Adherence to Initial PDE5 Inhibitor Treatment: Randomized OpenLabel Study Comparing Tadalafil Once a Day,Tadalafil on Demand,and Sildenafil on Demand in Patients with Erectile Dysfunction

IntroductionPhosphodiesterase type 5 (PDE5) inhibitor treatment for erectile dysfunction (ED) is frequently discontinued; adherence may vary depending on the initial regimen.AimTo evaluate the effects of initiating treatment with tadalafil once a day (OaD), tadalafil on demand (pro re nata [PRN]), or sildenafil PRN on treatment adherence.MethodsIn this multicenter, openlabel study, men (≥18 years) with ED, naïve to PDE5 inhibitors, were randomized (1:1:1) to tadalafil 5 mg OaD, tadalafil 10 mg PRN, or sildenafil 50 mg PRN. An 8week randomized treatment (RT) period (dose adjustment possible) was succeeded by 16 weeks of pragmatic treatment (switches between PDE5 inhibitors allowed).Main Outcome MeasuresTreatment adherence was measured as time to discontinuation of RT (any cause), estimated by Kaplan–Meier productlimit method. Treatmentgroup differences were estimated as hazard ratio (HR; Cox proportional hazards).ResultsSeven hundred seventy patients (mean age 53 years) were randomized to tadalafil OaD (N = 257), tadalafil PRN (N = 252), and sildenafil PRN (N = 261). Kaplan–Meier estimates for patients discontinuing RT were 52.2, 42.0, and 66.7%, respectively. Median time to discontinuation of RT was significantly longer for tadalafil OaD and PRN (130 and >168 days) compared with sildenafil (67 days) (HR [97.5% confidence interval]: 0.66 [0.51, 0.85] and 0.49 [0.37, 0.65]; P < 0.001). Reasons for discontinuation with significant differences between groups (P < 0.05) included “lack of efficacy (duration of erection)” (sildenafil 9.2% vs. tadalafil OaD 4.3%, PRN 2.8%), “time constraints due to short window of action” (sildenafil 4.2% vs. tadalafil OaD 0%, PRN 0.4%), and “feel medication controls my sexual life” (sildenafil 2.7% vs. tadalafil OaD 0%). No betweengroup differences were found in International Index of Erectile FunctionErectile Function domain change from baseline to end of RT (least squares mean: 9.4–10.0, P = 0.359) or discontinuations due to adverse events (1.2–1.6%). The most common adverse event (≥4%) was headache.ConclusionsED patients assigned to tadalafil OaD or PRN adhered significantly longer to initial treatment than patients assigned to sildenafil PRN. Improvement of erectile function and safety profiles were similar in all three treatment groups.     

Treating erectile dysfunction and central neurological diseases with oral phosphodiesterase type 5 inhibitors. Review of the literature

IntroductionErectile dysfunction (ED) is reported in a high percentage of patients with central neurological disorders (CND).AimAn up‐to‐date review on oral phosphodiesterase 5 inhibitors (PDE5): sildenafil, tadalafil, and vardenafil for individuals with CND and ED.Main Outcome MeasuresVarious questionnaires on ED, such as the International Index of Erectile Function composed of 15 questions.MethodsInternationally published clinical studies evaluating the efficacy and safety of PDE5 on subjects with CND and ED were selected.ResultsOverall, 28 articles on PDE5 used to treat patients with CND and ED were included. With each of the three PDE5 compared to placebo or erectile baseline, literature reported significant statistical improvement (P < 0.01; P < 0.05) only in patients with spinal cord injury (SCI). PDE5 efficacy was documented for SCI patients up to 10 years. The most frequent predicable factor for PDE5 success was the presence of upper motoneuron lesion. Each of the three clinical sildenafil studies documented statistically significant improvement on erectile function in Parkinson's patients (P < 0.01; P < 0.05). Two studies reported discordant results about sildenafil's effectiveness on multiple sclerosis (MS) patients; one on tadalafil showed significant statistical efficacy on erection versus baseline (P < 0.01; P < 0.05). The only spina bifida article determined that sildenafil remarkably improved erectile function. Overall, drawbacks were mostly slight‐moderate, except in subjects with multiple system atrophy where sildenafil caused severe hypotension.ConclusionsPDE5 represent first line ED therapy only for SCI patients, though treatment results through meta‐analysis were not possible. Encouraging results are reported for Parkinson's and MS patients. PDE5 use for other CND patients is limited for various reasons, such as ED and concomitant libido impairment caused by depression and/or sexual endocrinology dysfunctions, and because PDE5 may cause a worsening of neurological illness. Medical centers staffed by health professionals able to counsel patients on the possible use of PDE5 are needed. Lombardi G, Nelli F, Celso M, Mencarini M, and Del Popolo G. Treating erectile dysfunction and central neurological diseases with oral phosphodiesterase type 5 inhibitors. Review of the literature. J Sex Med 12;9:970–985.     

