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

Shih, Tsung‐Ming; Rowland, Tami C.; McDonough, John H.

doi:10.1124/jpet.106.111252

Cited by 84 publications

(62 citation statements)

References 18 publications

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“…The fact that there were no differences in the speed of seizure control between the intramuscular and intranasal routes at either treatment time would seem to indicate that the anticonvulsant pharmacodynamics of midazolam were essentially equivalent by these two routes. It should be noted that the intramuscular ED 50 s and seizure control latencies for midazolam obtained in this study are virtually identical to those obtained in previous studies using this model [3,11] and are also in close agreement with the results of Gilat et al . [20].…”

Section: Discussionsupporting

confidence: 92%

“…In contrast, the benzodiazepine midazolam (0.28-0.30 mg/kg) was highly successful (>90% rate) in terminating soman-induced seizures and time for seizure termination was twice as fast as with diazepam under similar conditions [7,8]. These same basic findings have also been demonstrated in extensive tests in a guinea pig model of nerve agent-induced seizures [4,6,[9][10][11] (National Research Council Publication No. 85-23, 1996) There are increasing numbers of clinical reports about the effectiveness of midazolam as an anticonvulsant for status epilepticus seizures when it is delivered either by the intranasal or buccal or sublingual route [12][13][14][15][16][17][18][19][20][21][22][23][24].…”

mentioning

confidence: 90%

“…For each animal in which the seizure was terminated, the latency to seizure termination was measured as the time from when the animal received midazolam treatment to the last observable epileptiform event in the EEG. These evaluation procedures and operational criteria for seizure control are identical to those used in previous studies utilizing this animal model [3,5,6,[9][10][11].Data analysis. Dose-effect curves for seizure termination were developed using quantal response probit analysis for each route of administration at each treatment time using 3-5 drug doses.…”

mentioning

confidence: 99%

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Comparison of the Intramuscular, Intranasal or Sublingual Routes of Midazolam Administration for the Control of Soman‐Induced Seizures*

McDonough¹,

Shura²,

LaMont³

et al. 2008

Basic Clin Pharma Tox

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This study evaluated the anticonvulsant effectiveness of midazolam to stop seizures elicited by the nerve agent soman when midazolam was administered by different routes (intramuscular, intranasal or sublingual) at one of two different times after the onset of seizure activity. Guinea pigs previously prepared with cortical electrodes to record brain electroencephalographic activity were pre-treated with pyridostigmine (0.026 mg/kg, intramuscularly) 30 min. before challenge with a seizure-inducing dose of the nerve agent soman (56 μ g/kg, subcutaneously), and 1 min. later, they were administered 2.0 mg/kg atropine sulfate admixed with 25.0 mg/kg 2-PAM Cl (intramuscularly). Groups of animals were administered differing doses of midazolam by the intramuscular, intranasal or sublingual route at either the onset of seizure activity or 40 min. after the onset of seizure activity that was detected in the electroencephalographic record. When given immediately after seizure onset, the anticonvulsant ED 50 of intramuscular midazolam was significantly lower than that of intranasal midazolam, which in turn was significantly lower than sublingual midazolam at that time. At the 40-min. treatment delay, the anticonvulsant ED 50 s of intramuscular or intranasal midazolam did not differ and both were significantly lower than the sublingual route. Higher doses of midazolam were required to stop seizures at the 40-min. treatment delay time compared to immediate treatment. The speed of seizure control for intramuscular or intranasal midazolam was the same while sublingual midazolam acted significantly slower. Midazolam was effective in treating soman-induced seizures when given by all three routes, but with differences in potency and speed of action.Nerve agent-induced seizures result from over-stimulation of susceptible brain circuits by abnormally high levels of the excitatory neurotransmitter acetylcholine that rapidly builds up after inhibition of the enzyme acetylcholinesterase by nerve agent [1]. These seizures, unless quickly stopped pharmacologically, rapidly progress to status epilepticus, a state of continuous seizure activity or episodes of seizure activity for greater than 30 min. with no recovery of consciousness between episodes. Status epilepticus itself is considered a medical emergency, and the longer seizures persist, the more difficult they are to stop pharmacologically [2]. Status epilepticus clinically responds (n.b. termination of seizures) only to a subset of anticonvulsant or antiepileptic drugs. Benzodiazepines are typically the most effective class of compounds and are used as the first drug of choice in treatment of this condition. Nerve agent-induced status epilepticus also responds to benzodiazepines [3,4], as well as to anticholinergic compounds [5] that have no therapeutic benefit in the treatment of epilepsy or seizures induced by clinical states other than nerve agents.The benzodiazepine diazepam is currently available in auto-injectors as an immediate field treatment to counteract nerve a...

