Dürmüller Niklaus, Guillaume Philippe, Lacroix Pierre, Porsolt Roger D, Moser Paul
Porsolt and Partners Pharmacology, 9bis rue Henri Martin, 92100 Boulogne-Billancourt, France.
J Pharmacol Toxicol Methods. 2007 Sep-Oct;56(2):234-8. doi: 10.1016/j.vascn.2007.03.006. Epub 2007 May 24.
The dog is frequently used for cardiovascular safety pharmacology and for toxicology studies, but is not often used for central nervous system (CNS) safety pharmacology purposes. We have therefore examined the electroencephalogram (EEG) in conscious dogs by means of radio-telemetry methods using the proconvulsant agent pentylenetetrazole (PTZ) as reference substance. Assessment of proconvulsant risk is an important aspect of CNS safety evaluation and the EEG is a sensitive technique for identifying pathologic brain activity, most importantly paroxysmal activity.
Dogs were implanted with epidural electrodes wired to subcutaneously placed radiotransmitters. Following baseline recording, the test substance was administered and the EEG and electromyogram (EMG) activities were recorded from dogs placed in slings. The EEG was assessed visually for abnormal activity and dogs were also continuously observed for the appearance of overt convulsive activity. The PTZ infusion was stopped and diazepam was administered as soon as clear and sustained EEG effects and/or behavioural symptoms occurred.
Slow i.v. infusion of PTZ (1.5 mg/kg/min) induced clear paroxysmal effects on the EEG trace in the form of spike and wave trains of 4-5 Hz. Paroxysmal activity associated with clonic convulsions occurred between 17 and 36 min after the start of infusion (a mean of 24 min) but in most cases paroxysmal activity was observed approximately 60 s prior to any overt convulsive activity.
These data show the usefulness of the telemetered dog EEG in safety pharmacology. The dog EEG is appropriate in situations where results from cardiovascular and CNS safety tests in the same species are required, or where the use of other species is contraindicated because of metabolic or pharmacokinetic particularities.
犬常用于心血管安全药理学和毒理学研究，但较少用于中枢神经系统（CNS）安全药理学研究。因此，我们通过无线电遥测方法，以惊厥剂戊四氮（PTZ）作为参考物质，对清醒犬的脑电图（EEG）进行了研究。惊厥风险评估是CNS安全评估的一个重要方面，而EEG是识别病理性脑活动（最重要的是阵发性活动）的一种敏感技术。
给犬植入硬膜外电极，并连接到皮下放置的无线电发射器。在进行基线记录后，给予受试物质，并记录置于吊床中的犬的EEG和肌电图（EMG）活动。通过肉眼评估EEG有无异常活动，同时持续观察犬是否出现明显的惊厥活动。一旦出现明确且持续的EEG效应和/或行为症状，立即停止PTZ输注并给予地西泮。
缓慢静脉输注PTZ（1.5 mg/kg/min）可在EEG上诱发明显的阵发性效应，表现为4 - 5 Hz的棘波和慢波序列。与阵挛性惊厥相关的阵发性活动在输注开始后17至36分钟之间出现（平均24分钟），但在大多数情况下，在任何明显的惊厥活动出现前约60秒即可观察到阵发性活动。
这些数据表明遥测犬EEG在安全药理学中的实用性。在需要同一物种心血管和CNS安全测试结果的情况下，或者由于代谢或药代动力学特殊性而禁忌使用其他物种的情况下，犬EEG是合适的。
