Basic mechanisms of antiepileptic drugs and their ...ally showed high efficacy in the treatment of...

Review

Basic mechanisms of antiepileptic drugs and theirpharmacokinetic/pharmacodynamic interactions:an update

W³adys³aw Lasoñ1,2, Monika Dudra-Jastrzêbska3,5, Konrad Rejdak4,

Stanis³aw J. Czuczwar3,5

�Department of Experimental Neuroendocrinology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków,

Poland

�Department of Drug Management, Institute of Public Health, Jagiellonian University, Medical College,

Grzegórzecka 20, PL 31-351 Kraków, Poland

�Department of Pathophysiology,

�Department of Neurology, Medical University of Lublin, Jaczewskiego 8,

PL 20-090 Lublin, Poland

�Department of Physiopathology, Institute of Agricultural Medicine, Jaczewskiego 2, PL 20-950 Lublin, Poland

Correspondence: W³adys³aw Lasoñ, e-mail: [email protected]

Abstract:

This article aims to summarize the current views of AED action and the promising new targets for the pharmacotherapy of epilepsy.In the first section of this paper, a neurobiological basis of epilepsy treatment and brief pharmacological characteristics of classicaland new AEDs will be presented. In the second part, the results of experimental studies that have combined AEDs with similar or dif-ferent mechanisms of action will be discussed.

Key words:

antiepileptic drugs, epilepsy, drug interactions, seizures

Abbreviations: AED(s) – antiepileptic drug(s), AMPA – �-amino-3-hydroxy-5-methyl-4-isoxazolepropionate, CBZ – carbamazepine,ESM – ethosuximide, FBM – felbamate, GABA – �-aminob-utyrate, GBP – gabapentin, LCM – lacosamide, LEV – leveti-racetam, LTG – lamotrigine, NMDA – N-methyl-D-aspartate,OXC – oxcarbazepine, PB – phenobarbital, PGB – pregabalin,PHT – phenytoin, RTG – retigabine, TGB – tiagabine, TPM – topi-ramate, VGB – vigabatrin, VPA – valproate, ZNS – zonisamide

Introduction

The beginning of a rational pharmacotherapy for epi-lepsy dates back to the second half of nineteenth cen-

tury when bromides were introduced as fairly effi-cient, but toxic, anticonvulsant agents. The first syn-thetic antiepileptic drug (AED) was phenobarbital(PB), which efficiently combated tonic seizures, in-hibited partial seizures to a lesser extent, and had noeffect in the absence epilepsy. Employment of electro-convulsive shock by Putnam and Merritt for thescreening of potential anticonvulsants in late 1930s[82] led to the discovery of diphenylhydantoin(phenytoin; PHT), which is a non-sedative still widelyused as an AED [67, 91]. The maximal electroconvul-sive shock test was the most valuable model for thediscovery of new AEDs because substances that pre-vented hind limb extension in rodents in this test usu-

�� 271

��

��

� ��

��

�� !�"��

��"�� #!�$� � �� !��!��

ally showed high efficacy in the treatment of partialand tonic-clonic seizures in the clinic. Seizures in-duced by the GABA receptor antagonist, pentylenete-trazole, are a very useful screening test for the identi-fication of AEDs, particularly drugs that are effectivein the treatment of myoclonic epilepsies. Despite theirlong history and the implementation of more ad-vanced pharmacological models, both of these testsare still broadly used in preclinical studies. Thechemical structure of the majority of AEDs marketedbefore 1965 was based on PB and comprised somederivatives of hydantoin and imides of succinic acid[67, 91]. From 1965 to 1990, several new AEDs withquite distinct chemical formulas appeared on thepharmaceutical market, such as benzodiazepines, imi-nostilbene (carbamazepine; CBZ) and carboxylic acidwith a branched aliphatic chain, known as valproicacid. In the 1990s, pharmaceutical companies launcheda battery of new generation AEDs represented byphenyltriazine (lamotrigine; LTG), a cyclic analog ofGABA (gabapentin; GBP), an aminosulfonic deriva-tive of monosaccharide (topiramate; TPM), a deriva-tive of nipecotic acid (tiagabine; TGB) and a deriva-tive of pyrrolidine (levetiracetam; LEV) [67, 119].According to physician expectation, an ideal AEDshould totally inhibit seizures without producing anyundesired effects. Regretfully, all known AEDs pos-sess limited clinical efficacy and frequently produceundesired symptoms, which range from mild distur-bances of central nervous system (CNS) functions tofatal cases of bone marrow damage or liver insuffi-ciency [67]. Therefore, the physician has to select theappropriate drug or combination of drugs that willprovide optimal suppression of epileptic attacks in anindividual patient accompanied with acceptable levelsof side effects. It is assumed that total control of epi-leptic attacks can be achieved in approximately 50%of patients, and a significant improvement can be ob-served in another 25% of patients. The ultimate suc-cess of epilepsy treatment depends on the type of epi-leptic attack, etiology and many other factors. Tominimize toxic effects, treatment with a single drug ispreferred. However, if the drug is not effective despiteits proper therapeutic blood level, substitution withanother drug rather than the administration of bothdrugs together is suggested. On the other hand, poly-therapy may be required, especially when more thanone kind of epileptic attacks is diagnosed in the samepatient [67, 91]. The measurement of drug plasma

blood levels facilitates the optimization of the phar-macotherapy of epilepsy during the first period ofdose adjustment, in cases of unsuccessful treatment,the appearance of toxic symptoms, and during poly-therapy. It should be kept in mind that the clinical effi-cacy of some drugs is not always strictly correlatedwith their blood levels, and therefore, the recom-mended drug concentrations should be regarded asa suggestion only. The final shape of the therapeuticprocedure will depend on the clinical estimation ofdrug efficiency and its toxic effects [113, 121].

Neurobiological basis of AED action

The molecular targets for classic, new generation andpotential AEDs are voltage-dependent sodium, cal-cium, potassium channels, h-channels, GABA� recep-tors, excitatory amino acid receptors, some enzymesand synaptic proteins [90, 92, 93]. The GABA mimeticeffects and the blockade of voltage dependent sodiumchannels dominate the other mechanisms of AEDs [7,13, 15, 68, 80, 90, 119]. GABA is the most importantinhibitory transmitter in the CNS and even slight defi-ciencies in GABAergic transmission lead to hyper-excitability and pathological neuronal discharges [63].

The balance between synaptic excitation and inhi-bition depends mainly on the correct anatomical andfunctional organization of the neuronal net, which iscomposed of glutamatergic neurons and GABAergicinterneurons [63, 119]. Although only 10–20% ofneurons synthesize GABA in cortical structures ofmammals, this amino acid efficiently controls thelevel of activity of all cortical neurons. The profi-ciency of synaptic inhibition in local neuronal loopsdepends on the divergence of innervation. The inner-vation of single GABAergic interneuron may inhibitseveral thousands of glutamatergic cells, or manyGABA interneurons may convergence on the sameglutamatergic cell. In contrast, GABA interneuronsare stimulated by glutamatergic neurons and inhibitedby other interneurons. GABA is the product of gluta-mate decarboxylation, and after its release to the syn-aptic cleft, it is taken up by glia and neuronal cells,where it is metabolized by GABA aminotransferase tosuccinic semialdehyde. Four transporters (GAT1-4)participate in GABA uptake. GABA exerts its phar-macological action via membrane GABA�, GABA�

272 ��

and GABA� receptors. GABA� and GABA� recep-tors are ionotropic receptors that form channels per-meable to Cl� ions in the neuronal membrane, whereasGABA� receptors are metabotropic. GABA� recep-tors play a role in the formation of fast inhibitorypostsynaptic potentials and, therefore, play a key rolein controlling seizure phenomena. GABA� receptoragonists enhance chloride channel conductance to de-crease resistance and increase hyperpolarization ofthe neuronal membrane [29]. As a consequence, thestimulation of GABA� receptors usually increasesseizure threshold in the presence of epilepsy, but notin the absence of epilepsy, and inhibits the spreadingof seizure activity [15, 68, 119]. Conversely, GABA�

receptor antagonists, such as bicuculline, picrotoxinor pentylenetetrazole, are some of the most potentseizure-inducing agents. Molecular cloning has re-vealed that the GABA� receptor forms a pentamericprotein complex that is composed of two � subunits,two � subunits that contain the GABA binding siteand one � or � subunit. The subunit composition (i.e.,the receptor configuration) determines the affinity andpharmacodynamic effectiveness of GABA� receptoragonists, modulators and antagonists. An enhancementof GABAergic inhibitory transmission is responsiblefor the antiepileptic effects of drugs that directly bindand activate GABA� receptors or influence GABAsynthesis, transport and metabolism [15, 26, 68, 119].

and GABA� receptors. GABA� and GABA� recep-tors are ionotropic receptors that form channels per-meable to Cl� ions in the neuronal membrane, whereasGABA� receptors are metabotropic. GABA� recep-tors play a role in the formation of fast inhibitorypostsynaptic potentials and, therefore, play a key rolein controlling seizure phenomena. GABA� receptoragonists enhance chloride channel conductance to de-crease resistance and increase hyperpolarization ofthe neuronal membrane [29]. As a consequence, thestimulation of GABA� receptors usually increasesseizure threshold in the presence of epilepsy, but notin the absence of epilepsy, and inhibits the spreadingof seizure activity [15, 68, 119]. Conversely, GABA�

receptor antagonists, such as bicuculline, picrotoxinor pentylenetetrazole, are some of the most potentseizure-inducing agents. Molecular cloning has re-vealed that the GABA� receptor forms a pentamericprotein complex that is composed of two � subunits,two � subunits that contain the GABA binding siteand one � or � subunit. The subunit composition (i.e.,the receptor configuration) determines the affinity andpharmacodynamic effectiveness of GABA� receptoragonists, modulators and antagonists. An enhancementof GABAergic inhibitory transmission is responsiblefor the antiepileptic effects of drugs that directly bindand activate GABA� receptors or influence GABAsynthesis, transport and metabolism [15, 26, 68, 119].

Glutamate is the main excitatory neurotransmitterin the CNS. It activates ionotropic receptors that arenamed after specific agonists, AMPA (�-amino-3hydroxy-5-methyl-4-isoxazolepropionate), NMDA (N-methyl-D-aspartate) and kainate receptors, and meta-botropic receptors that act via G protein influence onvarious second messenger systems and ion channelactivity. NMDA receptors consist of NR1 subunitscombined with one or more NR2 (A–D) subunits,which form channels that are permeable to sodiumand calcium ions. The activity of NMDA receptors isregulated via a strychnine-insensitive glycine-bindingsite and other modulatory sites, such as polyamine,Zn��, H�. At resting membrane potentials, the pore ofthis receptor is blocked by magnesium ions, which areremoved after membrane depolarization. The role ofNMDA receptors in experimental epileptogenesis,neuroplasticity, seizures and excitotoxicity has beenfirmly established. Antagonists of NMDA receptors,such as dizocilpine or ketamine, inhibit seizures in-duced by pentylenetetrazole, pilocarpine, maximalelectroshock or sensory stimulation. Furthermore,

they delay the development of amygdala kindling buthave a weaker effect on fully developed seizures inthis model. Unfortunately, both competitive and non-competitive NMDA receptor antagonists show seriousundesired effects, such as psychomotor, memory andcognitive disturbances, and psychotomimetic-like ef-fects in experimental animals and in initial clinicalstudies. Moreover, these undesired symptoms are en-hanced in experimental models of epilepsy [2, 48, 49,68]. Therefore, some allosteric modulators of NMDAreceptors, especially modulators that interact with thestrychnine-insensitive glycine-binding site and thepolyamine-binding site, are more promising as poten-tial AEDs [39, 68]. Antagonists of the glycine bindingsite and the polyamine-binding site show affinity forNR1/NR2A subunits and NR1A/NR2B complexes,respectively. The partial agonist of the glycine bind-ing site, D-cycloserine, exerts anticonvulsant activitymost likely via the desensitization of NMDA recep-tors. This compound also augments the seizure-suppressing effects of some AEDs and, in low doses,has a positive influence on memory processes. Thebeneficial effects in experimental models of seizureshave been observed after the concomitant administra-tion of glycine- and polyamine-binding site antagonists[39]. Lacosamide (LCM), an antagonist of the glycine-binding site on NMDA receptors, has been registeredas an AED in 2008 [5, 25, 33, 106]. Another exampleis felbamate, which shows inhibitory action onvoltage-dependent sodium channels and antagonisticactivity toward the glycine-binding site on NMDA re-ceptors [9, 68].

