Amir Krivoy

The possible use of oximes as antidotal therapy in organophosphate-induced brain damage

Organophosphate (OP) poisoning poses great danger to both military and civilian populations. OP-induced brain injury is characterized by rapid loss of consciousness, seizures, central respiratory inhibition as well as long-term behavioral changes in sub-lethal injuries. The pharmacological treatment of OP poisoning is based on anticholinergic and anticonvulsant drugs as well as oximes, which reactivate the non-aged inhibited enzyme. The commonly used oximes are quaternary compounds with questionable capacity to penetrate through the blood-brain barrier. This implies that the main beneficial effect of oximes may result from reactivation of AChE activity in respiratory muscles rather than in the brain. Importantly, data accumulated over the last few decades suggests a potential beneficial role for oximes in the brain, despite their polarity. Albeit the concentration of oximes in the central nervous system is significantly lower than in the plasma, they do gain access into the brain and are able to reactivate inhibited local AChE. Oximes may also attenuate OP-induced brain insult via different mechanisms other than AChE reactivation. In this review, we focus on the ability of oximes to act in the brain and protect the central nervous system from OP-induced injury, either by direct reactivation of AChE or by other pharmacological mechanisms. While this is a poorly investigated field we believe that the data supports the potential role of oximes in mitigating OP-induced neuronal injury, thus making them valuable in the treatment of severe casualties.

OP or not OP: the medical challenge at the chemical terrorism scene.

Since the 1995 Tokyo subway sarin attack, terrorist attacks involving weapons of mass destruction or other industrial chemicals present worldwide security and health concerns. On-scene medical triage and treatment in such events is crucial to save as many lives as possible and minimize the deleterious effects of the toxic agent involved. Since there are many chemicals that can be used as potential terrorist weapons, the medical challenge for the emergency medical services (EMS) is a combination of: (1) recognizing that a chemical terrorist attack (non-conventional) has occurred; and (2) identifying the toxic agent followed by proper antidotal treatment. The latter must be done as quickly as possible, preferably on-scene. The most valuable decision at this stage should be whether the agent is organophosphate (OP) or not OP, based on clinical findings observed by pre-trained, first responders. This decision is crucial, since only OP intoxication has readily available, rapidly acting, onscene, specific agents such as atropine and one of the oximes, preferably administered using autoinjectors. Due to the lack of a specific antidote, exposure to other agents (such as industrial chemicals, e.g., chlorine, bromide, or ammonia) should be treated on-scene symptomatically with non-specific measures, such as decontamination and supportive treatment. This paper proposes an algorithm as a cognitive framework for the medical teams on-scene. This algorithm should be part of the medical teams training for preparedness for chemical terrorist attacks, and the team should be trained to use it in drills. Implementing this path of thinking should improve the medical outcome of such an event.

Prevention of organophosphate-induced chronic epilepsy by early benzodiazepine treatment.

Poisoning with organophosphates (OPs) may induce status epilepticus (SE), leading to severe brain damage. Our objectives were to investigate whether OP-induced SE leads to the emergence of spontaneous recurrent seizures (SRSs), the hallmark of chronic epilepsy, and if so, to assess the efficacy of benzodiazepine therapy following SE onset in preventing the epileptogenesis. We also explored early changes in hippocampal pyramidal cells excitability in this model. Adult rats were poisoned with the paraoxon (450μg/kg) and immediately treated with atropine (3mg/kg) and obidoxime (20mg/kg) to reduce acute mortality due to peripheral acetylcholinesterase inhibition. Electrical brain activity was assessed for two weeks during weeks 4-6 after poisoning using telemetric electrocorticographic intracranial recordings. All OP-poisoned animals developed SE, which could be suppressed by midazolam. Most (88%) rats which were not treated with midazolam developed SRSs, indicating that they have become chronically epileptic. Application of midazolam 1min following SE onset had a significant antiepileptogenic effect (only 11% of the rats became epileptic; p=0.001 compared to non-midazolam-treated rats). Applying midazolam 30min after SE onset did not significantly prevent chronic epilepsy. The electrophysiological properties of CA1 pyramidal cells, assessed electrophysiologically in hippocampal slices, were not altered by OP-induced SE. Thus we show for the first time that a single episode of OP-induced SE in rats leads to the acquisition of chronic epilepsy, and that this epileptogenic outcome can be largely prevented by immediate, but not delayed, administration of midazolam. Extrapolating these results to humans would suggest that midazolam should be provided together with atropine and an oxime in the immediate pharmacological treatment of OP poisoning.

