OBJECTIVE To evaluate the overall treatment benefit of dapoxetine for premature ejaculation (PE), with specific emphasis on improvements in personal distress and interpersonal difficulty related to ejaculation. Although these factors are key elements of numerous sets of diagnostic criteria for PE, they have rarely been evaluated as outcome measures in clinical trials. PATIENTS AND METHODS In this randomized, double‐blind, placebo‐controlled, phase III trial we enrolled men aged ≥18 years, from the USA and Canada, who had a Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision, diagnosis of PE (1238 men). Men were randomized to receive placebo or dapoxetine 60 mg as needed or once daily for 9 weeks. The once‐daily treatment arm was included for analysis of withdrawal symptoms (primary endpoint; presented elsewhere). Patients completed the Premature Ejaculation Profile (PEP) on day 1 (before dosing), and on days 28 and 63 (or study endpoint), which comprised the outcome measures for perceived control over ejaculation, satisfaction with sexual intercourse, and personal distress and interpersonal difficulty related to ejaculation. The patient‐reported global impression of change in PE was reported on day 63 (or study endpoint). Treatment benefit measures included the composite criteria of at least a two‐category increase in perceived control over ejaculation and at least a one‐category decrease in personal distress related to ejaculation from baseline at study endpoint. RESULTS At baseline, ≈5% of patients in any treatment group reported ‘not at all’ or ‘a little bit’ of personal distress related to ejaculation, which increased to 54.3% of those receiving dapoxetine (vs 35.3% with placebo; P < 0.001). Similarly, 43.0% and 40.9% of men in the placebo and dapoxetine groups, respectively, reported ‘not at all’ or ‘a little bit’ of interpersonal difficulty related to ejaculation at baseline, which increased to 76.8% and 64.2% of those with dapoxetine and placebo, respectively (P < 0.001). The percentage of men who achieved the composite criteria with dapoxetine ‘as needed’ was 47.6%, vs 21.7% with placebo (difference from placebo, 25.9%; P < 0.001). The distribution of responses for the PEP among men who achieved the composite criteria was similar to that reported for men without PE in a previous observational study in the USA. The most common adverse events were nausea, dizziness, headache, diarrhoea and insomnia, which were more common with dapoxetine than with placebo. CONCLUSION Dapoxetine reduced the personal distress and interpersonal difficulty associated with PE, and was associated with patient‐reported improvements in their condition. The percentage of patients who achieved a composite of a two‐category or greater increase in perceived control over ejaculation and a one‐category or greater decrease in personal distress related to ejaculation was substantially greater than with placebo, as were all outcome measures.

Adenosine, a locally released and rapidly metabolized nucleoside, protects the heart from damage during ischemia by reducing oxygen demand and increasing oxygen supply. The aminothiophene derivative (2-amino-4,5-dimethylthien-3-yl)[3-(trifluoromethyl)phenyl]-met hanone (PD 81,723) has been shown to act as an allosteric enhancer of the adenosine A1 receptor in brain membranes and thyroid cells. The present study investigates the effects of PD 81,723 in spontaneously contracting right atria and electrically stimulated left atria isolated from Sprague-Dawley rats. N6-cyclopentyladenosine (CPA), an adenosine A1 receptor agonist, produced concentration-dependent inhibition of heart rate in right atria and contractile parameters in left atria. In the right atrium, 5 microM of PD 81,723 significantly shifted the concentration-response curves for CPA to the left, both in the absence and presence of a nonselective adenosine receptor antagonist, 8-(p-sulfophenyl)theophylline (8-SPT, 10 microM). In the left atrium, PD 81,723 also shifted the concentration-response curves for CPA to the left, but only in the presence of 8-SPT. Potentiation of CPA-induced negative chronotropic and inotropic responses with PD 81,723, although not significant, was also observed in the presence of a selective adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 1 nM). These results demonstrate that PD 81,723 enhances the direct negative chronotropic and inotropic effects of adenosine A1 receptor activation in rat atria.

