Dapoxetine , marketed as Priligy and Westoxetin , among other and brands, is the first developed specifically for the treatment of premature ejaculation (PE) in men the 18-64 year old boy. Dapoxetine works by inhibiting serotonin transporters, increasing serotonin action in the post synaptic cleft, and as a consequence promoting ejaculatory delays. As a member of the selective serotonin reuptake inhibitor (SSRI) family, dapoxetine was originally created as an antidepressant. However, unlike other SSRIs, dapoxetine is absorbed and removed rapidly in the body. The nature of rapid acting makes it suitable for PE treatment but not as an antidepressant.
Originally created by the pharmaceutical company Eli Lilly, dapoxetine is sold to Johnson & amp; Johnson in 2003 and filed as a New Drug Application for Food and Drug Administration (FDA) for PE treatment in 2004. Dapoxetine is sold in several European and Asian countries, and in Mexico. In the US, dapoxetine has been in stage III since 2003. However, it is expected to be marketed soon. In 2012, Menarini acquired the right to commercialize Dapoxetine in Europe, mostly Asia, Africa, Latin America and the Middle East.
Video Dapoxetine
Therapeutic use
Premature ejaculation
Randomized, double-blind, placebo-controlled trials have confirmed the efficacy of dapoxetine for PE treatment. Different doses have different effects on different types of PE. Dapoxetine 60 mg significantly increased the mean intravaginal latent time of ejaculation (IELT) compared with 30 mg dapoxetine in men with lifelong PE, but no difference in men with PE acquired. Dapoxetine, given 1-3 hours before the sexual episode, prolongs IELT and improves the sense of control and sexual satisfaction in men aged 18 to 64 years with PE. Because PE is associated with personal difficulties and relationship difficulties, dapoxetine provides assistance for men with PE to address this condition. Without a 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 the baseline, compared with three to eight fold when dapoxetine is used. However, this SSRI may need to be taken daily to achieve significant efficacy, and its relatively longer lifetime life increases the risk of drug accumulation and associated 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 is largely removed from the body within hours. Pharmacokinetics is more beneficial because it can minimize the accumulation of drugs in the body, habituation, and side effects.
Maps Dapoxetine
Contraindications
Contraindications are situations where drugs should not be used, as they can be harmful to the patient. Dapoxetine should not be used in men with moderate to severe liver disease and in those who receive CYP3A4 inhibitors such as ketoconazole, ritonavir, and telithromycin. Dapoxetine also can 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 antidepressants. If a patient stops using one of these drugs, he or she has to wait 14 days before using dapoxetine. If a patient stops taking dapoxetine, he or she has to wait 7 days before receiving these medications.
Adverse effects
The most common effects when taking dapoxetine are nausea, dizziness, dry mouth, headache, diarrhea, and insomnia. Termination due to dose-related side effects. According to McMahon in a recent study in Asia, the stopping rates were 0.3%, 1.7%, and 5.3% of the 1067 subjects studied with placebo, 30 mg dapoxetine, and 60 mg dapoxetine respectively. Unlike other SSRIs used to treat depression, which is associated with high incidence of sexual dysfunction, dapoxetine is associated with lower rates of sexual dysfunction. Taken as needed, dapoxetine has a very mild side effect of decreased libido (& lt; 1%) and ED (& lt; 4%).
Overdose
No cases of drug overdose were reported during clinical trials.
Interactions
With a phosphodiesterase (PDE5 inhibitor) inhibitor
Many men who suffer from PE also suffer from erectile dysfunction (ED). Treatment for these patients should consider drug-drug interactions between dapoxetine and PDE5 inhibitors such as tadalafil (Cialis) or sildenafil (Viagra). In the Dresser study (2006), plasma concentrations of 24 subjects were obtained. Half of the pool samples were treated with dapoxetine 60 mg tadalafil 20 mg; the other half were treated with dapoxetine 60 mg sildenafil 100 mg. The plasma samples were then analyzed using liquid-tandem chromatography mass spectrometry. The results showed that dapoxetine did not alter the pharmacokinetics of tadalafil or sildenafil.
With ethanol
Ethanol does not affect dapoxetine pharmacokinetic when taking simultaneously.
Action mechanism
The mechanism by which dapoxetine affects premature ejaculation remains unclear. However, it is suspected that dapoxetine works by inhibiting serotonin transporters and then increasing serotonin action in pre- and postsynaptic receptors. Human ejaculation is governed by various areas of the central nervous system (CNS). The ejaculatory pathway originates from spinal reflexes at the thoracolumbar and lumbosacral levels of the spinal cord activated by stimulation of the male genitalia. These signals are transmitted to the brainstem, which is then influenced by a number of nuclei in the brain such as the medial preoptic and paraventricular nulcei. Clement studies conducted on an anesthetized male rats indicate that administration of acute dapoxetine inhibits the ejaculatory ejection reflex at supraspinal level by modulating the activity of paraligoselular lateral nuclear neurons (LPGi). This effect leads to an increase in latitude of the motoneuron pamendal reflex (PMRD). However, it is unclear whether dapoxetine acts directly on LPGi or in the descending pathway where LPG is located.
