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Unknown impurity associated with the degradation process of dapoxetine base was isolated. The structure elucidation of this new compound using accurate mass data, IR and NMR spectroscopy is presented herein. The unambiguous resonance assignment concluded to the formation of geometrical isomers of cinnamyloxynaphtalenes via Cope elimination of dapoxetin-N-oxide, the major oxidative and metabolic degradation product of dapoxetine. An efficient and simple synthetic approach has also been developed for the synthesis of dapoxetine-N-oxide for the first time and cinnamyloxynaphtalene in order to confirm the proposed degradation pathway and structures of the degradation products. It was observed that the main degradation product of dapoxetine base when exposed to air is 1-(2E)-cinnamyloxynaphthalene, while its Z isomer was also confirmed as a minor impurity.
The present study implied that DA-8031 contributed to an effective co-coordinated inhibition of the expulsion phase of ejaculation by modulating BS muscle activity and the emission phase through blocking SVP rise. From these findings, DA-8031 is further expected to have clinical efficacy in human studies.
First of all, in electrical stimulation of an SBPdn model, an SBPdn in the pelvic canal of the spinal cord transected from rats was identified. Then an electromyogram (EMG) of the bulbospongiosus (BS) muscle was recorded during electrical stimulation of SBPdn after single intravenous (IV) dosing of DA-8031 and its reference drug, dapoxetine. In the second model, both seminal vesicle pressure (SVP) and the EMG profile of the BS muscle were recorded in PCA-induced ejaculation animals after treated with the same dosing regimen.
This randomized, double-blind, parallel-group, placebo-controlled, phase 3 trial, conducted in 22 countries, enrolled men (N=1162) > or = 18 yr of age who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision criteria for PE for > or = 6 mo, with an intravaginal ejaculatory latency time (IELT) < or = 2 min in > or = 75% of intercourse episodes at baseline.
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The study was a prospective, 12-week, open-label study to evaluate the efficacy and safety of flexible-dose dapoxetine in men with PE diagnosed by a Premature Ejaculation Diagnostic Tool score of at least 11, a self-estimated intravaginal ejaculation latency time (IELT) no longer than 2 minutes, and an International Index of Erectile Function erectile function domain score of at least 21.
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Dapoxetine is being developed as a treatment for premature ejaculation and has demonstrated rapid absorption and elimination in previous pharmacokinetic studies. Two open-label studies were conducted in healthy men: a parallel-group pharmacokinetic and safety study in young and elderly men and a randomized crossover food-effect study. Maximal plasma dapoxetine concentrations (C(max)) were similar in young and elderly men (338 and 310 ng/mL, respectively), as were the corresponding area under the plasma concentration versus time curve (AUC) values (2040 and 2280 ng x h/mL, respectively). When coadministered with food, C(max) was reduced by 11% (398 vs 443 ng/mL in the fed and fasted states, respectively), and the peak was delayed by approximately 30 minutes, indicating that food slowed the rate of absorption; however, systemic exposure to dapoxetine (ie, AUC) was not affected by food consumption. Thus, age or consumption of a high-fat meal has only a modest impact on dapoxetine pharmacokinetics in healthy men.
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Treatment-emergent adverse events (TEAEs) and concomitant therapy use during the 12-wk observational and the postobservational period were reported.
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No drugs are approved for treatment of premature ejaculation. Our aim was to determine the efficacy and tolerability of on-demand dapoxetine in patients with severe premature ejaculation.
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The Manichean diagnosis, psychogenic or organic, is the first and most frequent diagnostic scope managing sexual disorders. The aim of this Controversy is to discuss if this philosophy is still useful both in the conceptual and clinical perspective.
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From MEDLINE (Jan, 1950-Mar, 2008), EMBASE (Jan, 1980-Mar, 2008), The Cochrane Library (Issue 1, 2008) and CNKI (Jan, 1979-Mar, 2008), we retrieved and screened the randomized controlled trials (RCT) and randomized crossover trials (RT) as well as various related data, published and unpublished, on the treatment of PE with SSRIs. The methodological quality of the included trials was evaluated by 2 reviewers. Meta-analyses were conducted with RevMan 5.0 on the homogeneous studies.
Drug treatment is the first choice of treatment for lifelong premature ejaculation and may also be indicated for acquired premature ejaculation. Together with the patient, the clinician can choose which drug and which treatment strategy is most suitable for the patient and his partner.
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Our results confirm previous reports on the efficacy and safety of dapoxetine. Although less effective than dapoxetine, acupuncture had a significant ejaculation-delaying effect.
