A once‐per‐day, drug‐in‐food protocol for prolonged administration of antiepileptic drugs in animal models

Abstract

SUMMARYPurpose: Convenient and effective methods for administering potential antiepileptic drugs (AEDs) chronically should facilitate many experiments in animal models of chronic epilepsy with spontaneous recurrent seizures. This proof-of-principle study aimed to optimize a once-per-day, drug-in-food protocol by testing the effect of carbamazepine (CBZ) on the frequency of convulsive seizures in rats with kainate-induced epilepsy. Methods: Adult male rats were given repeated low-dose kainate injections until convulsive status epilepticus persisted for >3 h. After the rats developed spontaneous recurrent seizures, food pellets with CBZ (30, 100, or 300 mg/kg/day) were provided once per day in three 2-week trials (n = 7-9 rats) involving 5 days of CBZ or control treatment, separated by two recovery days within a trial. The total amount of food provided and consumed per day corresponded to a normal caloric diet (60 g/kg/ day). Key Findings: When provided once per day, all animals ate the CBZ-containing food irregularly but continuously throughout the 24-h day. With this daily feeding protocol, CBZ significantly reduced the frequency of spontaneous convulsive seizures in a dose-dependent manner. It is important to note that the effect of CBZ was consistent across the 5 days and throughout each day of the trials. With food administered at 9:00 a.m., and blood assayed at 5:00 p.m., higher food levels of CBZ resulted in higher plasma concentrations of CBZ. Significance: This AED-in-food protocol is simple, efficient, inexpensive, reliable, and noninvasive; it allows easier long-term drug administration and is less stressful and more humane than other methods of AED administration.

Animal models of temporal lobe epilepsy following systemic chemoconvulsant administration

“…For instance, a single intraperitoneal administration of topiramate or carbamazepine can reduce the frequency of spontaneous seizures but the anti-ictogenic effect is short-lasting (Grabenstatter et al, 2005(Grabenstatter et al, , 2007. The daily oral administration of carbamazepine however appears more effective since its effect is long-lasting and may even completely block seizure occurrence (Ali et al, 2012;Grabenstatter et al, 2007). However, it is unclear if non-convulsive seizures are also blocked since no study has been performed so far on kainic-acid treated animals implanted with depth electrodes and treated with anti-epileptic drugs for multiple consecutive days.…”

Correction of medication nonadherence results in better seizure outcomes than dose escalation in a novel preclinical epilepsy model of adherence

“…CBZ was selected as the test article because it is a first-line therapy clinically, and the daily dose of 300 mg/kg has been shown to achieve therapeutic concentrations acutely 27 and be effective at reducing seizure frequency in rats with acquired epilepsy. via a single feeder with unmedicated chow (ie, a 0% medicated diet).…”

Staged anticonvulsant screening for chronic epilepsy

“…Rats were continuously monitored with traditional wired EEG beginning 2 months after epileptogenic kainate administration Rats were treated with either drug‐containing food or food without the drug on day 1 and then observed through day 3 32, 38. On day 4, the rats were crossed over to the other treatment (i.e., placebo if the first treatment was celecoxib), and observed through day 6.…”

“…Repeat biochemical as well as electrophysiological confirmation in vitro comprised the second stage of screening. The final stage was comprised of double blind, crossover controlled, in vivo testing in the kainate model of severe chronic epilepsy9, 32 with seizure quantification by continuous electrographic monitoring 33…”