Diabetic nephropathy:Treatment with phosphodiesterase type 5 inhibitors

The importance of nitric oxide(NO) in vascular physiology is irrefutable;it stimulates the intracellular production of cyclic guanosine monophosphate(cGMP),initiating vascular smooth muscle relaxation.This biochemical process increases the diameter of small arteries,regulating blood flow distribution between arterioles and the microvasculature.The kidney is no exception,since NO predominantly dilates the glomerular afferent arterioles.It is now evident that the vascular production of cGMP can be augmented by inhibitors of phosphodiesterase type 5(PDE 5),the enzyme which breakdowns this cyclic nucleotide.This has clinical relevance,since diabetic nephropathy(DN) a major microvascular complication of diabetes mellitus and the most common cause of end-stage renal disease,increases intraglomerular capillary pressure,leading to glomerular hypertension.PDE 5 inhibitors may have,therefore,the potential to reduce glomerular hypertension.This review describes the use of PDE 5 inhibitors to improve the metabolic,haemodynamic and inflammatory pathways/responses,all of which are dysfunctional in DN.

Erectile potentials of a new phosphodiesterase type 5 inhibitor, DA-8159, in diet-induced obese rats

Aim： To examine the changes in the erectile function in diet-induced obese rats and investigate the oral efficacy of DA-8159, a new phosphodiesterase type 5 （PDE5） inhibitor, on penile erection in obese rats. Methods： The rats were fed a high-energy diet for 12 weeks and divided into three groups： an obesity-resistant （OR） control group, an obesity-prone （OP） control group, and an OP-DA-8159 treatment （DA-8159） group. The electrostimulation-induced erectile responses were measured in all groups. The body weight, plasma cholesterol, triglyceride and glucose levels were also measured. Results： In the OP control group, the maximum intracavernous pressure （ICP） and ICP/blood pressure （ICP/BP） ratio after electric stimulation were significantly lower than those in OR control group. The corresponding area under the curve （AUC） of the ICP/BP ratio, the detumescence time and the baseline cavernous pressure were also lower than those in the OR control group, but this difference was not significant. The body weight gain, plasma cholesterol and triglyceride level in the OP group were significantly higher than those in the OR group. After administering the DA-8159, a significant increase in the maximum ICP and the ICP/BP ratio were observed. The corresponding AUCs in the DA-8159 group were also higher than those in the two control groups. Furthermore, the detumescence time was significantly prolonged after treatment with DA-8159. Conclusion： These results demon- strate that diet-induced obesity affects the erectile function in rats and these erectile dysfunction （ED） can be improved by the treatment with DA-8159, indicating DA-8159 might be a treatment option for ED associated with obesity.

Incidence rate of prostate cancer in men treated for erectile dysfunction with phosphodiesterase type 5 inhibitors： retrospective analysis

The purpose of this study was to determine the incidence rate of prostate cancer among men with erectile dysfunction （ED） treated with phosphodiesterase type 5 inhibitors （PDE-5i） over a 7-year period vs. men with ED of the same age and with similar risk factors who were not treated with PDE-5i. In a retrospective review of electronic medical records and billing databases between the years 2000 and 2006, men with ED between the ages of 50 and 69 years and no history of prostate cancer prior to 2000 were identified. These individuals were divided into two groups： 2362 men who had treatment with PDE-5i, and 2612 men who did not have treatment. Demographic data in each group were compared. During the study period, 97 （4.1%） men with ED treated with PDE-5i were diagnosed with prostate cancer compared with 258 （9.9%） men with ED in the non-treated group （P〈00001）. A higher percentage of African Americans were treated with PDE-5i vs. those who were not （10.5% vs. 7.1%; P〈O.O001）. The PDE-5i group had lower documented diagnosis of elevated prostate-specific antigen （10.0% vs. 13.1%; P=-0.0008） and higher percentage of benign prostatic hyperplasia （38.4% vs. 35.1%; P=0.0149）. Men with ED treated with PDE-5i tended to have less chance （adjusted odds ratio： 0.4; 95% confidence intervals： 0.3-0.5; P〈0.0001） of having prostate cancer. Our data suggest that men with ED treated with PDE-5i tended to have less of a chance of beine diaenosed with orostate cancer. Further research is warranted.

Evaluation and diagnostic testing of erectile dysfunction in the era of phosphodiesterase type 5 inhibitors

The diagnosis and treatment of erectile dysfunction has changed dramatically since the availability of safe and effective oral therapies. Unfortunately, not all men can be adequately treated in this way, and might require more invasive testing to diagnose and treat the specific cause of their dysfunction. This review looks at the tests and strategies available for men who cannot be treated by oral therapy alone.

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.

