Diltiazem enhances the protective activity of oxcarbazepine against maximal electroshock-induced seizures in mice
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Department of Pathophysiology, Medical University, Lublin, Poland
Department of Cardiology, Medical University, Lublin, Poland
Department of Internal Medicine, Medical University, Lublin, Poland
Department of Obstetrics and Perinatology, Medical University, Lublin, Poland
Department of Physiopathology, Institute of Agricultural Medicine, Lublin, Poland
Corresponding author
Jarogniew J. Łuszczki   

Department of Pathophysiology, Medical University, Jaczewskiego 8, 20-090 Lublin, Poland.
J Pre Clin Clin Res. 2008;2(2):147-152
The aim of the study was to assess the eff ect of diltiazem (a calcium channel antagonist) on the anticonvulsant activity and acute adverse-eff ect potential of oxcarbazepine (a second-generation antiepileptic drug) in the maximal electroshock seizure (MES) model and chimney test in mice. Total brain concentrations of oxcarbazepine were measured with high pressure liquid chromatography (HPLC) to ascertain any pharmacokinetic contribution to the pharmacodynamic interaction between drugs. Results indicate that diltiazem (at a dose of 5 mg/kg, i.p.) signifi cantly enhanced the anticonvulsant activity of oxcarbazepine in the MES test in mice, by reducing the median eff ective dose (ED50 value) of oxcarbazepine from 14.25 to 9.87 mg/kg (P<0.01). In contrast, diltiazem at lower doses of 1.25 and 2.5 mg/kg had no signifi cant impact on the antiseizure action of oxcarbazepine in the MES test in mice. In the chimney test, diltiazem (up to 5 mg/kg, i.p.) did not signifi cantly aff ect the acute adverse eff ect potential of oxcarbazepine, and the median toxic dose (TD50 value) of the studied antiepileptic drug ranged from 74.16-62.91 mg/kg. Moreover, diltiazem (5 mg/kg) did not signifi cantly alter total brain oxcarbazepine concentrations as measured with HPLC. In conclusion, diltiazem ameliorates the pharmacological profi le of oxcarbazepine, when considering both the antiseizure and acute adverse eff ects of the antiepileptic drug in preclinical study on animals. The observed interaction between oxcarbazepine and diltiazem in the MES test was pharmacodynamic in nature; therefore, this favourable combination deserves more attention from a clinical point of view
Heinemann U, Hamon B: Calcium and epileptogenesis. Exp Brain Res 1986, 65, 1-10.
Czuczwar SJ, Turski WA, Kleinrok Z: Interactions of excitatory amino acid antagonists with conventional antiepileptic drugs. Metab Brain Dis 1996, 11, 143-152.
Jagiełło-Wojtowicz E, Czuczwar SJ, Chodkowska A, Szponar J, Kleinrok Z: Infl uence of calcium channel blockers on pentylenetetrazol and electroshock-induced convulsions in mice. Pol J Pharmacol Pharm 1991, 43, 95-101.
Kamiński R, Jasiński M, Jagiełło-Wojtowicz E, Kleinrok Z, Czuczwar SJ: Eff ect of amlodipine upon the protective activity of antiepileptic drugs against maximal electroshock-induced seizures in mice. Pharmacol Res1999, 40, 319-325.
Czuczwar SJ, Chodkowska A, Kleinrok Z, Małek U, Jagiełło-Wojtowicz E: Eff ects of calcium channel inhibitors upon the effi cacy of common antiepileptic drugs. Eur J Pharmacol 1990, 176, 75-83.
De Sarro GB, De Sarro A, Trimarchi GR, Nistico G: Eff ects of some calcium antagonists upon the activity of common antiepileptic compounds on sound-induced seizures in DBA/2 mice. Gen Pharmacol 1992, 23, 75-82.
De Sarro G, De Sarro A, Federico F, Meldrum BS: Anticonvulsant properties of some calcium antagonists on sound-induced seizures in genetically epilepsy prone rats. Gen Pharmacol 1990, 21, 769-778.
Czuczwar SJ, Małek U, Kleinrok Z: Influence of calcium channel inhibitors upon the anticonvulsant effi cacy of common antiepileptics against pentylenetetrazol-induced convulsions in mice. Neuropharmacology 1990, 29, 943-948.
Wajima Z, Yoshikawa T, Ogura A, Imanaga K, Shiga T, Inoue T, Ogawa R: The eff ects of diltiazem on hemodynamics and seizure duration during electroconvulsive therapy. Anesth Analg 2001, 92, 1327-1330.
Binnie CD, de Beukelaar F, Meijer JW, Meinardi H, Overweg J, Wauquier A, van Wieringen A: Open dose-ranging trial of fl unarizine as add-on therapy in epilepsy. Epilepsia 1985, 26, 424-428.
De Falco FA, Bartiromo U, Majello L, Di Geronimo G, Mundo P: Calcium antagonist nimodipine in intractable epilepsy. Epilepsia 1992, 33, 343-345.
Nakane Y, Seino M, Yagi A, Kaji S, Yamauchi T: Eff ects of fl unarizine therapy on intractable epilepsy. Arzneimittelforschung 1989, 39, 793- 798.
Overweg J, Binnie CD, Meijer JW, Meinardi H, Nuijten ST, Schmaltz S, Wauquier A: Double-blind placebo-controlled trial of fl unarizine as add-on therapy in epilepsy. Epilepsia 1984, 25, 217-222.