Dapoxetine is a short-acting selective serotonin reuptake inhibitor developed for the on-demand treatment of premature ejaculation and is approved in some European Union countries, as well as Mexico and Korea, for this indication. The pharmacokinetics of dapoxetine 30 mg and 60 mg in healthy Chinese (single dose), Japanese, and Caucasian men (single and multiple dose) were assessed in 2 studies. In the 3 ethnic groups, dapoxetine was rapidly absorbed following oral administration, with peak plasma concentrations evident approximately 1 hour after dosing, independent of dose, dosing frequency (single or multiple dosing), or ethnicity. Dapoxetine was eliminated in a biphasic manner with an apparent mean terminal half-life of 14 to 17 hours. There was a dose-proportional increase in dapoxetine maximum plasma concentration (C(max)) and area under concentration-time curves (AUCs). The single-dose pharmacokinetic parameters of dapoxetine metabolites were also similar for the 3 ethnic groups, as were the pharmacokinetics of dapoxetine and its metabolites following single and multiple dosing in Caucasian and Japanese men. Dapoxetine was well tolerated by all 3 ethnic groups.

The cardiovascular safety profile of dapoxetine, a novel selective serotonin reuptake inhibitor (SSRI) developed as an on-demand oral treatment for premature ejaculation (PE) in men, is evaluated. The cardiovascular assessment of dapoxetine was conducted throughout all stages of drug development, with findings from preclinical safety pharmacology studies, phase I clinical pharmacology studies investigating the effect of dapoxetine on QT/corrected QT (QTc) intervals in healthy men, and phase III, randomized, placebo-controlled studies evaluating the safety (and efficacy) of the drug. Preclinical safety pharmacology studies did not suggest an adverse electrophysiologic or hemodynamic effect with concentrations of dapoxetine up to 2-fold greater than recommended doses. Phase I clinical pharmacology studies demonstrated that dapoxetine did not prolong the QT/QTc interval and had neither clinically significant electrocardiographic effects nor evidence of delayed repolarization or conduction effects, with dosing up to 4-fold greater than the maximum recommended dosage. Phase III clinical studies of dapoxetine in men with PE indicated that dapoxetine was generally safe and well tolerated with the dosing regimens used (30mg and 60mg as required). Events of syncope were reported during the clinical development program, with the majority occurring during study visits (on site) on day 1 following administration of the first dose when various procedures (e.g. orthostatic maneuvers, venipunctures) were performed, suggesting that the procedures contributed to the incidence of syncope. This was consistent with previous reports showing that these and similar factors contribute to or trigger vasovagal syncope. Findings of the dapoxetine development program demonstrate that dapoxetine is associated with vasovagal-mediated (neurocardiogenic) syncope. No other associated significant cardiovascular adverse events were identified.

Adenosine, an endogenously produced nucleoside, has direct negative chronotropic and inotropic effects on right and left atrial tissues, respectively. Age-related differences in the effects of A1 adenosine receptor activation on atrial rhythmic and contractile function were investigated in adult (6-8 months) and senescent (23-24 months) Fischer 344 (F344) rats. Senescent right atria (RA) were more sensitive to the negative chronotropic effects of R-phenylisopropyladenosine (R-PIA), a selective A1 receptor agonist, than adult RA (EC50: 4.8 +/- 0.7 vs 10.8 +/- 1.5 nM). However, senescent left atria (LA) were 15.4% less responsive to the maximal negative inotropic effects of R-PIA than adult LA. R-PIA did not significantly change resting force from basal values in either age group, but 90% relaxation time was prolonged threefold in senescent LA compared with adults. Radioligand binding experiments with 1,3-[3H]dipropyl-8-cyclopentylxanthine, a selective adenosine A1 receptor antagonist, showed a 56% greater density (Bmax) of adenosine A1 receptor in senescent than adult without differences in affinities (Kd). The increased sensitivity of senescent RA to the negative chronotropic effects of adenosine A1 receptor stimulation suggests a role for adenosine in abnormal sinus node function that occurs more frequently with age. Adenosine A1 receptor stimulation has more effect on relaxation than contraction in senescent LA compared with LA from adult F344 rats. However, the increase in density of adenosine A1 receptors suggests a functional dissociation between the availability of binding sites and receptor activation.