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| A preliminary vaginal pharmacokinetics study was carried out to monitor drug substance in blood plasma. LC–MS/MS assay using positive ion electro-spray ionization (ESI) in multiple reaction monitoring (MRM) mode was found appropriate to develop selective, sensitive and reproducible analysis of compound 33, N-9 and internal standard (IS) in rabbit plasma. The pharmacokinetic analysis was processed non-compartmental model using Phoenix Win-Nonlin (version 6.3, Pharsight, MountainView, CA). The linear trapezoidal method with linear interpolation was used to calculate pharmacokinetic parameters. The mean peak plasma concentration ( Cmax) 4.87 ± 0.37 ng/mL of N-9 was achieved after vaginal dosing at 1.0 h. The terminal half-life of plasma concentration of N-9 was 1.45 ± 0.07 h. The systemic absorption of compound33 was below the limit of quantitation (Fig. 5). After vaginal administration, the presence of compound 33was very less in systemic circulation might be suggestive of minimal systemic adverse effects or minimal toxic effect. In summary, together with pharmacological findings, this study could provide useful clues and guidance,such as dosage regimen and application strategy of compound 33 as a lead candidate to be used as vaginal microbicide. In a systemic effort to identify a non-detergent prophylactic vaginal microbicide potentially capable of preventing sexual transmission of HIV/STDs as well as providing fertility control, a series of dithiocarbamate–thiourea hybrids as alkyl 4-(alkyl/aryl carbamothioyl)piperazine-1-carbodithioate (14–38 ) were synthesized and evaluated for multiple activities (anti- Trichomonas, spermicidal and RT inhibition). The intended dual action was achieved and several compounds exhibited all the three activities with remarkable safety against cervico-vaginal epithelial cells and vaginal flora. Among the safest structures, most promising compound33 exhibited considerable RT inhibition, anti- Trichomonas and spermicidal activities, which could be attributed to its utility as vaginal microbicide. Proposed docking analysis of 33 is notable and can be utilized as a guideline for designing of promising vaginal microbicide with RT inhibition potential. Compound 33 was also found pharmacokinetically safe in comparison to N-9 due to least vaginal absorption to systemic circulation. Further lead optimization is underway to develop novel vaginal microbicide possessing RT inhibitory activity in order to empower women to deal independently with their reproductive health and fertility. |
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武汉一心一译 
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周亚楠0623: 金币+60, 翻译EPI+1, ★★★很有帮助 2015-05-16 13:24:45
周亚楠0623: 金币+60, 翻译EPI+1, ★★★很有帮助 2015-05-16 13:24:45
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