Monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel, placebo-controlled clinical trial

Background

Tadalafil improved lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH; LUTS/BPH) in clinical studies but has not been evaluated together with an active control in an international clinical study.

Objective

Assess tadalafil or tamsulosin versus placebo for LUTS/BPH.

Design, setting, and participants

A randomised, double-blind, international, placebo-controlled, parallel-group study assessed men ≥45 yr of age with LUTS/BPH, International Prostate Symptom Score (IPSS) ≥13, and maximum urinary flow rate (Q_max) ≥4 to ≤15 ml/s. Following screening and washout, if needed, subjects completed a 4-wk placebo run-in before randomisation to placebo (n = 172), tadalafil 5 mg (n = 171), or tamsulosin 0.4 mg (n = 168) once daily for 12 wk.

Measurements

Outcomes were assessed using analysis of covariance (ANCOVA) or ranked analysis of variance (ANOVA) (continuous variables) and Cochran-Mantel-Haenszel test or Fisher exact test (categorical variables).

Results and limitations

IPSS significantly improved versus placebo through 12 wk with tadalafil (−2.1; p = 0.001; primary efficacy outcome) and tamsulosin (−1.5; p = 0.023) and as early as 1 wk (tadalafil and tamsulosin both −1.5; p < 0.01). BPH Impact Index significantly improved versus placebo at first assessment (week 4) with tadalafil (−0.8; p < 0.001) and tamsulosin (−0.9; p < 0.001) and through 12 wk (tadalafil −0.8, p = 0.003; tamsulosin −0.6, p = 0.026). The IPSS Quality-of-Life Index and the Treatment Satisfaction Scale–BPH improved significantly versus placebo with tadalafil (both p < 0.05) but not with tamsulosin (both p > 0.1). The International Index of Erectile Function–Erectile Function domain improved versus placebo with tadalafil (4.0; p < 0.001) but not tamsulosin (−0.4; p = 0.699). Q_max increased significantly versus placebo with both tadalafil (2.4 ml/s; p = 0.009) and tamsulosin (2.2 ml/s; p = 0.014). Adverse event profiles were consistent with previous reports. This study was limited in not being powered to directly compare tadalafil versus tamsulosin.

Conclusions

Monotherapy with tadalafil or tamsulosin resulted in significant and numerically similar improvements versus placebo in LUTS/BPH and Q_max. However, only tadalafil improved erectile dysfunction.

Trial registration

Clinicaltrials.gov ID NCT00970632     

Protective effect of tadalafil on ischemia/reperfusion injury of rat ovary

Background/Purpose

The aim of the study was to evaluate the effects of tadalafil (TDF) on ischemia/reperfusion (I/R) injury in rat ovaries.

Methods

Thirty-five female Sprague-Dawley rats were randomly divided into 5 groups (n = 7): sham (S), I/R1, I/R2, TDF1, and TDF2. In the I/R1 and TDF1 groups, 3-hour ischemia was followed by 12-hour reperfusion; and in the I/R2 and TDF2 groups, 3-hour ischemia was followed by 24-hour reperfusion. In the TDF groups, 30 minutes before reperfusion, a single dose of 5 mg/kg TDF was administered intraperitoneally. The ovarian tissue levels of malondialdehyde and nitric oxide (NO), and the activities of superoxide dismutase and catalase were measured biochemically. Tissue damage to ovarian tissue was scored by histopathologic examination.

Results

The tissue malondialdehyde levels were significantly higher and the catalase and superoxide dismutase activities were significantly lower in the I/R groups compared with the S and TDF groups (P < .05). The NO levels were significantly higher in the TDF1 group than the S and I/R1 groups (P < .05). Although the NO levels were increased in the TDF2 group compared with the I/R2 group, the difference was not significant. Ovarian tissue damage scores of the I/R groups were significantly higher than those of the S group (P < .05). Treatment with TDF significantly decreased the ovarian tissue damage scores in the TDF groups compared with the I/R groups (P < .05).

