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.     

伐地那非治疗ED的有效性及安全性研究

目的:探讨长期按需服用伐地那非治疗ED的有效性及安全性.方法:2007年3月至2010年1月,共筛选891例ED患者给予口服伐地那非20 mg,每3天1次,通过电话采用问卷调查的方式进行随访,了解ED患者一般资料,治疗的需求、态度、接受程度;服用药物后均要和伴侣性接触,治疗12周后对临床疗效、不良反应、患者以及伴侣满意...     

Vardenafil 20-mg demonstrated superior efficacy to 10-mg in Japanese men with diabetes mellitus suffering from erectile dysfunction

AIM: Vardenafil is a highly selective and potent phosphodiesterase type-5 inhibitor for the treatment of erectile dysfunction (ED). The efficacy of vardenafil has been demonstrated in a broad range of ED populations, but has not yet been assessed in Japanese patients with diabetes mellitus (DM), although DM is frequently associated with difficult-to-treat ED. This is the first study to investigate whether high-dose vardenafil (20 mg) can demonstrate superior efficacy to the usual dose (10 mg) in this subpopulation in Japan. METHODS: The study was a randomized, placebo-controlled, double-blind, multi-centre, parallel group comparison 12-week study. Following 4 weeks observation period, 778 patients aged 26-64 years old with ED and DM (HbA1c >12% at screening was excluded) both of more than 3 years duration were randomly allocated to one of the three groups, vardenafil 10 mg, 20 mg, or placebo (randomization ratio 3:3:1). Erectile function (EF) domain score of the International Index of Erectile Function was estimated as the primary efficacy parameter. RESULTS: Vardenafil 10 and 20 mg both significantly improved the EF domain score from 13.6 and 13.9 at baseline to 21.8 and 22.9 at last observation carried forward (LOCF), respectively, compared to placebo (13.7 at baseline to 16.3 at LOCF; p<0.0001). In addition, vardenafil 20 mg demonstrated superior efficacy to 10 mg (p<0.05), and the difference was more evident in severe ED patients (baseline EF domain score <11). The safety profile was comparable between these two doses (drug-related adverse events: 6.6, 22.0 and 24.2% in placebo, vardenafil 10 mg, and 20 mg arms, respectively). The most common adverse events were hot flush, headache and nasal congestion, which were mild in intensity and transient, and are known to be common to PDE5 inhibitors. CONCLUSION: In Japanese men with DM and ED, vardenafil 10 mg and 20 mg were effective in improving erectile function with comparable safety profiles. Vardenafil 20 mg demonstrated superior efficacy compared with 10 mg, suggesting incremental clinical benefit in using the higher dose in this difficult-to-treat population.     

Efficacy and tolerability of vardenafil in Asian men with erectile dysfunction

Aim： To evaluate the efficacy and tolerability of vardenafil, a phosphodiesterase type-5 （PDE-5） inhibitor, in men of Asian ethnicity with erectile dysfunction （ED）. Methods： In this prospective, double-blind, multinational study, Asian men were randomized to receive vardenafil （10 mg） or placebo （4：1 ratio） for 12 weeks. The primary efficacy variables were the International Index of Erectile Function erectile function domain （IIEF-EF）, and Sexual Encounter Profile （SEP） questions related to penetration and intercourse completion. Significant mean improvements were required in all three measures to show positive benefits of vardenafil treatment. Secondary efficacy variables included the Global Assessment Question （GAQ） on erection improvement. Results： Least-squares mean baseline IIEF-EF domain scores （vardenafil 14.6, placebo 13.4） were consistent with moderate ED. After 12 weeks, vardenafil treatment was associated with significant increases from the baseline in IIEF-EF domain scores compared with the placebo （22.4 vs. 14.3; P 〈 0.001）. Vardenafil was associated with significant improvements from baseline in least squares （LS） mean success rates for SEP-2 （vardenafil 82.2 vs. placebo 43.6; P 〈 0.001） and SEP-3 （vardenafil 66.1 vs. placebo 24.0; P 〈 0.001）. Positive GAQ responses were reported by 81.8% of vardenafil recipients vs. 24.3% of placebo recipients. Adverse events were reported by 25.4% of the vardenafil group, the majority mild and transient. Conclusion： Vardenafil （10 mg） is a highly effective and well-tolerated treatment for moderate ED in Asian men. These results add to the increasing amount of data demonstrating the safety and efficacy of vardenafil for the treatment of ED in a range of patient populations.     

