Administration Of Phosphodiesterase Type 5 Inhibitors Research Articles

Effect of phosphodiesterase type 5 inhibitors on surgical outcome of ventricular septal defect and pulmonary hypertension patients

BackgroundChildren with ventricular septal defect (VSD) and large systemic-to-pulmonary shunts eventually develop pulmonary hypertension (PH). The perioperative management of patients with VSD and PH is quite troublesome and still debatable, especially in developing countries where the different management options and standardization of treatment is not available. Oral phosphodiesterase type 5 (PDE-5) inhibitors are good treatment options being widely available, cheap, easy administration and do not require extensive monitoring. The aim of our study was to evaluate the effect of the PDE-5 inhibitors when given orally, early preoperative and continued for 3 months postoperative on controlling postoperative PH with its effect on right ventricle (RV) functions. Fifty-one patients were randomly assigned to either sildenafil or tadalafil, 1 week before and continued for 3 months after corrective surgery. The control group received a placebo.ResultsThere was no significant difference in the improvement in the right ventricle systolic pressure (RVSP) between both groups, early in the postoperative period (P = 0.255) and in follow-up (P = 0.259). There was also no significant difference in the changes in mean pulmonary artery pressure (mPAP), postoperatively and on follow-up (P = 0.788 and 0.059, respectively). There was a drop in RV functions in both groups postoperatively which improved on follow-up; however, it was not significant between both groups. The length of intensive care unit (ICU) stay was similar between both groups (P = 0.143).ConclusionPerioperative administration of PDE-5 inhibitors does not have an impact on the clinical course as regards improvement in pulmonary artery (PA) pressure, ventricular functions and ICU stay.

The Effect of Phosphodiesterase-type 5 Inhibitors on Erectile Function: An Overview of Systematic Reviews.

Background: Multiple systematic reviews explore the effect of phosphodiesterase type 5 (PDE5) inhibitors on erectile dysfunction (ED), with each study addressing specific outcomes. However, physicians and policymakers require a holistic approach of this topic.Objective: To summarize the current evidence regarding the efficacy and safety of PDE5 inhibitors for the management of ED through an overview of systematic reviews.Methods: Studies were identified by searching PubMed, Web of Science, Cochrane Library and Scopus databases, as well as sources of grey literature until June 12, 2021 (PROSPERO: CRD42020216754). We considered systematic reviews, meta-analyses or network meta-analyses of randomized trials that provided outcomes about the efficacy and safety of any approved PDE5 inhibitor (avanafil, sildenafil, tadalafil and vardenafil). We constructed forest plots for meta-analytic effects regarding the change in erectile function, adverse events and dropouts after administration of PDE5 inhibitors in the general population and in specific patient groups.Results: We included 23 studies with 154,796 participants and a total of 258 meta-analytic effects. Sildenafil 25 mg [Weighted Mean Difference (WMD): 13.08, 95% Confidence Interval (CI): 10.1-16.06] seemed to be statistically superior to all interventions in improving erectile function compared to placebo, but studies with low-dose sildenafil are lacking. Moreover, comparing among different PDE5 inhibitors, sildenafil 50 mg or sildenafil 100 mg were considered the most effective compounds in the general population. The latter derived, however, predominantly from indirect comparisons among different PDE5 inhibitors. Still, sildenafil 100 mg was associated with more treatment-related adverse events and dropouts. Interestingly, low-dose daily tadalafil may be more effective than high-dose on-demand tadalafil (WMD: 1.24, 95% CI: 0.03-2.44). Furthermore, testosterone and PDE5 inhibitors in patients with ED and hypogonadism seem to further improve symptoms, while the addition of a-blockers in patients with urinary symptoms treated with PDE5 inhibitors does not provide additional benefits (WMD: −0.8, 95% CI: −1.65-0.06).Conclusion: Although the efficacy and safety of PDE5 inhibitors, compared to placebo, is well-documented, the existing evidence comparing different PDE5 inhibitors is low. Therefore, high-quality, head-to-head, trials comparing different PDE5 inhibitors are necessary to determine their ideal dosage and formulation based on their safety and efficacy profile.Systematic Review Registration: PROSPERO, identifier [CRD42020216754].

The Role of Testosterone in Amplifying the Effect of a Phosphodiesterase Type 5 Inhibitor After Pelvic Irradiation