Nebivolol Potentiates the Efficacy of PDE5 Inhibitors to Relax Corpus Cavernosum and Penile Arteries from Diabetic Patients by Enhancing the NO/cGMP Pathway

IntroductionThe efficacy of oral pharmacotherapy for erectile dysfunction (ED) (i.e., type 5 phosphodiesterase [PDE5] inhibitors) is significantly reduced in diabetic patients. Nebivolol is a selective β₁‐blocker used for treating hypertension that has been shown to increase the efficacy of sildenafil to reverse ED in diabetic rats.AimTo evaluate the effects of nebivolol on the efficacy of the PDE5 inhibitors, sildenafil, tadalafil, and vardenafil to relax human corpus cavernosum (HCC) and vasodilate human penile resistance arteries (HPRA) from diabetic patients with ED (DMED). The influence of nebivolol on the capacity of these three PDE5 inhibitors to stimulate cyclic guanosine monophosphate (cGMP) production in HCC was also evaluated.MethodsHCC and HPRA were obtained from organ donors without ED (NEND; n = 18) or patients with diabetes undergoing penile prosthesis implantation (DMED; n = 19). Relaxations of HCC strips and HPRA to sildenafil, tadalafil, and vardenafil were evaluated in organ chambers and wire myographs. cGMP content in HCC was determined by ether extraction and quantification by ELISA.Main Outcome MeasuresEffects of nebivolol on PDE5 inhibitor‐induced relaxation of HCC, vasodilation of HPRA and cGMP accumulation in HCC.ResultsTreatment with nebivolol (1 μM) significantly potentiated sildenafil‐, tadalafil‐ and vardenafil‐induced relaxations of HCC and vasodilations of HPRA from both NEND and DMED. Enhancement of relaxant capacity by nebivolol resulted in reversion of the impairment of PDE5 inhibition‐induced responses in DMED and it was accompanied by enhancing the ability of PDE5 inhibitors to increase cGMP in HCC restoring reduced cGMP levels in HCC from DMED.ConclusionsNebivolol potentiated the capacity of PDE5 inhibitors to relax vascular structures of erectile tissue from diabetic patients by enhancing the nitric oxide (NO)/cGMP pathway in these tissues. These effects suggest a potential therapeutic utility of nebivolol as an adjunct to PDE5 inhibitors for the treatment of ED associated with diabetes. Martínez‐Salamanca JI, La Fuente JM, Cardoso J, Fernández A, Cuevas P, Wright HM, and Angulo J. Nebivolol potentiates the efficacy of PDE5 inhibitors to relax corpus cavernosum and penile arteries from diabetic patients by enhancing the NO/cGMP pathway. J Sex Med 2014;11:1182–1192.     

A Randomized Open‐Label Trial with a Crossover Comparison of Sexual Self‐Confidence and Other Treatment Outcomes Following Tadalafil Once a Day Vs. Tadalafil or Sildenafil On‐Demand in Men with Erectile Dysfunction

AimTo compare Sexual Self‐Confidence and other treatment outcomes following 8 weeks of treatment with tadalafil 5 mg once a day (OaD) vs. tadalafil 20 mg or sildenafil 100 mg as needed (pro re nata [PRN]) in patients with erectile dysfunction (ED).MethodsA randomized, open‐label, crossover study in men ≥18 years of age with history of ED and satisfactory response to current oral phosphodiesterase 5 (PDE5) inhibitor PRN. Data were analyzed with a mixed effects model for crossover design.Main Outcome MeasuresThe primary outcome measure was the Sexual Self‐Confidence domain of the Psychological and Interpersonal Relationship Scales (PAIRS) between tadalafil OaD and sildenafil PRN.Secondary Outcomes IncludedTime Concerns and Spontaneity domains of PAIRS, and the Self‐Esteem and Relationship (SEAR) scale.ResultsMen naive to tadalafil OaD were enrolled (N = 378), with 61–69% prior PDE5 inhibitor use. There were improvements in all PAIRS domains from baseline when comparing tadalafil OaD and PRN with sildenafil PRN (P < 0.001). The Sexual Self‐Confidence domain improved from baseline and was 0.50 ± 0.78 following tadalafil OaD, 0.5 ± 0.72 for tadalafil PRN, and 0.39 ± 0.67 for sildenafil PRN. The difference in least‐squares mean was 0.12 ± 0.04 (confidence interval [CI] = 0.04, 0.19; P = 0.001) between tadalafil OaD and sildenafil PRN and 0.01 ± 0.04 (CI = ?0.06, 0.08; P = 0.872) between tadalafil OaD and tadalafil PRN. The Time Concerns domain score was lower with tadalafil OaD than tadalafil PRN (P < 0.001). There were no differences in SEAR scores between treatments.ConclusionsTadalafil OaD and tadalafil PRN compared with sildenafil PRN demonstrated greater improvements in Sexual Self‐Confidence, Time Concerns, and Spontaneity. There was no significant difference in Sexual Self‐Confidence between tadalafil OaD and tadalafil PRN. Changes in SEAR, the erectile function domain of the International Index of Erectile Function, and the Erectile Dysfunction Inventory of Treatment Satisfaction scores from baseline to end point were similar. Rubio‐Aurioles E, Porst H, Kim ED, Montorsi F, Hackett G, Morales AM, Stuckey B, Būttner H, West TM, Huynh NN, Lenero E, Burns P, and Kopernicky V. A randomized open‐label trial with a crossover comparison of sexual self‐confidence and other treatment outcomes following tadalafil once a day vs. tadalafil or sildenafil on‐demand in men with erectile dysfunction. J Sex Med 2012;9:1418–1429.     

