Clinical Efficacy of Phosphodiesterase‐5 Inhibitor Tadalafil in Eisenmenger Syndrome—A Randomized,Placebo‐controlled,Double‐blind Crossover Study

Objectives. In a randomized double‐blind crossover trial, we compared the efficacy of phosphodiesterase‐5 (PDE‐5) inhibitor tadalafil with placebo in patients of Eisenmenger Syndrome (ES). The primary end point was the change in 6‐minute walk test distance (6 MWD). Secondary end points were the effect of the drug on systemic oxygen saturation (SO₂), pulmonary vascular resistance (PVR), systemic vascular resistance (SVR), effective pulmonary blood flow (EPBF), and World Health Organization (WHO) functional class. Background. ES is a disorder with limited treatment options. Uncontrolled studies have shown PDE‐5 inhibitors to be beneficial in patients of ES. Methods. Twenty‐eight symptomatic adult patients of ES with weight ≥30 kg in WHO class II and III were enrolled. Patients were given 40 mg of tadalafil or matching placebo for 6 weeks followed by crossover to the other drug after a washout period of 2 weeks. Assessment of WHO class, exercise capacity by 6 MWD, and various hemodynamic parameters by cardiac catheterization was done at baseline, after 6 weeks and at the end of the study. Results. All patients completed the study. There was significant increase in 6 MWD following drug administration compared with baseline (404.18 ± 69.54 m vs. 357.75 ± 73.25 m, P < .001). Compared with placebo, tadalafil produced significant decrease in PVR (?7.32 ± 1.58, P < .001), resulting in significant increase in EPBF (0.12 ± 0.05, P= .03), SO₂ % (1.72 ± 0.58, P= .007), and WHO functional class (1.96 ± 0.18 vs. 2.14 ± 0.44, P= .025), with no significant change in SVR (P= NS). Conclusion. In this first short‐term placebo‐controlled trial of tadalafil in patients of ES, the drug was well tolerated and significantly improved exercise capacity, functional class, SO₂, and pulmonary hemodynamics. http://www.clinicaltrial.gov/ct2/show/NCT01200732?term=NCT01200732&rank=1     

他达拉非增加小鼠脑实质淋巴瘤微血管通透性的研究

目的 研究他达拉非增加脑淋巴瘤内微血管通透性.方法 采用依文思蓝检测通透性、高效液相法检测氨甲喋呤浓度、以及电镜观察超微结构对比分析他达拉非对小鼠脑实质淋巴瘤模型脑微血管通透性的影响.结果 他达拉非组脑淋巴瘤血管通透性相较其他各组有显著增加(P＜0.05).氨甲喋呤在他达拉非组脑淋巴瘤组织中浓度增加近1.8倍,显著高于其他各组(P＜0.05).他达拉非组小鼠脑淋巴瘤脑微血管内皮细胞内电镜下见大量微囊液泡.结论 磷酸二酯酶抑制剂他达拉非可以显著增加小鼠脑淋巴瘤微血管的通透性.     

Effects of Once-Daily Tadalafil on Erectile Function in Men with Erectile Dysfunction and Signs and Symptoms of Benign Prostatic Hyperplasia

Background

Lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH; BPH-LUTS) may be associated with erectile dysfunction (ED).

Objective

To evaluate the effects of once-daily tadalafil on erectile function in men with ED and BPH-LUTS.

Design, setting, and participants

Post hoc analysis of a phase 2–3, multinational, randomized, double-blind, placebo-controlled, parallel-group study of men with ED and moderate-to-severe LUTS secondary to BPH who reported being sexually active. In contrast to typical ED trials, no sexual activity threshold was required to participate.

Interventions

Screening and 4-wk washout period for patients taking BPH and/or ED treatments; 4-wk placebo run-in period; then once-daily placebo or tadalafil 2.5, 5, 10, or 20 mg for 12 wk.

Measurements

International Index of Erectile Function–Erectile Function (IIEF-EF) domain score, International Prostate Symptom Score (IPSS), peak urinary flow rate (Q_max), and postvoid residual volume (PVR). Analyses were performed in men who reported being sexually active with a female partner and who expected to remain so throughout the study. IIEF-EF data are presented for the BPH/ED population overall and for subgroups stratified by baseline age group, body mass index, BPH-LUTS severity, prostate-specific antigen, prior α-blocker use, and prior ED therapy.

Results and limitations

Overall, 581 men were included (placebo, n = 115; tadalafil 2.5 mg, n = 113; tadalafil 5 mg, n = 117; tadalafil 10 mg, n = 120; tadalafil 20 mg, n = 116). IIEF-EF domain score improvements from baseline to end point with tadalafil were 5.4 (2.5 mg), 6.8 (5 mg), 7.9 (10 mg), and 8.2 (20 mg) versus 2.0 with placebo (least-squares means; all p values <0.001). IIEF-EF domain score improvements were observed with tadalafil for all subgroup analyses, with no significant differences between subgroup or subgroup-by-treatment interaction terms. IPSS improvements from baseline to end point were significantly greater for all tadalafil doses versus placebo (all p values <0.05). Changes in Q_max and PVR were small and not clinically meaningful.

Conclusions

These data support the use of once-daily tadalafil in men with ED and BPH-LUTS.

Trial registration

http://www.clinicaltrials.gov: NCT00384930.     

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.     