BackgroundAfter radiotherapy, the risk of hypogonadism increases, and the incidence of erectile dysfunction increases with time. AimWe investigated the effect of testosterone and a phosphodiesterase type 5 inhibitor (PDE5I) on erectile tissue after radiotherapy. Methods12 male Wistar rats were assigned to each of 5 groups (group C: control; group R: radiation; group RPT: radiation, testosterone, and a PDE5I; group RP: radiation and a PDE5I; and group RT: radiation and testosterone). A 12.5 Gy/fraction dose was administered to the rectum in groups R, RPT, RP, and RT. Udenafil (20 mg/kg) was administered daily via nasogastric tubes in group RPT and group RP for 4 weeks starting 1 day after radiotherapy. Testosterone enanthate (25 mg/kg, IM) was administered immediately after radiotherapy in group RT and group RPT. 6 rats from each group were used to evaluate endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), and NOX2, and cavernosal pressure was evaluated in the other 6 rats in each group. OutcomeTestosterone enhanced the effect of PDE5I on penile tissue after radiotherapy by amplifying the nitric oxide synthase activity. ResultseNOS mRNA expression increased in response to either testosterone replacement or PDE5I administration after radiotherapy. nNOS mRNA expression did not significantly increase in response to testosterone replacement, but testosterone significantly enhanced the effect of PDE5I on nNOS mRNA expression. Testosterone significantly amplified the effect of PDE5I on both eNOS and nNOS protein expression. Both testosterone and PDE5I reduced NOX2 protein expression. The intracavernosal pressure during electrical stimulation showed that testosterone alone did not significantly enhance erectile function. Clinical TranslationClinicians should consider both hypoxic tissue damage and hypogonadism during and after radiation, and the combination of testosterone and PDE5I could be more beneficial for preserving erectile tissue than either individual treatment. Strengths & LimitationsThis study describes the role of testosterone in amplifying the effect of a PDE5I on pelvic radiotherapy-induced hypogonadism. However, we did not show the time-dependent effects of testosterone and PDE5I. ConclusionsDespite the fact that the intracavernosal pressure during electrical stimulation did not significantly increase with testosterone replacement after radiotherapy, important changes in nitric oxide synthase activity and superoxide regulation might have amplifying effects on erectile tissue. Therefore, we recommend that physicians monitor testosterone levels and should not hesitate to combine testosterone and PDE5I in cases of radiation-induced hypogonadism if testosterone replacement is not contraindicated.Lee DS, Sohn DW. The Role of Testosterone in Amplifying the Effect of a Phosphodiesterase Type 5 Inhibitor After Pelvic Irradiation. J Sex Med 2020;17:1268–1279.

Administration of sildenafil citrate not able to reduced hs-CRP on erectile dysfunction patient at Doctor Soetomo Hospital, Surabaya, Indonesia

Background: Phosphodiesterase type-5 (PDE5) inhibitors was the first choice for the oral treatment of erectile dysfunction because of its ability to prevent endothelial dysfunction and restored erectile function properly. However, the inflammatory parameter such as hs-CRP can be used to assess the performance of PDE5 inhibitors as well as clinical questionnaires, IIEF-5, and EHS. So that, this study aims to determine the effect of PDE5 inhibitors administration such as sildenafil citrate 50 mg per day can decrease the value of hs-CRP, as well as increased the IIEF-5 and EHS at Dr. Soetomo General Hospital.Methods: A true clinical experimental studies used pretest and posttest control group design were carried out among 20 patients during 4 weeks. In the next 2 weeks, the crossover was conducted among respondents for the washout period whereas divided into 2 groups, control (K1 and K2) and treatment (P1 and P2). Data were analyzed using Statistical Package for the Social Sciences (SPSS) version 16.0 software for Windows.Results: The average age of group K1 and P2 was 51 ± 12.07 years old whereas 48.60 ± 15.40 years old in group P1 and K2. The research was conducted in Andrology Clinic of Doctor Soetomo Hospital in Surabaya during June to November 2017. The research data were not normally distributed, then analyzed by two-tail T-group tests and Wilcoxon test at significance level α=0.05. The results showed that PDE5 inhibitors did not decrease the hs-CRP significantly (p>0.05), but increased EHS (p<0.05) and increased IIEF-5 (p<0.05) significantly.Conclusion: This study concluded that the administration of sildenafil citrate per day by oral increased the EHS and IIEF-5, but not able to reduced hs-CRP in patients with erectile dysfunction significantly.

The effects of single versus combined therapy using LIM-kinase 2 inhibitor and type 5 phosphodiesterase inhibitor on erectile function in a rat model of cavernous nerve injury-induced erectile dysfunction.