Starreveld E, de Beukelaar F, Wilson AF, McLean DR, Findlay HP: Double-blind cross-over placebo controlled study of fl unarizine in patients with therapy resistant epilepsy. Can J Neurol Sci 1989, 16, 187-190.
Kułak W, Sobaniec W, Wojtal K, Czuczwar SJ: Calcium modulation in epilepsy. Pol J Pharmacol 2004, 56, 29-41.
Meyer FB, Anderson RE, Sundt TM Jr, Sharbrough FW: Selective central nervous system calcium channel blockers - a new class of anticonvulsant agents. Mayo Clin Proc 1986, 61, 239-247.
Hotson JR, Prince DA: A calcium-activated hyperpolarization follows repetitive fi ring in hippocampal neurons. J Neurophysiol 1980, 43, 409-419.
Macdonald RL, Greenfi eld LJ: Mechanisms of action of new antiepileptic drugs. Curr Opin Neurol 1997, 10, 121-128.
Trojnar MP, Kimber-Trojnar Z, Trojnar MK, Łuszczki JJ, Czuczwar SJ: Clinical considerations on the relationship between epilepsy and cardiovascular diseases. JPCCR 2007, 1, 6-8.
Brodie MJ, Schachter SC: Fast Facts. Epilepsy (2nd ed.). Health Press, Oxford 2001.
McLean MJ, Schmutz M, Wamil AW, Olpe HR, Portet C, Feldmann KF: Oxcarbazepine: mechanism of action. Epilepsia 1994, 35, 5-9.
Calabresi P, De Murtas M, Stefani A, Pisani A, Sancesario G, Mercuri NB, Bernardi G: Action of GP 47779, the active metabolite of oxcarbazepine, on the corticostriatal system. I. Modulation of corticostriatal synaptic transmission. Epilepsia 1995, 36, 990-996.
Stefani A, Pisani A, DeMurtas M, Mercuri NB, Marciani MG, Calabresi P. Action of GP 47779, the active metabolite of oxcarbazepine on the corticostriatal system. II. Modulation of High-Voltage-Activated Calcium Currents. Epilepsia 1995, 36, 997-1002.
Stefani A, Spadoni F, Bernardi G: Voltage-activated calcium channels: targets of antiepileptic drug therapy? Epilepsia 1997, 38, 959-965.
Waldmeier PC, Martin P, Stocklin K, Portet C, Schmutz M: Eff ect of carbamazepine, oxcarbazepine and lamotrigine on the increase in extracellular glutamate elicited by veratridine in rat cortex and striatum. Naunyn-Schmiedeberg’s Arch Pharmacol 1996, 354, 164- 172.
Łuszczki JJ, Trojnar MK, Trojnar MP, Kimber-Trojnar Ż, Szostakiewicz B, Zadrożniak A, Borowicz KK, Czuczwar SJ: Eff ects of three calcium channel antagonists (amlodipine, diltiazem and verapamil) on the protective action of lamotrigine in the mouse maximal electroshockinduced seizure model. Pharmacol Rep 2007, 59, 672-682.
Łuszczki JJ, Trojnar MK, Trojnar MP, Kimber-Trojnar Ż, Szostakiewicz B, Zadrożniak A, Borowicz KK, Czuczwar SJ: Eff ects of amlodipine, diltiazem, and verapamil on the anticonvulsant action of topiramate against maximal electroshock-induced seizures in mice. Can J Physiol Pharmacol 2008, 86, 113- 121.
Loscher W, Fassbender CP, Nolting B: The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. II. Maximal electroshock seizure models. Epilepsy Res 1991, 8, 79-94.
Łuszczki JJ, Borowicz KK, Świąder M, Czuczwar SJ: Interactions between oxcarbazepine and conventional antiepileptic drugs in the maximal electroshock test in mice: an isobolographic analysis. Epilepsia 2003, 44, 489-499.
Łuszczki JJ: Isobolographic analysis of interaction between oxcarbazepine and valproate in pentylenetetrazole-induced seizures in mice. JPCCR 2008, 2, 40-45.
Litchfi eld JT, Wilcoxon F: A simplifi ed method of evaluating dose-eff ect experiments. J Pharmacol Exp Ther 1949, 96, 99-113.
Łuszczki JJ, Zadrożniak A, Barcicka-Kłosowska B, Bednarski J, Misiuta-Krzesińska M, Filip D, Zwoliński J, Czernecki R: Infl uence of 7-nitroindazole and NG-nitro-L-arginine on the anticonvulsant activity of loreclezole in maximal electroshock-induced seizures in mice. JPCCR 2007, 1, 146-149.
Boissier JR, Tardy J, Diverres JC: Une nouvelle method e simple pour explorer l’action tranquilisante: le test de la cheminee. Med Exp (Basel) 1960, 3, 81-84.
Loscher W, Nolting B: The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. IV. Protective indices. Epilepsy Res 1991, 9, 1-10.
Hinkle DE, Wiersma W, Jurs SG: Applied statistics for the behavioral science, 3rd ed.). Houghton Miffl in Company, Boston 1994.
Łuszczki JJ, Czuczwar SJ: How signifi cant is the diff erence between drug doses infl uencing the threshold for electroconvulsions? Pharmacol Rep 2005, 57, 782-786.
Miljanich GP, Ramachandran J: Antagonists of neuronal calcium channels: structure, function, and therapeutic implications. Annu Rev Pharmacol Toxicol 1995, 35, 707-734.
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