Characterization of the anticonvulsant, behavioral and pharmacokinetic interaction profiles of stiripentol in combination with clonazepam, ethosuximide, phenobarbital, and valproate using isobolographic analysis.
OBJECTIVE
Isobolographic analysis was used to characterize the interactions between stiripentol (STP) and clonazepam (CZP), ethosuximide (ETS), phenobarbital (PB), and valproate (VPA) in suppressing pentylenetetrazole (PTZ)-induced clonic seizures in mice.


METHODS
The anticonvulsant and acute adverse (neurotoxic) effects of STP in combination with the various conventional antiepileptic drugs (AEDs), at fixed ratios of 1:3, 1:1, and 3:1, were evaluated in the PTZ and chimney tests in mice using the isobolographic analysis. Additionally, protective indices (PI) and benefit indices (BI) were calculated to identify their pharmacological profiles so that a ranking in relation to advantageous combination could be established. Moreover, adverse-effect paradigms were determined by use of the step-through passive avoidance task (long-term memory), threshold for the first pain reaction, grip-strength test (neuromuscular tone), and the hot plate test (acute thermal pain). Brain AED concentrations were also measured so as to ascertain any pharmacokinetic contribution to the pharmacodynamic interactions.


RESULTS
All AED combinations comprising of STP and CZP, ETS, PB, and VPA (at the fixed ratios of 1:3, 1:1 and 3:1) were additive in terms of clonic seizure suppression in the PTZ test. However, these interactions were complicated by changes in brain AED concentrations consequent to pharmacokinetic interactions. Thus STP significantly increased total brain ETS and PB concentrations, and decreased VPA concentrations, but was without effect on CZP concentrations. In contrast, PB significantly decreased and VPA increased total brain STP concentrations while CZP and ETS were without effect. Furthermore, while isobolographic analysis revealed that STP and CZP in combination, at the fixed ratios of 1:1 and 3:1, were supraadditive (synergistic; p < 0.05), the combinations of STP with CZP (1:3), ETS, PB, or VPA (at all fixed ratios of 1:3, 1:1, and 3:1) were barely additivity in terms of acute neurotoxic adverse effects in the chimney test. Additionally, none of the examined combinations of STP with conventional AEDs (CZP, ETS, PB, VPA--at their median effective doses from the PTZ-test) affected long-term memory, threshold for the first pain reaction, neuromuscular tone, and acute thermal pain.


CONCLUSIONS
Based on BI values, the combination of STP with PB at the fixed ratio of 1:3 appears to be a particularly favourable combination. In contrast, STP and CZP or ETS (at the fixed ratios of 1:1 and 3:1) were unfavorable combinations. However, these conclusions are confounded by the fact that STP is associated with significant pharmacokinetic interactions. The remaining combinations of STP with PB (1:1 and 3:1), CZP (1:3), ETS (1:3), and VPA (at all fixed ratios of 1:3, 1:1, and 3:1) do not appear to be potential favorable AED combinations.
Luszczki
Jarogniew J
JJ
Department of Pathophysiology, Medical University of Lublin, Lublin, Poland.
Ratnaraj
Neville
N
Patsalos
Philip N
PN
Czuczwar
Stanislaw J
SJ
D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D001923:Brain Chemistry / Q000187:drug effects; D002998:Clonazepam / Q000493:pharmacokinetics / Q000627:therapeutic use; D004148:Dioxolanes / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005013:Ethosuximide / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D051379:Mice; D020258:Neurotoxicity Syndromes / Q000209:etiology; D010433:Pentylenetetrazole; D010634:Phenobarbital / Q000493:pharmacokinetics / Q000627:therapeutic use; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*; D014635:Valproic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use
D000927:Anticonvulsants; D004148:Dioxolanes; D002998:Clonazepam; D005013:Ethosuximide; D014635:Valproic Acid; C021092:stiripentol; D010433:Pentylenetetrazole; D010634:Phenobarbital