Assessment of the Combined Treatment with Umbelliferone and Four Classical Antiepileptic Drugs Against Maximal Electroshock-Induced Seizures in Mice.
OBJECTIVE
The aim of this study was to determine the effects of umbelliferone (7-hydroxycoumarin; UMB) on the anticonvulsant potency of four classical antiepileptic drugs (carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB) and valproate (VPA)) in the mouse maximal electroshock-induced seizure (MES) model.


RESULTS
UMB administered systemically intraperitoneally (ip) in a dose of 150 mg/kg significantly elevated the threshold for maximal electroconvulsions (p < 0.05) in mice. Moreover, UMB (150 mg/kg) co-administered with PB and VPA significantly enhanced the anticonvulsant potency of these drugs by reducing their median effective doses (ED50 values) from 35.39 to 21.78 mg/kg (p < 0.01) for PB, and from 281.4 to 215.5 mg/kg (p < 0.01) for VPA. In contrast, UMB (150 mg/kg, ip) had no significant effect on the antiseizure activity of CBZ and PHT in the mouse MES model. Neither total brain PB, nor total brain VPA concentrations were altered after ip administration of UMB, indicating a pharmacodynamic nature of interactions between the tested drugs.


CONCLUSIONS
The selective potentiation of the anticonvulsant potency of PB and VPA by UMB, and lack of any pharmacokinetic interactions between drugs, make the combinations of UMB with PB or VPA worthy of consideration for epileptic patients who are refractory to standard antiepileptic treatment.
Isobolographic Analysis Laboratory, Institute of Rural Health, Lublin, Poland.
Mirosław
M
Zagaja
Marta
M
Andres-Mach
Krystyna
K
Skalicka-Woźniak
Anna R
AR
Rękas
Maria W
MW
Kondrat-Wróbel
Michał
M
Gleńsk
Jarogniew J
JJ
Łuszczki
D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004597:Electroshock; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D012640:Seizures / Q000517:prevention & control*; D014468:Umbelliferones / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000927:Anticonvulsants; D014468:Umbelliferones; C031477:7-hydroxycoumarin