We aimed to determine whether combination of LIM-kinase 2 inhibitor (LIMK2i) and phosphodiesterase type-5 inhibitor (PDE5i) could restore erectile function through suppressing cavernous fibrosis and improving cavernous apoptosis in a rat model of cavernous nerve crush injury (CNCI). Seventy 12-week-old Sprague–Dawley rats were equally distributed into five groups as follows: (1) sham surgery (Group S), (2) CNCI (Group I), (3) CNCI treated with daily intraperitoneal administration of 10.0 mg kg−1 LIMK2i (Group I + L), (4) daily oral administration of 20.0 mg kg−1 udenafil, PDE5i (Group I + U), and (5) combined administration of 10.0 mg kg−1 LIMK2i and 20.0 mg kg−1 udenafil (Group I + L + U). Rats in Groups I + L, I + U, and I + L + U were treated with respective regimens for 2 weeks after CNCI. At 2 weeks after surgery, erectile response was assessed using electrostimulation. Penile tissues were processed for histological studies and western blot. Group I showed lower intracavernous pressure (ICP)/mean arterial pressure (MAP), lower area under the curve (AUC)/MAP, decreased immunohistochemical staining for alpha-smooth muscle (SM) actin, higher apoptotic index, lower SM/collagen ratio, increased phospho-LIMK2-positive fibroblasts, decreased protein kinase B/endothelial nitric oxide synthase (Akt/eNOS) phosphorylation, increased LIMK2/cofilin phosphorylation, and increased protein expression of fibronectin, compared to Group S. In all three treatment groups, erectile responses, protein expression of fibronectin, and SM/collagen ratio were improved. Group I + L + U showed greater improvement in erectile response than Group I + L. SM content and apoptotic index in Groups I + U and I + L + U were improved compared to those in Group I. However, Group I + L did not show a significant improvement in SM content or apoptotic index. The number of phospho-LIMK2-positive fibroblasts was normalized in Groups I + L and I + L + U, but not in Group I + U. Akt/eNOS phosphorylation was improved in Groups I + U and I + L + U, but not in Group I + L. LIMK2/cofilin phosphorylation was improved in Groups I + L and I + L + U, but not in Group I + U. Our data indicate that combined treatment of LIMK2i and PDE5i immediate after CN injury could improve erectile function by improving cavernous apoptosis or eNOS phosphorylation and suppressing cavernous fibrosis. Rectification of Akt/eNOS and LIMK2/cofilin pathways appears to be involved in their improvement.

The development of rat models induced by cavernous nerve injury

Background and Objective: Erectile dysfunction (ED) caused by iatrogenic cavernous nerve injury (CNI) is a common complication in males undergoing pelvic surgery. Despite the advances in surgical techniques and the regular administration of phosphodiesterase type 5 inhibitors (PDE5i), recovery from CNI-induced ED remains to be a difficult process. Numerous CNI models have been established to explore the pathogenesis and design effective therapies suitable for human trials. This study aims to examine the studies referring to rat models of CNI induced ED. Methods: A literature review was performed through PubMed using the items “CNI” and “rat model.” We analyzed different types of CNI, the pathophysiology changes after CNI, and current and future strategies of therapy after CNI. Results: A large number of rat models with CNI-induced ED have been established for mimicking ED pathophysiology after radical pelvic surgery. The types of injury include crush, transection, excision, dissection, freezing, electrocautery, and irradiation. The pathophysiological assessments include changes in hemodynamics, nerve structure and morphology, oxidative stress, and inflammation of genes in the corpus cavernosum. The current therapeutic strategies include PDE5i administration, vacuum erection device, and other treatments aiming to decrease known pathologic damages. The future treatment direction may focus on gene transfer, growth factors (nerve and endothelium), cellular scaffolds, and endogenous stem cells to the penis. Conclusions: The CNI rat models are important experimental methods to mimic the nerve damage caused by the treatment of prostate cancer. Many research studies have demonstrated significant pathophysiological changes that occur in rat cavernous bodies after CNI. The ideal model for CNI-induced ED should be explored furthermore to improve the slow recovery of erectile function following CNI.

Erectile function recovery in men treated with phosphodiesterase type 5 inhibitor administration after bilateral nerve-sparing radical prostatectomy: a systematic review of placebo-controlled randomized trials with trial sequential analysis.

The impact of phosphodiesterase type 5 inhibitor (PDE5I) treatment modality (on-demand vs. daily), PDE5I half-life and time from surgery to PDE5I prescription on the achievement of drug-assisted erectile function (EF) recovery is uncertain. We systematically reviewed published randomized clinical trials (RCTs). We performed meta-analyses of data on 2317 men treated with PDE5Is after nerve-sparing radical prostatectomy (NSRP). A PubMed and SCOPUS search was performed for trials published from 1 January 1969 to 30 June 2016. PDE5Is are effective in achieving drug-assisted recovery of erectile function (EF). From a statistical standpoint, these studies were subjected to Trial Sequential Analysis to determine whether the pooled data were adequately powered to verify the study outcomes. On-demand treatment with PDE5Is was significantly better than daily treatment in recovering drug-assisted EF. This effect was maintained even when the drugs were stratified according with half-life. Although not based on head-to-head trials, Avanafil used on-demand was the most effective PDE5I in recovering drug-assisted EF. Whereas tadalafil was equally effective when used both on-demand and daily, vardenafil significantly improved drug-assisted EF recovery only when used on-demand. The start of PDE5I treatment six months or more after surgery compared to treatment started earlier did not negatively affect the rate of drug-assisted EF recovery or the possibility to have successful intercourse based on the Sexual Encounter Profile question-3 (SEP-3). Current trials do not support the hypothesis that PDE5I use recovers drug-unassisted EF, although chronic low-dose tadalafil administration may help to preserve erectile tissue integrity. Potential shortcomings in the trials design may partially explain these disappointing results and several questions concerning the recovery of drug-unassisted EF remain unanswered. Thus, there is a need for well-designed new RCTs requiring changes in the timing of PDE5I administration as well as in the dose and the treatment duration.

Tadalafil improves lean mass and endothelial function in nonobese men with mild ED/LUTS: in vivo and in vitro characterization.

