Phosphodiesterase Type 5 Inhibitor Therapy Research Articles

Iatrogenic esophageal dysmotility as a barrier to transplantation in pulmonary arterial hypertension

Esophageal dysmotility is identified as a contraindication to lung transplantation at some centers due to increased risks of acute rejection, pulmonary infection, and chronic lung allograft dysfunction. Phosphodiesterase-type 5 inhibitors (PDE5i) are a cornerstone pharmacotherapy for pulmonary arterial hypertension (PAH) and are known to exert off-target effects that may impact lung transplant candidacy, including impaired esophageal contractility and decreased lower esophageal sphincter tone. We report two patients with PAH who were initially declined listing for lung transplantation due to iatrogenic esophageal dysmotility induced by PDE5is. Upon discontinuation of PDE5i therapy, these patients experienced significant improvement in esophageal motility within 14 days and met criteria for transplant listing at their centers. Recognizing and mitigating the off-target effects of PDE5i medications is critical for maximizing access to transplant for patients with PAH.

(O-01) PREDICTORS OF INTRACAVERNOSAL INJECTION THERAPY IN MEN WITH ERECTILE DYSFUNCTION

Abstract Introduction & Objective Oral phosphodiesterase type 5 inhibitors (PDE5i) and intracavernosal injections (ICI) are effective treatments for erectile dysfunction (ED). However, the risk factors associated with the transition from oral therapy to ICI use remain less established. We aimed to identify predictive factors contributing to the progression from oral PDE5i to ICI therapy. Methods Retrospective chart review was conducted on patients presenting with erectile dysfunction at our clinic. Patients initiating therapy before clinical documentation or without follow-up were excluded. Statistical analysis utilized chi-square test, two-tailed student's t-test, and multivariable logistic regression performed in R. Results Among 259 men treated for ED, 61% (158) reported subjective improvement with oral PDE5i therapy alone, while 18% (46) initiated ICI therapy. Table 1 summarizes demographic information and cardiovascular risk factors. Men progressing to ICI had higher rates of hypertension (54.3% vs. 28.4%, p=0.0015), type 2 diabetes mellitus (32.6% vs. 11.4%, p=0.0013), and a history of radical prostatectomy (26.1% vs. 3.8%, p<0.001) compared to those satisfied with oral therapy. Significant predictors for ICI progression on multivariate analysis were history of radical prostatectomy (OR 19.4, [95% CI, 1.42-678.88]) and diabetes mellitus (OR 8.6, [95% CI, 1.36-76.49]). Two patients (4.3%) experienced priapism as a complication of ICI use. Among the patients using ICI, 54% (25/46) reported satisfaction with their erections. Conclusions Cardiovascular risk factors and a history of radical prostatectomy were more prevalent among patients progressing from oral therapy to ICI in our cohort. These findings may guide early counseling on ED treatment progression for patients with these predictive factors. Financing No conflict.

Nitric Oxide Resistance in Priapism Associated with Sickle Cell Disease: Mechanisms, Therapeutic Challenges, and Future Directions.

Patients with sickle cell disease (SCD) display priapism, a prolonged penile erection in the absence of sexual arousal. The current pharmacological treatments for SCD-associated priapism are limited and focused on acute interventions rather than prevention. Thus, there is an urgent need for new drug targets and preventive pharmacological therapies for this condition. This review focuses on the molecular mechanisms linked to the dysfunction of the NO-cyclic guanosine monophosphate (cGMP)-phosphodiesterase type 5 (PDE5) pathway implicated in SCD-associated priapism. In murine models of SCD, reduced NO-cGMP bioavailability in the corpus cavernosum is associated with elevated plasma hemoglobin levels, increased ROS levels that inactive NO, and testosterone deficiency that leads to eNOS downregulation. We discuss the consequences of the reduced cGMP-dependent PDE5 activity in response to these molecular changes, highlighting it as the primary pathophysiological mechanism leading to excessive corpus cavernosum relaxation, culminating in priapism. We also further discuss the impact of intravascular hemolysis on therapeutic approaches, present current pharmacological strategies targeting the NO-cGMP-PDE5 pathway in the penis, and identify potential pharmacological targets for future priapism therapies. In men with SCD and priapism, PDE5 inhibitor therapy and testosterone replacement have shown promising results. Recent preclinical research reported the beneficial effect of treatment with haptoglobin and NO donors. Significant strides have been made in understanding the pathophysiology of SCD-associated priapism. Significance Statement This review discusses the molecular changes that reduce NO-cGMP bioavailability in the penis in SCD and highlights pharmacological targets and therapeutic strategies for the treatment of priapism, including PDE5 inhibitors, hormonal modulators, NO donors, soluble guanylate cyclase stimulators, haptoglobin, hemopexin, and antioxidants.

Role of Aortic Stiffness in Predicting Response to Phosphodiesterase-5 Inhibitors in the Treatment of Erectile Dysfunction.

It is known that aortic stiffness (AS) increases in patients with erectile dysfunction (ED). Phosphodiesterase type-5 (PDE-5) enzyme inhibitors are used in the treatment of ED, and patients' responses to this treatment may vary. We aimed to investigate the role of AS in predicting the response of patients planned to take PDE-5 enzyme inhibitors due to ED. A total of 96 male patients with ED were included in the study. The International Index of Erectile Function (IIEF) questionnaire was used to evaluate the presence and severity of ED and the response to treatment. Transthoracic echocardiography was used to evaluate AS. There was a statistically significant difference between the aortic strain and aortic distensibility values of the study groups (p<0.001). The delta IIEF score had a high level of positive correlation with aortic strain (p<0.01, r=0.758) and a moderate level of positive correlation with aortic distensibility (p<0.01, r=0.574). We determined that in patients with ED, aortic strain and aortic distensibility measured non-invasively using transthoracic echocardiography are important parameters in predicting patients' response to PDE-5 inhibitor therapy.

