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.     

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.     

Novel PDE5 inhibitors for the treatment of male erectile dysfunction

Erectile dysfunction (ED) affects the lives of approximately 150 million men worldwide. ED may be a cause of male sub-fertility in a significant proportion of patients. There is now an expanding armamentarium for the management of ED, including oral agents such as phosphodiesterase type 5 (PDE5) inhibitors. PDE5 inhibitors may also be useful in situations of temporary ED in couples undergoing IVF. Two novel PDE5 inhibitors have been commercially launched in the European Union in the first quarter of 2003. This article reviews the pharmacology and clinical efficacy of these new agents and their potential role in treating patients with male sub-fertility.     

The PDE5 inhibitor sildenafil increases circulating endothelial progenitor cells and CXCR4 expression

IntroductionEndothelial progenitor cells (EPC) are a specific subtype of progenitor cells that can be isolated from circulating mononuclear cells, able to migrate from the bone marrow to the peripheral circulation where they contribute to vascular repair. CXC-motif chemochine receptor 4 (CXCR4) receptor seems to play a critical role in this process.AimTo assess the effects of sildenafil (a type 5 phosphodiesterase [PDE5] inhibitor) administration in 20 healthy young men.MethodsEvaluation of CXCR4 expression in circulating EPC before and 4 hours after in vivo administration of 100 mg sildenafil by flow cytometry and colony-forming unit.ResultsWe found that sildenafil increases circulating EPC number, the relative expression of CXCR4 on these cells and the ability to generate colonies in vitro.ConclusionsThese data allow us to suppose an involvement of PDE5 in bone marrow release and peripheral homing of EPC. Foresta C, De Toni L, Di Mambro A, Garolla A, Ferlin A, and Zuccarello D. The PDE5 inhibitor sildenafil increases circulating endothelial progenitor cells and CXCR4 expression. J Sex Med 2009;6:369–372.     

The role of PDE5 inhibitors in penile septal scar remodeling: assessment of clinical and radiological outcomes

IntroductionEffective oral medication for use in men with Peyronie's disease (PD) has been an area of interest of the medical community and lay public for decades. Isolated septal scars (ISS) without evidence of penile deformity is a relatively new clinical entity, and at present, there is paucity in the published literature regarding its treatment. Current research into the use of phosphodiesterase type 5 (PDE5) inhibitors in regulating penile erectile response has revealed an alternative role for PDE5 inhibitors in decreasing oxidative stress-associated inflammatory change as seen in PD.AimTo examine the presence of ISS and assess the efficacy of PDE5 inhibitor use in septal scar remodeling.MethodsRetrospective review of prospective database on all men who underwent penile Doppler ultrasound between December 2007 and December 2009.Main Outcome MeasuresOf the 65 men with ultrasonographic-confirmed ISS, 35 men received tadalafil 2.5 mg daily over a 6-month period. The clinical outcomes between the two groups were compared using International Index of Erectile Function (IIEF)-5 score and 6 months penile Doppler ultrasound follow up.ResultsThe mean age for the tadalafil group was 43.2 (20–65) years, similar to the control group at 44.2 (34–72) years. The length of time from onset to presentation was 22 (6 to 40) months. The majority of ultrasonographic-proven ISS was not clinically palpable and complaint of decreased penile rigidity (66%) was the predominant feature. Treatment with low-dose daily tadalafil did not result in any significant side effects (such as headache and flushing) or discontinuation. The tadalafil group reported higher IIEF-5 score (pretreatment 11/25 to post-treatment 18/25) (P < 0.01) and resolution of septal scar were recorded in 24 patients (69%) compared to three patients (10%) in the control group.ConclusionLow-dose daily tadalafil is a safe and effective treatment option in septal scar remodeling. Chung E, DeYoung L, and Brock GB. The role of PDE5 inhibitors in penile septal scar remodeling: Assessment of clinical and radiological outcomes.     