Phosphodiesterase type-5 inhibitor administration in diabetic men with erectile dysfunction (ED) is associated with reduced waist circumference. We evaluated potential effects of daily tadalafil administration on body composition and investigated its possible mechanism(s) of action in C2C12 skeletal muscle cells in vitro. Forty-three men on stable caloric intake (mean age 48.5 ± 7; BMI 25.5 ± 0.9 kg/m2) complaining mild ED and/or low urinary tract symptoms (LUTS)were randomly assigned to receive tadalafil (TAD) 5 mg/daily (once-a-day=OAD-TAD; n = 23) or 20 mg on-demand (on-demand=OD-TAD; n = 20) for 2 months. Primary outcomes were variations of body composition measured by Dual-energy X-ray absorptiometry; secondary outcomes were ED/LUTS questionnaire scores along with hormone (testosterone, estradiol, insulin) and endothelial function (Endopat2000) variations. OAD-TAD increased abdominal lean mass (p < 0.01) that returned to baseline after 2 months withdrawal. LUTS scores improved (p<0.01) in OD-TAD while ED scoresimproved (p < 0.01) in both groups. We found significant improvements in endothelial function (p < 0.05) that directly correlated with serum insulin (p < 0.01; r = 0.3641) and inversely correlated with estradiol levels (p < 0.01; r = 0.3655) even when corrected for potential confounders. Exposure of C2C12 cells upon increasing tadalafil concentrations (10-7 to 10-6 M) increased total androgen receptor mRNA and protein expression as well as myogenin protein expression after 24 and 72 h (2.8 ± 0.4-fold and 1.4 ± 0.02-fold vs. control, respectively, p < 0.05). Daily tadalafil improved lean mass content in non-obese men probably via enhanced insulin secretion, estradiol reduction, and improvement of endothelial function in vivo. The in vitro increased myogenin and androgen receptor protein expression in skeletal muscle cells suggests a translational action of phosphodiesterase type-5 on this receptor.

Management of erectile dysfunction in patients with preexisting cardiovascular disease

Erectile dysfunction (ED) is common among patients with cardiovascular diseases (CVD). Sexual problems usually precede the onset of CVD and should, therefore, be considered as a risk factor for cardiac events. Similarly, patients with preexisting CVD are at increased risk of experiencing ED. Therefore, ED and CVD might be considered as two different clinical manifestations of the same systemic disease. Moreover, these conditions share many common pathophysiological mechanisms. Patients with preexisting CVD and ED should be stratified according to their cardiovascular risk. Sexual activity is safe in patients at low risk of CVD and these individuals might be treated with pro-erectile medications. On the other hand, men at high risk of CVD should be reassessed and the cardiac condition should be stabilized before they might have sexual attempts. Recent evidence suggests that lifestyle changes, administration of phosphodiesterase type-5 inhibitors, and testosterone supplementation might improve sexual function and reduce the risk of experiencing CVD during follow-up.

AB023. Penile rehabilitation with phosphodiesterase type 5 inhibitors in men after nerve-sparing radical prostatectomy

Post-radical prostatectomy (RP) erectile dysfunction (ED) remains a challenge for the urologist. Despite the improvements in surgical technique, ED occurs between 20% and 90% in patients treated with bilateral nerve-sparing RP. Patient factors, cancer selection, type of surgery, surgical techniques, and surgeon factors represent the key significant contributors to erectile function recovery. The aim of a penile rehabilitation program is to preserve the functional smooth-muscle content of the corpus cavernosum during the neuropraxia period. Phosphodiesterase type 5 (PDE5) inhibitors are commonly used in rehabilitation programs. In animal models, such an approach could promote erectile function recovery, improve smooth muscle-to-collagen penile ration, reduce penile apoptotic index, preserve penile endothelial function and promote neuroprotection during nerve damage. Despite the strong basic science support from animal studies, discordant results have been reached in humans. The previous randomized trials comparing chronic versus on-demand PDE-5 inhibitors use after RP may be affected by improper patients’ selection in that only men at low risk of postoperative ED were included. These patients would recover erectile function regardless of the type of PDE5 inhibitor administration because of their excellent baseline profile. Prospective, randomized trials have shown a significant benefit of daily PDE5-I administration as compared with placebo in terms of postoperative EF recovery. Patients with intermediate risk of ED after surgery are the best candidates for daily treatment with PDE5 inhibitor after bilateral nerve-sparing RP. The maximal effect of penile rehabilitation may be found in those men with a certain (but not high) degree of systemic and erectile impairment preoperatively. In conclusion, penile rehabilitation could achieve faster and better natural erectile function after RP and should be started as early as possible. Chronic use of PDE5-I may confer the maximal gain as compared to the on-demand administration schedule. Attention should be pained to the observation that rehabilitation protocols are beneficial even in men with spontaneous erections postoperatively because further improvement in such patients was reported.

Penile rehabilitation and cancer spread.

