Phosphodiesterase Type 5 Inhibitors Treatment Research Articles

Phosphodiesterase type 5 inhibitors do not prevent curvature progression but shorten pain duration in the active phase of Peyronie’s Disease: A retrospective cohort study

Treatment with Phosphodiesterase Type 5 inhibitors (PDE5is) has shown promise in managing Peyronie’s disease (PD) during its active phase. In a retrospective cohort study of 133 PD patients, we compared daily PDE5i treatment (sildenafil 25 mg or tadalafil 5 mg) in Group 1 (n = 101) to no treatment in Group 2 (n = 32). The mean age ± SD was 58.5 ± 10, (range: 29-77) years in Group 1 and 59 ± 13.7 years (range: 23-80) in Group 2 (p = 0.5). Mean symptom onset-to-visit time was 10.6 ± 7.2 months (range: 1-37) in Group 1 and 11 ± 6.3 months (range 3-27) in Group 2 (p = 0.5). Mean penile curvature change was +0.87° (95% CI: -1.8, 3.5) in Group 1 and +5.72° (95% CI: 1.4, 10) in Group 2 (p = 0.07) between first and last observations. Group 1 experienced shorter mean pain duration (9.1 ± 4.7 months, range: 2.5-24) than Group 2 (12.2 ± 6.5 months, range: 5-28) (p = 0.04). When controlling for baseline curvature and symptom onset-to-visit time, there were no differences between groups (-4.7, 95% CI: -10, 0.6) (p = 0.08). In conclusion, continuous PDE5i treatment did not affect PD curvature progression but showed a promising effect on pain.

Predictors of Phosphodiesterase Type 5 Inhibitor Treatment Failure in Patients Diagnosed With Erectile Dysfunction.

Erectile dysfunction (ED) is a prevalent condition, especially in aging populations, with significant implications for quality of life. While phosphodiesterase type 5 inhibitors (PDE5Is) are the first-line treatment, a substantial percentage of patients do not respond satisfactorily. This study aimed to identify predictors of PDE5I treatment failure in ED patients. Data from January 2016 to January 2022 was reviewed for patients with ED who either failed PDE5I treatment or had a successful outcome. Demographic, medical, and laboratory data were collected and analyzed. Patients with contraindications or who did not complete the treatment were excluded. The treatment failure group comprised 288 patients, while 225 age-matched patients formed the control responder group. There were no significant differences in marriage duration, comorbidities, smoking, or BMI. However, HbA1c levels, free testosterone, and SHBG were significantly different between the two groups. This study found that high HbA1c levels, low free testosterone, and high sex hormone-binding globulin (SHBG) were associated with PDE5I treatment failure. Managing high HbA1c levels and addressing hormonal imbalances may enhance PDE5I treatment effectiveness in ED patients. However, further research is needed to explore other factors contributing to treatment outcomes.

Comparison of the effect of hyperbaric oxygen therapy and tadalafil daily use on erectile function: a prospective, double controlled study.

Erectile dysfunction (ED) is a worldwide health problem. Oral phosphodiesterase type 5 inhibitors (PDE5I) are used in its first-line treatment. This study aimed to compare the effects of hyperbaric oxygen (HBO) treatment with PDE5I treatment and determine the patient-dependent factors affecting the efficacy of the HBO treatment and duration of action of HBO treatment. Adult male patients who presented to the HBO unit for HBO treatment with non-urological indications and had ED based on the International Index for Erectile Function (IIEF-5) constituted the target population of this study. Participants were given HBO treatment (Group 1), no treatment (Group 2), or daily oral tadalafil 5mg treatment (Group 3). The treatment duration was 1month. Patients were assessed by IIEF-5 both initially and after the completion of 1month. There were significant increases in the mean IIEF-5 scores of the patients in Group 1 and Group 3 (p < 0.001, p < 0.001). However, there was no significant improvement in Group 2 (p = 0.496). Also, the post-treatment IIEF-5 scores of Group 1 and Group 3 were significantly higher than Group 2 (p < 0.001). There was no significant difference between the IIEF-5 scores and ∆IIEF-5 values of Group 1 and Group 3 (p = 0.166, p = 0.093). Evaluation regarding comorbidities revealed that patients with the peripheral vascular disease did not improve with HBO treatment (p = 0.285). HBO can improve erectile functions, and it can be a reasonable alternative for patients who cannot use PDE5Is due to comorbidities or treatment side effects.

The role of mechano-regulated YAP/TAZ in erectile dysfunction

Phosphodiesterase type 5 inhibitors (PDE5is) constitute the primary therapeutic option for treating erectile dysfunction (ED). Nevertheless, a substantial proportion of patients, approximately 30%, do not respond to PDE5i treatment. Therefore, new treatment methods are needed. In this study, we identified a pathway that contributes to male erectile function. We show that mechano-regulated YAP/TAZ signaling in smooth muscle cells (SMCs) upregulates adrenomedullin transcription, which relaxed the SMCs to maintain erection. Using single-nucleus RNA sequencing, we investigated how penile erection stretches the SMCs, inducing YAP/TAZ activity. Subsequently, we demonstrate that YAP/TAZ plays a role in erectile function and penile rehabilitation, using genetic lesions and various animal models. This mechanism relies on direct transcriptional regulation of adrenomedullin by YAP/TAZ, which in turn modulates penile smooth muscle contraction. Importantly, conventional PDE5i, which targets NO-cGMP signaling, does not promote erectile function in YAP/TAZ-deficient ED model mice. In contrast, by activating the YAP/TAZ-adrenomedullin cascade, mechanostimulation improves erectile function in PDE5i nonrespondent ED model rats and mice. Furthermore, using clinical retrospective observational data, we found that mechanostimulation significantly promotes erectile function in patients irrespective of PDE5i use. Our studies lay the groundwork for exploring the mechano-YAP/TAZ-adrenomedullin axis as a potential target in the treatment of ED.

