Anticonvulsant effectiveness of scopolamine against soman-induced seizures in African green monkeys.

Prolonged seizures are a hallmark feature of intoxication with anticholinesterase nerve agents such as soman. While benzodiazepine drugs are typically used to control these seizures, studies in both rats and guinea pigs have shown that potent, centrally acting anticholinergic drugs such as scopolamine can also terminate such seizures. The present study was performed to determine if scopolamine could produce similar anticonvulsant effects in a nonhuman primate model of soman intoxication.

The K7 Modulator, Retigabine, is an Efficacious Antiseizure Drug for Delayed Treatment of Organophosphate-induced Status Epilepticus.

Benzodiazepines are the primary treatment option for organophosphate (OP)-induced status epilepticus (SE), but these antiseizure drugs (ASDs) lose efficacy as treatment is delayed. In the event of a mass civilian or military exposure, significant treatment delays are likely. New ASDs that combat benzodiazepine-resistant, OP-induced SE are critically needed, particularly if they can be efficacious after a long treatment delay.

Comparison of neuropathology in rats following status epilepticus induced by diisopropylfluorophosphate and soman.

The increasing number of cases involving the use of nerve agents as deadly weapons has spurred investigation into the molecular mechanisms underlying nerve agent-induced pathology. The highly toxic nature of nerve agents restrict their use in academic research laboratories. Less toxic organophosphorus (OP) based agents including diisopropylfluorophosphate (DFP) are used as surrogates in academic research laboratories to mimic nerve agent poisoning.

Evaluation of fosphenytoin, levetiracetam, and propofol as treatments for nerve agent-induced seizures in pediatric and adult rats.

Multiple recent instances of nerve agent (NA) exposure in civilian populations have occurred, resulting in a variety of negative effects and lethality in both adult and pediatric populations. Seizures are a prominent effect of NAs that can result in neurological damage and contribute to their lethality. Current anticonvulsant treatments for NAs are approved for adults, but no approved pediatric treatments exist.

Characterization and treatment of spontaneous recurrent seizures following nerve agent-induced status epilepticus in mice.

Purpose: To develop and characterize a mouse model of spontaneous recurrent seizures following nerve agent-induced status epilepticus (SE) and test the efficacy of existing antiepileptic drugs.

Methods: SE was induced in telemeterized male C57Bl6/J mice by soman exposure, and electroencephalographic activity was recorded for 4-6 weeks. Mice were treated with antiepileptic drugs (levetiracetam, valproic acid, phenobarbital) or corresponding vehicles for 14 d after exposure, followed by 14 d of drug washout.

Screening for Efficacious Anticonvulsants and Neuroprotectants in Delayed Treatment Models of Organophosphate-induced Status Epilepticus.

Organophosphorus (OP) compounds are deadly chemicals that exert their intoxicating effects through the irreversible inhibition of acetylcholinesterase (AChE). In addition to an excess of peripheral ailments, OP intoxication induces status epilepticus (SE) which if left untreated may lead to permanent brain damage or death. Benzodiazepines are typically the primary therapies for OP-induced SE, but these drugs lose efficacy as treatment time is delayed.

Validating a model of benzodiazepine refractory nerve agent-induced status epilepticus by evaluating the anticonvulsant and neuroprotective effects of scopolamine, memantine, and phenobarbital.

Introduction: Organophosphorus nerve agents (OPNAs) irreversibly block acetylcholinesterase activity, resulting in accumulation of excess acetylcholine at neural synapses, which can lead to a state of prolonged seizures known as status epilepticus (SE). Benzodiazepines, the current standard of care for SE, become less effective as latency to treatment increases. In a mass civilian OPNA exposure, concurrent trauma and limited resources would likely cause a delay in first response time.

Comparative efficacy of valnoctamide and sec-butylpropylacetamide (SPD) in terminating nerve agent-induced seizures in pediatric rats.

Objectives: Children and adults are likely to be among the casualties in a civilian nerve agent exposure. This study evaluated the efficacy of valnoctamide (racemic-VCD), sec-butylpropylacetamide (racemic-SPD), and phenobarbital for stopping nerve agent seizures in both immature and adult rats.

