RESEARCH PAPER
Isobolographic analysis of interaction between oxcarbazepine and valproate in pentylenetetrazole-induced seizures in mice
 
More details
Hide details
1
Department of Pathophysiology, Medical University, Lublin, Poland; Department of Physiopathology, Institute of Agricultural Medicine, Lublin, Poland
CORRESPONDING AUTHOR
Jarogniew J. Łuszczki   

Łuszczki, Department of Pathophysiology, Medical University, Jaczewskiego 8, 20-090 Lublin, Poland.
 
J Pre Clin Clin Res. 2008;2(1):40–45
KEYWORDS
ABSTRACT
The objective of this study was to assess the characteristics of interaction between oxcarbazepine (OXC) and valproate (VPA) in pentylenetetrazole (PTZ)-induced clonic seizures in mice. The anticonvulsant effects produced by OXC and VPA in two-drug mixture at fi xed-ratios of 1:3, 1:1 and 3:1, were determined and statistically analyzed with type I isobolographic analysis for parallel dose-response relationship lines. Total brain concentrations of VPA were measured in order to ascertain any pharmacokinetic contribution to the pharmacodynamic interaction. Moreover, the acute adverse-effect profile for the combination of OXC with VPA was determined in the chimney test (motor coordination), step-through passive avoidance task (long-term memory), and grip-strength test (skeletal muscular strength) in mice. Results indicated that OXC combined with VPA at 3 fi xed-ratios of 1:3, 1:1 and 3:1 exerted additive interaction in PTZ-induced clonic seizures in mice, although the combination of OXC and VPA at the fi xed-ratio of 1:1 displayed a tendency towards supra-additivity (synergy) in the PTZ test in mice. Pharmacokinetic estimation of total brain antiepileptic (AED) concentrations revealed that OXC did not significantly affect total brain VPA concentrations; therefore, the observed interaction in the PTZ test was pharmacodynamic in nature. Evaluation of acute adverse effects for the combination of OXC with VPA revealed that neither drug had any impact on motor coordination, long-term memory, and skeletal muscular strength in mice. Based on this preclinical study, one can ascertain that the additive interaction between OXC and VPA against PTZ-induced seizures associated with lack of acute adverse effects and no pharmacokinetic interactions between drugs, deserve more attention from a clinical point of view.
 
REFERENCES (26)
1.
Kwan P, Brodie MJ: Early identifi cation of refractory epilepsy. New Eng J Med 2000, 342, 314-319.
 
2.
Stephen LJ, Brodie MJ: Seizure-freedom with more than one antiepileptic drug. Seizure 2002, 11, 349-351.
 
3.
Perucca E: Pharmacological principles as a basis for polytherapy. Acta ,Neurol Scand Suppl 1995, 162, 31-34.
 
4.
Loscher W, Wauquier A: Use of animal models in developing guiding principles for polypharmacy in epilepsy. Epilepsy Res 1996, Suppl. 11, 61-65.
 
5.
Berenbaum MC: What is synergy? Pharmacol Rev 1989, 41, 93-141. Erratum in: Pharmacol Rev 1990, 41, 422.
 
6.
Tallarida RJ: Drug synergism and dose-eff ect data analysis. Chapman & Hall/CRC, Boca Raton 2000.
 
7.
Łuszczki JJ, Czuczwar SJ: Isobolographic and subthreshold methods in the detection of interactions between oxcarbazepine and conventional antiepileptics - a comparative study. Epilepsy Res 2003, 56, 27-42.
 
8.
Loscher W, Honack D, Fassbender CP, Nolting B: The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. III. Pentylenetetrazole seizure models. Epilepsy Res 1991, 8, 171-189.
 
9.
Łuszczki JJ, Czuczwar SJ: Isobolographic characterisation of interactions among selected newer antiepileptic drugs in the mouse pentylenetetrazole-induced seizure model. Naunyn Schmiedebergs Arch Pharmacol 2005, 372, 41-54.
 
10.
Łuszczki JJ, Borowicz KK, Swiader 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.
 
11.
Litchfi eld JT, Wilcoxon F: A simplifi ed method of evaluating dose-eff ect.
 
12.
Łuszczki JJ, Czuczwar SJ: Isobolographic profi le of interactions between tiagabine and gabapentin: a preclinical study. Naunyn Schmiedebergs Arch Pharmacol 2004, 369, 434-446.
 
13.
Łuszczki JJ, Ratnaraj N, Patsalos PN, Czuczwar SJ: Isobolographic analysis of interactions between loreclezole and conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model. Naunyn Schmiedebergs Arch Pharmacol 2006, 373, 169-181.
 
14.
Porreca F, Jiang Q, Tallarida RJ: Modulation of morphine antinociception by peripheral (Leu5) enkephalin: a synergistic interaction. Eur J Pharmacol 1990, 179, 463-468.
 
15.
Loewe S: The problem of synergism and antagonism of combined drugs. Arzneimittelforschung 1953, 3, 285-290.
 
16.
Boissier JR, Tardy J, Diverres JC: Une nouvelle methode simple pour explorer l’action tranquilisante: le test de la cheminee. Med Exp (Basel) 1960, 3, 81-84.
 
17.
Łuszczki JJ, Świąder M, Parada-Turska J, Czuczwar SJ: Tiagabine synergistically interacts with gabapentin in the electroconvulsive threshold test in mice. Neuropsychopharmacology 2003, 28, 1817- 1830.
 
18.
Venault P, Chapouthier G, de Carvalho LP, Simiand J, Morre M, Dodd RH, Rossier J: Benzodiazepines impair and beta-carbolines enhance performance in learning and memory tasks. Nature 1986, 321, 864- 866.
 
19.
Łuszczki JJ, Wojcik-Cwikła J, Andres MM, Czuczwar SJ: Pharmacological and behavioral characteristics of interactions between vigabatrin and conventional antiepileptic drugs in pentylenetetrazole-induced seizures in mice: an isobolographic analysis. Neuropsychopharmacology 2005, 30, 958-973.
 
20.
Łuszczki JJ, Czuczwar SJ: Isobolographic characterization of interactions between vigabatrin and tiagabine in two experimental models of epilepsy. Prog Neuropsychopharmacol Biol Psychiatry 2007, 31, 529- 538.
 
21.
Tallarida RJ: Interactions between drugs and occupied receptors. Pharmacol Ther 2007, 113, 197-209.
 
22.
Łuszczki JJ: Isobolographic analysis of interaction between drugs with nonparallel dose-response relationship curves: a practical application. Naunyn Schmiedebergs Arch Pharmacol 2007, 375, 105-114.
 
23.
Łuszczki JJ, Ratnaraj N, Patsalos PN, Czuczwar SJ: Pharmacodynamic and pharmacokinetic interaction studies with loreclezole and felbamate, lamotrigine, topiramate and oxcarbazepine in the mouse maximal electroshock seizure model. Epilepsia 2005, 46, 344-355.
 
24.
Łuszczki JJ, Czuczwar SJ: Preclinical profi le of combinations of some second-generation antiepileptic drugs: an isobolographic analysis. Epilepsia 2004, 45, 895-907.
 
25.
Łuszczki JJ, Andres MM, Czuczwar SJ: Synergistic interaction of gabapentin and oxcarbazepine in the mouse maximal electroshock seizure model – an isobolographic analysis. Eur J Pharmacol 2005, 515, 54-61.
 
26.
Tallarida RJ, Stone DJ Jr, Raff a RB: Effi cient designs for studying synergistic drug combinations. Life Sci 1997, 61, 417-425.
 
eISSN:1898-7516
ISSN:1898-2395