Hypogonadal Men Nonresponders to the PDE5 Inhibitor Tadalafil Benefit from Normalization of Testosterone Levels with a 1% Hydroalcoholic Testosterone Gel in the Treatment of Erectile Dysfunction (TADTEST Study)

IntroductionAddition of testosterone (T) may improve the action of phosphodiesterase type 5 inhibitors (PDE5‐Is) in patients with erectile dysfunction not responding to PDE5‐Is with low or low‐normal T levels.AimsTo confirm this add‐on effect of T in men optimally treated with PDE5‐Is and to specify the baseline T levels at which such an effect becomes significant.MethodsA multicenter, multinational, double‐blind, placebo‐controlled study of 173 men, 45–80 years, nonresponders to treatment with different PDE5‐Is, with baseline total T levels ≤4 ng/mL or bioavailable T ≤ 1 ng/mL. Men were first treated with tadalafil 10 mg once a day (OAD) for 4 weeks; if not successful, they were randomized in a double‐blind, placebo‐controlled design to receive placebo or a 1% hydroalcoholic T gel (50 mg/5 g gel), to be increased to 10 mg T if results were clinically unsatisfactory.Main Outcomes MeasuresMean change from baseline in the Erectile Function Domain Score of the International Index of Erectile Function and rate of successful intercourses (Sexual Encounter Profile 3 question).ResultsErectile function progressively improved over a period of at least 12 weeks in both the placebo and T treatment groups. In the overall population with a mean baseline T level of 3.37 ± 1.48 ng/mL, no additional effect of T administration to men optimally treated with PDE5‐Is was encountered. The differences between the T and placebo groups were significant for both criteria only in the men with baseline T ≤3 ng/mL.ConclusionsThe maximal beneficial effects of OAD dosing with 10 mg tadalafil may occur only after as many as 12 weeks. Furthermore, addition of T to this PDE5‐I regimen is beneficial, but only in hypogonadal men with baseline T levels ≤3 ng/mL. Buvat J, Montorsi F, Maggi M, Porst H, Kaipia A, Colson MH, Cuzin B, Moncada I, Martin‐Morales A, Yassin A, Meuleman E, Eardley I, Dean JD, and Shabsigh R. Hypogonadal men nonresponders to the PDE5 inhibitor tadalafil benefit from normalization of testosterone levels with a 1% hydroalcoholic testosterone gel in the treatment of erectile dysfunction (TADTEST study).     

Phosphodiesterase type 5 (PDE5) inhibitors in erectile dysfunction: the proper drug for the proper patient

IntroductionErectile dysfunction (ED) is a very common multidimensional disorder affecting men worldwide. Physical illness, reaction to life stresses, or an unhappy couple relationship influence clinical outcome. Phosphodiesterase type 5 (PDE5) inhibitors are recognized as efficacious and well tolerated, and are the first‐line treatment for ED.Sildenafil, tadalafil, and vardenafil are the most widely used and studied PDE5 inhibitors. Data acquired during a routine diagnostic workup for ED should be taken into account when choosing the best PDE5 inhibitor for the individual patient, creating an individualized treatment plan, and going beyond “experience‐based” subjective opinion and unfounded ideas and prejudice regarding currently available drugs.AimAs the process of matching a given patient's profile to any selected PDE5 inhibitor often relies more on physician's personal convictions than on solid evidence, the aim of this review is to identify the main clinical, demographic, and relational factors influencing the choice of the PDE5 inhibitor to be used for the treatment of ED.MethodsA systematic literature search and current treatment guidelines were evaluated in a systematic manner.Main Outcome MeasuresThe main clinical, cultural, and demographical factors to be considered for the treatment of ED have been identified.ResultsMain factors influencing the choice of the treatment for ED have been described. A short list of items that may help in choosing the right PDE5 inhibitor for the treatment of different patients in daily clinical practice has been prepared.ConclusionsThe simple algorithms prepared should be a useful tool to be used in daily practice, which may help in choosing the right treatment for each subject affected by ED. Corona G, Mondaini N, Ungar A, Razzoli E, Rossi A, and Fusco F. Phosphodiesterase type 5 (PDE5) inhibitors in erectile dysfunction: The proper drug for the proper patient.     

Effects of a phosphodiesterase-5 (PDE5) inhibitor on endothelium-dependent relaxation of myometrial small arteries

OBJECTIVE: In preeclampsia, endothelium-dependent function is markedly aberrant. Myometrial resistance arteries from women with preeclampsia show a minimal, wholly nitric oxide-mediated, bradykinin-induced relaxation. Our aim was to test that phosphodiesterase 5 (PDE5) inhibition could improve endothelium-dependent function in preeclampsia.Study design Small arteries dissected from myometrial biopsies obtained at cesarean section from normal pregnant women (N=22) or women with preeclampsia (N=24) were mounted on wire or pressure myographs. Vessels were constricted (arginine vasopressin or U46619) and relaxed (bradykinin) before and after incubation with a PDE5 inhibitor, UK-343664. RESULTS: Endothelium-dependent vasodilatation was decreased in vessels from women with preeclampsia. 100 nmol/L UK-343664 did not affect normal pregnant but significantly improved relaxation of the vessels from women with preeclampsia. CONCLUSION: A PDE5 inhibitor enhances endothelial function of myometrial vessels from women with preeclampsia, such that the behavior of these arteries approximates to those from normal women. These agents offer a potential therapeutic strategy for the management of preeclampsia.     