Phosphodiesterase Type 5 Inhibitors Facilitate Noncontact Erections in Male Rats: Site of Action in the Brain and Mechanism of Action

IntroductionOrally active phosphodiesterase type 5 inhibitors (PDE5i), used in the treatment of erectile dysfunction, facilitate the relaxation of cavernous smooth muscle tissues by reducing the degradation of cyclic guanosine monophosphate.AimsThe aims of this article were to determine whether PDE5i facilitate penile erection and male sexual behavior by acting also on the central nervous system and to investigate their mechanism of action at central level.MethodsPDE5i (sildenafil, vardenafil, and tadalafil) given intraperitoneally (i.p.) (5 mg/kg and 10 mg/kg), intracerebroventricularly (i.c.v.) (10 µg and 50 µg), or into the ventral tegmental area (VTA) (10 µg) were tested in the noncontact erection test in male Sprague-Dawley rats screened for their ability to display or not display this sexual response. Extracellular dopamine was measured in the dialysate obtained from the nucleus accumbens by intracerebral microdialysis on injection of PDE5i into the VTA.Main Outcome MeasuresNoncontact erections were counted after intraperitoneal, intracerebroventricular, or intra-VTA treatment with PDE5i. Extracellular dopamine was measured in the dialysate from the nucleus accumbens when sildenafil or vardenafil was given into the VTA.ResultsPDE5i induced a significant increase of noncontact erections in male rats displaying this sexual response following intraperitoneal or intracerebroventricular administration at the highest dose tested. However, both doses significantly increased noncontact erections in male rats not displaying this sexual response. Similar results were found when PDE5i were injected into the caudal VTA. Noncontact erections increased concomitantly to a rise in extracellular dopamine in the dialysate from the nucleus accumbens.ConclusionsThe results suggest that PDE5i may increase sexual arousal by acting in the central nervous system. This effect may be mediated (at least in part) by the activation of mesolimbic dopaminergic neurons. Sanna F, Succu S, Boi A, Melis MR, and Argiolas A. Phosphodiesterase type 5 inhibitors facilitate noncontact erections in male rats: Site of action in the brain and mechanism of action. J Sex Med 2009;6:2680–2689.     

Timing of Dose Relative to Sexual Intercourse Attempt in Previous Sildenafil Citrate Users Treated with Tadalafil: A Geographical Comparison from a Single Arm,Open-Label Study

IntroductionPrevious research has demonstrated that sildenafil citrate users alter dosing-sexual attempt behavior when switched to tadalafil. The impact of geography and culture on sexual behavior with phosphodiesterase type 5 (PDE5) inhibitor treatment has not been fully investigated.AimTo describe and compare the changes in dosing-sexual attempt behavior with sildenafil citrate vs. tadalafil treatment across four distinct geographies: Asia, Australia/New Zealand (ANZ), Central Eastern Europe/Middle East (CEE/ME), and Latin America (LA).MethodsData from a single-arm, open-label clinical trial conducted in 21 countries from November 2002 to May 2004 were used in this analysis. Men with erectile dysfunction and a history of ≥6-week prior sildenafil citrate use continued sildenafil citrate treatment for 4 weeks then switched to tadalafil for 8 weeks. Dosing instructions were provided.Main Outcomes MeasuresTiming of dose and sexual intercourse was assessed through patient diaries for the final 4 weeks of each treatment period.ResultsA total of 2,760 men were enrolled: Asia 15.8%; ANZ 29.4%; CEE/ME 19.7%; LA 35.1%. The median time from dosing to intercourse was significantly increased during tadalafil treatment across all geographical regions; however, the magnitude of increase differed significantly by geography (P < 0.0001). The Asian cohort demonstrated the shortest duration between dosing and sexual intercourse attempts (irrespective of drug), and altered sexual behavior the least upon switching to tadalafil. The ANZ cohort demonstrated the longest duration between dosing and sexual intercourse attempts (irrespective of drug), and altered sexual behavior the most upon switching to tadalafil.ConclusionMen with a history of established sildenafil citrate use alter their dose-attempt behavior when treated with tadalafil irrespective of geography. However, the extent to which sexual behavior alters is not uniform across geographical regions, suggesting that dosing instructions and duration of drug effectiveness, in combination with personal and cultural preferences, may determine sexual behavior with PDE5 inhibitor use. Rubio-Aurioles E, Glina S, Abdo CHN, Hernandez-Serrano R, Rampazzo C, Sotomayor M, West TM, Gallagher GL, and Lenero E. Timing of dose relative to sexual intercourse attempt in previous sildenafil citrate users treated with tadalafil: A geographical comparison from a single arm, open-label study. J Sex Med 2009;6:2836–2850.     