Erectile response with vardenafil in sildenafil nonresponders: a multicentre, double-blind, 12-week, flexible-dose, placebo-controlled erectile dysfunction clinical trial

OBJECTIVE: To evaluate the efficacy of vardenafil in patients previously unresponsive to sildenafil. PATIENTS AND METHODS: A multicentre, double-blind, 12-week, flexible-dose, placebo-controlled trial was conducted, involving 463 men aged > or = 18 years with moderate-to-severe erectile dysfunction (ED) and who were unresponsive to sildenafil (by history). After a 4-week treatment-free run-in, patients received placebo or vardenafil 10 mg with the option to maintain current dose or to titrate by one dose level (5, 10 or 20 mg) based on efficacy and tolerability at 4 and 8 weeks. Outcome measures were the erectile function (EF) domain score of the International Index of Erectile Function, two Sexual Encounter Profile diary questions (vaginal penetration and maintenance of erection until successful completion of intercourse), and the Global Assessment Question (GAQ). RESULTS: There was significantly better EF with vardenafil than with placebo throughout the study. The least-square mean EF domain scores increased from 9.3 at baseline to 17.6 at the 'last' observation carried forward (LOCF) analysis with vardenafil (P < 0.001). Overall least-square mean per-patient success rates more than doubled for penetration (30.3% to 62.3%) and quadrupled for successful intercourse (10.5% to 46.1%) with vardenafil. Improved erections (positive response to the GAQ) were reported by 61.8% of patients receiving vardenafil and 14.7% of those receiving placebo at LOCF (P < 0.001). Normal EF (domain score > or = 26) was achieved by 30% of patients receiving vardenafil and 6% receiving placebo at LOCF (P < 0.001). Adverse events were infrequent and representative of the phosphodiesterase-5 inhibitor profile. CONCLUSION: Vardenafil is an effective and generally safe treatment for ED, even in men unresponsive to sildenafil (by history).     

Vardenafil improves urodynamic parameters in men with spinal cord injury: results from a single dose, pilot study

PURPOSE: We assessed urodynamic changes after vardenafil administration in spinal cord injured male patients on oxybutynin treatment. MATERIALS AND METHODS: We performed a single center, randomized, double-blind, placebo controlled trial in 25 patients with spinal cord injury who had erectile dysfunction and micturition disorders. A baseline urodynamic test was performed as well as a second urodynamic test 1 to 3 hours after the administration of 20 mg vardenafil and placebo in 15 and 10 cases, respectively. In all patients standard oral oxybutynin administration was not discontinued. Statistical assessment included the 3 urodynamic parameters maximum detrusor pressure during voiding, maximum cystometric capacity and detrusor overactivity volume. RESULTS: Placebo administration did not affect urodynamic parameters. After vardenafil administration maximum detrusor pressure was significantly decreased (59.3 vs 52.1 cm H(2)O, p <0.001) and maximum cystometric capacity considerably improved (233.5 vs 272 ml, p <0.001). The most dramatic variations were observed for detrusor overactivity volume (174 vs 218 ml, p <0.0001). In 7 patients with American Spinal Injury Association classification A and spinal cord injury above T6 we observed the most significant improvement in the evaluated urodynamic items, including maximum detrusor pressure 57 vs 52 cm H(2)O (p = 0.039), maximum cystometric capacity 253 vs 296 ml (p = 0.004) and detrusor overactivity volume 177 vs 229 ml (p = 0.003). CONCLUSIONS: This trial demonstrates that in spinal cord injured patients a single 20 mg vardenafil administration achieved a significant decrease in maximum detrusor pressure, an improvement in maximum cystometric capacity and a remarkable increase in detrusor overactivity volume value.     

Apomorphine sublingual as primary or secondary treatment for erectile dysfunction in patients with spinal cord injury

OBJECTIVES: To evaluate the effectiveness of apomorphine sublingual (SL) 3 mg, as a primary or secondary treatment for erectile dysfunction (ED) in patients with spinal cord injury (SCI), and to determine possible differences in efficacy considering clinical, urodynamic and neurophysiological findings. PATIENTS AND METHODS: The study included 22 patients with chronic SCI and neurogenic ED who were examined physically and by a video-urodynamic evaluation. A neurophysiological evaluation included somatosensory evoked potentials of the pudendal nerve, palmar and plantar sympathetic skin responses and bulbocavernous reflex recordings. Thereafter the patients received 8 tablets of apomorphine SL 3 mg and were asked to complete the International Index of Erectile Function questionnaire before and after treatment. Side-effects, subjective efficacy compared with other treatments and satisfaction with the SL administration were recorded. RESULTS: Of the 22 men, 11 had upper motor neurone lesions (six complete, five incomplete), eight lower motor neurone lesions (seven complete, one incomplete) and three had mixed lesions. In all, 12 patients took sildenafil citrate and five alprostadil intracavernosally beforehand, and five had used nothing to treat their ED. Seven patients had some response and reported that the drug helped them to obtain an erection, but only two reported erections sufficient for intercourse and would agree to continue apomorphine SL as their standard treatment; all the others reported being disappointed. Nine patients reported side-effects. There were no significant correlations for electrophysiological or urodynamic findings and treatment success. Of the 22 patients 20 preferred SL rather than the normal administration. CONCLUSIONS: Apomorphine SL, a D1/D2 dopamine agonist, facilitates erectile function in a heterogeneous group of patients with no significant relationship with any of the assessed urodynamic or electrophysiological variables. The overall low rates of response either for primary or secondary treatment suggests that apomorphine will have limited applicability in patients with SCI.     