This year, the Editorial Board has given much attention to convergence. By systematically combining diverse fields of study, efforts have been made to overcome the limitations of existing interpretations. The convergent status of rehabilitation exercises and the need to overcome medical and societal problems through convergence, which was emphasized during the MERS (Middle East respiratory syndrome) outbreak, were introduced. Now, in the last issue of the year, we reconsider the concept of penile rehabilitation, which has until now been recognized as safe. We suggest an urgent need to conduct high-quality prospective studies with regard to the biochemical recurrence of cancer, specifically with regard to the mechanism by which phosphodiesterase type 5 inhibitors (PDE5I) may affect the course of prostate cancer when taken after radical prostatectomy. Drugs like Viagra and Cialis work by deactivating the enzyme PDE5-a chemical that takes away an erection after sex by limiting blood supply. However, scientists now think that malignant melanoma is fueled by a faulty gene (a family of serine-threonine protein kinases, BRAF) which suppresses the enzyme PDE5, suggesting that PDE5 plays an important role in preventing the spread of cancer cells, including prostate cancer cells. It is feared that Viagra, and drugs like it, could be mimicking the effect of the mutated BRAF gene. The early administration of PDE5I after radical prostatectomy is helpful in the patient’s fast recovery of erectile function, and it is often used clinically as a means of penile rehabilitation. However, according to one recent retrospective analysis of patients who received bilateral nerve-sparing radical prostatectomy, it was suggested that taking PDE5I might be associated with the biochemical recurrence of prostate cancer (Loeb et al., 2015; Michl et al., 2015). Hence, the relationship between PDE5I medication and the biochemical recurrence of prostate cancer needs to be reviewed, based on reports of the impact of PDE5I on prostate cancer progression in prospective studies that used PDE5I for the purpose of penile rehabilitation after radical prostatectomy. By using data up to December 2014 from PubMed, Embase, and the Cochrane Library, a search was performed for prospective case-control studies evaluating the effects of PDE5I intake after radical prostatectomy on erectile dysfunction. From the selected studies, comparisons were made according to the surgical method for prostate cancer, the type and administration method of PDE5I, the method for evaluating erectile functionality, and adverse events (Gallina et al., 2015; Li et al., 2014; Vehmas, 2015). All 15 randomized prospective studies investigated nerve-sparing radical prostatectomy patients; in 12 studies, the patients underwent bilateral nerve-sparing surgery and in three studies, the patients underwent unilateral nerve sparing. In terms of the type of PDE5I, sildenafil was used in seven studies, tadalafil was used in seven, and vardenafil was used in one. In 11 of the studies, patients were administered PDE5I every day after nerve-sparing radical prostatectomy, and in four studies patients were only administered PDE5I as needed. Questionnaires used to assess erectile function included the International Index of Erectile Function (IIEF), the Sexual Encounter Profile, the Sexual Health Inventory for Men, and the Erectile Dysfunction Inventory of Treatment Satisfaction. The IIEF was used in all but two studies, either by itself or together with other instruments. Complications after the administration of PDE5I were observed in seven of the 15 studies, and these were mild complications such as headaches, indigestion, hot flashes, and nasopharyngitis. The remaining six studies did not include information on safety and complications of PDE5I intake after surgery. There were no studies that reported follow-up monitoring of prostate cancer after radical prostatectomy. Studies to date have only focused on the therapeutic effects of PDE5I in restoring erectile functionality, and studies on the effects of PDE5I on prostate cancer are lacking. It is currently not possible to perform a meta-analysis. Therefore, there is a need for further prospective case-control studies on the association of biochemical recurrence of prostate cancer with the intake of PDE5I after radical prostatectomy. Next year, JER aims to look even closer at rehabilitation-related assessments from different academic perspectives and to introduce these interests to readers.

AB020. Penile rehabilitation with PDE5 inhibitors in men following radical prostatectomy

Post-radical prostatectomy (RP) erectile dysfunction (ED) remains a challenge for the urologist. Despite the improvements in surgical technique, ED occurs between 20% and 90% in patients treated with bilateral nerve-sparing RP. Patient factors, cancer selection, type of surgery, surgical techniques, and surgeon factors represent the key significant contributors to erectile function recovery. The aim of a penile rehabilitation program is to preserve the functional smooth-muscle content of the corpus cavernosum during the neuropraxia period. Phosphodiesterase type 5 (PDE5) inhibitors are commonly used in rehabilitation programs. In animal models, such an approach could promote erectile function recovery, improve smooth muscle-to-collagen penile ration, reduce penile apoptotic index, preserve penile endothelial function and promote neuroprotection during nerve damage. Despite the strong basic science support from animal studies, discordant results have been reached in humans. The previous randomized trials comparing chronic versus on-demand PDE-5 inhibitors use after RP may be affected by improper patient selection in that only men at low risk of postoperative ED were included. These patients would recover erectile function regardless of the type of PDE5 inhibitor administration because of their excellent baseline profile. Prospective, randomized trials have shown a significant benefit of daily PDE5-I administration as compared with placebo in terms of postoperative EF recovery. Patients with intermediate risk of ED after surgery are the best candidates for daily treatment with PDE5 inhibitor after bilateral nerve-sparing RP. The maximal effect of penile rehabilitation may be found in those men with a certain (but not high) degree of systemic and erectile impairment preoperatively. In conclusion, penile rehabilitation could achieve faster and better natural erectile function after RP and should be started as early as possible. Chronic use of PDE5-I may confer the maximal gain as compared to the on-demand administration schedule. Attention should be pained to the observation that rehabilitation protocols are beneficial even in men with spontaneous erections postoperatively because further improvement in such patients was reported.