Civilian Adult Self Injections of Atropine – Trimedoxime (TMB4) Auto-Injectors

Introduction. The clinical effects of self injections of atropine–trimedoxime auto-injectors distributed to the civilian population as a field antidote for nerve agent attack were assessed. Methods. Data on self injections by adults (≥18 years) were collected from the Israel Poison Information Center and a hospital Emergency Departments records during a 2-year period. The data included demographics, time interval from injection, type of auto-injector, clinical manifestations and atropinization score. Results. Sixty-five patients, all with unintentional self injections, were reported. Systemic atropine effects were observed in 24 patients, but no severe atropinization. The atropinization score was significantly higher in the 2 mg atropine dose group than in the two lower dose groups, which were in the normal range. No specific adverse effects attributable to trimedoxime were observed. Intravenous fluids and physostigmine were not required. Conclusion. Only mild reactions were observed following self-injection of atropine trimedoxime auto-injectors in adults, attesting to their relative safety under these conditions.

Is rivastigmine safe as pretreatment against nerve agents poisoning? A pharmacological, physiological and cognitive assessment in healthy young adult volunteers

Rivastigmine, a reversible cholinesterase inhibitor, approved as a remedy in Alzheimers disease, was suggested as pretreatment against nerve agents poisoning. We evaluated the pharmacokinetic, pharmacodynamic, physiologic, cognitive and emotional effects of repeated rivastigmine in young healthy male adults, in a double blind, placebo controlled crossover trial. Three groups completed 3 treatment periods: 0, 1.5 and 3mg twice a day, for a total of 5 intakes. Parameters monitored were: vital signs, ECG, laboratory tests, sialometry, visual accommodation, inspiratory peak flow, and cognitive function tests. Adverse reactions were mild. Peak blood levels and peak cholinesterase inhibition increased with repeated intakes, and high variability and non-linear pharmacokinetics were demonstrated. In addition, two cognitive functions were affected (perceptual speed and dynamic tracking). The complicated pharmacological profile and the high inter-personal variability limit the potential use of rivastigmine as pretreatment for war fighters and first responders.

Early in vivo MR spectroscopy findings in organophosphate-induced brain damage-potential biomarkers for short-term survival.

Organophosphates are highly toxic substances, which cause severe brain damage. The hallmark of the brain injury is major convulsions. The goal of this study was to assess the spatial and temporal MR changes in the brain of paraoxon intoxicated rats. T2‐weighted MRI and 1H‐MR‐spectroscopy were conducted before intoxication, 3 h, 24 h, and 8 days postintoxication. T2 prolongation mainly in the thalami and cortex was evident as early as 3 h after intoxication (4–6% increase in T2 values, P < 0.05). On spectroscopy, N‐acetyl aspartate (NAA)/creatine and NAA/choline levels significantly decreased 3 h postintoxication (>20% decrease, P < 0.005), and 3 h lactate peak was evident in all intoxicated animals. On the 8th day, although very little T2 changes were evident, NAA/creatine and choline/creatine were significantly decreased (>15%, P < 0.05). Animals who succumbed had extensive cortical edema, significant higher lactate levels and a significant decrease in NAA/creatine and NAA/choline levels compared to animals which survived the experiment. Organophosphates‐induced brain damage is obvious on MR data already 3 h postintoxication. In vivo spectroscopic changes are more sensitive for assessing long‐term injury than T2‐weighted MR imaging. Early spectroscopic findings might be used as biomarkers for the severity of the intoxication and might predict early survival. Magn Reson Med, 2012.

Safety of Biological/Chemical Respiratory Protection Filter for Patients in Need of Oxygen Supplementation

BACKGROUND During the 2003 war in Iraq, Israel faced the problem of supplying biological/chemical respiratory protection for a population in need of ventilator support. The devices in use were insufficient in terms of protective value, costs, and availability. An adaptor was developed to allow connection between respirators and the standard biological/chemical filter canister. OBJECTIVE As part of the safety protocol for such a device, an investigation was made to determine the possibility of combustion of the biological/chemical filter canister, because of a possible exothermic reaction between the inspired oxygen-enriched air flow passing through the canister and the activated charcoal component of the filter. METHODS A mechanical ventilator generated airflow with a frequency of 24 breaths per minute and a 500-mL tidal volume, for 90 minutes, through 14 standard filter canisters in a sealed chamber at a temperature of 25 degrees C and through seven canisters at a temperature of 30 degrees C. Incremental levels of oxygen (21-100%) were used for each set of canisters. The temperature of each filter was recorded throughout the examination. RESULTS There was no elevation in the final temperature of the filters after 90 minutes of airflow with high oxygen levels. There were no signs of ignition. CONCLUSION High oxygen levels passing through the activated carbon in the filter canister placed between the mechanical ventilator and the patient do not cause a combustion reaction, making it a safe means for respiratory protection for patients undergoing mechanical ventilation.