Additive interactions between retigabine and oxcarbazepine in the chimney test and the model of generalized tonic-clonic seizures in mice

Abstract

Summary Introduction. Patients with pharmacoresistant epilepsy are usually treated with two or more antiepileptic drugs (AEDs). The search for therapeutically efficacious AED combinations is still a challenging issue for clinicians and epileptologists throughout the world. Aim. To determine the interaction profile for the combination of retigabine (RTG) and oxcarbazepine (OXC) in both, the model of tonic-clonic seizures, the maximal electroshock (MES)-induced seizure model and chimney test (motor performance) in adult male albino Swiss mice. Methods. Isobolographic analysis (type I) was applied to characterize interactions for the combination of RTG with OXC with respect to its anticonvulsant and acute side (neurotoxic) effects, as determined in the MES and chimney tests, respectively. Results. The combination of RTG with OXC at the fixed-ratios of 1:3, 1:1 and 3:1 produced additive interactions in the MES test in mice. Similarly, the combination of RTG with OXC at the fixed-ratio of 1:1 produced additive interaction with a tendency towards sub-additivity in the chimney test in mice. Measurement of total brain concentrations of both AEDs revealed that RTG did not affect total brain concentrations of OXC and inversely, OXC had no impact on RTG’s total brain concentrations, confirming pharmacodynamic interaction between the drugs. Conclusions. The additive pharmacodynamic interactions in both the MES and chimney tests in mice were observed for the combination of RTG with OXC.

Interactions of retigabine with topiramate in the mouse tonic-clonic seizure model and chimney test – an isobolographic analysis

“…In this test, the mice had to climb backwards up a transparent plastic tube (3 cm inner diameter, 30 cm length) within 1 min., as described in more detail elsewhere [11,12]. The acute neurotoxic effects of RTG and TPM observed in the animals in the chimney test were expressed as their median toxic doses (TD 50 values), i.e., doses of AEDs that disturbed motor coordination in 50% of the tested animals.…”

“…Similarly, the neurotoxic (adverse) effects of the mixture of RTG with TPM were determined and expressed as the TD 50 exp value, i.e., the dose of the mixture required to impair motor coordination in 50% of mice subjected to the chimney test. This experimental procedure has been described in more detail elsewhere [11,12,19].…”

“…The combinations of RTG with carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC) and phenytoin (PHT) exerted additive interaction in the mouse MES model [10][11][12]. The combination of RTG with levetiracetam (LEV) exerted both additive and supra-additive interactions in the mouse MES model [13].…”

“…Maximal electroconvulsions in mice were produced by an alternating current (50 Hz, 25 mA, 500 V, 0.2 s stimulus duration) delivered via ear-clip electrodes, and the tonic hind limb extension (seizure activity) in animals was taken as the endpoint. The anticonvulsant potency of RTG and TPM was determined as their median effective doses (ED 50 values), i.e., doses of AEDs that suppressed 50% of the animals tested against maximal electro-convulsions, as described in more detail elsewhere [10][11][12]18]. The animals received increasing doses of RTG and TPM to obtain an increasing percentage of protection from tonic hind limb extension that allowed the construction of dose-response effect lines for RTG and TPM.…”

“…The anticonvulsant potency of the mixture of RTG with TPM was determined and expressed as the ED 50 exp value, i.e., the dose of the mixture required to suppress tonic hind limb extension in 50% of the mice. This procedure has been described in more detail elsewhere [11,12].…”