Penile Rehabilitation after Prostate Cancer Treatment: Which Is the Right Program?

The management of sexual complications after treatment of localized prostate cancer, such as erectile dysfunction, changes in the length of the penis, pain during sexual intercourse, and lack of orgasm, is still an unsolved problem with an important impact on patients’ quality of life. In this review, we summarize the current scientific literature about the rehabilitation of erectile dysfunction after prostate cancer treatment. The therapy for penile rehabilitation includes different types of treatments: the combination of phosphodiesterase type 5 inhibitors (PDE5-I) and the vacuum erectile device (VED) are considered first-line treatment options. When therapy begins, the duration of treatment, the dosage and the drug used all play very important roles in the treatment outcome. Intracavernous injection (ICI) therapy represents the second-line option for patients ineligible for PDE5-I therapy. Technological development has led to the emergence of devices for the stimulation of the penis without the use of drugs, such as penile vibratory stimulation (PVS) for stimulation of ejaculation in spinal cord injury and low-intensity extracorporeal shockwave therapy (LIESWT). The rapid diffusion of the latter, thanks to its easy use, attains good results without side effects. The panorama of penile rehabilitation after PC treatments is vast and many studies are needed, especially on new technologies, to find the best therapeutic regimen possible, personalized to the patient’s characteristics and the type of treatment for PC.

A network meta-analysis on the vasomodulators for portopulmonary hypertension

Abstract Background In patients with portopulmonary hypertension (PoPH) who are eligible and awaiting liver transplant, guidelines recommend lowering pulmonary pressures with vasomodulators as a bridge to transplant. However, efficacy of each vasomodulator class as a bridge to transplant remains unknown. Purpose This review compares the use of endothelin receptor antagonists (ERA), phosphodiesterase type-5 inhibitors (PDE5-I), prostacyclin (PC) and combination therapy in its pulmonary pressure-lowering effects and pre-transplant mortality in this strictly selected subset of patients. Methods A search conducted on Medline and Embase on articles relating to vasomodulator use in PoPH for pulmonary pressure-lowering effects and mortality. Network analysis was conducted to summarize the evidence. Surface under the cumulative ranking curve (SUCRA) was used to rank treatments. Results Ten studies with 180 patients were included. SUCRA analysis demonstrated largest mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) lowering effects in ERA and combination therapy, followed by PDE5-I and PC. mPAP-lowering effects were largest in ERA (MD −19.440, CI: −62.280 to 23.400) and combination therapy (MD −18.223, CI: −29.677 to −6.770) when compared to PDE5-I (table 1). Pre-transplant mortality were comparable between ERA, PDE5-I and combination therapy. Both ERA (RR:0.349. CI: 0.137–0.891) and PDE5-I (RR: 0.279, CI: 0.091–0.854) had significantly lower mortality than PC (table 2). Conclusion This meta-analysis provides preliminary evidence that ERA have shown larger pulmonary pressure-lowering effects than PDE5-I in PoPH patients who were eligible for LT. Both ERA and PDE5-I have comparable mortality outcomes, with unfavorable outcomes in PC users. Funding Acknowledgement Type of funding sources: None.

THE ROLE OF PROVOCATIVE TESTING DURING HEMODYNAMIC ASSESSMENT TO IMPROVE PULMONARY HYPERTENSION DIAGNOSIS IN OLDER ADULTS