Selectivity of Avanafil,a PDE5 Inhibitor for the Treatment of Erectile Dysfunction: Implications for Clinical Safety and Improved Tolerability

IntroductionPhosphodiesterase type 5 (PDE5) inhibitors are indicated for the treatment of erectile dysfunction (ED); however, they can also inhibit other PDE isozymes, affecting their target tissues (e.g., PDE1: heart; PDE6: retina; and PDE11: skeletal muscle), which in some cases can cause unwanted side effects and therapy discontinuation. Data from in vitro studies showed that avanafil, a PDE5 inhibitor for the treatment of ED, exhibited strong selectivity toward PDE5 and against all other PDE isozymes.AimTo review the inhibitory effects of avanafil for PDE isozymes compared with those of sildenafil, tadalafil, and vardenafil and to discuss these results within the context of clinical trial safety observations.MethodsReview of in vitro selectivity data for avanafil (published primary data from a peer‐reviewed journal and scientific congress abstracts); PubMed search for pertinent publications on PDE5 inhibitor safety data; and review of published articles and abstracts from avanafil phase 1, 2, and 3 clinical trials.Main Outcome MeasuresA low incidence of some PDE‐related adverse events may be reflected by the high selectivity of avanafil against non‐PDE5 isozymes.ResultsAvanafil is highly selective toward PDE5 and against all other PDE isozymes tested. Lower selectivity against PDE1, PDE6, and PDE11 is consistent with results from randomized, placebo‐controlled, phase 3 trials in which musculoskeletal and hemodynamic adverse events were reported in <2% of patients and no color vision‐related abnormalities were reported with avanafil doses up to 200 mg once daily.ConclusionsData suggest that avanafil may confer a safety benefit, in terms of a lower incidence of specific adverse events, by virtue of its high specificity to PDE5 and its overall selectivity against other PDE isozymes. Wang R, Burnett AL, Heller WH, Omori K, Kotera J, Kikkawa K, Yee S, Day WW, DiDonato K, and Peterson CA. Selectivity of avanafil, a PDE5 inhibitor for the treatment of erectile dysfunction: Implications for clinical safety and improved tolerability. J Sex Med 2012;9:2122–2129.     

The ENDOTRIAL Study: A Spontaneous,Open-Label,Randomized, Multicenter,Crossover Study on the Efficacy of Sildenafil,Tadalafil, and Vardenafil in the Treatment of Erectile Dysfunction

IntroductionThe three effective, commercially available drugs for the treatment of erectile dysfunction—sildenafil, vardenafil, and tadalafil—inhibit the same substrate, the erectolytic enzyme phosphodiesterase type 5 (PDE5). Although there are pharmacological differences between these three compounds, few comparative studies have been conducted to date.AimThe aim of this study was to determine the efficacy of sildenafil, tadalafil, and vardenafil in a randomly assigned 8-week fixed regimen.MethodsThis was a spontaneous, open-label, randomized, multicenter, crossover study where the patients were randomized to receive sildenafil 50 mg, sildenafil 100 mg, tadalafil 20 mg, or vardenafil 20 mg.Main Outcome MeasuresThe primary outcome included the posttreatment analysis of erectile function domains of the abridged International Index of Erectile Function (IIEF5+1). The secondary objectives included the analysis of peak-systolic velocities (PSVs), end-diastolic velocities (EDVs), and resistive index (RI), and the estimate of the percentage of men with normal penile hemodynamic parameters after each treatment.ResultsIn all groups of patients taking sildenafil 50 mg, sildenafil 100 mg, tadalafil 20 mg, and vardenafil 20 mg at a frequency reflecting the common treatment regimens in real life, there was a statistically significant baseline-to-end point improvement in subjective perception of erectile function measured by IIEF5+1. When the four groups were compared, the treatments were not different in modifying IIEF5+1 and penile flow parameters. However, the within-group analysis showed that PSV improved in the sildenafil 50 mg group and that PSV together with RI significantly ameliorated in patients receiving 100 mg of sildenafil. Regression analysis confirmed an independent effect of sildenafil on hemodynamic efficacy parameters.ConclusionsAn overall equivalence was demonstrated in the subjective perception of treatment benefits for all the PDE5i tested. However, sildenafil, in a dose-dependent manner, was the unique PDE5i able to ameliorate some of the penile flow parameters within the 8-week treatment period. These findings should be interpreted conservatively because of the observational nature of the study. Jannini EA, Isidori AM, Gravina GL, Aversa A, Balercia G, Bocchio M, Boscaro M, Carani C, Corona G, Fabbri A, Foresta C, Forti G, Francavilla S, Granata ARM, Maggi M, Mansani R, Palego P, Spera G, Vetri M, and Lenzi A on behalf of the Endotrial Study Group. The ENDOTRIAL study: A spontaneous, open-label, randomized, multicenter, crossover study on the efficacy of sildenafil, tadalafil, and vardenafil in the treatment of erectile dysfunction. J Sex Med 2009;6:2547–2560.     

