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Dapoxetine ((+)-(S)-N,N-dimethyl-(a)-[2-(1-naphthalenyloxy)ethyl]-benzenemethanamine) hydrochloride market as Priligy, Kutub, or Duratia; is the first compound developed specially for the treatment of Premature ejaculation (PE) in men 18-24 years old. [1] Dapoxetine works by inhibiting serotonin transporter, increasing serotonin’s action at the post synaptic cleft, and as a consequence promoting ejaculatory delay.[2]As a member of selective serotonin reuptake inhibitors(SSRI) family, Dapoxetine was initially created as an antidepressant. However, unlike other selective serotonin reuptake inhibitors(SSRIs), dapoxetine is absorbed and eliminated rapidly in the body. Its fast acting property makes it suitable for the treatment of PE but failed as an antidepressant.[3]

Originally created by Eli Lily 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.[4]Dapoxetine has been sold in several European and Asia countries, and lately in Mexico. In the US, Dapoxetine is in phase III development and expected to be marketed soon.[2]

Therapeutic uses

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Premature ejaculation
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Randomize, double blind, placebo-control trials have confirm the efficacy of dapoxetine for the treatment of PE. [5] Different dosage has different impacts on different type of PE. Dapoxetine 60mg significantly improves the mean intravaginal ejaculation latency time (IELT) compare to that of dapoxetine 30mg in men with lifelong PE, but there is no different in men with acquire PE.[6]Dapoxetine, given 1-3 hours before sexual episode, prolongs intravaginal ejaculation latency time(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 disease.[7] Because lack of specific approval treatment for PE in the US and some other countries, other SSRIs such asfluoxetine, 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 antidepressant increasing IELT from two to nine fold above base line in comparison of three to eight fold when dapoxetine is used.[6]

However, these SSRIs must be taken daily in order to achieve meaningful efficacy, and their long half-life results in the risk of the drug accumulation and as a consequence increased of adverse effects such as decreasing sexual libido and causing erectile dysfunction.[8] Dapoxetine, in other hands, is a fast-acting SSRI. It is rapidly absorbed and eliminated from the body within few hours. This favorable pharmacokinetics minimizes the risk of the drug’s accumulation in the body, and therefore reducing side effects.[3]

Depression
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Conventional SSRIs are used to treat depression. As a member of the SSRIs class, dapoxetine was originally an antidepressant. Its half- life is 1.4 hours after oral administration. This is the shortest half-life among all of the SSRIs, and was account for its failure as an antidepressant.[9] So do not use dapoxetine for the treatment of depression.

Contraindications

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  1. Hypersensitivity of dapoxetine hydrochloride or any other of excipients.
  2. Significant pathological cardiac conditions such as heart failure, permanent pacemaker, or other significant ischemic heart disease.
  3. Hepatic impairment.
  4. Concomitant administration with CYP3A4 inhibitors such as ketoconazole, ritonavir, or telithromycine.
  5. Concomitant intake with the followed drugs:

Dapoxetine cannot be used concurrently with the drugs mentioned in 5. If a patient is taking one of these drugs, he should wait 14 days after stop taking these drugs before starting on dapoxetine. If he is on dapoxetine, he should wait for 7 days after discontinuing of dapoxetine before taking these drugs.[2]

Adverse effects

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The most common effects when taking dapoxetine are nausea, dizziness, dry mouth, headache, diarrhea, insomnia, and loss of libido.[10] 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 30mg, and dapoxetine 60mg respectively. .[11]

Overdose
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No case of the drug overdose has been reported during clinical trials.[12]

Interactions
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  • With phosphodiesterase inhibitors (PDE-5)

Most men that have PE also suffer from erectile dysfunction (ED). Treatment for these patients should consider the drug-drug interaction between dapoxetine and phosphodiesterase inhibitors(PDE-5) such as tadalafil (Cialis) or sildenafil (Viagra). In Dresser study, plasma concentration of 24 subjects was obtained. Half of the sample pool were treated with dapoxetine 60mg + tadalafil 20mg; the other half were treated with dapoxetine 60mg + sildenafil 100mg. 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. [1]

  • With ethanol

Ethanol doesn’t effect the pharmacokinetic of dapoxetine when taking concurrently with dapoxetine. [13]

Mechanism of actions

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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[14]Human ejaculation is regulated by various areas in the central nervous system (CNS).[15]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.[16]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.This effects cause an increasing 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.[17]