Glutamatergic AMPA receptors play the main rolein the mediation of excitatory synaptic conductance inthe central nervous system. AMPA receptor complexesconsist of various combinations of four homologousGluR1-GluR4 subunits and function as cation channelsthat are permeable for Na� and K� ions and, in someconfigurations, also to calcium ions. Complexes thatcontain the GluR2 subunit show low permeability tocalcium ions. In the presence of an agonist, the AMPAreceptor undergoes desensitization. However, inhibi-tors of desensitization, such as cyclothiazide, are posi-tive allosteric modulators of this receptor [24]. Nega-tive allosteric modulators of AMPA receptors are 2,3-benzodiazepines. NMDA receptor-dependent calciumion influx and the subsequent activation of protein ki-nases lead to the phosphorylation of AMPA receptorand to an increase in its activity. This process may beresponsible for the pathological hyperactivity of gluta-

�� 273

Mechanisms of antiepileptic drug actions��

matergic conductance and epileptoidal neuronal dis-charges. Phosphatases, including calcineurin, dephos-phorylate AMPA receptors and decrease their activity.Antagonists of AMPA and kainate receptors inhibitseizures in chemical (e.g., pentylenetetrazole, bicu-culline) and genetic models of seizures [38]. Theyalso potentiate the anticonvulsant effects of classicalAEDs, such as PB or valproate (VPA) [13]. Theseagents affect motor coordination and memory pro-cesses to a lesser extent than NMDA receptor antago-nists. Among the already registered AEDs that pos-sess the ability to block AMPA receptors, one shouldalso mention barbiturates and TPM.

The non-competitive AMPA receptor antagonist,talampanel, shows a broad spectrum of anticonvulsantactivity and is currently being tested in clinical trials[35, 36]. Kainate receptors are less abundant in thebrain than AMPA receptors, but their broad distribu-tion suggests that they are present in a majority ofneurons. Kainate receptors consist of GluR5-GluR7and KA1-KA2 subunits, and their activity can be af-fected by the same ligands that bind to AMPA recep-tors, although with various preferences. GluR5 andGluR6 subunits form homomeric channels, but theother subunits are parts of heteromeric combinationswith GluR5 and GluR6 subunits. The activation ofpostsynaptic kainate receptors leads to long-term neu-ronal depolarization and augmented intracellular Ca��

influx, which may play a role in changes in synapticplasticity and in the seizurogenic and neurotoxic ef-fects of kainate. The potent epileptogenic and neurotoxiceffects of kainate may be also connected to the presynap-tic inhibition of GABA release, because this agent de-creases GABA� and GABA� receptor-dependent inhibi-tory synaptic potentials in the CA1 hippocampal field.Presynaptic kainate receptors can be also involvedduring an enhancement of glutamate release, as theactivation of these receptors increases calcium ionconcentration in synaptosomes [39, 45, 68, 90]. Theabove-mentioned facts suggest that modulators of kai-nate receptor activity should not be overlooked as po-tential AEDs [13, 65, 90]. In addition to ionotropicexcitatory amino acid receptors, there are eight meta-botropic glutamate receptor (mGluR) subtypes thatare classified into three groups based on amino acidsequence similarity, agonist pharmacology and thesignal transduction pathways to which they couple.The activation of group I mGluRs (i.e., mGlu� andmGlu�) stimulates inositol phosphate metabolism andthe mobilization of intracellular Ca��. Agonists of

group II (i.e., mGlu� and mGlu�) and group III (i.e.,mGlu and mGlu��) mGluRs inhibit adenylyl cyclase.A fourth group of mGluRs that couple to phospholi-pase D has been also reported. Group I mGluRs arelocalized postsynaptically on both glutamatergic cor-tical and hippocampal neurons and on GABAergic in-terneurons. Their activation causes the phosphoryla-tion and inactivation of many types of potassiumchannels, which results in depolarization and neuronalhyperexcitability. Group II and III mGluRs are inhibi-tory presynaptic autoreceptors on glutamatergic neu-ronal endings or inhibitory presynaptic heterorecep-tors that are localized on some GABAergic neuronalterminals. Agonists of group I mGluRs evoke seizuresin experimental animals and elongate the duration ofboth interictal and ictal discharges in hippocampalslices; their antagonists act in the opposite way. In-deed, some antagonists of mGlu� or mGlu� receptorsand several agonists that act on group III mGluRsshow anticonvulsant activity in animal models of gen-eral epilepsy or in the absence epilepsy. Therefore,these agents may be regarded as potential AEDs [40,70, 90]. Furthermore, the agonist of group II mGluRs,LY354740, markedly enhances the antiepileptic activ-ity of diazepam [40]. After its release, the uptake ofglutamate within the human brain is mediated by 5subtypes of high-affinity, sodium-dependent excita-tory amino acid transporters (EEATs) that are local-ized in the cell membranes of astrocytes (EAAT1,EAAT2) and neurons (EAAT3-5). Excessive activityof the glutamatergic system plays an essential role inthe pathomechanism of epileptic attacks of variousetiologies [13, 68]. Attenuation of excitatory trans-mission to inhibit ictal neuronal activity can be achievedthrough a decrease in glutamate synthesis, the modula-tion of presynaptic receptors or the calcium-dependentrelease of the glutamate, an increase in glutamate uptakeand a decrease of postsynaptic glutamate receptor activi-ties [13, 68]. Several AEDs inhibit glutamatergic systemactivity; however, these effects seem to play a minorrole in their mechanisms of action.

Voltage-gated sodium channels (VDSCs) are pro-teins that are comprised of four repeated domains ofsix transmembrane segments, which form sodiumion-selective pores. The brain contains subtypes I, II,IIa, III and VI of sodium channels, which are sensitiveto tetrodotoxin, and their conductance ranges from 2.5to 25 pS. VDSCs are responsible for the generation ofaction potentials and are the main targets for manyAEDs, including PHT, CBZ and LTG [68, 69, 90, 91,

274 ��

117, 119]. These drugs block sodium channels duringhigh frequency discharges, but in therapeutic concen-trations, they have no effect on physiological synaptictransmission. They show an ability to inhibit both re-petitive action potentials in the epileptic focus and thespreading of epileptic discharges. Voltage-dependentcalcium channels (VDCCs) are divided into severalsubtypes, L, N, P/Q, T and R, according to their elec-trophysiological characteristics. VDCCs are formedof an �1 subunit, which is the sensor of the potential,and �2, �, � and � subunits which regulate the kinet-ics and amplitude of calcium currents. Blockade of Nor P/Q channels inhibits the presynaptic release of ex-citatory amino acids. However, a potential role forthese channels in AED action has not been elucidated.The low-voltage calcium channel, T, plays an essen-tial role in the mechanism of the thalamo-cortical os-cillatory activity and the generation of spike-wavedischarges; it also plays a pathological role in the ab-sence epilepsy [90, 91, 119].

Potassium channels are classified into the inward rec-tifier (K �) superfamily, which comprises the recep-tor-coupled ATP-sensitive and voltage-dependent chan-nels, and the shaker-related superfamily which includesCa��-activated potassium channels. The muscarine-sensitive Kv7 (KCNQ) type potassium channels areresponsible for a slowly activating current whosethreshold is near resting potential and play an essen-tial role in neuronal repolarisation and hyperpolarisa-tion that follows paroxysmal depolarization shifts [3,61, 120–123]. It has been well established that Kv7/KCNQ/M potassium channels mediate the M-currentwhich inhibits repetitive firing and burst generation.There are four neuronal Kv7 subunits (Kv7.2– Kv7.5)which serve as the target for some recently approvedAED retigabine and currently being tested in earlyclinical phases ICA-105665 [3, 120, 121, 123]. Someof these channels, such as the muscarine-sensitiveKCNQ2, are important regulators of neuronal excit-ability. An involvement of potassium channels in themechanism of AEDs, with the exception of retiga-bine, remains largely unknown [119]. Mutations ofmembrane ion channels and receptors disturb bioelec-tric neuronal activity and are an important causativefactor in the pathogenesis of epilepsy [1, 122]. In-deed, some genes whose mutations lead to distur-bances in brain development, metabolism, neurode-generation and abnormal neuronal activity are oftenassociated with certain inherited types of epilepsies.Channelopathies due to the mutation of subunits of

voltage-dependent sodium, potassium, calcium andchloride neuronal channels deserve special attention[44]. A single amino acid mutation can significantlyalter ion channel kinetic parameters and the affinity ofits ligands. Thus substitution of lysine with methio-nine in the �2 subunit of the GABA� receptor de-creases inhibitory postsynaptic potentials. On theother hand, the substitution of alanine with asparaginein the �1 subunit lowers GABA� receptor sensitivity,elongates the time of its desensitization and shortensthe opening time for chloride channels. Changes inthe same locus can be reflected in the heterogenousphenotype, whereas, the same epileptic syndromemay be caused by various genetic defects. The wellknow genetically determined epilepsy syndromes in-clude benign familial neonatal or infantile convul-sions (BFNC or BFIC), autosomal dominant noctur-nal frontal lobe epilepsy (ADNFLE), absence epi-lepsy, myoclonic epilepsies, generalized idiopathicepilepsies and febrile seizures. Mutation in neuronalpotassium channel subunits (KCNQ2 or KCNQ3) areassociated with benign familial neonatal convulsions(BFNC), whereas mutation of voltage-gated sodiumchannels are the substrate for generalized epilepsy withfebrile seizures plus [1]. Furthermore, some other ge-netic disorders e.g., cereidolipofuscinosis, galactosialo-sidosis or gangliosidosis GM1, have epileptic seizuresas one of their symptoms [1, 102].

According to Sills [100], the mechanistic classes ofcurrent AEDs contain fast Na� channel blockers (e.g.,PHT, CBZ, LTG, oxcarbazepine, rufinamide, and esli-carbazepine), slow Na� channel blockers (e.g., laco-samide), high-voltage Ca�� channel blockers (e.g.,GBP, pregabalin), low-voltage Ca�� channel blockers(e.g., ethosuximide), GABA� receptor activators (e.g.,PB, benzodiazepines, stiripentol), GABA transami-nase inhibitors (e.g., vigabatrin; VGB), GABA uptakeinhibitors (e.g., TGB), SV2A ligands (e.g., LEV), andmultiple mechanism drugs (e.g., VPA, felbamate,TPM, and zonisamide (ZNS)). In fact, the majority ofAEDs show multiple mechanisms, although the inter-ference of a drug with one of the above-mentionedsingle targets (i.e., ion channel, membrane receptor,enzyme) is underlined. Therefore, one can proposeother classifications of AEDs that are based on theprimary, secondary and tertiary mechanisms of theiraction. The best-recognized primary mechanisms,such as the blockade of Na� or Ca�� channels and themodulation of the GABAergic system, are importantfor the prevention (through an enhancement of seizure

�� 275


threshold) and suppression of ongoing abnormal neu-ronal activity. The secondary action may involve in-teractions with additional protein targets, such as car-bon anhydrase, or interference with endogenous anti-convulsant systems (e.g., adenosine, neurosteroids,neuropeptides, and antioxidant systems). These mecha-nisms may act in a synergistic or an additive way to po-tentiate the primary mechanisms of action. The tertiarymechanism of AEDs, including the long-term effectson neuroplastic processes (e.g., neurotrophin, cytoki-nes, hormone synthesis and release) and genetic andepigenetic effects, could be involved in the delay ofmorphological changes, neuroplasticity and epilepto-genesis (i.e., adaptive changes in the neuronal, endo-crine and immune systems), which thus changes thecourses of evolution and involution of epilepsy [4, 48].

Although the primary action is the most useful andwidely accepted basis for mechanistic classificationand the designing of AEDs, the secondary and tertiarymechanisms should not be disregarded in the prepara-tion of the “personal” characteristics of a given AED.It remains an open question whether such a full neuro-chemical characteristic of an AED is more helpful inpredicting the spectrum of its clinical efficacy and un-desirable effect profile than the simple, but “trun-cated”, classification system compromised solely ofthe primary mechanism of AED action. Furthermore,the thorough knowledge of the mechanisms of AEDactions may provide a better rationale for the existingopinion that the combination of drugs with differentmechanisms is preferable in the polytherapy of epi-lepsy. According to Gil-Nagel [31], the mode of ac-tion may predict the spectrum of efficacy and side-effect profile of AEDs to some extent. Therefore, se-lective sodium channel blockers (e.g., PHT, CBZ,OXC, ESL) are only effective in partial and secondarygeneralized tonic-clonic seizures, but drugs witha single GABAergic mechanism are likely to havea narrow spectrum of efficacy in partial seizures only.He also stressed that selective calcium channel block-ers (e.g., ESM, GBP, PGB) may not be effective in pri-mary generalized tonic-clonic seizures. AlthoughAEDs with multiple mechanisms (e.g., TPM, LEV,LTG, VPA, ZNS) are likely to be broad spectrum, theyusually have a single predominant mechanism at thera-peutic concentrations. The author concluded thatknowledge of a mechanism of action may be useful forthe selection of broad spectrum AEDs in unknowntypes of epilepsy and in guiding add-on and substitu-tion decisions.

