Pilot carisbamate pharmacokinetic studies. A, steady-state plasma CRS levels decline during administration of a fixed dose of 90 mg/kg three times daily (n = 9–10 per time point). B, the decline in steady-state plasma CRS levels is prevented by administration of increasing doses of CRS three times daily as shown (n = 3–10 per time point). In both studies, doses were delivered at 7 AM, 3 PM, and 11 PM daily.
Study design and power analyses. A, antiepileptogenesis study. Immediately after rpFPI, animals were randomly assigned to treatment with either vehicle or CRS with equal probability. Treatment commenced 15 min after injury and continued for 2 weeks. Epidural electrodes were implanted 2 weeks after injury, and 48 h of ECoG recordings were obtained from each rat on postinjury weeks 4 and 12. B, nonparametric power analyses for antiepileptogenesis study. Graph shows group sizes required to provide 80% power to detect the indicated antiepileptic effects (one-tailed α = 0.05). ▴ indicate group sizes required to detect uniform decreases in seizure frequency. ○ indicate group sizes required to detect increases in the incidence of seizure-freedom. C, antiepileptic study. Rats received rpFPI, and epidural electrodes were implanted 3 weeks after injury, allowing 1 week for recovery before predrug recording. Animals were randomized to treatment groups in a 1:1 proportion before their first ECoG recordings. Each 3-week testing sequence consisted of three 1-day ECoG recordings on the first week (Baseline I) before drug exposure, on the second week of testing (Drug on) during which the animal was on the drug after a 48-h wash-on period, and on the third week (Baseline II) during which the animal was off the drug after the washoff period. Thus, 72 h of ECoG recordings were acquired from each rat during each week of the 3-week test sequence (∼216 h total per rat). D, nonparametric power analysis for antiepileptic study. Graph shows group size required to provide 80% power to detect uniform decreases in seizure frequency (one-tailed α = 0.05). Data are from Eastman et al. (2010).
CRS did not decrease FPI-induced epileptogenesis. A, log-transformed frequencies of G1, G2, G3, neocortical (G1 + G2), spreading (G2 + G3), and all (G1–3) seizures in vehicle-treated (CON) and CRS-treated rats at 4 weeks post-FPI. B, log-transformed frequencies of seizure, as in A at 12 weeks postinjury. C and D, duration of seizures at 4 (C) and 12 (D) weeks after injury. E and F, log-transformed times spent seizing at 4 (E) and 12 (F) weeks post-FPI. Both vehicle- and CRS-treated groups had seizure frequency and duration and time spent seizing consistent with historical data from untreated animals. G, the mean [CRS]plasma remained above 10 μg/ml through day 9 of the 14-day protocol. The low, but detectable, levels of CRS seen in some vehicle-treated (CON) rats were attributed to coprophagous ingestion of CRS excreted by CRS-treated cage mates. H, despite the wide range of [CRS]plasma measured in individual rats, there was no apparent relationship between [CRS]plasma and seizure frequency at either 4 or 12 weeks after injury. Plasma CRS levels are the means of measurements at days 2 and 9.
CRS had no effect on neocortical seizures at 5 weeks post-FPI. A and B, frequencies of all seizures recorded from individual vehicle-treated (A) and CRS-treated (B) rats before, during, and after week 5 treatment are shown on logarithmic scale. C and D, log-transformed frequencies of G1, G2, and G3 seizures in the vehicle-treated (C) and CRS-treated (D) groups. There was no significant decrease in any seizure type. E and F, log-transformed times spent in G1, G2, and G3 seizure in the vehicle-treated (E) and CRS-treated (F) group. There was no significant decrease in the neocortical seizures that predominate at this stage of the evolution of FPI-induced PTE. Decreases, with respect to week 4, in the times spent in rare G3 seizures seemed significant at both weeks 5 and 6 (*, p ≤ 0.047). G, log-transformed frequency of all seizures in the vehicle- and CRS-treated groups. The frequency of seizure was not significantly decreased with respect to the week 4 pretreatment baseline at any time point in either group. H, log-transformed seizure duration was stable in both treatment groups over the course of the study. I, the antiepileptic effects determined during (week 5) and after (week 6) CRS treatment showed no significant correlation with plasma CRS levels. Effect is computed as log(frequencyweek 4/frequencyweek x).
CRS decreased neither neocortical nor limbic seizures at 17 weeks postinjury. A and B, frequencies (A) and durations (B) of all seizures recorded from individual rats before, during, and after week 17 CRS administration are shown on a logarithmic scale. C and D, mean log-transformed frequencies of (C) and times spent in (D) G1, G2, and G3 seizures before, during, and after week 17 treatment with CRS. There was no significant decrease in any seizure type. E and F, mean log-transformed frequencies of (E) and times spent in (F) neocortical (G1 + G2) and limbic (G3) seizures before, during, and after week 17 treatment with CRS. There was no significant decrease in either seizure class.
Antiepileptic and antiepileptogenic properties of CRS on seizures of different duration. A and B, histograms showing the frequency of seizures of differing durations before, during, and after CRS treatment at 4, 5, and 6 weeks post-FPI (A) and at 16, 17, and 18 weeks (B). C and D, antiepileptic effects based on all detectable clinical seizures (C) or using only clinical seizures lasting longer than 5 s (D). In either case, no significant antiepileptic effect was detected. E and F, histograms showing the frequency of seizures of differing durations in vehicle-treated (CON) and CRS-treated rats at 4 (E) and 12 (F) weeks after injury in the antiepileptogenic study. Seizure frequency was not affected by prophylactic treatment, and both the shortest and longest seizures appeared equally after vehicle or CRS. G and H, log-transformed seizure frequencies determined on the basis of all detectable clinical seizures (G) or just those lasting longer than 5 s (H) at 4 and 12 weeks postinjury in the antiepileptogenic study. To display log-transformed frequencies as positive values with a zero minimum, they are plotted as log(frequencyobserved/frequencyfloor).
Electrographic and behavioral features of G1, G2, and G3 seizures recorded during CRS administration. A, a typical G3 seizure. Active exploration is evident in frames captured before the onset of electrographic activity that is first detected simultaneously by perilesional (4–5) and contralateral (1–5) electrodes. Static posture is evident in two frames captured during the electrographic discharge, and movement resumes after termination of the G3 seizure. B, a typical G2 seizure. Postural changes are evident in frames taken before onset of an electrographic discharge that is first detected by the perilesional electrode (4–5) and spreads both caudally and contralaterally to be detected by all four epidural electrodes. Animal's posture is static in frames captured during the electrographic discharge and movement resumes after termination of the G2 seizure. A head-shaking artifact detected by all four electrodes is clearly distinguishable. C, a typical short G1 seizure. Active exploratory behavior is evident in changes in the animal's position in frames captured shortly before the onset of a brief G1 seizure detected only by the perilesional electrode (4–5). Ictal motion arrest is indicated by the animal's static posture in frames captured (arrest) during the electrographic discharge. Resumption of exploration is evident after termination of the discharge. Electrode montage in A applies to A to C. Numbers shown to the left of ECoG traces indicate recording and reference electrodes as shown in the Inset. In A to C, dotted boxes show electrographic activity during motion arrest on an expanded time scale. Gray arrows indicate ECoG seizure onset.