PDE5抑制剂对IVF中临时性ED患者的治疗效果及其对精液的影响

目的 探讨5型磷酸二酯酶(PDE5)抑制剂对常规体外受精(IVF)中临时性勃起功能障碍(ED)患者的治疗效果及其对精液的影响.方法 根据服用不同的PDE5抑制剂将89名临时性ED患者分为三组:他达拉非组、伐地那非组和西地那非组,观察患者获取精液的成功率,比较三组患者服药前1个月和服药后3h内的精液量、精液密度和精子活动力(a级+b级).结果 76(85.4%)名患者勃起功能改善,成功获取精液,三组患者的取精成功率差异无统计学意义(P>0.05);与服药前相比,三组患者服药后的精液量、精子密度及精子活动力差异无统计学意义(P>0.05).结论 PDE5抑制剂是治疗临时性ED患者的有效药物,PDE5抑制剂对IVF中临时性ED患者的精液参数无明显影响.     

磷酸二酯酶抑制剂：有效性和新用途

van Driel MF等人对磷酸二酯酶5(PDE5)抑制剂进行了一项综述性研究。目前有3种不同的PDE5抑制剂被用于治疗男性勃起功能障碍(ED),包括西地那非、伐地那非和他达拉非。     

磷酸二酯酶5（PDE5）抑制剂的药理学和药物相互作用：α受体阻滞剂的相互作用

目前全球共有3种治疗勃起功能障碍的磷酸二酯酶5(PDE5)抑制剂:西地那非、伐地那非和他达拉非。每种药物对不同病因引起的ED均有效,包括男性血管性ED。PDE5存在于动、静脉系统的血管平滑肌     

磷酸二酯酶5抑制剂之间的比较

就目前可供选择的治疗ED的方法中，口服型磷酸二酯酶5（PDE5）抑制剂被推荐为一线治疗选择。Wright进行了一项研究，对日前获批的三种PDE5抑制剂：枸橼酸西地那非片（西地那非），盐酸伐地那非（伐地那非）和他达拉非进行比较性分析。结果显示3种药物具有类似的疗效和不良反应。西地那非和伐地那非有类似的分子结构，但他达拉非的结构却有不同，这也反映在其不同于前两者的药代动力学参数。就起效时间（实现勃起、成功完成性交）而言，35％使用西地那非的患者为14min、21％使用伐地那非的患者为10min、而16％使用他达拉非的患者为16min。     

根治性前列腺切除术后勃起功能障碍的PDE5抑制剂治疗现状

前列腺癌根治性前列腺切除术(RRP)术后勃起功能障碍(ED)的发生率10%~100%,保留神经的根治性前列腺切除术(NS-RRP)术后ED也超过三分之一。5型磷酸二酯酶(PDE5)抑制剂可用于各种原因ED的治疗。西地那非、伐地那非和他达拉非临床应用显示对RRP术后勃起功能的治疗有相似的作用,保留双侧神经的患者,服用西地那非的有72%的成功勃起率(阴道插入);服用伐地那非20 mg和10 mg的反应率是71.1%和59.7%;服用他达拉非的所有患者,平均成功的插入率是54%,平均成功性交率是41%,术后有某种程度勃起的患者,平均成功的插入率和成功性交率是69%和52%。但未有三者对RRP术后ED治疗的直接比较。     

枸橼酸西地那非和他达拉非治疗未经5型磷酸二酯酶抑制剂治疗男性勃起功能障碍患者的开放式、多中心、随机化、交叉比较研究

为了比较未经5型磷酸二酯酶（PDE5）抑制剂治疗的男性勃起功能障碍（ED）患者对治疗药物-枸橼酸西地那非（西地那非）和他达拉非的偏好性以及治疗药物的疗效和耐受性，有研究者进行了一项有关西地那非和他达拉非（按需服药）的开放式、交叉临床研究。在为期4周的基线评估后，入选的367例男性勃起功能障碍患者（平均年龄为54岁）经随机化分组，一组先服用西地那非12周，之后再服用他达拉非12周；     

西地那非是安全、可信赖的ED治疗药物

自从PDE5抑制剂西地那非开始应用于临床后,勃起功能障碍(ED)的治疗发生了根本性的改变。海绵体内或尿道内注射血管活性物质或阴茎假体植入的机械辅助方法等已经几乎停止应用。PDE5抑制剂他达拉非和伐地那非的出现令人关注这3种药物的有效性和副作用。Gresser U等为此对相关文献进行了回顾。西地那非已被证实是非常有效的医药产品,已经有长达6年的服药追踪随访研究。     

他达拉非每日一次在勃起功能障碍中的应用:来自患者及其性伴侣的观点

勃起功能障碍(ED)是一种影响男性健康并危害两性关系的常见疾病.5型磷酸二酯酶(PDE5)抑制剂的诞生,使这些患者家庭的性生活质量获得了显著改善.这类药物被公认为大多数ED患者的一线用药.目前,有3种PDE5抑制剂--西地那非、他达拉非和伐地那非被批准在有性行为需求时使用,但其中只有他达拉获批可以每日服用1次.本综述总结了ED患者及其性伴侣对PDE5抑制剂的观点,并通过与他达拉非按需服用以及其他PDE5抑制剂类药物进行比较,明确了他达拉非每日1次的治疗方案是否有助于改善ED患者的心理状况(譬如性自信心、性行为自发性和时间顾虑).     

