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Keywords:

  • Epilepsy;
  • Epileptogenesis;
  • Disease-modification;
  • Seizures

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Summary: Purpose: The current treatment of epilepsy focuses exclusively on the prophylaxis or suppression of seizures and thus provides merely a symptomatic treatment, without clear influence on the course of the disease. There is a need for new drugs that act at different molecular targets than currently available antiepileptic drugs (AEDs) and for new therapies designed to block the process of epileptogenesis. In recent years, different research lines have examined the epileptogenic process in order to understand the different stages in this process, and with the hope that early recognition and intervention could prevent the development or progression of epilepsy. In animals, acquired epilepsy is studied most commonly with the kindling model and status epilepticus models. In the present study, we used the kindling model to evaluate whether the novel AED lacosamide affects kindling-induced epileptogenesis. This drug does not seem to act by any of the mechanisms of currently available AEDs, but the exact molecular mechanisms of action of lacosamide have not yet been clarified.

Methods: Groups of 9–10 rats were treated with either vehicle or different doses of lacosamide (3, 10, or 30 mg/kg/day) over 22–23 days during amygdala kindling.

Results: Daily administration of lacosamide during kindling acquisition produced a dose-dependent effect on kindling development. While the drug was inactive at 3 mg/kg/day, significant retardation of kindling was observed at 10 mg/kg/day, by which the average number of stimulations to reach kindling criterion was increased by >90%. A significant inhibitory effect on kindling acquisition was also observed with 30 mg/kg/day, but this dose of lacosamide was associated with adverse effects.

Conclusions: The present data demonstrate that lacosamide, in addition to exerting anticonvulsant activity, has the potential to retard kindling-induced epileptogenesis. Whether this indicates that lacosamide possesses antiepileptogenic or disease-modifying potential needs to be further evaluated, including studies in other models of acquired epilepsy.

Lacosamide (SPM 927; R-2-acetamido-N-benzyl-3-methoxypropionamide), also formerly called harkoseride, is a member of a series of functionalized amino acids initially synthesized as antiepileptic drug (AED) candidates (Bialer et al., 2002; Hovinga, 2003). Lacosamide was evaluated in the AED Development Program of the Epilepsy Branch of the National Institutes of Health (NIH) and found to be more potent and effective in several animal models as compared to other AEDs (Hovinga, 2003; Stoehr et al., submitted). Lacosamide protects against seizures in various animal models, including maximal electroshock seizures (MES) in mice and rats, the 6-Hz refractory seizure model in mice, hippocampal kindling in rats, sound-induced seizures in Frings mice and self-sustaining status epilepticus in rats (Bialer et al., 2004). The molecular mechanisms of action of lacosamide have not yet been clarified. In phase II clinical trials in patients with medically resistant partial seizures, lacosamide showed significant antiepileptic efficacy (Bialer et al., 2004). The drug is currently undergoing phase III clinical trials in patients with epilepsy and patients with diabetic neuropathic pain.

In addition to developing novel AEDs with high efficacy and tolerability, a major aim of current epilepsy research is to develop drugs which, in addition to suppressing seizures, alter the underlying epileptogenic process and, in doing so, the course of the disease and its prognosis (Löscher, 2002a; Löscher and Schmidt, 2004; Pitkänen, 2004; Pitkänen and Kubova, 2004). Drugs exerting such antiepileptogenic or disease-modifying potential could be used to either prevent acquired epilepsy or alter its natural course. A number of animal models, including the kindling and poststatus epileptic models of temporal lobe epilepsy, are widely used for studies on epileptogenic processes and on drug targets by which epilepsy can be prevented or modified (Löscher, 2002b; Pitkänen, 2002a,b). Kindling describes the phenomenon that repeated application of an initially subconvulsive electrical stimulus to limbic brain areas such as the amygdala leads to the development of seizures increasing in severity and duration with ongoing stimulation (McIntyre et al., 2002). Some clinically established AEDs, including valproate and levetiracetam, retard kindling during the treatment period and, following drug withdrawal, change seizure characteristics as compared to controls, indicating “disease-modifying” (plastic) changes induced by drug treatment (Löscher, 2002b). Most AEDs, however, either do not induce any effects on kindling acquisition or only induce effects during the treatment period. The aim of the present experiment was to evaluate the effects of lacosamide on the development of kindling in comparison with vehicle-treated controls.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Animals

