A series of optically active 2-hydroxytetrahydrothienopyridine derivatives were designed and synthesized as prodrugs of clopidogrel thiolactone in order to overcome clopidogrel resistance. The final compounds were evaluated for their inhibitory effect on ADP-induced platelet aggregation in rats. Compound 9a was selected for further in vitro and in vivo metabolism studies, since its potency was comparable to that of prasugrel and was much higher than that of clopidogrel. Preliminary pharmacokinetic study results showed that the bioavailability of clopidogrel thiolactone generated from 9a was 6-fold higher than that generated from clopidogrel, implying a much lower clinically effective dose for 9a in comparison with clopidogrel. In summary, 9a (vicagrel) holds great promise as a more potent and a safer antiplatelet agent that might have the following advantages over clopidogrel: (1) no drug resistance for CYP2C19 poor metabolizers; (2) lower dose-related toxicity due to a much lower effective dose; (3) faster onset of action.

Prasugrel has a more rapid, more potent antiplatelet effect with less interindividual response variability when compared to clopidogrel. Those therapeutic advantages are attributed to features of its chemical structure that favor the metabolic conversion of prasugrel to its active metabolite. However, the increased risk of bleeding has been associated with a greater antiplatelet effect and dosing profile; this is especially the case in those patients who are at a higher risk of bleeding complications. It is therefore important for an optimal dosing strategy of prasugrel to be identified to provide a formulation that has the best balance for efficacy and safety.

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To determine the impact of two varying doses of dexmedetomidine (DEX) on the onset and duration of neuromuscular blockade of rocuronium (ROC) under the condition of sevoflurane anesthesia. Eighty-one patients, American Society of Anesthesiologists Class I–II, were stochastically allocated to control group (group C) and two DEX groups (group D1 and group D2). In group D1 and group D2, DEX (0.5 and 1.0 µg/kg, respectively) was administrated 10 min before induction of general anesthesia. In group C, equivalent saline was infused by the same way. We monitored heart rate (HR), blood pressure, and train-of-four (TOF) values of all subjects in the period of anesthesia. We recorded times to reach TOF value 0 (T0, from injection of ROC to disappearance of all four twitches) as the onset time and TOF value 25% (T25, ratio of fourth twitch to first twitch,) as clinical duration of neuromuscular blockade. A total of 81 patients were randomized, 75 of whom accepted treatment, including group D1 ( n = 25), D2 ( n = 25), and C ( n = 25). T0 time of three groups was found to be similar. The duration of action for ROC in group D2 was 62.76 ± 6.33 min, which was much longer than that in group D1 and group C, which were 42.64 ± 3.92 and 42.56 ± 4.04 min ( p < 0.05), respectively. At T2 (after DEX administration) and T4 time point (10 min after trachea intubation), compared with group C, the changes of heart rate (HR) and blood pressure in DEX groups (group D1 and group D2) show greatly differences. Otherwise, there were no obvious differences among different groups at the other monitoring point-in-time. DEX infusion in general anesthesia has no obvious effect on the onset of ROC, but it is capable of prolonging its clinical effect time, which can provide reference for rational application of DEX and ROC in general anesthesia.