BACKGROUND Pulmonary Hypertension (PH) complicates cardiac and respiratory diseases. Hemodynamic classification of PH broadly defines 2 subsets: pulmonary arterial hypertension (PAH) and PH of left heart disease (PH-LHD). In older patients, particularly with cardiovascular risk factors, clinical and hemodynamic characteristics of PAH and PH-LHD overlap. Thus clinicians face a therapeutic dilemma; PAH therapy may be underutilized in PAH patients to avoid inadvertent administration to PH-LHD patients. Our goal was to evaluate the utility of right heart catheterization(RHC) with exercise to support clinical decisions regarding use of PAH therapy in older adults suspected of having PH with risk factors for PH-LHD. METHODS AND RESULTS Retrospective cohort study of patients referred by a PH program for RHC with exercise to evaluate suspected or confirmed PH, between 2017-2020. Consecutive patients >50 years and at least 1 cardiovascular risk factor (BMI>30kg/m2, HTN, diabetes, hypercholesterolemia, ischemic heart disease, atrial fibrillation(AF)) were included. Primary outcome: use of PAH therapy at the time of RHC and in follow-up. Secondary outcomes: patient reported quality of life (QOL) at time of RHC and in follow-up, using SF36 assay. 61 patients were included in our study, mean age:69±10 years, 56% women. Over 90% patients has 2 or more risk factors for PH-LHD, 34% had a history of AF. At time of RHC, although more than 30% were known to have PH, PAH therapy was prescribed to 20% of patients; phosphodiesterase type 5 inhibitors (PDE5i) n=9, endothelin antagonists (ETA) n=1, and dual therapy (PDE5i+ETA) n=1. Baseline RHC demonstrated no PH in 22 patients (36%) and PH in 39 (64%): 27 with PAH, and 12 with PH-LHD. After exercise RHC, 14 (23%) had no PH, 44 were diagnosed with PH:16 with PAH and 28 with PH-LHD. In follow-up, the proportion of cohort treated with PAH therapy increased to 28%, mostly patients confirmed to have PAH at rest and exercise. PAH therapy included single PDE5i (8 patients), single ETA (5 patients), or combination therapy (with 2 or more PAH medications, 4 patients). Improvement in the physical functioning (median 10, IQR 23.8) and overall health (median 25, IQR 43.8) aspects of QOL were seen at 1 year follow-up. CONCLUSION Among patients with suspected or confirmed PH, and high burden of cardiovascular risk factors, use of PAH therapies is low. Exercise RHC increased the proportion of patients diagnosed with PH and shifted the classification in a proportion from PAH to PH-LHD. QOL improved as well. Pulmonary Hypertension (PH) complicates cardiac and respiratory diseases. Hemodynamic classification of PH broadly defines 2 subsets: pulmonary arterial hypertension (PAH) and PH of left heart disease (PH-LHD). In older patients, particularly with cardiovascular risk factors, clinical and hemodynamic characteristics of PAH and PH-LHD overlap. Thus clinicians face a therapeutic dilemma; PAH therapy may be underutilized in PAH patients to avoid inadvertent administration to PH-LHD patients. Our goal was to evaluate the utility of right heart catheterization(RHC) with exercise to support clinical decisions regarding use of PAH therapy in older adults suspected of having PH with risk factors for PH-LHD. Retrospective cohort study of patients referred by a PH program for RHC with exercise to evaluate suspected or confirmed PH, between 2017-2020. Consecutive patients >50 years and at least 1 cardiovascular risk factor (BMI>30kg/m2, HTN, diabetes, hypercholesterolemia, ischemic heart disease, atrial fibrillation(AF)) were included. Primary outcome: use of PAH therapy at the time of RHC and in follow-up. Secondary outcomes: patient reported quality of life (QOL) at time of RHC and in follow-up, using SF36 assay. 61 patients were included in our study, mean age:69±10 years, 56% women. Over 90% patients has 2 or more risk factors for PH-LHD, 34% had a history of AF. At time of RHC, although more than 30% were known to have PH, PAH therapy was prescribed to 20% of patients; phosphodiesterase type 5 inhibitors (PDE5i) n=9, endothelin antagonists (ETA) n=1, and dual therapy (PDE5i+ETA) n=1. Baseline RHC demonstrated no PH in 22 patients (36%) and PH in 39 (64%): 27 with PAH, and 12 with PH-LHD. After exercise RHC, 14 (23%) had no PH, 44 were diagnosed with PH:16 with PAH and 28 with PH-LHD. In follow-up, the proportion of cohort treated with PAH therapy increased to 28%, mostly patients confirmed to have PAH at rest and exercise. PAH therapy included single PDE5i (8 patients), single ETA (5 patients), or combination therapy (with 2 or more PAH medications, 4 patients). Improvement in the physical functioning (median 10, IQR 23.8) and overall health (median 25, IQR 43.8) aspects of QOL were seen at 1 year follow-up. Among patients with suspected or confirmed PH, and high burden of cardiovascular risk factors, use of PAH therapies is low. Exercise RHC increased the proportion of patients diagnosed with PH and shifted the classification in a proportion from PAH to PH-LHD. QOL improved as well.

Assisting the Heart to Assist the Lungs: LVAD Support in Restrictive Physiology and Pulmonary Hypertension

<h3>Introduction</h3> Pulmonary hypertension (PH) is a risk factor for mortality after heart transplantation (HTx). We present a case of treatment of post-capillary PH in a small pediatric patient with restrictive physiology using continuous flow ventricular assist device (VAD) support to achieve candidacy for HTx. <h3>Case Report</h3> A 4.5 year old female (0.57m²) with a history of acute myeloid leukemia and anthracycline chemotherapy in infancy developed mildly depressed left ventricular (LV) function at 2 years of age. Hemodynamic catheterization (cath) showed pre- and post-capillary PH secondary to LV diastolic dysfunction and restrictive physiology (Table). She was cautiously initiated on PDE5 inhibitor therapy (sildenafil) while maintaining LV reverse remodeling therapies. Her heart failure (HF) symptoms and biventricular systolic function worsened over the subsequent 2 years. Subsequent caths showed increasing PVRi, which was responsive to 100% FiO2 and inhaled nitric oxide (iNO), but also accompanied by increase in LV end-diastolic pressures (LVEDP). She was transitioned to endothelin receptor antagonist therapy (bosentan), but continued to worsen clinically, requiring initiation of milrinone. Due to her underlying restrictive physiology leading to worsening PH and severely depressed right ventricular (RV) function, a HeartWare HVAD (cannulation LV to Aorta) was implanted to allow aggressive optimization of PH therapies with simultaneous LV decompression. This enabled up-titration of bosentan as well as re-addition of sildenafil. After PH therapies including VAD implantation, PVRi decreased from a high of 10.7 WU.m2 to 4.7 WU.m2, and marked decline of LVEDP from 22 mmHg pre-VAD to 5 mmHg. She underwent HTx 6 months after VAD implantation, and was discharged home 12 days post-HTx on sildenafil. <h3>Summary</h3> VAD support in tandem with optimal PH therapies is a feasible strategy to treat post-capillary PH, optimize pulmonary vasculature to reduce RV dysfunction, and enable a successful bridge to HTx.