Methods: Female and male postnatal day (PND) 21, 28, and 70 (adult) rats, previously implanted with electroencephalography (EEG) electrodes were exposed to seizure-inducing doses of the nerve agents sarin or VX and EEG was recorded continuously.

Assessment of mouse strain differences in baseline esterase activities and toxic response to sarin.

Genetics likely play a role in various responses to nerve agent (NA) exposure, as genetic background plays an important role in behavioral, neurological, and physiological responses. This study uses different mouse strains to identify if mouse strain differences in sarin exposure exist. In Experiment 1, basal levels of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterase (CE) were measured in different strains of naïve mice to account for potential pharmacokinetic determinants of individual differences.

Behavioral, Pharmacokinetic, and Cardiovascular Evaluation of Candidate Oximes in African Green Monkeys.

Oxime reactivators are critical antidotes after organophosphate pesticide or nerve agent poisoning, directly restoring the function of inhibited acetylcholinesterase. In the continuing search for more broad-spectrum acetylcholinesterase reactivators, this study evaluated one of the leading next-generation oxime reactivators: methoxime, (1,1'-trimethylene bis[4-(hydroxyimino)methyl]pyridinium dichloride (MMB-4). The pharmacokinetics of both salts of MMB-4 (dichloride [2Cl] and dimethanesulphonate [DMS]) were characterized across a range of relevant doses (19, 58, and 116 µmol/kg, intramuscular) in a nonhuman primate model (male African green monkeys), and only subtle differences were observed between the salts.

Evaluating mice lacking serum carboxylesterase as a behavioral model for nerve agent intoxication.

Mice and other rodents are typically utilized for chemical warfare nerve agent research. Rodents have large amounts of carboxylesterase in their blood, while humans do not. Carboxylesterase nonspecifically binds to and detoxifies nerve agent.

Age-dependent behaviors, seizure severity and neuronal damage in response to nerve agents or the organophosphate DFP in immature and adult rats.

Exposure to nerve agents (NAs) and other organophosphates (OPs) can initiate seizures that rapidly progress to status epilepticus (SE). While the electrographic and neuropathological sequelae of SE evoked by NAs and OPs have been characterized in adult rodents, they have not been adequately investigated in immature animals. In this study postnatal day (PND) 14, 21 and 28 rat pups, along with PND70 animals as adult controls, were exposed to NAs (sarin, VX) or another OP (diisopropylfluorophosphate, DFP).

Dexmedetomidine stops benzodiazepine-refractory nerve agent-induced status epilepticus.

Nerve agents are highly toxic chemicals that pose an imminent threat to soldiers and civilians alike. Nerve agent exposure leads to an increase in acetylcholine within the central nervous system, resulting in development of protracted seizures known as status epilepticus (SE). Currently, benzodiazepines are the standard of care for nerve agent-induced SE, but their efficacy quickly wanes as the time to treatment increases.

Plasma Concentration of Meloxicam in Pediatric Rats.

In this study, we compared the plasma concentrations of meloxicam in pediatric rat pups (ages: 7, 14, 21, and 28 d) with those of young adult rats. Adult rats received 1.34 mg/kg SC meloxicam to determine the target peak plasma concentration (Cmax) for comparison with the pediatric animals.

The role of genetic background in susceptibility to chemical warfare nerve agents across rodent and non-human primate models.

Genetics likely play a role in various responses to nerve agent exposure, as genetic background plays an important role in behavioral, neurological, and physiological responses to environmental stimuli. Mouse strains or selected lines can be used to identify susceptibility based on background genetic features to nerve agent exposure. Additional genetic techniques can then be used to identify mechanisms underlying resistance and sensitivity, with the ultimate goal of developing more effective and targeted therapies.

The synthetic neuroactive steroid SGE-516 reduces status epilepticus and neuronal cell death in a rat model of soman intoxication.

Organophosphorus nerve agents (OPNAs) are irreversible inhibitors of acetylcholinesterase that pose a serious threat to public health because of their use as chemical weapons. Exposure to high doses of OPNAs can dramatically potentiate cholinergic synaptic activity and cause status epilepticus (SE). Current standard of care for OPNA exposure involves treatment with cholinergic antagonists, oxime cholinesterase reactivators, and benzodiazepines.

