- Addition of ketamine to standard-of-care countermeasures for acute organophosphate poisoning improves neurobiological outcomes. [Journal Article]
- NNeurotoxicology 2018 Aug 30; 69:37-46
- Rats poisoned with sarin enter into ahyper-cholinergic crisis characterized by excessive salivation, respiratory distress, tremors, seizures, and death. Through the use of rescue medications and an a...
Rats poisoned with sarin enter into ahyper-cholinergic crisis characterized by excessive salivation, respiratory distress, tremors, seizures, and death. Through the use of rescue medications and an anticonvulsant, death can be avoided in many animals, with the long-term consequences of poisoning partly ameliorated, especially when countermeasures are made available immediately after exposure. However, when anticonvulsant measures are delayed by as little as 30 min, clinical, neurological, cognitive, and psychiatric abnormalities may persist long after the initial exposure. This study sought to determine if the addition of the NMDA receptor antagonist Ketamine to human standard-of-care countermeasures consisting of two rescue medications (2-PAM and atropine) and an anti-convulsant (Midazolam), would afford protection against persistent neurobiological compromise. Rats were exposed to sarin (105 μg/kg via subcutaneous injection), and treated 1 min later with 2-PAM and Atropine Methyl Nitrate (IM) to minimize mortality. One of four anti-convulsant protocols was then initiated at 50 min postsarin:Midazolam alone (MDZ, a single injection (IM) at 0.66 mg/kg); Ketamine alone (KET, a series of five injections (IM) of Ketamine at 7.5 mg/kg, 90 min apart); Midazolam + low dose Ketamine (MDZ + lowKET, a single injection of Midazolam (IM) at 0.66 mg/kg, plus five sequential doses of ketamine (IM) at 2.5 mg/kg, starting at the time of Midazolam dosing and then 90 min apart); Midazolam + high dose Ketamine (MDZ + highKET, a single injection of Midazolam (IM) at 0.66 mg/kg, plus five sequential injections of 7.5 mg/kg Ketamine (IM), starting at the time of Midazolam dosing and then 90 min apart). Animals were preassigned to groups culled at post-exposure Days 1, 7 or 30, for histopathology. For all surviving animals, EEG activity was monitored through skull electrodes for 24-h beginning immediately after sarin exposure. Surviving animals also underwent 24-h EEG monitoring on Days 6, 13, and/or 29, post-sarin. Memory assessment using the Morris Water Maze was performed on Days 1, 4, 7, 14 and 30. Following sarin exposure, 85% of surviving animals demonstrated status epilepticus within 20 min. Each of the anti-convulsant protocols was sufficient to stop convulsions within 1 h of anti-convulsant administration, but all of the animals still showed signs of electrographic status for an additional 2-12 h, without substantial differentiation between treatment groups. However, for post-sarin hours 13-24, the MDZ + highKET group showed significantly less severe EEG abnormalities than the MDZ and KET groups (Mood's Median Test, p < 0.005). At one month post-exposure, 90% of animals that had received Midazolam alone still showed evidence of some epileptiform activity. In contrast, 90% of animals that had received Midazolam + high dose Ketamine combination therapy had EEG profiles that were within normal limits. This difference in EEG outcomes was highly significant (Mood's Median Test, p < 0.001). Likewise, on the water maze, the majority of animals that had received Midazolam combined with either high or low dose Ketamine therapy returned to near baseline levels of mnemonic performance within 2 weeks, whereas the majority of the animals that had received midazolam alone or ketamine alone demonstrated persistent and significant memory impairments even at one month postexposure (Mood's Median Test, p < 0.005). With respect to neuronal necrosis, animals in the MDZ + highKET group showed significantly less overall damage than animals in other treatment groups (Mood's Median Test, p < 0.001). Of special note were findings in the hippocampus, where only 12% of animals in the MDZ + highKET group showed evidence of necrosis on H&E staining, whereas 100% of animals in the KET group, 70% of animals in the MDZ group, and 40% of animals in the MDZ + lowKET group showed evidence of hippocampal necrosis. Overall, the data demonstrate that Ketamine augmentation of an atropine, 2PAM, and Midazolam standard-ofcare for sarin exposure provides clinically-relevant additional protection against the negative neurobiological consequences of sarin, even when initiation of the anti-convulsant countermeasures is delayed by 50 min.