Conclusions

Tadalafil is effective in preventing tissue damage induced by I/R in rat ovaries.     

An evaluation of semen characteristics in men 45 years of age or older after daily dosing with tadalafil 20mg: results of a multicenter, randomized, double-blind, placebo-controlled, 9-month study

OBJECTIVES: Assess the effects on spermatogenesis of daily tadalafil 20mg over three spermatogenesis cycles in men >or= 45 yr. METHODS: In this double-blind, placebo-controlled, noninferiority study, healthy men (or with mild erectile dysfunction) were randomized to receive tadalafil 20mg (n=125) or placebo (n=128) for 9 mo followed by a 6-mo, treatment-free period. Semen and serum samples were provided at baseline and every 10-12 wk. The primary outcome was the proportion of subjects with >or= 50% reduction in sperm concentration at end point. Secondary outcomes included sperm concentration, number per ejaculate, motility and morphology; serum concentrations of testosterone, luteinizing and follicle-stimulating hormones; and tolerability. RESULTS: Of 253 men enrolled, 191 (75%) completed treatment phase: 2 of 96 (2.1%, placebo) and 12 of 95 (12.6%, tadalafil) subjects had >or= 50% reduction in sperm concentration. Tadalafil was noninferior to placebo because the upper 95% confidence interval for the difference in proportions of tadalafil and placebo subjects with a >or= 50% reduction in sperm concentration was 17.5%, significantly less than the prespecified noninferiority margin of 20% (p=0.015). Ninety-four percent (179 of 191) of men completed the 6-mo, treatment-free period: Baseline sperm concentration levels were restored in 8 of 12 (tadalafil) and 1 of 2 (placebo) men. There were no significant differences between groups in secondary end points. Common treatment-emergent adverse events were headache, back pain, dyspepsia, gastroesophageal reflux disease, and myalgia. Twelve (9.6%) tadalafil and seven (5.5%) placebo subjects discontinued because of adverse events. CONCLUSIONS: This study demonstrated no deleterious effects of 9 mo of daily tadalafil 20mg on spermatogenesis or hormones related to testicular function in men >or= 45 yr.     

Prescribing all phosphodiesterase 5 inhibitors to a patient with erectile dysfunction--a realistic and feasible option in everyday clinical practice--outcomes of a simple treatment regime

Objective

In clinical practice, to apply and evaluate outcomes of a treatment regime, in which the patient had the opportunity to try all the available phosphodiesterase 5 (PDE5) inhibitors.

Methods

Patients eligible for treatment with PDE5 inhibitors were prescribed 8 tablets with a shorter-acting substance (four tablets sildenafil 100 mg and four tablets vardenafil 20 mg) and eight tablets with a long-acting substance (tadalafil 20 mg). Outcomes of the regime were recorded.

Results

Of the 186 patients, 64 (34%) had not been treated previously (naïve), and 122 (66%) were undergoing treatment for their erectile dysfunction. The overall treatment response was 89% (165 of 186 patients); 78% (n = 145 of 186 patients) tested all three substances. No significant difference in choice between long- and shorter-acting medications in the overall material was observed. Two thirds of the naïve patients (n = 64) preferred a shorter-acting substance (p < 0.01). Every fifth man requested both a shorter- and a long-acting medication to accommodate his need.

Conclusion

If patients are given the opportunity in clinical practice to try all three available PDE5 inhibitors, the overall response rate is very high, almost 90%. No significant difference in patient preference between long- and shorter-acting drugs was observed. Treatment choice was based mainly on efficacy or duration of effect.     

