Dapoxetine

Brief Introduction

Premature ejaculation (PE) is the most common male sexual dysfunction. Dapoxetine hydrochloride,marketed as Priligy and Westoxetin, is a class of PE treatment drugs known as selective serotonin reuptake inhibitors (SSRI) , was the first drug originally approved for the on-demand treatment of men 18–64 years old with PE.
Dapoxetine works by inhibiting the serotonin transporter, increasing serotonin's action at the post synaptic cleft, and as a result promoting ejaculatory delay. Dapoxetine was initially developed 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.
Used for the treatment of premature ejaculation and erectile dysfunction. Over 98% of men taking this drug will naturally gain a improved erection quality with prolonged time and more frequencies.

Physical and chemical properties

White crystal powder with sweet taste and no odor, hygroscopic and soluble in water. It has a stable chemical property with the melting point at 175~177℃.

PE treatment

Premature ejaculation (PE) is a common problem worldwide and has significant impact not only on the sufferer but on the partner in terms of self-esteem, interpersonal distress and sexual satisfaction. Tricyclic antidepressants and clomipramine are the most widely used drugs for the treatment of 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 type 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, giving 1–3 hours before sexual episode, prolongs IELT, 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, interrelationship difficulty, dapoxetine provides help for men with PE to overcome this condition. Because lack of specific approval treatment for PE in the US and some other countries, other SSRIs such as fluoxetine, paroxetine, sertraline, fluvoxamine, and citalopram have been used as off label drugs to treat PE. Waldinger's meta analysis shows that the use of these conventional antidepressants increasing IELT from two to ninefold above base line in comparison of three to eightfold when dapoxetine is used. However, these SSRIs must be taken daily in order to achieve meaningful efficacy, and the long half-life increases the risk of the drug accumulation and as a consequence increased of adverse effects such as decreasing sexual libido and causing erectile dysfunction. Dapoxetine, on the other hand, is a fast-acting SSRI. It is rapidly absorbed and eliminated from the body within a few hours. This favorable pharmacokinetics minimizes the risk of the drug's accumulation in the body, and therefore reducing side effects.

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.

Development in Marketing internationally

Originally developed by Eli Lilly pharmaceutical company, dapoxetine was sold to Johnson & Johnson in 2003 and submitted as a New Drug Application to the Food and Drug Administration (FDA) for the treatment of PE in 2004.Dapoxetine is sold in some European and Asian countries, and in Mexico. In the US, dapoxetine has been in phase III development since 2003. However, it was rejected by FDA last year. In 2012, Menarini acquired the rights to sell Dapoxetine in Europe, most of Asia, Africa, Latin America and the Middle East.

Synthesis

There are many ways to synthesize dapoxetine, which can be divided into two categories. The first category is achiral synthesis where pure S-configuration dapoxetine is obtained from the resolution of racemic dapoxetine or its intermediate. The other is the methods of asymmetric synthesis, where S-configuration dapoxetin is directly obtained through metal catalysis or enzyme catalysis without resolution .

• Achiral synthesis methods

• Asymmetric synthesis methods

Usage and Dosage

Oral administration of one pill 20-30 mins before sexual intercourse； it can be taken irregularly; it’s better to take it with an empty stomach; avoid fatty food during administration; no tea before administration. Its effect is significant when the user under sexual stimulus.

Adverse effects

The most common effects when taking dapoxetine are nausea, dizziness, dry mouth, headache, diarrhea, and insomnia, which will soon disappear. 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 on loss of libido (<1%) and ED (<4%).

Contraindications

A contraindication is a situation in which a drug should not be used, because it may be harmful to the patient. Juveniles, children and pregnant women are not allowed to take dapoxetine.  Dapoxetine should not be used in men with moderate to severe hepatic impairment and in those receiving CYP3A4 inhibitors such as ketoconazole, ritonavir, and telithromycine. Dapoxetine can also not be used in patients with heart failure, permanent pacemaker, or other significant ischemic heart disease. Caution is advised in men receiving thioridazine, monoamine oxidase inhibitors, SSRIs, serotonin-norepinephrine reuptake inhibitors, or tricyclic antidepressant. If a patient stops taking one of these drugs, he should wait for 14 days before taking dapoxetine. If a patient stops taking dapoxetine, he should wait for 7 days before receiving these drugs.

Interactions

• With phosphodiesterase inhibitors (PDE5 inhibitors)

• With ethanol

References

http://www.nature.com/articles/srep07269
https://en.wikipedia.org/wiki/Dapoxetine

Uses

Antidepressant.

Uses

Dapoxetine-d7 Hydrochloride is a Labelled Dapoxetine (D185700). A selective serotonin reuptake inhibitor (SSRI).

Definition

ChEBI: Dapoxetine is a member of naphthalenes.

Clinical Use

Dapoxetine is a selective serotonin re-uptake inhibitor (SSRI) which has been approved in Finland and Sweden for the treatment of premature ejaculation.Dapoxetine was discovered and developed by Lilly and was licensed to Alza, a wholly-owned subsidiary of Johnson & Johnson.

Synthesis

Several synthetic routes for the preparation of dapoxetine have been disclosed, all on gram scale. Based on the routes and yields, the most likely process route is described in the scheme 4. Commercially available (R)-(+)-3-chloro-1-phenyl- 1-propanol (19) was reacted with 1-naphthol in the presence of 50% aqueous sodium hydroxide in DMF to give ether 20 in 90% yield. Activation of the secondary alcohol was accomplished through treatment of 20 with methane sulfonyl chloride and triethylamine with catalytic DMAP. Upon complete conversion to the corresponding mesylate, dimethylamine was added to the reaction mixture. The addition of hydrochloric acid in ethyl acetate to the resultant crude product gave dapoxetine hydrochloride (IV) in 67% yield. Purification of this material by re-crystallization from isopropanol provided IV in 86% yield and in 99.6% ee.