Synthesis and Technology Optimization of Dapoxetine Hydrochloride / 中国药房

OBJECTIVE：To optimize the synthesis process of dapoxetine hydrochloride. METHODS ：By chiral synthesis ， asymmetric reduction was carried out by using 3-chlorophenylacetone as raw material ，（1S，2R）-（-）-1-amino-2-indanol as catalyst，and borane- N，N-diethylaniline （DEANB） as reducing agent. Then ，it was reacted with α-naphthol etherification， sulfonation，dimethylamine substitution ，and HCl salt formation reaction to obtain the final products. The products were characterized by NMR and MS. The synthesis reaction of intermediate Ⅰ，intermediate Ⅱ，intermediate Ⅲ and the final product were optimized. RESULTS ：The final product was dapoxetine hydrochloride with purity of 99.8％ and yield of 58.9％. Compared with traditional splitting technology ，the chiral synthesis technology of this study did not need splitting ，and the yield of the technology was significantly higher than that of splitting technology reported in literature （31.9％）. The optimized technology reduced the generation of impurities and improved the product quality. CONCLUSIONS ：The improved technology has milder reaction conditions ，shorter synthesis route and higher yield.

Qiaoshao Prescription improves premature ejaculation in male rats by increasing the content of 5-hydroxytryptamine / 中华男科学杂志

<p><b>Objective</b>To observe the intervention effect of Qiaoshao Prescription (QSP) on premature ejaculation (PE) induced by 8-OH-DPAT in male rats and explore its possible action mechanism.</p><p><b>METHODS</b>Seventy-two male Wistar rats were equally randomized into six groups, blank control, PE model control, low-, medium- and high-dose QSP, and dapoxetine. The PE model was established by injection of 8-OH-DPAT into the subarachnoid space of the lumbosacral spinal cord. Four weeks after modeling, the rats in the blank control and PE model control groups with gavaged with normal saline at 10 ml/kg/d, those in the low-, medium- and high-dose QSP groups with QSP at 5, 10 and 20 g/kg/d respectively once a day, and those in the dapoxetine group with dapoxetine hydrochloride at 300 mg/kg at 3 hours before mating. Forty-five female Wistar rats were injected subcutaneously with 20 μg estradiol benzoate after removal of bilateral ovaries to induce estrous estrus. Two and 4 weeks later, the male rats were mated with the female ones for 30 minutes per time and meanwhile observed for the mating behavior of the males, including mounting latency (ML), intromission latency (IL), ejaculation latency (EL), mounting frequency (MF), intromission frequency (IF), and ejaculation frequency (EF). After the 4th week of mating, the hypothalamus of the animals was isolated and weighed, and the content of 5-hydroxytryptamine (5-HT) was measured.</p><p><b>RESULTS</b>Compared with the blank control group, the PE model controls showed significantly decreased content of 5-HT in the hypothalamus(1 257.1 vs 923.4 ng/g, P<0.05), ML (［11.22 ± 3.60］ vs ［8.69 ± 2.48］ s, P<0.05), IL (［22.33 ± 2.45］ vs ［12.08±1.39］ s, P<0.05), MF (［13.28 ± 3.24］ vs ［7.53 ± 1.84］ times, P<0.05), and EL (［712.35 ± 36.77］ vs ［502.35 ± 46.72］ s, P<0.05). In comparison with the PE model controls, the rats of the QSP and dapoxetine groups exhibited remarkably increased content of 5-HT (P<0.05) and prolonged EL (P<0.05).</p><p><b>CONCLUSIONS</b>Qiaoshao Prescription can prolong EL in PE rats, which might be associated with the increased content of 5-HT in the hypothalamus. Further studies, however, are needed on its underlying mechanisms.</p>

Preparation of tadalafil-dapoxetine coamorphous complex with evaluation of dissolution and physical stability / 药学学报

