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.     

A successful treatment of tadalafil in incontinentia pigmenti with pulmonary hypertension

We describe a female infant with incontinentia pigmenti complicated by severe pulmonary arterial hypertension that was markedly improved by tadalafil administration. The infant was referred to our institution because of neonatal seizures and generalized skin rash at the age of 1 day. She was diagnosed with incontinentia pigmenti on skin biopsy findings. In addition to incontinentia pigmenti, she had pulmonary arterial hypertension without structural heart disease. The pulmonary hypertension rapidly worsened at the age of 2 months and was confirmed by cardiac catheterization. The pulmonary artery pressure was equal to systemic pressure but it decreased in response to nitric oxide inhalation. We, therefore, initiated treatment with tadalafil of 1 mg/kg/day. The follow-up cardiac catheterization performed at 9 months revealed dramatic improvement in the pulmonary artery pressure. An IKBKG mutation with deletion of exons 4–10 was detected in the blood of both the patient and her mother. Our experience indicates that tadalafil may be beneficial in treating pulmonary arterial hypertension associated with incontinentia pigmenti.     

Tadalafil improves short-term memory by suppressing ischemia-induced apoptosis of hippocampal neuronal cells in gerbils

Cerebral ischemia resulting from transient or permanent cerebral artery occlusion leads to neuronal cell death, and eventually causes neurological impairments. Tadalafil (Cialis^®) is a long-acting phosphodiesterase type-5 (PDE-5) inhibitor used to treat erectile dysfunction. The therapeutic effects of PDE-5 inhibitors on chronic obstructive pulmonary disease, prostate hyperplasia, hypertension, and coronary heart disease have been reported. The present study investigated the effects of tadalafil on short-term memory, cyclic guanosine monophosphate (cGMP) level, apoptotic neuronal cell death, and cell proliferation in the hippocampus following transient global ischemia in gerbils. For this study, a step-down avoidance task, cGMP assay, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, and immunohistochemistry for caspase-3 and 5-bromo-2′-deoxyuridine were performed. The results revealed that ischemic injury increased apoptotic neuronal cell death in the hippocampal CA1 region, impaired short-term memory, and decreased cGMP level. Ischemic injury enhanced cell proliferation in the hippocampal dentate gyrus. Tadalafil treatment improved short-term memory by suppressing ischemia-induced apoptotic neuronal cell death in the hippocampal CA1 region, and decreased cGMP level. Also, tadalafil suppressed the ischemia-induced increase in cell proliferation in the hippocampal dentate gyrus. We showed that tadalafil can overcome ischemia-induced apoptotic neuronal cell death, thus facilitates recovery following ischemic cerebral injury.     

明目蒺藜丸联合聚乙烯醇滴眼液治疗干眼症的临床研究

目的 制备他达拉非片并考察其体内外释药特性。方法 以溶出度为评价指标,筛选他达拉非片各辅料用量及包衣增重。用相似因子（f₂）法比较自制制剂与参比制剂在0.5% SDS溶液、含0.5% SDS的0.1 mol/L的盐酸溶液、含0.5% SDS的pH 4.5醋酸钠缓冲液、含0.5% SDS的pH 6.8磷酸盐缓冲液中溶出曲线的相似性。比较二者在Beagle犬体内的药动学特征。结果 他达拉非片处方为他达拉非20 mg、乳糖50M 227.625 mg、羟丙基纤维素L 10.5 mg、交联羧甲基纤维素钠19.6 mg、SDS 0.525 mg、微晶纤维素M102 70 mg、硬脂酸镁1.75 mg,包衣增质量范围2%～4%。自制与参比制剂在4种溶出介质中的f₂均大于65,二者体外溶出行为相似。2种制剂在Beagle体内的药动学参数AUC_0~t、C_max、t_max均无显著性差异,自制他达拉非片的相对生物利用度为（101.67±8.99）%。结论 成功制备他达拉非片,其体外溶出和体内药动学行为与参比制剂相似。     

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.

西地那非联合小剂量他达拉非治疗重度勃起功能障碍的临床观察

目的探讨重度勃起功能障碍更简单易行的治疗方法。方法本文选择汉中市人民医院泌尿外科2016年10月至2019年2月门诊收治的重勃起功能障碍的65例患者。随机分为联合用药组(n=33)和单一用药组(n=32)。单一用药组使用西地那非片100mg,按需口服治疗;联合用药组在单一用药组的基础上,联合口服他达拉非5mg,每天1次。观察比较两组患者的疗效及不良反应发生情况。选用男科国际常用的疗效评估方法:勃起功能国际问卷(IIEF-5)评分、勃起硬度(EHS)评分,来评估疗效。结果联合用药组效果明显优于单一用药组,两组差异有显著统计学意义(P<0.05)。结论西地那非和他达那非联合使用治疗重度勃起功能障碍,较单用西地那非临床疗效显著,并不显著增加副作用。可以有效改善患者生活质量,值得推广应用。     