(094) Synergy Between Orally Administered Phosphodiesterase-type-5-inhibitors and Topically Delivered Nitric-oxide in Eliciting Erectile Responses

Abstract Introduction Phosphodiesterase-type-5-inhibitors (PDE5i) represent first-line FDA-approved oral treatments for erectile dysfunction (ED). However, because their mode of action is dependent on the production of nitric oxide (NO) from nerve endings, patients that suffer neurogenic ED (for example, following the procedures for radical prostatectomy (RP) or resulting from diabetes) are commonly refractory to PDE5i treatment. We recently demonstrated proof-of-principle for increased efficacy of topically applied NO-releasing microparticles (NO-MP) in eliciting an erectile response when used in combination with the orally administered PDE5i, sildenafil. However, there are several other FDA approved PDE5i used to treat ED, which, although acting through the common mechanism of PDE5 inhibition, exhibit several characteristics that potentially could impact clinical and commercial translation of combination therapy. Objective The goal of the present studies was to determine if other commercially available PDE5i besides sildenafil (avanafil, tadalafil and vardenafil) also act cooperatively when used in combination with NO-MP to elicit an erectile response. Methods Sprague-Dawley rats underwent bi-lateral transection of the cavernous nerve (CN), as a model of RP, one-week prior to determining erectile response to treatment. We investigated the effect of oral administration of 0.05mg sildenafil/kg, 0.005mg tadalafil/kg, 0.01mg vardenafil/kg and 0.1mg avanafil/kg (approximately equivalent to clinical doses of 2.5mg, 0.25mg, 0.5mg and 5mg, respectively, administered to an 80 kg patient) 30 minutes prior to being anesthetized for the determination of erectile response by intracorporal pressure (ICP) and systemic blood pressure (BP). Baseline ICP and BP were recorded for 30 minutes, at which time 100 mg of NO-MP (or control, blank-MP) were applied to the rat penile shaft. The ICP and systemic BP were used to determine the time to the first erectile response, duration of the erectile responses, the maximal and average ICP/BP responses and the number of spontaneous erections per hour. Results Although oral treatment by PDE5i alone resulted in no observable erectile response, topical application of NO-MP resulted in spontaneous erectile responses. When NO-MP were applied in combination with oral PDE5i treatment, all PDE5i resulted in faster times to the first erectile response (on average 11 minutes compared to 22 minutes when NO-MP were used alone; P-value=0.041) and greater numbers of spontaneous erections (on average 4.6 erections per hour compared to 2.0 when NO-MP were used alone, P-value=0.043). Although there were no significant differences between any of the PDE5i when used in combination with NO-MP with respect to the average erectile responses per hour, duration of erectile response, and maximal ICP/BP, there was a trend in the vardenafil and avanafil treated animals for a more rapid onset of the erectile responses than observed with sildenafil and tadalafil. Conclusions Although knowledge of the molecular pathways that lead to an erection provide a rationale for a synergistic effect between PDE5i and NO in eliciting an erectile response, our results provide the first evidence of such synergy. Our results suggest a novel treatment strategy for patients with ED refractory to PDE5i, namely any of the FDA-approved oral PDE5 inhibitors used in combination with formulations that topically deliver NO to corporal tissue. Disclosure Yes, this is sponsored by industry/sponsor: Zylo Therapeutics, Inc Clarification Industry funding only - investigator initiated and executed study Any of the authors act as a consultant, employee or shareholder of an industry for: Zylo Therapeutics, Inc

Efficacy of phosphodiesterase type 5 inhibitors in patients with erectile dysfunction after nerve-sparing radical prostatectomy: a systematic review and meta-analysis.

BackgroundNerve-sparing radical prostatectomy (NSRP) had to be performed because approximately 94% of patients are diagnosed with localized prostate cancer (PCa). Although NSRP is generally done to improve functional outcomes, erectile dysfunction (ED) is one of the most prevailing complications after radical prostatectomy (RP). Phosphodiesterase type 5 inhibitors (PDE5-Is) are the most well-known treatment agent for postoperative ED. This study aimed to assess the efficacy of PDE5-Is in patients with ED after NSRP.MethodsIn this systematic literature review, randomized controlled trials on the efficacy and safety of PDE5-Is in patients who underwent NSRP were searched in MEDLINE, EMBASE, and the Cochrane Controlled Trials Register using the OVID platform. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Cochrane Review Methods. The quality of the evidence of the outcome data was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach.ResultsA total of 14 trials involving 2,822 patients were included. Significant improvements in the International Index of Erectile Function—Erectile Function (IIEF) domain score [mean difference (MD) =4.93; 95% confidence interval (CI): 4.14–5.71; P<0.00001] and erectile function recovery events [odds ratio (OR) =2.06; 95% CI: 1.45–2.94; P<0.0001] were observed after PDE5-I treatment. A higher positive response to Sexual Encounter Profile (SEP) question 2 (OR =2.27; 95% CI: 1.80–2.86; P<0.00001) and question 3 (OR =2.78; 95% CI: 1.97–3.91; P<0.00001) was also found after PDE5-I treatment. However, the incidence of treatment-emergent adverse events (TEAEs) was higher after PDE5-I treatment than after placebo treatment (OR =2.91; 95% CI: 1.84–4.61). Furthermore, the incidence of headache (OR =3.38; 95% CI: 2.40–4.75) and flushing (OR =9.44; 95% CI: 4.30–20.70) was also significantly higher after PDE5-I treatment (P<0.00001). In terms of the quality of the evidence of the outcome data, inconsistency problems were detected in all outcomes and imprecision problems in most outcomes.DiscussionPDE5-I treatment was more effective to placebo treatment in patients with ED after NSRP. No clinically serious complications were found in spite of the incidence of TEAEs being higher after PDE5-I treatment.