- Prolonged paralysis in a child with organophosphate pesticide poisoning. [Journal Article]
- SAS Afr Med J 2018 05 25; 108(6):468-470
- A 17-month-old boy presented to a local community health centre in Cape Town, South Africa, with severe organophosphate pesticide poisoning (OPP), necessitating the use of intravenous atropine to con...
A 17-month-old boy presented to a local community health centre in Cape Town, South Africa, with severe organophosphate pesticide poisoning (OPP), necessitating the use of intravenous atropine to control cholinergic symptoms, as well as emergency intubation for ongoing respiratory distress. He required prolonged ventilatory support in the intensive care unit at his referral hospital and had subsequent delayed neurological recovery, spending 8 days in hospital.We present this case to emphasise the importance of adequate atropinisation in the management of severe OPP and to highlight the dangers of inappropriate use of suxamethonium for intubation in patients with OPP.
- Novichok agents: a historical, current, and toxicological perspective. [Journal Article]
- TCToxicol Commun 2018; 2(1):45-48
- The Novichok, or "newcomer" class of nerve agents are lesser characterized, weaponized organophosphate agents. The use of known Novichok agents in warfare is banned under the Chemical Weapons Convent...
The Novichok, or "newcomer" class of nerve agents are lesser characterized, weaponized organophosphate agents. The use of known Novichok agents in warfare is banned under the Chemical Weapons Convention of 1997. Novichok agents are considered more potent than VX gas and can be applied in unitary and binary forms. Like other nerve agents, Novichok agents irreversibly bind acetylcholinesterase and produce a cholinergic toxidrome. Uniquely, these agents are thought to also target neurons in the peripheral nervous system. Delayed treatment or massive exposure may therefore cause a debilitating neuropathy. The recent 2018 assassination attempt of Russian dissident Sergei Skripal and his daughter Yulia in the United Kingdom highlights the importance of recognizing the potential lethal effects of these nerve agents. Treatment of Novichok agent poisoning is similar to management of other nerve agents. Given increasing worldwide incidents attributed to chemical weapons such as Novichok agents, clinicians should know how to rapidly recognize symptoms of acute poisoning and administer life-saving antidotal therapy, when indicated.
- Acute cholinergic syndrome in a patient with Alzheimer's disease taking the prescribed dose of galantamine. [Journal Article]
- PPsychogeriatrics 2018 Jul 11
- Catalytic bioscavengers as countermeasures against organophosphate nerve agents. [Review]
- CBChem Biol Interact 2018 Aug 25; 292:50-64
- Recent years have seen an increasing number of incidence, in which organophosphate nerve agents (OPNAs) have been used against civilians with devastating outcomes. Current medical countermeasures aga...
Recent years have seen an increasing number of incidence, in which organophosphate nerve agents (OPNAs) have been used against civilians with devastating outcomes. Current medical countermeasures against OPNA intoxications are aimed at mitigating their symptoms, but are unable to effectively prevent them. In addition, they may fail to prevent the onset of a cholinergic crisis in the brain and its secondary toxic manifestations. The need for improved medical countermeasures has led to the development of bioscavengers; proteins and enzymes that may prevent intoxication by binding and inactivating OPNAs before they can reach their target organs. Non-catalytic bioscavengers such as butyrylcholinesterase, can rapidly bind OPNA molecules in a stoichiometric and irreversible manner, but require the administration of large protein doses to prevent intoxication. Thus, many efforts have been made to develop catalytic bioscavengers that could rapidly detoxify OPNAs without being inactivated in the process. Such enzymes may provide effective prophylactic protection and improve post-exposure treatments using much lower protein doses. Here we review attempts to develop catalytic bioscavengers using molecular biology, directed evolution and enzyme engineering techniques; and natural or computationally designed enzymes. These include both stoichiometric scavengers and enzymes that can hydrolyze OPNAs with low catalytic efficiencies. We discuss the catalytic parameters of evolved and engineered enzymes and the results of in-vivo protection and post-exposure experiments performed using OPNAs and bioscavengers. Finally, we briefly address some of the challenges that need to be met in order to transition these enzymes into clinically approved drugs.
