New findings in pharmacological effects induced by antihistamines: from PET studies to knock‐out mice
New findings in pharmacological effects induced by antihistamines: from PET studies to knock‐out mice
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抗组胺药物药理作用的新发现：从 PET 研究到基因敲除小鼠
DOI：
10.1046/j.1365-2222.1999.00008.x-i1
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发表时间：
1999
影响因子：
6.1
通讯作者：
Takehiko Watanabe
中科院分区：
文献类型：
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作者：
Kazuhiko Yanai;N. Okamura;Masaaki Tagawa;M. Itoh;Takehiko Watanabe
抗组胺药是治疗过敏性疾病的有效药物。抗组胺药的安全性问题是至关重要的，因为它们在当前的医疗实践中广泛使用。为了更好地了解抗组胺药对中枢神经系统（CNS）的药理作用，我们采用了正电子发射断层扫描（PET）和基因靶向两种新方法来研究组胺H1受体。在口服或静脉注射抗组胺药后，用[11C]‐多塞平（一种强效H1拮抗剂）检测年轻男性志愿者组胺H1受体占用情况。在其他研究中，在服用抗组胺药之前和之后，也用速视镜测量了认知表现。将缺乏H1受体的突变小鼠用于行为和神经化学实验，以重新评估H1受体的作用。抗组胺药引起的H1受体在人额叶皮层的占据与临床试验中报道的嗜睡发生率显著相关，并且占据与认知能力受损成正比。对H1受体敲除小鼠的行为研究证实了H1受体在觉醒、睡眠-觉醒周期、运动、伤害感觉和攻击行为中的作用。通过PET和基因靶向重新评估H1拮抗剂诱导的药理作用。虽然在小鼠中没有观察到通过破坏H1受体基因而产生的任何严重影响，但在人类中，按照推荐剂量服用第一代抗组胺药后，认知能力受损。
Antihistamines are efficacious drugs to be used for the symptomatic relief of allergic diseases. The safety issue of antihistamines is of central importance because of their widespread use in current medical practice. To better understand the pharmacological effects of antihistamines on the central nervous system (CNS), we used two kinds of new methods, positron emission tomography (PET) and gene targeting regarding on histamine H1 receptors. The histamine H1 receptor occupancy was examined in young male volunteers with[11C]‐doxepin (a potent H1 antagonist) after the oral or intravenous administration of antihistamines. In other studies, the cognitive performance was also measured tachistoscopically before and after taking antihistamines. The mutant mice lacking H1 receptors were used in the behavioural and neurochemical experiments to re‐evaluate the role of H1 receptors. The H1‐receptor occupancy in the human frontal cortex caused by antihistamines is significantly correlated with the reported values of incidence of sleepiness in clinical trials, and the occupancy is well proportional to the impaired cognitive performance. The behavioural studies of the H1‐receptor knock‐out mice confirmed the role of H1 receptors in arousal, the sleep–wake cycle, locomotion, nociception and aggressive behaviour. The pharmacological effects induced by H1 antagonism were re‐evaluated by the PET and gene‐targetting. Although any serious effects could not be observed in mice by the destruction of the H1‐receptor gene, the cognitive performance was impaired in humans after taking first generation antihistamines in recommended doses.
DOI：
--
发表时间：
1996-07
期刊：
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
影响因子：
--
作者：
N. Volkow;J. Fowler;S. Gatley;J. Logan;G. Wang;Yu-Shin Ding;S. Dewey
通讯作者：
N. Volkow;J. Fowler;S. Gatley;J. Logan;G. Wang;Yu-Shin Ding;S. Dewey