Nitric oxide‐mediated signal transmission in bladder vasculature underlies the therapeutic actions of PDE5 inhibitors in the rat

Background and PurposeWhile the bladder vasculature is considered as a target of PDE5 inhibitors to improve bladder storage dysfunctions, its characteristics are largely unknown. Thus, the functional and morphological properties of arteries/arterioles of the bladder focusing on the NO‐mediated signal transmission were explored.Experimental ApproachDiameter changes in rat bladder arteries/arterioles were measured using a video‐tracking system. Intercellular Ca2+ dynamics in pericytes or smooth muscle cells (SMCs) of suburothelial arterioles were visualised using transgenic mice expressing GCaMP6 under control of the NG2‐ or parvalbumin‐promoter. The perivascular innervation was investigated using fluorescence immunohistochemistry.Key ResultsIn rat suburothelial arterioles and vesical arteries, tadalafil (100 nM) attenuated nerve‐evoked sympathetic vasoconstrictions. In both vascular segments, tadalafil‐induced inhibition of sympathetic vasoconstriction was prevented by N ω‐propyl‐l‐arginine hydrochloride (l‐NPA, 1 μM), an nNOS inhibitor or N ω‐nitro‐l‐arginine (l‐NA, 100 μM). Both vascular segments were densely innervated with nNOS‐positive nitrergic nerves in close apposition to tyrosine hydroxylase‐immunoreactive sympathetic nerves. In pericyte‐covered pre‐capillary arterioles of the mouse bladder where sympathetic nerves were absent, nerve stimulation evoked transient reductions in pericyte Ca2+ levels that were shortened by l‐NPA and abolished by l‐NA. In SMC‐containing arterioles, tadalafil (10 nM) caused a l‐NPA‐sensitive suppression of sympathetic Ca2+ transients. In mice, nitrergic perivascular nerves were distributed in the arterioles and the pre‐capillary arterioles.Conclusion and ImplicationsBoth nitrergic nerve and nerve‐evoked endothelial NO release appear to be involved in vasodilatory signal transmission in bladder vasculature. The NO‐mediated signal transmission is a potential target for PDE5 inhibitor therapy in bladder dysfunctions.

Phosphodiesterase type 5 inhibitor therapy provides sustained relief of symptoms among patients with chronic pelvic pain syndrome.

BackgroundChronic prostatitis/chronic pelvic pain syndrome type III (CP/CPPS) is associated with pelvic pain, sexual dysfunction and irritative voiding. Sustained symptom relief has proven difficult with alpha blockers, antibiotics, and nonsteroidal anti-inflammatory drugs (NSAIDs). Phosphodiesterase type 5 (PDE5) inhibitors (PDE5is) have the potential to alleviate bladder urgency, relax the pelvic floor, and correct underlying erectile dysfunction; however, few studies have investigated the application of PDE5i’s to CP/CPPS. The purpose of this study was to assess the effect of long-term PDE5i therapy on symptoms among patients with diagnosed CP/CPPS.MethodsA group of patients older than 18 years diagnosed with CP/CPPS presenting from 2009 to 2018 were followed prospectively while they were being prescribed off-label PDE5i therapy for symptoms. National Institute of Health chronic prostatitis symptom index (CPSI) scores before PDE5i therapy initiation and after at least 3 months were utilized to assess impact on symptoms.ResultsA total of 25 patients (mean age 44.4±12.9 years) met study criteria. The mean duration of PDE5i therapy was 1.3±1.6 years. Continued use of daily PDE5is was associated with significant decreases in total CPSI, pain, urinary symptom and quality of life scores [total CPSI: −12.8, standard deviation (SD) 9.5; pain: −6.1, SD 4.1; urinary symptoms: −2.4, SD 2.1; quality of life: −4.5, SD 3.9; P<0.001].ConclusionsThis prospective data suggests that PDE5i therapy is associated with durable decreases in CP/CPPS symptoms past 3 months.

Crowdsourcing the public’s perception of microsurgical and nonsurgical interventions for erectile dysfunction

Given the rise in conditions predisposing to erectile dysfunction (ED) such as prostate cancer, coronary artery disease, sleep apnea, and diabetes, addressing ED with both medical and surgical therapies is necessary. As such, it is necessary to quantify and assess the public’s perception of currently available nonsurgical interventions for ED in comparison with surgical treatments and outcomes. A prospective cross-sectional study was conducted with random volunteers recruited through an Internet crowdsourcing service, Amazon Mechanical Turk© (Seattle, WA). Survey responses were crowdsourced to analyze the prevalence of erectile dysfunction across the US population and patient opinions regarding adverse outcomes of novel microsurgical treatment options for ED. Patient feelings towards existing surgical and nonsurgical treatment options, as well as microsurgical intervention, were also surveyed. Study participants on average rated phosphodiesterase type 5 inhibitor (PDE5i) treatment for mild ED at 58.38, moderate ED at 48.62, and severe ED at 50.54. Furthermore, patients rated microsurgical intervention (VAS = 74.55) almost 20 points higher on the visual analog scale as compared with any other intervention. This demonstrated a significantly higher satisfaction with microsurgical intervention as opposed to PDE5i therapy (VAS = 52.51), vacuum erection device (VED) use (VAS = 39.77), or even surgical placement of a penile prosthesis (VAS = 54.82). Utility data indicates that many men undergoing nonsurgical therapy for ED are unhappy with their current medical treatment yet are willing to consider surgical interventions. As such, novel interventions must become more accessible to patients and presented as realistic options for their treatment. Level of evidence: Level III, not ratable.