Ten Years of Phosphodiesterase Type 5 Inhibitors in Spinal Cord Injured Patients

IntroductionThe majority of men with spinal cord injury (SCI) require chronic treatment for erectile dysfunction (ED), but most of them, prior to taking phosphodiesterase type 5 (PDE5) inhibitors, stopped therapy due to side-effects or low compliance rate.AimAnalysis of literature on oral PDE5 inhibitors in individuals with SCI and ED in order to evaluate how much their release changed the management of ED in SCI subjects and what remains to be seen of their potential or limits.Main Outcome MeasuresQuestionnaires on sexual function.Methods18 internationally published clinical studies that enrolled SCI males treated with at least one of the PDE5 inhibitors were analyzed.ResultsThe small numbers of papers with large and diverse outcome measures did not consent a meta-analysis of treatment results. 705 used sildenafil, 305 vardenafil and 224 tadalafil. Median age was less than 40 years. Only 1 study excluded tetraplegic individuals. For measures of ED evaluated, 11 out of 13 studies reported a significant statistical improvement with PDE5 inhibitors versus placebo or erectile baseline (P < 0.01, or p < 0.005). The most frequent predicable factor for the therapeutic success of PDE5 inhibitors was upper motoneuron lesion. Statistical impact on ejaculation success rates was shown in at least one paper for all PDE5 inhibitors (p < 0.05). Overall, 15 patients, (7 using sildenafil), discontinued the therapies due to drawbacks. Only 1 sildenafil study reported a follow-up maximum of 24 months.ConclusionsLiterature suggests that all oral PDE5 inhibitors represent a safe and effective treatment option for ED caused by SCI. Further research is needed on head-to-head comparative trials and SCI patient preference for these drugs; their impact on ejaculation and orgasm function, their early use after SCI for increasing the recovery rate of a spontaneous erection, and their effectiveness and tolerability in the long-term are still to be investigated. Lombardi G, Macchiarella A, Cecconi F, and Del Popolo G. Ten years of phosphodiesterase type 5 inhibitors in spinal cord injured patients. J Sex Med 2009;6:1248–1258.     

A Return to Normal Erectile Function with Tadalafil Once Daily after an Incomplete Response to As‐Needed PDE5 Inhibitor Therapy

IntroductionAn optimal outcome of an erectile dysfunction (ED) treatment is to enable a return to normal erectile function (as defined by an International Index of Erectile Function—Erectile Function [IIEF‐EF] domain score ≥26). As‐needed (PRN) phosphodiesterase type 5 (PDE5) inhibitor treatment does not always result in a return‐to‐normal erectile function.AimThe combined studies evaluated whether treatment with tadalafil once daily would allow men to return to normal erectile function who had less than normal IIEF‐EF domain scores while using a maximum dose of a PRN PDE5 inhibitor treatment.MethodsMen were ≥18 years of age, sexually active, reported a ≥3‐month history of ED, and had been taking the maximum dose of sildenafil citrate, vardenafil, or tadalafil PRN. Randomization to once‐daily therapy with tadalafil 2.5 mg to 5 mg (N = 207), tadalafil 5 mg (N = 207), or placebo (N = 209) for 12 weeks followed a 4‐week maximum dose PRN PDE5 treatment and 4‐week nondrug lead periods. Two identical double‐blind, randomized, placebo‐controlled studies were conducted; combined results are reported.Main Outcome MeasureThe main outcome measure was the percentage of subjects with a return‐to‐normal erectile function (IIEF‐EF domain score ≥ 26) when treated with tadalafil once daily compared with placebo.ResultsIn subjects not achieving normal erectile function with the maximum dose of a PRN PDE5 inhibitor, a higher percentage of subjects treated with tadalafil had an IIEF‐EF domain score ≥26 at end point (tadalafil 2.5‐ to 5‐mg group [39%]; tadalafil 5‐mg group [40%]) compared with the placebo group (12.1%; P < 0.001). Tadalafil was generally well tolerated and adverse events observed were consistent with previous reports of tadalafil once daily.ConclusionsTreatment with tadalafil once daily significantly improved erectile function in men with mild to mild‐moderate impairments in erectile function following PRN PDE5 inhibitor treatment. Kim ED, Seftel AD, Goldfischer ER, Ni X, and Burns PR. A return to normal erectile function with tadalafil once daily after an incomplete response to as‐needed PDE5 inhibitor therapy. J Sex Med 2014;11:820–830.     