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Premature ejaculation (PE), whose pathophysiology is still not clearly identified, is the most common male sexual dysfunction, yet it remains underdiagnosed and undertreated. The aims of this paper are to provide a scientific and pharmacologic rationale, and to discuss to what extent selective serotonin reuptake inhibitors (SSRIs) can help patients with PE.
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In this study, we describe and validate a rapid and sensitive method for quantitation of dapoxetine in rat plasma by using ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometry (UPLC-ESI/MS/MS). Plasma samples were prepared by protein precipitation with acetonitrile, and sildenafil was used as an internal standard (IS). The mobile phase consisted of 0.5% formic acid/acetonitrile (60:40, v/v); a C18 reversed-phase column (2.0 × 50 mm, 1.7 μm) was used for chromatographic separation. Multiple reaction monitoring (MRM) was used in the positive ion mode for mass spectrometric detection. The calibration curve for dapoxetine was linear (r(2)=0.999) in the concentration range of 1-500 ng/mL. The intra- and inter-day precision was between 3.8% and 8.3%, and the intra- and inter-day accuracy was between 101.1% and 109.0%. Dapoxetine was found to be stable in various conditions with the recoveries>87.0% (RSD <7.2%). The method was found to be specific, precise, and accurate, and no matrix effect was observed. Our results suggest that this method can be successfully applied in pharmacokinetic studies of dapoxetine in rat plasma.
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Pudendal motoneuron reflex discharges elicited by bilateral electrical stimulation of the dorsal nerves of the penis were used as an experimental model of the expulsion reflex of ejaculation to investigate the effect of acute intravenous delivery of dapoxetine, a short acting selective serotonin reuptake inhibitor, in anesthetized rats. Dapoxetine was compared with paroxetine, the selective serotonin reuptake inhibitor of reference.
Premature ejaculation (PE) is a common male sexual disorder which is associated with substantial personal and interpersonal negative psychological consequences. Pharmacotherapy of PE with off-label antidepressant selective serotonin reuptake inhibitors (SSRIs) is common, effective and safe. Development and regulatory approval of drugs specifically for the treatment of PE will reduce reliance on off-label treatments and serve to fill an unmet treatment need. The objective of this article is to review evidence supporting the efficacy and safety of dapoxetine in the treatment of PE. MEDLINE, Web of Science, PICA, EMBASE and the proceedings of major international and regional scientific meetings were searched for publications or abstracts published during the period 1993-2012 that used the word 'dapoxetine' in the title, abstract or keywords. This search was then manually cross referenced for all papers. This review encompasses studies of dapoxetine pharmacokinetics, animal studies, human phase I, II and III studies, independent postmarketing and pharmacovigilance efficacy and safety studies and drug-interaction studies. Dapoxetine is a potent SSRI which is administered on demand 1-3 h prior to planned sexual contact. It is rapidly absorbed and eliminated, resulting in minimal accumulation, and has dose-proportional pharmacokinetics which are unaffected by multiple dosing. Dapoxetine 30 mg and 60 mg has been evaluated in five industry-sponsored randomized, double-blind, placebo-controlled studies in 6081 men aged at least 18 years. Outcome measures included stopwatch-measured intravaginal ejaculatory latency time (IELT), Premature Ejaculation Profile (PEP) inventory items, Clinical Global Impression of Change (CGIC) in PE, and adverse events. Mean IELT, all PEP items and CGIC improved significantly with both doses of dapoxetine versus placebo (all p <0.001). The most common treatment-related adverse effects included nausea (11.0% for 30 mg, 22.2% for 60 mg), dizziness (5.9% for 30 mg, 10.9% for 60 mg), and headache (5.6% for 30 mg, 8.8% for 60 mg), and evaluation of validated rated scales demonstrated no SSRI class-related effects with dapoxetine use. Dapoxetine, as the first drug developed for PE, is an effective and safe treatment for PE and represents a major advance in sexual medicine.
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In the treated group, the median IELT was 3 min vs. 1.5 min before and after treatment (P<0.05). PEDT in the treated group was reduced to 11.76±1.68 from 15.83±2.30 after treatment (P<0.05). Besides, patient's SLS was improved from 1.30±0.05 to 6.30±0.04 (P<0.05), and spouse's SLS was increased from 1.30±0.to 6.10±0.06 (P<0.05); CMSS was decrease from 14.86±3.02 to 9.62±2.87 (P<0.05). In addition, no significant AE was observed in both groups.