Efficacy and Safety of Combined Phosphodiesterase Type 5 Inhibitors as a Salvage Medical Treatment in Patients with Erectile Dysfunction after Nerve-Sparing Radical Prostatectomy

Purpose Penile rehabilitation therapy using phosphodiesterase type 5 inhibitors (PDE5i) is used widely as a first-line therapy in patients with erectile dysfunction (ED) after radical prostatectomy (RP). However, many patients undergoing such therapy still complain of inappropriate erectile function (EF). Therefore, we evaluated the efficacy and safety of combined PDE5i therapy as a salvage medical treatment in patients nonresponsive to initial penile rehabilitation using daily PDE5i after nerve-sparing RP. Methods We retrospectively reviewed 58 nonresponders (Erection Hardness Score [EHS] of 2 or less) to penile rehabilitation using tadalafil (5 mg) daily for more than 12 weeks and who subsequently received combined PDE5i therapy (tadalafil [5 mg] once daily with sildenafil [50 mg] or udenafil [100 mg] on demand). Success after combined therapy is defined by EHS scores of 3 or 4. Safety was assessed by observing drug tolera-bility and adverse events. Results Of the 58 patients, combined therapy was successful in 39.7% of cases. The mean preoperative International Index of Erectile Function (IIEF-5) score was significantly higher in the success group after combined&nbsp;PDE5i therapy compared with the failure group (success group, 15.9 &plusmn; 5.1 versus failure group, 12.3 &plusmn; 5.6; p = 0.018). According to ED classification based on preoperative IIEF-5 scores, the success rates of no/mild/mild-to-moderate ED group and moderate/severe ED group were 50.0% (18/36) and 22.7% (5/22), respec-tively (p = 0.039). The success and failure groups did not differ significantly in any other characteristic. The drugs were tolerated well by all patients and no serious adverse events were observed. Conclusion Combined PDE5i therapy improves EF in patients nonresponsive to standard penile rehabilitation using daily PDE5i after nerve-sparing RP, especially for patients without preoperative moderate or severe ED. In such patients, combined PDE5i therapy could be considered before invasive therapies.

A meta-analysis of the safety and efficacy of bosentan therapy combined with prostacyclin analogues or phosphodiesterase type-5 inhibitors for pulmonary arterial hypertension.

Bosentan is an effective drug for the treatment of pulmonary arterial hypertension (PAH). The aim of the present meta-analysis was to examine the evidence concerning the efficacy and safety of bosentan therapy combined with prostacyclin analogues or phosphodiesterase type 5 (PDE-5) inhibitors for treating PAH. Eligible published studies were collected from Embase, PubMed, The Cochrane Library and the www.clinicaltrials.gov website. Heterogeneity was assessed using the Cochran Q-statistic test. Results were presented as risk ratios or mean differences with 95% confidence intervals (CI). A total of five studies, comprising 310 patients were included for analysis. No significant improvements in six-minute walk distance (6MWD; mean difference, 16.43 m), clinical worsening (risk ratio, 0.54) and the World Health Organization functional classification (class I: risk ratio, 1.17; class II: risk ratio, 1.18) were observed in patients treated with bosentan in combination with prostacyclin analogues or PDE-5 inhibitors. However, a significant reduction in the mean pulmonary artery pressure (mPAP; 95% CI: −17.06, −6.83; P<0.0001) following bosentan combination therapy was observed. Comparisons of adverse event rates in the bosentan combination therapy (55.6%) and monotherapy (51.8%) suggested that there is no reduction in adverse events (risk ratio, 1.10). The results indicated that bosentan combined with prostacyclin analogues or PDE-5 inhibitors may not improve 6MWD, cardiac function, clinical worsening and adverse events. However, bosentan combined with prostacyclin analogues or PDE-5 inhibitor therapy was able to significantly reduce mPAP compared with the effect of bosentan monotherapy.

Mirabegron, A Selective β3-Adrenoceptor Agonist Causes an Improvement in Erectile Dysfunction in Diabetic Rats.

To investigate the possible beneficial effect of mirabegron [a selective β3-adrenoceptor (AR) agonist] treatment on erectile dysfunction (ED) in streptozotocin-induced diabetic rats. Sprague-Dawley rats (n=20) were divided into two groups: control group and streptozotocin-induced diabetic group. In vivo erectile responses were evaluated after intracavernosal injection of mirabegron (0.4 mg/kg) in rats. The relaxation responses to electrical field stimulation (EFS, 10 Hz), sodium nitroprusside (SNP, 10 nM) and sildenafil (1 μM) of corpus cavernosum (CC) strips were examined after the incubation with mirabegron (10 μM). β3-ARs expression and localization were determined by Western blot and immunohistochemical analyses in CC tissue. In vivo erectile responses of diabetic rats [intracavernasal pressure (ICP) / mean arterial pressure, 0.17±0.01] were decreased, which were restored after administration of mirabegron (0.75±0.01, P<0.001). The basal ICP (7.1±0.6 mmHg) in diabetic rats was markedly increased after mirabegron (36.1 ±5.4 mmHg, P<0.01). Mirabegron caused markedly relaxation in diabetic rat CC after phenylephrine precontraction. The relaxation responses to EFS and sildenafil were reduced in diabetic CC, which were increased in the presence of mirabegron. Mirabegron enhanced SNP-induced relaxation response in both groups. The expression and immunoreactivity of β3-ARs localized to CC smooth muscle were observed in control and diabetic rats. This is the first study to show that intracavernosal administration of mirabegron improved erectile function and neurogenic relaxation of CC in diabetic rats. These results may be supported by further studies using combinations of mirabegron and phosphodiesterase type 5 (PDE5) inhibitors for the treatment of diabetic ED, especially in patients who do not respond to PDE5 inhibitor therapy.