Changes in cMRI parameters following a switch to riociguat from phosphodiesterase type 5 inhibitors (PDE5i) in patients with pulmonary arterial hypertension: a REPLACE substudy

Abstract Background The REPLACE study investigated the effect of switching to riociguat (RIO) in patients with pulmonary arterial hypertension receiving PDE5i but still at intermediate risk. The centrally adjudicated composite primary endpoint was clinical improvement in the absence of clinical worsening, where clinical improvement was defined as meeting at least two of the following criteria: 6-minute walk distance (6MWD), increase by ≥10% or ≥30 m from baseline (BL) to Wk 24; World Health Organization functional class (WHO FC) I or II at Wk 24; or N-terminal prohormone of brain natriuretic peptide reduction of ≥30% from BL to Wk 24. Twice as many patients switching to RIO (45/111, 41%) met the primary endpoint compared with those remaining on PDE5i (23/113, 20%); odds ratio (OR): 2.78 (95% confidence interval [CI] 1.53–5.06); p=0.0007. Purpose Assess changes in right and left ventricular (RV; LV) function using cardiac magnetic resonance imaging (cMRI) in a subgroup of patients participating in REPLACE. Methods REPLACE was a randomised, open-label, 24-week, Phase 4 study (NCT02891850). Patients in WHO FC III, with 6MWD 165–440 m, were randomised to switch to RIO 2.5 mg–max tid or remain on PDE5i. Background endothelin receptor antagonist therapy was permitted in both arms. cMRI was performed on a subset of patients from the full analysis set as an exploratory substudy. The following parameters were measured at BL and Wk 24: RV and LV end-diastolic and end-systolic volumes (RVEDV; RVESV; LVEDV; LVESV), RV stroke volume and stroke volume index (RVSV; RVSVI), LV stroke volume (LVSV), RV ejection fraction (RVEF), and pericardial effusion. Results Twenty-seven patients participated in the cMRI substudy. This comprised 11/111 (10%) patients in the RIO arm (mean [standard deviation {SD}] 40.0 [12.4] years), and 16/113 (14%) patients (mean 44.5 [17.6] years) in the PDE5i arm. Like the main population, the treatment response in the cMRI subpopulation favoured RIO versus PDE5i (OR: 6.11 [95% CI 0.90–41.60]). From BL to Wk 24, RVEDV and RVESV decreased in the RIO treatment arm but increased in the PDE5i treatment arm (Table 1). Similar, but less pronounced, changes were observed for the left ventricle (LVESV, LVEDV). RVSV and RVEF levels were close to normal at BL and did not increase in either arm at Wk 24 (Table 1). Pericardial effusion, which was present in 5 patients in each group at BL, decreased in 1 patient in the RIO arm and no patients in the PDE5i arm. Conclusions Decreases in RVEDV and RVESV suggest improvements in cardiac function in the RIO arm compared with the PDE5i arm. Values for RVEF and RVSVI were close to normal at BL and did not change at Wk 24. Improvements in cMRI parameters were in line with the clinical improvement observed in patients switching to RIO in the overall population. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): The REPLACE study was co-funded by Bayer AG (Berlin, Germany) and Merck Sharp &amp; Dohme Corp., a subsidiary of Merck &amp; Co., Inc. (Kenilworth, NJ, USA)