Pharmacokinetics

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  • Absorption

Dapoxetine is a white powder substance and water-soluble. Taken 1-3 hours before sexual intercourse, it is rapidly absorbed in the body. Its maximum plasma concentration (Cm) is reached 1-2 hours after oral administration. The Cm and AUC (Area Under the plasma vs. time Curve) are dose dependent. The Cm and Tm (time needed to obtain the maximum plasma concentration) after single doses of dapoxetine 30mg and 60mg are 297 and 498ng/mL at 1.01 and 1.27 hours respectively. A high fat meal does reduce the Cm slightly, but it is insignificant. In fact, food doesn’t alter dapoxetine pharmacokinetics. Dapoxetine can be taken with or without food.[18]

  • 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 162L. Its initial half-life is 1.31hours (30mg dose) and 1.42 hours (60mg dose,) and its terminal half life is 18.7 hours (30mg dose) and 21.9 hours (60mg dose).[19]

  • 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 serotonin reuptake inhibitor and contributes no clinical effect. The other products presented less than 3% in the plasma are desmethyldapoxetine and didesmethydapoxetine, which are equipotent to dapoxetine.[20]

  • 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 30mg and 60mg respectively.[21]

Synthesis

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Currently very few methods are used to synthesize (s)-dapoxetine. This novel approach consists of only six steps in which three main steps are shown above. The initial reactant is trans cinnamyl alcohol which is commercial available. Sharpless asymmetric epoxidation and Mitsunobu reaction have been used to produce expected (S)-dapoxetine. The overall yield is 35% . This method is considered a good choice compare to the known method due to high yield and easy obtainable reactants.[22]

Regulatory history

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Dapoxetine was created by Eli Lilly and in phase I clinical trial as an antidepressant. However, It never worked out well as a medication for the treatment of depression and was shelved for a while before subsequently developed to treat Premature ejaculation(PE). In December 2003, Eli Lilly sold patent of dapoxeine to Pharmaceutical Product Development(PPD) for 65 million US dollars in cash. Eli Lilly may also received royalties payment from PPD if the sale exceeds certain amount. ALZA is the current owner of dapxetine. However, PPD will receive milestone payment and drug royalties from ALZA. If approval, dapoxetine will be marketed in the US by Ortho McNeil. Ortho McNeil (Canada)as well as Janssen –Ortho Inc, or Janssen-Cilag are all units of Johnson & Johnson. Dapoxetine is currently in phase III clinical trials, pending review by the Federal Drug Administration (FDA).[23]

Dapoxetine is currently marketed and approved in more than 50 countries .[24]. 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 Malaysia, Philippines, Argentina, and Uruguay.[2]