Erectile potentials of a new phosphodiesterase type 5 inhibitor,DA-8159,in diet-induced obese rats

Aim:To examine the changes in the erectile function in diet-induced obese rats and investigate the oral efficacy of DA-8159,a new phosphodiesterase type 5(PDE5)inhibitor,on penile erection in obese rats.Methods:The rats were fed a high-energy diet for 12 weeks and divided into three groups:an obesity-resistant(OR)control group,an obesity- prone(OP)control group,and an OP-DA-8159 treatment(DA-8159)group.The electrostimulation-induced erectile responses were measured in all groups.The body weight,plasma cholesterol,triglyceride and glucose levels were also measured.Results:In the OP control group,the maximum intracavernous pressure(ICP)and ICP/blood pressure(ICP/BP)ratio after electric stimulation were significantly lower than those in OR control group.The corresponding area under the curve(AUC)of the ICP/BP ratio,the detumescence time and the baseline cavernous pressure were also lower than those in the OR control group,but this difference was not significant.The body weight gain,plasma cholesterol and triglyceride level in the OP group were significantly higher than those in the OR group. After administering the DA-8159,a significant increase in the maximum ICP and the ICP/BP ratio were observed.The coerrsponding AUCs in the DA-8159 group were also higher than those in the two control groups.Furthermore,the detumescence time was significantly prolonged after treatment with DA-8159.Conclusion:These results demon- strate that diet-induced obesity affects the erectile function in rats and these erectile dysfunction(ED)can be im- proved by the treatment with DA-8159,indicating DA-8159 might be a treatment option for ED associated with obesity.

磷酸二酯酶5在心力衰竭中作用的研究进展

磷酸二酯酶5(PDE5)是环磷酸鸟苷(cGMP)特异性水解酶,是由一氧化氮(NO)激活的可溶性鸟苷酸环化酶(sGC)靶向cGMP产生的。PDE5催化cGMP中磷酸二酯键的水解,从而将cGMP转化为无活性的5′-GMP形式,cGMP-PKG轴功能障碍将引起心脏重塑,是心力衰竭(HF)的主要原因之一。但PDE5抑制剂治疗心力衰竭的临床疗效存在争议。本文总结了近年来PDE5在心力衰竭中的作用机制和研究进展,对未来临床应用PDE5靶向治疗心力衰竭具有重要的指导意义。

Effects of phosphodiesterase 5 inhibitors on sperm parameters and fertilizing capacity

The aim of this review study is to elucidate the effects that phosphodiesterase 5 （PDE5） inhibitors exert on spermatozoa motility, capacitation process and on their ability to fertilize the oocyte. Second messenger systems such as the cAMP/adenylate cyclase （AC） system and the cGMP/guanylate cyclase （GC） system appear to regulate sperm functions. Increased levels of intracytosolic cAMP result in an enhancement of sperm motility and viability. The stimulation of GC by low doses of nitric oxide （NO） leads to an improvement or maintenance of sperm motility, whereas higher concentrations have an adverse effect on sperm parameters. Several in vivo and in vitro studies have been carried out in order to examine whether PDE5 inhibitors affect positively or negatively sperm parameters and sperm fertilizing capacity. The results of these studies are controversial. Some of these studies demonstrate no significant effects of PDE5 inhibitors on the motility, viability, and morphology of spermatozoa collected from men that have been treated with PDE5 inhibitors. On the other hand, several studies demonstrate a positive effect of PDE5 inhibitors on sperm motility both in vivo and in vitro. In vitro studies of sildenafil citrate demonstrate a stimulatory effect on sperm motility with an increase in intracellular cAMP suggesting an inhibitory action of sildenafil citrate on a PDE isoform other than the PDE5. On the other hand, tadalafil＇s actions appear to be associated with the inhibitory effect of this compound on PDE11. In vivo studies in men treated with vardenafil in a daily basis demonstrated a significantly larger total number of spermatozoa per ejaculate, quantitative sperm motility, and qualitative sperm motility; it has been suggested that vardenafil administration enhances the secretory function of the prostate and subsequently increases the qualitative and quantitative motility of spermatozoa. The effect that PDE5 inhibitors exert on sperm parameters may lead to the improvement of the outcome of assisted reproductive technology （ART） programs. In the future PDE5 inhibitors might serve as adjunct therapeutical agents for the alleviation of male infertility.

