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首页> 外文期刊>Pharmacology, Biochemistry and Behavior >Tolerance to anticonvulsant effects of some benzodiazepines in genetically epilepsy prone rats.
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Tolerance to anticonvulsant effects of some benzodiazepines in genetically epilepsy prone rats.

机译：对易患遗传性癫痫的大鼠中某些苯二氮卓类药物的抗惊厥作用的耐受性。

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The development of tolerance to the anticonvulsant effects of clonazepam, clobazam, and diazepam were studied in genetically epilepsy-prone rats following intraperitoneal (IP) or oral administration. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation (109 dB, 12-16 kHz). All compounds showed 60 min after IP injection antiseizure activity with ED50 against clonus of 0.24 mumol kg-1 for clonazepam, 0.72 mumol kg-1 for diazepam, and 3.9 mumol kg-1 for clobazam. After 120 min of oral administration the ED50 against clonus of 2.37 mumol kg-1 for clonazepam, 15.8 mumol kg-1 for diazepam, and 30 mumol kg-1 for clobazam. The dose chosen for the chronic treatment were 2.5 mumol kg-1 for clonazepam, 15 mumol kg-1 for diazepam, and 30 mumol kg-1 for clobazam. The animals were treated three times daily for 4 or 6 weeks. Auditory stimulation was administered 60 min after drug IP injection on various days. During treatment, tolerance was observed as a loss of drug anticonvulsant effects. No changes of occurrence of audiogenic seizures was observed in rats treated with vehicle. Tolerance to the anticonvulsant activity developed most rapidly during clobazam treatment, less rapidly following diazepam treatment, and most slowly during clonazepam treatment. Sixty minutes after IP injection on various days of chronic treatment the motor impairment induced by these benzodiazepines was also studied by means of a rotarod apparatus. The tolerance to the motor impairment developed more rapidly than the anticonvulsant effects. The response to auditory stimulation to benzodiazepines was stopped 24 and 48 h after chronic treatment with these compounds, showing no residual drug effects and that rats were still tolerant. The genetically epilepsy-prone rats is a reliable and sensitive model for studying long-term effects of anticonvulsant drugs.
机译：在腹膜内（IP）或口服给药后，对易发遗传性癫痫的大鼠研究了对氯硝西am，氯巴沙姆和地西epa的抗惊厥作用耐受性的发展。通过听觉刺激（109 dB，12-16 kHz）评估癫痫发作的抗惊厥作用。 IP注射后60分钟，所有化合物均显示出抗癫痫活性，其中ED50对氯硝西clo为0.24μmol·kg-1，地西epa为0.72μmol·kg-1和氯巴氮嗪为3.9μmol·kg-1的克隆的抗癫痫活性。口服120分钟后，针对氯硝西against的凝集素的ED 50抵抗力为2.37μmol·kg-1，对于地西m为1.58μmol·kg-1，对于氯硝西am为30μmol·kg-1。选择用于慢性治疗的剂量对于氯硝西am为2.5μmol·kg-1，对地西epa为15μmol·kg-1，对于氯巴沙姆为30μmol·kg-1。每天对动物进行3次治疗，持续4或6周。药物IP注射后60分钟，在各天给予听觉刺激。在治疗期间，观察到耐受性是药物抗惊厥作用的丧失。在用媒介物处理的大鼠中未观察到发源性癫痫发作的发生变化。抗惊厥活性的耐受性在氯巴沙姆治疗期间发展最快，在地西epa治疗后发展较慢，在氯硝西treatment治疗过程中发展最慢。腹膜内注射后60天，在各种慢性治疗中，还通过旋转仪研究了这些苯二氮卓类药物引起的运动障碍。对运动障碍的耐受性比抗惊厥作用发展得更快。用这些化合物长期治疗后24和48小时，对苯二氮卓类听觉刺激的反应停止，显示没有残留的药物作用，并且大鼠仍然耐受。遗传易发癫痫的大鼠是研究抗惊厥药物长期作用的可靠且敏感的模型。

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