Inhibitory effects of sildenafil and tadalafil on inflammation,oxidative stress and nitrosative stress in animal model of bronchial asthma

BackgroundCyclic neucleotides are involved in many cellular functions including smooth muscle relaxation, inflammation, and signal transduction. Sildenafil and tadalafil are phosphodiesterase-5 (PDE-5) inhibitors which prevent the degradation of cyclic neucleotide i.e. guanosine 3′,5′ cyclic monophosphate (cGMP) and increase the levels of cGMP. In this study sildenafil and tadalafil were evaluated for their anti-inflammatory, anti-oxidative and anti-nitrosative stress potential in animal model of bronchial asthma.MethodsWistar rats were sensitized with 10 mg intraperitoneal (ip) ovalbumin adsorbed to 10 μg of aluminum hydroxide on day 0. Animals were given sildenafil (1 and 3 mg/kg ip) and tadalafil (1 and 3 mg/kg ip) from day 1 to day 14. Also, on day 14 animals were challenged with ovalbumin (1 mg ip). After 24 h, samples were collected to analyze interleukin-4 (IL-4) and tumour necrosis factor-α (TNF-α), in serum and bronchoalveolar lavage fluid (BALF). The oxidative stress markers malondialdehyde (MDA), reduced glutathione (GSH) and nitric oxide metabolites (NO_x) were also measured in serum.ResultsPre-treatment with sildenafil (1 and 3 mg/kg ip) and tadalafil (1 and 3 mg/kg ip) significantly reduced the levels of pro-inflammatory cytokines IL-4 and TNF-α in rat serum and BALF. In addition, pre-treatment with both the drugs decreased the levels of MDA and NO_x and increased the levels of GSH in serum.ConclusionsSildenafil and tadalafil decreased pro-inflammatory cytokines in serum and BALF. Both drugs inhibit oxidative and nitrosative stress in animal model of bronchial asthma and could have a therapeutic potential in bronchial asthma.     

他达拉非不同治疗方案对手淫取精困难患者的临床研究

目的比较他达拉非不同治疗方案对手淫取精困难患者的临床效果。方法选取本中心2012年1月~2013年5月收治的取精困难患者48例,将患者分为A、B组,每组各24例。A组患者取卵前1个月每日给予5 mg他达拉非,B组患者取卵日给予20 mg他达拉非。两组患者在取卵前1个月均配合手淫取精训练。比较两组患者取卵当日的取精成功率。结果 A组成功取精17例,取精成功率为70.83%,B组成功取精10例,取精成功率为41.67%,两组比较,差异有统计学意义（P=0.042）。结论对于取精困难患者,长期小剂量他达拉非治疗联合手淫取精训练可有效提高其取卵当日的取精成功率。     

他达拉非联合复方玄驹胶囊对56例早泄合并ED患者的临床观察

目的:观察他达拉非联合复方玄驹胶囊对早泄合并ED患者的临床疗效。方法:将来我院男科门诊就诊的106例被确诊为早泄合并ED的患者,分成治疗组和对照组两组。治疗组56例患者给予每晚口服他达拉非5mg,同时联合复方玄驹胶囊3粒/次,3次/d,连续1个月;对照组50例患者仅给予口服复方玄驹胶囊3粒/次,3次/d,连续1个月。结果:106例患者均完成了本次临床研究,所有患者治疗1个月后,治疗组患者的阴道内射精潜伏时间(IELT)平均可延长至2.01min;对照组患者的IELT也可平均延长1.07min,两组患者经治后,IELT与治疗前相比较均有显著性的差异(P0.01),且治疗组与对照组相比较差异也有统计学意义(P0.05);两组无论是患者本人还是其伴侣性生活满意度均较治疗前显著提高(P0.01),治疗组与对照组之间差异有统计学意义(P0.05)。结论:他达拉非联合复方玄驹胶囊能提高早泄合并ED患者及其性伴侣的性生活满意度,延长患者的阴道射精潜伏时间,对早泄合并ED患者有较好的疗效。     

Role of Serum High-Sensitivity C-Reactive Protein as a Predictor of Therapeutic Response to Tadalafil in Patients With Erectile Dysfunction: A Prospective Observational Study

