The use of carbamates and atropine in the protection of animals against poisoning by 1,2,2-trimethylpropyl methylphosphonofluoridate

Berry, W.K.; Davies, D. R.

doi:10.1016/0006-2952(70)90256-x

Cited by 183 publications

(49 citation statements)

References 7 publications

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“…Such an association between mortality and status epilepticus is well recognized in the clinical medical literamre (Shorvon, 1994;Towne et al, 1994;Krumholz et al, 1995). The fact that control of nerve agent seizures is so strongly linked to protection from the lethal effects of nerve agents may explain the requirement for the high doses of atropine that have been routinely used in studies of the protective effects of carbamate pretreatment (Berry and Davis, 1970;Dimhuber et al, 1979;Maxwell et al, 1988) or oxime therapies (Melchers et al, 1994;Worek and Szinicz, 1993;Worek et al, 1994;Koplovitz et al, 1995). These findings lend perspective to the older reports that inclusion of a benzodiazepine to standard atropine and oxime therapy would increase the protective ratios against OP nerve agent exposure (Rump et al, 1973;Johnson and Wilcox, 1975;Boskovic, 1981).…”

Section: Discussionmentioning

confidence: 99%

Control of Nerve Agent-Induced Seizures is Critical for Neuroprotection and Survival

Shih¹,

Duniho²,

McDonough³

2002

103

196

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Section: Discussionmentioning

confidence: 99%

Control of Nerve Agent-Induced Seizures is Critical for Neuroprotection and Survival

Shih¹,

Duniho²,

McDonough³

2002

103

196

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“…A combined regimen of prophylaxis and therapy is the most effective medical countermeasure for dealing with the threat of nerve agent poisoning to military personnel (Moore et al, 1995;Sidell, 1997;Aas, 2003). Pretreatment with carbamate cholinesterase inhibitors, such as pyridostigmine bromide (PB), shields a fraction of cholinesterase in the periphery from irreversible inhibition by the nerve agents (Berry and Davis, 1970;Dirnhuber et al, 1979). In the event of nerve agent poisoning, immediate treatment with an anticholinergic drug, such as atropine sulfate, will antagonize the effects of excess ACh at muscarinic receptor sites, and an oxime, such as pyridine-2-aldoxime methylchloride (2-PAM), is used to reactivate inhibited AChE (Moore et al, 1995;Taylor, 2001).…”

mentioning

confidence: 99%

Anticonvulsants for Nerve Agent-Induced Seizures: The Influence of the Therapeutic Dose of Atropine

Shih

Rowland²,

McDonough³

2006

J Pharmacol Exp Ther

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Two guinea pig models were used to study the anticonvulsant potency of diazepam, midazolam, and scopolamine against seizures induced by the nerve agents tabun, sarin, soman, cyclosarin, O-ethyl S-(2-(diisopropylamino)ethyl)methylphosphonothioate (VX), and O-isobutyl S-(2-diethylamino)ethyl)-methyl phosphonothioate (VR). Animals instrumented for electroencephalogram recording were pretreated with pyridostigmine bromide (0.026 mg/kg i.m.) 30 min before challenge with 2 ϫ LD 50 (s.c.) of a nerve agent. In model A, atropine sulfate (2.0 mg/kg i.m.) and pyridine-2-aldoxime methylchloride (2-PAM; 25.0 mg/kg i.m.) were given 1 min after nerve agent challenge, and the tested anticonvulsant was given (i.m.) 5 min after seizure onset. In model B, a lower dose of atropine sulfate (0.1 mg/kg i.m.) was given along with 2-PAM 1 min after nerve agent challenge, and the anticonvulsant was given at seizure onset.With the lower dose of atropine, seizure occurrence increased to virtually 100% for all agents; the time to seizure onset decreased for sarin, cyclosarin, and VX; the signs of nerve agent intoxication were more severe; and coma resulted frequently with cyclosarin. The anticonvulsant ED 50 doses for scopolamine or diazepam were, in general, not different between the two models, whereas the anticonvulsant ED 50 values of midazolam increased 3-to 17-fold with the lower atropine dose. Seizure termination times were not systematically effected by the different doses of atropine. The order of anticonvulsant effectiveness within each model was scopolamine Ն midazolam Ͼ diazepam. The findings indicate that the dose of atropine given as antidotal therapy can significantly influence measures of nerve agent toxicity and responsiveness to anticonvulsant therapy.