伐地那非的药效学和药代动力学

伐地那非是一种强效、高选择性的 5型磷酸二酯酶 (PDE5 )抑制剂 ,对PDE5的抑制作用约为西地那非的 10倍。该药能显著增强阴茎勃起功能 ;而且起效迅速 ,患者口服后最早 10min即可充分勃起完成性交 ,是迄今为止起效最快的PDE5抑制剂。伐地那非口服绝对生物利用度为 15 % ,可被迅速吸收 ,血浆清除半衰期约为 4～ 5h。药效学、药代动力学、安全性及耐受性研究表明 ,伐地那非是一个治疗ED的安全、有效的口服药物。     

伐地那非治疗抑郁症合并勃起功能障碍的有效性和安全性

勃起功能障碍 (erectiledysfunction ,ED)与抑郁症常合并存在 ,两者可相互恶化 ,给患者带来更大的痛苦 ,因而更加需要迫切、有效的治疗方法。最近的DRIVER(DepressionRelatedImprovementwithVardenafilforErectileResponse)试验结果表明 ,磷酸二酯酶 5 (PDE5 )抑制剂伐地那非不仅能改善ED合并抑郁症男性的勃起功能 ,而且能减轻抑郁症状 ,改善生活质量 ;且使用安全 ,耐受性好。     

伐地那非治疗糖尿病患者的勃起功能障碍

勃起功能障碍 (erectiledysfunction ,ED)在糖尿病患者中发生率要高于非糖尿病人群 ,而且更难治疗。伐地那非是一种高选择性的新型磷酸二酯酶 5抑制剂 ,是广泛ED人群的一线治疗药物。最近发表的大型临床试验表明 ,无论糖尿病合并ED的患者基线时的病情严重程度如何 ,也无论他们的血糖控制情况如何 ,伐地那非都能有效地改善其勃起功能 ,而且使用安全 ,耐受性良好     

长期低剂量PDE5抑制剂治疗勃起功能障碍的新进展

勃起功能障碍(ED)是一类常见的疾病,严重影响患者及其伴侣的生活质量,5型磷酸二酯酶(PDE5)抑制剂是治疗ED的首选药物,新近发现给予ED患者长期低剂量PDE5抑制剂同样安全有效,使得性生活更自然更方便,并为难治性ED患者提供了一种新的治疗选择,其机制在于改善阴茎血管内皮细胞的功能以及增加和(或)维持平滑肌细胞数量促进ED改善,但该方法是否能够使患者在服药结束后维持勃起功能依然是当前研究的热点。     

Evolution of phosphodiesterase type 5 inhibitors in treatment of erectile dysfunction in Taiwan

Erectile dysfunction (ED) is a prevalent form of male sexual dysfunction. Phosphodiesterase type 5 (PDE5) inhibitor is the first-line treatment for ED. Numerous well-designed and -conducted clinical trials and postmarketing studies have established the safety and efficacy of PDE5 inhibitors for the treatment of ED. Ever since the first approval of sildenafil in 1998, PDE5 inhibitors have had several advances in their clinical use. More new agents with different pharmacokinetic profiles and new formulations were marketed. Conventional on-demand administration expanded to daily dosing. These advances provide more flexibility in clinical treatment of ED for patients and physicians. Moreover, clinical indications of PDE5 inhibitors extend from treatment of ED to pulmonary arterial hypertension and signs and symptoms of benign prostatic hyperplasia because of the distribution of PDE5 enzyme in human organs and tissues. The evolution of PDE5 inhibitors heralds a remarkable medical history from bench to clinical practice.     