Tadalafil (TD), a phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction, has a low oral bioavailability due to its extremely poorly aqueous solubility. The aim of this study was to enhance its solubility and dissolution by coamorphization with dapoxetine (DP), a selective serotonin reuptake inhibitor to manage premature ejaculation. Coamorphous TD-DP (molar ratio, 1:1) was prepared by solvent-evaporation method and characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FTIR). The supersaturated dissolution of TD from coamorphous TD-DP was investigated in various aqueous media and compared to that of crystalline TD. In addition, physical stability of coamorphous system was also evaluated under the conditions of 40℃/75% relative humidity (RH) and 25℃/60% RH for 90 days. DSC thermogram and PXRD pattern indicated the formation of the coamorphous TD-DP. In comparison to original TD crystal, the dissolution of TD from coamorphous system were significantly enhanced in various media (water, 0.01 mol·L-1 HCl and pH 4.5 phosphate buffer). In addition, no crystallization phenomenon of the prepared coamorphous system was observed until 90 days' storage under 25℃/60% RH. However, when temperature and humidity were increased to 40℃/75% RH, the coamorphous TD-DP was recrystallized easily.

The effect of 8-OH-DPAT and dapoxetine on gene expression in the brain of male rats during ejaculation

The 5-HTreceptor agonist 8-hydroxy-2-[di--propylamino] tetralin (8-OH-DPAT) promotes ejaculation of male rats, whereas dapoxetine delays this process. However, the gene expression profile of the brain at ejaculation following administrationof these two compounds has not been fully elucidated. In the present study, a transcriptomic BodyMap was generated by conducting mRNA-Seq on brain samples of male Sprague-Dawley rats. The study included four groups: pre-copulatory control (CK) group, ejaculation (EJ) group, 0.5 mg/kg 8-OH-DPAT-ejaculation group (DPAT), and 60 mg/kg dapoxetine-ejaculation (DAP) group. The resulting analysis generated an average of approximately 47 million sequence reads. Significant differences in the gene expression profiles of the aforementioned groups were observed in the EJ (257 genes), DPAT (349 genes) and the DAP (207 genes) compared with the control rats. The results indicate that the expression ofandwas significantly different after treatment with 8-OH-DPAT, whereas the expression ofwas significantly different after treatment with dapoxetine. Other genes, such as,and, exhibited significant differences in expression after the two treatments and are related to bladder cancer, renal cell carcinoma and sexual addiction. The present study reveals the basic pattern of gene expression that was activated at ejaculation in the presence of 8-OH-DPAT or dapoxetine, providing preliminary gene expression information during rat ejaculation.

Diagnosis and Treatment of Premature Ejaculation by Urologists in South Korea

PURPOSE: This study discusses the treatment of premature ejaculation (PE) using various approaches with the goal of evaluating the methods of diagnosis and treatment of PE in clinical practice in 2014 in South Korea. MATERIALS AND METHODS: We surveyed 200 urologists and andrologists who treated patients with PE from July 1, 2014 to July 29, 2014 using an online questionnaire. The questionnaire was composed of 4 parts: disease, comorbidities, diagnosis, and treatment. Using the answers to this survey, current trends in the diagnosis and treatment of PE were investigated using weighted averages. RESULTS: The median number per month of patients who were diagnosed with PE was 14 patients (interquartile range, 7~24). The time to ejaculation necessary for a diagnosis of PE was considered to be <1 minute by 12% of respondents, <2 minutes by 27%, <3 minutes by 28%, <5 minutes by 13%, and 20% stated that diagnosis was based on a patient's subjective complaint. The treatment methods preferred by PE patients were reported to be pharmacological treatment (87%), surgical treatment (9.5%), and behavioral management (3.5%). The treatment methods used by respondents were pharmacological treatment (77%), surgical treatment (15%), and behavioral management (14%). The most commonly used pharmacological treatment was the oral administration of dapoxetine (97%). CONCLUSIONS: In 2014 in South Korea, various methods were used to diagnose and treat PE. The most commonly used treatment for PE was the oral administration of dapoxetine. It was also found that surgical treatment was applied in some cases.