Long-term phosphodiesterase 5 inhibitor administration reduces inflammatory markers and heat-shock proteins in cavernous tissue of Zucker diabetic fatty rat (ZDF/fa/fa).

Oxidative stress and nitrosative stress present in type 2 diabetes mellitus (T2DM) and metabolic syndrome (MS) induce inflammatory response in diverse tissues including cavernous tissue (CT). Heat-shock proteins (HSPs) have an important role in modulating and repairing tissue injury, although their participation in CT in T2DM is unclear. Beyond the specific action of phosphodiesterase type 5 inhibitors (PDE5i) on erectile function, it has been proposed that chronic administration of these agents improves endothelial function and ameliorates fibrotic changes. The aim of this study was to determine in CT of Zucker Diabetic Fatty (ZDF) rat, an experimental model of T2DM and MS: (1) the degree of oxidative stress and nitrosative stress; (2) the magnitude of inflammatory markers such as tumor necrosis factor-α (TNFα) and interleukin 6 (IL6); (3) immunoexpression of HSP70 and HSP27; (4) how a long-term PDE5i administration may modify these variables. For 6 months, (1) untreated ZDF; (2) ZDF+Sildenafil (Sil) and (3) control Lean Zucker Rat (LZR) received no treatment, were studied. Penises were processed for functional 'in vitro' studies, oxidative and nitrosative stress evaluation and immunohistochemistry in CT using TNFα; IL6; nitrotyrosine, HSP70 and HSP27 antibodies. ZDF+Sil presented better relaxation in corporal strips versus untreated ZDF. Furthermore, ZDF+Sil presented less lipoperoxidation in CT versus untreated ZDF. The activity of antioxidant enzymes CuZn superoxide dismutase (CuZnSOD) and glutathione peroxidase (GPx) was also reduced in untreated ZDF in CT along with a decrease in glutathione versus untreated ZDF. Nitrotyrosine expression was increased in untreated-ZDF rats versus ZDF+Sil and LZR. TNFα and IL6 were decreased in CT in ZDF+Sil versus untreated ZDF. Additionally, the expression of HSP70 and HSP27 was reduced in CT in ZDF+Sil versus untreated ZDF. In conclusion, this study provides substantial evidence supporting a protective role of a long-term therapy with Sil on CT in a recognized animal model of T2DM and MS.

Penile rehabilitation after radical prostatectomy: does it work?

ContextErectile dysfunction (ED) represents one of the most common long-term side effects in patients with clinically localized prostate cancer (PCa) undergoing nerve-sparing radical prostatectomy (RP).ObjectiveTo analyze the role of penile rehabilitation in the recovery of erectile function (EF) after nerve-sparing RP.Evidence synthesisPenile rehabilitation is defined as the use of any intervention or combination with the goal not only to achieve erections sufficient for satisfactory sexual intercourses, but also to return EF to preoperative levels. The concept of rehabilitation is based on the implementation of protocols aimed at improving oxygenation, preserving endothelial structure, and preventing smooth muscle structural alterations. Nowadays, the most commonly adopted approaches for penile rehabilitation after nerve-sparing RP are represented by the administration of phosphodiesterase type-5 inhibitors (PDE5-Is), intracorporeal injection therapy, vacuum erection devices (VED), and the combination of these therapies. Several basic science studies support the rational for the adoption of penile rehabilitation protocols. Particularly, rehabilitation, set as early as possible, seems to be better than leaving the erectile tissues unassisted. On the other hand, results from solid prospective randomized trials finally assessing the long-term beneficial effects of PDE5-Is, intracavernosal injections, or VED on EF recovery after surgery are still lacking.ConclusionsAlthough preclinical evidences support the rationale for penile rehabilitation after nerve-sparing RP, clinical studies reported conflicting results regarding its efficacy on long-term EF recovery. Nowadays, which is the optimal rehabilitation program still represents a matter of debate.

Effects of tadalafil administration on plasma markers of exercise-induced muscle damage, IL6 and antioxidant status capacity.