Journal watch

Mike Kirby, Editor on Trends in Urology and Men's Health, picks some interesting recent papers and highlights the ‘take-home’ message. Hiramatsu I, Tsujimura A, Soejima M, et al. Tadalafil is sufficiently effective for severe chronic prostatitis/chronic pelvic pain syndrome in patients with benign prostatic hyperplasia. Int J Urol 2020;27:53–7. This study investigated the efficacy of tadalafil 5mg daily in 74 patients with benign prostatic hyperplasia (BPH) and chronic prostatitis (CP)/chronic pelvic pain syndrome (CPPS) over a 12-week period. Patients were classified as having moderate or severe urinary tract symptoms, and voiding symptoms were compared in those with high (≥4) and low (<4) pain subscores based on the National Institutes of Health Chronic Prostatitis Symptom Index (CPSI). At baseline, the CPSI pain subscore was high in 32.4% of patients, and the International Prostate Symptom Score (IPSS) was significantly higher in the group with a high pain score. After treatment, IPSS, CPSI, and pain subscores were all significantly improved. The change in the CPSI scores correlated positively with the change in the IPSS. The decrease in the IPSS was significantly greater in the group with the high pain subscore than the group with the low pain subscore. Men with lower urinary tract symptoms (LUTS) may often have BPH, but also complain of lower abdominal pain and/or perineal discomfort, which has been described as CP or CPSS.1,2 When assessed by IPSS, the degree of histological prostatic inflammation has been shown to be positively correlated with the severity of LUTS. CPPS is a difficult condition to treat, but PDE5 inhibitors have been shown to exert an anti-inflammatory effect on endothelial cells, which leads to a reduction in pro-inflammatory cytokines.3,4 This has been demonstrated in expressed prostatic secretions and semen from men with CPPS whose secretions contained a higher level of TNF alpha, which is one of the markers of inflammation.5 In this study, men with the highest pain score also had a higher IPSS. Tadalafil was the treatment of choice because it has been shown to have a positive effect on oxidation, blood flow, inflammation and endothelial function. An interesting finding was that the change in the pain score correlated positively with the change in the IPSS. Alpha-blockers and 5-alpha reductase inhibitors are the most commonly prescribed medications for BPH. Tadalafil has been approved for the last five years to treat men with BPH, with or without erectile dysfunction. However, until the drug recently became available as a generic, there were cost barriers to initiating this treatment. This preliminary study suggests that tadalafil is effective in treating patients with BPH and quite severe CPPS. It therefore seems logical that in patients with BPH, who also complain of perineal discomfort and pain, tadalafil might be a good treatment choice. Furthermore, the latest Clinical Knowledge Summary from NICE recommends more frequent dosing of Tadalfail 5mg daily, and even up to 10–20mg daily if on-demand treatment fails or is inappropriate. This would seem to settle the issue! Santi D, Granata ARM, Guidi A, et al. Six months of daily treatment with vardenafil improves parameters of endothelial inflammation and of hypogonadism in male patients with type 2 diabetes and erectile dysfunction: a randomized, double-blind, prospective trial. Eur J Endocrinol 2016;174:513–22. This prospective, investigator-initiated, randomised, placebo-controlled, double-blind trial investigated whether long-term chronic treatment with vardenafil improved systemic endothelial function in 54 men with type 2 diabetes mellitus (T2DM) and erectile dysfunction (ED). The study involved a 24-week treatment phase with vardenafil or placebo, 10mg twice daily and patients were followed up for the same duration. The evaluated parameters included the International Index of Erectile Function 15 (IIEF 15), flow-mediated dilation (FMD), serum interleukin-6 (IL-6), endothelin 1 (ET-1), testosterone and gonadotropins. International index of erectile function (IIEF) erectile function improved during vardenafil treatment (p<0.001), and by the end of the treatment period, both FMD and IL-6 had also improved significantly (p=0.040 and p=0.019, respectively). FMD correlated with serum testosterone levels (p<0.001). Testosterone levels increased significantly with vardenafil treatment, returning to the eugonadal range in hypogonadal men, without changes in gonadotrophin levels. There were no relevant side-effects from chronic vardenafil treatment. T2DM is essentially an inflammatory condition associated with endothelial dysfunction, which in turn leads to the comorbidities that we see every day in clinical practice. Endothelial dysfunction reduces the availability of nitric oxide, which is associated with pro-inflammatory cytokines.1 Clinical trials using chronic phosphodiesterase type 5 inhibitors (PDE5i) in diabetic men have illustrated a beneficial effect on flow-mediated dilatation and IL-6 serum levels.2 In this study, the investigators demonstrated a reduction in endothelial inflammation, which was maintained after treatment withdrawal, suggesting a long-lasting positive effect. The increase in testosterone level may be a consequence, of course, of improved sexual activity related to the PDE5i treatment or, perhaps, through a direct effect on testicular vasodilatation, Leydig cell function or both. The authors speculate that chronic vardenafil treatment, by reducing endothelial dysfunction, may reduce mortality risk, and this has been demonstrated in other observational studies.3,4 Older men often have comorbidities, including T2DM, atherosclerosis, endothelial dysfunction and testosterone deficiency. Chronic use of a daily PDE5i drug offers physicians an opportunity to address multiple vascular comorbidities with one therapeutic agent, and move hypogonadal men into the eugonadal range. Moon S, Chung HS, Yu JM, et al. The Association Between Obesity and the Nocturia in the U.S. Population. Int Neurourol J 2019;23(2):169–76. In this study, the researchers investigated the association between obesity and nocturia, using a nationally representative sample of 14 135 adults from the National Health and Nutrition Examination Survey (NHANES) between 2005–2012. The methods included multivariate logistic regression analysis to find the odds ratio (OR) of obesity for nocturia, analysis of the OR of BMI for nocturia, and subgroup analysis based on age, sex, and hypertension. As compared with participants without obesity, those with a BMI ≥30kg/m2 had a significantly higher OR for nocturia (OR 1.39, 95%; CI 1.28–1.50), and there was a dose-dependent relationship between BMI and OR for nocturia. Similar results were found in the subgroup analysis. Further analysis, using 1:1 matching data, found a significant association between obesity and the prevalence of nocturia (OR 1.25; 95%; CI 1.10–1.41). Nocturia is a highly prevalent condition that can negatively affect quality of life1 due to the frequent need to wake up at night to void. It is often associated with comorbidities.2 Obesity is a risk factor for type 2 diabetes, hypertension, cardiac disease and stroke - and obesity may well be reversible with a change in lifestyle. Nocturia has been found to be more common in obese patients,3 and BMI has been positively associated with nocturia in the general population.4 The NHANES data set is enormous and has provided plenty of epidemiological data. It is interesting that in this population, 32.7% of the participants had nocturia occurring two or more times per night. This may be the result of increasing urine production or increasing frequency of urination, and may be related to night-time eating or drinking, especially alcohol,5 and those with central obesity may have increased intrabdominal pressure.6 Men may suffer from an enlarging prostate, related to the metabolic effects of obesity,5 and obesity may therefore increase the risk of nocturia by causing BPH.7 Previous studies have shown that weight reduction8 and exercise programmes9 can improve nocturia. These are data that we can inform our patients about and perhaps provide them with increased motivation to achieve the necessary weight loss and take more exercise. The full reference list is available at trendsinmenshealth.com/article/

Undiagnosed prediabetes status is associated with a reduced effectiveness of phosphodiesterase type 5 inhibitors in men with erectile dysfunction.