勃起功能障碍患者服用5型磷酸二酯酶抑制剂用药习惯

Mulhall JP等人进行了一项研究,摘要:大量关于患者使用5型磷酸二酯酶(PDE_5)抑制剂喜好的研究结果不尽相同。此外,PDE_5抑制剂的实际临床治疗模式信息有限。目的:评估万艾可(枸橼酸西地那非),艾力达(伐地那非),或希爱力(他达拉非)初始治疗勃起功能障碍(ED)临床治疗模式。方法:初次服用西地那非,伐地那非,他达拉非的病人经过NDCHealth's智能健康库的筛选。对继续服药、     

三种PDE5抑制剂的药代动力学、起效时间和维持时间

勃起功能障碍（Erectile dysfunction，ED）是指不能达到或维持勃起足以进行满意的性生活^[1]。ED的治疗目前仍主要应用口服药物治疗。西地那非（Sildenafil）、伐地那非（Vardenafil）和他达拉非（Tadalafil）是其中研究较多的3种。西地那非由美国辉瑞（Pfizer）公司研制生产的一种磷酸二脂酶5（phosphodiesterase5，PDE5）抑制剂，     

The effects of three phosphodiesterase type 5 inhibitors on ejaculation latency time in lifelong premature ejaculators: a double-blind laboratory setting study

Study Type – Therapy (RCT)
Level of Evidence 1b What’s known on the subject? and What does the study add? Several authors have reported their experience with PDE5 inhibitors alone or in combination with selective serotonin re‐uptake inhibitors for treating premature ejaculation. However, to our knowledge, this is the first laboratory design study to evaluate the effects of three PDE5 inhibitors throughout the ejaculation process in men with lifelong premature ejaculation. In this laboratory setting study PDE5 inhibitors seem to prolong ELT but the difference from placebo is significant only in vardenafil. The quality of penile rigidity is better with PDE5 inhibitors in the post‐ejaculatory period but the difference is significant only in sildenafil and vardenafil.

OBJECTIVE

? To evaluate the effects of three phosphodiesterase type 5 (PDE5) inhibitors on the ejaculation process in men with lifelong premature ejaculation using a double‐blind laboratory setting.

PATIENTS AND METHODS

? Eighty men with lifelong premature ejaculation, 20 in each group, received placebo, vardenafil (10 mg), sildenafil (50 mg) or tadalafil (20 mg) in a double‐blind study design. Placebo or PDE5 inhibitor was ingested after at least 2 h fasting and non‐smoking. The subjects were placed in a silent room immediately and real‐time penile rigidity and tumescence was monitored. ? Subjects read some magazines or newspapers without any sexually stimulating material for 1.5 h. At the end of this period audiovisual sexual stimulation began with a video film and after the 8th minute the subject began vibratory stimulation to the frenular area. ? At the beginning of ejaculation the patient stopped stimulation. When the patient began and stopped stimulation, the light near the observer turned on and off and the observer calculated the ejaculation period with a chronometer. The elapsed time was the ejaculation latency time (ELT) in seconds. ? There was no interaction between subjects and observer during the test. The ELT, and the qualities of base and tip rigidities during ELT and after ejaculation were calculated.

RESULTS

? Median age of patients was 29 (range 22–39) years and median duration of premature ejaculation was 60 (range 7–180) months and there was no significant difference between groups. Median duration of vibratory stimulation (ELT) of subjects who received placebo was 48.5 s: 53.5 s for sildenafil, 70.0 s for tadalafil and 82.5 s for vardenafil. Compared with the placebo group, ELT was significantly longer only in subjects receiving vardenafil (P = 0.019). ? In the post‐ejaculatory refractory period, times to last recorded base rigidities were significantly longer than placebo in vardenafil and sildenafil groups with better erection quality (P < 0.01 for each).

CONCLUSIONS

? The PDE5 inhibitors seem to prolong ELT and the quality of penile rigidity is better with PDE5 inhibitors in post‐ejaculatory period. ? These findings suggest that PDE5 inhibitors might have some beneficial effects in men with lifelong premature ejaculation.     

伐地那非治疗难治性勃起功能障碍的最新进展

5型磷酸二酯酶(phosphodiesterase 5,PDE5)在阴茎勃起功能中所起的作用越来越引起人们的关注。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)的许多病理状态,并导致一些慢性疾病的发生。本文回顾了伐地那非治疗ED患者的有效性和安全性。结果表明,伐地那非对于合并异常脂蛋白血症和高血压、糖尿病、抑郁症、前列腺切除术后、外伤性脊髓损伤、西地那非治疗无效、肾移植术后、慢性前列腺炎和早泄的ED患者安全有效,为这些难治性ED患者提供了一种合理的治疗选择。另外,伐地那非还能延长ED患者的勃起时间。     

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.     