Pharmacokinetics
- Absorption
Dapoxetine is a white powder substance and insoluble in water. Taken 1-3 hours before sexual activity, it is quickly absorbed in the body. The maximum plasma concentration (C max ) reaches 1-2 hours after oral administration. C max and AUC (Area Below plasma vs. time curve) depends on the dose. C max and Tm (the time required to obtain maximum plasma concentration) after a single dose of dapoxetine 30 mg and 60 mg were 297 and 498 ng/mL at 1.01 and 1.27 hours respectively. High fat foods do reduce C max slightly, but not significantly. In fact, food does not alter the pharmacokinetics of dapoxetine. Dapoxetine may be taken with or without food.
- Distribution
Dapoxetine is absorbed and distributed rapidly in the body. More than 99% of dapoxetine is bound by plasma proteins. The average steady state volume was 162 L. The initial half was 1.31 h (30 mg dose) and 1.42 h (dose 60 mg), and the terminal half-life time was 18.7 h (30 mg dose) and 21, 9 hours (60 mg dose).
- Metabolism
Dapoxetine is extensively metabolized in the liver and kidneys by some enzymes such as CYP2D6, CYP3A4, and flavin monooxygenase 1 (FMO1). The main product at the end of the metabolic pathway is the circulation of dapoxetine N-oxide, which is a weak SSRI and gives no clinical effect. Other products presented less than 3% in plasma are desmethyldapoxetine and didesmethydapoxetine. Desmethyldapoxetine is approximately equipotent with dapoxetine.
- Excrescence
The dapoxetine metabolite was rapidly removed in the urine with terminal half-life of 18.7 and 21.9 hours for a single dose of 30 mg and 60 mg, respectively.
Security and tolerability
- Cardiovascular safety
Dapoxetine cardiovascular safety profile has been studied extensively during drug development. Phase I trial showed that dapoxetine had no clinically significant electrocardiographic effect or delayed repolarization effect, with doses up to four times greater than the recommended maximum dose of 60 mg. Phase III studies in men with PE showed safety and tolerance to dapoxetine profiles at doses of 30 and 60 mg. No cardiovascular damage was found.
- Neurocognitive security
SSRI studies in patients with major psychiatric disorders prove that SSRIs are potentially associated with certain neurocognitive side effects such as anxiety, akathisia, hypomania, mood swings, or suicidal thoughts. However, there are no studies of SSRI effects in men with PE. McMahon's research in 2012 shows that dapoxetine has no effect on mood and is not associated with anxiety or suicide.
- Withdrawal syndrome
The incidence of antidepressant withdrawal syndrome symptoms in men who use dapoxetine to treat premature ejaculation has been described by reviewers as low or no different from the incidence of symptoms as in men drawn from placebo treatment. Lack of chronic serotonergic stimulation with dapoxetine on-demand minimizes the action of serotonin potency in the synaptic cleft, thus reducing the risk of DESS.
Synthesis
Currently very few methods are used to synthesize ( S ) - dapoxetine. This new approach consists of only six steps in which the three main steps are shown above. Initial reactants are commercially available commercially available alcohol-commercially available alcohols. Epoxidation asymmetric and Mitsunobu's unknown reactions have been used to produce the expected ( S ) - dapoxetine. The overall result is 35%. This method is considered a good choice compared to known methods because of high yield and easily accessible reactants.
Regulatory history
Dapoxetine was created by Eli Lilly and in phase I clinical trials as an antidepressant. However, it never works well as a remedy for the treatment of depression and is temporarily stored before it is then developed to treat PE. In December 2003, Eli Lilly sold a patent of dapoxetine to Pharmaceutical Products Development (PPD) worth 65 million US dollars in cash. Eli Lilly may also receive royalty payments from PPD if the sale exceeds a certain amount.
ALZA is the current owner of dapoxetine. However, PPD will receive payment of milestones and drug royalties from ALZA. If approved, dapoxetine will be marketed in the US by Ortho McNeil pharmaceutical, Inc. Ortho McNeil and Janssen-Ortho Inc., or Janssen-Cilag are all Johnson & amp; Johnson. As in 2005, Dapoxetine in phase III clinical trials, awaiting review by the Federal Drug Administration (FDA).
Dapoxetine has been marketed and approved in over 50 countries. Dapoxetine has been approved in Italy, Spain, Mexico, South Korea and New Zealand in 2009 and 2010; marketed in Sweden, Austria, Germany, Finland, Spain, Portugal, and Italy. It has also been approved in France, Russia, Malaysia, Philippines, Argentina and Uruguay.
Trade name
Dapoxetine is sold under various brand names including Dumax, Duratia, Joybox, Pole, Lejam, Pentenal-30, Priligy, Sustinex, Ever Long, and Westoxetin.
See also
- Premature ejaculation
- Serotonin
- Serotonin transporter
- SSRI
- Serotonergic system
- serotonin receptors
References
Source of the article : Wikipedia
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