The efficacy of phosphodiesterase type 5 inhibitors (PDE5i) in patients with erectile dysfunction (ED) and undiagnosed prediabetes (PreDM) has been scantly analysed. We aimed to assess rates of and predictors of response to oral treatment in a cohort of ED men naïve for PDE5i with either normo-glycaemia or PreDM or diabetes mellitus (DM). Complete data from 466 men were analysed. Comorbidities were scored with the Charlson Comorbidity Index (CCI). Patients completed the International Index of Erectile Function (IIEF) at baseline and after 3 months of PDE5i treatment. Treatment response was evaluated using the minimal clinically important difference (MCID) (mild: +2; moderate: +5; severe: +7 from baseline IIEF-EF). PreDM status was defined as for the American Diabetes Association (2015) criteria. Descriptive statistics and logistic regression models tested the association between clinical predictors and MCID response. Overall, 253 (56.7%), 105 (23.5%) and 88 (19.7%) patients had normo-glycaemia (=controls), PreDM and DM, respectively. Diabetic and PreDM men were older, had higher BMI, higher CCI scores and lower total testosterone (tT) (all p < 0.01) compared to controls. Median baseline IIEF-EF was lower both in PreDM (14.0 vs. 18.0; p < 0.05) and DM patients (10.0 vs. 18.0; p < 0.001) than in controls. IIEF-EF improved in all groups after treatment (all p < 0.001), but scores were higher in controls compared to both PreDM and DM men at 3-mos assessment (26.0 vs. 20.0 vs. 17.5, respectively; all p < 0.001). Controls more frequently achieved significant MCID than both PreDM and DM patients (65.3 vs. 22.9 vs. 11.8%, respectively; p < 0.01). Age (p < 0.001), baseline IIEF-EF (p < 0.001), and DM status (p = 0.02) were independently associated with MCID. In conclusion, patients with undiagnosed PreDM depicted lower rates of response to PDE5i than normoglycemic men. These findings suggest that even milder forms of glucose impairment are associated with a poorer PDE5i effectiveness in men with ED.

Androgen Deficiency and Phosphodiesterase Type 5 Expression Changes in Aging Male: Therapeutic Implications.

The age-related decline of serum T occurs in ~20–30% of adult men and it is today defined as late-onset hypogonadism (LOH). In the elderly, such decline becomes more prevalent (up to 60%) and shows-up with erectile dysfunction (ED) and hypoactive sexual desire. A large body of experimental evidences have shown that the combination of T replacement therapy (TRT) and phosphodiesterase type 5 inhibitors (PDE5i) is, usually, effective in restoring erectile function in patients with LOH and ED who have not responded to monotherapy for sexual disturbances. In fact, PDE5is potentiate the action of nitric oxide (NO) produced by endothelial cells, resulting in a vasodilator effect, while T facilitates PDE5i effects by increasing the expression of PDE5 in corpora cavernosa. Meta-analytic data have recognized to PDE5i a protective role on the cardiovascular health in patients with decreased left ventricular ejection fraction. In addition, several studies have shown pleiotropic beneficial effects of these drugs throughout the body (i.e., on bones, urogenital tract and cerebral, metabolic, and cardiovascular levels). TRT itself is able to decrease endothelial dysfunction, oxidative stress and inflammation, thus lowering the cardiovascular risk. Furthermore, untreated hypogonadism could be the cause of PDE5i ineffectiveness especially in the elderly. For these reasons, aging men complaining ED who have LOH should undergo TRT before or at the moment when PDE5i treatment is started.

Sexual Rehabilitation After Nerve-Sparing Radical Prostatectomy: Free-of-Charge Phosphodiesterase Type 5 Inhibitor Administration Improves Compliance to Treatment