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 90%

mentioning

confidence: 99%

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Comparison of the Intramuscular, Intranasal or Sublingual Routes of Midazolam Administration for the Control of Soman‐Induced Seizures*

McDonough¹,

Shura²,

LaMont³

et al. 2008

Basic Clin Pharma Tox

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“…Subcutaneous administration of VX has been previously shown to induce seizures, which can be terminated by appropriate anticonvulsant treatment (Shih and McDonough, 2000;Shih et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

A novel approach to assessing percutaneous VX poisoning in the conscious guinea‐pig

Mumford

Price

Wetherell

2008

J of Applied Toxicology

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Nerve agents like VX (S-2-diisopropylaminoethyl-O-ethyl-methylphosphonothiolate) are potent irreversible acetylcholinesterase (AChE) inhibitors. Following percutaneous nerve agent exposure there is a slower rate of absorption, later onset and longer duration of signs of poisoning. Relatively little is known about the physiological effects of percutaneously applied nerve agent in unanaesthetised laboratory animals. Heart rate (ECG), brain electrical activity (EEG), body temperature, locomotor activity and clinical signs were monitored following percutaneous application of VX to conscious guinea-pigs.A fall in heart rate (bradycardia) preceded incapacitation following the highest VX dose, and occurred in the absence of incapacitation at the lower doses. Following the highest dose of VX (0.592 mg kg(-1)) three out of four animals died within 24 h. The lower two doses of VX (0.296 and 0.148 mg kg(-1)), produced extended periods of bradycardia in the absence of observable signs of poisoning. Bradycardia preceded, or occurred in the absence of, a temperature decrease; seizure-like EEG changes were not observed at any of the VX doses tested. Acetylcholinesterase activity was significantly inhibited in the blood and most brain areas at 48 h. There were significant dose-related decreases in body weight at 24 and 48 h following VX. This preliminary study suggests that decreased heart rate may be an early sign of the toxic effects of VX, whereas temperature and observable clinical signs are not good early indicators of percutaneous VX poisoning in this animal model. Future studies will use this model to assess the benefit of administering medical countermeasures in response to a defined decrease in heart rate.

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“…The existing pretreatments against CWNA toxicity are centered on the development of reversible cholinesterase inhibiting compounds such as pyridostigmine bromide [4]. Post-exposure treatments include AChE re-activator 2-pralidoxime, anti-cholinergic drug atropine sulfate and anticonvulsant diazepam [5][6][7]. But current treatments do not completely protect against CWNA induced neuropathology and behavioral deficits.…”

Section: Introductionmentioning

confidence: 99%

Protective efficacy of catalytic bioscavenger, paraoxonase 1 against sarin and soman exposure in guinea pigs

Valiyaveettil

Alamneh

Rezk³

et al. 2011

Biochemical Pharmacology

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

Cited by 84 publications

References 18 publications

Comparison of the Intramuscular, Intranasal or Sublingual Routes of Midazolam Administration for the Control of Soman‐Induced Seizures*

Comparison of the Intramuscular, Intranasal or Sublingual Routes of Midazolam Administration for the Control of Soman‐Induced Seizures*

A novel approach to assessing percutaneous VX poisoning in the conscious guinea‐pig

Protective efficacy of catalytic bioscavenger, paraoxonase 1 against sarin and soman exposure in guinea pigs

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