Dapoxetine: Hoạt chất ức chất tái hấp thu serotonin dùng để điều trị xuất tính sớm

In addition to IELT, both doses of dapoxetine improved patient reported outcome measures compared to placebo (96). Dapoxetine was comparably effective both in men with lifelong and acquired PE (96,101,102). Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed medications for the treatment of a variety of mood disorders such as depression (62). The use of SSRIs to treat PE is based on the observation that delayed ejaculation and anorgasmia are common side effects of this class of drugs (41,63). SSRIs, either alone at low doses or in combination with psychosexual counseling are widely accepted as first line treatments for lifelong PE (14). Men with acquired PE generally receive targeted therapy aimed at resolving the underlying etiology of their PE, either with or without the addition of SSRIs (10).

Table 4.

• This medication is typically taken “on-demand”, 1-3 hours before sexual activity, once daily.
• Dapoxetine is a selective serotonin reuptake inhibitor, a medicine that is used for the treatment of premature ejaculation in adult men.
• Though PE is a non-life-threatening condition, like ED, it has a serious impact on patient and partner quality of life.
• Historically, attempts to explain the aetiology of PE have included a diverse range of biological and psychological theories.

Both 5-HT2C and 5-HT1B receptors are distributed within the hypothalamus and in the lumbosacral areas of the spinal cord, along with 5-HT1A receptors (18). Preclinical safety pharmacology studies did not suggest an adverse electrophysiologic or hemodynamic effect with concentrations of dapoxetine up to twofold greater than recommended doses. Phase III clinical studies of dapoxetine in men with PE indicated that dapoxetine was generally safe and well tolerated with the dosing regimens used (30 mg and 60 mg as required) Buvat et al. 2009; Kaufman et al. 2009; McMahon et al. 2010, 2011; Pryor et al. 2006; Shabsigh et al. 2008.

Animal studies of dapoxetine

Apart from a number of behavioral approaches, the treatment of PE consists of primarily off-label use of oral selective serotonin reuptake inhibitors (SSRIs) via either on-demand or daily delivery. However, various undesirable side-effects of these medications have led researchers to search for and develop new therapeutic approaches for PE. Dapoxetine is a short-acting SSRI developed specifically for the treatment of PE. Early trials with dapoxetine have documented successful outcomes without serious short- or long-term side-effects.

The basic hypothesis of this study was that drugs for the treatment of PE produce their effects by inhibiting intraluminal pressure elevations of the seminal tract. All serotonergic agents tested significantly inhibited the increase in seminal vesicle pressure induced by hypogastric nerve stimulation. All serotonergic drugs were documented to exhibit significant inhibitory effects on the contractile responses of the seminal vesicle, whereas minimal (ser-traline) to no effects (fluoxetine and paroxetine) were observed in the vasal pressure responses. As 50%–70% of the ejaculatory volume is produced by the seminal vesicle, this organ is a greater contributor than the vas deferens in ejaculatory volume (Coffey 1988).

Based on these results, doses of 30 mg and 60 mg were chosen for further investigation in phase III efficacy and safety studies. The metabolites of dapoxetine include dapoxetine-N-oxide, desmethyldapoxetine and didesmethyldapoxetine. Dapoxetine-N-oxide does not have any clinical efficacy, while desmethyldapoxetine and didesmethyldapoxetine have similar efficacy to dapoxetine, but as they comprise far smaller percentages of circulating dapoxetine species (less than 3%) their clinical effects are limited (80). At 24 hours, plasma dapoxetine concentrations drop to 3.5% and 3.9% of peak concentrations for 30 and 60 mg doses, respectively (80). The pharmacokinetics of dapoxetine are unaffected by multiple dosing with minimal apparent accumulation (80). In contrast, chronic use of paroxetine and sertraline has a 8- and 2-fold increases in plasma concentrations, respectively (85,86).

Similar outcomes were also reported for premature ejaculation profile and treatment-emergent adverse events. Dapoxetine was rapidly absorbed, with mean maximal plasma concentrations of 297 and 498 ng/mL at 1.01 and 1.27 hours after single doses of dapoxetine 30 and 60 mg, respectively (Table 1). Elimination of dapoxetine was rapid and biphasic, with an initial half-life of 1.31 and 1.42 hours, and a terminal half-life of 18.7 and 21.9 hours following single doses of dapoxetine 30 and 60 mg, respectively. The pharmacokinetics of dapoxetine and its metabolites were not affected by repeated daily dosing and steady state plasma concentrations were reached within 4 days, with only modest accumulation of dapoxetine (approximately 1.5-fold) (Fig. 2B).

Another two phase II clinical trials investigated the efficacy and tolerability of 20, 40, 60, and 100 mg dapoxetine in order to determine the appropriate on-demand doses of dapoxetine for further study in large-scale phase III clinical trials (Hellstrom et al 2005). Both double-blind, multi-center, randomized, placebo-controlled, 3-period cross-over phase II studies enrolled men with PE, based on DSM-IV-TR criteria and IELT. Subjects were instructed to take study drug prior to the anticipated sexual intercourse (1–3 hours prior in study 1, and 1–2 hours prior in study 2) and to attempt sexual intercourse ≥ twice weekly. The primary endpoint was IELT measured with a stopwatch held by the female partner. In study 1, 128 of 157 patients (20 mg and 40 mg dapoxetine), and in study 2, 130 of 166 https://www.truccosposa.it/understanding-testosterone-enanthate-3/ (60 mg and 100 mg dapoxetine) randomized subjects completed the trials.

Sildenafil has been reported to cause a clinically significant improvement in the total duration of erections during visual sexual stimulation when evaluated with sexual function questionnaires and Rigiscan devices (Boolell et al 1996; Sadovsky et al 2001). Because the ejaculatory latency time may be dependent on the duration of erection, any increase in the duration of erection may in turn prolong the ejaculatory latency time (Kameya et al 1997). In this regard, it is recognized that sildenafil may conceivably increase the ejaculatory latency time and contribute to prolongation of ejaculation. There are several possible mechanisms that can explain the efficacy of sildenafil in the treatment of PE. Sildenafil may inhibit the contractile responses of the seminal vesicles, vas deferens, prostate, urethra, and even the skeletal muscles.

Despite these results, sildenafil reduces anxiety, increase confidence, and gives a perception of ejaculatory control (54). There is some evidence to support the efficacy and safety of off-label on-demand or daily dosing of PDE-5 inhibitors in the treatment of lifelong PE in men with normal erectile function (51-53). However, treatment of lifelong PE with PDE5-inhibitors in such situations is not recommended (level of evidence 4) and further evidence-based research is encouraged to understand these conflicting data (14). Even in more extreme cases of PE, in which baseline IELT was very short, treatment with dapoxetine effectively increased IELT.

It is limited to heterosexual men engaging in vaginal intercourse as there are few studies available on PE research in homosexual men or during other forms of sexual expression. Preliminary recommendations of the American Psychiatric Association’s Diagnostic and Statistical Manual V (DSM-V) Committee suggest a DSM-V definition which parallels the definition recently adopted by the International Society for Sexual Medicine Segraves, 2010. Adequately powered randomized, controlled trials were considered the strongest form of evidence but all other articles were also considered. Our study is limited by its small patient number, short follow-up time, and the use of a single dose of dapoxetine. The absence of a placebo group are other relevant limitations, however, for a study Initiated by researchers, we could not get a standard placebo without the supported by the company.