Metrics for Evaluation of Age-Related Changes in Erectile Capacity in a Rodent Model

IntroductionStimulation of the cavernous nerve elicits increases in intracavernosal pressure (ICP) and visible penile erection (VPE) in rats. The observed penile erection can be characterized by the change in ICP and the ratio of ICP over blood pressure (BP; systemic blood pressure).AimWe evaluated correlations between ICP, BP, ICP/BP, and VPE, and the magnitude of the nerve stimulation required to elicit those responses in order to evaluate age-related changes in erectile function in a rodent model.MethodsNine young (3 months) and 10 old (18 months) rats were used. Under anesthesia cavernous nerve stimulation was performed at stimulation strengths ranging from 0.1 to 10 mA.Main Outcome MeasuresThe ICP, BP, ICP/BP, and VPE responses to cavernous nerve stimulation were quantified and compared.ResultsSignificant correlations were observed between ICP and ICP/BP in both young (r² = 0.886) and old (r² = 0.962) rats. If the ratio ICP/BP was taken as a metric of VPE and non-erection, then the threshold value for observing a VPE in the majority of animals was ≥0.5 in both young and old rats. However, higher current stimulation was required in the old than in the young animals to achieve erections. Moreover, both the maximal ICP and ICP/BP ratios achieved during erection were also lower in the old (85 ± 2 cmH₂O and 0.6 ± 0.02, respectively) than young (106 ± 3 cmH₂O and 0.75 ± 0.02, respectively) rats (P < 0.0001).ConclusionOld rats without obvious comorbidities were capable of penile erections, but those erections were accompanied by reduced ICP responses to cavernous nerve stimulation, implying apparently reduced penile rigidity. Taken together our current observations indicate that ICP, ICP/BP, and VPE provide useful metrics/indices of erectile capacity/function, and, moreover, that improved understanding of the inter-relationships among these parameters provides a frame work for further exploration of the mechanistic basis for age-related erectile dysfunction. Zhao W, Sato Y, Melman A, Andersson K-E, and Christ G. Metrics for evaluation of age-related changes in erectile capacity in a rodent model. J Sex Med 2009;6:1885–1892.     

10-Year analysis of adverse event reports to the Food and Drug Administration for phosphodiesterase type-5 inhibitors

IntroductionTo ensure public safety all Food and Drug Administration (FDA)‐approved medications undergo postapproval safety analysis. Phosphodiesterase type‐5 inhibitors (PDE5‐i) are generally regarded as safe and effective.AimWe performed a nonindustry‐sponsored analysis of FDA reports for sildenafil, tadalafil, and vardenafil to evaluate the reported cardiovascular and mortality events over the past 10 years.MethodsSummarized reports of adverse events (AEs) for each PDE5‐i were requested from the Center for Drug Evaluation and Research within the FDA. These data are available under the Freedom of Information Act and document industry and nonindustry reports of AEs entered into the computerized system maintained by the Office of Surveillance and Epidemiology.Main Outcome MeasureThe data were analyzed for the number of AE reports, number of objective cardiovascular events, and reported deaths.ResultsOverall, 14,818 AEs were reported for sildenafil. There were 1,824 (12.3%) reported deaths, and reports of cardiovascular AEs numbered 2,406 (16.2%). Tadalafil was associated with 5,548 AEs and 236 deaths were reported. Vardenafil was associated with 6,085 AEs and 121 reports of deaths. The percentage of reported severe cardiovascular disorders has stabilized at 10% to 15% of all AE reports for sildenafil and tadalafil and 5% to 10% for vardenafil. Only 10% of AE reports sent to the FDA for PDE5‐i were from pharmaceutical manufacturers.ConclusionReports of deaths associated with PDE5‐i remain around 5% of total reported events. Despite inherent limitations from evaluating FDA reports of AEs, it is important that these reports be reviewed outside pharmaceutical industry support in order to provide due diligence and transparency. Lowe G and Costabile RA. 10‐year analysis of adverse event reports to the Food and Drug Administration for phosphodiesterase type‐5 inhibitors. J Sex Med 2012;9:265–270.     

A randomized, double-blind, placebo-controlled, parallel study to assess the efficacy and safety of once-a-day tadalafil in men with erectile dysfunction who are naïve to PDE5 inhibitors

IntroductionThe majority of subjects included in previous tadalafil once‐a‐day clinical trials were non‐naïve to previous phosphodiesterase 5 (PDE5) inhibitors on demand. A study on PDE5 inhibitor naïve subjects was therefore warranted.AimTo evaluate the efficacy and safety of once‐a‐day tadalafil in PDE5 inhibitor‐naïve men with erectile dysfunction (ED).Main Outcomes MeasuresPrimary efficacy end points were changes from baseline to end point in the International Index of Erectile Function (IIEF) Erectile Function (EF) domain score and the per‐subject proportion of “yes” responses to sexual encounter profile (SEP) question 2 (SEP2) and question 3 (SEP3).MethodsPDE5 inhibitor‐naïve men with ED (N = 217) were randomized in a 1:2 ratio to receive placebo or tadalafil 5 mg once a day for 12 weeks. Enrollment began in January 2009 and the last subject completed in January 2010.ResultsAt end point, least square mean change from baseline IIEF‐EF domain score (7.3 vs. 3.4), SEP2 (23.8% vs. 12.2%) and SEP3 (39.5% vs. 21.5%), was significantly larger for tadalafil vs. placebo (all P < 0.001). The most common adverse events (AEs) in tadalafil‐treated subjects were back pain, nasopharyngitis, dyspepsia, headache, and myalgia. Four subjects (2.7%) in the tadalafil group and one subject (1.4%) in the placebo group discontinued because of AEs.ConclusionsIn PDE5 inhibitor‐naïve men, tadalafil once a day significantly improved EF compared with placebo. Safety results were consistent with previous tadalafil once‐a‐day clinical trials. Montorsi F, Aversa A, Moncada I, Perimenis P, Porst H, Barker C, Shane MA, and Sorsaburu S. A randomized, double‐blind, placebo‐controlled, parallel study to assess the efficacy and safety of once‐a‐day tadalafil in men with erectile dysfunction who are naïve to PDE5 inhibitors. J Sex Med 2011;8:2617–2624.     

