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Dapoxetine HCL (129938-20-1)

Dapoxetine or Dapoxetine Hydrochloride (Dapoxetine HCL, CAS No.129938-20-1) is a medication marketed as Priligy and Westoxetin, among and other brands, is the first compound developed specially for the treatment of premature ejaculation (PE) in men 18–64 years old.


What is Dapoxetine?

Dapoxetine, marketed as Priligy and Westoxetin, among and other brands, is the first compound developed specially for the treatment of premature ejaculation (PE) in men 18–64 years old. Dapoxetine works by inhibiting the serotonin transporter, increasing serotonin's action at the post synaptic cleft, and as a consequence promoting ejaculatory delay. As a member of the selective serotonin reuptake inhibitor (SSRI) family, dapoxetine was initially created as an antidepressant. However, unlike other SSRIs, dapoxetine is absorbed and eliminated rapidly in the body. Its fast acting property makes it suitable for the treatment of PE but not as an antidepressant.



The usages of Dapoxetine

Premature ejaculation
Randomized, double blind, placebo-controlled trials have confirmed the efficacy of dapoxetine for the treatment of PE. Different dosage has different impacts on different types of PE. Dapoxetine 60 mg significantly improves the mean intravaginal ejaculation latency time (IELT) compared to that of dapoxetine 30 mg in men with lifelong PE, but there is no difference in men with acquired PE. Dapoxetine, given 1–3 hours before sexual episode, prolongs IELT and increases the sense of control and sexual satisfaction in men of 18 to 64 years of age with PE. Since PE is associated with personal distress and interrelationship difficulty, dapoxetine provides help for men with PE to overcome this condition. With no drug approved specifically for treatment for PE in the US and some other countries, other SSRIs such as fluoxetine, paroxetine, sertraline, fluvoxamine, and citalopram have been used off-label to treat PE. Waldinger's meta-analysis shows that the use of these conventional antidepressants increases IELT two- to nine-fold above baseline, compared to three- to eight-fold when dapoxetine is used. However, these SSRIs may need to be taken daily in order to achieve meaningful efficacy, and their comparatively longer half-lives increase the risk of drug accumulation and a corresponding increase of adverse effects such as reduced libido. Dapoxetine, on the other hand, is generally categorized as a fast-acting SSRI. It is more rapidly absorbed and mostly eliminated from the body within a few hours. These pharmacokinetics are more favorable in that they might minimize drug accumulation in the body, habituation, and side effects.



The effect of Dapoxetine

Interactions
With phosphodiesterase inhibitors (PDE5 inhibitors)
Many men that have PE also suffer from erectile dysfunction (ED). Treatment for these patients should consider the drug–drug interaction between dapoxetine and PDE5 inhibitors such as tadalafil (Cialis) or sildenafil (Viagra). In Dresser study (2006), plasma concentration of 24 subjects was obtained. Half of the sample pool were treated with dapoxetine 60 mg + tadalafil 20 mg; the other half were treated with dapoxetine 60 mg + sildenafil 100 mg. These plasma samples were then analyzed using liquid chromatography-tandem mass spectrometry. The results showed that dapoxetine does not alter the pharmacokinetic of tadalafil or sildenafil.


With ethanol
Ethanol doesn't affect the pharmacokinetics of dapoxetine when taking concurrently.

Mechanism of actions
The mechanism through which dapoxetine affects premature ejaculation is still unclear. However, it is presumed that dapoxetine works by inhibiting serotonin transporter and subsequently increasing serotonin's action at pre and postsynaptic receptors Human ejaculation is regulated by various areas in the central nervous system (CNS). The ejaculatory pathway originates from spinal reflex at the thoracolumbar and lumbosacral level of spinal cord activated by stimuli from male genital. These signals are relayed to the brain stem, which then is influenced by a number of nuclei in the brain such as medial preoptic and paraventricular nulcei. Clement's study performed on anaesthetized male rats showed that acute administration of dapoxetine inhibits ejaculatory expulsion reflex at supraspinal level by modulating activity of lateral paragigantocellular nucleus (LPGi) neurons. These effects cause an increase in pudendal motoneuron reflex discharge (PMRD) latency. However, it is unclear whether dapoxetine acts directly on LPGi or on the descending pathway in which LPGi located.