Efficacy and safety of Yimusake Tablets plus dapoxetine hydrochloride in the treatment of premature ejaculation / 中华男科学杂志

<p><b>Objective</b>To evaluate the effect and safety of Yimusake Tablets combined with dapoxetine hydrochloride and either of them used alone in the treatment of premature ejaculation (PE).</p><p><b>METHODS</b>We randomly assigned 180 PE patients to oral medication of Yimusake Tablets at 1.5 g per night (group A), dapoxetine hydrochloride at 30 mg at 1－3 hours before anticipated sexual activity (group B), the Yimusake Tablets plus dapoxetine hydrochloride simultaneously (group C), all for 8 weeks. After 4 and 8 weeks of medication, we recorded and compared the changes in the intravaginal ejaculation latency time (IELT), measures of the PE profile (PEP), and adverse events among the three groups of patients.</p><p><b>RESULTS</b>The treatment was accomplished and complete data obtained from 154 of the patients, 56 in group A, 52 in group B, and 46 in group C. After 4 and 8 weeks of medication, the mean IELT was dramatically prolonged in all the three groups as compared with the baseline (P<0.01), most significantly at 8 weeks in group C (［2.08±0.68］ min), followed by B (［1.76±0.52］ min) and A (［1.47±0.44］ min), with statistically significant differences among the three groups (P<0.01). The PEP measures were remarkably improved in group A at 8 weeks (P<0.05), and both in B and C at 4 and 8 weeks (P<0.05), most significantly at 8 weeks in group C (P<0.05), in which the patients scored 1.96±0.77 in perception of control over ejaculation, 2.62±0.98 in satisfaction with sexual intercourse, 3.04±0.62 in PE-related distress, and 3.57±0.80 in PE-induced difficult relationship with their partners, all markedly improved as compared with groups A and B (P<0.05). Adverse reactions were observed in 2 cases (3.6%) in group A, 6 cases (9.6%) in B, and 5 cases (10.9%) in C. No severe adverse events occurred in any of the patients during the study.</p><p><b>CONCLUSIONS</b>Combined medication of Yimusake Tablets and dapoxetine hydrochloride, with its advantages of effectiveness and safety, deserves to be recommended for the treatment of PE.</p>

Efficacy and safety of Qiaoshao Formula () on patients with lifelong premature ejaculation of Gan (Liver) depression and Shen (Kidney) deficiency syndrome: A randomized controlled trial / 中国结合医学杂志

<p><b>OBJECTIVE</b>To observe the effificacy and safety of Qiaoshao Formula (, QSF) on patients with lifelong premature ejaculation (LPE) of Gan (Liver) depression and Shen (Kidney) defificiency syndrome.</p><p><b>METHODS</b>A total of 60 LPE patients were randomly divided into treatment (QSF) and control (dapoxetine) groups. The treatment group received QSF twice a day and the control group received dapoxetine 1 to 2 h prior to planned sexual intercourse for 4 weeks. The outcomes included intra-vaginal ejaculation latency time (IELT), premature ejaculation diagnostic tool (PEDT), clinical global impression of change (CGIC), scores of Chinese medicine symptoms (CMSS), sex life satisfaction (SLS) and adverse events (AEs).</p><p><b>RESULTS</b>In the treated group, the median IELT was 3 min vs. 1.5 min before and after treatment (P<0.05). PEDT in the treated group was reduced to 11.76±1.68 from 15.83±2.30 after treatment (P<0.05). Besides, patient's SLS was improved from 1.30±0.05 to 6.30±0.04 (P<0.05), and spouse's SLS was increased from 1.30±0.to 6.10±0.06 (P<0.05); CMSS was decrease from 14.86±3.02 to 9.62±2.87 (P<0.05). In addition, no significant AE was observed in both groups.</p><p><b>CONCLUSION</b>QSF may be effective and safe on LPE patients with Gan depression and Shen defificiency syndrome.</p>

Pharmacokinetics interaction of dapoxetine with different doses of green tea extract in male healthy volunteers using midazolam as CYP3A4 enzyme probe.

