Midazolam as an anticonvulsant antidote for organophosphate intoxication—A pharmacotherapeutic appraisal

Abstract

SUMMARY Objective This review summarizes the therapeutic potential of midazolam as an anticonvulsant antidote for organophosphate (OP) intoxication. Methods Benzodiazepines are widely used for acute seizures and status epilepticus (SE), a neurological emergency of persistent seizures that can lead to severe neuronal damage or death. Midazolam is a benzodiazepine hypnotic with a rapid onset and short duration of action. Results Midazolam is considered the new drug of choice for persistent acute seizures and SE, including those caused by neurotoxic OPs and nerve agents. Midazolam is a positive allosteric modulator of synaptic GABA-A receptors in the brain. It potentiates GABAergic inhibition and thereby controls hyperexcitability and seizures. Midazolam is administered intravenously or intramuscularly to control acute seizures and SE. Due to its favorable pharmacokinetic features, midazolam is being considered as a replacement anticonvulsant for diazepam in the antidote kit for nerve agents. Clinical studies such as the recent RAMPART trial have confirmed the anticonvulsant efficacy of midazolam in SE in prehospital settings. Significance In experimental models, midazolam is effective when given at the onset of seizures caused by nerve agents. However, benzodiazepines are less effective at terminating seizures when given 30 min or later after OP exposure or seizure onset likely because of internalization or down-regulation of synaptic, but not extrasynaptic, GABA-A receptors, which can lead to diminished potency and seizure recurrence.

Clinical Potential of Neurosteroids for CNS Disorders

“…For example, neurosteroids are found to be more effective anticonvulsants than benzodiazepines because their target receptor remains unaffected by the complex dynamics of seizures [118]. Presently there is an unmet medical need for medical countermeasures against nerve agent intoxication seizures in the delayed setting where benzodiazepines have proven to be ineffective.…”

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).…”

Neurosteroids for the potential protection of humans against organophosphate toxicity

“…Atropine sulfate (Atropen®) autoinjectors are available in a variety of doses (0.25, 0.5, 1, and 2 mg), specifically designed for caregiver or self‐administration. Midazolam is being considered as a replacement anticonvulsant for diazepam for treatment of OP intoxication …”