TY - JOUR
T1 - Conventional anticonvulsant drugs in the guinea-pig kindling model of partial seizures
T2 - Effects of acute phenytoin
AU - Gilbert, T. H.
AU - Bharadia, V.
AU - Teskey, G. C.
N1 - Funding Information:
Acknowledgements This study was supported by a research grant and scholarship from NSERC awarded to G.C.T. and T.H.G., respectively. We thank Heather Lawrence, Kaley Bellward, Marie Monfils, Connie Legare and Shelaine Moore for technical assistance.
PY - 2001
Y1 - 2001
N2 - This study addressed some of the controversial issues surrounding the anticonvulsant effect of phenytoin, and the predictive validity of the guinea-pig kindling model for the screening of anticonvulsant drugs. Following an intraperitoneal injection of either 50 or 75 mg/kg phenytoin, we analysed plasma concentrations of phenytoin at various time intervals. Behavioural toxicity was assessed at 0.5 h postinjection using quantitative locomotor tests, as well as scores on a sedation/muscle relaxation rating index. The anticonvulsant efficacy of phenytoin was evaluated from measurements of afterdischarge threshold (ADT), afterdischarge duration (ADD) and behavioural seizure severity at three phases of kindling: non-kindled, kindling acquisition (early and late) and kindled (50+ ADs). ADD and seizure severity were also measured in response to both threshold and suprathreshold kindling stimulation. Plasma levels of phenytoin corresponded to the human therapeutic range at the time of behavioural testing and kindling. Phenytoin did not exert significant adverse effects in guinea-pigs on both the behavioural tests and rating index. Phenytoin increased ADT in non-kindled and kindled guinea-pigs and effectively reduced ADD and seizure severity, indicating that the guinea-pig model correctly predicted phenytoin's anticonvulsant effect. Phenytoin produced reliable anticonvulsant activity in the guinea-pig at threshold stimulation but a somewhat reduced efficacy on seizure severity at suprathreshold stimulation intensities. Kindling in the guinea-pig is a valid model of human partial seizures.
AB - This study addressed some of the controversial issues surrounding the anticonvulsant effect of phenytoin, and the predictive validity of the guinea-pig kindling model for the screening of anticonvulsant drugs. Following an intraperitoneal injection of either 50 or 75 mg/kg phenytoin, we analysed plasma concentrations of phenytoin at various time intervals. Behavioural toxicity was assessed at 0.5 h postinjection using quantitative locomotor tests, as well as scores on a sedation/muscle relaxation rating index. The anticonvulsant efficacy of phenytoin was evaluated from measurements of afterdischarge threshold (ADT), afterdischarge duration (ADD) and behavioural seizure severity at three phases of kindling: non-kindled, kindling acquisition (early and late) and kindled (50+ ADs). ADD and seizure severity were also measured in response to both threshold and suprathreshold kindling stimulation. Plasma levels of phenytoin corresponded to the human therapeutic range at the time of behavioural testing and kindling. Phenytoin did not exert significant adverse effects in guinea-pigs on both the behavioural tests and rating index. Phenytoin increased ADT in non-kindled and kindled guinea-pigs and effectively reduced ADD and seizure severity, indicating that the guinea-pig model correctly predicted phenytoin's anticonvulsant effect. Phenytoin produced reliable anticonvulsant activity in the guinea-pig at threshold stimulation but a somewhat reduced efficacy on seizure severity at suprathreshold stimulation intensities. Kindling in the guinea-pig is a valid model of human partial seizures.
KW - Afterdischarge threshold
KW - Antiepileptic drugs
KW - Behavioural toxicity
KW - Epilepsy
UR - http://www.scopus.com/inward/record.url?scp=0034789508&partnerID=8YFLogxK
U2 - 10.1007/s002210100852
DO - 10.1007/s002210100852
M3 - Journal Article
C2 - 11685400
AN - SCOPUS:0034789508
SN - 0014-4819
VL - 140
SP - 469
EP - 478
JO - Experimental Brain Research
JF - Experimental Brain Research
IS - 4
ER -