In the first part of this paper, a brief pharmacologicalcharacterization of classic and new AEDs based on thedominant mechanism of action, along with their otherneurochemical properties, will be presented. In the sec-ond part, the results of experimental studies of the com-bination of AEDs with similar or different mechanismsof action will be discussed.

AEDs that enhance GABAergic system

activity

Barbiturates

PB was the first efficient synthetic AED. It possessesrelatively low toxicity, and it is cheap and still widelyused in clinical practice. Although the majority of barbi-turates prevent seizures, only some of them, includingPB, can be used for the treatment of epilepsy becausethey show maximal seizure-suppressing activity in doseslower than doses that induce somnolence. PB is active,although not very selective, in almost all preclinical teststhat are used for screening of potential AEDs. It inhibitstonic hind limb extension in the maximal electroconvul-sive shock test, pentylenetetrazole-induced clonic sei-zures and amygdala kindling [67, 91].

The mechanism of action of PB is most likely connectedwith an enhancement of synaptic inhibition via a positivemodulatory effect of this drug on GABA� receptors.

The possible involvement of GABA� receptors inthe antiepileptic properties of barbiturates was ini-tially controversial because the sleep-inducing pento-barbital had a stronger effect on GABA� receptor ac-tivity than the recognized AED, PB. Further studieshave provided evidence that barbiturates potentiatepre- and postsynaptic activity by increasing the prob-ability and time of GABA� receptor-dependent chloridechannel openings [116]. Intracellular recordings ofmouse cortical and spinal cord neurons has shownthat in therapeutic concentrations, PB enhances thecellular response to iontophoretically administeredGABA. Furthermore, patch-clamp analysis of singleion channels provided evidence that PB elongated thetime but had no effect on the frequency, of GABA�

receptor-dependent neuronal discharges [116]. Theelectrophysiological data correlate well with results ofradioreceptor assays that show that barbiturates bindto the ionophore part of the GABA� receptor complex

276 ��

to enhance GABA affinity to this receptor and inhibitits dissociation. Functional binding of barbituratescan occur even when the configuration of the GABA�

receptor complex is composed of the same subunits,such as � or � (1–3). In supratherapeutic concentra-tions, PB restricts the sustained repetitive neuronaldischarges, and this mechanism may be of signifi-cance in extinguishing status epilepticus with highdoses of PB. In addition to the positive modulatory ef-fect on GABA� receptors, barbiturates can blockVDCCs, intensify voltage-dependent potassium chan-nel activity and inhibit AMPA-receptor-related gluta-matergic transmission [20, 101, 119].

The main indications for barbiturates are general-ized tonic-clonic seizures, partial seizures and drug-resistant status epilepticus [67].

Mephobarbital

This is an N-methyl derivative of PB, which undergoesN-demethylation in the liver reticular endoplasmic sys-tem. The pharmacological activity of mephobarbitalduring long-term therapy results from an accumulationof PB. The indications are similar to PB [26].

Primidone

This is desoxybarbiturate, which is transformed to anamide of phenylethylmalonic acid and to PB. Primi-done shows similar efficacy to PB in the maximalelectroconvulsive shock, but it is less active in thepentylenetetrazole test. Primidone is indicated in gen-eralized tonic-clonic seizures, partial seizures, psy-chomotor and myoclonic seizures [67, 91].

Benzodiazepines

Benzodiazepines are far more effective in inhibitingpentylenetetrazole-induced clonic seizures than sei-zures induced by the maximal electroconvulsiveshock test. For example, clonazepam is an extremelypotent anticonvulsant in the pentylenetetrazole test,but it is almost inactive in the maximal electroconvul-sive shock test. Benzodiazepines prevent seizurespreading in the kindling model and in the model ofgeneralized seizures induced by electrical stimulationof the amygdala, but they do not suppress the abnor-mal neuronal discharges in the site of stimulation.

The antiepileptic activity of benzodiazepines aremainly connected with the positive allosteric modula-

tion of GABA� receptors and an intensification ofsynaptic inhibition [91, 116]. Electrophysiologicalmeasurements demonstrated that therapeutic concen-trations of benzodiazepines increase the frequency butnot the conductance or the time of opening ofGABA�-related chloride channels. Benzodiazepinesenhance the effects of GABA but not the effects thatare produced by other amino acids that increase theconductance of chloride channels, including glycine,�-alanine and taurine. The selective enhancement ofthe effect of GABA is reflected by the shift of thedose-response curve to the left without any alterationin the maximal effect. This effect means an increasedsensitivity of neurons to GABA in the presence of thesame number of accessible chloride channels [91].Subunit composition is of vital importance for thebinding and pharmacological effects of benzodi-azepines, and the co-expression of �, � and � subunitsis required. It has been postulated that � (1–6) subunitsparticipate in the modulation of GABA� receptor func-tion by benzodiazepines, and the � subunits (1–3) de-termine benzodiazepine binding. The � subunit isfound in GABA� receptor complexes, which are in-sensitive to benzodiazepines. Repeated administrationof benzodiazepines leads to the development of toler-ance via a decrease in the ability to enhance theGABA�-dependent chloride current and a reductionin the number of binding sites [101]. Besides the in-teraction with the GABA� receptor, benzodiazepinesinhibit adenosine uptake and block voltage-dependentsodium and calcium channels. The latter mechanismis confirmed by the observation that in the high con-centrations that are used in the treatment of status epi-lepticus, diazepam and some other benzodiazepinesinhibit the sustained high-frequency neuronal dis-charges in manner similar to PHT, CBZ and VPA.

Benzodiazepines are recommended for the treat-ment of pycnoleptic states of unconsciousness,myoclonic-astatic, propulsive attacks and in statusepilepticus [67, 89].

Tiagabine (TGB)

TGB, which is a derivative of nipecotic acid, sup-presses seizures in the maximal electroconvulsiveshock test and partial and tonic-clonic seizures in themodel of amygdala kindling [18]. TGB is a potent andselective inhibitor of the GABA GAT-1 transporter,and it inhibits the uptake of this amino acid from thesynaptic cleft to glia and neuronal cells [41]. In accor-

�� 277


dance with this neurochemical mechanism, electro-physiological data indicate that TGB elongates theduration of inhibitory synaptic currents in CA1 hippo-campal neurons. TGB has no effect on biogenic amineuptake and does not bind to the majority of neuro-transmitter receptors, although it shows a slight affin-ity for histamine and benzodiazepine receptors.

This drug is indicated as an add-on therapy indrug-resistant partial and secondary generalized epi-leptic fits [6, 21, 78, 94].

Vigabatrin

This is analog of GABA (�-vinyl-GABA) and showspotent anticonvulsive effects in amygdala kindlingand in models of audiogenic and chemical seizuresevoked by pentylenetetrazole, picrotoxin and strych-nine [67, 91]. The effectiveness of VGB in the maxi-mal electroconvulsive shock test is controversial.A paradoxical pro-convulsive effect of VGB in theelectroconvulsive test was also observed, but it mightbe due to the withdrawal of this drug.

VGB is an irreversible inhibitor of GABA transami-nase (GABA-T) and, therefore, evokes a long-term in-crease of GABA concentrations in brain tissue, an ef-fect that correlates well with the AED action. VGB in-hibits both neuronal and glial GABA-T; however, itshows a stronger affinity for the enzymes that are pres-ent in neurons [41]. Depolarizing stimuli, such as anextracellular increase in potassium ions during sei-zures, release the accumulated GABA from presynap-tic terminals to intensify GABAergic transmission. Inaddition to inhibiting GABA-T, VGB decreases gluta-mate and aspartate content in brain tissue [41].

This AED is recommended in the treatment of pro-pulsive fits of unconsciousness (monotherapy), partialand complex epilepsy in adults and partial epilepsyand in Lennox-Gastaut syndrome in children as an ad-junctive drug [21, 32, 117].

AEDs affecting the activity of cation

channels (Na+, Ca2+, K+)

Phenytoin (PHT)

PHT (diphenylhydantoin) effectively inhibits all kindsof partial and generalized tonic-clonic seizures butfails to counteract generalized absences. The drug dis-

plays anticonvulsant activity without any prominentdepression of the CNS. In the toxic range, there mightbe central excitation, and lethal doses are accompa-nied by decerebrate rigidity. The most characteristicactivity of PHT is its ability to affect seizures inducedby maximal electroshock in experimental animals.The characteristic tonic phase of seizure activity maybe completely blocked, but the duration of clonic sei-zures may be extended [67, 91, 115]. AEDs that areeffective against human generalized tonic-clonic con-vulsions share this pattern of activity. Furthermore,PHT does not exert any protective action againstpentylenetetrazole-induced clonic seizures. In in vitro

studies performed on mouse spinal cord neurons, thisAED limits high frequency repetitive firing. This par-ticular effect correlates with a slower reactivation ofVDSCs, and interestingly, the higher the frequency ofchannel openings are, the better the inhibitory effectof PHT on this parameter (i.e., use-dependence). It isnoteworthy that the block of high frequency repetitivefiring occurs within the therapeutic range of PHT inthe spinal cord fluid, which is highly correlated withthe free plasma concentration of this AED. This con-centration is responsible for the selective blockade ofVDSCs, and no effects of PHT on glutamate orGABA neuronal activity are observed [91, 119]. With5–10 fold higher concentrations, PHT may exert toxiceffects due to a number of mechanisms, includinga depression of basal neuronal activity or an enhance-ment of GABA-mediated events. Apart from its basicmechanism of action, PHT may lower the conduc-tance of calcium channels and limit calmodulin-dependent phosphorylations in the CNS [115, 119].

This AED is indicated in partial, generalizedtonic-clonic, and psychomotor seizures [77].

Carbamazepine (CBZ)

CBZ, a dibenzoazepine derivative, shares many phar-macological effects with PHT, although there are alsoconsiderable differences. Apart from the antiepilepticactivity, CBZ is effective in manic-depressive patientsresistant to lithium carbonate. Similar to PHT, thisAED limits the high frequency-sustained repetitivefiring of cortical or spinal neurons that results from itspreferential binding to the inactivated forms ofVDSCs. This particular effect leads to slower transi-tions to the activated forms [51]. In the therapeuticconcentration range, CBZ does not affect GABA- orglutamate-mediated neuronal events [34]. 10,11-

278 ��

Epoxycarbamazepine, a metabolite of CBZ, exerts anidentical profile of activity, and this may indicate thatthe metabolite participates in the final effects of theparent drug [66]. In addition, CBZ reduces neuronalcalcium influx. In contrast to PHT, CBZ is a ligand ofA� and A� adenosine receptors and displays some af-finity for benzodiazepine receptors. CBZ is indicatedin the treatment of generalized tonic-clonic and sim-ple or complex partial seizures [85].

Oxcarbazepine (OXC)

This AED is a keto analog of CBZ and, undergoes arapid metabolic transition to the active 10-monohydroxy derivative, which is subsequently glu-curonidated and eliminated via the kidneys. OXCpossesses similar mechanisms of action to CBZ, but itis a weaker activator of microsomal (cytochrome P-450)enzymes [83]. However, OXC may significantly acti-vate CYP3A and reduce the effective concentration oforal contraceptives [84].

Its main indication is in the treatment of partial sei-zures [19].

Lamotrigine (LTG)

LTG [6-(2,3-Dichlorophenyl)-1,2,4-triazine-3,5-diami-ne] inhibits tonic seizures induced by maximal elec-troshock and partial and secondarily generalized con-vulsions in the kindling model. However, it is ineffec-tive against pentylenetetrazole-induced clonic seizures[17, 79]. Similarly to PHT and CBZ, LTG preferen-tially binds to the slowly inactivating conformation ofVDSCs, which is encountered during prolonged depo-larization or epileptic discharges. This mechanism ofaction may be associated with the ability of LTG tocontrol partial secondarily generalized seizures. LTGhas a broader spectrum of anticonvulsant activitycompared to PHT and CBZ, which may suggest theexistence of other mechanisms of action. For exam-ple, LTG reduces veratridine-induced synaptic releaseof glutamate or aspartate at micromolar concentra-tions through the blockade of presynaptic sodiumchannels. This AED is an effective antagonist ofAMPA glutamate receptors [12, 42, 55]. Consideringthe novel mechanism of LTG, it is emphasized thatthis drug can block dendritic action potentials and en-hance currents that are carried by h channels [57, 91].The main indications for LTG include partial seizures

with or without secondarily generalized tonic-clonicseizures and Lennox-Gastaut syndrome [22, 27].