Forty female Wistar rats were purchased at a body weight of 200–220 g (Harlan Winkelmann, Borchen, Germany). Following arrival, the rats were kept under controlled environmental conditions (24–25°C; 50–60% humidity; 12 h light/dark cycle; light on at 6:00 h a.m.) with free access to standard laboratory chow (Altromin 1324 standard diet) and tap water. Before being used in the experiments, the rats were allowed to adapt to the new conditions for at least 1 week. All experiments were performed within the same day time to minimize possible effects of circadian variation. All animal experiments were carried out in accordance with the European Communities Council Directive of 24 November 1986 (86/609/EEC) and were formally approved by the animal subjects review board of our institution. All efforts were made to minimize the number of animals used and their suffering.

Electrode implantation

Electrodes were implanted in all rats used for this study. For implantation, animals were anesthetized with chloral hydrate (360 mg/kg, i.p.), the skull surface was exposed, and a bipolar electrode was implanted into the right hemisphere aimed at the basolateral amygdala using the following stereotaxic coordinates according to the atlas of Paxinos and Watson (1986): 2.2-mm caudal, 4.8-mm lateral, 8.5-mm ventral (all respective to bregma). The electrodes consisted of two twisted Teflon-coated stainless steel wires (250-μm diameter). A screw, which served as grounding electrode, was positioned over the left parietal cortex. Bipolar and ground electrodes were connected to plugs, and the electrode assembly and anchor screws were held in place with dental acrylic cement applied to the exposed skull surface. After surgery, the rats were treated with antibiotics for 1 week to prevent infection.

Drug administration and kindling procedure

From the 40 electrode-implanted rats, two rats could not be included in the experiments because of death during anaesthesia or misplacement of the electrode. The remaining 38 rats were randomly distributed to the following treatment groups: group 1, vehicle control (n = 9); group 2, lacosamide 3 mg/kg/day (n = 9); group 3, lacosamide 10 mg/kg day (n = 10); group 4, lacosamide 30 mg/kg/day (n = 10). Since it was not possible to treat and kindle so many rats at the same time, half of the animals of each group were electrode-implanted, drug-treated and kindled in a first phase of the experiment, followed by the second half of the rats in a second phase. At the end of the two phases, data from all rats were combined for analysis. Lacosamide was obtained from Schwarz BioSciences GmbH (Monheim, Germany). Drug solutions were freshly prepared in saline and injected at a volume of 3 ml/kg. Vehicle controls obtained the same injection volume of saline instead of drug. Doses and pretreatment time of lacosamide were chosen on the basis of its anticonvulsant effects in seizure models in rodents, including the kindling model in rats (Bialer et al., 2002; Hovinga, 2003).

The initial (prekindling) afterdischarge threshold (ADT) was determined 2 weeks after electrode implantation and was considered when animals were randomly assigned to the treatment groups. Determination of the initial ADT was performed using an ascending stairstep procedure as described previously (Freeman and Jarvis, 1981). The initial current intensity was 50 μA, and the current intensity was increased in fixed steps of about 20% of the previous current (i.e., 60, 75, 90, 110, 130, 160, 200, 240, 280, 330, 400, 480, 500, 590, 700, 840, 1000 μA, respectively) at intervals of 1 min until an afterdischarge of at least 3 s duration was elicited. On the day after prekindling ADT determination, chronic treatment with 0.9% saline or lacosamide (3, 10, or 30 mg/kg/day) dissolved in 0.9% saline was started. Vehicle or drug was administered i.p. once daily, 5 days per week in the afternoon. The injection volume was 3 ml/kg.

Animals were kindled by once daily stimulation of the amygdala (stimulation strength 20% above individual initial ADT, 1 ms, monophasic square-wave pulses, 50 Hz for 1 s, five times per week). The stimulations were performed 30 min after each i.p. injection in the afternoon and were continued for 22–23 days. Rats were not kindled or treated over the weekends. Following termination of treatment, rats of the saline treated group and the lacosamide 30 mg/kg treated group were again stimulated after a washout period of 2.5 months on average to determine whether treatment with lacosamide exerted any enduring antiepileptogenic or disease-modifying effect similar to that previously described for levetiracetam (Löscher et al., 1998). Unfortunately, the group treated with 10 mg/kg lacosamide during kindling acquisition could not be included in this experiment, because too many rats of this group had lost their electrode assembly at the time (2.5 months) after washout used for this trial.

