- 作者: Tsung-Ming Shih John H. McDonough, Jr. Irwin Koplovitz
- 作者服務機構: PHarmacology and Drug Assessment Divisions, US Army Mediceal Research Institute of Chemical Defense, Aberdeen Proveing Ground, Md., USA
- 中文摘要: --
- 英文摘要: This report describes studies of anticonvulsants for theorganophosphorus (OP) nerve agent soman: a basicresearch effort to understand how different pharmaco-logical classes of compounds influence the expression ofseizure produced by soman in rats, and a drug screeningeffort to determine whether clinically useful antiepilep-tics can modulate soman-induced seizures in rats, Elec-troencephalographic(EEG)recordings were used inthese studies. Basic studies were conducted in rats pre-treated with HI-6 and challenged with 1.6 × LD soman.Antimuscarinic compounds were extremely effective inblocking(pretreatment) or terminating soman seizureswhen given 5 min after seizure onset. However, signifi-cantly higher doses were required when treatment wasdelayed for more than 10 min, and some antimuscariniccompounds lost anticonvulsant efficacy when treatmentwas delayed for more than 40 min. Diazepam blockedseizure onset, yet seizures could recur after an initial peri-od of anticonvulsant effect at doses ≦2.5 mg/kg. Diaze-pam could terminate ongoing seizures when given 5 minafter seizure onset, but doses up to 20 mg/kg were inef-fective when treatment was delayed for 40 min. TheGABA uptake inhibitor, tiagabine, was ineffective inblocking or terminating soman motor convulsions or sei-zures.The glutamate receptor antagonists, NBQX, GYKI52466, and memantine, had weak or minimal antiseizureactivity, even at doses that virtually eliminated signs ofmotor convulsions. The antinicotinic, mecamylamine,was ineffective in blocking or stopping seizure activity.Pretreatment with a narrow range of doses of az-adrener-gic agonist, clonidine, produced variable protection(40-60%)against seizure onset; treatment after seizure onsetwith clonidine was not effective. Screening studies inrats, using HI-6 pretreatment, showed that benzodiaze-pines(diazepam, midazolam and lorazepam)were quiteeffective when given 5 min after seizure onset, but losttheir efficacy when given 40 min after onset. The barbitu-rate, pentobarbital, was modestly effective in terminat-ing seizures when given 5 or 40 min after seizure onset,while other clinically effective antiepileptic drugs, trime-thadione and valproic acid, were only slightly effectivewhen given 5 min after onset. In contrast, phenytoin, car-bamazepine, ethosuximide, magnesium sulfate, lamotri-gine, primidone, felbamate, acetazolamide, and keta-mine were ineffective.
- 中文關鍵字: --
- 英文關鍵字: Organophosphorus compounds. Nerve agents. Soman. Convulsions. Seizures. EEG activity. Anticonvulsants. Anti-epileptic drugs. Anticholinergic drugs. Benzodiazepines. NMDA antagonists