糖尿病勃起功能障碍患者服用PDE5抑制剂的疗效及安全性Meta分析

目的:系统评价磷酸二酯酶5(PDE5)抑制剂治疗糖尿病患者勃起功能障碍的临床疗效及安全性,为其治疗提供临床证据。方法:通过计算机检索2013年12月以前Medline、Embase、Cocbrane Library、中国学术期刊全文数据库(CNKI)、万方数据库、维普数据库(VIP)、浙江省高校数字图书馆(ZADL),并阅读检索文章及参考文献,纳入PDE5抑制剂治疗糖尿病患者勃起功能障碍的随机对照试验(RCT)。对纳入研究的方法学用Jadad量表评价,以国际勃起功能指数(IIEF-EF)、IIEF第3问题(IIEF-Q3)、IIEF第4问题(IIEF-Q4)、阴茎插入成功率(SEP-2)、完成性交成功率(SEP-3)及GAQ总体评价问卷为主要疗效评价指标。采用Review manager 5.1.0软件进行Meta分析。结果:共有13篇研究被纳入,所有纳入研究Jadad评分均为3分以上高质量试验。10篇文献IIEF-EF评分采用固定效应模型Meta分析,合并WMD=5.79,95%CI为(4.91,6.66),P0.001。6篇文献IIEF-Q3评分采用固定效应模型Meta分析,合并WMD=0.96,95%CI为(0.83,1.08),P0.001。6篇文献IIEF-Q4评分采用固定效应模型Meta分析,合并WMD=1.11,95%CI为(0.98,1.25),P0.001。2篇文献SEP-2评分采用固定效应模型Meta分析,合并WMD=20.08,95%CI为(13.76,26.04),P0.001。5篇文献SEP-3评分采用固定效应模型Meta分析,合并WMD=25.56,95%CI为(22.24,28.80),P0.001。11篇文献GAQ评分采用随机效应模型Meta分析,OR=6.20,95%CI为(3.65,10.52),P0.001。11个试验药物不良反应采用随机效应模型Meta分析,OR=7.43,95%CI为(4.11,13.44),P0.001。结论:PDE-5抑制剂能安全有效地改善男性糖尿病患者的勃起功能。     

伐地那非治疗耻骨后前列腺根治切除术后的勃起功能障碍

超过三分之一的患者在行保留性神经的前列腺根治切除术后会出现勃起功能障碍(ED)。最近的研究表明,磷酸二酯酶 5(PDE5)抑制剂伐地那非可改善保留单侧或双侧神经的耻骨后前列腺根治切除术后ED患者的勃起功能,而且安全性良好。     

Impact of penile rehabilitation with low-dose vardenafil on recovery of erectile function in Japanese men following nerve-sparing radical prostatectomy

Erectile dysfunction （ED） is a major complication after radical prostatectomy （RP）; however, debatecontinues regarding the efficacy of penile rehabilitation in the recovery of the postoperative erectile function （EF）. This study includeda total of 103 consecutive sexually active Japanese men with localized prostate cancer undergoing nerve-sparing RP, and analyzed the postoperative EF, focusing on the significance of penile rehabilitation. In this series, 24 and 79 patients underwent bilateral and unilateral nerve-sparing RPs, respectively, and 10 or 20 mg of vardenafil was administered to 35 patients at least once weekly, who agreed to undergo penile rehabilitation. Twelve months after RP, 48 （46.6%） of the 103 patients were judged to have recovered EF sufficient for sexual intercourse without any assistance. The proportion of patients who recovered EF in those undergoing penile rehabilitation （60.0%） was significantly greater than that in those without penile rehabilitation （38.2%）. Of several parameters examined, the preoperative International Index of Erectile Function-5 （IIEF-5） score and nerve-sparing procedure were significantly associated with the postoperative EF recovery rates in patients with and without management by penile rehabilitation, respectively. Furthermore, univariate analysis identified the preoperative IIEF-5 score, nerve-sparing procedure and penile rehabilitation as significant predictors of EF recovery, among which the preoperative IIEF-5 score and nerve-sparing procedure appeared to be independently associated with EF recovery. Considering these findings, despite the lack of independent significance, penile rehabilitation with low-dose vardenafil could exert a beneficial effect on EF recovery in Japanese men following nerve-sparing RP.     

Erectile function and male reproduction in men with spinal cord injury: a review

Spinal cord injury (SCI) in men results in defects in erectile function, ejaculatory process and male reproductive potential. There are alterations in the capacity of men with SCI to achieve reflexogenic, psychogenic and nocturnal erections. The sexual function in different stages after SCI and the types of erections depend mainly on the completeness of the injury and the level of neurological damage. Furthermore, most of the SCI men demonstrate defects concerning the entrance of semen into the posterior urethra and the expulsion of the semen through the penile urethra and the urethral orifice. In addition, SCI men develop defects in the secretory function of the Leydig cells, Sertoli cells and the male accessory genital glands. The overall result is a decreased quality of the semen is recovered either with penile vibratory stimulation (PVS) or with electroejaculation. Nowadays the therapeutic andrological approach of SCI men focuses on achievement of erectile function, recovery of spermatozoa and assisted reproductive technology. The first line of therapy recommended for infertility in SCI men is collection of semen via PVS with concomitant evaluation of total motile sperm yields for assisted conception which may include intravaginal insemination, intrauterine insemination, or in vitro fertilisation/intracytoplasmic sperm injection. Patients failing PVS may be referred for electroejaculation or surgical sperm retrieval.     

