

In all, 80 men without erectile dysfunction (ED) but with lifelong premature ejaculation (PE) were included in the study. The men were divided equally in to four groups and received either placebo, vardenafil (10 mg), sildenafil (50 mg) or tadalafil (20 mg) in a double‐blind study design. The men attended the laboratory following 3 days of sexual abstinence and placebo or one of the PDE5 inhibitors was ingested after ≥2 h of fasting and non‐smoking. The men were then immediately placed in a silent room and real‐time penile rigidity and tumescence monitoring with Rigiscan Plus (Rigiscan Plus® System, Osbon Medical Systems, Augusta, GA, USA) began. The men read some magazines or newspapers that contained no sexually stimulating material for 1.5 h. There was no interaction between the men and observer during the test period. Times to first measured and total durations of base and tip rigidities, and also total and per minute rigidity were evaluated.

RESULTS

The recorded base and/or tip rigidity ratios were 40% (eight of 20), 71% (12/17), 47% (nine of 19) and 70% (14/20) in men who took placebo, sildenafil, tadalafil and vardenafil, respectively (P= 0.126). The ratio of men who could obtain ≥60% base and/or tip rigidities were 10% (two of 20), 41% (seven of 17), 26% (five of 19) and 55% (11/20) in placebo, sildenafil, tadalafil and vardenafil groups, respectively (P < 0.05). The median time to first measured base rigidity was 58.0, 21.5, 54.5 and 57 min with placebo, sildenafil, tadalafil and vardenafil, respectively (P= 0032). The median total duration of recorded base rigidity was 4.0, 27.5, 10.0 and 11.5 min in men who took placebo, sildenafil, tadalafil and vardenafil, respectively (P= 0.013). The median total base rigidity (area under the curve) was 72.8, 699.0, 360.5 and 553.0 with placebo, sildenafil, tadalafil and vardenafil, respectively (P= 0.016).

CONCLUSIONS

Significant penile rigidities were obtained with PDE5 inhibitors during the short test period, with no sexual stimulation, in laboratory conditions. This finding might support the use of PDE5 inhibitors in men who need penile rehabilitation.     

Prevalence and medical management of erectile dysfunction in Asia

Erectile dysfunction (ED) is an important worldwide health issue that has a significant negative impact on the quality of life and life satisfaction of both the affected individual and his partner. Here we review the prevalence of ED in Asia, associated factors that may influence sexual attitudes and sexual behaviours, and randomized clinical trials (RCTs) of phosphodiesterase-5 (PDE-5) inhibitors to evaluate the clinical efficacy and safety of PDE-5 inhibitors in Asian men. We searched for English-language articles in MEDLINE and PubMed from January 2000 to September 2010. Our results showed that the overall reported prevalence rate of ED in Asia ranged widely, from 2% to 88%. This finding indicates that ED is a common and major health problem in this region. However, sociocultural and economic factors in Asia prevent people from seeking and obtaining appropriate medical care. We found reports on five kinds of PDE-5 inhibitors for the management of ED: sildenafil, vardenafil, tadalafil, udenafil and mirodenafil. The results of RCTs showed that these five PDE-5 inhibitors are more effective than placebo in improving erectile function in Asian men with ED and that these drugs have similar efficacy and safety profiles.     

Gene therapy and erectile dysfunction： the current status

Current available treatment options for erectile dysfunction （ED） are effective but not without failure and/or side effects. Although the development of phosphodiesterase type 5 （PDE5） inhibitors （i.e. sildenafil, tadalafil and vardenafil） has revolutionized the treatment of ED, these oral medications require on-demand access and are not as effective in treating ED related to diabetic, post-prostatectomy and severe veno-occlusive disease states. Improvement in the treatment of ED is dependent on understanding the regulation of human corporal smooth muscle tone and on the identification of relevant molecular targets. Future ED therapies might consider the application of molecular technologies such as gene therapy. As a potential therapeutic tool, gene therapy might provide an effective and specific means for altering intracavernous pressure ＂on demand＂ without affecting resting penile function. However, the safety of gene therapy remains a major hurdle to overcome before being accepted as a mainstream treatment for ED. Gene therapy aims to cure the underlying conditions in ED, including fibrosis. Furthermore, gene therapy might help prolong the efficacy of the PDE5 inhibitors by improving penile nitric oxide bioactivity. It is feasible to apply gene therapy to the penis because of its location and accessibility, low penile circulatory flow in the flaccid state and the presence of endothelial lined （lacunar） spaces. This review provides a brief insight of the current role of gene therapy in the management of ED.