Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
5-Year IF – 2.0, IF – 1.9, JCI (2024) – 0.43
Scopus CiteScore – 4.3
Q1 in SJR 2024, SJR score – 0.598, H-index: 49 (SJR)
ICV – 161.00; MNiSW – 70 pts
Initial editorial assessment and first decision within 24 h

ISSN 1899–5276 (print), ISSN 2451-2680 (online)
Periodicity – monthly

Download original text (EN)

Advances in Clinical and Experimental Medicine

2018, vol. 27, nr 7, July, p. 881–886

doi: 10.17219/acem/69132

Publication type: original article

Language: English

Download citation:

  • BIBTEX (JabRef, Mendeley)
  • RIS (Papers, Reference Manager, RefWorks, Zotero)

Isobolographic additivity among lacosamide, lamotrigine and phenobarbital in a mouse tonic-clonic seizure model

Maria W. Kondrat-Wróbel1,B,C,D, Jarogniew J. Łuszczki1,2,A,C,D,E,F

1 Department of Pathophysiology, Medical University of Lublin, Poland

2 Isobolographic Analysis Laboratory, Institute of Rural Health, Lublin, Poland

Abstract

Background. Epilepsy is a serious neurological disease affecting about 1% of people worldwide (65 million). Seizures are controllable with antiepileptic drugs (AEDs) in about 70% of epilepsy patients, however, there remains about 30% of patients inadequately medicated with these AEDs, who need a satisfactory control of their seizure attacks. For these patients, one of the treatment options is administration of 2 or 3 AEDs in combination.
Objectives. To determine the anticonvulsant effects of a combination of 3 selected AEDs (i.e., lacosamide – LCM, lamotrigine – LTG and phenobarbital – PB) at the fixed-ratio of 1:1:1 in a mouse maximal electroshock-induced (tonic-clonic) seizure model by using isobolographic analysis.
Material and Methods. Seizure activity was evoked in adult male albino Swiss mice by a current (sinewave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. Type I isobolographic analysis was used to detect interaction for the 3-drug combination.
Results. With type I isobolographic analysis, the combination of LCM, LTG and PB (at the fixed-ratio of 1:1:1) exerted additive interaction in the mouse maximal electroshock-induced (tonic-clonic) seizure model.
Conclusion. The combination of LCM with LTG and PB produced additive interaction in the mouse tonicclonic seizure model, despite various molecular mechanisms of action of the tested AEDs.

Key words

antiepileptic drugs, isobolographic analysis, maximal electroshock, 3-drug combination

References (41)

