The anticonvulsant activity of ropizine in the rat.
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Biomedical subjects
Publications and source records attributed to H L Edmonds.
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Studies were conducted on a colony of purebred beagle dogs. Animals with spontaneous seizures were classed as epileptic beagles (EB). Those without spontaneous seizures were termed nonepileptic beagles (NEB). The median convulsant current for maximal electroshock seizure (MES) threshold was 175(194-158)mA for EB and 390 (417-364) mA for NEB. Similarly the median convulsant dose of pentylenetetrazol (PTZ) was 7.9 (10.1-6.2) mg/kg for EB and 20.2 (24.2-17.6) mg/kg for NEB. Following pretreatment with graded doses of ropizine (SC 13504), the median protective dose against MES was 6.0(9.2-3.9) mg/kg in EB and 3.2(4.8-2.1) mg/kg in NEB. Based on the incidence of ataxia, EB had a median toxic dose (TD50) of 14.0(16.5-11.9) mg/kg, while in NEB it was 18.0(23.6-13.7)mg/kg. The TD50 doses were unable to protect against a convulsive dose of PTZ. It is concluded first that ropizine may have anti-grand mal activity but apparently lacks an anti-petit mal action. Secondly, EB are more sensitive than NEB to the convulsive effects of electric current and PTZ, yet less responsive to the anticonvulsant actions of ropizine.
Dose-response studies were performed on freely moving rats bearing chronically implanted electrodes. The effects of intracortical injections of penicillin, bicuculline, and conjugated estrogens (Premarin) were determined on EEG activity and motor performance. Bicuculline in doses of 0.025 and 0.05% regularly produced spike and afterdischarge (AD) patterns of rapid onset (less than 10 sec,) brief duration (less than 20 min), and marked intensity. Lower doses had little or no effect. Premarin 1% and penicillin 100 international units produced spike and AD patterns of slower onset (5 min), longer duration (up to 2 hr), and mild intensity. Smaller doses generally produced no AD activity, whereas larger doses produced epileptic patterns severe enough to preclude their use in operant studies. Penicillin and Premarin both produced a significant decrease in operant-response rate in animals trained to bar press on a FR 20 schedule. A marked variability was noted in the behavioral responses of individual rats to the disruptive effects of the epileptogens.
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1. A common 'stroke model', the rat middle cerebral artery occlusion preparation, was used to compare photocoagulation with mechanical occlusion. 2. Areas of cerebral infarction and of vascular leakage were compared using these two methods. The general pattern of damage was similar, with central infarcted areas surrounded by larger vascular leakage areas. 3. The two models differed in the extent of their vascular leakage areas and in their response to the cerebroprotective agent flunarizine. 4. We conclude that the two models are not equivalent, probably because they do not damage the vascular endothelium to the same degree.
1. We hypothesized that burst activity induced in rat hippocampal tissue by a high-K+ medium in vitro would be increased by a previous episode of global ischaemia, severe enough to induce persistent neurological dysfunction. 2. Male Wistar rats that were subjected to 9 min of chest compression, sufficient to reduce blood pressure (BP) to zero, showed evidence of neurological damage attributed to a global ischaemic insult. Hindlimb function was impaired for 24-48 h and a susceptibility to sound-induced seizures was induced in 25 to 35 rats. The seizure susceptibility cleared spontaneously within 2 weeks in 10 of 25 rats. 3. Hippocampal slices from postischaemic rats were prepared, tested for viability and were then exposed to an 8.0 mmol/L K+ artificial cerebrospinal fluid in vitro. Spontaneous epileptiform bursting activity in the high-K+ medium was not increased. Instead, burst size decreased with time after ischaemia. 4. The decrement in bursting activity is attributed to loss of cellular activity or integrity. These changes correlate with functional changes described by others, but not necessarily to histologically verifiable cell death. The time course of these changes was remarkably long, continuing for almost 3 weeks. Thus, a less-than-lethal ischaemia appears to induce neuronal changes, possibly reversible, that continue for at least 20 days after the global ischaemic insult.
The sleep-wakefulness (S-W) patterns in 4 genetically epileptic beagles were studied. As compared to normal beagles, there was no change in the percentage time spent in the different stages of S-W. However, epileptic dogs tended towards more and shorter S-W epochs and they had a statistically significant shortening of both REM and deep slow wave sleep (dSWS) latency. The antiepileptics diazepam, phenytoin, flunarizine and phenobarbital did not yield marked effects on S-W patterns, but the REM and dSWS latencies were affected. It is suggested that epileptic beagles may be useful in experimental analysis of epilepsy as well as in drug development.
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