- Organophosphorus poisoning in animals and enzymatic antidotes. [Journal Article]
- ESEnviron Sci Pollut Res Int 2018 Jun 29
- Organophosphorus compounds (OPs) are neurotoxic molecules developed as pesticides and chemical warfare nerve agents (CWNAs). Most of them are covalent inhibitors of acetylcholinesterase (AChE), a key...
Organophosphorus compounds (OPs) are neurotoxic molecules developed as pesticides and chemical warfare nerve agents (CWNAs). Most of them are covalent inhibitors of acetylcholinesterase (AChE), a key enzyme in nervous systems, and are therefore responsible for numerous poisonings around the world. Many animal models have been studied over the years in order to decipher the toxicity of OPs and to provide insights for therapeutic and decontamination purposes. Environmental impact on wild animal species has been analyzed to understand the consequences of OP uses in agriculture. In complement, various laboratory models, from invertebrates to aquatic organisms, rodents and primates, have been chosen to study chronic and acute toxicity as well as neurobehavioral impact, immune response, developmental disruption, and other pathological signs. Several decontamination approaches were developed to counteract the poisoning effects of OPs. Among these, enzyme-based strategies are particularly attractive as they allow efficient external decontamination without toxicity or environmental impact and may be of interest for treatment. Approaches using bioscavengers for prophylaxis, treatment, and external decontamination are emphasized and their potential is discussed in the light of toxicological observations from various animal models. The relevance of animal models, regarding their cholinergic system and the abundance of naturally protecting enzymes, is also discussed for better extrapolation of results to human.
- Amitraz Poisoning: The (Un) Common Poisoning. [Journal Article]
- JEJ Emerg Trauma Shock 2018 Apr-Jun; 11(2):140-142
- Pesticide poisoning is always a clinical conundrum for the emergency physician (EP), the complexity of which increases when the pesticide has no antidote! Over the past decade, there has been a sharp...
Pesticide poisoning is always a clinical conundrum for the emergency physician (EP), the complexity of which increases when the pesticide has no antidote! Over the past decade, there has been a sharp increase in cases of Amitraz poisoning, a pesticide routinely used in veterinary medicine, available without a prescription. The usual presentation includes bradycardia, hypotension, poor sensorium, and miosis. In the absence of accurate history, these clinical features can be confused with the cholinergic toxidrome of organophosphorus poisoning. There is a dearth of literature regarding the presentation and protocols for the management of Amitraz poisoning with data mostly based on animal studies and pediatric case reports. Currently, the available medical literature in the form of case reports and case series form an invaluable source of information to the EP to formulate a working diagnosis and methodical approach to this pesticide. Here, we present two case reports highlighting the characteristic clinical features and bringing to light how an organized approach to the toxin can give satisfactory results.
- Inflammatory and oxidative mechanisms potentiate bifenthrin-induced neurological alterations and anxiety-like behavior in adult rats. [Journal Article]
- TLToxicol Lett 2018 Sep 15; 294:73-86
- Bifenthrin (BF) is a synthetic pyrethroid pesticide widely used in several countries to manage insect pests on diverse agricultural crops. Growing evidence indicates that BF exposure is associated wi...
Bifenthrin (BF) is a synthetic pyrethroid pesticide widely used in several countries to manage insect pests on diverse agricultural crops. Growing evidence indicates that BF exposure is associated with an increased risk of developing neurodegenerative disorders. However, the mechanisms by which BF induces neurological and anxiety alterations in the frontal cortex and striatum are not well known. The present in vivo study was carried out to determine whether reactive oxygen species (ROS)-mediated oxidative stress (OS) and neuroinflammation are involved in such alterations. Thirty-six Wistar rats were thus randomly divided into three groups and were orally administered with BF (0.6 and 2.1 mg/kg body weight, respectively) or the vehicle (corn oil), on a daily basis for 60 days. Results revealed that BF exposure in rats enhanced anxiety-like behavior after 60 days of treatment, as assessed with the elevated plus-maze test by decreases in the percentage of time spent in open arms and frequency of entries into these arms. BF-treated rats also exhibited increased oxidation of lipids and carbonylated proteins in the frontal cortex and striatum, and decreased glutathione levels and antioxidant enzyme activities including superoxide dismutase, catalase and glutathione peroxidase. Treatment with BF also increased protein synthesis and mRNA expression of the inflammatory mediators cyclooxygenase-2 (COX-2), microsomal prostaglandin synthase-1 (mPGES-1) and nuclear factor-kappaBp65 (NF-kBp65), as well as the production of tumor necrosis factor-α (TNF-α) and ROS. Moreover, BF exposure significantly decreased protein synthesis and mRNA expression of nuclear factor erythroid-2 (Nrf2) and acetylcholinesterase (AChE), as well as gene expression of muscarinic-cholinergic receptors (mAchR) and choline acetyltransferase (ChAT) in the frontal cortex and striatum. These data suggest that BF induced neurological alterations in the frontal cortex and striatum of rats, and that this may be associated with neuroinflammation and oxidative stress via the activation of Nrf2/NF-kBp65 pathways, which might promote anxiety-like behavior.