Pharmacokinetics
Absorption
Dapoxetine is a white powder substance and water- insoluble. Taken 1–3 hours before sexual activity, it is rapidly absorbed in the body. Its maximum plasma concentration (Cmax) is reached 1–2 hours after oral administration. The Cmax and AUC (Area Under the plasma vs. time Curve) are dose dependent. The Cmax and Tm (time needed to obtain the maximum plasma concentration) after single doses of dapoxetine 30 mg and 60 mg are 297 and 498 ng/mL at 1.01 and 1.27 hours respectively. A high fat meal does reduce the Cmax slightly, but it is insignificant. In fact, food doesn't alter dapoxetine pharmacokinetics. Dapoxetine can be taken with or without food.


Distribution
Dapoxetine is absorbed and distributed rapidly in the body. Greater than 99% of dapoxetine is bound to the plasma protein. The mean steady state volume is 162 L. Its initial half-life is 1.31 hours (30 mg dose) and 1.42 hours (60 mg dose,) and its terminal half life is 18.7 hours (30 mg dose) and 21.9 hours (60 mg dose).


Metabolism
Dapoxetine is metabolized extensively in the liver and kidney by multiple enzymes such as CYP2D6, CYP3A4, and flavin monooxygenase 1 (FMO1). The major product at the end of the metabolic pathway is circulating dapoxetine N-oxide, which is a weak SSRI and contributes no clinical effect. The other products presented less than 3% in the plasma are desmethyldapoxetine and didesmethydapoxetine. Desmethyldapoxetine is approximately equipotent to dapoxetine.


Excretion
The metabolites of dapoxetine are eliminated rapidly in the urine with a terminal half-life of 18.7 and 21.9 hours for a single dose of 30 mg and 60 mg respectively.




The side effect of Dapoxetine

The most common effects when taking dapoxetine are nausea, dizziness, dry mouth, headache, diarrhea, and insomnia. Discontinuation due to adverse effects is dose related. According to McMahon in recent study in Asia, the rate of discontinuation is 0.3%, 1.7%, and 5.3% of 1067 studied subjects with placebo, dapoxetine 30 mg, and dapoxetine 60 mg respectively. Unlike other SSRIs used to treat depression, which have been associated with high incidences of sexual dysfunction, dapoxetine is associated with low rates of sexual dysfunction. Taken as needed, dapoxetine has very mild adverse effects of decreased libido (<1%) and ED (<4%).





The Safety and tolerability of Dapoxetine

Cardiovascular safety
The cardiovascular safety profile of dapoxetine has been studied extensively during the drug development. Phase I trials showed that dapoxetine had neither clinical significant electrocardiographic effects nor delayed repolarization effects, with dosing up to four-fold greater than the maximum recommended dosage which is 60 mg. Phase III studies in men with PE showed a safety and well tolerate profile of dapoxetine with dosing of 30 and 60 mg. There is no cardiovascular adverse had been found.


Neurocognitive safety
Studies of SSRIs in patients with major psychiatric disorders prove that SSRIs are potentially associated with certain neurocognitive adverse effects such as anxiety, akathisia, hypomania, changes in mood, or suicidal thought. However, there is no study on the effects of SSRIs in men with PE. McMahon’s study in 2012 showed that dapoxetine has no effect on mood and is not associated with anxiety or suicidality.


Withdrawal syndrome
The incidence of antidepressant discontinuation syndrome symptoms in men using dapoxetine to treat premature ejaculation has been described by reviewers as low or no different from the incidence of such symptoms in men withdrawn from placebo treatment. The lack of chronic serotonergic stimulation with on-demand dapoxetine minimizes the potentiation action of serotonin at synaptic cleft, thus decreasing the risk of DESS.





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