Mechanism of action of aripiprazole predicts clinical efficacy and a favourable side-effect profile
Mechanism of action of aripiprazole predicts clinical efficacy and a favourable side-effect profile
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DOI：
10.1177/026988110401800308
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发表时间：
2004-09-01
影响因子：
4.1
通讯作者：
Nabeshima, T
中科院分区：
文献类型：
--
作者：
Hirose, T;Uwahodo, Y;Nabeshima, T
阿立哌唑的抗精神病疗效通常与典型或非典型抗精神病药的锥体外系症状、心血管效应、镇静或血清蛋白升高无关。本研究的目的是阐明阿立哌唑的作用机制，这是其有利临床特征的基础。阿立哌唑的临床前疗效和副作用的特点进行了评估，使用几种药物行为测试系统在小鼠和大鼠，在体内和体外，并与其他传统和非典型抗精神病药物。每一种抗精神病药物都能诱导僵住症，并抑制阿扑吗啡诱导的刻板症。阿立哌唑的僵住症易感性比为6.5，奥氮平和利培酮均为4.7。阿立哌唑、奥氮平和利培酮的上睑下垂责任比分别为14、7.2和3.3。阿立哌唑轻微增加利血平化小鼠前脑中的DOPA蓄积，在最高剂量下减少5-HTP蓄积，并表现出对5-甲氧基-N，N-二甲基-色胺诱导的头部抽搐的较弱抑制。阿立哌唑未抑制毒扁豆碱或去甲肾上腺素诱导的大鼠致死性。总之，与非典型抗精神病药相比，阿立哌唑显示出良好的临床前疗效和副作用特征。这种特性可能是由于其对D-2和5-HT 1A受体的高亲和力部分激动剂活性及其对5-HT 2A受体的拮抗作用。
The antipsychotic efficacy of aripiprazole is not generally associated with extrapyramidal symptoms, cardiovascular effects, sedation or elevations in serum protactin that characterize typical or atypical antipsychotics. The aim of this study was to clarify the mechanism of action of aripiprazole that underlies its favourable clinical profiles. The preclinical efficacy and side-effect profiles of aripiprazole were evaluated using several pharmaco-behavioural test systems in mice and rats, both in vivo and ex vivo, and compared with those of other conventional and atypical antipsychotics. Each of the antipsychotics induced catalepsy and inhibited apomorphine-induced stereotypy. The catalepsy liability ratios for these drugs were 6.5 for aripiprazole, 4.7 for both olanzapine and risperidone. The ptosis Liability ratios for aripiprazote, olanzapine and risperidone were 14, 7.2 and 3.3, respectively. Aripiprazole slightly increased DOPA accumulation in the forebrain of reserpinised mice, reduced 5-HTP accumulation at the highest dose and exhibited a weaker inhibition of 5-methoxy-N,N-dimethyl-tryptamine-induced head twitches. Aripiprazole did not inhibit physostigmine- or norepinephrine-induced lethality in rats. In conclusion, aripiprazole shows a favourable preclinical efficacy and side-effect profile compared to atypical antipsychotics. This profile may result from its high affinity partial agonist activity at D-2 and 5-HT1A receptors and its antagonism of 5-HT2A receptors.