- Optimization of Cholinesterase-Based Catalytic Bioscavengers Against Organophosphorus Agents. [Journal Article]
- FPFront Pharmacol 2018; 9:211
- Organophosphorus agents (OPs) are irreversible inhibitors of acetylcholinesterase (AChE). OP poisoning causes major cholinergic syndrome. Current medical counter-measures mitigate the acute effects b...
Organophosphorus agents (OPs) are irreversible inhibitors of acetylcholinesterase (AChE). OP poisoning causes major cholinergic syndrome. Current medical counter-measures mitigate the acute effects but have limited action against OP-induced brain damage. Bioscavengers are appealing alternative therapeutic approach because they neutralize OPs in bloodstream before they reach physiological targets. First generation bioscavengers are stoichiometric bioscavengers. However, stoichiometric neutralization requires administration of huge doses of enzyme. Second generation bioscavengers are catalytic bioscavengers capable of detoxifying OPs with a turnover. High bimolecular rate constants (kcat/Km > 106M-1min-1) are required, so that low enzyme doses can be administered. Cholinesterases (ChE) are attractive candidates because OPs are hemi-substrates. Moderate OP hydrolase (OPase) activity has been observed for certain natural ChEs and for G117H-based human BChE mutants made by site-directed mutagenesis. However, before mutated ChEs can become operational catalytic bioscavengers their dephosphylation rate constant must be increased by several orders of magnitude. New strategies for converting ChEs into fast OPase are based either on combinational approaches or on computer redesign of enzyme. The keystone for rational conversion of ChEs into OPases is to understand the reaction mechanisms with OPs. In the present work we propose that efficient OP hydrolysis can be achieved by re-designing the configuration of enzyme active center residues and by creating specific routes for attack of water molecules and proton transfer. Four directions for nucleophilic attack of water on phosphorus atom were defined. Changes must lead to a novel enzyme, wherein OP hydrolysis wins over competing aging reactions. Kinetic, crystallographic, and computational data have been accumulated that describe mechanisms of reactions involving ChEs. From these studies, it appears that introducing new groups that create a stable H-bonded network susceptible to activate and orient water molecule, stabilize transition states (TS), and intermediates may determine whether dephosphylation is favored over aging. Mutations on key residues (L286, F329, F398) were considered. QM/MM calculations suggest that mutation L286H combined to other mutations favors water attack from apical position. However, the aging reaction is competing. Axial direction of water attack is not favorable to aging. QM/MM calculation shows that F329H+F398H-based multiple mutants display favorable energy barrier for fast reactivation without aging.
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- Magnesium sulfate and calcium channel blocking drugs as antidotes for acute organophosphorus insecticide poisoning - a systematic review and meta-analysis. [Journal Article]
- CTClin Toxicol (Phila) 2018; 56(8):725-736
- CONCLUSIONS: Both preclinical and clinical data suggest that magnesium sulfate and calcium channel blocking drugs might be promising adjunct treatments for acute organophosphorus insecticide poisoning. However, evidence is currently insufficient to recommend their use. Mechanistic and large multi-center randomized controlled trials testing calcium channel blocking drugs and magnesium sulfate are required to provide the necessary evidence, with careful identification of the insecticides ingested and measurement of surrogate markers of toxicity, including butyrylcholinesterase activity.