Pharmacokinetic Studies of Intramuscular Midazolam in Guinea Pigs Challenged with Soman

Abstract

Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Studies have demonstrated that benzodiazepine compounds are effective at antagonizing seizure activity produced by the organophosphate (OP) cholinesterase inhibitor soman. In this present study we have investigated the pharmacokinetics of midazolam and its associated effects on electroencephalographic (EEG) activity following intramuscular (im) injection to soman-exposed guinea pigs (Crl:(HA)BR).Prior to experiments, the animals were surgically implanted with EEG leads to monitor seizure activity. For the study, animals were administered the following pretreatment/OP/treatment regimen. Pyridostigmine bromide (0.026 mg/kg, im) was given 30 min prior to soman (56 gtg/kg, 2 x LDso; subcutaneously, sc), followed in one minute by atropine sulfate (2 mg/kg, im) and pralidoxime chloride (25 mg/kg, im). All animals receiving this regimen developed seizure activity. Midazolam 0.8 mg/kg, im, was administered 5 min after onset of seizure activity. Based on EEG data, animals were categorized as either seizure-terminated or seizure not-terminated at 30 min following anticonvulsant administration. Serial blood samples were collected *In conducting the research described in this report, the investigators complied with the regulations and standards of the Animal Welfare Act and adhered to the principles of the Guide for the Care and Use of Laboratory Animals (NRC 1996 for the plasma midazolam analysis; the assay was accomplished with a gas chromatograph/mass spectrometer. The mean time to seizure termination was 8.8 ± 1.6 min. The mean time-plasma concentration data were fit to standard pharmacokinetic models. The following parameter estimates were determined from the model-fit for seizure terminated and not-terminated animals respectively: apparent volumes of distribution (Vd) were 1.4 and 1.7 1/kg; area under the time-concentration curves (AUC), 15,990 and 15,120 ng . minrml; times to maximal plasma concentration (Tma,), 1.66 and 2.91 min and maximal plasma concentrations (Cmnx) 535.1 and 436.6 ng/ml. These data indicate that im injection of midazolam is effective at terminating ongoing soman-induced seizure activity. Additionally, the relatively short Tmax and latency to seizure termination demonstrate the rapidity of drug absorption and action respectively.

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

“…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].…”

“…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.…”

Efficacy of the GluK1/AMPA Receptor Antagonist LY293558 against Seizures and Neuropathology in a Soman-Exposure Model without Pretreatment and its Pharmacokinetics after Intramuscular Administration

“…Muscarinic antagonists, benzodiazepines, and glutamate receptor antagonists have been tested, showing varying efficacies that depend on several factors, such as the timing of administration after exposure, dose, or drug treatment combinations. All of the animal models used in these experiments involve a pretreatment (Shih et al, 2003;Capacio et al, 2004;Joosen et al, 2009;Figueiredo et al, 2011), or, when no pretreatment is given, oximes and atropine are administered together within 1 minute after exposure (e.g., Moffett et al, 2011). Such protocols of drug administration increase survival rate and allow studies of other parameters but do not mimic a real-life situation in which exposure can be unexpected and pretreatment is not an option, and medical assistance may not be available within a minute after exposure.…”

“…Research aimed at developing effective medical countermeasures to terminate seizure activity and prevent brain damage by nerve agent exposure has traditionally used models in which the animal is pretreated with an oxime or pyridostigmine. Usually, pretreatment is administered 30 minutes before nerve agent exposure, followed by atropine administration within 1 minute after exposure (e.g., Shih et al, 2003;Capacio et al, 2004;Joosen et al, 2009;Figueiredo et al, 2011). The reactivation of inhibited acetylcholinesterase by the oxime and the blockade of muscarinic receptors by atropine prevent acute death from cardiorespiratory depression and allow the subsequent testing of anticonvulsant compounds.…”

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).…”