Interactions between riluzole and conventional antiepileptic drugs – a comparison of results obtained in the subthreshold method and isobolographic analysis

Abstract

The exact types of pharmacodynamic interactions between riluzole and conventional antiepileptic drugs were evaluated in two available ways, the subthreshold and isobolographic analysis. Maximal electroshock test in mice was used as an animal model for generalized tonic-clonic convulsions. In the first method, riluzole (1.25-2.5 mg/kg) significantly raised the electroconvulsive threshold in mice. The drug administered at its subprotective dose of 0.3125 mg/kg enhanced the antiseizure activity of carbamazepine and phenobarbital, while, when applied at the higher dose of 0.625 mg/kg, it potentiated also the action of valproate and diphenylhydantoin. Riluzole (0.625) alone and in combinations with antiepileptic drugs did not produced any motor or log-term memory deficit. Results obtained from isobolographic analysis determined pure additive interaction between riluzole and all used conventional antiepileptic drugs. Since riluzole did not change plasma concentrations of co-administered antiepileptics, pharmacokinetic interactions, at least in terms of their free plasma levels, do not seem probable. The results of the present study confirm significant antiseizure properties of riluzole in the model of generalized tonic-clonic epileptic attacks. Moreover, comparison of effects obtained from both methods evaluating drug interactions strongly indicates a crucial role of the isobolographic analysis in verification and supplementation data achieved from the subthreshold method.

Interactions of MRZ 2/576 with Felbamate, Lamotrigine, Oxcarbazepine and Topiramate in the Mouse Maximal Electroshock-Induced Seizure Model

“…Similarly, additivity was reported for the combina-tions of riluzole with carbamazepine, phenytoin, phenobarbital and valproate in the maximal electroshock seizure test in mice [20] . In contrast, the combinations of felbamate with valproate, phenobarbital, clonazepam and ethosuximide in the pentylenetetrazole-induced seizure model exerted antagonistic interactions with isobolographic transformation of data, although the subthreshold method indicated that antiepileptic drugs potentiated their anticonvulsant effects in mice [21] .…”

“…0.7, and sub-additivity (antagonism) is evident if the sum of ED 50 fractions is 1 1.3 [18,19] . This experimental procedure has been described in detail in our earlier studies [20][21][22] .…”

K Channel Openers as New Anti-arrhythmic Agents

“…The KCNQ channel (M channel) agonists retigabine, R-L3 and BMS-204352, may be useful for treatment of hypertension, cardiac arrhythmia, epilepsy, and incontinence, while BK channel activators might be used to treat hypertension, stroke, and overactive bladder disorder [19]. The KCNK channel activator riluzole has antiseizure effects in the treatment of epilepsy [20] and may be useful as an antiarrhythmic agent as well. Furthermore, specific channel agonists might be of use in treating several other disorders caused by ion channel dysfunctions, e.g., migraine, episodic ataxia, autosomal dominant deafness, hypokalemic periodic paralysis, and erectile dysfunction [21,22].…”

Activators of Cation Channels: Potential in Treatment of Channelopathies: Fig. 1.

“…Large conductance channel activators could become important in treatment of stroke, hypertension and overactive bladder disorders (Malysz et al, 2004). The activation of KCNK channels by Riluzole exerts significant antiseizure properties (Borowicz et al, 2004). Other possible indications for specific channel openers are reviewed (Cooper and Jan, 1999;Lawson and Dunne, 2001).…”