The use of the dog electroencephalogram (EEG) in safety pharmacology to evaluate proconvulsant risk.

INTRODUCTION: The dog is frequently used for cardiovascular safety pharmacology and for toxicology studies, but is not often used for central nervous system (CNS) safety pharmacology purposes. We have therefore examined the electroencephalogram (EEG) in conscious dogs by means of radio-telemetry methods using the proconvulsant agent pentylenetetrazole (PTZ) as reference substance. Assessment of proconvulsant risk is an important aspect of CNS safety evaluation and the EEG is a sensitive technique for identifying pathologic brain activity, most importantly paroxysmal activity. METHODS: Dogs were implanted with epidural electrodes wired to subcutaneously placed radiotransmitters. Following baseline recording, the test substance was administered and the EEG and electromyogram (EMG) activities were recorded from dogs placed in slings. The EEG was assessed visually for abnormal activity and dogs were also continuously observed for the appearance of overt convulsive activity. The PTZ infusion was stopped and diazepam was administered as soon as clear and sustained EEG effects and/or behavioural symptoms occurred. RESULTS: Slow i.v. infusion of PTZ (1.5 mg/kg/min) induced clear paroxysmal effects on the EEG trace in the form of spike and wave trains of 4-5 Hz. Paroxysmal activity associated with clonic convulsions occurred between 17 and 36 min after the start of infusion (a mean of 24 min) but in most cases paroxysmal activity was observed approximately 60 s prior to any overt convulsive activity. DISCUSSION: These data show the usefulness of the telemetered dog EEG in safety pharmacology. The dog EEG is appropriate in situations where results from cardiovascular and CNS safety tests in the same species are required, or where the use of other species is contraindicated because of metabolic or pharmacokinetic particularities.

New perspectives in CNS safety pharmacology.

International requirements for central nervous system (CNS) safety pharmacology are reviewed. Procedures for initial CNS safety screening (core battery studies) can be conducted from the beginning of the drug discovery process, but at latest before first studies in man. They should include assessment of general behaviour, locomotor activity and motor coordination, but can also include studies of pain sensitivity, convulsive threshold and interaction with hypnotics. Follow-up studies, to be conducted later in the drug development process but before product approval, cover assessment of higher cognitive function, electroencephalogram (EEG) and drug dependence/abuse liability. Procedures for assessing cognitive function can include, in order of complexity, passive avoidance, Morris and radial mazes and operant behaviour tasks (delayed alternation, repeated acquisition). EEG can include the quantified EEG (QEEG) and studies of the sleep/wakefulness cycle. Drug dependence/abuse procedures can include precipitated and nonprecipitated withdrawal (drug dependence), and place preference, drug discrimination and self-administration (drug abuse). In contrast to core battery CNS procedures, conducted exclusively in rodents, follow-up studies can include higher species, in particular primates.

Preclinical profiling and safety studies of ABT-769: a compound with potential for broad-spectrum antiepileptic activity.

PURPOSE: The objective of this study was to characterize the antiseizure and safety profiles of ABT-769 [(R)-N-(2 amino-2-oxoethyl)spiro[2,5]octane-1-carboxamide]. METHODS: ABT-769 was tested for protection against maximal electroshock and pentylenetetrazol-induced seizures in the mouse and for suppression of electrically kindled amygdala seizures and spontaneous absence-like seizures in the rat. The central nervous system safety profile was evaluated by using tests of motor coordination and inhibitory avoidance. The potential for liver toxicity was assessed in vitro by using a mitochondrial fatty acid beta-oxidation assay. Teratogenic potential was assessed in the mouse. RESULTS: ABT-769 blocked maximal electroshock, subcutaneous pentylenetetrazol and intravenous pentylenetetrazol-induced seizures with median effective dose (ED50) values of 0.25, 0.38, and 0.11 mmol/kg, p.o., respectively. No tolerance was evident in the intravenous pentylenetetrazol test after twice-daily dosing of ABT-769 (0.3 mmol/kg, p.o.) for 4 days. ABT-769 blocked absence-like spike-wave discharge (ED50, 0.15 mmol/kg, p.o.) and shortened the cortical and amygdala afterdischarge duration of kindled seizures (1 and 3 mmol/kg, p.o.). The protective indices (ED50 rotorod impairment/ED50 seizure protection) were 4.8, 3.2, and 10.9 in the maximal electroshock, subcutaneous pentylenetetrazol and intravenous pentylenetetrazol seizure tests, respectively. ABT-769 did not affect inhibitory avoidance performance (0.1-1 mmol/kg, p.o.). ABT-769 did not affect mitochondrial fatty acid beta-oxidation or induce neural tube defects. CONCLUSIONS: ABT-769 is an efficacious antiseizure agent in animal models of convulsive and nonconvulsive epilepsy and has a favorable safety profile. ABT-769 has a broad-spectrum profile like that of valproic acid. Its profile is clearly different from those of carbamazepine, phenytoin, lamotrigine, topiramate, vigabatrin, and tiagabine.