金不换与雪上一枝蒿不同比例配伍的减毒增效作用

目的:探讨金不换水提物(WVBF)配伍雪上一枝蒿总生物碱(CFA)的解毒作用及对药效的影响。方法:建立斑马鱼心血管模型,评价心血管毒性;上下法测小鼠不同比例CFA-WVBF的半数致死量(LD50);以热板法和扭体法比较CFAWVBF 1∶2和1∶5配伍组对小鼠中枢和外周镇痛作用的影响。结果:在心血管毒性评价实验中,单药CFA除了200 mg·L~(-1)组外,别的质量浓度组对斑马鱼心率都没有影响,不诱发斑马鱼心律不齐,CFA 66.6,200 mg·L~(-1)可诱发斑马鱼毒性表型(P0.05)。在不同配伍组心血管毒性评价实验中,除了CFA-WVBF 1∶5配伍组,别的实验组都诱发明显的心血管毒性表型(P0.05)。CFA-WVBF 4个不同比例(5∶1,2∶1,1∶2,1∶5)的LD50依次增加,都高于单独CFA的LD50(P0.05)。在中枢镇痛实验中,CFA-WVBF按1∶2和1∶5配伍组均可提高小鼠的舔足痛阈值,其中按CFA-WVBF 1∶2混合给药组(20 mg·kg~(-1))的镇痛率比单独给予CFA(20 mg·kg~(-1))和阿司匹林组(200 mg·kg~(-1))的镇痛率要高(P0.05),而在给药90 min时1∶2配伍组的镇痛率与CFA组接近,都高于阿司匹林组(P0.05),说明CFA-WVBF 1∶2配伍组有减毒存效作用,按1∶5给药的镇痛率比单独给CFA明显增高,在30,60,90 min也逐渐增加(P0.05),说明CFA-WVBF 1∶5配伍组有减毒增效和延效作用。在外周镇痛方面,各配伍给药组均能有效抑制冰乙酸所致小鼠扭体反应,其中CFA-WVBF 1∶2配伍组的扭体抑制率低于单独给予CFA组(P0.05);CFA-WVBF 1∶5配伍组的扭体抑制率略高于CFA组(P0.05)。表明在外周镇痛方面,CFA-WVBF 1∶2配伍组有减毒减效作用,CFA-WVBF 1∶5配伍组有较弱的减毒增效作用。结论:CFA-WVBF配伍可以减轻CFA诱发的斑马鱼心血管毒性和小鼠急性毒性,CFA-WVBF 1∶2,1∶5配伍组可以提高中枢镇痛效应,CFA-WVBF 1∶5配伍组还可以增加外周镇痛作用,因此CFA-WVBF 1∶5配伍组减毒增效作用最好。

Decreasing Toxicity and Increasing Efficacy Through Different Compatibilities of Veratrilla baillonii and Aconitum brachypodum

Objective:To investigate the detoxication effect and efficacy of water extract from Veratrilla baillonii(WVBF) with compatibility of total alkaloids from Aconitum brachypodum(CFA). Method:The cardiovascular toxicity was evaluated by using zebra fish cardiovascular model; up-and-down method was used to calculate the median lethal dose (LD₅₀) of CFA and WVBF of different compatibility proportions; then acetic acid induced writhing response and hot plate method were used to observe and compare the central and peripheral analgesic effects of CFA-WVBF 1:2 group and CFA-WVBF 1:5 group. Result:In cardiovascular toxicity evaluation experiment, if CFA was used alone, it had no effect on heart rate and did not induce arrhythmia of zebra fish except 200 mg·L^-1 group; 66.6, 200 mg·L^-1 groups induced toxicity phenotype (P<0.05). In different compatibilities experiment, all the experimental groups induced obvious cardiovascular toxicity except CFA-WVBF 1:5 group (P<0.05). The LD₅₀ of CFA-WVBF compatibilities (5:1, 2:1, 1:2, 1:5) was increasing in turn, and all of them were higher than the LD₅₀ of CFA alone (P<0.05). In the central analgesia experiment,CFA-WVBF 1:2 group and CFA-WVBF 1:5 group can enhance foot pain threshold, and the analgesia effects of CFA-WVBF 1:2 group (CFA-WVBF, 20 mg·kg^-1) were better than those of CFA (20 mg·kg^-1) alone group and aspirin group (200 mg·kg^-1), but the analgesia percentage in CFA-WVBF 1:2 group was similar to that in CFA group and higher than that in aspirin group (P<0.05) after 90 minutes, indicating that CFA-WVBF 1:2 group could reduce toxicity and keep efficacy. The analgesia percentage in CFA-WVBF 1:5 group was higher than that in the CFA alone (20 mg·kg^-1) group, and was gradually increased after 30, 60, 90 minutes, indicating that CFA-WVBF 1:5 group could reduce toxicity, enhance efficacy and extend efficacy (P<0.05). In peripheral analgesia experiment, different proportions of CFA and WVBF groups could inhibit acetic acid induced writhing response. The writhing inhibition rate in CFA-WVBF 1:2 group was lower than that of CFA alone group (P<0.05); and the writhing inhibition rate in CFA-WVBF 1:5 group was slightly higher than that of CFA alone group (P<0.05), indicating that the CFA-WVBF 1:2 group could reduce toxicity and decrease efficacy but the CFA-WVBF 1:5 group could reduce toxicity and enhance analgesic efficacy slightly (P<0.05). Conclusion:Different compatibilities of CFA and WVBF can decrease CFA-induced cardiovascular toxicity in zebra fish and acute toxicity in mice; CFA-WVBF 1:2 group and CFA-WVBF 1:5 group can increase central analgesic efficacy, and CFA-WVBF 1:5 group also can enhance peripheral analgesic efficacy. Therefore, CFA-WVBF 1:5 group shows the best effect in decreasing toxicity and increasing efficacy.