Exposure to organophosphorus compounds: best practice in managing timely, effective emergency responses.

Increasing indications, reports and studies demonstrate that threats from the deliberate use of chemical weapons remain high and are evolving. One of the deadliest classes of chemical weapons are the organophosphorus nerve agents. It is now clear that both state and non-state actors have the ability to deploy and use these types of weapons against individuals and the wider civilian population posing a real and significant threat.

Interdependent Factors of Demand-Side Rationale for Chemical, Biological, Radiological, and Nuclear Medical Countermeasures.

The deliberate use of chemical, biological, radiological, and nuclear (CBRN) materials in war or terrorist attacks is perceived as a great threat globally. In the event of a release of CBRN agents, protection by means of medical countermeasures (MedCMs) could reduce health vulnerability. Nonetheless, for some diseases caused by these agents, innovative MedCMs do not exist and many of those that do might not be readily available.

Superior efficacy of HI-6 dimethanesulfonate over pralidoxime methylsulfate against Russian VX poisoning in cynomolgus monkeys (Macaca fascicularis).

Organophosphorus nerve agents still represent a serious risk to human health. In the French armed forces, the current emergency treatment against OP intoxications is a fully licensed wet-dry dual-chambered autoinjector (Ineurope ®), that contains pralidoxime methylsulfate (2-PAM) to reactivate inhibited acetylcholinesterase (AChE), atropine sulfate (AS) and avizafone chlorhydrate (AVZ). While this treatment is effective against several of the known nerve agents, it shows little efficacy against the Russian VX (VR), one of the most toxic compounds.

Electro-behavioral phenotype and cell injury following exposure to paraoxon-ethyl in mice: Effect of the genetic background.

Organophosphorus compounds (OP) are irreversible inhibitors of both central and peripheral cholinesterases (ChE). They still represent a major health issue in some countries as well as a terrorist and military threat. In order to design appropriate medical counter-measures, a better understanding of the pathophysiology of the poisoning is needed.

Cognitive and emotional impairments after cutaneous intoxication by CEES (a sulfur mustard analog) in mice.

Cognitive and emotional disorders have been reported in veterans intoxicated with sulfur mustard (SM) a chemical weapon belonging to the category of vesicating agents. However, the intense stress associated with the SM intoxication may render difficult determining the exact role played by SM intoxication itself on the emergence and maintaining of cognitive disorders. Animal's model would allow overcoming this issue.

Modeling and simulation of organophosphate-induced neurotoxicity: Prediction and validation by experimental studies.

Exposure to organophosphorus (OP) compounds, either pesticides or chemical warfare agents, represents a major health problem. As potent irreversible inhibitors of cholinesterase, OP may induce seizures, as in status epilepticus, and occasionally brain lesions. Although these compounds are extremely toxic agents, the search for novel antidotes remains extremely limited.

Beneficial effects of a ketamine/atropine combination in soman-poisoned rats under a neutral thermal environment.

Exposure to organophosphorus (OP) compounds, such as pesticides and the chemical warfare agents (soman and sarin), respectively represents a major health problem and a threat for civilian and military communities. OP poisoning may induce seizures, status epilepticus and even brain lesions if untreated. We recently proved that a combination of atropine sulfate and ketamine, a glutamatergic antagonist, was effective as an anticonvulsant and neuroprotectant in mice and guinea-pigs exposed to soman.

Time course of lewisite-induced skin lesions and inflammatory response in the SKH-1 hairless mouse model.

Data on the toxicity of lewisite (L), a vesicant chemical warfare agent, are scarce and conflicting, and the use of the specific antidote is not without drawbacks. This study was designed to evaluate if the SKH-1 hairless mouse model was suitable to study the L-induced skin injuries. We studied the progression of lesions following exposure to L vapors for 21 days using paraclinical parameters (color, transepidermal water loss (TEWL), and biomechanical measurements), histological assessments, and biochemical indexes of inflammation.

Topical efficacy of dimercapto-chelating agents against lewisite-induced skin lesions in SKH-1 hairless mice.