Topiramate (TPM)

TPM is a monosaccharide derivative with a broadspectrum of anticonvulsant activity [99, 118]. Thisdrug is effective in a variety of animal models of epi-lepsy, including maximal electroshock, pentylenete-trazole-induced and kindled partial and secondarilygeneralized seizures [13]. TPM reduces voltage-dependent sodium currents in cerebellar granulaecells, and this action is similar to PHT regarding theinactivation of sodium channels. In addition, TPM ac-tivates a hyperpolarizing potassium current, enhancesGABA-mediated actions, and diminishes glutamate-induced excitation via AMPA receptors. Interestingly,this antiepileptic interacts with the GABA� receptorcomplex at a site different from either barbiturate- orbenzodiazepine-binding sites. TPM is also a weak in-hibitor of carbonic anhydrase [13, 91].

This AED is recommended against many types of epi-leptic seizures, including drug-resistant convulsions [67].

Ethosuximide (ESM)

ESM is an imide of succinic acid that is effective againstpentylenetetrazole-induced clonic convulsions but notagainst tonic seizures induced by maximal electroshock.This drug is also not effective against kindled seizures.This pharmacological profile is in good correlation withthe clinical activity of ESM against generalized ab-sences. Its mechanism of action is related to the reduc-tion of the low threshold T calcium current in the tha-lamic neurons. This current is apparently involved in thegeneration of rhythmic 3 Hz spike-wave discharges thatare typical of absence seizures [12]. At therapeutic con-centrations, ESM inhibits T calcium currents in rat ven-tral basal or guinea pig thalamic neurons but does not af-fect the T calcium channel voltage-dependent inactiva-tion kinetics, repetitive neuronal firing, or the enhance-ment of GABA- mediated events [91].

This AED is effective against generalized absences [67].

Valproate (VPA)

Contrary to PHT and ESM, VPA [di-n-propylaceticacid] is an effective inhibitor of seizure activity ina variety of experimental animal models. VPA blocksthe tonic hind limb extension in the maximal electro-

�� 279


shock test and displays a protective activity againstkindled seizures and pentylenetetrazole-induced clonicconvulsions at doses that are lower than toxic concen-trations [67]. Its mechanism of action is still a matterof controversy. At a therapeutic concentration, VPAreduces high frequency repetitive firing in mouse cor-tical or spinal neurons [47]. This particular activity re-sembles PHT or CBZ to a considerable degree andseems to be related to the longer period of time thatthe sodium channel needs to recover from the inacti-vation state. However, VPA does not modify neuronalresponses to iontophoretically applied GABA. ThisAED is responsible for the moderate inhibition of Tcalcium channel activity. An additional mechanism isone that is involved in its effect on GABA metabolism.Brain GABA concentrations are elevated by VPA andin in vitro studies, VPA stimulates the GABA synthe-sizing enzyme, glutamate decarboxylase, and inhibitsGABA metabolizing enzymes, GABA transaminase,succinic semialdehyde dehydrogenase, and aldehydereductase.

The drug also reduces the activity of voltage-dependent T-type calcium channels. There has been noproof for a correlation between the increase in brainGABA and the anticonvulsant activity of VPA [67, 91].

This AED may be used for the therapy of absences,myoclonic, partial, and tonic-clonic seizures [67].

Retigabine

RTG [N-(2-amino-4-(4-fluorobenzylamino)-phenyl) car-bamic acid ethyl ester]. This drug shows anticonvul-sant properties in a variety of animal models, includ-ing maximal electroconvulsive shock, amygdala kin-dling, pentylenetetrazole-, picrotoxin-, and NMDA-induced seizures and in genetic models of epilepsy [3,17]. The anticonvulsant action of this drug resultsmainly from the opening of voltage-gated KCNQ2/3potassium channels, which are abundantly expressedin the brain, are associated with seizures and appear tocontrol neuronal excitability via the M-current [89]. Ithas been found that RTG activates neuronal KCNQ-type potassium channels by inducing a large hyperpo-larizing shift of steady-state activation. Importantly, re-tigabine activates neuronal Kv7.2-Kv7.5 (KCNQ2-KCNQ5) potassium channel subunits but not on car-

diac Kv 7.1 (KCNQ1) channel [122–124]. Molecularstudies demonstrated that RTG binds to hydrophobicpocket formed upon channel opening between the cyto-plasmic parts S5 and S6 involving Trp236 and the chan-nel’s gate, which account for the marked shift involtage-dependent activation [122, 123].

In higher concentrations, RTG potentiates GABA-induced currents in rat cortical neurons. This drugalso inhibits 4-aminopyridine-induced glutamate re-lease and the de novo synthesis of GABA in the hip-pocampus [71]. This drug has been recently registeredas adjunctive treatment of partial onset seizures withor without secondary generalization in adults aged 18years and above with epilepsy [10, 72, 79].

Zonisamide (ZNS)

ZNS is an aromatic sulfonamide derivative that showsanticonvulsant activity in the maximal electroshocktest and the kindling model of epilepsy [43]. Thisdrug effectively inhibits partial or secondarily gener-alized convulsions, but it is ineffective against minimalpentylenetetrazole-induced seizure activity, which isa model of myoclonic seizures [56, 72]. ZNS is an in-hibitor of T calcium channels and, similar to PHT andCBZ, it reduces high frequency repetitive firing inspinal cord neurons, which is probably dependent onthe longer inactivation time of VDSCs [95, 107].

Its main recommendation is drug-resistant partialseizures in the form of an adjuvant drug [97, 107, 125].

Antagonists of receptors for excitatory

amino acids

Felbamate (FBM)

FBM is a dicarbamate that is active against bothmaximal electroshock and pentylenetetrazole-inducedconvulsions [108]. In vitro studies have documentedthat FBM is an NMDA receptor antagonist at thera-peutic concentrations, and moreover, it potentiatesGABA-mediated events in hippocampal neurons.A simultaneous reduction and enhancement of excita-tory and inhibitory neurotransmission, respectively,may play a considerable role in FBM’s broad spec-trum of anticonvulsive activity. Due to a risk of aplas-tic anemia, this AED has limited recommendations

280 ��

and may be used practically as an adjuvant inLennox-Gastaut syndrome [76, 77].

Lacosamide (LCM)

LCM, (R)-2-acetamido-N-benzyl-3-methoxypropion-amide, demonstrates high anticonvulsant activity ina broad range of animal models of partial onset andpharmacoresistant seizures, generalized tonic-clonicseizures and status epilepticus [104]. LCM preventspsychomotor seizures in the 6 Hz model and sound-induced seizures in an audiogenic model. The drug isalso effective in the maximal electroshock test and theamygdala and hippocampal kindling models. How-ever, the effectiveness of LCM was less pronouncedagainst clonic seizures induced by pentylenetetrazole,bicuculline or picrotoxin in rodents [5]. The anticon-vulsant mechanism in humans is not fully understood.LCM neither influences voltage-activated potassiumchannels nor VDCCs. The drug selectively enhancessodium channel slow inactivation with no influenceon fast inactivation [5].

According to clinical trials that have evaluated theefficacy and safety of LCM, the drug is a safe and aneffective agent for the adjunctive treatment of refrac-tory partial-onset seizure [25]. LCM is still beingevaluated in clinical trials as a treatment for chronicrefractory neuropathy and pain in diabetic neuropathy.LCM is also considered as a therapy for migraine pro-phylaxis and fibromyalgia syndrome [33, 67].

Talampanel

Talampanel [7-acetyl-5-(4-amino-phenyl)-8,9dihydro-8-methyl-7H-1,3-dioxolo(4,5H)-2,3-benzodiazepine] isa new allosteric inhibitor of the AMPA receptor witha weak ability to inhibit kainate receptors [35]. It hasno activity at NMDA receptors. TLP treatment sup-presses seizures in the maximal electroshock and pen-tylenetetrazole tests in rodents but is only weakly ac-tive in animal models of absence epilepsy [35]. Ac-cording to the results from a phase 2 trial of TLP foradults with recurrent gliomas, the treatment was welltolerated but had no significant activity as a singleagent [36]. This drug is still being examined in pre-clinical and clinical trials as a treatment for patientswith amyotrophic lateral sclerosis, adults with partialseizures or advanced Parkinson’s disease [125].

AEDs sharing other or unknown

mechanism of action

Acetazolamide

Acetazolamide is a prototype inhibitor of carbonic an-hydrase and shows potent anticonvulsant activityagainst maximal electroshock-induced convulsionsand, at higher dosages, against convulsions producedby the GABA� receptor antagonists, pentylenetetra-zole and bicuculline. As an uncompetitive anhydraseinhibitor in central glial cells, acetazolamide is re-sponsible for the elevation of carbon dioxide in theextraneuronal space and in neurons themselves. How-ever, how this event is involved in the inhibition ofseizure activity is still a matter of dispute [67, 91].

The apparent disadvantage of this AED is the quickdevelopment of tolerance to its anticonvulsant action.Acetazolamide may be transiently effective againsttonic-clonic, partial, and absence seizures [86].

Sulthiame

Sulthiame is an inhibitor of carbonic anhydrase [62,91, 111, 112]. It is recommended in epileptic seizuresof focal origin with or without secondary generaliza-tion, especially benign partial epilepsies in childhood,such as rolandic epilepsy [67].

Gabapentin (GBP)

In rodents, GBP [1-(aminomethyl)cyclohexaneaceticacid] inhibits the tonic hind limb extension produced bymaximal electroshock and pentylenetetrazole-inducedclonic seizures. This profile of activity is similar to VPA[13]. The mechanism of action of GBP is not fully un-derstood. In addition to being a cyclic analog of GABA,this AED does not bind to GABA� receptors. However,GBP may promote the release of an extravesicular poolof this amino acid neurotransmitter. In addition, GBPcan increase the synthesis of brain GABA probably via

an enhancement of glutamate decarboxylase activity.This AED also reduces the activity of the aminotransfe-rase, BCAA, which results in a reduced synthesis of glu-tamate. GBP and its structurally related drug – prega-balin – bind to the proteins of cortical neurons with anamino acid sequence that is identical to the �� subunitsof the voltage-operated calcium L-type channel [100].However, it has no effect on the activity of L-, T-, or N-

�� 281


type calcium channels that are located in spinal dorsalroot neurons [91, 110].

This AED is recommended against partial seizureswith/or without secondary generalization. GBP canalso be helpful in the treatment of chronic pain (e.g.,neuropathic), migraine and bipolar disorder [67].

Levetiracetam (LEV)

LEV [(S)-2-(2-oxopyrrolidin-1-yl)butanamide] possessesa unique pharmacological profile of activity. It counter-acts partial and secondarily generalized tonic-clonicconvulsions in the kindling model, but it is ineffectiveagainst maximal electroshock- or pentylenetetrazole-induced seizures [67, 91, 119]. Its mechanism of actionhas not been clarified. There is no convincing evidencepointing to the interaction of LEV with VDSCs or glu-tamate receptors. However, it reverses the effects ofnegative allosteric modulators of GABA� receptors,�-carboline or zinc ions [88]. An involvement ofGABA-mediated events in the anticonvulsant activityof this AED is uncertain. LEV binds selectively to thesynaptic vesicle protein, SV2A which is located in syn-aptic vesicles of the rat brain [88]. This protein is in-volved in the exocytosis of neurotransmitters, particu-larly glutamate. There is some evidence that SV2A isinvolved in the mediation of the in vivo anticonvulsantactivity of LEV [119]. Clinical use of LEV is mainlyrestricted to drug-resistant partial seizures, mainly inthe form of an add-on therapy.

A summary of the mechanisms of action of AEDsis listed in Table 1.

Pregabaline (PGB)

PGB [(S)-(+)-3-isobutyl-GABA] inhibits maximal elec-troshock and GABA A receptor antagonists-inducedthreshold clonic seizures in rodents. It is also effectiveagainst audiogenic seizures in DBA/2 mice and sup-press hippocampal kindling in rats. The mechanism ofPGB action has not been fully elucidated. This drugbinds to �� type 1 and 2 subunits of voltage-gatedcalcium channels, decreases calcium inward currents,and lowers glutamate brain concentration. PGB doesnot interact with GABA receptors, uptake or metabo-lism. PGB is recommended against refractory partialseizures as an add-on therapy [51].

Interactions concerning AEDs

Pharmacokinetic interactions

Pharmacokinetics concerns problems that are relatedto drug absorption, distribution, metabolism andelimination from the body [28]. Consequently, theremight be interactions that occur at these levels, for ex-ample, at the metabolic level. If there are pharmaco-logically active metabolites of a drug, then the exist-ing interactions may involve the parent drug and/orthese metabolites [for review see 83].

