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Hydrolytic Enzymes for the Synthesis of Pharmaceuticals
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Sergio González-Granda, Vicente Gotor-Fernández
(S)-Dapoxetine is a serotonin re-uptake inhibitor used for the treatment of anxiety, bulimia, depression and premature ejaculation, among other disorders. Its chemoenzymatic synthesis has been developed by stereoselective hydrolysis of 3-amino-3-phenylpropionic methyl ester using Pseudomonas cepacia lipase (PSL). For this KR 5 equiv. of water were used as hydrolytic agent using 1,4-dioxane as solvent at 45°C (Scheme 9.5, top), obtaining both the unaltered (R)-amino ester and the (S)-carboxylic acid with excellent selectivities (Rodríguez-Mata et al., 2010). Alternatively, the resolution of 2,2,2-trifluorethyl ester has been reported through an alcoholysis reaction using 10 equiv. of methanol (You et al., 2013). The Carica papaya lipase (CPL) acted as a stereoselective biocatalyst, so after optimisation of the reaction conditions the (R)-trifluorethyl ester and the (S)-methyl ester were attained in enantiopure form at 50% conversion (Scheme 9.5, bottom). Both processes highly improved in terms of stereoselectivity the attempts to resolve an O-protected amino alcohol through lipase-catalysed N-acylation (Torre et al., 2006). Synthesis of (S)-Dapoxetine by hydrolysis or alcoholysis stereoselective reactions.
Ejaculation Disorders
Published in Philipa A Brough, Margaret Denman, Introduction to Psychosexual Medicine, 2019
In May 2014, the NICE (National Institute for Health and Care Excellence) approved the use of dapoxetine for certain patients with premature ejaculation. The NICE website shows the key points: Dapoxetine is a short-acting selective serotonin-reuptake inhibitor (SSRI). It is the first pharmacological treatment for premature ejaculation to be licensed in the UK. In a pooled analysis of 4 randomised controlled trials (RCTs) in men with premature ejaculation there was a statistically significant increase in intra-vaginal ejaculatory latency time (IELT) with Dapoxetine ‘on demand’ compared with placebo ‘on demand’, although an increase in IELT was also seen with placebo.
Physiology of normal sexual function
Published in Jacques Corcos, David Ginsberg, Gilles Karsenty, Textbook of the Neurogenic Bladder, 2015
Pierre Clément, Hélène Gelez, François Giuliano
Neurochemical regulation Similar to the erectile function, various neurotransmitters and neurohormones participate in the control of ejaculation. However, less is known about the neurochemical regulation of ejaculation despite the recent progress in this field. Several lines of experimental evidence support the involvement of dopamine in ejaculation. It was shown that D2/D3 receptors stimulation promotes seminal emission and ejaculation in conscious rats and trigger ejaculation in anesthetized rats likely by acting in MPOA.233,234 A great body of evidence supports the inhibitory role of cerebral 5-HT on ejaculation in the rat model. The stimulation of somatodendritic 5-HT1A autoreceptors regulating 5-HT neurons firing has been demonstrated to shorten the ejaculatory latency time.235 However, as suggested by Rehman et al.,236 5-HT1A receptors at different locations (brain, raphe nuclei, spinal cord, and autonomic ganglia) may modulate ejaculation in opposing ways. Stimulation of postsynaptic 5-HT2C receptors was responsible for inhibition of male rat ejaculatory behavior.237 In humans, as well, 5-HT tone is major in the control of ejaculation with, globally, an inhibitory action. Lengthened ejaculation latency is a frequent side effect of the antidepressants SSRIs, which increase 5-HT bioavailability within the CNS.238 This led to the development of dapoxetine, the first authorized medicine for the treatment of premature ejaculation effective on demand. Activation of the cholinergic muscarinic receptors in MPOA has been shown to reduce the ejaculatory threshold in copulating male rats.239 Delivered either systemically or centrally, OT decreases ejaculation latency and postejaculatory interval (i.e., refractory period) in copulating male rats.240
Optimization of taste-masked dapoxetine oral thin films using factorial design: in vitro and in vivo evaluation
Published in Pharmaceutical Development and Technology, 2021
Ibrahim A. El-said, Ahmed A. Aboelwafa, Omaima N. ElGazayerly
Dapoxetine ((+)‐S)‐N, N‐dimethyl‐(a)‐[2‐(1‐naphthalenyloxy)ethyl]‐benzenemethanamine)HCl is a ‘selective serotonin (5-Ht) reuptake inhibitor (SSRI)’ (McCarty and Dinsmore 2012). Dapoxetine is originally generated as an antidepressant, but it’s now mainly used in the management of premature ejaculation (Pryor et al. 2006). Dapoxetine affects premature ejaculation by increasing serotonin's action at pre and postsynaptic receptors (Gengo et al. 2005). The pharmacokinetic parameters of dapoxetine are characterized by 42% bioavailability, Tmax = 1.27-1.8 h, Cmax 349-398 ng/ml and elimination half-life 1.5–1.6 h (Andersson et al. 2006; McMahon 2012). Dapoxetine is metabolized widely in the kidney and liver by various enzymes such as CyP3A4, CyP2D6, and flavin monooxygenase 1 (FMO1). The main metabolite is a weak SSRI and has no clinical effect; resulting in reduced bioavailability. Furthermore, oral dapoxetine has a bitter taste, currently marketed only as oral coated tablets (Priligy®), and this is a big challenge that limits its formulation commercially as fast oral disintegration systems, therefore it’s important to exploit other dosage forms (Turkyilmaz and Yelken 2015).
Novel instantly-dispersible nanocarrier powder system (IDNPs) for intranasal delivery of dapoxetine hydrochloride: in-vitro optimization, ex-vivo permeation studies, and in-vivo evaluation
Published in Drug Development and Industrial Pharmacy, 2018
Shahinaze A. Fouad, Rehab N. Shamma, Emad B. Basalious, Mohamed M. El-Nabarawi, Saadi A. Tayel
Premature ejaculation is a common male sexual dysfunction that is treated by various therapeutic remedies including selective serotonin reuptake inhibitors (SSRIs) [1]. Dapoxetine (D), as dapoxetine hydrochloride, is the only licensed SSRI drug for treatment of premature ejaculation in adult men [2]. D acquires very rapid absorption from the gastrointestinal tract giving high serum concentrations (after ≈ 1.29 h) [3] and very short elimination half-life of 1.31 h [4]. Owing to its unique pharmacological profile, it has been used as a successful ‘episodic’, ‘as-needed’ or ‘on-demand’ treatment of PE where, a rapid effect of the medication is needed [2]. However, oral administration of D suffers from hepatic first pass metabolism which results in its poor bioavailability (42%) [5]. Thus, formulating intranasal systems of D would avoid the hepatic route and consequently improve D bioavailability. However, D acquires limited solubility at neutral pH of body fluids, which hampers its absorption through the nasal mucosa.
Outcome of hyaluronic acid gel injection in glans penis for treatment of lifelong premature ejaculation: A pilot study
Published in Arab Journal of Urology, 2023
Ahmed Sakr, Hazem Elgalaly, Mohamed M. Seleem, Mostafa Kamel, Ahmed I. El-Sakka, Ibrahim M. Ibrahim
In fact, these results appears promising when compared to that of Dapoxetine 30 or 60 mg taken 1 to 2 hours before intercourse, which leads in a 2.5- and 3.0-fold increase in IELT, increased ejaculatory control, decreased discomfort and increased satisfaction [16].