Medical Meeting Reports

Sexual Function: Medical and Non-surgical Therapy (II)

Author: Nelson E. Bennett, MD

Phosphodiesterase-5 (PDE-5) inhibitors have revolutionized the the face of erectile dysfunction. Sildinafil, Tadalafil, and Vardenafil have all been proven to be safe and effective in most men. The group from the Mayo Clinic (Abstract 871) in Jacksonville presented an abstract that investigated whether Vardenafil can effectively treat patients who have failed Sildenafil at the 100 mg dose. After evaluating 331 patients complaining of Sildenafil refractory ED with intracavernous pharmaco-testing (ICI) and color duplex Doppler ultrasound (CDDU). They found that a small percentage of these men were rescued with Vardinafil dosing. Furthermore, the majority of Sildenafil failures were in older men with severe arterial insufficiency. The comment was made that urologists should be vigilant in the diagnosing the true cause of ED in those patients whom sildenafil is ineffective.

When Sildenafil was marketed in the late 1990's, it's concomitant use with nitrates was contraindicated. Numerous studies since then have investigated the cardiac effects of PDE-5's. Three groups from have added to this literature. The group from Cornell University Hospital (Abstract 872) analyzed correspondence to determine which patients were given permission to cease NTG use (prior to starting sildenafil) by their prescribing physician and to define predictors of receiving such permission. Letters were mailed to the nitrate-prescribing physician requesting that consideration be given to cessation of NTG. Answers were compiled as well as demographic information on the patients and physicians. Logistic regression analysis was conducted to define predictors of 'yes' and 'no' responses to the mailed-out letter. Their findings concluded that in patients using NTG medications on a prn basis, a significant proportion will be permitted to discard the medication when a letter was sent to the prescribing physician. Patients <65 years, who used NTG medication infrequently and were in possession of the medication for more than 6 months were the patients most likely to receive a positive response to the letter.

An international group of investigators led by Hellstrom (Abstract 873) retrospectively evaluated the cardiovascular (CV) safety of vardenafil when used concomitantly with antihypertensive therapies (AHT), including alpha1-blockers. Drug-related CV adverse event (AE) data were compiled from 5091 vardenafil and 2949 placebo-treated patients in 17 phase III studies in men with erectile dysfunction (ED) for >6 months receiving vardenafil 2.5, 5, 10, or 20mg or placebo for 12 to 26 weeks. They concluded that Vardenafil has a clinically acceptable CV safety profile, with no increase in drug-related CV-AEs other than dizziness. Additionally, neither alpha-blockers nor anti-hypertensive therapies increased drug-related cardiovascular adverse event rates in vardenafil-treated patients.

An interesting abstract (Abstract 875) from the MOMENTUS (Multiple Observations in Men with ED in National Tadalafil Study in the US) trial assessed the response to tadalafil 20 mg in patients with ED and co-mordid conditions such as cardiovascular disease, diabetes, hypertension, hyperlipidemia, depression, or BPH/prostatectomy. 1911 men with ED were enrolled into 8 predefined groups based of race, age, and type of comorbid condition. The study is a multicenter, open-label study, evaluated the efficacy and safety of tadalafil 20 mg dosed as needed (up to once a day), for 12 weeks after a 4-week treatment-free period. Group 7 was chosen because they best represent demographic characteristics matched those of the majority of patients in pivotal tadalafil clinical studies. This group of patients with a high prevalence of significant comorbid conditions that impact EF, showed a robust response to tadalafil 20 mg. Tadalafil was well tolerated.

The DSM V defines premature ejaculation (PE) as the "persistent or recurrent ejaculation with minimal sexual stimulation before, on or shortly after minimal sexual stimulation before, on or after penetration and before the person wishes it..." which is associated with "marked or interpersonal difficulty..." PE has a reported incidence of 30% and is therefore the most common type of sexual dysfunction. The year 2005 saw the presentation of the introductory studies for the first drug specifically targeted for the treatment of premature ejaculation. Dapoxetine is an ultra-short acting seratonin selective reuptake inhibitor with no antidepressive effects. The medication would ideally be taken 1-3 hours before anticipated sexual intercourse and can increase intravaginal ejaculatory latency time. Three abstracts presented data on the safety, tolerability, and pharmacology of dapoxetine. Hellstrom and colleagues (Abstract 877) presented a dual phase II analysis to determine the appropriate prn doses of dapoxetine to evaluate for further study in large-scale phase III clinical trials. In this dual double-blind, multicenter, randomized, placebo-controlled, 3-period crossover phase II studies enrolled men with PE, based on DSM-IV criteria and intravaginal ejaculatory latency time (IELT). 128/157 randomized subjects completed Study 1 (dapoxetine 20 mg and 40 mg), and 130/166 randomized subjects completed Study 2 (dapoxetine 60 mg and 100 mg). All 4 doses demonstrated statistically significant improvements in IELT over placebo (up to a mean change of 2.23 minutes from baseline IELT. The most commonly reported adverse events (AEs) were nausea, diarrhea, dizziness, and headache. The incidence of some AEs, including nausea, diarrhea, dizziness headache, insomnia, and nervousness appeared to be dose related. Overall, prn administration of dapoxetine 60 mg was better tolerated than dapoxetine 100 mg.

Gengo and Modi from Johnson and Johnson R&D each presented abstracts describing the receptor binding and ethanol interactions of dapoxetine. In Abstract 878, Gengo and colleagues reported that dapoxetine binds to 5-HT, NE, and DA reuptake transporters and inhibits 5-HT, NE, and DA uptake with the following rank order of potency: NE < 5-HT >> DA. Modi's group (Abstract 879) determined that coadministration of ethanol with dapoxetine did not produce significant changes in dapoxetine PK. Mean peak plasma concentrations of dapoxetine, occurring ~1.5 hours after oral administration, were 531 ± 210 ng/mL and 492 ± 160 ng/mL following dapoxetine + ethanol and dapoxetine alone, respectively; 90% confidence intervals (CIs) for the ratio of mean AUCinf for dapoxetine and its metabolites all fell within 80%-125%, indicating that ethanol did not affect dapoxetine PK.