title: Enhanced efficacy of anticonvulsants when combined with levetiracetam in soman-exposed rats.
abstract: Results from studies based on microinfusions into seizure controlling brain sites (area tempestas, medial septum, perirhinal cortex, posterior piriform cortex) have shown that procyclidine, muscimol, caramiphen, and NBQX, but not ketamine, exert anticonvulsant effects against soman-induced seizures. The purpose of the present study was to examine whether levetiracetam (Keppra(®)) may enhance the anticonvulsant potency of the above drugs to become optimally effective when used systemically. Levetiracetam has a unique profile in preclinical models of epilepsy and has been shown to increase the potency of other antiepileptic drugs. The rats were pretreated with pyridostigmine (0.1mg/kg) to enhance survival and received anticonvulsants 20 min after onset of seizures evoked by soman (1.15 × LD(50)). The results showed that no single drug was able to terminate seizure activity. However, when levetiracetam (LEV; 50mg/kg) was combined with either procyclidine (PCD; 10mg/kg) or caramiphen (CMP; 10mg/kg) complete cessation of seizures was achieved, but the nicotinic antagonist mecamylamine was needed to induce full motor rest in some rats. In a subsequent experiment, rats were pretreated with HI-6 (125 mg/kg) to enhance survival and treatment started 40 min following seizure onset of a soman dose of 1.6 × LD(50). LEV (50mg/kg) combined with either PCD (20mg/kg) or CMP (20mg/kg) terminated seizure activity, but the survival rate was considerably higher for LEV+PCD than LEV+CMP. Both therapies could also save the lives of rats that were about to die 5-10 min after seizure onset. Thus, the combination of LEV and PCD or CMP may make up a model of a future autoinjector being effective regardless of the time of application.
authors.affiliation: Norwegian Defence Research Establishment, Protection Division, P.O. Box 25, NO-2027 Kjeller, Norway. trond.myhrer@ffi.no
authors.forename: Trond
authors.initials: T
authors.lastname: Myhrer
authors.forename: Siri
authors.initials: S
authors.lastname: Enger
authors.forename: Morten
authors.initials: M
authors.lastname: Jonassen
authors.forename: Pål
authors.initials: P
authors.lastname: Aas
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D000931:Antidotes / Q000494:pharmacology; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000494:pharmacology; D003517:Cyclopentanes / Q000494:pharmacology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D007928:Lethal Dose 50; D000077287:Levetiracetam; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009118:Muscimol / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology; D011352:Procyclidine / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D012999:Soman / Q000633:toxicity*; D013997:Time Factors
chemical_list: D000927:Anticonvulsants; D000931:Antidotes; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D003517:Cyclopentanes; D018733:Nicotinic Antagonists; D011810:Quinoxalines; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D009118:Muscimol; D000077287:Levetiracetam; D012999:Soman; C004519:caramiphen; D011352:Procyclidine; D010889:Piracetam