Giardina William J, Dart Michael J, Harris Richard R, Bitner Robert S, Radek Richard J, Fox Gerard B, Chemburkar Sanjay R, Marsh Kennan C, Waring Jeffrey F, Hui Julia Y, Chen Jinhua, Curzon Peter, Grayson George K, Komater Victoria A, Ku Yiyin, Lockwood Mark, Miner Holly M, Nikkel Arthur L, Pan Jia Bao, Pu Yu-Ming, Wang Lei, Bennani Youssef, Durmuller Niklaus, Jolly Robert, Roux Sylvain, Sullivan James P, Decker Michael W
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-6125, USA.
Epilepsia. 2005 Sep;46(9):1349-61. doi: 10.1111/j.1528-1167.2005.02905.x.
The objective of this study was to characterize the antiseizure and safety profiles of ABT-769 [(R)-N-(2 amino-2-oxoethyl)spiro[2,5]octane-1-carboxamide].
ABT-769 was tested for protection against maximal electroshock and pentylenetetrazol-induced seizures in the mouse and for suppression of electrically kindled amygdala seizures and spontaneous absence-like seizures in the rat. The central nervous system safety profile was evaluated by using tests of motor coordination and inhibitory avoidance. The potential for liver toxicity was assessed in vitro by using a mitochondrial fatty acid beta-oxidation assay. Teratogenic potential was assessed in the mouse.
ABT-769 blocked maximal electroshock, subcutaneous pentylenetetrazol and intravenous pentylenetetrazol-induced seizures with median effective dose (ED50) values of 0.25, 0.38, and 0.11 mmol/kg, p.o., respectively. No tolerance was evident in the intravenous pentylenetetrazol test after twice-daily dosing of ABT-769 (0.3 mmol/kg, p.o.) for 4 days. ABT-769 blocked absence-like spike-wave discharge (ED50, 0.15 mmol/kg, p.o.) and shortened the cortical and amygdala afterdischarge duration of kindled seizures (1 and 3 mmol/kg, p.o.). The protective indices (ED50 rotorod impairment/ED50 seizure protection) were 4.8, 3.2, and 10.9 in the maximal electroshock, subcutaneous pentylenetetrazol and intravenous pentylenetetrazol seizure tests, respectively. ABT-769 did not affect inhibitory avoidance performance (0.1-1 mmol/kg, p.o.). ABT-769 did not affect mitochondrial fatty acid beta-oxidation or induce neural tube defects.
ABT-769 is an efficacious antiseizure agent in animal models of convulsive and nonconvulsive epilepsy and has a favorable safety profile. ABT-769 has a broad-spectrum profile like that of valproic acid. Its profile is clearly different from those of carbamazepine, phenytoin, lamotrigine, topiramate, vigabatrin, and tiagabine.
本研究的目的是对ABT-769[（R）-N-（2-氨基-2-氧代乙基）螺[2,5]辛烷-1-甲酰胺]的抗癫痫作用和安全性进行表征。
对ABT-769进行了测试，以观察其对小鼠最大电休克和戊四氮诱导的癫痫发作的保护作用，以及对大鼠电点燃杏仁核癫痫发作和自发性失神样癫痫发作的抑制作用。通过运动协调测试和抑制性回避测试评估中枢神经系统安全性。使用线粒体脂肪酸β氧化试验在体外评估肝毒性潜力。在小鼠中评估致畸潜力。
ABT-769可阻断最大电休克、皮下注射戊四氮和静脉注射戊四氮诱导的癫痫发作，口服给药的半数有效剂量（ED50）值分别为0.25、0.38和0.11 mmol/kg。在每天两次口服ABT-769（0.3 mmol/kg），持续4天的静脉注射戊四氮试验中，未观察到明显的耐受性。ABT-769可阻断失神样棘波放电（ED50，0.15 mmol/kg，口服），并缩短点燃癫痫发作的皮质和杏仁核后放电持续时间（1和3 mmol/kg，口服）。在最大电休克、皮下注射戊四氮和静脉注射戊四氮癫痫发作试验中，保护指数（ED50旋转棒损伤/ED50癫痫保护）分别为4.8、3.2和10.9。ABT-769不影响抑制性回避行为（0.1-1 mmol/kg，口服）。ABT-769不影响线粒体脂肪酸β氧化，也不诱导神经管缺陷。
ABT-769在惊厥性和非惊厥性癫痫动物模型中是一种有效的抗癫痫药物，并且具有良好的安全性。ABT-具有与丙戊酸类似的广谱特性。其特性明显不同于卡马西平、苯妥英、拉莫三嗪、托吡酯、氨己烯酸和噻加宾。