A good example of an interaction at the level ofdrug absorption is the oral use of activated charcoal,which significantly reduces the absorption of variousdrugs, including AEDs [83].

The distribution of AEDs is closely associated tothe degrees of their binding to blood albumins, andany interactions are likely when at least 90% of anAED is protein bound. PHT, TGB, and VPA fulfillthis condition [91]. It is noteworthy that VPA can dis-place PHT from the protein bound form, which resultsin an increase in its free form that is responsible forthe therapeutic effect. Compensative mechanisms areusually activated, and the enhanced metabolism ofPHT is responsible for the eventual reduction of its to-tal blood concentration. Transiently, the free plasmaconcentration of PHT may even be elevated due to theinhibitory effect of VPA on PHT metabolism [83].The estimation of total blood PHT concentration maybe misleading because its reduction may be accompa-nied by toxicity that results from the transient increasein free plasma concentration [84]. A VPA-like effecttowards PHT may be exerted by phenylbutazone ortolbutamide. AEDs, which are not protein bound toa considerable degree, are usually devoid of the inter-actions mentioned above. These AEDs include ESM,GBP, PGB, and VGB [85].

Because of different metabolic pathways, meta-bolic interactions can occur at the level of cytochromeP-450 (CYP) or UDP-glucuronosyltransferase (UGT)enzymes. The first pathway is involved in the metabo-lism of CBZ, FBM, PB, PHT, TGB, TPM and ZNS.The second pathway metabolizes LTG and VPA [87].Among a variety of liver CYP isoenzymes for the me-tabolism of AEDs, CYP3A4, CYP2C9, and CYP2C19are mainly responsible [96]. It is remarkable thatCBZ, PB, PHT, and primidone are activators of CYPisoenzymes, but VPA is a CYP inhibitor. Conse-

282 ��

quently, activators may accelerate their own metabo-lism or the metabolism of other drugs [83]. For exam-ple, CBZ enhances the metabolic breakdown of olan-zapine and warfarin [83]. Although newer AEDs aregenerally devoid of diffuse stimulatory effects ona series of CYP isoenzymes, they can enhance the ac-tivity of a particular CYP isoform. For example, OXCactivates CYP3A isoenzymes, which are involved inthe metabolism of oral contraceptive drugs [30, 84] ordihydropyridine calcium channel antagonists. TPM isa weak activator of the CYP3A4 isoenzyme, but atdaily doses exceeding 200 mg, it may reduce the ef-fectiveness of oral contraception [84]. Due to the in-

hibitory effect of VPA on CYP isoenzymes, this par-ticular AED may significantly elevate the plasma con-centrations of PB or PHT [74, 75, 103]. In addition tothe inhibitory influence on CYP or UGT (see below),VPA is also an inhibitor of epoxide hydrolase, whichis the enzyme that plays a role in the metabolism ofCBZ. Eventually, VPA may cause an increase in theconcentration of carbamazepine-10,11-epoxide, whichmay manifest in the form of an enhanced toxicity withplasma CBZ concentrations in the therapeutic range [83].

Among the many UGT isoenzymes, UGT1A4 isassociated with the glucuronidation of LTG, andUGT1A3 is associated with the glucuronidation of

�� 283


Tab. 1. Mechanisms of action of AEDs

AED Increasein GABA level

Affinityto GABA�receptor

Blockadeof sodiumchannels

Blockadeof calciumchannels

Inhibitionof glutamate

excitation

Activationof potassium

channels

Other

Benzodiazepines +

Carbamazepine + + (L-type) +

Ethosuximide + (T-type)

Phenobarbital + + + + +

Phenytoin + +

Valproate + + (T-type) +

Felbamate + + + (L-type) + +

Gabapentin + (N-, P/Q-type)

Lamotrigine + + + (N-, P/Q-, R-, T-type) + +

Levetiracetam + + (N-type) +

Oxcarbazepine + + (N-, P-type) +

Tiagabine +

Topiramate + + + + (L-type) + +

Vigabatrin +

Zonisamide + + (N-, P-, T-type) + +

Bivaracetam +

Carabersat +

Carisbamate +

Eslicarbazepine +

Ganaxolone +

Lacosamide +

Pregabalin + (N-, P/Q-type)

Retiagabine + + + Kv7.2-7.5

Stiripentol + +

Talampanel +

+ – Action experimentally proven. Controversial mechanisms were not included

VPA [28, 46]. Another isoenzyme, UGT2B7, mayalso be involved in the metabolism of VPA [38]. Be-cause VPA is an UGT inhibitor, it may affect the me-tabolism of LTG. In contrast, OXC is an UGT activa-tor, and it accelerates the metabolism of LTG [83].

Interactions involving AEDs at the level of renalexcretion are rare. Nevertheless, drugs that alkalizeurine can reduce the tubular reabsorption of PB,which may be of therapeutic significance in the caseof a PB overdose [85]. FBM, GBP, LEV, TPM andVGB undergo renal elimination, but any participationof the active tubular transport in this process has notyet been confirmed. In fact, active tubular transport isrequired for the pharmacokinetic interactions to occur.However, the possibility of the interactions of AEDswith other drugs that are excreted in the same waycannot be excluded [83, 84].

Pharmacokinetic interactions among AEDs inclinical conditions may concern either classical AEDsor both, classical and newer AEDs. Considering thefirst type of interactions, one cannot always predictthe final outcome based on the influence of AEDs onmetabolizing enzymes. The plasma concentration ofPB may be elevated not only by VPA but also by PHT.Furthermore, PB administered in low doses may re-duce the plasma level of PHT, but when it is given inthe higher dose range, it exerts an opposite effect [83].Both PHT and PB lead to a reduction in the plasmaconcentration of CBZ [83], but as mentioned above,VPA elevates the plasma concentration of CBZ-10,11-epoxide. Generally, CBZ, PB and PHT causea decrease in the plasma concentration of VPA [83].Regarding the second type of interactions, there isevidence that VGB may significantly reduce theplasma levels of PHT and CYP activators, includingLTG, TGB, TPM and ZNS. In contrast, VPA producesan increase in the concentration of LTG [83]. A thirdtype of interaction could also be found, an interactionbetween newer AEDs themselves. These interactionsare rarer, mainly because of the better pharmacokineticprofiles of these AEDs. However, OXC retained thefeature of CBZ to stimulate CYP enzymes, although toa lesser degree, and this mechanism may lower theplasma concentrations of LTG and TPM [83].

Certainly, the drugs that are prescribed in epilepticpatients for indications other than epilepsy can alsoaffect the concentrations of AEDs in plasma [60, 73,84]. There are many possibilities for these interac-tions; therefore, only the most important ones thatcause substantial modifications of the AED concen-

trations are mentioned below. The competition ofmacrolides, erythromycin, clarithromycin, and olean-domycin with CBZ for the isoenzyme CYP3A4 maycause a several-fold increase in the plasma concentra-tions of this AED. Moreover, significant elevations inCBZ concentration are observed in combinations withdanazol, fluconazole, diltiazem, cimetidine, ticlopid-ine, and isoniazid [60]. Isoniazid can also inducea considerable rise in the plasma concentration ofethosuximide. Diltiazem, cimetidine, ticlopidine, orisoniazid cause a rise in the plasma concentration ofPHT, which may precipitate toxicity in some patients.Aspirin may produce toxic effects in patients on VPA;there might be a substantial increase in the plasmaconcentration of this AED, which is displaced by as-pirin from plasma albumin. Also, aspirin inhibits themetabolic degradation of VPA. A significant rise inthe plasma level of VPA may be a consequence ofisoniazid co-administration. Other drugs, such as ke-toconazole, naproxen, ibuprofen, and mefenamicacid, produce a similar effect on the plasma concen-tration of VPA, but the clinical significance of theseinteractions is unknown [60]. Interestingly, there islimited data on the interactions between PB and otherdrugs. One important interaction is between this AEDand activated charcoal, which eventually results ina strong inhibition of the absorption of PB from theintestines. This interaction is of therapeutic signifi-cance for the management of a PB overdose. Thepharmacokinetic parameters of the newer AEDs canbe hardly influenced by other drugs [60, 83].

Pharmacodynamic interactions

In contrast to pharmacokinetic interactions, pharma-codynamic interactions occur without any significantchanges in the plasma or brain concentrations of thecombined drugs. In clinical testing, the basic pharma-cokinetic parameters are estimated in the plasma orserum. In contrast, drug brain concentrations may betaken into consideration in experimental studies. Thisis quite remarkable because changes in the plasmaconcentrations of AEDs are not necessarily followedby respective changes in brain drug levels. Pharmaco-dynamic interactions assume that the net activity ofthe two combined AEDs results from the summationof their individual receptor or non-receptor effects. Toevaluate the nature of these interactions, a basic con-vulsive test may be applied, for example, in the maxi-mal electroshock test in rodents (a model of human

284 ��

clonic-tonic and partial seizures, to a certain degree),the pentylenetetrazole test (a model of myoclonicconvulsions), and the amygdala-kindled convulsionsin rats (a model of partial seizures) [49]. The availabledata have been generally derived from the maximalelectroshock test with the use of isobolographicanalysis. Fewer results have been obtained in the pen-tylenetetrazole test, and only isolated data have beenavailable from amygdala-kindled seizures in rats. Theanticonvulsant activity of AEDs is usually displayedas ED�� values (in mg/kg) that are the median dosesnecessary to protect 50% of animals against seizures.A synergy (or hyper additive synergy) is defined whenthe actual anticonvulsant effect of two combinedAEDs is greater than the theoretical sum of their indi-vidual effects. If the experimentally denoted anticon-vulsant effect is not significantly different from thetheoretical sum, then an addition (or additive synergy)occurs. Finally, when the experimental effect is lowerthan the theoretical one, then an antagonism is evi-dent. Apart from the interactions of the anticonvulsantactivity, interactions that are based on neurotoxicityneed to be performed to fully characterize the natureof interactions among AEDs. Certainly, the best inter-actions from a preclinical point of view are character-ized by anticonvulsant synergy and neurotoxic antago-nism [16]. The interaction index, which is a helpful pa-rameter that characterizes the nature of interactions,may be calculated by dividing a given, experimentallyobtained ED�� (or TD��) and the respective theoreticalED�� value. As a matter of fact, the interaction indexis separately calculated for the anticonvulsant activityand neurotoxic effects. The benefit index, which char-acterizes both the anticonvulsant activity and neuro-toxicity, may be calculated by dividing the respectiveprotective indices, the experimental and theoretical.Usually when the benefit index exceeds the value of1.3, the combination of two AEDs is promising froma preclinical point of view. However, isobolographycan precisely characterize the final outcome of an in-teraction between two AEDs for various fixed drug-dose ratio combinations in terms of synergy, additionor antagonism. Details of how to perform an isobolo-graphic analysis may be found in a series of papers [8,14, 50, 52, 109, 114].

Interactions among classical AEDs

If not stated otherwise, the results listed below wereobtained in the maximal electroshock test in mice.

A combination of PB with PHT exerts an additive an-ticonvulsant effect, but the neurotoxic effects wereantagonistic. However, the protective index of PHTalone was higher than for the combined treatment[14]. However, there are also data that point to the an-ticonvulsant synergy of this particular combination.Because there was no neurotoxicity measured in thisstudy, any calculation of the protective index is im-possible. When CBZ was co-administered with PB,anticonvulsant and neurotoxic addition was evident.Identical interactions occurred for the combinationsof VPA with CBZ or PB for the anticonvulsant activ-ity. Respective antagonism or additivity was ob-served, which makes the combination of VPA + CBZsuperior from the preclinical point of view. A com-bined treatment of VPA with PHT produces synergyin the convulsive test and neurotoxic additivity. Theprotective index of this combination was considerablybetter than the protective index for these AEDs whengiven alone. In the pentylenetetrazole test in mice,very similar results were found for the combinedtreatment of VPA with ESM [14].

Interactions between classical and newer AEDs

Generally, the results presented below have been ob-tained in the maximal electroshock test in mice. Drugratios were calculated based on the ED��s of AEDs incombinations. The ratio of 1:1 means that AEDs wereput into a mixture in equal fractions of their ED��s.Ratios of 3:1 or 1:3 point to 75% of the ED�� of drugA and 25% of ED�� of drug B or 25% of the ED�� ofdrug A and 75% of the ED�� of drug B, respectively.

