Antiepileptic and Antiepileptogenic Performance of Carisbamate after Head Injury in the Rat: Blind and Randomized Studies

Abstract

Carisbamate (CRS) exhibits broad acute anticonvulsant activity in conventional anticonvulsant screens, genetic models of absence epilepsy and audiogenic seizures, and chronic spontaneous motor seizures arising after chemoconvulsant-induced status epilepticus. In add-on phase III trials with pharmacoresistant patients CRS induced Ͻ30% average decreases in partial-onset seizure frequency. We assessed the antiepileptogenic and antiepileptic performance of subchronic CRS administration on posttraumatic epilepsy (PTE) induced by rostral parasaggital fluid percussion injury (rpFPI), which closely replicates human contusive closed head injury. Studies were blind and randomized, and treatment effects were assessed on the basis of sensitive electrocorticography (ECoG) recordings. Antiepileptogenic effects were assessed in independent groups of control and CRS-treated rats, at 1 and 3 months postinjury, after completion of a 2-week prophylactic treatment initiated 15 min after injury. The antiepileptic effects of 1-week CRS treatments were assessed in repeated measures experiments at 1 and 4 months postinjury. The studies were powered to detect ϳ50 and ϳ40% decreases in epilepsy incidence and frequency of seizures, respectively. Drug/vehicle treatment, ECoG analysis, and [CRS] plasma determination all were performed blind. We detected no antiepileptogenic and an equivocal transient antiepileptic effects of CRS despite [CRS] plasma comparable with or higher than levels attained in previous preclinical and clinical studies. These findings contrast with previous preclinical data demonstrating large efficacy of CRS, but agree with the average effect of CRS seen in clinical trials. The data support the use of rpFPI-induced PTE in the adolescent rat as a model of pharmacoresistant epilepsy for preclinical development.

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

“…Such proof-of-concept was also reported in a study that used a TBI model in rats, in which mild passive focal cooling following rostral parasagittal fluid percussion injury in rats was associated with potent and persistent prevention and modification of epileptic seizures [39]. In contrast, the experimental AED carisbamate was without effect on epileptogenesis in this model [38].…”

“…Based on findings of functional (prokindling) alterations after depth electrode implantation in the absence of electrical stimulation in rats, Löscher [37] has proposed that amygdala kindling may present a model of TBI, in which the consequences of penetrating brain injury (by the depth electrode) are facilitated by electrical stimulation. More recently, D'Ambrosio and colleagues [38,39] have used rostral parasagittal fluid percussion injury as a model of TBI in rats and started to evaluate AEDs and other treatments for antiepileptogenic effects in this model.…”

Optimized methods for epilepsy therapy development using an etiologically realistic model of focal epilepsy in the rat

“…Consistent with previous reports (Curia et al., 2011; Eastman et al, 2010, 2011), seizure frequencies varied greatly among the 16 rats in which seizures were detected, but each rat’s seizure frequency remained relatively stable from day to day regardless of montage. Thus, when seizure frequencies were determined on the basis of 24 h recordings, the daily mean frequency of the full cohort of 17 rats fluctuated modestly about the overall weekly mean, with absolute deviations from the weekly mean no greater than 15% or 37% for seizures detected with the full or occipital montages, respectively (Fig.…”

“…These simulations were similar in principle to those we reported previously (Eastman et al, 2010, 2011), but were designed to assess the effects of different experimental variables (Table 2), such as seizure definitions, recording montages, and duration of recordings on the statistical power to detect the treatment effects. The seizure activity of each rat was represented as a list of all the seizure onset times observed during the week of continuous monitoring.…”

“…Detailed characterization of the electrobehavioral seizures generated by this neocortical epileptic focus has permitted the use of realistic seizure detection criteria that are based on clinical practice and are consistent with the ILAE definition of epileptic seizure (D’Ambrosio and Miller, 2010). We also have established statistical methods to efficiently detect effects of investigational ASDs in the presence of non-responders (Eastman et al, 2010, 2011). These studies were based on periodic recordings (24–72 h/week) as a compromise to keep costs down while still sampling much of the variability in seizure frequency.…”