Erectile Dysfunction and Obstructive Sleep Apnoea-What is the Link and What can We do about it? A Descriptive Review of the Current Literature

Erectile dysfunction (ED) and obstructive sleep apnoea (OSA) are increasingly common conditions seen in primary and secondary care. With shared risk factors and associated comorbidities men often suffer with both. The aim of this study is to review the literature to consider why there is a correlation, and clinically how assessment and management of such patients could be adjusted. A structured review of current literature was performed using search terms ‘erectile dysfunction' or 'erectile function' or 'Erection' or 'Sexual dysfunction' AND 'Sleep apnoea/apnea' or 'sleep disorder'. Descriptive analysis categorized results into: The association between OSA and ED; the pathophysiological hypotheses; the role of OSA treatment; and the role of ED treatment. Higher prevalence of ED in patients with OSA is demonstrated, particularly in men with more severe OSA disease, reaching 80% in some studies. However, the pathophysiological explanation remains unclear with a number of hypotheses researched. CPAP is the mainstay of treatment for OSA, and short and long-term benefits to sexual function are demonstrated in men with severe OSA from it’s use. Further improvement in ED and quality of life can be achieved by additional PDE5 inhibitor therapy. With the increasing evidence base showing higher rates of ED in OSA patients there is certainly a role for clinicians in both OSA and ED clinics to enquire about each condition. A referral to their counterpart for consideration of combination treatment with CPAP and a PDE5 inhibitor for both of these problematic, life changing diseases is recommended-particularly in those with severe disease. Further investigation is needed to try and establish any pathophysiological link, and the impact of treatment in less severe cases.

Real-World Switching to Riociguat: Management and Practicalities in Patients with PAH and CTEPH

PurposeA proportion of patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) do not achieve treatment goals or experience side effects on their current therapy. In such cases, switching patients to a new drug while discontinuing the first may be a viable and appropriate treatment option. CAPTURE was designed to investigate how physicians manage the switching of patients to riociguat in real-world clinical practice. Observations from the study were used to assess whether recommendations in the riociguat prescribing information are reflected in clinical practice.MethodsCAPTURE was an international, multicenter, uncontrolled, retrospective chart review that collected data from patients with PAH or inoperable or persistent/recurrent CTEPH who switched to riociguat from another pulmonary hypertension (PH)-targeted medical therapy. The primary objective of the study was to understand the procedure undertaken in real-world clinical practice for patients switching to riociguat.ResultsOf 127 patients screened, 125 were enrolled in CAPTURE. The majority of patients switched from a phosphodiesterase type 5 inhibitor (PDE5i) to riociguat and the most common reason for switching was lack of efficacy. Physicians were already using the recommended treatment-free period when switching patients to riociguat from sildenafil, but a slightly longer period than recommended for tadalafil. In line with the contraindication, the majority of patients did not receive riociguat and PDE5i therapy concomitantly. Physicians also followed the recommended dose-adjustment procedure for riociguat.ConclusionSwitching to riociguat from another PH-targeted therapy may be feasible in real-world clinical practice in the context of the current recommendations.

Effect of Riociguat on Pulmonary Arterial Compliance in Patients With Pulmonary Arterial Hypertension (PAH) in the Respite Study