Anticonvulsant discovery through animal models of status epilepticus induced by organophosphorus nerve agents and pesticides.

Organophosphorus pesticides (OPs) and nerve agents (NAs) are highly toxic chemicals that pose a significant threat to human health worldwide. These compounds induce status epilepticus (SE) by irreversibly blocking the ability of acetylcholinesterase to break down acetylcholine at neural synapses. Animal models of organophosphate-induced SE are a crucial resource for identifying new anticonvulsant therapies.

Analysis of Nerve Agent Metabolites from Hair for Long-Term Verification of Nerve Agent Exposure.

Several methods for the bioanalysis of nerve agents or their metabolites have been developed for the verification of nerve agent exposure. However, parent nerve agents and known metabolites are generally rapidly excreted from biological matrixes typically used for analysis (i.e.

The potential of sec-butylpropylacetamide (SPD) and valnoctamide and their individual stereoisomers in status epilepticus.

sec-Butylpropylacetamide (SPD) is a one-carbon homologue of valnoctamide (VCD), a chiral constitutional isomer of valproic acid's (VPA) corresponding amide--valpromide. Racemic-SPD and racemic-VCD possess a unique and broad-spectrum antiseizure profile superior to that of VPA. In addition, SPD blocks behavioral and electrographic status epilepticus (SE) induced by pilocarpine and the organophosphates soman and paraoxon.

N-acetyl-aspartyl-glutamate and inhibition of glutamate carboxypeptidases protects against soman-induced neuropathology.

N-acetyl-aspartyl-glutamate (NAAG) is the most abundant neuropeptide in the mammalian brain. In a variety of animal models of brain injury, the administration of NAAG-related compounds, or inhibitors of glutamate carboxypeptidases (GCPs; the enzymes that hydrolyze NAAG), were shown to be neuroprotective. This study determined the impact of the administration of three NAAG-related compounds, NAAG, β-NAAG (a NAAG homologue resistant to degradation), and 2-phosphonomethyl pentanedioic acid (2-PMPA; an inhibitor of GCP enzymes), on the neuropathology that develops following exposure to the nerve agent, soman.

Enantioselective pharmacodynamic and pharmacokinetic analysis of two chiral CNS-active carbamate derivatives of valproic acid.

Objective: 2-Ethyl-3-methylbutyl-carbamate (EMC) and 2-isopropylpentyl-carbamate (IPC) are among the most potent anticonvulsant carbamate derivatives of valproic acid. EMC and IPC are chiral compounds. Consequently, the aim of the current study was to comparatively evaluate the pharmacokinetic (PK) and pharmacodynamic (PD anticonvulsant activity) profile of EMC and IPC individual enantiomers.

(-)-Phenserine attenuates soman-induced neuropathology.

Organophosphorus (OP) nerve agents are deadly chemical weapons that pose an alarming threat to military and civilian populations. The irreversible inhibition of the critical cholinergic degradative enzyme acetylcholinesterase (AChE) by OP nerve agents leads to cholinergic crisis. Resulting excessive synaptic acetylcholine levels leads to status epilepticus that, in turn, results in brain damage.

Stereoselective anticonvulsant and pharmacokinetic analysis of valnoctamide, a CNS-active derivative of valproic acid with low teratogenic potential.

Objective: Valnoctamide (VCD), a central nervous system (CNS)-active chiral constitutional isomer of valpromide, the corresponding amide of valproic acid (VPA), is currently undergoing phase IIb clinical trials in acute mania. VCD exhibits stereoselective pharmacokinetics (PK) in animals and humans. The current study comparatively evaluated the pharmacodynamics (PD; anticonvulsant activity and teratogenicity) and PK of the four individual stereoisomers of VCD.

Valnoctamide and sec-butyl-propylacetamide (SPD) for acute seizures and status epilepticus.

sec-Butyl-propylacetamide (SPD) is a one-carbon homolog of valnoctamide (VCD), a chiral constitutional isomer of valproic acid's (VPA) corresponding amide valpromide. VCD has potential as a therapy in epilepsy including status epilepticus (SE) and neuropathic pain, and is currently being developed for the treatment of bipolar disorder. Both VCD and SPD possess two stereogenic carbons in their chemical structure.