Combinations of GBP in a variety of fixed drug ra-tios with many AEDs (e.g., CBZ, PB, PHT, VPA) ex-erted anticonvulsant synergy, and only in one case,a combination with PB, a pharmacokinetic factor con-tributed to the final effect [8]. A very good profile ofinteraction has been observed for LTG + VPA (1:1)with anticonvulsant synergy and neurotoxic antago-nism being evident. Although the anticonvulsant syn-ergy occurred for a combination of LTG with PB (at1:1 and 1:3), the same kind of interaction was alsonoted for neurotoxicity (at the ratio of 1:1). This resultindicates that the net result of this interaction is nega-tive at the ratio of 1:1. An even worse outcome hasbeen found for the combined treatment of LTG andCBZ at ratios of 1:1 and 3:1. In the ratio of 1:3, onlya tendency toward antagonism was observed. In allthree ratios, additive neurotoxic activity with a trend

�� 285


towards synergy was evident [59]. According toShank et al. [99], various drug ratios combinations ofTPM with PB or CBZ showed anticonvulsant syn-ergy, and an additivity of TPM with PHT was shown.Unfortunately, the neurotoxic effects of these combi-nations were not evaluated. Therefore, the full pre-clinical profile of the combinations of TPM with clas-sical AEDs is not available. Few data can be found oninteraction of RTG with other AEDs. RTG enhancedprotective effects of CBZ, diazepam, FBM, LTG,PHT, PB and VPA against audiogenic seizures inDBA/2 mice without affecting pharmacokinetic pa-rameters of these drugs [23]. Furthermore, the isobo-lographic analysis showed a clear-cut synergy for thecombination of retigabine with valproate and no ef-fect of these drug combinations on motor coordina-tion, long term memory or muscular strength was ob-served [59].

In the pentylenetetrazole test in mice, a combina-tion of VGB with PB displayed a promising preclini-cal profile with the anticonvulsive synergy accompa-nied by moderate toxicity. However, this interactionwas not free from the pharmacokinetic mechanismbecause there was an increase in the brain PB concen-tration [58]. There are examples that some AEDs incombinations undergo many pharmacokinetic interac-tions. Stiripentol, when co-administered with ESM,PB or VPA in different fixed-dose ratios produces ad-ditivity in the pentylenetetrazole test in mice [56].However, brain concentrations of PB and ESM wereelevated, but the concentration of VPA was reduced.

In addition, PB diminished and VPA increased thebrain level of stiripentol. Regarding neurotoxicity, allcombinations of stiripentol with the classical AEDswere also additive. These examples clearly indicatehow important it is to verify the pharmacokinetic ef-fect on the pharmacodynamic effects.

Interactions among newer AEDs

As in previous interactions, the co-administration ofnewer AEDs was mainly performed using the maxi-mal electroshock test in mice [51]. In a variety of doseratios (1:3, 1:1, 3:1), LEV exerts synergy when com-bined with TPM or OXC. Especially, these combina-tions were associated with positive neurotoxic pro-files [126]. Also, a combination of OXC with GBPseems preclinically attractive because the anticonvul-sant synergy was accompanied by no neurotoxicity.A very good preclinical profile may be ascribed to thecombined treatment of TPM with LTG, especially atthe fixed dose ratio of 1:1. At this ratio, the anticon-vulsant synergy was associated with neurotoxic an-tagonism [54]. The anticonvulsant synergy was alsoevident for a combination of GBP with TGB in allthree fixed dose ratios of 1:3, 1:1 and 3:1 with no neu-rotoxicity for the 1:3 and 3:1 ratios [55]. When GBPwas combined with LTG, an anticonvulsant synergywith no neurotoxicity was shown. However, brain GBPconcentration was significantly elevated. It is remark-able that a clear-cut antagonism has been observed forthe combined treatment of OXC with LTG regarding the

286 ��

Tab. 2. Effects of combinations of some antiepileptics (AEDs) evaluated experimentally with isobolography in mice

Drug ADrug B

LTG OXC TGB TPM VGB VPA

CBZ Ant�� Add�� Add�� S�� NE NE

GBP S* S� S�� S�� S� S��

LEV Add� S� NE S� NE Add�

OXC Ant�� – Add� S�� NE Add��

TGB Add�� Add �� – Add�� S�� Add��

TPM S�� S�� Add�� – NE NE

VPA S�� Add�� S�� NE Add� –

Ant – Antagonism; S – synergy; Add – additivity; * – the increased level of GBP in brain has been observed; � – no neurotoxicity observed for an-tiepileptics at the fixed dose ratio of 1:1, recorded in the chimney test or passive avoidance task; �� – additive neurotoxicity in the chimney testcalculated by isobolography; �� – antagonistic neurotoxicity; � – synergistic neurotoxicity; CBZ – carbamazepine; GBP – gabapentin; LEV –levetiracetam; LTG – lamotrigine; – – no possibility of combination; �� – neurotoxicity not evaluated; NE – not evaluated by isobolography; OXC– oxcarbazepine; � – synergistic neurotoxic effects; TGB – tiagabine; TPM – topiramate; VGB – vigabatrin; VPA – valproate

anticonvulsant activity. This preclinically negative re-sult was paralleled by synergistic neurotoxicity. In thethreshold electroshock test in mice, combinations ofVGB with TGB at 1:3, 1:1 and 3:1 fixed-dose ratioswere additive with no neurotoxicity [52]. In the sametest, a combination of VGB with GBP exerted anti-convulsant synergy at the dose ratio of 1:3, but thedose ratios of 1:1 and 3:1 were additive. Neurotoxic-ity was not found for any of these dose ratios [57].

The results of the combined treatments with AEDsare listed in Table 2.

Are there correlations between

preclinical and clinical data on the

interactions among AEDs?

Due to intensive preclinical research and clinical tri-als, there are now approximately 30 available AEDs.It is obvious that the pathophysiology of an epilepticseizure is similar in experimental animals and hu-mans. Also, the mechanisms utilized by AEDs to in-hibit convulsions in experimental and clinical epilep-tology are identical, although there might be differ-ences in pharmacokinetic profiles. Taking this intoconsideration, one may conclude that the experimen-tal studies on AED combinations can have quite a sig-nificant predictive value. A number of AED combina-tions have been presented [103–105] with positiveclinical outcomes (the results of preclinical studies areshown in parentheses): PHT + PB (addition/synergy),VPA + CBZ (addition), PHT + CBZ (addition), CBZ+ TPM (synergy), CBZ + GBP (synergy), CBZ + LTG(antagonism), VPA + LTG (synergy), TPM + LTG(synergy). As can be seen from the above data, theonly discrepancy concerns the combined treatment ofCBZ + LTG, which was scored as positive in clinicalconditions in contrast to the experimental evaluationthat pointed to an evident antagonism. Can this dis-crepancy be interpreted in terms of the low predictivevalue of preclinical data on AED combinations? Pre-clinical research on this issue assumes addition as asimple summation of the partial protective effects ofAEDs. Consequently, if a partial protective effect ofdrug A amounts to 35% in non-seizing mice and thatof drug B to 45%, then a combined treatment of thesedrugs should result in a total protection within 80% ifthere is an additive interaction. The final protective

effect of 60%, although exceeding the partial effectsof drugs A and B (a positive finding in clinical condi-tions), is regarded as an antagonism from the preclini-cal point of view. This might be a reason for some po-tential discrepancies in the interpretation of experi-mental and clinical data. The clinical evaluation ofthis particular AED combination (CBZ + LTG) is nothomogenous. The existing clinical evidence alsopoints to a better outcome of LTG monotherapy vs.

the combination of CBZ + LTG and to an increase inseizure frequency in 18% of patients who take thiscombination [14, 74, 83].

Is the mechanism of action of AEDs

relevant to clinical practice?

Individually tailored treatment for a given patient,which is adequate for particular seizure syndrome ordemographic characteristics, is an attractive conceptin the modern management of epilepsy. However, itshould be emphasized that the mechanism of action isonly a supplementary factor in the process of selec-tion of proper AED for an individual patient. Manyother factors, such as efficacy, tolerability and safety,are the main criteria for the selection of AEDs, al-though other properties, such as pharmacokinetics andease of use, are also important [121]. There are practi-cal implications of a detailed knowledge of the modeof action for a particular drug. Accumulating clinicalexperience suggests that drugs with complex mecha-nisms of action that influence different ion channelsor neurotransmitter systems, seem to display broaderclinical efficacy for the suppression of both focal andgeneralized seizures. In contrast, drugs that actthrough a more specific mechanism are effective innarrower clinical spectrums. Another interesting issueis whether the etiology of epilepsy impacts the drugeffect. There is only limited clinical evidence thata particular pathomechanism of a given epileptic syn-drome might preferentially respond to an AED witha specific mechanism of action. This concept is sup-ported by studies investigating the use of VGB,a GABA mimetic drug, in the treatment of infantilespasms. A meta-analysis of 10 clinical studies demon-strated that of the 313 patients without tuberous scle-rosis complex, 170 (54%) had a complete cessation oftheir infantile spasms, but 73 of the 77 patients with

�� 287


tuberous sclerosis complex (95%) had a complete ces-sation of their seizures. It was concluded that VGBshould be considered as a first-line monotherapy forthe treatment of infantile spasms in infants with eithera confirmed diagnosis of tuberous sclerosis or those athigh risk, i.e., infants with a first-degree relative withtuberous sclerosis complex [32]. The above findingsgive some hope that further investigation of thepathomechanism of selected epileptic syndromes maypave the way for individually directed drug selectionsthat act not only on seizure suppression but also onepileptogenesis.

Conclusions

The management of resistant epileptic patients withAED combinations is based on the pharmacodynamicinteractions between AEDs, and only combinationsthat show the best preclinical profiles need to be con-sidered. Pharmacodynamics may be complicated bythe pharmacokinetic interactions of both the AEDsthat are used in the combined treatment and otherdrugs that are prescribed for other than epilepsy rea-sons. A failure of the combined treatment with AEDsmay result from the above-mentioned pharmacoki-netic factors. Also, the pharmacodynamic interactionsof AEDs with non-AEDs cannot be underestimated.Both the experimental and clinical data indicate thatmethylxanthines (e.g., theophylline, pentoxifylline)and caffeine significantly reduce the protective effi-cacy of AEDs [11]. Patients receiving methylxanthinemedications or heavy coffee drinkers may experienceno or considerably reduced benefits from combinedAED treatment even though these combinations arerationally chosen. Although the choice of specificdrug is still mainly based on clinician’s experience,the better understanding of pathogenesis of epilepsyand mechanisms of the AED action should allow a ra-tional approach to be applied [37].

Acknowledgment:

This manuscript has been inspired by the

GlaxoSmithKline-supported Conference “AED therapy: does MoA

matter?” in London, June 2010.

References:

1. Armijo JA, Shushtarian M, Valdizan EM, Cuadrado A,de las Cuevas I, Adin J: Ion channels and epilepsy. CurrPharm Des, 2005, 11, 1975–2003.

2. Barnes GN, Slevin JT: Ionotropic glutamate receptor biol-ogy: effect on synaptic connectivity and function in neuro-logical disease. Curr Med Chem, 2003, 10, 2059–2072.

3. Barrese V, Miceli F, Soldovieri MV, Ambrosino P, IamottiFA, Cilio MR, Taglialatela M: Neuronal potassium chan-nel openers in the management of epilepsy: role and po-tential of retigabine. Clin Pharmacol, 2010, 2, 225–236.

4. Basta-Kaim A, Budziszewska B, Leœkiewicz M, KuberaM, Jag³a G, Nowak W, Czuczwar SJ, Lasoñ W: Effectsof new antiepileptic drugs and progabide on themitogen-induced proliferative activity of mouse spleno-cytes. Pharmacol Rep, 2008, 60, 925–932.

5. Beyreuther BK, Freitag J, Heers C, Krebsfänger N,Scharfenecker U, Stöhr T: Lacosamide: a review of pre-clinical properties. CNS Drug Rev, 2007, 13, 21–42.

6. Bialer M: New antiepileptic drugs that are second gen-eration to existing antiepileptic drugs. Expert Opin In-vestig Drugs, 2006, 15, 637–647.

7. Bialer M, Johannessen SI, Kupferberg HJ, Levy RH,Perucca E, Tomson T: Progress report on new antiepilep-tic drugs: a summary of the Eigth Eilat Conference(EILAT VIII). Epilepsy Res, 2007, 73, 1–52.

8. Borowicz KK, Œwi¹der M, £uszczki J, Czuczwar SJ:Effect of gabapentin on the anticonvulsant activity ofantiepileptic drugs against maximal electroshock in mice– an isobolographic analysis. Epilepsia, 2002, 43,956–963.