SESSION TITLE: Pulmonary Hypertension - Advances in Management and Therapy SESSION TYPE: Original Investigation Slide PRESENTED ON: Tuesday, October 31, 2017 at 02:45 PM - 04:15 PM PURPOSE: Pulmonary arterial compliance (PAC) is defined as stroke volume/(systolic pulmonary arterial pressure-diastolic pulmonary arterial pressure) and is a measure of pulmonary stiffness and a physiological sign of ventricular afterload. This post hoc analysis of data from patients with PAH in the RESPITE (Riociguat clinical Effects Studied in Patients with Insufficient Treatment response to PDE5 inhibitors) study aimed to assess the effect on PAC of switching from phosphodiesterase type 5 inhibitors (PDE5i) to riociguat. METHODS: RESPITE (NCT02007629) was a prospective, multicenter, uncontrolled, open-label, single-arm, Phase IIIb trial. Sixty-one patients with PAH were enrolled based on prespecified criteria indicating they had an insufficient response to PDE5i therapy. Following a 1-3-day PDE5i treatment-free period, riociguat was adjusted to the optimal dose (up to 2.5 mg three times daily). Right heart catheterization was performed at baseline and at Week 24. RESULTS: At baseline, mean (standard deviation) PAC was 1.22 (0.62) mL/mmHg (n=59) which had increased by 0.22 (0.64) mL/mmHg (n=48) (95% CI 0.036-0.407; p=0.02) at Week 24. Patients who achieved WHO functional class (FC) I/II at Week 24 (n=26) showed an increase in PAC from baseline of 0.41 (0.68) mL/mmHg. However, those patients who remained in WHO FC III (n=22) showed no change (+0.002 [0.51] mL/mmHg). Additionally, the 16 patients who met the combined endpoint at Week 24 of freedom from clinical worsening, achievement of WHO FC I/II, and a ≥30 m improvement in 6-minute walking distance (6MWD), also had a greater improvement in PAC (+0.55 [0.81] mL/mmHg) than the 32 patients not achieving this endpoint (+0.06 [0.46] mL/mmHg). The change from baseline in PAC correlated significantly with change from baseline in cardiac index (r=0.46, p=0.0009), mean pulmonary arterial pressure (r=-0.55, p<0.0001), and pulmonary vascular resistance (r=-0.55, p<0.0001). No significant correlations were observed between change from baseline in PAC and in 6MWD or N-terminal prohormone of brain natriuretic peptide. CONCLUSIONS: In the RESPITE trial, riociguat was found to improve PAC in patients with PAH who had switched from PDE5i. CLINICAL IMPLICATIONS: This post hoc analysis demonstrates the clinical relevance of assessing PAC for a more complete assessment of right ventricular function, and suggests that determination of PAC may help to predict outcomes in patients with PAH. DISCLOSURE: Thenappan Thenappan: Grant monies (from sources other than industry): American Heart Association, Fiduciary position (of any organization, association, society, etc, other than ACCP: Nominal consultant fee from Gilead and Actelion Marius Hoeper: Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Bayer, Gilead, GSK, Pfizer, MSD - Lectures and consultations Paul Corris: Grant monies (from industry related sources): Bayer - University Research Fund, Consultant fee, speaker bureau, advisory committee, etc.: Bayer, Actelion, GSK Hossein-Ardeschir Ghofrani: Grant monies (from industry related sources): Actelion, Bayer, Pfizer, Novartis, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Bayer, GSK, Novartis, Pfizer, Bellerophon Therapeutics - Board membership, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Bayer, GSK, Novartis, Pfizer, Bellerophon Therapeutics, United Therapeutics - Consultancy, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Bayer, GSK, Novartis, Pfizer, United Therapeutics - Paid lectures, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Bayer, GSK, Novartis, Pfizer, United Therapeutics - Travel/accomodation expenses James Klinger: Other: Actelion, Bayer, Gilead Sciences, Ikaria, Lung Biotechnology, NH-NHLBI, Pfizer, United Therapeutics - Research support , Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics, Bayer David Langleben: Consultant fee, speaker bureau, advisory committee, etc.: Bayer Healthcare Pharmaceuticals, Actelion, Gilead, GSK, Ikaria - Personal fees, Other: Bayer Healthcare Pharmaceuticals, Actelion, Gilead, GSK, Ikaria - Non-Financial Support Robert Naeije: Consultant fee, speaker bureau, advisory committee, etc.: Actelion, GSK - Personal Fees, Grant monies (from industry related sources): Reata, Other: Actelion, Bayer, Lung Biotechnology Corporation - Advisory Board Member Fees Gérald Simonneau: Grant monies (from industry related sources): Actelion, Bayer, GSK, Novartis, Lilly, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Bayer, GSK, Novartis, Lilly, Other: Pfizer - Non-Financial Support Pavel Jansa: Other: Actelion, Bayer AG - Investigator, Consultant fee, speaker bureau, advisory committee, etc.: Bayer AG, AOP Stephan Rosenkranz: Grant monies (from industry related sources): Actelion, Bayer, Novartis, Pfizer, United Therapeutics, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Bayer, Gilead, GSK, Novartis, Pfizer, United Therapeutics Ekkehard Grünig: Grant monies (from industry related sources): Bayer, Actelion, GSK, Lilly, Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: Bayer, Miltenyi, Novartis, United Therapeutics, Other: Alexion - Non-Financial Support Christian Meier: Employee: Bayer AG Dennis Busse: Employee: Chrestos Concept GmbH & Co. KG Raymond Benza: Grant monies (from industry related sources): Bayer AG The following authors have nothing to disclose: Laura Scelsi No Product/Research Disclosure Information

THE EFFECT OF COMBINED α1-ADRENERGIC BLOCKERS AND PDE-5 INHIBITORS THERAPY ON IPSS, IIEF-5, QMAX AND PVR PATIENTS BPH WITH LUTS AND ERECTILE DYSFUNCTION