BackgroundIn December 2006, the region of Tuscany (Italy) authorized the free-of-charge provision of phosphodiesterase type 5 inhibitors (PDE5I) for all patients with Tuscan citizenship who undergo nerve-sparing radical prostatectomy (NSRP). ObjectiveTo compare sexual rehabilitation outcomes in patients with low risk of erectile dysfunction and minimal comorbidities who received PDE5Is free of charge (PDE5I-F) with those who paid for PDE5Is (PDE5I-P) after bilateral NSRP. MethodsWe reviewed prospectively recorded clinical data of 2,368 patients with Tuscan (PDE5I-F) and non-Tuscan (PDE5I-P) citizenship treated with NSRP at 3 different institutions in Tuscany from 2008 to 2013. Inclusion criteria for the final analysis were open or robot-assisted bilateral NSRP; low risk of postoperative erectile dysfunction according to the Briganti risk stratification tool; no smoking and no drug and alcohol abuse; no cardiovascular risk factors; no major surgery before and after NSRP; no neoadjuvant or adjuvant treatment; and no biochemical relapse. Dropout was defined as an interruption longer than 40 days of the treatment protocol indicated in the inclusion criteria. Treatment compliance was defined as more than 90% consumption of the prescribed PDE5I. OutcomesThe Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) and the Italian version of the University of California–Los Angeles Prostate Cancer Index sexual function (UCLA-PCI-s) questionnaires were administered to assess patients' satisfaction with PDE5I treatment and sexual function. ResultsOverall, 648 patients in the PDE5I-F group and 182 in the PDE5I-P group met the inclusion criteria and were eligible for the study. Patients had comparable preoperative and surgical characteristics. The PDE5I-F group had a significantly higher early rehabilitation onset (P < .001), lower treatment dropout at 12, 24, and 36 months (P < .001 for all comparisons), and higher compliance to the treatment protocol at 6 and 12 months (P = .01 and P < .001, respectively). At multivariable analysis, the PDE5I-F protocol was an independent predictor of an EDITS score higher than 50 (hazard ratio = 1.54, P = .03) and a UCLA-PCI-s score higher than 50 (hazard ratio = 3.12, P = .01) after adjusting for the effects of several clinical features. Clinical ImplicationsThe free-of-charge protocol has a significant impact on patients' satisfaction with PDE5I treatment. Strengths and LimitationsTo our knowledge, this is the first study comparing free vs paid access to a sexual rehabilitation protocol. Major limitations are the observational nature of the study and the different population sizes of the 2 groups. ConclusionsIn a selected cohort of patients after NSRP, free-of-charge access to a sexual rehabilitation protocol was significantly associated with higher early rehabilitation onset, major compliance to the protocol, minor treatment dropout, and higher satisfaction rate of patients.Siena G, Mari A, Canale A, et al. Sexual Rehabilitation After Nerve-Sparing Radical Prostatectomy: Free-of-Charge Phosphodiesterase Type 5 Inhibitor Administration Improves Compliance to Treatment. J Sex Med 2018;15:120–123.

Calidad de la vida sexual de varones heterosexuales con lesión medular en tratamiento farmacológico para la disfunción eréctil y de sus compañeras

ObjectiveTo assess the quality of sexual life reported by spinal cord-injured men treated with oral drugs for erectile dysfunction (ED) and their female partners. Material and methodMen with spinal cord injuries (SCI) complaining of ED and their female partners were evaluated using the Sexual Life Quality Questionnaire (SLQQ), a fully validated instrument in Spain. Two studies were conducted. A transversal study (1) on patients who were already on treatment with phosphodiesterase type 5 inhibitors (PDE5Is) and their partners, with 73 couples providing valid data. An additional prospective study (2) assessed SCI patients naive to PDE5Is in which both the patients and their spouses answered the SLQQ before treatment and after 3 months taking PDE5Is regularly, with 12 couples completing the study. ResultsThe SLQQ scores of SC injured men on PDE5Is (study 1) were under the remembered pre-lesion level, with lower scores reported by those with complete lesions (P<.2 vs incomplete). Their partners’ SLQQ scores were apparently similar to pre-injury times. The SLQQ scores of the patients and their partners were well correlated (r = 0.57, P<.0001), and they both reported high treatment satisfaction. Study 2: Untreated SCI patients reported very low SLQQ scores that were improved by PDE5Is treatment (P<.004), albeit without reaching the pre-injury level. A similar trend was found in their partners. Again both patients and partners reported high treatment satisfaction scores (P <.001). ConclusionThe sexual life quality levels of SC injured men on PDE5Is and their able-bodied spouses are well correlated. Both partners report high treatment satisfaction scores.

Effects of Phosphodiesterase Type 5 (PDE-5) Inhibitors in the Management of Pulmonary Arterial Hypertension: A Systematic Review and Meta-analysis Pointing on Peak VO2

Background: In settings where new drugs for pulmonary arterial hypertension (PAH) are not possible due to lack of availability and cost; PDE-5 inhibitors such as sildenafil is the drug of choice in the management of PAH. In this study we performed a meta-analysis to evaluate the effects of oral sildenafil in PAH, pointing on peak VO2 improvement. Methods: We retrieved randomized controlled trials (RCTs) of the effects of PDE-5 inhibitors, sildenafil in patients with PAH using PubMed, Medline, Embase, Cochrane Library, Google scholar and manual search from 2011 to 2016. Random controlled trials that compared oral sildenafil with placebo were selected. Data for populations, interventions, and outcomes were extracted independently by 2 investigators, and disagreements were resolved by consensus. Quality assessment was performed using the Cochrane risk-of-bias tool. Results: Four randomized controlled clinical trials including a total of three hundred thirty six patients were identified in the primary analysis, with 51.5% patients in the PDE-5 inhibitors treatment group and 48.5% patients in the placebo group. Two studies show reduction in statistical significance of mPAP (MD -4.15, 95% CI -17.28 to 8.98; P<0.00001) and PVR (MD -51.27, 95% CI -127.63 to 25.10; P<0.00001. Other three studies shown statistical significance in reduction of mPCWP (MD -2.70, 95% CI -7.14 to 1.75; P<0.0003). Other two studies which accessed the quality of life show no much differences among the two groups (MD 1.18, 95% CI -4.92 to 7.27; P<0.00001). However, all four trials, shown no statistical significant improvement in peak VO2, of patients allocated to PDE-5 inhibitors group, sildenafil compared to the placebo group with heterogeneity (MD 0.61, 95% CI -0.37 to 1.59, P=0.21, I2=34%). Conclusion: The results of present review suggest that treatment with PDE-5 inhibitors; sildenafil reduced mPAP, PVR and mPCWP but could not significantly improve the peak VO2.