Patterns of treatment with PDE5 inhibitors in the clinical practice in Italy： longitudinal data from the Erectile Dysfunction Observational Study

The Erectile Dysfunction Observational Study （EDOS） is a 6-months observational prospective multicentric study enrolling men with erectile dysfunction （ED） who asked, to be started on a treatment or to change a previous treatment. Aims of the study were to analyse the pattern of treatment and compare the efficacy of treatments used. Patients were enrolled during a normal hospital visit and were prescribed a treatment for ED. They were asked at baseline and after 3 and 6 months, to answer a set of questions from the International Index of Erectile Function, Erectile Dysfunction Inventory of Treatment Satisfaction （EDITS） and Short Form of the Psychological and Interpersonal Relationships Scale questionnaires （SF-PAIRS）. Clinicians were free to prescribe any therapy for ED available in the market, and to change therapy at any time during the study. Out of 1 338 patients, available for analysis at 6 months, 624 （47%） changed their treatment during the study and 714 （53%） continued with the drug prescribed at baseline. Patients assuming tadalafil had a significantly higher probability of maintaining the same treatment compared to sildenafil or vardenafil. There was no clinically significant difference in terms of efficacy, patient satisfaction, self-confidence and spontaneity between the different inhibitors of PDE5. The ‘time concerns＇ domain score of SF-PAIRS, was statistically better in patients assuming tadalafil. In conclusion sildenafil, vardenafil and tadalafil show similar efficacy in the clinical practice. However, patients receiving tadalafil display a lower risk to discontinue or change the treatment.

Effect of Icariin on Cyclic GMP Levels and on the mRNA Expression of cGMP-binding cGMP-specific Phosphodiesterase (PDE5) in Penile Cavernosum

Summary： To further investigate the mechanisms of action of icariin （ICA）, we assessed the effects of ICA on the in vitro formation of cGMP and cAMP in isolated rabbit corpus cavernosum. Isolated segments of rabbit corpus cavernosum were exposed to increasing concentrations of ICA and the dose-dependent accumulation of cGMP and cAMP was determined in the tissues samples by means of ^125I radioimmunoassay. Responses of the isolated tissues preparations to ICA were compared with those obtained with the reference compounds sildenafil （Sild）. Furthermore, the effects of ICA on the mRNA expression of specific cGMP-binding phosphodiesterase type Ⅴ （PDE5） in rat penis were also observed. After incubation with ICA for 6 h or 14 h respectively, the levels of PDE5 mRNA were examined by reverse transcriptase polymerase chain reaction （RT-PCR）. The results showed that ICA increased cGMP concentrations directly （P〈0.05）, but there was no significant effect on cAMP concentrations （P〉0.05）. In the presence of sodium nitroprusside （SNP）, a stimulatory agent of cGMP, both ICA and Sild increased cGMP concentrations with increasing dose （P〈0.01）. Their EC50 was 4.62 （ICA） and 0.42 （Sild） μmol/L respectively. Under the same condition, ICA and Sild unaltered cAMP level significantly （P〉0.05）. There were PDE5A 1 and PDE5A2 mRNA expressions in rat cor- pus cavernosum with PDE5A2 being the dominant isoform. ICA could obviously inhibit these two isoforms mRNA expression in rat penis, and decrease PDE5A1 more pronouncedly （P〈 0.01）. The present study indicated that the aphrodisiac mechanisms of icariin involved the NO-cGMP signal transduction pathway, with increasing cGMP levels in the corpus cavernosum smooth muscle. The inhibitory effect of icariin on PDE5 mRNA expression, especially on PDE5A1, might account for its molecular mechanisms for its long-term activity.

The use of antimuscarinics,phosphodiesterase type Ⅴ inhibitors and phytotherapy for lower urinary tract symptoms in men

Besides the mainstay of α-blockers and 5α-reductase inhibitors,other forms of medical therapy complete the armamentarium in the treatment of lower urinary tract symptoms(LUTS)in men.These treatments can target specific symptoms as well as associated symptoms that would affect the quality of life of the patients.Many patients are bothered by storage symptoms,more so than the voiding symptoms.Antimuscarinics are efficacious and safe,provided the patients do not have high post void residual urine.Many patients with LUTS also have erectile dysfunction,and phosphodiesterase type Ⅴ inhibitors are effective in relieving both LUTS as well as erectile dysfunction for such patients.Phytotherapy provides a popular and safe treatment for LUTS,however,the efficacy of the treatment has not been proven in well conducted prospective randomized controlled studies.