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.     

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.     

Endothelial Antioxidant Administration Ameliorates the Erectile Response to PDE5 Regardless of the Extension of the Atherosclerotic Process

IntroductionThe lack of phosphodiesterase type 5 inhibitor effects in patients with erectile dysfunction (ED) of arterial origin may be caused by an endothelial dysfunction that causes a series of biochemical alterations leading to a reduced nitric oxide (NO) bioavailability and increased oxidative stress.AimThe aim of this study was to evaluate the effects of the treatment with endothelial antioxidant compounds (EAC) on the erectile response to sildenafil in patients with arterial ED already treated with sildenafil (100 mg twice a week for 8 weeks).Mean Outcome MeasuresA patient was considered responsive when the 5-item International Index of Erectile Function questionnaire score increased by >5 points.MethodsFifty-three patients with arterial ED, hypertension, and diabetes mellitus were randomly given, for 8 weeks, EAC (1 dose/day) and, after a wash out of 8 weeks, sildenafil (100 mg) plus EAC. The patients were divided into the following four groups: A (N = 12): patients with ED alone; B (N = 14): patients with ED plus atheromasic plaques and/or increased intima-media thickness of common carotid arteries; C (N = 14): patients with ED plus lower limb artery abnormalities; and D (N = 13): patients with ED plus carotid and lower limb artery abnormalities.ResultsThe administration of EAC plus sildenafil resulted in a significantly higher number of responsive patients (N = 36, 68%) compared with sildenafil alone (N = 24, 45%) or EAC alone (N = 17, 32%). The percentage of patients who successfully responded to the combined treatment increased in the various groups. It was 83%, 64%, 71%, and 54%, respectively, for groups A, B, C, and D. Furthermore, patients treated with EAC and sildenafil reached a successful response in a shorter length of time (3 weeks) compared with patients responsive to sildenafil (5.2 weeks) or EAC (5.7 weeks) alone.ConclusionEAC administration to patients with arterial ED improved the success rate to sildenafil. These data suggest that, in such patients, a combined treatment may be considered to increase bioavailable NO and to neutralize radical oxygen species, which in turn inactive NO. Vicari E, La Vignera S, Condorelli R, and Calogero AE. Endothelial antioxidant administration ameliorates the erectile response to PDE5 regardless of the extension of the atherosclerotic process.     

Severity of ED: relationship to treatment-seeking and satisfaction with treatment using PDE5 inhibitors

IntroductionResearch in the past 20 years has demonstrated that erectile dysfunction (ED) is an area of concern for men and their partners.AimThe current study was designed to evaluate the impact of the perceived severity of ED on treatment‐seeking behavior and satisfaction with treatment among men with ED.Main Outcome MeasuresParticipants completed a questionnaire to assess the above variables, as well as the duration of ED.MethodsParticipants were 410 men with ED who were primarily recruited over the Internet via men’s health websites.ResultsThe results demonstrated that men with more severe ED compared with men with milder ED were more likely to have discussed their ED with their partner and doctor, have sought assistance for their ED problem, but they were also less satisfied with the effectiveness of phosphodiesterase type 5 inhibitors, and said they were less likely to use them in the future. Men with more severe ED were also less likely to want ED medication to last for 24 hours.ConclusionsImplications of these findings for the treatment of men with different levels of ED are discussed. McCabe M, and Matic H. Severity of ED: Relationship to treatment‐seeking and satisfaction with treatment using PDE5 inhibitors. J Sex Med 2007;4:145–151.     

