| Objective: The Phase I trial was to investigate the tolerability and adverse effect of tetrodotoxin (TTX), determine the single maximum and accumulation tolerated dose in healthy volunteers and conform the available and safe dose range for the subsequent Phase II trial. Methods: Forty-nine healthy volunteers were involved in the single dose tolerance study by seven groups, by intramuscular injection of 10μg, 20μg, 30μg, 40μg, 45μg, 50μg, 55μg respectively. In each group, six persons were administered TTX and one was administered placebo randomly. At the end of the trial the volunteers who had been administered placebo were placed in one group. Seven healthy volunteers were in -volved in the accumulation tolerance study, by intramuscular injection of 40μg (tid) for ten days. Results: The seven single-dose groups could tolerate TTX, the amount of the adverse effect in the below 30ug dose was lower than that in the placebo group.and two subjects of the multiple dosing tolerance trial fell off. The most common adverse effects were insensible feeling of the tip of the tongue, oral lip and digit, while other effects induced were dizziness, drowsiness, myasthenia of limbs, nausea, anorexia. Most of adverse effects were light and tolerated, but one subject (female, 50μg group) vomited one hour after administration of TTX and abnormal PfV1 of electrocardiogram (ECG) occurred in another one (male, 50μg group). The vital sign and laboratory examination (blood and urine routine, hepatic function, renal function) did not change remarkably before and after the TTX was used in most subjects. The hepatic and myocardial function of three subjects in the multiple dosing tolerance trial was abnormal, but the subjects had no subjective symptoms. Ten days follow-up the values were normal. Conclusion: TTX was tolerated in Chinese healthy volunteers in the single dose trial, and the dosage below 40ug per time was safe, but individual difference occurred in the multiple-doses trial (Accumulated dose is 1200ug) because two cases left the trial ahead of schedule. 15μg~30μg, bid-tid was a recommended dosage for phase II clinical trial. The abnormal hepatic and myocardial function which couldn' t be determined relation to TTX should catch the attention of the clinical application of TTX.Objective: The study was to explore the effect of Guiyuan tablets on the conditioned place preference (CPP) induced by morphine and to observe whether Guiyuan tablets itself has psychological dependence. Then the effect of chronic morphine on Long-term potentiation (LTP) investigated at Dentate Gyrus (DG) granular cell synapses of rats in vivo and the interference of Guiyuan tablets with the effect. Method: Morphine was injected (5 mg-kg"1, one time/day ,sc) to rats for 7 days ,causing strong place preference in rats. The rats were pretreated 15 min before each injection of morphine during the 7 days training phase with Guiyuan tablets (12.5, 25 , 37.5 and 50mg.kg-1,sc)and treated with Guiyuan tablets(50mg.kg-1, one time/day ,ig)for 12 days after formation of CPP induced by morphine. The present study also aimed to observe the effect of Guiyuan tablets on acquisition and maintenance of CPP induced by morphine and to examine the changes of LTP. Results: (l)5mg-kg"] morphine (sc) induced a significant place preference in rats; (2) The correspondence amplification of PS at each point of time and average PS amplitude post- high frequency stimulation (HFS) at DG of rats in vivo from the morphine group are stronger than those of the normal group; (3)But two different doses of Guiyuan tablets did not induce CPP and affect DG-LTP of hippocampus in rats; (4) 25, 37.5 and 50mg-kg"' can block development of morphine -induced CPP in a dose- dependent manner and Guiyuan tablets (25, 37.5 mg-kg"1) could antagonize the enhancement effect of morphine on DG-LTP;(5)Guiyuan tablets (50mg-kg"' ) can enhance extinction of morphine-induced CPP, while it had no effect on DG-LTP. Conclusion: Morphine can induce a significant place preference in rats; the enhancement of LTP after the formation of morphine-induced CPP, but when CPP disappeared, the enhancement of PS was not observed, which suggests that hippocampal LTP was related to drug addiction to some degree.Guiyuan tablets which didn't induce CPP not only antagonize acquisition of morphine-induced CPP , but also enhance extinction of CPP. The enhancement facilitation of LTP which was induced in...
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