奥沙西泮对衰老的BN/BiRij大鼠抗惊厥作用的药效学

Pharmacodynamics of the anticonvulsant effect of oxazepam in aging BN/BiRij rats.

作者信息

Stijnen A M, Postel-Westra I, Langemeijer M W, Hoogerkamp A, Voskuyl R A, van Bezooijen C F, Danhof M

机构信息

Center for Bio-Pharmaceutical Sciences, University of Leiden, The Netherlands.

出版信息

Br J Pharmacol. 1992 Sep;107(1):165-70. doi: 10.1111/j.1476-5381.1992.tb14481.x.

DOI:10.1111/j.1476-5381.1992.tb14481.x

PMID:1330159

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1907588/

Abstract

The purpose of this investigation was to examine the influence of increasing age on the pharmacokinetics and the time course of the anticonvulsant response of oxazepam in BN/BiRij rats as an animal model of aging. 2. Oxazepam was administered intravenously in a dose of 12 mg kg-1 body weight and the anticonvulsant effect intensity was measured as elevation above baseline of a threshold for induction of localized seizure activity (TLS). Direct cortical stimulation with ramp shaped electrical pulse trains of increasing intensity was used to determine this threshold. 3. The pharmacological effect vs. time profile showed in young rats an anticonvulsant component followed by proconvulsant component which is suggestive for the occurrence of acute tolerance and/or withdrawal syndrome. With increasing age the proconvulsant component disappeared, resulting in a monophasic effect profile (anticonvulsant effect only) at the age of 35 months with significantly higher anticonvulsant effect intensity immediately following drug administration. No age-related changes in the pharmacokinetic parameters of oxazepam were observed. 4. In five animals of each age group, benzodiazepine receptor binding characteristics were determined in vitro with [3H]-flunitrazepam as a ligand. Both receptor density and affinity did not show age-related changes. Available literature data on post-receptor events do not indicate conclusive age-related changes. 5. It is concluded, that the observed change in the pharmacodynamics of anticonvulsant effect of oxazepam can be explained by the disappearance of the tolerance/withdrawal phenomenon. This is compatible with a decreased efficiency of homeostatic control mechanisms in the elderly.

摘要

本研究的目的是在作为衰老动物模型的BN/BiRij大鼠中，研究年龄增长对奥沙西泮药代动力学及抗惊厥反应时程的影响。2. 以12 mg kg⁻¹体重的剂量静脉注射奥沙西泮，抗惊厥效应强度通过局部癫痫发作活动阈值（TLS）高于基线的升高幅度来测量。使用强度递增的斜坡形电脉冲串直接刺激皮层来确定该阈值。3. 药理效应与时间曲线显示，年轻大鼠中存在抗惊厥成分，随后是促惊厥成分，这提示急性耐受性和/或戒断综合征的发生。随着年龄增长，促惊厥成分消失，在35月龄时呈现单相效应曲线（仅抗惊厥效应），给药后立即出现显著更高的抗惊厥效应强度。未观察到奥沙西泮药代动力学参数的年龄相关变化。4. 在每个年龄组的5只动物中，以[³H]氟硝西泮为配体在体外测定苯二氮䓬受体结合特性。受体密度和亲和力均未显示年龄相关变化。关于受体后事件的现有文献数据未表明明确的年龄相关变化。5. 得出结论，奥沙西泮抗惊厥效应药效动力学中观察到的变化可通过耐受性/戒断现象的消失来解释。这与老年人稳态控制机制效率降低相一致。