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。     

Hypogonadism and erectile dysfunction: the role for testosterone therapy

The role of low testosterone levels in erectile dysfunction (ED) remains unclear. Both organic and psychogenic factors contribute to ED, with vasculogenic causes being the most common etiology. Approximately 10-20% of patients with ED are diagnosed with hormonal abnormalities. At the physiologic level, two second messenger systems are involved in mediating erections, one involving cyclic adenosine monophosphate (cAMP) and the other involving cyclic guanosine monophosphate (cGMP). PDE5 inhibitors such as sildenafil promote the cGMP pathway, while alprostadil affects the cAMP pathway. Evidence is strong that, in animal systems, testosterone has direct effects on erectile tissue. However, although testosterone clearly has an impact on libido in humans, its effect on penile function is less clear. Evaluation of ED includes medical, sexual, and psychosocial history assessments, as well as laboratory tests to check for diabetes and hormonal abnormalities. Initial interventions should involve correction of potentially reversible causes of ED, such as hypogonadism. First-line therapy for other patients is typically oral PDE5 inhibitors, such as sildenafil, tadalafil, or vardenafil. For patients who fail treatment with PDE5 inhibitors, local therapies such as intracavernous alprostadil are highly successful. Recent data also support the success of combination therapy with sildenafil and testosterone. This opens the possibility of other combinations of testosterone and other treatments of ED. The ability to exploit multiple pathways in the physiologic processes leading to erection may help improve therapy for ED.     

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.     

Efficacy of vardenafil and sildenafil in facilitating penile erection in an animal model

Vardenafil and sildenafil are potent and specific phosphodiesterase type 5 (PDE 5) inhibitors. In human penile cavernosal smooth muscle cells, we have previously shown that vardenafil has a lower biochemical inhibition constant (Ki) than sildenafil. In this study, we compared the efficacy of vardenafil and sildenafil in facilitating penile erection in a rabbit model. Penile erections were elicited by submaximal (2.5 or 6 Hz) pelvic nerve stimulation (PNS) repeated every 5 minutes for 30 minutes with or without intravenous (i.v.) administration of vardenafil (1-30 microg/kg) or sildenafil (10-30 microg/kg). Erectile response was assessed by continuously recording intracavernosal pressure (ICP) and systemic arterial pressure (SAP). All data were expressed as a ratio of ICP:SAP. I.v. administration of either PDE 5 inhibitor facilitated PNS-induced erection and increased ICP:SAP in a dose-dependent manner, reaching peak response at approximately 5 minutes. However, the threshold dose at which facilitation of erection occurred was lower for vardenafil (3 microg/kg) than for sildenafil (10 microg/kg). At the 10-microg/kg dose (i.v.), the response duration was significantly greater with vardenafil (169 +/- 23 seconds) than with sildenafil (137 +/- 31 seconds). Direct intracavernosal (i.c.) injection of 1-30 microg/kg vardenafil or sildenafil also caused dose-dependent increases in ICP:SAP in the absence of PNS. Response durations increased in a dose-dependent manner and lasted more than 5 times that of i.v. drug administration coupled with PNS. Irrespective of the route of administration (i.c. or i.v.), at equivalent doses, vardenafil was significantly more efficacious than sildenafil in facilitating pelvic nerve-mediated penile erection and in eliciting erection in the absence of PNS. The increases in ICPs occurred more quickly, were of larger magnitude, and were sustained for longer durations for vardenafil than for sildenafil. On the basis of the biochemical data and physiological responses from this study, further clinical evaluation of vardenafil as treatment for erectile dysfunction is warranted.     

The future of erectile dysfunction (ED)

About 30-40 % of ED patients are non-responders to PDE 5 inhibitor monotherapy. Lifestyle modifications and physical activity with weight loss enhance PDE 5 inhibitor responsiveness. The same applies for combination therapies such PDE 5 inhibitors + L-Arginine 3.000mg, PDE 5 inhibitors + statins and PDE 5 inhibitors + Yohimbine. Combination of daily dosing with Tadalafil 5 mg and on demand application of sildenafil or vardenafil can improve responsiveness and erection hardness (personal experiences). Guanylate cyclase activators or RhoA-kinase inhibitors, either as monotherapy or in combination with PDE 5 inhibitors have shown in preclinical settings the potential to improve erectile function and represent targets for new ED drugs in the future. Immunophilin ligands were able to ameliorate erectile function after cavernous nerve injury due to pelvic surgery. Although having shown convincing efficacy both in animals and humans the centrally acting Melanocortin Receptor (MCR) Agonists were given up for ED treatment because of unfavorable side-effects.Promising targets for ED therapy in the future is gene therapy with several targets as well as stem cell therapy with adipose-derived or muscle-derived stem cells.     

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.     

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。