Improved seizure control by alternating therapy of levetiracetam and valproate in epileptic rats.
OBJECTIVE
Tolerance to drug treatment is a serious problem in the treatment of epilepsy. We previously showed that tolerance to levetiracetam (LEV) developed within 4 days after the start of the treatment in a rat model for spontaneous seizures after electrically induced status epilepticus. In the current study we tested whether the development of tolerance to LEV could be prevented by alternating between LEV and valproate (VPA) treatment.


METHODS
Before starting the alternating therapy with LEV and VPA (3 day LEV-3 day VPA, two cycles), we assessed the efficacy of VPA monotherapy by administering VPA to chronic epileptic rats via osmotic minipumps during 7 days. The anticonvulsive effects were determined by continuous video-EEG (electroencephalography) monitoring, and the concentration of VPA and LEV was measured in plasma using gas chromatography.


RESULTS
VPA significantly suppressed spontaneous seizures in chronic epileptic rats for 5 days. Hereafter, seizure frequency increased to pretreatment values despite adequate VPA blood levels. Seizure duration was reduced for 6 days during treatment. Seizure severity was reduced throughout the 7-day treatment period. Alternating treatment of LEV and VPA did not prevent development of tolerance; however, seizures were suppressed significantly longer compared to VPA and LEV monotherapy.


CONCLUSIONS
Because alternating treatment with LEV and VPA led to a prolonged effective seizure control in the animal model, it would be worthwhile to explore the possibilities of using an alternating treatment protocol in pharmacoresistant patients in whom an effective treatment is hampered by tolerance to antiepileptic drugs.
van Vliet
Erwin A
EA
Epilepsy Institute in The Netherlands (SEIN), Achterweg, Heemstede, The Netherlands.
Edelbroek
Peter M
PM
Gorter
Jan A
JA
D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D018891:Dentate Gyrus / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004351:Drug Resistance; D004361:Drug Tolerance; D004558:Electric Stimulation; D004569:Electroencephalography / Q000379:methods / Q000706:statistics & numerical data; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics / Q000517:prevention & control; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy / Q000235:genetics / Q000517:prevention & control; D006801:Humans; D000077287:Levetiracetam; D008297:Male; D010889:Piracetam / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy / Q000209:etiology; D016896:Treatment Outcome; D014635:Valproic Acid / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*
D000927:Anticonvulsants; D000077287:Levetiracetam; D014635:Valproic Acid; D010889:Piracetam