A randomized, double-blind, placebo-controlled, cross-over study to assess the efficacy of tadalafil (Cialis) in the treatment of erectile dysfunction following three-dimensional conformal external-beam radiotherapy for prostatic carcinoma

PURPOSE: Erectile dysfunction after three-dimensional conformal external-beam radiotherapy (3DCRT) for prostatic carcinoma is reported in as many as 64% of those patients. The purpose of this study was to determine the efficacy of the oral drug tadalafil (Cialis) in patients with erectile dysfunction after radiotherapy for prostatic carcinoma. METHODS AND MATERIALS: Patients (N=358) who completed radiotherapy at least 12 months before the study were approached by mail. All patients had been treated by 3DCRT; 60 patients were included and entered a double-blind, placebo-controlled, cross-over study lasting 12 weeks. They received 20 mg of tadalafil or placebo for 6 weeks. Drug or placebo was taken on demand at patient's discretion, with no restrictions regarding the consumption of alcohol or food, at least once a week and no more than once daily. At 6 weeks patients crossed over to the alternative treatment. Data were collected using the Sexual Encounter Profile (SEP) and the International Index of Erectile Function (IIEF) questionnaires. Side effects were also recorded. RESULTS: Mean age at study entry was 69 years. All patients completed the study. For almost all questions of the IIEF questionnaire there was a significant increase in mean scores from baseline with tadalafil, but not with placebo. Sixty-seven percent of the patients reported an improvement of erectile function with tadalafil (placebo: 20%), and 48% reported successful intercourse with tadalafil (placebo: 9%) (p<0.0001). Side effects were mild or moderate. CONCLUSIONS: Tadalafil is an effective treatment for erectile dysfunction after 3DCRT for prostatic carcinoma with successful intercourse reported in almost 50% of the patients, and it is well tolerated.     

Ultrastructural Study of Clitoral Cavernous Tissue and Clitoral Blood Flow From Type 1 Diabetic Premenopausal Women on Phosphodiesterase-5 Inhibitor

Background

The effects of phosphodiesterase-type 5 (PDE5) inhibitors on the in vivo clitoral structure of women with diabetes have never been investigated.

Acute effect of phosphodiesterase type 5 inhibitor on serum oxidative status and prolidase activities in men with erectile dysfunction

OBJECTIVES:

To investigate the acute effect of phosphodiesterase type 5 (PDE5) inhibitor on erectile dysfunction by evaluating serum oxidative status and prolidase activity.

METHODS:

Serum samples of 36 patients with erectile dysfunction and 30 control cases were analyzed for total antioxidant status, total oxidant status, and prolidase activity, before and after the administration of tadalafil citrate.

RESULTS:

Before and after tadalafil citrate administration, serum total antioxidant status, total oxidant status, and prolidase were 1.1±0.0 vs. 1.6±0.0 µmol H₂O₂ Eq/L, 10.3±1.1 vs. 6.9±1.2 µmol H₂O₂ Eq/L, and 236.4±19.5 vs. 228.2±19.2 U/L, respectively (p<0.0001 for all).

CONCLUSIONS:

Evaluation of serum oxidative status and prolidase activity confirmed the beneficial acute effects of PDE5 inhibitor in patients with erectile dysfunction.     

他达拉非结合坦洛新治疗慢性前列腺炎伴性功能障碍的80例疗效观察

目的:观察他达拉非结合坦洛新治疗80例慢性前列腺炎伴性功能障碍的临床疗效。方法:我院于2009年3月至2013年3月接收慢性前列腺炎伴性功能障碍患者240例,随机分为他达拉非组(A组)、坦洛新组(B组)和他达拉非结合坦洛新组(C组),每组各80例。A组仅给予药物他达拉非,B组采用坦洛新进行治疗,C组同时给予他达拉非和坦洛新两种药物,比较三组患者的治疗效果,观察三组患者治疗前后NIH-CPSI的积分变化。结果:C组的总有效率为90.00%,与A组(57.50%)和B组(60.00%)相比较差异显著(P<0.05),具有统计学意义。A组和B组之间未见显著性差异(P>0.05)。C组患者的NIHCPSI积分变化包括排尿障碍、生活质量以及NIH-CPSI积分变化与A组和B组相比具有明显差异(P<0.05),A组和B组之间未见明显差异(P>0.05)。结论:他达拉非结合坦洛新治疗慢性前列腺炎伴性功能障碍不失为一种优良的治疗方案,值得在临床上推广使用。     

Tadalafil population pharmacokinetics in patients with erectile dysfunction

Objective The purpose of this study was to characterize pharmacokinetics of tadalafil (Cialis) and potential sources of variability in patients with erectile dysfunction (ED). Methods Population models were developed to describe tadalafil pharmacokinetics in 227 patients with mild to severe ED in a phase III trial. Parallel groups of patients received 2, 5, or 10 mg tadalafil or placebo orally, as needed, for 12 weeks. Results Tadalafil pharmacokinetics in patients with ED were linear with respect to dose and duration of treatment, and a one-compartment model adequately described the data. The absorption rate was rapid (1.86 h⁻¹), and the typical population estimates of the apparent oral clearance (CL/F) and apparent volume of distribution were 1.6 l/h and 63.8 l, respectively. Disposition parameters showed a moderate degree of interindividual variability (39–45%). The value of CL/F decreased slightly with increasing serum γ-glutamyl transferase (GGT) concentration, the only statistically significant covariate detected. Systemic exposure to tadalafil was not influenced by age, weight, smoking status, alcohol consumption, liver enzyme status, ED severity, cardiovascular condition, or diabetes mellitus. Conclusion Pharmacokinetics in the efficacy/safety trial population are essentially similar to pharmacokinetics in healthy subjects, and no patient-specific factor warranting clinical consideration of dose regimen adjustment was identified in these analyses. This research was funded by Lilly ICOS LLC, Indianapolis, IN, and Bothell, WA. Financial disclosure Authors are present (S.T. Forgue) or previous (A. Staab, C. Tillmann) employees of Eli Lilly and Company or have received financial contractual support from this company (I. Troconiz, J. Rapado). S.T. Forgue owns stock in Eli Lilly & Company.