Objective: This study aimed to investigate the pharmacokinetics interaction of dapoxetine with different doses of green tea extract in healthy volunteers using midazolam (CYP3A4 probe).Method and materials: Twelve healthy males were included in a random three-way crossover study. Each volunteer received dapoxetine 60 mg and midazolam 7.5 mg concurrently after drinking 250 ml of water, 250 ml of fresh extract of 2 gram of green tea or 250 ml of fresh extract of 4 gram of green tea with one week washout period. Plasma samples were analyzed for dapoxetine and midazolam using HPLC.Results: The co-administration of dapoxetine with 4 gm green tea extract significantly increased dapoxetine AUC∞ (from 3218.74 μg.hr/L to 4207.65 μg.hr/L, P< 0.05) and dapoxetine Cmax (from 433.1 μg/L to 601.1 μg/L,P< 0.05) with a decrease in CL and t1/2 only after administration of 4 gm green tea extract. There was a significant increase in midazolam AUC∞ (from 41.123 μg.hr/L to 58.55 μg.hr/L, P< 0.05) and midazolam Cmax (from 36.07 μg/L to 53.53 μg/L,P< 0.05) with a decrease in CL and t1/2only after administration of 4 gm green tea extract. However, the intake of 2 gram green tea extract showed no significant change in either dapoxetine or midazolam AUC or Cmax (p≥0.05). Conclusion: High dose of green tea intake increases dapoxetine bioavailability by the inhibiting CYP3A4 enzyme as indicated by the change in midazolam pharmacokinetic. Taking high dose of green tea with dapoxetine should be avoided. However, normal dose of green tea is safe for dapoxetine co-administration.

New Approach and Treatment of Premature Ejaculation / 대한남성과학회지

Premature ejaculation (PE) is the most common form of male sexual dysfunction. Until very recently, scientific investigation of PE has been hampered by a lack of standardized definitions and objective, validated questionnaires. In recent years both the definition and the management of PE have changed from the traditional authority-based to a more evidence-based approach. In 2007, the International Society for Sexual Medicine (ISSM) established an ad hoc committee consisting of 21 internationally recognized experts, to establish a new definition of PE including intravaginal ejaculation latency time (IELT). As diagnostic tools, a brief self-administered questionnaire, the premature ejaculation diagnostic tool (PEDT), was developed and validated. Current accepted treatment options of PE include behavior therapy, topical desensitizing agents, selective serotonin reuptake inhibitors (SSRIs), clomipramine, tramadol, PDE-5 inhibitors. However, it should be noted that all of the medications currently used for treatment of PE were originally developed to treat other medical disorders such as depression or erectile dysfunction. Dapoxetine, a new SSRI, has a unique pharmacokinetic profile, with a short time to maximum serum concentration, and rapid elimination. By 24 hours, plasma concentrations are less than 5% of peak values. These attributes make Dapoxetine suitable for on-demand therapy of PE. This paper reviewed new diagnostic tools and treatment options for PE.

Dapoxetine in treatment of premature ejaculation:A systematic review / 北京大学学报(医学版)

Objective:To assesss the effectiveness of dapoxetine in the treatment of premature ejaculation.Methods:Both English and Chinese studies involving men with prematrue ejaculation who were treated with dapoxetine from the Cochrane Library,MEDLINE,EMBASE and CNKI,CBM,VIP between 1979 and 2009.were included in the randomized controlled trials(RCTs) and the data processed by RevMan.Results:Five RCTs involving 4433 patients were included in the Meta analysis,of which 3 were of grade A and 2 were of grade B according to the quality evaluation of methodology.Intravaginal ejaculatory latency time(IELT),patient-reported global impression of change(PGI),satisfaction with sexual intercourse(SWSI),perceived control over ejaculation(PCOE),personal distress related to ejaculation(PDRE) were used for assessment.Meta analysis based on included studies of patients having been treated with dapoxetine for 9-24 weeks showed that:(1) the difference of the patients' IELT between treatment group and control group was statistically significan [P