With each stimulation, seizure severity was scored according to Racine (1972) by an observer blinded to the treatment conditions: 1, immobility, eye closure, ear twitching, twitching of vibrissae, sniffing, facial clonus; 2, head nodding associated with more severe facial clonus; 3, clonus of one forelimb; 3.5, bilateral clonus without rearing; 4, bilateral clonus accompanied by rearing; 4.5, generalized clonic seizures without rearing and falling (e.g., because of direct loss of balance); 5, rearing and falling accompanied by generalized clonic seizures. Stimulations were terminated when all rats of the saline treated group (group 5) had reached kindling criterion (a stage 5 seizure).

During the kindling process, afterdischarge duration (ADD) was recorded in addition to seizure severity and ADT. ADD was defined as the period of high amplitude spiking (at least 1 Hz frequency and twice the prestimulation amplitude) in the electroencephalogram (EEG) of the BLA electrode, including the time of stimulation.

Recording of adverse effects of drug treatment

The rectal body temperature was measured on the last day of the experimental period shortly before and 30 min after the drug administration. Body weight was recorded daily. Rats were closely observed for behavioral adverse effects during the drug trials by placing them daily in an open field in the time between drug injection and amygdala stimulation. Vehicle controls were handled the same way as lacosamide-treated rats.

Statistical analysis

For calculating group differences in kindling rate, i.e., number of stimulations to reach stage 5 or total ADD to reach stage 5, rats not reaching stage 5 seizures were included in the analysis as follows: for number of stimulations to reach stage 5, the maximum number of stimulations (22–23) of such rats was used for calculation of group means; for total ADD to reach stage 5, the total (cumulative) ADD of the maximum number of stimulations (22–23) of such rats was used. Significance of differences between groups was calculated by either one-way or two-way analysis of variance (ANOVA) followed by post hoc testing for individual differences (Dunnett's or Dunn's test). Tests used were two-sided and a p < 0.05 was considered significant.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Prekindling ADT

The mean prekindling ADT was 208 ± 65 μA in the vehicle control group, 140 ± 20 μA in the lacosamide 3 mg/kg/day group, 196 ± 38 μA in the lacosamide 10 mg/kg/day group and 182 ± 40 μA, in the lacosamide 30 mg/kg/day group, respectively. Analysis of data by ANOVA did not indicate significant differences in prekindling ADT between groups.

Acquisition of kindling

Once daily treatment with 3 mg/kg lacosamide did not significantly affect the development of kindling, whereas an inhibitory effect on acquisition of kindling was exhibited at daily doses of 10 mg/kg and 30 mg/kg (Fig. 1). Treatment was terminated on day 22 or day 23. By this time, all of the vehicle-treated animals reached the kindling criterion, i.e., a generalized stage 5 seizure, while two out of 10 of the rats treated with 10 mg/kg lacosamide and three out of 10 of the rats treated with 30 mg/kg lacosamide did not reach kindling criterion over this time. In addition to decreasing seizure severity during kindling acquisition (Fig. 1B, C), lacosamide 10 and 30 mg/kg, significantly decreased the duration of afterdischarges associated with kindled seizures (Fig. 1E, F).

image

Figure 1. Effect of different doses of lacosamide on acquisition of kindling upon repeated daily stimulation of the basolateral amygdala in rats. In AC, development of seizure severity is shown, while DF illustrate development of afterdischarge duration. Data are mean values ± SEM of 9–10 rats per group and are shown for each stimulation day. (A) and (D) show data for vehicle and lacosamide, 3 mg/kg/day, (B) and (E) vehicle and lacosamide, 10 mg/kg/day, and (C) and (F) vehicle and lacosamide, 30 mg/kg/day, respectively. Analysis of seizure severity data by two-way ANOVA indicated significant differences between controls and lacosamide for the 10 mg/kg group (p < 0.0001) and the 30 mg/kg group (p < 0.0001) but not the 3 mg/kg group (p = 0.3239). Analysis of ADD data by two-way ANOVA indicated significant differences between controls and lacosamide for the 10 mg/kg group (p < 0.0001) and the 30 mg/kg group (p < 0.0001) but not the 3 mg/kg group (p = 0.3239). Results from post hoc testing of individual differences between controls and treated group are marked by asterisk (p < 0.05).