9. Brodie MJ: Felbamate: a new antiepileptic drug. Lancet,1993, 341, 1445–1446.

10. Brodie MJ, Lerche H, Gil-Nagel A, Elger C, Hall S,Shin P, Nohria V, Mansbach H; RESTORE 2 StudyGroup: Efficacy and safety of adjunctive ezogabine(retigabine) in refractory partial epilepsy. Neurology,2010, 75, 1817–1824.

11. Chroœciñska-Krawczyk M, Rastnaraj N, Patsalos PN,Czuczwar SJ: Effect of caffeine on the anticonvulsanteffects of oxcarbazepine, lamotrigine and tiagabine ina mouse model of generalized tonic-clonic seizures.Pharmacol Rep, 2009, 61, 819–826.

12. Coulter DA, Huguenard JR, Prince DA: Calcium cur-rents in rat thalamocortical relay neurones: kinetic prop-erties of the transient, low-threshold current. J Physiol,1989, 414, 587–604.

13. Czapiñski P, B³aszczyk B, Czuczwar SJ: Mechanisms ofaction of antiepileptic drugs. Curr Top Med Chem, 2005,5, 3–14.

14. Czuczwar SJ, Kap³añski J, Œwiderska-Dziewit G, Ger-gont A, Kroczka S, Kacinski M: Pharmacodynamic in-teractions between antiepileptic drugs: preclinical databased on isobolography. Expert Opin Drug Metab Toxi-col, 2009, 5, 1–6.

15. Czuczwar SJ, Patsalos PN: The new generation ofGABA enhancers. CNS Drugs, 2001, 15, 339–350.

16. Czuczwar SJ, Borowicz KK: Polytherapy in epilepsy:the experimental evidence. Epilepsy Res, 2002, 52, 15–23.

288 ��

17. Czuczwar P, Wojtak A, Cioczek-Czuczwar A, Parada-Turska J, Maciejewski R, Czuczwar SJ: Retiga-bine:the newer potential antiepileptic drug. PharmacolRep, 2010, 62, 211–219.

18. Dalby NO, Nielsen EB: Comparison of the preclinicalanticonvulsant profiles of tiagabine, lamotrigine, gaba-pentin and vigabatrin. Epilepsy Res, 1997, 28, 63–72.

19. Dam M, Ekberg R, Løyning Y, Waltimo O, Jakobsen K:A double-blind study comparing oxcarbazepine and car-bamazepine in patients with newly diagnosed, previouslyuntreated epilepsy. Epilepsy Res, 1989, 3, 70–76.

20. Davies JA: Mechanisms of action of antiepileptic drugs.Seizure, 1995, 4, 267–271.

21. Deckers CLP, Czuczwar SJ, Hekster YA, Keyser A,Kubova H, Meinardi H, Patsalos PN et al.: Selection ofantiepileptic drug polytherapy based on mechanism ofaction: The evidence reviewed. Epilepsia, 2000, 41,1364–1374.

22. De Romanis F, Sopranzi N: Lamotrigine in the therapyof resistant epilepsy. Clin Ter, 1999, 150, 279–282.

23. De Sarro G, Di Paola ED, Conte G, Pasculli MP, DeSarro A: Influence of retigabine on the anticonvulsantactivity of some antiepileptic drugs against audiogenicseizures in DBA/2 mice. Naunyn Schmiedebergs ArchPharmacol, 2001, 363, 330–336

24. De Sarro G, Gitto R, Russo E, Ibbadu GF, Barreca ML,De Luca L, Chimirri A: AMPA receptor antagonists aspotential anticonvulsant drugs. Curr Top Med Chem,2005, 5, 31–42.

25. Doty P, Rudd GD, Stoehr T, Thomas D: Lacosamide.Neurotherapeutics, 2007, 4, 145–148.

26. Dichter MA, Brodie MJ: New antiepileptic drugs.N Engl J Med, 1996, 334, 1583–1590.

27. Dickins M, Chen C: Lamotrigine. Chemistry, biotrasfor-mation and pharmacokinetics. In: Antiepileptic Drugs.Eds. Levy RH, Mattson RH, Meldrum BS, Perucca E,Lippincott, Williams & Wilkins, Philadelphia, 2002,370–379.

28. Eadie MJ: Formation of active metabolites of anticonvul-sant drugs. A review of their pharmacokinetic and thera-peutic significance. Clin Pharmacokinet, 1991, 21, 27–41.

29. Enz R, Cutting GR: Molecular composition of GABACreceptors. Vision Res, 1998, 38, 1431–1441.

30. Fattore C, Cippola G, Gatti G, Limido GL, Sturm Y,Bernsconi C, Perucca E: Induction of ethinylestradioland levonorgestrel metabolism by oxcarbazepine inhealthy women. Epilepsia, 1999, 40, 783–787.

31. Gil-Nagel A: Does mode of action predict spectrum ofefficacy and side-effect profile? In: Antiepileptic DrugTherapy: Does Mechanism of Action Matter? RadissonEdwardian Heathrow Hotel, London, UK, Monday 7June 2010.

32. Hancock E, Osborne JP: Vigabatrin in the treatment ofinfantile spasms in tuberous sclerosis: literature review.J Child Neurol, 1999, 14, 71–74.

33. Harris JA, Murphy JA: Lacosamide and epilepsy. CNSNeurosci Ther, 2010, 15.

34. Hough CJ, Irwin RP, Gao XM, Rogawski MA, ChuangDM: Carbamazepine inhibition of N-methyl-D-aspartate-evoked calcium influx in rat cerebellar granule cells.J Pharmacol Exp Ther, 1996, 276, 143–149.

35. Howes JF, Bell C: Talampanel. Neurotherapeutics, 2007,4, 126–129.

36. Iwamoto FM, Kreisl TN, Kim L, Duic JP, Butman JA,Albert PS, Fine HA: Phase 2 trial of talampanel, a gluta-mate receptor inhibitor, for adults with recurrent malig-nant gliomas. Cancer, 2010, 116, 1776–1782.

37. Jacobs MP, Fischbach GD, Davis MR, Dichter MA, Dingle-dine R, Lowenstein DH, Morrell MJ et al.: Future directionsfor epilepsy research. Neurology, 2001, 57, 1536–1542.

38. Jakus R, Graf M, Ando RD, Balogh B, Gacsaly I, LevayG, Kantor S, Bagdy G: Effect of two noncompetitiveAMPA receptor antagonists GYKI 52466 and GYKI53405 on vigilance, behavior and spike-wave dischargesin a genetic rat model of absence epilepsy. Brain Res,2004, 1008, 236–244.

39. Kalia LV, Kalia SK, Salter MW: NMDA receptors inclinical neurology: excitatory times ahead. Lancet Neu-rol, 2008, 7, 742–755

40. K³odziñska A, Bijak M, Chojnacka-Wójcik E, KroczkaB, Swiader M, Czuczwar SJ, Pilc A: Roles of group IImetabotropic glutamate receptors in modulation of sei-zure activity. Naunyn Schmiedebergs Arch Pharmacol,2000, 361, 283–288.

41. Leach JP, Sills GJ, Majid A, Butler E, Carswell A,Thompson GG, Brodie MJ: Effects of tiagabine and vi-gabatrin on GABA uptake into primary cultures of ratcortical astrocytes. Seizure, 1996, 5, 229–234.

42. Lee CY, Fu WM, Chen CC, Su MJ, Liou HH: Lamotrigineinhibits postsynaptic AMPA receptor and glutamate re-lease in the dentate gyrus. Epilepsia, 2008, 49, 888–897.

43. Leppik IE: Zonisamide: chemistry, mechanism of action,and pharmacokinetics. Seizure, 2004, 13, Suppl 1, S5-9,discussion S10.

44. Lerche H, Weber YG, Jurkatt-Rott K, Lehmann-Horn F:Ion channel defects in idiopathic epilepsies. Curr PharmDes, 2005, 11, 2737–2752.

45. Leœkiewicz M, Lasoñ W: The neurochemical mecha-nisms of temporal lobe epilepsy: an update (Polish).Przegl Lek, 2007, 64, 960–964.

46. Liston HL, Markovitz JS, Devane L: Drug glucuronida-tion in clinical psychopharmacology. J Clin Psychophar-macol, 2001, 21, 500–515.

47. Löscher W: Basic pharmacology of valproate: a reviewafter 35 years of clinical use for the treatment of epi-lepsy. CNS Drugs, 2002, 16, 669–694.

48. Löscher W, Köhling R: Functional, metabolic, and syn-aptic changes after seizures as potential targets for antie-pileptic therapy. Epilepsy Behav, 2010, 19, 105–113.

49. Löscher W, Schmidt D: Which animal models should beused in the search for new antiepileptic drugs? A pro-posal based on experimental and clinical considerations.Epilepsy Res, 1988, 2, 145–181.

50. £uszczki JJ: Isobolographic analysis of interaction be-tween drugs with nonparallel dose-response relationshipcurves: a practical application. Naunyn-Schmiedeberg’sArch Pharmacol, 2007, 375, 105–114.

51. £uszczki JJ: Third-generation antiepileptic drugs:mechanisms of action, pharmacokinetics and interac-tions. Pharmacol Rep, 2009, 61, 197–216.

52. £uszczki JJ, Czuczwar SJ: Isobolographic characteriza-tion of interactions between vigabatrin and tiagabine in

�� 289


two experimental models of epilepsy. Prog Neuropsy-chopharmacol Biol Psychiatry, 2007, 30, 529–538.

53. £uszczki JJ, Czuczwar SJ: Preclinical profile of combina-tions of some second-generation antiepileptic drugs: anisobolographic analysis. Epilepsia, 2004, 45, 895–907.

54. £uszczki JJ, Czuczwar M, Kiœ J, Pasztelan M, Krysa J,Czuczwar SJ: Interactions of lamotrigine with topiramateand first generation antiepileptic drugs in the maximalelectroshock test in mice: an isobolographic analysis.Epilepsia, 2003, 44, 1003–1013.

55. £uszczki JJ, Kolacz A, Wojda E, Czuczwar M, PrzesmyckiK, Czuczwar SJ: Synergistic interaction of gabapentin withtiagabine in the hot-plate test in mice: an isobolographicanalysis. Pharmacol Rep, 2009, 61, 459–467.

56. £uszczki JJ, Ratnaraj N, Patsalos P, Czuczwar SJ: Char-acterization of the anticonvulsant, behavioral, and phar-macokinetic interaction profiles of stiripentol in combi-nation with clonazepam, ethosuximide, phenobarbital,and valproate using isobolographic analysis. Epilepsia,2006, 47, 1841–1854.

57. £uszczki JJ, Ratnaraj N, Patsalos PN, Czuczwar SJ:Isobolographic and behavioral characterizations of inter-actions between vigabatrin and gabapentin in two experi-mental models of epilepsy. Eur J Pharmacol, 2008, 595,13–21.

58. £uszczki JJ, Wójcik-Æwik³a J, Andres MM, CzuczwarSJ: Pharmacological and behavioral characteristics ofinteractions between vigabatrin and conventional antiepi-leptic drugs in pentylenetetrazole-induced seizures inmice: an isobolographic analysis. Neuropsychopharma-cology, 2005, 30, 958–973.

59. £uszczki JJ, Wu JZ, Raszewski G, Czuczwar SJ: Isobo-lographic characterization of interactions of retigabinewith carbamazepine, lamotrigine, and valproate in themouse maximal electroshock-induced seizure model.Naunyn Schmiedebergs Arch Pharmacol, 2009, 379,163–179.

60. Majkowski J, Patsalos PN: Interaction between antiepi-leptic and non-epileptic drugs. In: Antiepileptic Drugs.Combination Therapy and Interactions. Eds. MajkowskiJ, Bourgeois B, Patsalos P, Mattson R, Cambridge Uni-versity Press, Cambridge, 2005, 139–177.

61. Maljevic S., Wuttke TV, Seebohm G, Lerce H: Kv7channelopathies. Eur J Physiol, 2010, 460, 277–288.

62. Masuda Y, Karasawa T, Shiraishi Y, Hori M, Yoshida K,Shimizu M: 3-Sulfamoylmethyl-1,2-benzisoxazole, anew type of anticonvulsant drug. Pharmacological pro-file. Arzneimittelforschung, 1980, 30, 477–483.

63. Mathews GC: The dual roles of GABA in seizures andepilepsy generate more excitement. Epilepsy Curr, 2007,7, 28–30.

64. Mattson RH: Efficacy and adverse effects of establishedand new antiepileptic drugs. Epilepsia, 1995, 36, Suppl2, S13–S26.

65. Matute C: Therapeutic Potential of kainate receptors.CNS Neurosci Ther, 2010, 6.

66. McLean MJ, Macdonald RL: Carbamazepine and 10,11-epoxycarbamazepine produce use- and voltage-dependent limitation of rapidly firing action potentialsof mouse central neurons in cell culture. J PharmacolExp Ther, 1986, 238, 727–738.