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“…Irreversible inhibition of acetylcholinesterase (AChE) results in cholinergic over-activity as a consequence of the acetylcholine accumulation. Research has demonstrated that OP-induced lethality can be reduced utilizing a carbamate cholinesterase inhibitor (pretreatment) followed by atropine and oxime treatment postexposure (Berry and Davies, 1970;Dirnhuber et al, 1979;Fleisher and Harris, 1965;Gordon et al, 1978;Leadbeater et al, 1985). As a result, a combined regimen of prophylaxis (i.e., pretreatment) and postexposure therapy has been suggested to be the most effective countermeasure for intoxication (Dunn and Sidell, 1989;Sidell, 1992).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic Studies of Intramuscular Midazolam in Guinea Pigs Challenged with Soman

Capacio

Byers

Merk

et al. 2004

Drug and Chemical Toxicology

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Studies have demonstrated that benzodiazepine compounds are effective at antagonizing seizure activity produced by the organophosphate (OP) cholinesterase inhibitor soman. In this present study we have investigated the pharmacokinetics of midazolam and its associated effects on electroencephalographic (EEG) activity following intramuscular (im) injection to soman-exposed guinea pigs (Crl:(HA)BR).Prior to experiments, the animals were surgically implanted with EEG leads to monitor seizure activity. For the study, animals were administered the following pretreatment/OP/treatment regimen. Pyridostigmine bromide (0.026 mg/kg, im) was given 30 min prior to soman (56 gtg/kg, 2 x LDso; subcutaneously, sc), followed in one minute by atropine sulfate (2 mg/kg, im) and pralidoxime chloride (25 mg/kg, im). All animals receiving this regimen developed seizure activity. Midazolam 0.8 mg/kg, im, was administered 5 min after onset of seizure activity. Based on EEG data, animals were categorized as either seizure-terminated or seizure not-terminated at 30 min following anticonvulsant administration. Serial blood samples were collected *In conducting the research described in this report, the investigators complied with the regulations and standards of the Animal Welfare Act and adhered to the principles of the Guide for the Care and Use of Laboratory Animals (NRC 1996 for the plasma midazolam analysis; the assay was accomplished with a gas chromatograph/mass spectrometer. The mean time to seizure termination was 8.8 ± 1.6 min. The mean time-plasma concentration data were fit to standard pharmacokinetic models. The following parameter estimates were determined from the model-fit for seizure terminated and not-terminated animals respectively: apparent volumes of distribution (Vd) were 1.4 and 1.7 1/kg; area under the time-concentration curves (AUC), 15,990 and 15,120 ng . minrml; times to maximal plasma concentration (Tma,), 1.66 and 2.91 min and maximal plasma concentrations (Cmnx) 535.1 and 436.6 ng/ml. These data indicate that im injection of midazolam is effective at terminating ongoing soman-induced seizure activity. Additionally, the relatively short Tmax and latency to seizure termination demonstrate the rapidity of drug absorption and action respectively.

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The use of carbamates and atropine in the protection of animals against poisoning by 1,2,2-trimethylpropyl methylphosphonofluoridate

Cited by 183 publications

References 7 publications

Control of Nerve Agent-Induced Seizures is Critical for Neuroprotection and Survival

Control of Nerve Agent-Induced Seizures is Critical for Neuroprotection and Survival

Anticonvulsants for Nerve Agent-Induced Seizures: The Influence of the Therapeutic Dose of Atropine

Pharmacokinetic Studies of Intramuscular Midazolam in Guinea Pigs Challenged with Soman

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