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The vehicle control rats developed stage 5 seizures after an average of 8.6 ± 0.7 stimulations (Table 1). This average kindling rate was not significantly altered by treatment with 3 mg/kg lacosamide, while rats treated with either 10 or 30 mg/kg lacosamide needed significantly more stimulations to develop a stage 5 seizure (Table 1). The cumulative ADD to reach stage 5 was calculated by summing individual ADDs until the first stage 5 seizure was reached. The cumulative ADD to stage 5 was 202 s on average in the vehicle control, which was not significantly affected by any dose of lacosamide, although there was a nonsignificant increase in cumulative ADD of 86% by treatment with 10 mg/kg (Table 1). Animals treated with 30 mg/kg lacosamide had a significant shorter cumulative ADD to reach the first stage 4 seizure (70.8 ± 16.0 s) than the vehicle control (175 ± 24 s; Table 1). This difference was due to the fact that the ADD of each induced seizure was shorter in lacosamide treated animals (Fig. 1) and not because these rats needed less stimulations to reach a stage 4 seizure (Table 1).

Table 1. The effect of lacosamide on the stepwise progression of kindling
GroupNumber of stimulations to reachTotal ADD [s] to reach
Stage 2Stage 3Stage 4Stage 5Stage 2Stage 3Stage 4Stage 5
  1. The table gives mean values (± SEM) of the number of stimulations to reach the respective seizure stage and of the cumulative duration of afterdischarges (ADD) to reach the respective seizure stage. As described in the Statistics section, rats that did not reach kindling criteria in the 10 mg/kg (n = 2) and 30 mg/kg (n = 3) lacosamide groups were included by assigning them values for the maximum numbers of stimulations performed (see Statistics). Analysis of data by ANOVA indicated significant differences between groups for number of stimulations to reach stage 5 (p = 0.0014) and cumulative ADD to reach stage 4 (p = 0.0331), and stage 5 (p = 0.0486). Significant differences between individual treatment groups and the control group are marked by asterisk (p < 0.05).

Control4.1 ± 0.53 6.7 ± 0.717.7 ± 0.628.6 ± 0.6929.6 ± 6.25 122.1 ± 23.61174.8 ± 23.88201.7 ± 28.68
(n = 9) 
3 mg/kg3.4 ± 0.73 7.0 ± 0.83 7.2 ± 0.868.0 ± 0.8529.7 ± 8.62 102.7 ± 19.54113.0 ± 21.69170.8 ± 31.86
(n = 9) 
10 mg/kg6.5 ± 0.9910.3 ± 1.2110.5 ± 1.1916.5 ± 1.48*38.4 ± 12.03106.6 ± 21.44117.9 ± 25.97374.3 ± 60.97
(n = 10) 
30 mg/kg5.5 ± 1.5410.0 ± 1.9610.5 ± 1.9014.6 ± 2.63*37.8 ± 13.27 61.4 ± 15.23  70.8 ± 16.03*207.1 ± 74.22
(n = 10) 

In the analysis shown in Table 1, rats that did not reach kindling criteria in the 10 mg/kg and 30 mg/kg lacosamide groups were included by assigning them values for the maximum numbers of stimulations performed (see Statistics). If the data from the rats that did not meet criteria were removed from the analysis, there were still significant differences in kindling rate between the lacosamide and saline groups (ANOVA: p = 0.0012), indicating a real effect on the group as a whole and not just on certain rats. Compared to the average kindling rate of controls (8.6 ± 0.7 stimulations; n = 10), both the 10 mg/kg group (15.0 ± 1.28; n = 8) and the 30 mg/kg group (13.1 ± 2.3; n = 7) exhibited significantly higher kindling rates (p < 0.05) when removing rats that did not meet criteria from the comparison.

