No abstract

Background: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking. Methods: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide. Results: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (–0.2%) in the placebo group ( P =0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus –9±193 [–0.9%] mL/min, P =0.012), ventilatory equivalents of carbon dioxide (–0.8 versus –0.06, P =0.014), and work rate (+3.8 versus +0.34 W, P =0.021). There was no an improvement in myocardial performance index (–0.02 vs 0.01, P =0.030), but no change in reactive hyperemia index, or serum brain-type natriuretic peptide level. Conclusions: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02741115.

Introduction Alprostadil is approved for treatment of male erectile dysfunction (ED) by injection or urethral insertion. Topical delivery of alprostadil offers an improved alternative. Aim To evaluate the long-term safety and efficacy of topical alprostadil cream. Methods This was a multicenter, open-label, long-term study in 1,161 patients (998 double-blind rollover; 163 naïve) with ED. For the first 4 weeks, patients could administer eight doses of 200 mcg alprostadil to the penis meatus before intercourse (up to 2 per/week). Patients then self-selected to administer 300 or 100 mcg doses if hypo-responsive or hyper-responsive, respectively, or 200 mcg if no change, for up to 9 months (2 doses/week). Main Outcome Measures Safety evaluated patient/partner adverse events (AEs), changes in vital signs, clinical laboratory tests, physical examinations, and electrocardiograms. Efficacy assessed International Index of Erectile Function, Sexual Encounter Profile, Patient Self Assessment of Erection, and Global Assessment Questionnaire. Results Approximately 12% of patients discontinued due to hypo-/hyper-responsiveness, 16% withdrew consent for a variety of reasons, and less than 5% discontinued because of AEs. The majority of patients (73%) selected 300 mcg alprostadil as the final dose. The most common AEs involved application site burning or erythema (12.2%), meatal or glans pain (4.4%), and prolonged or painful erection (1.3%). Only 5 (0.4%) patients reported a prolonged erection of ≥4 hours (priapism). Vaginal burning or itching (2.1%) was reported most frequently by partners. The majority of patients (74%) demonstrated an overall improvement in erectile function on most end-points, especially after adjusting dose strength to their individual responsiveness. Conclusions Topical alprostadil cream was considered effective and safe by most patients and their partners, with most AEs limited to the application site. Dose adjustment to 300 mcg alprostadil facilitated the greatest improvement in erectile function in the majority of patients. A separate report will integrate patient data from the open-label extension and prior double-blind studies.

In two multicenter, placebo controlled, phase 2 studies, patients with mild-to-moderate (n ¼ 161, Study 1) or severe (n ¼ 142, Study 2) erectile dysfunction (ED) were randomized to receive placebo, 0.05, 0.1, or 0.2 mg (Study 1) or placebo, 0.1, 0.2, or 0.3 mg (Study 2) of topically applied alprostadil (containing a proprietary skin permeation enhancer). The primary efficacy end point in both studies was the change in erectile function (EF) score from baseline to final visit. The changes from baseline for EF scores were À0.8 7 1.1, 1.8 7 1.1, 0.7 7 1.2, and 3.7 7 1.2 (Po0.01; Study 1) and 2.7 7 1.3, 6.29 7 1.4, 6.49 7 1.5, and 9.44 7 1.5 (Po0.001; Study 2) for ascending dose groups in each study. Topical alprostadil was well tolerated with the most common adverse event being urogenital pain. These results suggest this topical alprostadil formulation may be a potentially useful agent for the treatment of ED.

This study evaluated the efficacy and safety of three doses of topical alprostadil USP (prostaglandin E1) cream in 8 patients with Female Sexual Arousal Disorder (FSAD). Each patient was administered a single intravaginal dose of placebo followed by escalating intravaginal doses of the active drug at 2-week intervals. Alprostadil's effectiveness in enhancing subjective and physiological arousal during visual sexual stimulation was supported by patient ratings and physician assessments of vaginal erythema and transudate volume. Photoplethysmography measurement of vaginal pulse amplitude was not able to demonstrate treatment sensitivity in the present study. Adverse events included mild cases of vaginal itching and burning. The data support further investigation of the use of alprostadil for FSAD.