High impact information on LY 210448

• PURPOSE: 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 [1].
• Pudendal motoneuron reflex discharges induced by penile dorsal nerve stimulation were measured before and 60 minutes after a single intravenous injection of dapoxetine or paroxetine, each tested at 3 doses (1, 3 and 10 mg/kg) or after a single injection of vehicle [1].
• Pharmacokinetics of dapoxetine, a new treatment for premature ejaculation: Impact of age and effects of a high-fat meal [2].
• 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 [2].
• RESULTS: Pharmacodynamic and pharmacokinetic measurements confirm that 'on demand' dapoxetine has a rapid onset of action and is rapidly cleared after sexual intercourse [3].

Biological context of LY 210448

• The pharmacokinetics of dapoxetine metabolites, desmethyldapoxetine and dapoxetine-N-oxide, was similarly unaffected by multiple dosing [4].
• Men with moderate-to-severe premature ejaculation in stable, heterosexual relationships took placebo (n=870), 30 mg dapoxetine (874), or 60 mg dapoxetine (870) on-demand (as needed, 1-3 h before anticipated sexual activity) [5].

Associations of LY 210448 with other chemical compounds

• Tadalafil did not affect the pharmacokinetics of dapoxetine, whereas sildenafil increased the dapoxetine AUCinf by 22%; these effects were deemed not clinically important [6].

Analytical, diagnostic and therapeutic context of LY 210448

• A column-switching high-performance liquid chromatographic (HPLC) method is described for the determination of dapoxetine and its mono- and di-desmethyl metabolites in human plasma [7].
• Determination of dapoxetine, an investigational agent with the potential for treating depression, and its mono- and di-desmethyl metabolites in human plasma using column-switching high-performance liquid chromatography [7].
• 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 [4].
• On-demand dapoxetine, and SSRI with a short half-life, recently has been shown to significantly increase intravaginal latency time and PE patient-related outcomes in phase 3 clinical trials [8].
• RESULTS: Compared with control (NaCl 0.9%, intrathecally), intrathecal injection of dapoxetine (1 and 80mug) significantly increased amplitude of DNP-elicited PMRDs in a similar fashion than serotonin (5-HT; 10 and 100mug, intrathecally) [9].

References