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Of 495 subjects randomized, 429 completed the study. Arithmetic mean average IELT significantly increased with dapoxetine vs. placebo at end point (5.2 vs. 3.4 minutes) and weeks 4, 8, and 12 (P ≤ 0.002 for all). Men who described their PE at least "better" using the CGIC were significantly greater with dapoxetine vs. placebo at end point (56.5% vs. 35.4%) and weeks 4, 8, and 12 (P ≤ 0.001 for all). Significantly better outcomes were also reported with dapoxetine vs. placebo on PEP measures. Incidence of TEAEs was 20.0% and 29.6% in placebo- and dapoxetine-treated subjects, respectively (P = 0.0135). TEAEs led to discontinuation in 1.6% of subjects in both groups. Most frequent TEAEs were known adverse drug reactions of dapoxetine treatment including nausea (9.2%), headache (4.4%), diarrhea (3.6%), dizziness (2.4%), and dizziness postural (2.4%).
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Dapoxetine significantly improved all aspects of PE and was generally well tolerated in this broad population.
Thermal behavior of DAP and VAR were confirmed using by semi-empirical molecular orbital calculations. The purity values were found to be 99.97% and 99.95% for dapoxetine and vardenafil hydrochlorides, respectively. The purity of dapoxetine and vardenafil hydrochlorides is similar to that found by reported methods according to DSC data.
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Integrated pharmacotherapy and cognitive behavioral therapy (CBT) may achieve superior treatment outcomes in some patients. Phosphodiesterase type 5 inhibitors alone or in combination with selective serotonin reuptake inhibitors (SSRIs) should be limited to men with acquired PE secondary to comorbid erectile dysfunction (ED). New on-demand rapid-acting SSRIs, oxytocin receptor antagonists, or single agents that target multiple receptors may form the foundation of more effective future on-demand medication.
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Treatment with dapoxetine or alternative care/nondapoxetine.
The ejaculation distribution theory (EDT) postulates a biological continuum of the intravaginal ejaculation latency time (IELT) in men. Such an continuum has recently been found in two epidemiological stopwatch studies. In addition, a continuum of ejaculation latency time has also been demonstrated in laboratory rats. It is suggested that the invariable parts of ejaculation, i.e. premature and retarded ejaculation are highly influenced by genetic and neurobiological factors. In contrast, superimposed on biological roots, ejaculation of men, in the middle part of the continuum, is probably more easily influenced by environmental and psychological factors. A meta-analysis of 35 daily SSRI and clomipramine treatment studies demonstrated a similar efficacy for paroxetine, clomipramine, sertraline and fluoxetine, with paroxetine exerting the strongest effect on ejaculation. Based on fundamental insights into serotonergic neurotransmission, it is suggested that on-demand conventional SSRI treatment will not lead to similarly impressive ejaculation delay as that found after daily conventional SSRI treatment. Future studies with SSRIs with short half-lives, short T(max) and high C(max )should elucidate whether these pharmacokinetic properties are able to affect the pharmacodynamics of 5-HT neurons in such a way that immediate clinically relevant ejaculation delay occurs.
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Dapoxetine is a serotonin transporter inhibitor currently in development for the treatment of premature ejaculation. This randomized, 2-sequence, 2-treatment crossover study assessed the single- and multiple-dose pharmacokinetics of dapoxetine following once-daily administration of dapoxetine 30 mg and 60 mg to healthy male volunteers. Dapoxetine was rapidly absorbed following oral administration, with peak plasma concentrations reached approximately 1 hour after dosing; plasma concentrations after single doses of dapoxetine decreased rapidly to approximately 5% of peak concentrations by 24 hours. Elimination was biphasic, with an initial half-life of approximately 1.4 hours and a terminal half-life of approximately 20 hours. Dapoxetine showed time-invariant pharmacokinetics and dose proportionality between doses, and its pharmacokinetics was unaffected by multiple dosing. The pharmacokinetics of dapoxetine metabolites, desmethyldapoxetine and dapoxetine-N-oxide, was similarly unaffected by multiple dosing. There were no serious adverse events; the most commonly reported adverse events were diarrhea, dizziness, and nausea.
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PE, rapid ejaculation, early ejaculation and SSRIs were employed as the keywords, and relevant articles about the use of SSRIs and their possible mechanisms in the treatment of PE were selected.
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Randomised controlled trials (RCTs) in adult men with PE were eligible (or non-RCTs in the absence of RCTs). RCT data were extrapolated from review articles when available. The primary outcome was intravaginal ejaculatory latency time (IELT). Data were meta-analysed when possible. Other outcomes included sexual satisfaction, control over ejaculation, relationship satisfaction, self-esteem, quality of life, treatment acceptability and adverse events (AEs).