隔日小剂量他达拉非治疗2型糖尿病勃起功能障碍

目的:探讨隔日小剂量他达拉非治疗2型糖尿病功能障碍的临床疗效及安全性。方法:110例2型糖尿病功能障碍患者隔日口服他达拉非5mg,共8周。采用国际勃起功能指数问卷(IIEF-5)评分、性生活日记中插入成功率和性交中成功保持勃起至完成性交的成功率、并辅助阴茎勃起硬度等级评定作为治疗前后疗效评价指标。结果:110例患者勃起功能改善者为81例,有效率73.6%;治疗后IIFE-5评分有显著提高;治疗后性生活日记中插入成功率和性交中成功保持勃起至完成性交的成功率明显增高;治疗后阴茎勃起硬度达到Ⅲ级以上有81例;治疗期间无明显不良反应发生。结论:长期隔日小剂量他达拉非可有效治疗2型糖尿病勃起功能障碍,且耐受性良好,可作为临床上一种经济有效的方法。     

Are phosphodiesterase type 5 inhibitors effective for the management of lower urinary symptoms suggestive of benign prostatic hyperplasia?

AIM: To review the efficacy of phosphodiesterase type 5 inhibitors(PDE5-Is) in lower urinary tract symptoms(LUTS) suggestive of benign prostate hyperplasia(LUTS/BPH). METHODS: A comprehensive research was conducted to identify all publications relating to benign prostate hyperplasia and treatment with sildenafil, vardenafil and tadalafil. To assess the efficacy, the changes in total international prostate symptom score(IPSS), IPSS subscore including voiding, storage and quality of life(Qo L), Benign prostatic hyperplasia Impact Index(BII), maximum urinary flow rate(Qmax) and the International Index of Erectile Function(IIEF) were extracted. A meta-analytical technique was used for the analysis of integrated data from the included studies to evaluate the mean difference in the results. RESULTS: Total IPSS score, IIEF and BII showed a significant improvement in trials in which LUTS/BPH with or without erectile dysfunction(ED) were compared with the placebo. For LUTS/BPH, the mean differences of total IPSS score, IIEF and BII are-2.17, 4.88 and-0.43, P 0.00001, respectively. For LUTS/BPH with comorbid ED, the mean difference are-1.97, 4.54 and-0.52, P 0.00001, respectively. PDE5-Is appear to improve IPSS storage, voiding and Qo L subscore(mean difference =-0.71,-1.23 and-0.33, P 0.00001, respectively). Although four doses of tadalafil(2.5, 5, 10 and 20 mg) failed to reach significance in Qmax(mean difference = 0.22, P = 0.10), the 5 mg dose of tadalafil significantly improved the Qmax(mean difference = 0.33, P = 0.03).CONCLUSION: PED5-Is demonstrated efficacy for improving LUTS in BPH patients with or without ED and could be considered to be the first line treatment for LUTS/BPH.     

二地鳖甲煎联合他达拉非治疗糖尿病性勃起功能障碍35例

目的?探讨二地鳖甲煎联合小剂量他达拉非治疗糖尿病性勃起功能障碍（DED）的临床疗效。方法?选取70例DED患者,随机将其分为治疗组和对照组各35例,治疗组给予二地鳖甲煎汤剂每日1剂,分早晚2次口服,他达拉非片5?mg每晚1次口服,连续使用8周;对照组口服他达拉非片5?mg每晚1次,连续服用8周。治疗前后进行IIEF-5评分以及夜间阴茎勃起检查。结果?2组治疗后IIEF-5评分以及夜间阴茎勃起检查结果均有显著提高（P<0.01）,治疗后治疗组优于对照组（P＜0.05）。2组均未出现严重不良反应。结论?二地鳖甲煎联合小剂量他达拉非治疗DED安全有效,值得临床推广。      

Hemodynamic effects of ambrisentan-tadalafil combination therapy on progressive portopulmonary hypertension

Intravenous epoprostenol is recommended for World Health Organization functional class(WHO-FC) Ⅳ patients with pulmonary arterial hypertension(PAH) in the latest guidelines. However, in portopulmonary hypertension(PoP H) patients, advanced liver dysfunction and/or thrombocytopenia often makes the use of intravenous epoprostenol challenging. Here we report the cases of two WHO-FC Ⅳ PoP H patients who were successfully treated with a combination of two oral vasodilators used to treat PAH: ambrisentan and tadalafil. Oral vasodilator therapy using a combination of ambrisentan and tadalafil may be a safe and effective therapeutic option for WHO-FC Ⅳ PoP H patients and should be considered for selected patients with severe and rapidly progressing PoP H.