Nasal midazolam as a novel anticonvulsive treatment against organophosphate-induced seizure activity in the guinea pig

Abstract

Seizures and status epilepticus, which may contribute to brain injury, are common consequences of exposure to organophosphorus (OP) cholinesterase inhibitors. Effective management of these seizures is critical. To investigate the efficacy of nasal midazolam as an anticonvulsive treatment for OP exposure, as compared to intramuscular midazolam, guinea pigs were connected to a recording swivel for electrocorticograph (ECoG) monitoring and clinical observation. The experimental paradigm consisted of pyridostigmine pretreatment (0.1 mg/kg i.m.) 20 min prior to sarin exposure (1.2x LD(50,) 56 micro g/kg i.m.). One minute post-exposure, atropine (3 mg/kg i.m.) and TMB-4 (1 mg/kg im) were administered. Within 3-8 min after sarin exposure all animals developed electrographic seizure activity (EGSA), with convulsive behavior. Treatment with midazolam (1 mg/kg i.m.) 10 min after the onset of EGSA abolished EGSA within 389+/-181 s. The same dose was not effective, in most cases, when given 30 min after onset. However, a higher dose (2 mg/kg) was found efficacious after 30 min (949+/-466 s). In contrast, nasal application of midazolam (1 mg/kg) was found most effective, with significant advantages, in amelioration of EGSA and convulsive behavior, when given 10 min (216+/-185 s) or 30 min (308+/-122 s) following the onset of EGSA ( P<0.001). Thus, nasal midazolam could be used as a novel, rapid and convenient route of application against seizure activity induced by nerve agent poisoning.

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

“…Nasal application of midazolam is reportedly more effective with additional advantages such as rapid and convenient route of application. 60,61 However, the speed of anticonvulsant activity of midazolam is found to be similar for the i.m. and intranasal routes of administration.…”

“…Midazolam appears effective in treating soman‐induced seizures when given by all three routes, but with differences in potency and speed of action. Nasal application of midazolam is reportedly more effective with additional advantages such as rapid and convenient route of application . However, the speed of anticonvulsant activity of midazolam is found to be similar for the i.m.…”

Complex View on Poisoning with Nerve Agents and Organophosphates

“…Other anticholinergics may be even more efficacious. The centrally acting anticholinergics (benactyzine, biperidene) can be very useful in the therapy and reduce the necessary amounts of benzodiazepine anticonvulsants (9,51,75). Nerve agents have a long-term effect on the behavior of experimental animals lasting months after intoxication with low doses of nerve agents and were eliminated with pharmacological pretreatment followed by antidotal treatment (9,12,69,77).…”

Characterization of early plasma concentrations of midazolam in pigs after administration by an autoinjector

“…Therefore, the drug has been suggested as a possible replacement for diazepam in the US army [7]. Midazolam has a further advantage when administered through the nasal route [8,9], although at this point, at least for battlefield application, this route does not seem practical yet. In a comparison between the various benzodiazepines for the control of somaninduced seizures in guinea-pigs, midazolam was found to be the most potent and rapidly acting [10].…”