Purpose: Assess the efficacy of combined α1-adrenergic blocker (tamsulosin 0,4 mg) and PDE5 inhibitor (tadalafil 5 mg) therapy compared to tadalafil or tamsulosin alone in treating patient BPH with LUTS and ED. Material and methods: A randomised, double blind experimental study assessed 36 sexually active men with ED and LUTS suggestive of BPH. All patients were randomized to 3 groups: tamsulosin 0,4 mg (n=12), tadalafil 5mg (n=12), and combination of tamsulosin 0,4 mg and tadalafil 5 mg (n= 12), once daily for 6 weeks. Changed in IPSS scores and QoL index, IIEF-5 scores, Qmax, PVR and blood pressure were assessed and compared to baseline. Complication and serious adverse event were also monitored. Outcomes were assessed using ranked analysis of variance (ANOVA) and Kruskall-Wallis depends on data distribution and homogenity.Results: Tamsulosin 0,4 mg once daily for 6 weeks were significantly improved IPSS score and QoL index and Qmax from baseline. Tadalafil 5 mg once daily for 6 weeks were significantly improved IPSS score, QoL index and IIEF-5 index from baseline. Combined tamsulosin and tadalafil therapy were significantly improved IPSS score, QoL index, IIEF-5 index and Qmax from baseline. Significantly better improvement on IIEF-5 dan Qmax from baseline were observed on the combination of tamsulosin and tadalafil compared to monotherapy with tamsulosin or tadalafil after 6 weeks in patients BPH with LUTS and erectile dysfunction. There was no significant decreased in systolic and diastolic blood pressure from combined treatment compared to single treatment.Conclusions: Combined tamsulosin and tadalafil therapy was significantly better in improving IIEF aObjective: Assess the efficacy of combined α1-adrenergic blocker (tamsulosin 0.4 mg) and PDE5 inhibitor (tadalafil 5 mg) therapy compared to tadalafil or tamsulosin alone in treating patient Benign Prostate Hyperplasia (BPH) with lower urinary tract symptom (LUTS) and erectile dysfunction (ED). Material &amp; methods: A randomised, double blind experimental study assessed 36 sexually active men with ED and LUTS suggestive of BPH. All patients were randomized to 3 groups: tamsulosin 0.4 mg (n=12), tadalafil 5mg (n=12), and combination of tamsulosin 0.4 mg and tadalafil 5 mg (n= 12), once daily for 6 weeks. Changed in IPSS scores and QoL index, IIEF-5 scores, Qmax, PVR and blood pressure were assessed and compared to baseline. Complication and serious adverse event were also monitored. Outcomes were assessed using ranked analysis of variance (ANOVA) and Kruskall-Wallis depends on data distribution and homogenity. Results: Tamsulosin 0.4 mg once daily for 6 weeks were significantly improved IPSS score, QoL index and Qmax from baseline. Tadalafil 5 mg once daily for 6 weeks were significantly improved IPSS score, QoL index and IIEF-5 index from baseline. Combined tamsulosin and tadalafil therapy were significantly improved IPSS score, QoL index, IIEF-5 index and Qmax from baseline. Significantly better improvement on IIEF-5 dan Qmax from baseline were observed on the combination of tamsulosin and tadalafil compared to monotherapy with tamsulosin or tadalafil after 6 weeks in patients BPH with LUTS and erectile dysfunction. There was no significant decreased in systolic and diastolic blood pressure from combined treatment compared to single treatment. Conclusion: Combined tamsulosin and tadalafil therapy was significantly better in improving IIEF and Qmax, but not significantly better in improving IPSS and PVR compared to monotherapy with tamsulosin or tadalafil alone. Combined therapy was well tolerated without serious adverse effect.nd Qmax, but not significantly better in improving IPSS and PVR compared to monotherapy with tamsulosin or tadalafil alone. Combined therapy was well tolerated without serious adverse effect.

Sexual Dysfunction in Type 2 Diabetes at Diagnosis: Progression over Time and Drug and Non-Drug Correlated Factors.

AimsTo present the longitudinal data of the SUBITO-DE study, a prospective survey involving male patients with new or recently diagnosed type 2 diabetes mellitus (T2DM) (<24 months).Materials and MethodsSexual function was assessed in male patients with T2DM at baseline (phase 1) and after a mean follow-up of 18 months (phase 2). Standard metabolic parameters and sexual and depressive symptoms were evaluated.ResultsSix of the 499 enrolled patients died of different causes during phase 1. Of the 493 surviving men invited to participate in phase 2, 450 (mean age 59.0±9.0 years) (90.2%) accepted and 43 (8.2%) were lost to follow-up. As compared to baseline, the proportion of the men who reported improvement in erectile dysfunction (ED) at follow-up was nearly double that of the men who reported worsening of ED (22.6% vs. 12.8%). The increase in frequency of sexual activity the men reported at follow-up assessment indicates that many never treated before baseline were taking an ED drug during the study period (106 subjects). Phosphodiesterase type 5 inhibitors (PDE5i) were the ED drugs most commonly taken at both baseline and follow-up. An overall improvement over baseline values was observed in metabolic targets for T2DM and depressive symptoms. Conversely, no change in lifestyle behaviors was recorded during the study.ConclusionsSexual dysfunction is a major concern in men with T2DM. The SUBITO-DE study demonstrates that, when combined with adequate counseling and tailored PDE5i therapy, an integrated approach to achieving metabolic targets in men with T2DM can improve sexual function as well as depressive symptoms.

Clinical use of alprostadil topical cream in patients with erectile dysfunction: a review.

Erectile dysfunction (ED) is a common and debilitating disorder seen in over 50% of men older than 70 years. Oral phosphodiesterase type 5 (PDE5) inhibitors are the mainstay of treatment for ED, but cannot be used by a significant subset of patients due to systemic side effects and drug–drug interactions. Second-line therapy may include intracavernosal therapies, but are associated with poor compliance due to their invasive nature. Alprostadil has a mechanism of action different from that of PDE5 inhibitors. Clinical trials have shown topical alprostadil cream to be effective, increasing the erectile function (EF) score of the International Index of EF by up to 13 points from baseline. It has also proven to be safe and well tolerated, with mild-to-moderate and transient treatment-related adverse events that are generally localized to the application site. Topical alprostadil cream is a safe and effective second-line therapy for ED, indicated for those who cannot tolerate, or are not satisfied with, oral PDE5 inhibitor therapy.