Physical exercise is associated with enhanced production of reactive oxygen species, which if uncontrolled can result in tissue injury. Phosphodiesterase type 5 inhibitors (PDE5i) exhibit protective effect against oxidative stress, both in animals and healthy/unhealthy humans. However, the effect of a chronic administration of PDE5i, particularly combined with physical exercise, has never been investigated. The present study was designed to evaluate the effect of the long-acting PDE5i tadalafil on oxidative status and muscle damage after exhaustive exercise in healthy males included in a double-blind crossover trial. Tadalafil, having a putative antioxidant activity, may reduce oxidative damage after strenuous exercise. Each volunteer randomly received two tablets of placebo or tadalafil (20 mg/day) with 36 h of interval before performing exhaustive exercise. After 2 weeks of washout, the volunteers were crossed over. Blood samples were collected immediately before exercise, immediately after, and during recovery (15, 30, 60 min). Plasma total antioxidant status, glutathione homeostasis (GSH/GSSG), malondialdehyde (MDA), protein carbonyls, creatine kinase (CK), lactate dehydrogenase (LDH) and the inflammatory cytokine interleukin 6 were assessed. Tadalafil administration per se affected redox homeostasis (GSH/GSSG -36%; p < 0.05), cellular (CK +75% and LDH +36%; p < 0.05) and oxidative damage (MDA +41% and protein carbonyls +50%; p < 0.05) markers. The exhaustive exercise increased all the above-reported biochemical parameters, with subjects from the tadalafil group showing significantly higher values with respect to the placebo group. A prolonged exposure to tadalafil decreases antioxidant capacity at resting condition, therefore making subjects more susceptible to the oxidative stress induced by an exhaustive bout of exercise.

Is chronic inhibition of phosphodiesterase type 5 cardioprotective and safe? A meta-analysis of randomized controlled trials.

BackgroundThe myocardial effects of phosphodiesterase type 5 inhibitors (PDE5i) have recently received consideration in several preclinical studies. The risk/benefit ratio in humans remains unclear.MethodsWe performed a meta-analysis of randomized, placebo-controlled trials (RCTs) to evaluate the efficacy and safety of PDE5i on cardiac morphology and function. From March 2012 to December 2013 (update: May 2014), we searched English-language studies from MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and SCOPUS-selecting RCTs of continuous PDE5i administration that reported cardiovascular outcomes: cardiac geometry and performance, afterload, endothelial function and safety. The pooled estimate of a weighted mean difference between treatment and placebo was obtained for all outcomes using a random effects model. A test for heterogeneity was performed and the I2 statistic calculated.ResultsOverall, 1,622 subjects were treated, with 954 randomized to PDE5i and 772 to placebo in 24 RCTs. According to our analysis, sustained PDE5 inhibition produced: (1) an anti-remodeling effect by reducing cardiac mass (−12.21 g/m2, 95% confidence interval (CI): −18.85; −5.57) in subjects with left ventricular hypertrophy (LVH) and by increasing end-diastolic volume (5.00 mL/m2; 95% CI: 3.29; 6.71) in non-LVH patients; (2) an improvement in cardiac performance by increasing cardiac index (0.30 L/min/m2, 95% CI: 0.202; 0.406) and ejection fraction (3.56%, 95% CI: 1.79; 5.33). These effects are parallel to a decline of N-terminal-pro brain natriuretic peptide (NT-proBNP) in subjects with severe LVH (−486.7 pg/ml, 95% CI: −712; -261). PDE5i administration also produced: (3) no changes in afterload parameters and (4) an improvement in flow-mediated vasodilation (3.31%, 95% CI: 0.53; 6.08). Flushing, headache, epistaxis and gastric symptoms were the commonest side effects.ConclusionsThis meta-analysis suggests for the first time that PDE5i have anti-remodeling properties and improve cardiac inotropism, independently of afterload changes, with a good safety profile. Given the reproducibility of the findings and tolerability across different populations, PDE5i could be reasonably offered to men with cardiac hypertrophy and early stage heart failure. Given the limited gender data, a larger trial on the sex-specific response to long-term PDE5i treatment is required.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-014-0185-3) contains supplementary material, which is available to authorized users.

AB63. Controversial issues in erectile dysfunction

Erectile dysfunction (ED) is a prevalent medical condition. With the advent of phosphodiesterase type 5 (PDE-5) inhibitors, the treatment of ED has been revolutionized during the last two decades. Although there are great advances in the diagnosis and treatment of ED, there are two common controversial issues in our practice that merit further discussion.First, psychogenic or organic ED? ED is traditionally classified as organic and psychogenic based on the etiology. Many problems arise with this distinction. Psychogenic ED is a misnomer because it is based on an obsolete view of mind-body distinctions, ignores the manifestations of neurobiology of psychological disorders and the fundamental meaning of psychosomatic result, is too often diagnosed by exclusion and may indicate that ED all result from mind problem. All ED of organic origin therefore also has a psychogenic aspect. Every patient whose ED is mainly due to an organic disorder builds his own world of fear, anxiety, worry, depression, and distress around his disorder. The distinction between psychogenic and organic ED has become counterproductive in the diagnosis, classification and treatment of ED. This distinction should be abandoned, not just from the taxonomy of ED, but also from systematic thinking about the causes of erection and its disorders.Second, is it possible to “ED” with oral pharmacotherapy? Clinical and basic science have provided convincing evidence that ED is predominately a disease of vascular etiology correlating with diabetes mellitus, hypertension, atherosclerosis, hyperlipidemia, smoking, and obesity. Chronic administration of PDE-5 inhibitors has reportedly been associated with increased persistent vascular and endothelial function. Clinical studies have revealed a potential protective role of these compounds on endothelial function in short- and long-term assessments. Data available from animal models also support the evidence of potential benefits induced on endothelial function. However, these studies were limited by small case numbers, short-term follow-up. Evidence to support the reversal of ED by chronic administration of a PDE5 inhibitor is still lacking. An improvement of endothelial function is not equivalent to recovery of erectile function. The downside of continuing to promote the precept of chronic dosing as a cure for ED might result in the emotional and financial cost to our patients, the disillusionment by our referring colleagues, and the loss of our scientific credibility.

