Delayed Adjunctive Treatment of Organophosphate-Induced Status Epilepticus in Rats with Phenobarbital, Memantine, or Dexmedetomidine

Abstract

Nonstandard abbreviations: 2-pyridine aldoxime methyl chloride (2-PAM), antiseizure drug (ASD), CounterACT Neurotherapeutics Screening (CNS), Countermeasures Against Chemical Threats (CounterACT), dexmedetomidine (DMT), diisopropyl-phosphate (DFP), electroencephalogram (EEG), Fluoro-Jade B (FJB), memantine (MEM), midazolam (MDZ), N-methyl-D-aspartate (NMDA), organophosphate (OP), organophosphate nerve agent (OPNA), phenobarbital (PHB), Potassium permanganate (KMnO₄), Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART), region of interest (ROI), status epilepticus (SE).

Combination of antiseizure medications phenobarbital, ketamine, and midazolam reduces soman‐induced epileptogenesis and brain pathology in rats

“…In mice exposed to a seizure-inducing dose of soman, a low dose of phenobarbital monotherapy (20 mg/kg) resulted in a delay in onset to SRS but did not reduce neuropathology. 41 Higher doses of phenobarbital as evaluated against DFP in rats 17,18 or combination of lower doses of phenobarbital with other antiseizure medications as used in the current study may be needed to improve neuroprotection. These findings demonstrate the efficacy of combining subanesthetic doses of antiseizure medications in reducing cholinergicinduced SE and epileptogenesis.…”

“… 16 Similar dose‐response effects of phenobarbital as an adjunct to midazolam were observed following exposure to the pesticide diisopropyl fluorophosphate (DFP). 17 , 18 The latter studies, however, did not investigate the effect of phenobarbital adjunct treatment on epileptogenesis and neuronal cell death at an endpoint longer than 24 or 72 hours. The antiseizure effects of phenobarbital occur in other seizure models, including maximal electroshock, picrotoxin, and electrical hippocampal stimulation.…”

Dose-Dependency of Toxic Signs and Outcomes of Paraoxon Poisoning in Rats

“…In the second phase this could be compensated by the administration of the GABA A /benzodiazepine receptor antagonists, such as barbiturates (e.g., pentobarbital, thiopental sodium) and benzodiazepines (e.g., diazepam or midazolam) (50,51). In the third phase, these seizures can be stopped by the administration of N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine, dizocilpine (MK-801) or ketamine (52)(53)(54)(55). The reason for this is the fact that in the meanwhile the seizures became glutamatergic in its origin (56).…”

Refractory and Super-Refractory Status Epilepticus in Nerve Agent-Poisoned Rats Following Application of Standard Clinical Treatment Guidelines

“…This is further reason to avoid iterative benzodiazepine administration, as time spent waiting for benzodiazepines to fail may reduce the efficacy of more promising therapies. PHB and VPA were chosen for comparison because, in addition to their frequent use against benzodiazepine-refractory SE, PHB and derivatives of VPA have previously been shown to terminate organophosphate-induced SE (White et al, 2012;Shekh-Ahmad et al, 2013, 2015Bar-Klein et al, 2014;Haines et al, 2019;Jackson et al, 2019;Reddy et al, 2020;Spampanato et al, 2020). It is also possible that other common second-line antiseizure drugs like FOS and LEV would provide greater benefit against NA-induced SE.…”