References

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  1. ^ a b Dresser, M. J., Desai, D., Gidwani, S., Seftel, A. D., & Modi, N. B. (2006). Dapoxetine, a novel treatment for premature ejaculation, does not have pharmacokinetic interactions with phosphodiesterase-5 inhibitors. International Journal of Impotence Research, 18(1), 104-110. doi: Doi 10.1038/Sj.Ijir.3901420.
  2. ^ a b c d Government, A. ( 2010). Australian Public Assessment Report for Dapoxetine (D. o. H. a. A. T. G. Administration, Trans.).
  3. ^ a b Andersson, K. E., Mulhall, J. P., & Wyllie, M. G. (2006). Pharmacokinetic and pharmacodynamic features of dapoxetine, a novel drug for 'on-demand' treatment of premature ejaculation. Bju International, 97(2), 311-315. doi: Doi 10.1111/J.1464-410x.2006.05911.X
  4. ^ McCarty, E., & Dinsmore, W. (2012). Dapoxetine: an evidence-based review of its effectiveness in treatment of premature ejaculation. Core Evid, 7, 1-14. doi: 10.2147/CE.S13841
  5. ^ McMahon, C. G., McMahon, C. N., & Leow, L. J. (2006). New agents in the treatment of premature ejaculation. Neuropsychiatr Dis Treat, 2(4), 489-503.
  6. ^ a b Pryor, J. L., Althof, S. E., Steidle, C., Rosen, R. C., Hellstrom, W. J. G., Shabsigh, R., . . . Kell, S. (2006). Efficacy and tolerability of dapoxetine in treatment of premature ejaculation: an integrated analysis of two double-blind, randomised controlled trials. Lancet, 368(9539), 929-937.
  7. ^ Shabsigh, R., Broderick, G. A., Miloslavsky, M., & Bull, S. (2006). Dapoxetine has long-term efficacy in the treatment of premature ejaculation. Journal of Urology, 175(4), 297-298.
  8. ^ Montague, D. K., Jarow, J., Broderick, G. A., Dmochowski, R. R., Heaton, J. P., Lue, T. F., . . . Sharlip, I. D. (2004). AUA guideline on the pharmacologic management of premature ejaculation. [Guideline Practice Guideline]. J Urol, 172(1), 290-294. doi: 10.1097/01.ju.0000132159.61156.ea
  9. ^ Wyllie, M. G. (2010). The Dapoxetine Paradox. Bju International, 105(8), 1041-1042. doi: Doi 10.1111/J.1464-410x.2010.09250.X
  10. ^ Buvat, J., Tesfaye, F., Rothman, M., Rivas, D. A., & Giuliano, F. (2009). Dapoxetine for the Treatment of Premature Ejaculation: Results from a Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial in 22 Countries. European Urology, 55(4), 957-968. doi: Doi 10.1016/J.Eururo.2009.01.025
  11. ^ McMahon, C. G., Kim, S. W., Park, N. C., Chang, C. P., Rivas, D., Tesfaye, F., . . . Aquilina, J. W. (2010). Treatment of Premature Ejaculation in the Asia-Pacific Region: Results from a Phase III Double-blind, Parallel-group Study of Dapoxetinejsm_1560256..268. J Sex Med, 7, 12.
  12. ^ Jhanjee, A., Kumar, P., Bhatia, M. S., & Srivastava, S. (2011). Dapoxetine-A Novel Drug for Premature Ejaculation. Delhi Psychiatry Journal, 14(1), 5.
  13. ^ Modi, N. B., Dresser, M., Desai, D., & Jazrawi, R. P. (2005). Dapoxetine for the treatment of premature ejaculation: Lack of interaction with ethanol. Journal of Urology, 173(4), 239-239.
  14. ^ Gengo, P. J., View, M., Giuliano, F., McKenna, K. E., Chester, A., Lovenberg, T., . . . Gupta, S. K. (2005). Monoaminergic transporter binding and inhibition profile of dapoxetine, a medication for the treatment of premature ejaculation. Journal of Urology, 173(4), 239-239.
  15. ^ Goldstein, I. (2003, 11/17/12). The Central Mechanisms of Sexual Function Retrieved 11/11/12, 2012, fromhttp://www.bumc.bu.edu/sexualmedicine/publications/the-central-mechanisms-of-sexual-function/
  16. ^ Giuliano, F., & Clement, P. (2005). Physiology of ejaculation: emphasis on serotonergic control. [Review]. Eur Urol, 48(3), 408-417. doi: 10.1016/j.eururo.2005.05.017
  17. ^ Clement, P., Bernabe, J., Gengo, P., Denys, P., Laurin, M., Alexandre, L., & Giuliano, F. (2007). Supraspinal site of action for the inhibition of ejaculatory reflex by dapoxetine. European Urology, 51(3), 825-832. doi: Doi 10.1016/J.Eururo.2006.10.011
  18. ^ McMahon, C. G., Althof, S. E., Kaufman, J. M., Buvat, J., Levine, S. B., Aquilina, J. W., . . . Porst, H. (2011). Efficacy and safety of dapoxetine for the treatment of premature ejaculation: integrated analysis of results from five phase 3 trials. [Meta-Analysis Research Support, Non-U.S. Gov't]. J Sex Med, 8(2), 524-539. doi: 10.1111/j.1743-6109.2010.02097.x
  19. ^ Dapoxetine: a guide to its use in premature ejaculation (D. T. Perspective, Trans.). (2011) (Vol. 27, pp. 1-4).
  20. ^ Dresser, M., Lindert, K., Lin, D., Gidwani, S., Gupta, S. K., & Modi, N. B. (2004). Pharmacokinetics of single and multiple escalating doses of dapoxetine in healthy volunteers. Clinical Pharmacology & Therapeutics, 75(2), P32-P32. doi: Doi 10.1016/J.Clpt.2003.11.123
  21. ^ Cite error: The named reference ”Modi” was invoked but never defined (see the help page).
  22. ^ Venkatesan, K., & Srinivasan, K. V. (2008). A stereoselective synthesis of (S) dapoxetine starting from trans-cinnamyl alcohol. arkivoc, 16, 9.
  23. ^ Dapoxetine: LY 210448. (2005). [Review]. Drugs R D, 6(5), 307-311.
  24. ^ Priligy® for Premature Ejaculation: Partnership with Menarini. (2012) Retrieved 11/17, 2012, from http://www.furiex.com/pipeline/marketed-products/priligy/
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