PTU-126 Stromal targeting with phosphodiesterase type 5 inhibitors in oesophageal adenocarcinoma

Introduction The UK has the highest age-standardised incidence of oesophageal adenocarcinoma (EAC) worldwide. Deaths from EAC have risen by 50% since the 1970’s and 10-year survival is 1 in 10. An activated stroma (defined by α-SMA positive, Cancer Associated Fibroblasts (CAF)) is associated with poor prognosis across tumour types. We have shown the presence of CAF to be more predictive of survival in EAC than traditional pathological markers. 1 Stromal targeting is a novel area in cancer treatment, no currently licensed drugs are effective in targeting CAF. We describe the repurposing of Phosphodiesterase Type 5 inhibitors (PDE5i) for use in the treatment of EAC. Method The effect of PDE5i on EAC CAF was studied using small molecule inhibitors and siRNA knock down in primary cell culture and functional assays; collagen gel contraction, Transwell® invasion and 3D organotypic culture. Weighted correlation gene network analysis (WCGNA) was carried out on publically available gene microarray. Results PDE5 expression was upregulated in CAF extracted from EAC patients, compared to matched normal fibroblasts (n = 3). PDE5i significantly decreased the expression of α-SMA by CAF. Functional effects were investigated and a significant decrease in collagen-1 gel contraction (p = 0.012) was observed. Cancer cell migration (p Conclusion Stromal targeting by CAF inactivation is a new potential treatment for hard to treat solid organ malignancies. We have compelling evidence that PDE5i treatment of EAC CAF significantly decreases; α-SMA expression, contractility and the ability to promote cancer cell invasion. Recent evidence supports the role of CAFs in tumourigenesis and immune modulation, 2,3 PDE5 inhibition of the CAF phenotpye offers the possibility of increased drug deliver (chemo/immunotherapy) and host immune cell infiltration, decreased local and distant cancer growth and invasion. The time is right for the first human trial of PDE5i as an anti-cancer therapy. Disclosure of interest None Declared. References Underwood et al . Cancer-associated fibroblasts predict poor outcome and promote periostin-dependent invasion in oesophageal adenocarcinoma. J Pathol. 2015 Han et al . Molecular mechanism underlying the tumor-promoting functions of carcinoma-associated fibroblasts. Tumour Biol. 2015 Fearon, et al . The carcinoma-associated fibroblast expressing fibroblast activation protein and escape from immune surveillance. Cancer Immunol Res . 2014

A Detailed Analysis of the Association Between Postoperative Phosphodiesterase Type 5 Inhibitor Use and the Risk of Biochemical Recurrence After Radical Prostatectomy

A recent study reported a detrimental effect of phosphodiesterase type 5 inhibitors (PDE5-Is) on biochemical recurrence (BCR) after radical prostatectomy (RP) for prostate cancer (PCa). We tested the association between PDE5-I use, PDE5-I therapy scheme, number of PDE5-I pills taken, and BCR in 2579 patients treated with bilateral nerve-sparing RP for PCa between 2004 and 2013 at a single center. Patients were categorized according to PDE5-I use within 2 yr after surgery as on demand, rehabilitation schedule (daily PDE5-I use for at least 3 mo), and no PDE5-I use. Multivariable (MVA) Cox regression models tested the association between PDE5-I and BCR. The same analyses were repeated using the number of PDE5-I pills taken by each patient. Overall, 674 patients (26.1%) received PDE5-Is. At MVA analysis, PDE5-I use, type of administration schedule, and number of PDE5-I pills were not significantly associated with higher risk of BCR (all p ≥ 0.2) after accounting for multiple confounders including time from RP to PDE5-I use. While awaiting further studies, patients should not be denied PDE5-I treatment after RP. Patient summaryAmong patients treated with radical prostatectomy, phosphodiesterase type 5 inhibitor use was not associated with an increased risk of biochemical recurrence, regardless of the therapeutic regimen used.

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.

Synergistic Effects of BAY 60-4552 and Vardenafil on Relaxation of Corpus Cavernosum Tissue of Patients with Erectile Dysfunction and Clinical Phosphodiesterase Type 5 Inhibitor Failure

Overall efficacy rates of phosphodiesterase type 5 inhibitors (PDE5-i) for erectile dysfunction (ED) are 60-70%. PDE5-i treatment failures currently have to resort to invasive treatment options for restoration of erectile function. AIMS.: To assess changes in the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)/protein kinase (PKG) pathway in human corpus cavernosum (HCC) of PDE5-i nonresponders compared with healthy controls. To evaluate the effects of BAY 60-4552, a stimulator of soluble guanylate cyclase (sGC), and vardenafil on relaxation of HCC strips from PDE5-i nonresponders. mRNA expression, morphological localization of the NO/cGMP/PKG pathway, and relaxant capacity of both compounds alone or combined. Analysis of variance, t-test or Mann-Whitney test based upon number of groups and normality of data. HCC tissues were harvested after consent from individuals undergoing penile prosthesis implantation (patients) and potent patients undergoing transurethral surgery (healthy controls, needle biopsy). HCC tissues of patients were compared with those of healthy controls for the expression of mRNA coding for PDE5A, eNOS, PKGα1, PKG2, sGCα1, sGCα2, sGCβ1, sGCβ2, α-smooth muscle actin (aSMA) and β-actin by quantitative polymerase chain reaction (qPCR). The respective proteins were localized using immunofluorescence. Tissue strips of patients were precontracted with phenylepinephrine followed by incubation with 1 μM of either vardenafil or BAY 60-4552, or both simultaneously. The main targets in the NO/cGMP/sGC pathway were downregulated in PDE5-i nonresponders. The pathway was morphologically located to HCC smooth muscle, of which the overall content was preserved in ED patients based on aSMA expression. BAY 60-4552 and vardenafil have synergistic effects on relaxation of HCC of PDE5-i nonresponders. The main limitation is the small amount of control tissue precluding functional testing on these samples. Despite downregulation of the NO/cGMP/PKG pathway, combining BAY 60-4552 with vardenafil significantly enhanced relaxation HCC strips of PDE5-i nonresponders.

