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

Abstract

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...

Investigation of oxidative stress in blood, brain, kidney, and liver after oxime antidote HI-6 application in a mouse experimental model

“…The protection of AChE by reversible inhibitors, such as pyridostigmine, is applicable in the early phase of intoxication (Haigh et al, 2010). A symptomatic manifestation of intoxication can be reduced by the application of an anticholinergic drug, such as atropine, and/or an anticonvulsant, such as benzodiazepine (McDonough et al, 2009). Causative treatment, based on the cleavage of organophosphate residuum from AChE by an oxime reactivator, is the second way suitable for treatment and can resolve central, nicotinic, as well as muscarinic signs of exposure (Buckley et al, 2005).…”

Comparing the Antiseizure and Neuroprotective Efficacy of LY293558, Diazepam, Caramiphen, and LY293558-Caramiphen Combination against Soman in a Rat Model Relevant to the Pediatric Population

“…It should be noted that another benzodiazepine, midazolam, is being tested as a possible better alternative to diazepam (Capacio et al, 2004;McDonough et al, 2009;Reddy and Reddy, 2015). The data reported so far show that midazolam can protect against nerve agent-induced brain damage in adult or young-adult rats, if it is administered at the time of exposure (Chapman et al, 2015), at the onset of seizures (RamaRao et al, 2014), or after 5 min of seizure activity (Gilat et al, 2005); however, if it is given 1 h after exposure, it does not prevent histological damage, despite its antiseizure efficacy and beneficial effects on behavioral performance and inflammatory responses (Chapman et al, 2015).…”

Efficacy of antidotes (midazolam, atropine and HI-6) on nerve agent induced molecular and neuropathological changes

“…Diazepam was also found to be not always completely effective in protecting animals against soman-induced neuropathology [19,20]. In a search for safer and more effective anticonvulsant BZs against OP-induced seizure and neuronal damage, Midazolam (MDZ), a non-selective and full positive allosteric modulator of GABA action at a variety of GABAA receptor subtypes [21], has recently been considered a possible anticonvulsant replacement for DZ [22]. The advantages that have been attributed to MDZ include its rapid bioavailability and the ease of administration by intranasal, sublingual, and intramuscular routes [22].…”