Progression of kindling following the washout period

Following the washout period, seizure severity and ADD did not differ significantly between the groups which were previously treated with saline or were previously treated with 30 mg/kg lacosamide (Fig. 2). All animals reached seizure stage 5 during the four stimulation days, although there was a trend that kindling criterion (i.e., a stage 5 seizure) was more slowly reached in the lacosamide-pretreated rats (Fig. 2).

image

Figure 2. Progression of kindling, i.e., development of seizure severity and afterdischarge duration, following the washout period in previously saline-treated rats and previously lacosamide (30 mg/kg) treated rats. Data are mean values + SEM of nine rats per group. There was no significant difference between controls and lacosamide-pretreated rats.

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Adverse effects

In rats treated with lacosamide, no significant effects on body weight or body temperature were recorded compared to the vehicle control (not illustrated). During the course of the experiment, the behavior of the lacosamide-treated animals did not obviously differ from the behavior of the vehicle control for the 3 mg/kg and 10 mg/kg treatment groups. However, in five of 10 rats treated with 30 mg/kg/day lacosamide, spontaneous seizures could be detected between 10 and 25 min following administration, i.e., in the time interval between drug administration and stimulation. In two of these rats a spontaneous seizure occurred once while in the other three animals a spontaneous seizure was detected twice. The seizures occurred between day 7 and day 23 of the kindling acquisition period, and were generalized seizures (stage 4 or 5 seizures) with one exception in which a focal stage 2 seizure was observed. Because the animals were not continuously observed during the experiments, we cannot exclude that additional spontaneous seizures occurred in any of the groups.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

In previous experiments in fully kindled rats, lacosamide was shown to block secondarily generalized seizures with an ED50 of 13.5 mg/kg (Perucca and Kupferberg, 2002). At higher doses (25 mg/kg), lacosamide suppressed both focal and generalized seizures in five of eight hippocampus-kindled rats. The present data on kindling acquisition following stimulation of the basolateral amygdala show that lacosamide significantly retards kindling at daily doses of 10 or 30 mg/kg, while 3 mg/kg were ineffective in this regard. At 10 mg/kg, the average number of stimulations to reach kindling criterion, i.e., a fully kindled stage 5 seizure, was increased by >90%. There was also a 90% increase in the cumulative ADD needed to reach stage 5 seizures which, however, did not quite reach the level of statistical significance. At 30 mg/kg, the major effect on kindling development was a significant shortening of ADD associated with kindling stimuli. A similar effect has previously been observed with levetiracetam (Löscher et al., 1998). With the latter drug, this effect on ADD was still present long after drug withdrawal (Löscher et al., 1998). After a prolonged washout period following treatment with lacosamide, 30 mg/kg, a trend but no significant difference to controls was observed.

While treatment with 3 or 10 mg/kg/day lacosamide was tolerated by the rats without any observed adverse effects, drug-induced seizures were observed in 50% of the rats treated with 30 mg/kg/day. These generalized (stage 4 or 5) seizures first occurred after 8 days of kindling, i.e., in partially kindled rats. Kindling is known to increase the sensitivity of rats to proconvulsant drug effects (Löscher, 1999). Thus, the fact that seizures were observed after administration of 30 mg/kg lacosamide, but not lower doses of the drug, seems to indicate that this compound has a dose-dependent liability to exert proconvulsant activity in this model. This is in apparent contrast to results from the AED Development Program of the NIH which indicate that in the subthreshold metrazol test there was no evidence for proconvulsant activity even at toxic doses (Stoehr et al., submitted). In this respect, it is important to note that major AEDs such as phenytoin, gabapentin or carbamazepine are also known to exert proconvulsant activity at high, supra-therapeutic doses (Perucca et al., 1998). It has also been observed that many patients with partial seizures experience an increase in seizures when a new AED (e.g., topiramate, levetiracetam, tiagabine) is added to their therapy, however, such an increase occurs no more frequently with active drug compared to placebo (Somerville, 2002). In a large Phase 2 trial with lacosamide, a similar proportion of subjects experienced increased seizure frequency in the placebo and adjunctive lacosamide groups (Data on file, Schwarz Pharma, 2005).