Physical Activity and PDE5 Inhibitors in the Treatment of Erectile Dysfunction: Results of a Randomized Controlled Study

IntroductionPhysical activity (PhA) has proven to be a protective factor for normal erectile function in numerous epidemiological studies.AimThe aim of this study was to establish if PhA could have a therapeutic role in the treatment of erectile dysfunction (ED).MethodsThis was a randomized, open-label study. A total of 60 patients complaining of ED were studied. Patients were assessed at baseline and after 3 months of study treatment. At baseline, patients were randomized to receive phosphodiesterase type 5 inhibitor (PDE5i) alone (group A) or PDE5i plus regular (≥3 hours/week), aerobic, non-agonistic PhA (group B).Main Outcome MeasuresAll subjects completed the International Index of Erectile Function (IIEF-15) questionnaire and performed total testosterone (TT).ResultsMean PhA was 3.4 hours/week in group B vs. 0.43 in group A; mean energy expenditure in group B was 1,868 kcal/ week or 22.8 metabolic equivalent (MET)/week. IIEF restoration of ED occurred in 77.8% (intervention group) vs. 39.3% (control) (P < 0.004). The IIEF-15 score resulted in statistical improvement in intervention group in all the domains but one (orgasm): erectile function 24.7 vs. 26.8 (P = 0.003); confidence (Q15) 3.53 vs. 4.07 (P = 0.006); sexual desire 6.46 vs. 7.18 (P = 0.028); intercourse satisfaction 9.85 vs. 11.25 (P = 0.001); total satisfaction 7.17 vs. 8.07 (P = 0.009); total score 56.2 vs. 61.07 (P = 0.007). TT was statistically similar in the two groups; separate analysis in each group showed statistical increase in group B 4.24 vs. 4.55 (P = 0.012). At multivariate logistic regression analysis, PhA was the only independent variable for normal erection (P = 0.010) (95% confidence interval [CI] 0.036–0.643), higher sexual satisfaction (P = 0.022) (95% CI 0.084–0.821) and normal total IIEF-15 score (P = 0.023) (95% CI 0.85–0.837).ConclusionIn this randomized controlled pilot study, PDE5i plus PhA was more effective than PDE5i alone in the treatment of ED. Maio G, Saraeb S, and Marchiori A. Physical activity and PDE5 inhibitors in the treatment of erectile dysfunction: Results of a randomized controlled study.     

Toward Personalized Sexual Medicine (Part 2): Testosterone Combined with a PDE5 Inhibitor Increases Sexual Satisfaction in Women with HSDD and FSAD,and a Low Sensitive System for Sexual Cues

IntroductionLow sexual desire in women may result from a relative insensitivity of the brain for sexual cues. Administration of sublingual 0.5 mg testosterone (T) increases the sensitivity of the brain to sexual cues. Sexual stimulation in the brain is necessary for phosphodiesterase type 5 inhibitor (PDE5i)-mediated increase in genital sexual response. Accordingly, a single dose of T+PDE5i might enhance sexual responsiveness, especially in women with low sensitivity for sexual cues.AimTo assess the hypothesis that treatment with on-demand use of T+PDE5i improves sexual functioning, particularly in women who suffer from Hypoactive Sexual Desire Disorder (HSDD) as the result of a relative insensitivity for sexual cues.MethodsIn a randomized, double-blind, placebo-controlled, crossover design, 56 women with HSDD underwent three medication treatment regimes (placebo, T+PDE5i, and T with a serotonin _1A receptor agonist; see also parts 1 and 3), which lasted 4 weeks each. In a participant-controlled ambulatory psychophysiological experiment at home (the first week of each drug treatment), physiological and subjective indices of sexual functioning were measured. In a bedroom experiment (the subsequent 3 weeks), sexual functioning was evaluated following each sexual event after the self-administration of study medication. Subjective evaluation of sexual functioning was also measured by weekly and monthly reports.Main Outcome MeasuresSubjective: sexual satisfaction, experienced genital arousal, sexual desire. Physiological: vaginal pulse amplitude. Cognitive: preconscious attentional bias.ResultsT+PDE5i, as compared with placebo, significantly improved physiological and subjective measures of sexual functioning during ambulatory psychophysiological lab conditions at home and during the sexual events, in women with low sensitivity for sexual cues.ConclusionsThe present study demonstrated that on-demand T+PDE5i is a potentially promising treatment for women with HSDD, particularly in women with low sensitivity for sexual cues. Poels S, Bloemers J, van Rooij K, Goldstein I, Gerritsen J, van Ham D, van Mameren F, Chivers M, Everaerd W, Koppeschaar H, Olivier B, and Tuiten A. Toward personalized sexual medicine (part 2): Testosterone combined with a PDE5 inhibitor increases sexual satisfaction in women with HSDD and FSAD, and a low sensitive system for sexual cues. J Sex Med 2013;10:810–823.     

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.