A 6-month, prospective, observational study of PDE5 inhibitor treatment persistence and adherence in Middle Eastern and North African men with erectile dysfunction

Background:Erectile dysfunction (ED) negatively impacts quality of life. Phosphodiesterase type 5 inhibitors (PDE5Is) are effective in treating ED; however, rates of discontinuation remain high.Objectives:To assess on-demand PDE5I treatment persistence and adherence through 6 months in Middle Eastern and North African (MENA) men with ED in a prospective, non-interventional, observational trial.Research design and methods:Enrolled men were ≥18 years old from Saudi Arabia, Egypt, and the United Arab Emirates, PDE5I naïve, and sexually active. PDE5Is were selected per routine clinical practice. Persistence was defined as use of ≥1 dose during the prior 4 weeks, adherence as compliance with dosing instructions during the most recent dose. Logistic regression models were used to identify factors associated with persistence and adherence.Main outcome measures:Persistence and Adherence Questionnaire; Partner Relationship Questionnaire; Self-Esteem and Relationship Questionnaire; International Index of Erectile Function (IIEF); Erectile Dysfunction Inventory of Treatment Satisfaction.Results:Patients’ (n = 493) mean age was 49.8 years, mean BMI was 29.3, and the majority (n = 354, 71.8%) were from Saudi Arabia. Tadalafil was the most prescribed PDE5I (69.6%), versus sildenafil (15.4%), or vardenafil (15.0%). Patients’ mean IIEF–Erectile Function scores improved from moderate to mild and Erection Hardness Scores (SD) improved from 1.8 (1.0) at baseline to 3.5 (0.7) at 6 months. At 6 months, 64.9% of patients were treatment persistent (tadalafil, 68.8%, sildenafil, 65.8%, and vardenafil, 45.9%) and 59.6% were adherent. Factors significantly predictive (p < 0.05) of persistence at 6 months included age, employment status, and ED severity. Factors significantly predictive of adherence were age, employment status, and duration of ED. Interpretation of differences between drugs was limited by substantial differences in prescription rates between countries.Conclusions:At 6 months, 64.9% of men were treatment persistent. In this study, age, employment status, ED severity, and duration of ED were associated with persistence and/or adherence.

Combination of Vacuum Erection Device and PDE5 Inhibitors as Salvage Therapy in PDE5 Inhibitor Nonresponders with Erectile Dysfunction

IntroductionOral phosphodiesterase type 5 inhibitors (PDE5i) have improved treatment options for erectile dysfunction (ED). In case of unresponsiveness to PDE5i, alternative therapies are considered. AimTo evaluate whether combination of vacuum erection device (VED) and PDE5i is effective as salvage therapy in subjects with ED in whom PDE5i alone failed. MethodsFrom September 2007 to May 2008, we evaluated 69 men (aged 36–82 years) in whom PDE5i treatment at the highest recommended dose, with at least 4–6 attempts at intercourse during a 3 months period, had failed. The clinical efficacy of combination therapy was evaluated using the International Index of Erectile Function-5 (IIEF-5) questionnaire, Sexual Encounter Profile (SEP)-2, SEP-3, and Global Patient Assessment Scale (GPAS). Main Outcome MeasuresScores on IIEF-5, SEP-2, SEP-3, and GPAS before and after combination therapy were measured. ResultsAfter 4 weeks of combination therapy, the mean IIEF-5 score increased significantly over baseline from 9.0 to 17.6 (P < 0.001). Of the 34 subjects with a SEP-2 response of “no” at baseline, 27 (79%) responded “yes” after combination therapy (P < 0.001). Of the 50 subjects with a SEP-3 response of “no” at baseline, 35 (70%) responded “yes” after combination therapy (P < 0.001). Furthermore, of the 42 subjects with a GPAS response of “not at all” or “slightly” improved at baseline, 31 (74%) responded “moderately” or “greatly” improved after combination therapy (P < 0.001). One subject (1.5%) experienced device-related intermittent penile pain, which resolved after 4 days without any action. ConclusionsStatistically significant improvements over baseline were seen in IIEF-5, SEP-2, SEP-3, and GPAS measures following 4 weeks of combination therapy of PDE5i and VED. This study supports the use of PDE5i with VED in men in whom PDE5i alone failed. This combination therapy may be offered to patients not satisfied with PDE5i alone before being switched to more invasive alternatives. Canguven O, Bailen J, Fredriksson W, Bock D, and Burnett AL. Combination of vacuum erection device and PDE5 inhibitors as salvage therapy in PDE5 inhibitor nonresponders with erectile dysfunction. J Sex Med 2009;6:2561–2567.