Preoperative erectile function is the only predictor of the use of a high number of phosphodiesterase type-5 inhibitors after bilateral nerve-sparing radical prostatectomy.

It is well known that the administration of phosphodiesterase type-5 inhibitors (PDE5-Is) may improve erectile function (EF) recovery after bilateral nerve-sparing radical prostatectomy (BNSRP). The aim of our study was to identify predictors of the use of a high number of PDE5-Is (one or more per week) after surgery among 184 patients taking proerectile medications on demand. At a mean follow-up of 22.7 months, 116 patients (63%) recovered EF. Overall, EF recovery rates at 1- and 2- year follow-up were 47.3% and 65.4%, respectively. Overall, 43 (23.4%) patients used one or more PDE5-Is per week. Preoperative EF was the only predictor of the use of one or more PDE5-Is per week after BNSRP. This held true even after adjusting our analyses for age at surgery, body mass index and EF at 1 month after surgery. Particularly, patients fully potent before surgery had roughly 2.1-fold higher probability of using one or more pills per week compared with their counterparts with some degree of preoperative erectile dysfunction (ED; odds ratio: 2.16; 95% confidence interval: 1.03-4.37). In conclusion, preoperative EF represents the only determinant of the use of a higher number of PDE5-Is after surgery. Patients with better preoperative EF might represent individuals more motivated to achieve satisfactory sexual function after surgery. These observations should provide physicians with better preoperative patient counseling and management of postoperative ED.

Evaluation of Current Errors Within the Administration of Phosphodiesterase-5 Inhibitors After More Than 10 Years of Use

To detect current errors within the administration of phosphodiesterase type 5 inhibitors (PDE5is) and evaluate and elucidate what percentage of patients could be recovered for oral therapy with different subtypes of PDE5is through a re-education program. Two hundred fifty patients remitted to the andrology unit were prospectively analyzed. Patients' chief complaint was erectile dysfunction despite treatment with PDE5i. The International Index of Erectile Function was used to measure erectile function. A structured interview was developed to evaluate the most frequent errors within the administration of PDE5is. A re-education program was offered to patients with incomplete or incorrect use of PDE5is according to the structured interview, classifying them into true nonresponders or false nonresponders. Finally, the percentage of patients who could be recovered for oral therapy with other PDE5is was analyzed. A total of 172 patients (69%) presented some error within drug administration. The most common error was not trying >1 PDE5i (41%). A re-education program was offered to these nonresponders, and 115 (66.9%) accepted. Up to 27 (23.5%) did not respond to the re-education program and were classified as true nonresponders, whereas 88 (76.5%) had a positive response to treatment and were thus included in the false nonresponder group. Two-thirds of patients remitted to our andrology unit and cataloged as nonresponders were in fact using PDE5i in suboptimal conditions. Offering patients more accurate information provided almost 76% with good results using PDE5is and could therefore be successfully treated with these drugs.

Acute effects of physical exercise and phosphodiesterase’s type 5 inhibition on serum 11β-hydroxysteroid dehydrogenases related glucocorticoids metabolites: a pilot study

Endogenous glucocorticoids (GC) rapidly increase after acute exercise, and the phosphodiesterase's type 5 inhibitor (PDE5i) tadalafil influences this physiological adaptation. No data exist on acute effects of both acute exercise and PDE5i administration on 11β-hydroxysteroid dehydrogenases (11β-HSDs)-related GC metabolites. We aimed to investigate the rapid effects of exercise on serum GC metabolites, with and without tadalafil administration. A double blind crossover study was performed in eleven healthy male volunteers. After the volunteers randomly received a short-term administration of placebo or tadalafil (20 mg/die for 2 days), a maximal exercise test to exhaustion on cycle ergometer was performed. Then, after a 2-week washout period, the volunteers were crossed over. Blood samples were collected before starting exercise and at 5 and 30 min of recovery (+5-Rec, +30-Rec). Serum ACTH, corticosterone (Cn), cortisol (F), cortisone (E), tetrahydrocortisol (THF), tetrahydrocortisone (THE), cortols, cortolones and respective ratios were evaluated. Pre-Ex THF was higher after tadalafil. Exercise increased ACTH, Cn, F, E, THE, cortols and cortolones after both placebo and tadalafil, and THF after placebo. The F/E ratio increased at +5-Rec and decreased at +30-Rec after placebo. Compared to placebo, after tadalafil lower ACTH, F and Cn, higher THF/F and THE/E, and not E (at +5-Rec) and F/E modifications were observed. Acute exercise rapidly influences serum GC metabolites concentrations. Tadalafil influences both GC adaptation and 11β-HSDs activity during acute exercise. Additional researches on the effects of both exercise and PDE5i on tissue-specific 11β-HSDs activity at rest and during physiological adaptation are warranted.