SYNERGISTIC EFFECTS OF PHENYTOIN AND LEVETIRACETAM COMBINATION THERAPY ON ATTENUATION POST-TRAUMATIC NONCONVULSIVE SEIZURES.

Post-traumatic seizures during the emergent state of traumatic brain injury (TBI) are deemed detrimental to the recovery of TBI patients. Phenytoin (PHT) and levetiracetam (LEV) are the commonly prescribed drugs as prophylaxis. Although LEV has become more favorable than PHT owing to its improved safety profile, many patients are still intractable to the monotherapy of either drug. In this study we applied the isobolographic approach to evaluate PHT + LEV combination therapy against penetrating ballistic-like brain injury (PBBI) induced nonconvulsive seizures (NCS) in rats, aimed at achieving synergism with properly paired dose ratios of the two drugs. NCS were induced by PBBI and detected by EEG recording for 72 h. PHT and LEV were tested at the following dose ratios (PHT/LEV): 1.8/6.3, 3.6/12.7, 7.2/25.4, or 14.5/50.7 mg/kg, which were derived from previous monotherapy results of each drug. Treatments were given intravenously twice/day for three days. Control animals received matching vehicle treatments. The results showed that except for the lowest dose ratio, PHT + LEV combination therapy significantly reduced NCS frequency and total seizure duration by 61%-84% across the three high dose ratios (as compared to vehicle treatments). The highest dose ratio also significantly reduced NCS incidence from 65% (Vehicle) to 25% and delayed NCS latency from 39 h (vehicle) to 57 h post-injury. The dose equivalent analysis of the isobolographic design indicated an achievement of synergism because the observed effects across all dose ratios exceeded the expected additive effects. Compared to our previous results of a PHT or LEV monotherapy derived from the identical TBI, the combined treatments of PHT + LEV outperformed the monotherapy of each individual drug by achieving statistically defined synergism. Critically, the doses of each drug used in combination were 2-3 fold lower than the monotherapy doses required of each drug, which may alleviate the safety concerns of these drugs used in TBI patients. [ABSTRACT FROM AUTHOR]