Lewisite is a potent chemical warfare arsenical vesicant that can cause severe skin lesions. Today, lewisite exposure remains possible during demilitarization of old ammunitions and as a result of deliberate use. Although its cutaneous toxicity is not fully elucidated, a specific antidote exists, the British anti-lewisite (BAL, dimercaprol) but it is not without untoward effects.

Treatment of status epilepticus with ketamine, are we there yet?

Status epilepticus (SE), a neurological emergency both in adults and in children, could lead to brain damage and even death if untreated. Generalized convulsive SE (GCSE) is the most common and severe form, an example of which is that induced by organophosphorus nerve agents. First- and second-line pharmacotherapies are relatively consensual, but if seizures are still not controlled, there is currently no definitive data to guide the optimal choice of therapy.

Ketamine combinations for the field treatment of soman-induced self-sustaining status epilepticus. Review of current data and perspectives.

Organophosphorus nerve agents (NA), potent irreversible cholinesterase inhibitors, could induce severe seizures, status epilepticus (SE), seizure-related brain damage (SRBD) and lethality. Despite the lack of data in the case of NA, clinical evidences suggest that SE survivors could suffer from neurological/cognitive deficits and impairments such as spontaneous recurrent seizures (epilepsy) after a latent period of epileptogenesis. It is beyond doubt that an effective and quick management of the initial seizures and prevention of SRBD are critical to prevent these long-term consequences, explaining why most experimental data are focusing on the 5-40min post-exposure time frame.

Ketamine does not impair heat tolerance in rats.

Exposure to organophosphorus compounds, either pesticides or chemical warfare agents such as soman or sarin, represents a major health problem. Organophosphorus poisoning may induce seizures, status epilepticus and even brain lesions if untreated. Ketamine, an antagonist of glutamatergic receptors, was recently proved to be effective in combination with atropine sulfate as an anticonvulsant and neuroprotectant in mice and guinea pigs exposed to soman.

Prediction of neuroprotective treatment efficiency using a HRMAS NMR-based statistical model of refractory status epilepticus on mouse: a metabolomic approach supported by histology.

This work presents a model combining quantitative proton HRMAS NMR data and PLS-DA for neuropathology and neuroprotection evaluation. Metabolic data were also confronted to histopathological results obtained using the same experimental conditions. Soman, when not lethal, can induce status epilepticus (SE), brain damage, histological lesions, and profound cerebral metabolic disorders as revealed using (1)H HRMAS NMR.

Cyclooxygenase-2 contributes to VX-induced cell death in cultured cortical neurons.

The link between cell death and increased cyclooxygenases-2 (COX-2) activity has not been clearly established. In this study, we examined whether COX-2 activation contributed to the mechanism of neurotoxicity produced by an organophosphorous nerve agent in cultured rat cortical neurons. Exposure of neuronal cells to the nerve agent, VX resulted in an increase in COX enzyme activity in the culture media.

Combinations of ketamine and atropine are neuroprotective and reduce neuroinflammation after a toxic status epilepticus in mice.

Epileptic seizures and status epilepticus (SE) induced by the poisoning with organophosphorus nerve agents (OP), like soman, are accompanied by neuroinflammation whose role in seizure-related brain damage (SRBD) is not clear. Antagonists of the NMDA glutamate ionotropic receptors are currently among the few compounds able to arrest seizures and provide neuroprotection even during refractory status epilepticus (RSE). Racemic ketamine (KET), in combination with atropine sulfate (AS), was previously shown to counteract seizures and SRBD in soman-poisoned guinea-pigs.

A new use for an old method: the Woelcke myelin stain for counting degenerating neurons in the brain of mice following status epilepticus.

The Woelcke method is classically used for myelin staining. Degenerating neurons can be revealed histologically by hemalun and phloxin (H&P) where they appear "eosinophilic". In the first 24 h following soman-induced status epilepticus, we observed that the Woelcke method also revealed condensed, dark blue/black cells (W+ cells) in the gray matter of brain regions known to be sites of seizure-related brain damage, marked by the presence of eosinophilic cells.