  1. Kwan P, Schachter SC, Brodie MJ. Drug-resistant epilepsy. N Engl J Med. 2011;365:919–926.
  2. Stephen LJ, Brodie MJ. Seizure freedom with more than one antiepileptic drug. Seizure. 2002;11:349–351.
  3. Stephen LJ, Forsyth M, Kelly K, Brodie MJ. Antiepileptic drug combinations – Have newer agents altered clinical outcomes? Epilepsy Res. 2012;98:194–198.
  4. Barker-Haliski M, Sills GJ, White HS. What are the arguments for and against rational therapy for epilepsy? Adv Exp Med Biol. 2014;813: 295–308.
  5. Perucca E. Pharmacological principles as a basis for polytherapy. Acta Neurol Scand Suppl. 1995;162:31–34.
  6. Deckers CL, Czuczwar SJ, Hekster YA, et al. Selection of antiepileptic drug polytherapy based on mechanisms of action: The evidence reviewed. Epilepsia. 2000;41:1364–1374.
  7. Luszczki JJ, Czuczwar SJ. Preclinical profile of combinations of some second-generation antiepileptic drugs: An isobolographic analysis. Epilepsia. 2004;45:895–907.
  8. Errington AC, Stohr T, Heers C, Lees G. The investigational anticonvulsant lacosamide selectively enhances slow inactivation of voltage-gated sodium channels. Mol Pharmacol. 2008;73:157–169.
  9. Rogawski MA, Tofighy A, White HS, Matagne A, Wolff C. Current understanding of the mechanism of action of the antiepileptic drug lacosamide. Epilepsy Res. 2015;110:189–205.
  10. Biton V, Gil-Nagel A, Isojarvi J, Doty P, Hebert D, Fountain NB. Safety and tolerability of lacosamide as adjunctive therapy for adults with partial-onset seizures: Analysis of data pooled from three randomized, double-blind, placebo-controlled clinical trials. Epilepsy Behav. 2015;52:119–127.
  11. Zadeh WW, Escartin A, Byrnes W, et al. Efficacy and safety of lacosamide as first add-on or later adjunctive treatment for uncontrolled partial-onset seizures: A multicentre open-label trial. Seizure. 2015;31: 72–79.
  12. Glauser T, Ben-Menachem E, Bourgeois B, et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2013;54:551–563.
  13. Loscher W. Single versus combinatorial therapies in status epilepticus: Novel data from preclinical models. Epilepsy Behav. 2015;49: 20–25.
  14. 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.
  15. Tallarida RJ. Revisiting the isobole and related quantitative methods for assessing drug synergism. J Pharmacol Exp Ther. 2012;342:2–8.
  16. Kondrat-Wróbel MW, Łuszczki JJ. Interaction of three-drug combination of lacosamide, carbamazepine and phenobarbital in the mouse maximal electroshock-induced seizure model – An isobolographic analysis. Health Prob Civil. 2016;10(1):55–61.
  17. Luszczki JJ. Isobolographic analysis of interaction for three-drug combination of carbamazepine, phenobarbital and topiramate in the mouse maximal electroshock-induced seizure model. Pharmacology. 2016;97:259–264.
  18. Żółkowska D, Zagaja M, Miziak B, et al. Isobolographic assessment of interactions between retigabine and phenytoin in the mouse maximal electroshock-induced seizure model and chimney test. Health Prob Civil. 2016;10(4):54–59.
  19. Loewe S. The problem of synergism and antagonism of combined drugs. Arzneimittelforschung. 1953;3:285–290.
  20. Luszczki 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.
  21. Luszczki 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.
  22. Litchfield JT, Wilcoxon F. A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther. 1949;96:99–113.
  23. Luszczki JJ, Wu JZ, Raszewski G, Czuczwar SJ. Isobolographic characterization of interactions of retigabine with carbamazepine, lamotrigine, and valproate in the mouse maximal electroshock-induced seizure model. Naunyn Schmiedebergs Arch Pharmacol. 2009;379:163–179.
  24. Luszczki JJ. Isobolographic analysis of interaction between drugs with nonparallel dose-response relationship curves: A practical application. Naunyn Schmiedebergs Arch Pharmacol. 2007;375:105–114.
  25. Tallarida RJ. Quantitative methods for assessing drug synergism. Genes Cancer. 2011;2:1003–1008.
  26. Luszczki JJ, Czuczwar SJ. Biphasic characteristic of interactions between stiripentol and carbamazepine in the mouse maximal electroshock-induced seizure model: A three-dimensional isobolographic analysis. Naunyn Schmiedebergs Arch Pharmacol. 2006;374:51–64.
  27. Luszczki JJ, Czuczwar M, Kis J, et al. Interactions of lamotrigine with topiramate and first-generation antiepileptic drugs in the maximal electroshock test in mice: An isobolographic analysis. Epilepsia. 2003;44:1003–1013.
  28. Shandra A, Shandra P, Kaschenko O, Matagne A, Stohr T. Synergism of lacosamide with established antiepileptic drugs in the 6-Hz seizure model in mice. Epilepsia. 2013;54:1167–1175.
  29. Nakatani Y, Masuko H, Amano T. Effect of lamotrigine on Na(v)1.4 voltage-gated sodium channels. J Pharmacol Sci. 2013;123:203–206.
  30. Pisani A, Bonsi P, Martella G, et al. Intracellular calcium increase in epileptiform activity: Modulation by levetiracetam and lamotrigine. Epilepsia. 2004;45:719–728.
  31. Stohr T, Kupferberg HJ, Stables JP, et al. Lacosamide, a novel anti-convulsant drug, shows efficacy with a wide safety margin in rodent models for epilepsy. Epilepsy Res. 2007;74:147–154.
  32. Mathers DA, Wan X, Puil E. Barbiturate activation and modulation of GABA(A) receptors in neocortex. Neuropharmacology. 2007;52: 1160–1168.
  33. Twyman RE, Rogers CJ, Macdonald RL. Differential regulation of gamma-aminobutyric acid receptor channels by diazepam and phenobarbital. Ann Neurol. 1989;25:213–220.
  34. Rho JM, Donevan SD, Rogawski MA. Direct activation of GABAA receptors by barbiturates in cultured rat hippocampal neurons. J Physiol. 1996;497(2):509–522.
  35. Ko GY, Brown-Croyts LM, Teyler TJ. The effects of anticonvulsant drugs on NMDA-EPSP, AMPA-EPSP, and GABA-IPSP in the rat hippocampus. Brain Res Bull. 1997;42:297–302.
  36. Boissier JR, Tardy J, Diverres JC. A new simple method to explore the “tranquillizing” action: The chimney test [in French]. Pharmacology. 1960;3:81–84.
  37. Luszczki JJ, Czernecki R, Wojtal K, Borowicz KK, Czuczwar SJ. Agmatine enhances the anticonvulsant action of phenobarbital and valproate in the mouse maximal electroshock seizure model. J Neural Transm. 2008;115:1485–1494.
  38. Venault P, Chapouthier G, de Carvalho LP, et al. Benzodiazepine impairs and beta-carboline enhances performance in learning and memory tasks. Nature. 1986;321:864–866.
  39. Luszczki JJ, Wojcik-Cwikla 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.
  40. Meyer OA, Tilson HA, Byrd WC, Riley MT. A method for the routine assessment of fore- and hindlimb grip strength of rats and mice. Neurobehav Toxicol. 1979;1;233–236.
  41. Nieoczym D, Luszczki JJ, Czuczwar SJ, Wlaz P. Effect of sildenafil on the anticonvulsant action of classical and second-generation antiepileptic drugs in maximal electroshock-induced seizures in mice. Epilepsia. 2010;51:1552–1559.
© Wroclaw Medical University