Subacute Hemolysis in Sickle Cell Mice Causes Priapism Secondary to NO Imbalance and PDE5 Dysregulation

IntroductionRecent research suggests that priapism in sickle cell disease (SCD) is due to dysregulation of penile erection homeostasis including alteration of nitric oxide synthase (NOS) and phosphodiesterase type 5 (PDE5) activities by excessive levels of reactive oxygen species (ROS) released during hemolysis. It is unknown if subacute exposure to hemolysis is sufficient or if chronic reconditioning of erectile tissues is required for perturbation of homeostatic pathways and whether PDE5 inhibitor (PDE5I) treatment can restore erectile homeostasis in the subacute setting.AimsThe aim of this study was to investigate the effects of subacute hemolysis (3‐month exposure) on priapism and NO pathway regulation.MethodsMice underwent bone marrow transplantation with either SCD (BM‐SS) or wild‐type (WT) bone marrow. BM‐SS mice were treated with sildenafil 100 mg/kg/day. We measured intracavernous pressure (ICP) measurements with or without cavernous nerve stimulation following bone marrow transplantation to assess for priapism.Main Outcome MeasuresICP and frequency of erections were assessed. Penile tissues were analyzed for NOS, protein kinase G (PKG), PDE5, and ROS activities.ResultsBM‐SS mice demonstrated a priapism phenotype. PDE5I treatment reduced the frequency of erections in BM‐SS mice (1.7 ± 1.1 vs. 5.5 ± 2.8 erections per hour, P < 0.05). Penile tissues from BM‐SS mice demonstrated decreased NOS, PKG, PDE5 and elevated ROS activities compared with that of control mice. PDE5I treatment increased NOS (11.6 ± 1.3% vs. 7.8 ± 2.3%, P < 0.05) and PDE5 (76.3 ± 9.8% vs. 52.3 ± 11.1%, P < 0.05) activities and decreased ROS activity (137.8 ± 12.1% vs. 199.1 ± 11.3%, P < 0.05) compared with non‐PDE5I treated BM‐SS mice. PKG activity was increased beyond control levels with PDE5I treatment (158.4 ± 10.3%, P < 0.05).ConclusionShort‐term hemolysis is sufficient to establish a priapism phenotype and results in loss of erectile function. PDE5I treatment ameliorates priapism, in part, because of restored NO balance with decreased ROS generation and increased PDE5 activity. Sopko NA, Matsui H, Hannan JL, Berkowitz D, Champion HC, Hsu LL, Musicki B, Burnett AL, and Bivalacqua TJ. Subacute Hemolysis in Sickle Cell Mice Causes Priapism Secondary to NO Imbalance and PDE5 Dysregulation. J Sex Med 2015;12:1878–1885.     

Effects of Phosphodiesterase Inhibitors on the Contractile Responses of Isolated Human Seminal Vesicle Tissue to Adrenergic Stimulation

IntroductionIt has been suggested that the capability of the phosphodiesterase 5 (PDE5) inhibitor sildenafil citrate (VIAGRA) to retard the ejaculatory response may include modulation of the contraction of seminal vesicle (SV) smooth muscle. In fact, it has been shown that PDE inhibitors can reverse the tension of isolated human SV tissue and enhance the production of cyclic AMP and cyclic GMP.AimThe aim of this study was to examine the effects of selective phosphodiesterase (PDE) inhibitors on both the spontaneous and electrically induced phasic contractions of isolated human SV smooth muscle.Main Outcome MeasuresTo measure the inhibition exerted by PDE inhibitors vinpocetine (PDE1-inhibitor), rolipram (PDE4-inhibitor), sildenafil, and vardenafil (PDE5-inhibitors) on the phasic contractile response of isolated SV tissue.MethodsUsing the organ bath technique, the effects of increasing concentrations of the PDE inhibitors (1 nM–10 µM) were investigated on phasic contractions of SV tissue strips either mediated by means of electrical field stimulation (EFS) or the alpha₁-adrenoceptor agonist norepinephrine.ResultsThe contractile activity in response to EFS was dose-dependently reversed by the PDE inhibitors. The rank order of efficacy was: rolipram > sildenafil ≥ vardenafil > vinpocetine. Mean maximum inhibition of contraction was determined as ?89.6% (rolipram), ?61.3% (sildenafil), ?62% (vardenafil), and ?46% (vinpocetine). No differences were registered with regard to the effects of sildenafil and vardenafil on the inhibition of the contraction amplitudes. The frequency of the spontaneous contractions (amplitudes/5 minutes) was reduced by 50% in the presence of 2 µM rolipram, 5 µM sildenafil or vardenafil, and 8 µM vinpocetine.ConclusionOur results demonstrate that PDE inhibitors can inhibit EFS-induced and spontaneous contractile activity of isolated human SV tissue. These findings might be of importance with regard to the pharmacological treatment of premature ejaculation.Ückert S, Bazrafshan S, Sonnenberg JE, and Kuczyk MA. Effects of phosphodiesterase inhibitors on the contractile responses of isolated human seminal vesicle tissue to adrenergic stimulation. J Sex Med 2009;6:408–414.     

