Indapamide enhances the protective action of carbamazepine, phenobarbital, and valproate  against maximal electroshock-induced seizures in mice.
OBJECTIVE
To determine the influence of indapamide on the protective action of numerous conventional and second-generation antiepileptic drugs (carbamazepine, lamotrigine, oxcarbazepine, phenobarbital, topiramate and valproate) in the mouse maximal electroshock seizure model.


METHODS
Electroconvulsions were evoked in Albino Swiss mice by a current (sine-wave, 0.2 s stimulus duration) delivered via auricular electrodes. Adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations.


RESULTS
Indapamide (up to 3 mg/kg, i.p., 120 min before the test) neither altered the threshold for maximal electroconvulsions, nor protected the animals against maximal electroshock-induced seizures in mice. Moreover, indapamide (3 mg/kg, i.p.) significantly enhanced the anticonvulsant action of carbamazepine, phenobarbital and valproate, but not that of lamotrigine, oxcarbazepine or topiramate in the maximal electroshock seizure test in mice. Indapamide (1.5 mg/kg) had no impact on the anticonvulsant action of all studied antiepileptic drugs in the maximal electroshock seizure test in mice. Estimation of total brain antiepileptic drug concentrations revealed that the observed interaction between indapamide and phenobarbital was complicated by a significant pharmacokinetic increase in total brain concentrations of phenobarbital. In contrast, indapamide had no impact on the total brain concentrations of carbamazepine and valproate in mice.


CONCLUSIONS
The selective potentiation of the anticonvulsant action of carbamazepine and valproate by indapamide and lack of any pharmacokinetic interactions between drugs, make the combinations of indapamide with carbamazepine or valproate of pivotal importance for epileptic patients taking these drugs together.
Department of Pathophysiology, Medical University of Lublin, Lublin, Poland.
J
J
Kozinska
K M
KM
Sawicka
A
A
Zadrozniak
E
E
Wojda
M
M
Andres-Mach
M
M
Dudra-Jastrzebska
J J
JJ
Luszczki
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000032:analysis / Q000627:therapeutic use*; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D004232:Diuretics / Q000008:administration & dosage / Q000627:therapeutic use*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004597:Electroshock; D004827:Epilepsy / Q000188:drug therapy; D007190:Indapamide / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D011897:Random Allocation; D012640:Seizures / Q000188:drug therapy* / Q000517:prevention & control; D013223:Statistics as Topic
D000927:Anticonvulsants; D000959:Antihypertensive Agents; D004232:Diuretics; D007190:Indapamide