Jarogniew J Łuszczki1,2, Dominika Podgórska3, Justyna Kozińska4, Marek Jankiewicz5, Zbigniew Plewa6, Mateusz Kominek7, Dorota Żółkowska8, Magdalena Florek-Łuszczki9. 1. Department of Pathophysiology, Medical University, Jaczewskiego 8b, 20-090, Lublin, PL, Poland. jarogniew.luszczki@umlub.pl. 2. Isobolographic Analysis Laboratory, Institute of Rural Health, Lublin, Poland. jarogniew.luszczki@umlub.pl. 3. Department of Pathophysiology, Medical University, Jaczewskiego 8b, 20-090, Lublin, PL, Poland. 4. Chair and Clinic of Hematooncology and Bone Marrow Transplantation, Medical University, Lublin, Poland. 5. Chair and Clinic of Cardiology, Medical University, Lublin, Poland. 6. Department of General, Oncological and Minimally Invasive Surgery, 1st Military Clinical Hospital, Lublin, Poland. 7. Clinic of Orthopedics and Traumatology, Medical University, Lublin, Poland. 8. Department of Neurology, School of Medicine, University of California-Davis, Sacramento, CA, USA. 9. Department of Medical Anthropology, Institute of Rural Health, Lublin, Poland.
Abstract
BACKGROUND: Combination therapy consisting of two or more antiepileptic drugs (AEDs) is usually prescribed for patients with refractory epilepsy. The drug-drug interactions, which may occur among currently available AEDs, are the principal criterion taken by physicians when prescribing the AED combination to the patients. Unfortunately, the number of possible three-drug combinations tremendously increases along with the clinical approval of novel AEDs. AIM: To isobolographically characterize three-drug interactions of phenobarbital (PB) with lamotrigine (LTG), oxcarbazepine (OXC), pregabalin (PGB) and topiramate (TPM), the maximal electroshock-induced (MES) seizure model was used in male albino Swiss mice. MATERIALS AND METHOD: The MES-induced seizures in mice were generated by alternating current delivered via auricular electrodes. To classify interactions for 6 various three-drug combinations of AEDs (i.e., PB + TPM + PGB, PB + OXC + TPM, PB + LTG + TPM, PB + OXC + PGB, PB + LTG + PGB and PB + LTG + OXC), the type I isobolographic analysis was used. Total brain concentrations of PB were measured by fluorescent polarization immunoassay technique. RESULTS: The three-drug mixtures of PB + TPM + PGB, PB + OXC + TPM, PB + LTG + TPM, PB + OXC + PGB, PB + LTG + PGB and PB + LTG + OXC protected the male albino Swiss mice from MES-induced seizures. All the observed interactions in this seizure model were supra-additive (synergistic) (p < 0.001), except for the combination of PB + LTG + OXC, which was additive. It was unable to show the impact of the studied second-generation AEDs on total brain content of PB in mice. CONCLUSIONS: The synergistic interactions among PB and LTG, OXC, PGB and TPM in the mouse MES model are worthy of being transferred to clinical trials, especially for the patients with drug resistant epilepsy, who would benefit these treatment options.
BACKGROUND: Combination therapy consisting of two or more antiepileptic drugs (AEDs) is usually prescribed for patients with refractory epilepsy. The drug-drug interactions, which may occur among currently available AEDs, are the principal criterion taken by physicians when prescribing the AED combination to the patients. Unfortunately, the number of possible three-drug combinations tremendously increases along with the clinical approval of novel AEDs. AIM: To isobolographically characterize three-drug interactions of phenobarbital (PB) with lamotrigine (LTG), oxcarbazepine (OXC), pregabalin (PGB) and topiramate (TPM), the maximal electroshock-induced (MES) seizure model was used in male albino Swiss mice. MATERIALS AND METHOD: The MES-induced seizures in mice were generated by alternating current delivered via auricular electrodes. To classify interactions for 6 various three-drug combinations of AEDs (i.e., PB + TPM + PGB, PB + OXC + TPM, PB + LTG + TPM, PB + OXC + PGB, PB + LTG + PGB and PB + LTG + OXC), the type I isobolographic analysis was used. Total brain concentrations of PB were measured by fluorescent polarization immunoassay technique. RESULTS: The three-drug mixtures of PB + TPM + PGB, PB + OXC + TPM, PB + LTG + TPM, PB + OXC + PGB, PB + LTG + PGB and PB + LTG + OXC protected the male albino Swiss mice from MES-induced seizures. All the observed interactions in this seizure model were supra-additive (synergistic) (p < 0.001), except for the combination of PB + LTG + OXC, which was additive. It was unable to show the impact of the studied second-generation AEDs on total brain content of PB in mice. CONCLUSIONS: The synergistic interactions among PB and LTG, OXC, PGB and TPM in the mouseMES model are worthy of being transferred to clinical trials, especially for the patients with drug resistant epilepsy, who would benefit these treatment options.
Entities:
Keywords:
Antiepileptic drugs; Drug interactions; Drug synergism; Isobolographic analysis; Maximal electroshock
Authors: Jacqueline A French; H Steve White; Henrik Klitgaard; Gregory L Holmes; Michael D Privitera; Andrew J Cole; Ellinor Quay; Samuel Wiebe; Dieter Schmidt; Roger J Porter; Alexis Arzimanoglou; Eugen Trinka; Emilio Perucca Journal: Epilepsia Date: 2013-08 Impact factor: 5.864
Authors: Patrick Kwan; Alexis Arzimanoglou; Anne T Berg; Martin J Brodie; W Allen Hauser; Gary Mathern; Solomon L Moshé; Emilio Perucca; Samuel Wiebe; Jacqueline French Journal: Epilepsia Date: 2009-11-03 Impact factor: 5.864