Based on the present data with 10 mg/kg, lacosamide has the potential to retard kindling-induced epileptogenesis. In this respect, lacosamide is similar to clinically established AEDs such as valproate, phenobarbital, lamotrigine, topiramate, or levetiracetam, but clearly superior to drugs such as carbamazepine and phenytoin, which do not retard kindling (Löscher, 2002b). However, in contrast to levetiracetam (Löscher et al., 1998), the effect of lacosamide on kindling was lost after a long period of washout. We previously demonstrated that after termination of daily treatment with levetiracetam during kindling acquisition, duration of behavioral seizures and of afterdischarges recorded from the amygdala remained to be significantly shorter compared to vehicle controls, although amygdala stimulations were continued in the absence of drug (Löscher et al., 1998). These data thus indicated that levetiracetam not simply masked the expression of kindled seizures through an anticonvulsant action, but exerted a true antiepileptogenic or disease-modifying effect. Our finding was subsequently confirmed by Stratton et al. (2003), who reported that, following cessation of drug treatment, prior levetiracetam treatment appeared to delay or prevent the expected increase in ADD, which was not observed with lamotrigine or, in the present study, lacosamide. Whether this indicates that lacosamide lacks a “true” antiepileptogenic or disease-modifying activity cannot be concluded from these data. Instead, this question needs further exploration, including studies in poststatus epilepticus models of epilepsy.

The precise mode of action by which lacosamide exerts its effects has not yet been elucidated. Lacosamide belongs to a novel class of AEDs, termed functionalized amino acids (Cortes et al., 1985). More than 250 of these compounds that conform to the general N-benzyl-2-acetamidopropionamide structure were synthesized and screened in animal model systems. Functionalized amino acids have substitutions that generate an asymmetric carbon atom, giving rise to R- and S-enantiomers (Perucca and Kupferberg, 2002). Stereoselectivity for anticonvulsant activity resides only in the R configuration. The lead compound, lacosamide (Choi et al., 1996), is an optical antipode of the naturally occurring amino acid l-serine. Though lacosamide has been tested in radioligand-binding experiments on more than 100 receptors, ion channels and enzymes, no significant displacement of binding could be detected at a concentration of 10 μM (Bialer et al., 2002; Errington et al., 2006). Furthermore, voltage-gated calcium, sodium and potassium currents were not affected by lacosamide in standard assays (Errington et al., 2006). It has been suggested that lacosamide may act as an antagonist of the N-methyl-d-aspartate subtype of glutamate receptors through an interaction with the strychnine-insensitive glycine site (Bialer et al., 2001; Perucca and Kupferberg, 2002). However, radioligand binding experiments have provided inconsistent results and generally do not support this conclusion. In vitro functional experiments using mouse cortical neurons, it was shown that at low concentrations lacosamide attenuated glutamate-evoked currents and enhanced GABA evoked currents but only after prolonged pretreatment times (Bialer et al., 2002). Lacosamide at 100 μM produced a significant reduction in the rate of excitatory postsynaptic currents (EPSC's) and inhibitory postsynaptic currents (IPSC's) in cultured cortical cells and blocked spontaneous action potentials (EC50 61 μM) (Errington et al., 2006). However, these results do not suggest a specific molecular mechanism. In contrast to phenytoin, lacosamide did not affect sustained repetitive firing in primary cortical cultures (Errington et al., 2006). Additional preclinical data, although preliminary, suggest a multimodal mode of action (Bialer et al., 2002; Duncan and Kohn, 2005; Lees et al., 2006).

Epilepsy is currently the most prevalent neurological disorder worldwide. The long-term administration of AEDs remains the mainstay of treatment for epilepsy. Unfortunately, current medications are ineffective for approximately one-third of patients with epilepsy, so that novel, more efficacious treatments with new mechanisms (or combinations of mechanisms) of action are urgently needed (Brodie, 2001; Löscher and Schmidt, 2004). The present data from the kindling model of temporal lobe epilepsy add to the available literature indicating that lacosamide is a potent and efficacious novel AED and demonstrate that this drug, in addition to exerting anticonvulsant activity, has the potential to retard kindling-induced epileptogenesis.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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