PDE5 inhibitors promote recovery of peripheral neuropathy in diabetic mice

Diabetes mellitus affects an estimated 422 million people worldwide.Peripheral neuropathy is one of the most common and disabling complications of diabetes.There is currently no effective treatment for diabetic neuropathy,

Statin, testosterone and phosphodiesterase 5-inhibitor treatments and age related mortality in diabetes

AIMTo determine how statins, testosterone (T) replacement therapy (TRT) and phosphodiesterase 5-inhibitors (PDE5I) influence age related mortality in diabetic men.METHODSWe studied 857 diabetic men screened for the BLAST study, stratifying them (mean follow-up = 3.8 years) into: (1) Normal T levels/untreated (total T > 12 nmol/L and free T > 0.25 nmol/L), Low T/untreated and Low T/treated; (2) PDE5I/untreated and PDE5I/treated; and (3) statin/untreated and statin/treated groups. The relationship between age and mortality, alone and with T/TRT, statin and PDE5I treatment was studied using logistic regression. Mortality probability and 95%CI were calculated from the above models for each individual.RESULTSAge was associated with mortality (logistic regression, OR = 1.10, 95%CI: 1.08-1.13, P < 0.001). With all factors included, age (OR = 1.08, 95%CI: 1.06-1.11, P < 0.001), Low T/treated (OR = 0.38, 95%CI: 0.15-0.92, P = 0.033), PDE5I/treated (OR = 0.17, 95%CI: 0.053-0.56, P = 0.004) and statin/treated (OR = 0.59, 95%CI: 0.36-0.97, P = 0.038) were associated with lower mortality. Age related mortality was as described by Gompertz, r2 = 0.881 when Ln (mortality) was plotted against age. The probability of mortality and 95%CI (from logistic regression) of individuals, treated/untreated with the drugs, alone and in combination was plotted against age. Overlap of 95%CI lines was evident with statins and TRT. No overlap was evident with PDE5I alone and with statins and TRT, this suggesting a change in the relationship between age and mortality.CONCLUSIONWe show that statins, PDE5I and TRT reduce mortality in diabetes. PDE5I, alone and with the other treatments significantly alter age related mortality in diabetic men.

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),P<0.001。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),P<0.001。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),P<0.001。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),P<0.001。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),P<0.001。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),P<0.001。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),P<0.001。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。

疏肝理气活血法对肝郁气滞大鼠阴茎海绵体PDE5活性影响的实验研究

目的 :探求肝郁气滞阴茎海绵体组织中Ⅴ型磷酸二酯酶 (PDE5 )活性及疏肝理气活血中药对其影响。 方法 :采用与人类精神性应激十分相似的非损伤性应激刺激法 ,制造肝郁气滞型SD大鼠动物模型 4 0只 ,随机法将大鼠分为 :空白组 ;肝郁证造模组 (简称模型组 ) ;萎康凝胶高剂量给药组 (高剂量组 )和低剂量给药组 (低剂量组 ) 4组 ,每组 10只。以免疫组化与计算机图像分析技术测定海绵体组织中PDE5活性。 结果 :高剂量组阴茎海绵体组织中PDE5活性与模型组差异有显著性 (P <0 .0 1)。 结论 :肝郁气滞可导致阴茎海绵体组织中PDE5活性增强 。

PDE5抑制剂对精子活力及受精功能影响的研究进展

磷酸二酯酶-5(PDE5)抑制剂常用于治疗阴茎勃起功能障碍。近年来,研究发现PDE5抑制剂对精子的活力和受精功能有影响,尤其在适当药物浓度时能显著提高精子运动能力。该文就PDE5抑制剂对精子活力和受精功能的影响进行综述。

PDE5抑制剂治疗ED研究进展

勃起功能障碍(ED)是中老年人的常见疾病。自1998年西地那非用于临床治疗ED以来,ED的治疗进入了一个新阶段。西地那非以其疗效确切、安全性高成为首选治疗。近年来新的PDE5抑制剂伐地那非和他达拉非相继问世,为口服药治疗ED提供了更多选择。本文就PDE5抑制剂的基础与临床研究成果作一综述,以期为临床医生选择使用提供参考。

PDE5抑制剂治疗缺血再灌注损伤研究进展

5型磷酸二酯酶(PDE5)抑制剂常用于治疗男性阴茎勃起功能障碍。近年来,有实验研究表明PDE5抑制剂可用于治疗器官组织缺血再灌注损伤,本文就PDE5抑制剂治疗缺血再灌注损伤的基础和临床研究成果作一综述,以期为临床医生选择使用PDE5抑制剂提供理论依据。

PDE5抑制剂也是勃起功能障碍治疗的引经良药

引经理论是中医药独特的理论,与现代靶向给药体系有一定的相通之处。现代药理研究揭示了引经实质的一些科学内涵,可能与引经药改变了药物在体内的分布,改变了药物的代谢有关。现代医学中,磷酸二酯酶5抑制剂(PDE5i)在ED治疗上应用广泛,主要作用机制为增加动脉供血和改善阴茎血管内皮功能为主。中医学也逐步与现代医学互鉴融合,在中西医结合治疗ED时也常用PDE5i,目前主流观点为活血、补肾等作用。但PDE5i也具有引经药的一些显著特征和优点,可以在中医药理论的指导下,纳入到ED的中医药治疗体系中来,发挥增效作用。

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。