IntroductionHigh-sensitivity C-reactive protein (hs-CRP), a marker of inflammation, is known to be elevated in patients with erectile dysfunction (ED). However, its role in predicting therapeutic response to phosphodiesterase-5 inhibitors is incompletely understood.AimThe aim of this study was to understand the relationship among hs-CRP, mechanism of ED, and therapeutic response of ED to tadalafil, a phosphodiesterase-5 inhibitor.MethodsA total of 282 men (mean age 36.6 ± 12.0 years) with ED were included. All subjects underwent detailed evaluation, including estimation of a 6-item abbreviated version of the International Index of Erectile Function (IIEF-6) score, penile Doppler studies, and measurement of hs-CRP. IIEF-6 scoring and hs-CRP measurement were repeated after 6 weeks of tadalafil therapy (10 mg/day). The patients were categorized into vasculogenic and nonvasculogenic ED groups based on penile Doppler findings.Main Outcome MeasureThe main outcome measure was the therapeutic response to tadalafil, in relation to the mechanism of ED and hs-CRP levels.ResultsVasculogenic ED was much less common (23.8% of the subjects) than non-vasculogenic ED. Subjects with vasculogenic ED were older, had higher prevalence of cardiovascular risk factors, had more severe (mean IIEF-6 score 9.2 ± 4.6 vs 14.8 ± 4.7; P < .001) and longer duration ED, and responded less favorably to therapy (response rate 10.4% vs 75.0%; P < .001). Those showing improvement with tadalafil had lower hs-CRP at baseline (median 1.5 mg/L [interquartile range 0.9?2.3] vs 2.0 mg/L [interquartile range 1.1?3.1; P = .034]) and had proportionately greater reduction in its level. However, on multivariate analysis, only shorter duration of ED (P = .008), non-vasculogenic origin (P = .025), and higher IIEF-6 score at baseline (P = .013) were independent predictors of response to treatment.Clinical ImplicationsSerum hs-CRP is elevated in patients who are less likely to respond to vasodilator therapy but does not have an independent predictive value for this purpose.Strengths & LimitationsThis is the largest study to evaluate the relationship among the mechanism of ED, serum hs-CRP level, and therapeutic response of ED to tadalafil. All patients underwent a penile Doppler study to characterize the type of ED. The limitations were nonrandomized nature of the study and nearly 22% dropout rate.ConclusionSerum hs-CRP level is higher in vasculogenic ED compared with non-vasculogenic ED, and is associated with poorer response to tadalafil therapy. However, this association is not independent of underlying risk factors and mechanism of ED.Jamaluddin, Bansal M, Srivastava GK, et al. Role of Serum High-Sensitivity C-Reactive Protein as a Predictor of Therapeutic Response to Tadalafil in Patients With Erectile Dysfunction: A Prospective Observational Study. J Sex Med 2019;16:1912–1921.     

Tadalafil for the treatment of benign prostatic hyperplasia

Introduction: In men, lower urinary tract symptoms (LUTS) are primarily attributed to benign prostatic hyperplasia (BPH). Therapeutic options are targeted to relax prostate smooth muscle and/or reduce prostate enlargement.

Areas covered: This article reviews the major preclinical and clinical data on PDE5 inhibitors with a specific focus on tadalafil. It includes details of the role of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) – PDE5 pathway in the LUT organs (bladder and prostate) in addition to the available data on tadalafil in patients with LUTS secondary to BPH with or without erectile dysfunction (ED).

Expert opinion: Preclinical and clinical data have clearly demonstrated that PDE5 inhibitors induce bladder and prostate relaxation, which contributes to the improvement seen in storage symptoms in both animal models of bladder and prostate hypercontractility. Tadalafil is effective both as a monotherapy and add-on therapy in patients with LUTS secondary to BPH. Furthermore, as LUTS-BPH and ED are urological disorders that commonly coexist in aging men, tadalafil is more advantageous than α1-adrenoceptors and should be used as the first option. Tadalafil is a safe and tolerable therapy and unlike α1- adrenoceptors and 5-alpha reductase inhibitors, which can cause sexual dysfunctions, tadalafil improves sexual function.