Sildenafil Promotes eNOS Activation and Inhibits NADPH Oxidase in the Transgenic Sickle Cell Mouse Penis

IntroductionSickle cell disease (SCD)‐associated vasculopathy in the penis is characterized by aberrant nitric oxide and phosphodiesterase (PDE) 5 signaling, and by increased oxidative stress. Preliminary clinical trials show that continuous treatment with PDE5 inhibitor sildenafil unassociated with sexual activity decreases priapic activity in patients with SCD. However, the mechanism of its vasculoprotective effect in the penis remains unclear.AimsWe evaluated whether continuous administration of PDE5 inhibitor sildenafil promotes eNOS function at posttranslational levels and decreases superoxide‐producing enzyme NADPH oxidase activity in the sickle cell mouse penis.MethodsSCD transgenic mice were used as an animal model of SCD. WT mice served as controls. Mice received treatment with the PDE5 inhibitor sildenafil (100 mg/kg/day) or vehicle for 3 weeks. eNOS phosphorylation on Ser‐1177 (positive regulatory site), eNOS interactions with heat‐shock protein 90 (HSP90) (positive regulator), phosphorylated AKT (upstream mediator of eNOS phosphorylation on Ser‐1177), an NADPH oxidase catalytic subunit gp91(phox), and a marker of oxidative stress (4‐hydroxy‐2‐nonenal [HNE]) were measured by Western blot.Main Outcome MeasuresEffect of continuous sildenafil treatment on eNOS posttranslational activation, NADPH oxidase catalytic subunit, and oxidative stress in the penis of the sickle cell mouse.ResultsContinuous treatment with sildenafil reversed (P < 0.05) the abnormalities in protein expressions of P‐eNOS (Ser‐1177), eNOS/HSP90 interaction, P‐AKT, protein expression of gp91(phox), and 4‐HNE, in the sickle cell mouse penis. Sildenafil treatment of WT mice did not affect any of these parameters.ConclusionOur findings that sildenafil enhances eNOS activation and inhibits NADPH oxidase function in the sickle cell mouse penis offers a vasculoprotective molecular basis for the therapeutic effect of sildenafil in the penis in association with SCD. Musicki B, Bivalacqua TJ, Champion HC, and Burnett AL. Sildenafil promotes eNOS activation and inhibits NADPH oxidase in the transgenic sickle cell mouse penis. J Sex Med 2014;11:424–430.     

Effects of sildenafil and tadalafil on ischemia/reperfusion injury in fetal rat brain

Objective.?The aim of the present study was to evaluate the effects of phosphodiesterase type 5 (PDE5) inhibitory drugs, sildenafil and tadalafil, in ischemia/reperfusion (I/R)-induced oxidative injury in fetal rat brain.

Methods.?Timed pregnant adult Wistar rats were randomly assigned to the following groups (n?=?6 for each group): saline?+?none I/R (1), saline?+?I/R (2), sildenafil?+?none I/R (3); sildenafil?+?I/R (4), tadalafil?+?none I/R (5) and tadalafil?+?I/R (6). Fetal ischemia was induced by clamping the utero-ovarian artery bilaterally. Fetuses were delivered and 268 fetal rats were decapitated. Malondialdehyde (MDA) levels and, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were assessed in fetal brain tissue homogenates by spectrophotometric methods.

Results.?In saline?+?I/R group, MDA levels were increased and, SOD and GSH-Px activities were decreased significantly comparing with saline?+?none I/R group. Both tadalafil and sildenafil treatment decreased the MDA levels significantly in ischemia/reperfusion groups, whereas this effect was significantly more potent with tadalafil. SOD levels were significantly decreased in all groups after I/R. Tadalafil seems to be more effective than sildenafil by means of increasing GSH-Px activity significantly after I/R.

Conclusion.?Our results indicate some beneficial effects of PDE5 inhibitory drugs, especially tadalafil, on oxidative I/R injury in fetal rat brains.