Efficacy and safety of on demand tadalafil in the treatment of East and Southeast Asian men with erectile dysfunction: a randomized double-blind, parallel, placebo-controlled clinical study

Aim:To assess the efficacy and safety of tadalafil in comparison to a placebo,when taken on demand for 12 weeksby East/Southeast Asian men with erectile dysfunction(ED).Methods:This multicenter,randomized,double-blind,parallel group,placebo-controlled study was conducted at 17 centers across East and Southeast Asia between August2002 and February 2003.Men more than 18 years of age with mild to severe ED of various etiologies were randomizedto receive a placebo or 20 mg of tadalafil taken as needed(maximum once daily).Efficacy assessments included theInternational Index of Erectile Function,the Sexual Encounter Profile diary and Global Assessment Questions.Results:Tadalafil significantly improved erectile function as compared to the placebo(P<0.001).At the endpoint,the pa-tients receiving 20 mg of tadalafil reported a greater mean per patient percentage of successful intercourse attempts(Sexual Encounter Profile question 3:70.9% compared to 33.5% in the placebo)and a greater proportion of improvederections(Global Assessment Question:86.2% compared to 30.1%).Most(≥3%)treatment emergent adverseevents were mild or moderate.The most common treatment emergent adverse events were headache,back pain,dizziness and dyspepsia.Conclusion:Tadalafil was an effective and well-tolerated treatment for ED in East andSoutheast Asian men.(Asian J Androl 2006 Nov;8:685-692)     

Clinical usefulness of urodynamic assessment for maintenance of bladder function in patients with spinal cord injury

AIMS: The vast majority of spinal cord lesions cause neurogenic bladder disorders. Detrusor hyperreflexia presents a major risk factor for renal damage in these patients. We evaluated the long-term results of patients with spinal cord injury treated at our institution. METHODS: Eighty spinal cord injury patients (60 male, 20 female; mean age 29.6 years) with at least one follow-up visit a year for a minimum of five consecutive years, were included in this retrospective analysis. Follow-up included urodynamic evaluation, sonography of the upper and lower urinary tract, urine examination, and evaluation of renal function. Treatment modifications were based on the urodynamic findings. RESULTS: Mean follow-up was 67.3 months (range 60-103 months). At initial presentation, 51 patients performed intermittent catheterization, 7 had indwelling catheters, 10 utilized reflex voiding, 2 patients presented with a Brindley stimulator, 10 patients used abdominal straining. At the end of our study, no patient had signs of renal damage. To achieve that goal, 8 patients underwent sphincterotomy, 3 received a Brindley stimulator, 3 underwent bladder augmentation, one Kock pouch was performed, and 12 patients were treated with botulinum-A-toxin injections in the detrusor. Twenty-two patients received intravesical anticholinergic therapy. In merely three patients, treatment was not modified during the entire follow-up. CONCLUSIONS: In the long term, treatment strategy of neurogenic bladder dysfunction in patients with spinal cord injury had to be modified in almost all patients. 18.8% underwent surgery. For protection of the upper urinary tract and maintenance of continence, regular urodynamic follow-up is warranted.     

脊髓损伤中钙蛋白酶的作用

脊髓损伤后可发生不同程度的神经坏死和组织变性,导致脊髓神经功能障碍。脊髓继发性损伤过程中钙蛋白酶(calpain)在脊髓损伤中发挥重要作用。Calpain为一Ca2+依赖性半胱氨酸蛋白酶,该酶包括2种同分异构体μ-calpain和m-calpain,分别由微摩尔和毫摩尔浓度的Ca2+激活。细胞内calpain以非活性酶原形式存在,细胞内游离Ca2+浓度升高后,calpain酶原被活化,引起calpain活化后一系列分子生物化学的改变,在脊髓引起细胞凋亡或损伤。应用calpain的特异性抑制剂进行干预后,脊髓calpain的表达和活性受到抑制,脊髓的病理改变和细胞凋亡得到缓解,神经功能得以保护。该文将calpain在脊髓损伤发展过程中的作用作一综述。