Luszczki Jarogniew J, Czuczwar Stanislaw J
Department of Pathophysiology, Medical University, Jaczewskiego 8, PL-20-090 Lublin, Poland.
Epilepsy Res. 2003 Sep;56(1):27-42. doi: 10.1016/j.eplepsyres.2003.08.003.
Until now, a character of interactions among the antiepileptic drugs (AEDs), in some experimental models of epilepsy, has been determined alternatively with subthreshold and isobolographic methods. In order to elicit the precise and adequate method for evaluating two drug interactions, the comparative study was performed in the maximal electroshock-induced seizure test in mice. In this experimental model, the exact types of interactions among oxcarbazepine (OXC) and conventional AEDs (diphenylhydantoin, phenobarbital, valproate, carbamazepine, and clonazepam) were determined with both methods. Results from the subthreshold method showed a considerable reduction of ED(50) values of clonazepam, diphenylhydantoin and valproate (after administration of OXC at the highest subthreshold dose of 2.5 mg/kg), whilst ED(50)s of carbamazepine or phenobarbital were almost unchanged when OXC (2.5 mg/kg) was co-administered with these AEDs. Results from the 2-dimensional (2-D) isobolographic analysis of interactions for a 50% anticonvulsant effect, for three fixed drug dose ratio combinations of 1:2, 1:1, and 2:1, indicate antagonism between OXC and diphenylhydantoin as regards their anticonvulsant (protective) activity. Furthermore, the interactions between OXC and clonazepam occurred either antagonistic (for the fixed-ratios of 1:4 and 1:3) or synergistic (for the fixed-ratio combinations of 1:1 and 2:1) depending on the proportions of used drugs. Remaining interactions between OXC and carbamazepine, OXC and valproate, or OXC and phenobarbital (for the fixed-ratios of 1:3, 1:1, and 3:1) were isobolographically additive for a 50% anticonvulsant effect tested. The 3-dimensional (3-D) isobolographic analysis of interactions between OXC and CZP revealed that the dual character of interactions (antagonistic and synergistic) observed for a 50% anticonvulsant effect (ED(50)) was also present for additional drug-dose effects tested, i.e. ED(16) and ED(84). The 3-D isobologram for the combination of OXC with CZP clearly visualized either synergy or antagonism between the drugs in combinations.Distinct differences resulting from two experimental methods prove evidently the superiority of isobolographic analysis over the subthreshold method. The former clearly and adequately detects the exact types of interactions between two AEDs, becoming a potent and powerful paradigm for further studies evaluating the character of interactions among AEDs.
到目前为止，在一些癫痫实验模型中，抗癫痫药物（AEDs）之间相互作用的特点是通过阈下剂量法和等效应线图法交替确定的。为了找出评估两种药物相互作用的精确且合适的方法，我们在小鼠最大电休克诱导惊厥试验中进行了对比研究。在这个实验模型中，用这两种方法确定了奥卡西平（OXC）与传统AEDs（苯妥英、苯巴比妥、丙戊酸盐、卡马西平和氯硝西泮）之间相互作用的确切类型。阈下剂量法的结果显示，氯硝西泮、苯妥英和丙戊酸盐的半数有效剂量（ED(50)）值显著降低（在给予最高阈下剂量2.5mg/kg的OXC后），而当OXC（2.5mg/kg）与这些AEDs联合使用时，卡马西平或苯巴比妥的ED(50)几乎不变。对于50%抗惊厥作用，针对1:2、1:1和2:1三种固定药物剂量比组合的二维（2-D）相互作用等效应线图分析表明，就其抗惊厥（保护）活性而言，OXC与苯妥英之间存在拮抗作用。此外，OXC与氯硝西泮之间的相互作用根据所用药物的比例，要么表现为拮抗作用（对于1:4和1:3的固定比例），要么表现为协同作用（对于1:1和2:1的固定比例组合）。对于测试的50%抗惊厥作用，OXC与卡马西平、OXC与丙戊酸盐或OXC与苯巴比妥之间的其余相互作用（对于1:3、1:1和3:1的固定比例）在等效应线图上呈相加性。OXC与氯硝西泮（CZP）之间相互作用的三维（3-D）等效应线图分析表明，对于50%抗惊厥作用（ED(50)）观察到的相互作用的双重性质（拮抗和协同）在测试的其他药物剂量效应中也存在，即ED(16)和ED(84)。OXC与CZP组合的3-D等效应线图清楚地显示了联合用药中药物之间的协同或拮抗作用。两种实验方法产生的明显差异清楚地证明了等效应线图分析相对于阈下剂量法的优越性。前者能够清晰且充分地检测出两种AEDs之间相互作用的确切类型，成为评估AEDs之间相互作用特点的进一步研究的有力范例。
