title: Synergistic combinations of anticonvulsant agents: what is the evidence from animal experiments?
abstract: OBJECTIVE
  Combination therapy is often used in the treatment of seizures refractory to monotherapy. At the same time, the pharmacodynamic mechanisms that determine the combined efficacy of antiepileptic drugs (AEDs) are unknown, and this prevents a rational use of these drug combinations. We critically evaluate the existing evidence for pharmacodynamic synergism between AEDs from preclinical studies in animal models of epilepsy to identify useful combinations of mechanisms and to determine whether study outcome depends on the various research methods that are in use.
  
  
  METHODS
  Published articles were included if the studies were placebo-controlled, in vivo, or ex vivo animal studies investigating marketed or experimental AEDs. The animal models that were used in these studies, the primary molecular targets of the tested drugs, and the methods of interpretation were recorded. The potential association of these factors with the study outcome (synergism: yes or no) was assessed through logistic regression analysis.
  
  
  RESULTS
  In total, 107 studies were identified, in which 536 interaction experiments were conducted. In 54% of these experiments, the possibility of a pharmacokinetic interaction was not investigated. The majority of studies were conducted in the maximal electroshock model, and other established models were the pentylenetetrazole model, amygdala kindling, and the DBA/2 model. By far the most widely used method for interpretation of the results was evaluation of the effect of a threshold dose of one agent on the median effective dose (ED50) of another agent. Experiments relying on this method found synergism significantly more often compared with experiments relying on other methods (p<0.001). Furthermore, experiments including antagonists of the AMPA receptor were more likely to find synergism in comparison with all other experiments (p<0.001).
  
  
  CONCLUSIONS
  Intensive preclinical research into the effects of AED combinations has not led to an understanding of the pharmacodynamic properties of AED combinations. Specifically, the majority of the preclinical studies are not adequately designed to distinguish between additive, synergistic, and antagonistic interactions. Quantitative pharmacokinetic-pharmacodynamic studies of selectively acting AEDs in a battery of animal models are necessary for the development of truly synergistic drug combinations.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Gorlaeus Laboratories, Leiden, The Netherlands.
authors.forename: Daniël M
authors.initials: DM
authors.lastname: Jonker
authors.forename: Rob A
authors.initials: RA
authors.lastname: Voskuyl
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
mesh_terms: D000679:Amygdala / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004597:Electroshock; D004827:Epilepsy / Q000188:drug therapy*; D006801:Humans; D007473:Ion Channels / Q000187:drug effects; D007696:Kindling, Neurologic / Q000502:physiology; D016015:Logistic Models; D010433:Pentylenetetrazole; D017981:Receptors, Neurotransmitter / Q000187:drug effects; D012107:Research Design / Q000592:standards
chemical_list: D000927:Anticonvulsants; D007473:Ion Channels; D017981:Receptors, Neurotransmitter; D010433:Pentylenetetrazole