67. McNamara JO: Pharmacotherapy of the epilepsies In:The Pharmacological Basis of Therapeutics. Eds. Brun-ton LL, Lazo JS, Parker KL, Goodman and Gilman’s11th edition, McGraw-Hill Medical Publishing Division,New York, 2006, 501–526.

68. Meldrum BS, Rogawski MA: Molecular targets for an-tiepileptic drug development. Neurotherapeutics, 2007,4, 18–61.

69. Miller AA, Wheatley P, Sawyer DA, Baxter MG,Roth B: Pharmacological studies on lamotrigine, a novelpotential antiepileptic drug: I. Anticonvulsant profile inmice and rats. Epilepsia, 1986, 27, 483–489.

70. Moldrich RX, Chapman AG, De Sarro G, Meldrum BS:Glutamate metabotropic receptors as targets for drug ther-apy in epilepsy. Eur J Pharmacol, 2003, 22, 476, 3–16.

71. Mora G, Tapia R: Effects of retigabine on the neurode-generation and extracellular glutamate changes inducedby 4-aminopyridine in rat hippocampus in vivo. Neuro-chem Res, 2005, 30, 1557–1565.

72. Nasreddine W, Beydoun A, Atweh S, Abou-Khalil B:Emerging drugs for partial onset seizures. Expert OpinEmerging Drugs, 2010, 15, 415–431.

73. Parker AC, Pritchard B, Preston T, Choonara I: Inductionof CYP1A2 activity by carbamazepine in children usingthe caffeine breath test. Br J Clin Pharmacol, 1998, 45,176–178.

74. Patsalos PN: Pharmacokinetic principles and mecha-nisms of drug interactions. In: Antiepileptic Drugs.Combination Therapy and Interactions. Eds. MajkowskiJ, Bourgeois B, Patsalos P, Mattson R, Cambridge Uni-versity Press, Cambridge, 2005, 47–56.

75. Patsalos PN, Lascelles PT: Effect of sodium valproate onplasma protein binding of diphenylhydantoin. J NeurolNeurosurg Psychiat, 1977, 40, 570–574.

76. Pellock JM, Faught E, Leppik IE, Shinnar S, ZupancML: Felbamate: consensus of current clinical experience.Epilepsy Res, 2006, 71, 89–101.

77. Pennell PB, Ogaily MS, Macdonald RL: Aplastic anemiain a patient receiving felbamate for complex partial sei-zures. Neurology, 1995, 45, 456–460.

78. Perucca E: The clinical pharmacology and therapeuticuse of the new antiepileptic drugs. Fund Clin Pharmacol,2001, 15, 405–407.

79. Plosker GL, Scott LJ: Retigabine: in partial seizures.CNS Drugs, 2006, 20, 601–608, discussion 609–610.

80. Poolos NP, Migliore M, Johnston D: Pharmacologicalupregulation of h-channels reduces the excitability of py-ramidal neuron dendrites. Nat Neurosci, 2002, 5, 767–774.

81. Porter RJ, Partiot A, Sachdeo R, Nohria V, Alves WM:205 Study Group: Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures.Neurology, 2007, 68, 1197–1204.

82. Putnam TJ, Merritt HH: Experimental determination ofthe anticonvulsant properties of some phenyl derivatives.Science, 1937, 85, 525–526.

83. Rambeck B, May TW: Interactions between antiepilepticdrugs. In: Antiepileptic Drugs. Combination Therapyand Interactions. Eds. Majkowski J, Bourgeois B,Patsalos P, Mattson R, Cambridge University Press,Cambridge, 2005, 111–138.

290 ��

84. Reddy DS: Clinical pharmacokinetic interactions be-tween antiepileptic drugs and hormonal contraceptives.Expert Rev Clin Pharmacol, 2010, 3, 183–192.

85. Reinikainen KJ, Keränen T, Halonen T, Komulainen H,Riekkinen PJ: Comparison of oxcarbazepine and carba-mazepine: A double-blind study. Epilepsy Res, 1987, 1,284–289.

86. Reiss WG, Oles KS: Acetazolamide in the treatment ofseizures. Ann Pharmacother, 1996, 30, 514–519.

87. Rendic S, Di Carlo FJ: Human cytochrome P450 en-zymes: a status report summarizing their reactions, sub-strates, inducers, and inhibitors. Drug Metab Rev, 1997,29, 413–580.

88. Rigo JM, Hans G, Nguyen L, Rocher V, Belachew S:The anti-epileptic drug levetiracetam reverses the inhibi-tion by negative allosteric modulators of neuronalGABA- and glycine-gated currents. Br J Pharmacol,2002, 136, 659–672.

89. Riss J, Cloyd J, Gates J, Collins S: Benzodiazepines inepilepsy: pharmacology and pharmacokinetics. ActaNeurol Scand, 2008, 118, 69–86.

90. Rogawski M: Diverse mechanisms of antiepileptic drugsin the development pipeline. Epilepsy Res, 2006, 69,273–294.

91. Rogawski MA, Porter RJ: Antiepileptic drugs: Pharma-cological mechanisms and clinical efficacy with consid-eration of promising developmental stage compounds.Pharmacol Rev, 1990, 42, 223–286.

92. Rostock A, Tober C, Rundfeldt C, Bartsch R, Engel J,Polymeropoulos EE, Kutscher B et al.: D-23129: a newanticonvulsant with a broad spectrum activity in animalmodels of epileptic seizures. Epilepsy Res, 1996, 23,211–223.

93. Sabers A, Gram L: Newer anticonvulsants: Comparativereview of drug interactions adverse effects. Drugs, 2000,60, 23–33.

94. Schachter SC: A review of the antiepileptic drug tiaga-bine. Clin Neuropharmacol, 1999, 22, 312–317.

95. Schauf CL: Zonisamide enhances slow sodium inactiva-tion in Myxicola. Brain Res, 1987, 9, 413, 185–188.

96. Scheyer RD: Valproic acid: drug interactions. In: Antie-pileptic Drugs. Ed. Levy RH, Mattson RH, Meldrum BS,Perucca E, Lippincott, Williams & Wilkins, Philadelphia,2002, 801–807.

97. Schulze-Bonhage A: Zonisamide in the treatment of epi-lepsy. Expert Opin Pharmacother, 2010, 11, 115–126.

98. Schumacher TB, Beck H, Steinhäuser C, Schramm J,Elger CE: Effects of phenytoin, carbamazepine, and ga-bapentin on calcium channels in hippocampal granulecells from patients with temporal lobe epilepsy. Epilep-sia, 1998, 39, 355–363.

99. Shank RP, Gardocki JF, Vaught JL, Davis CB, SchupskyJJ, Raffa RB, Dodgson SJ et al.: Topiramate: preclinicalevaluation of structurally novel anticonvulsant. Epilep-sia, 1994, 35, 450–460.

100. Sills GJ: Combining mechanisms: how can experimentalstudies inform clinical practice? The Conference Antie-pileptic drug therapy: does mechanism of action matter?Radisson Edwardian Heathrow Hotel, London, UK,Monday 7 June 2010.

101. Sills GJ: The mechanisms of action of gabapentin andpregabalin. Curr Opin Pharmacol, 2006, 6, 108–113.

102. Singh R, Gardner RJ, Crossland KM, Sheffer IE, Berko-vic SF: Chromosomal abnormalities and epilepsy: a re-view for clinicians and gene hunters. Epilepsia, 2002, 43,127–140.

103. Spina E, Perucca E, Levy R: Predictability of metabolicantiepileptic drug interactions. In: Antiepileptic Drugs.Combination Therapy and Interactions. Eds. MajkowskiJ, Bourgeois B, Patsalos P, Mattson R, Cambridge Uni-versity Press, Cambridge, 2005, 57–92.

104. Stafstrom CE: Mechanisms of action of antiepilepticdrugs: the search for synergy. Curr Opin Neurol, 2010,23, 157–163.

105. Stephen LJ, Brodie MJ: Seizure freedom with more thanone antiepileptic drug. Seizure, 2002, 11, 349–351.

106. Stöhr T, Kupferberg HJ, Stables JP, Choi D, Harris RH,Kohn H, Walton N, White HS: Lacosamide, a novelanti-convulsant drug, shows efficacy with a wide safetymargin in rodent models for epilepsy. Epilepsy Res,2007, 74, 147–154.

107. Suzuki S, Kawakami K, Nishimura S, Watanabe Y, YagiK, Seino M, Miyamoto K: Zonisamide blocks T-type cal-cium channel in cultured neurons of rat cerebral cortex.Epilepsy Res, 1992, 12, 21–27.

108. Swinyard EA, Sofia RD, Kupferberg HJ: Comparativeanticonvulsant activity and neurotoxicity of felbamateand four prototype antiepileptic drugs in mice and rats.Epilepsia, 1986, 27, 27–34.

109. Tallarida RJ: An overview of drug combination analysiswith isobolograms. J Pharmacol Exp Ther, 2007, 113,197–209.

110. Taylor CP, Gee NS, Su TZ, Kocsis JD, Welty DF, BrownJP, Dooley DJ et al.: A summary of mechanistic hypothe-sis of gabapentin pharmacology. Epilepsy Res, 1998, 29,233–249.

111. Temperini C, Innocenti A, Mastrolorenzo A, ScozzafavaA, Supuran CT: Carbonic anhydrase inhibitors. Interac-tion of the antiepileptic drug sulthiame with twelvemammalian isoforms: kinetic and X-ray crystallographicstudies. Bioorg Med Chem Lett, 2007, 17, 4866–4872.

112. Thiry A, Dogné JM, Supuran CT, Masereel B: Anticon-vulsant sulfonamides/sulfamates/sulfamides with carbonicanhydrase inhibitory activity: drug design and mechanismof action. Curr Pharm Des, 2008, 14, 661–671.

113. Tomson T: Drug selection for the newly diagnosed pa-tient: when is a new generation antiepileptic drug indi-cated? J Neurol, 2004, 251, 1043–1049.

114. Trojnar MP, Kimber-Trojnar ¯, Trojnar MK, CzuczwarSJ: A review of experimental data on efficacy ofantiepileptic drug combinations in seizure models – anisobolographic analysis. Epileptologia, 2006, 14, 301–311.

115. Tunnicliff G: Basis of the antiseizure action of pheny-toin. Gen Pharmacol, 1996, 27, 1091–1097.

116. Twyman RE, Rogers CJ, Macdonald RL: Differentialregulation of gamma-aminobutyric acid receptor chan-nels by diazepam and phenobarbital. Ann Neurol, 1989,25, 213–220.

117. Walker MC, Sander JW: New antiepileptic drugs. ExpertOpin Invest Drugs, 1999, 10, 1497–1510.

�� 291


118. Wauquier A, Zhou S: Topiramate: a potent anticonvul-sant in the amygdala-kindled rat. Epilepsy Res, 1996, 24,73–77.

119. White HS, Smith MD, Wilcox KS: Mechanism of action ofantiepileptic drugs. Int Rev Neurobiol, 2007, 81, 85–110.

120. Wickenden AD: Potassium channels as anti-epilepticdrug targets. Neuropharmacology, 2002, 43, 1055–1060.

121. Willmore LJ: Clinical pharmacology of new antiepilepticdrugs. Neurology, 2000, 55, 17–24.

122. Wolff H, Castle NA, Pardo LA: Voltage-gated potassiumchannels as therapeutic drug targets. Nat Rev Drug Dis-cov, 2009, 8, 982–1001.

123. Wuttke TV, Lerche H: Novel anticonvulsant drugs target-ing voltage-dependent ion channels. Expert Opin Inves-tig Drugs, 2006, 15, 1167–1177.

124. Wuttke TV, Seebohm G, Bail S, Maljevic S, Lerche H:The new anticonvulsant retigabine favors voltage-dependent opening of the Kv7.2 (KCNQ2) channel bybinding to its activation gate. Mol Pharmacol, 2005, 67,1009–1017.

125. www.clinicaltrials.gov126. Zaccara G, Gangemi PF, Bendoni L, Menge GP,

Schwabe S, Monza GC: Influence of single and repeateddoses of oxcarbazepine on the pharmacokinetic profile offelodipine. Ther Drug Monit, 1993, 15, 39–42.

Received: February 24, 2011; in the revised form: March 14,

2011; accepted: March 18, 2011.

292 ��

Basic mechanisms of antiepileptic drugs and their ...ally showed high efficacy in the treatment of...

Documents

Transcript of Basic mechanisms of antiepileptic drugs and their ...ally showed high efficacy in the treatment of...