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  • 1
    Electronic Resource
    Electronic Resource
    Anticonvulsants for soman-induced seizure activity (1999)
    Springer
    Journal of biomedical science 6 (1999), S. 86-96 
    Details
    ISSN: 1423-0127
    Keywords: Organophosphorus compounds ; Nerve agents ; Soman-Convulsions ; Seizures ; EEG activity ; Anticonvulsants ; Anti-epileptic drugs ; Anticholinergic drugs ; Benzodiazepines ; NMDA antagonists
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract This report describes studies of anticonvulsants for the organophosphorus (OP) nerve agent soman: a basic research effort to understand how different pharmacological classes of compounds influence the expression of seizure produced by soman in rats, and a drug screening effort to determine whether clinically useful antiepileptics can modulate soman-induced seizures in rats. Electroencephalographic (EEG) recordings were used in these studies. Basic studies were conducted in rats pretreated with HI-6 and challenged with 1.6×LD50 soman. Antimuscarinic compounds were extremely effective in blocking (pretreatment) or terminating soman seizures when given 5 min after seizure onset. However, significantly higher doses were required when treatment was delayed for more than 10 min, and some antimuscarinic compounds lost anticonvulsant efficacy when treatment was delayed for more than 40 min. Diazepam blocked seizure onset, yet seizures could recur after an initial period of anticonvulsant effect at doses ≤2.5 mg/kg. Diazepam could terminate ongoing seizures when given 5 min after seizure onset, but doses up to 20 mg/kg were ineffective when treatment was delayed for 40 min. The GABA uptake inhibitor, tiagabine, was ineffective in blocking or terminating soman motor convulsions or seizures. The glutamate receptor antagonists, NBQX, GYKI 52466, and memantine, had weak or minimal antiseizure activity, even at doses that virtually eliminated signs of motor convulsions. The antinicotinic, mecamylamine, was ineffective in blocking or stopping seizure activity. Pretreatment with a narrow range of doses of α2-adrenergic agonist, clonidine, produced variable protection (40–60%) against seizure onset; treatment after seizure onset with clonidine was not effective. Screening studies in rats, using HI-6 pretreatment, showed that benzodiazepines (diazepam, midazolam and lorazepam) were quite effective when given 5 min after seizure onset, but lost their efficacy when given 40 min after onset. The barbiturate, pentobarbital, was modestly effective in terminating seizures when given 5 or 40 min after seizure onset, while other clinically effective antiepileptic drugs, trimethadione and valproic acid, were only slightly effective when given 5 min after onset. In contrast, phenytoin, carbamazepine, ethosuximide, magnesium sulfate, lamotrigine, primidone, felbamate, acetazolamide, and ketamine were ineffective.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02256439
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  • 2
    Electronic Resource
    Electronic Resource
    Effects of repeated injection of sublethal doses of soman on behavior and on brain acetylcholine and choline concentrations in the rat (1990)
    Springer
    Psychopharmacology 101 (1990), S. 489-496 
    Details
    ISSN: 1432-2072
    Keywords: Soman ; Organophosphorus compounds ; Cholinesterase inhibitors ; Repeated exposure ; Adaptation ; Acetylcholine ; Choline ; Cholinesterase activity ; Toxicity ; Hyper-reactivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of repeated exposure to a sublethal dose (60 µg/kg; 0.4 LD50) of soman on brain regional acetylcholine (ACh) and choline (Ch) levels, spinal cord cholinesterase (ChE) activity and on water consumption, body weight and gross behavioral changes were examined. Male rats were dosed once a week or three times a week and at 24 h after 2, 4 or 6 weeks of dosing, selected brain tissues and behavior were examined. During the 6-week period, there was no difference between control and soman-dosed rats in water consumption or body weight under either treatment regimen. The animals treated once a week adapted to this exposure regimen well. They exhibited no change in the levels of ACh or Ch in any of the brain areas when examined at the end of 2, 4 or 6 weeks, nor did they show any obvious signs of poisoning. The total ChE activity fluctuated between 70 and 100% of control. When treated three times a week, however, survivors (90%) of the somantreated rats developed signs that progressed in severity to a hyper-reactivity syndrome which consisted of an exaggerated reaction to mild tactile stimuli. Brain ACh levels did not change and ChE activity showed inhibition of 40, 58 and 75% when measured at 2, 4 and 6 weeks, respectively. At the end of 6 weeks, the levels of Ch, except in the striatum, were significantly elevated in brainstem, cerebral cortex, hippocampus, midbrain, and cerebellum (52%, 147%, 68%, 46%, and 91%, respectively), indicating that Ch metabolism in neuronal membranes may be altered following more frequent low-dose soman exposures.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02244227
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Comparison of several oximes on reactivation of soman-inhibited blood, brain and tissue cholinesterase activity in rats (1993)
    Springer
    Archives of toxicology 67 (1993), S. 637-646 
    Details
    ISSN: 1432-0738
    Keywords: Soman ; Organophosphorus compounds ; Nerve agents ; Cholinesterase ; Oximes ; Enzyme reactivation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The ability of three oximes, HI-6, MMB-4 and ICD-467, to reactivate cholinesterase (ChE) inhibited by the organophosphorus compound soman was compared in blood (plasma and erythrocytes), brain regions (including spinal cord) and peripheral tissues of rats. Animals were intoxicated with soman (100 μg/kg, SC; equivalent to 0.9 × LD50 dose) and treated 1 min later with one of these oximes (100 or 200 μmol/kg, IM). Toxic sign scores and total tissue ChE activities were determined 30 min later. Soman markedly inhibited ChE activity in blood (93–96%), brain regions (ranging from 78% to 95%), and all peripheral tissues (ranging from 48.9% to 99.8%) except liver (11.9%). In blood, treatment with HI-6 or ICD-467 resulted in significant reactivation of soman-inhibited ChE. In contrast, MMB-4 was completely ineffective. HI-6 and ICD-467 were equally effective at the high dose. At the low dose ICD-467 treatment resulted in significantly higher plasma ChE than HI-6 treatment, whereas HI-6 treatment resulted in higher erythrocyte ChE than ICD-467 treatment. However, none of these three oximes reactivated or protected soman-inhibited ChE in the brain. In all peripheral tissues (except liver) studied, MMB-4 was not effective. HI-6 reactivated soman-inhibited ChE in all tissues except lung, heart, and skeletal muscle. ICD-467 was highly effective in reactivating ChE in all tissues and afforded a complete recovery of ChE to control levels in intercostal muscle and salivary gland. Oxime treatments did not modify the toxic scores produced by soman. However, treatment with the high dose (200 μmol/kg) of ICD-467 depressed respiration and two of the six rats died in 10 min. These observations indicate that MMB-4 is completely ineffective in protecting and/or reactivating soman-inhibited ChE, HI-6 is an effective ChE reactivator as reported earlier in rats and other species, and the imidazolium oxime ICD-467 is a powerful reactivator of somaninhibited ChE; however, its toxic interactions with soman may not be related to tissue ChE levels.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01974071
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    Paper (German National Licenses)
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