The potential role of bioscavenger in the medical management of nerve-agent poisoned casualties

Abstract

The provision of effective Medical Countermeasures (MedCM) for all agents and routes of exposure is a strategic goal of defence research and development. In the case of military autoinjector-based therapies for nerve agent poisoning, current treatment effectiveness is limited by the oxime reactivator being effective against only certain agents, by rapid clearance times of the drugs and because the doses may not be optimal for treatment of severe poisoning. Prolonged poisoning by nerve agents entering the body through the skin is also challenging. Since casualty handling timelines have reduced significantly in recent years, it may be sufficient for first aid therapy to provide protection for only a few hours until further medical treatment is available. Therefore, the traditional evaluation of first aid therapy in animal models of survival at 24 h may not be appropriate. At various echelons of medical care, further therapeutic interventions are possible. The current basis for the medical management of nerve-agent poisoned casualties is derived mainly from clinical experience with pesticide poisoning. Adjunct therapy with a bioscavenger (such as human butyrylcholinesterase (huBChE)), could have utility as a delayed intervention by reducing the toxic load. It has previously been demonstrated that huBChE is an effective post-exposure therapy against percutaneous VX poisoning. It is recommended that the scope of animal models of nerve agent MedCM are extended to cover evaluation of both first aid MedCM over significantly reduced timescales, and subsequent supportive therapeutic and medical management strategies over longer timescales. In addition to bioscavengers, these strategies could include repeated combined and individual therapy drugs to alleviate symptoms, other classes of drugs or ventilatory support. Crown Copyright [2016] Published by Elsevier Ireland Ltd. This is an open access article under the Open Government Licence (OGL) (http://www.nationalarchives.gov.uk/doc/open-government-licence/version/3/).

Beyond traditional CBRN force protection – a future of CBRN hardened super-soldiers?

“…These findings led to the hypothesis that BuChE might be developed as an effective nerve agent MCM that would confer a similar protective effect against nerve agent exposure in the average human -effectively conferring a super-detoxification ability to the recipient. This hypothesis is supported by extensive research and clinical trials undertaken to develop a operationalised MCM (14,16,18,19,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). The human BuChE gene has also recently been incorporated into a bacterial host, for the purpose of large scale production of therapeutic BuChE.…”

Acetylcholinesterase: The “Hub” for Neurodegenerative Diseases and Chemical Weapons Convention

“…BChE is found in plasma, being responsible for hydrolysis of different esters, property that has been studied to understand a series of metabolic events or for treatment of cocaine addiction, for example. Furthermore, it has been extensively studied due to its stoichiometric reaction with organophosphorus compounds, which indicates that it is not only a biomarker of exposure to these toxic chemicals but also a potential treatment for intoxication, acting as bioscavenger of nerve agents [61][62][63][64][65][66][67][74][75][76][77][78][79][80][81][82][83].…”

“…Finally, the acyl pocket site (APS) is the point where the difference between AChE and BChE may be assessed, with AChE having a smaller APS than BChE, determining the size of the substrate to be hydrolyzed [61][62][63][64][65][66][67][85][86][87][88][89][90][91][92][93]. Biomolecules 2020, 10, x 6 of 21 these toxic chemicals but also a potential treatment for intoxication, acting as bioscavenger of nerve agents [61][62][63][64][65][66][67][74][75][76][77][78][79][80][81][82][83].…”

Optimization of Cholinesterase-Based Catalytic Bioscavengers Against Organophosphorus Agents

“…However, in the past 30 years no major improvement has been made in classical pharmacological treatment of OP poisoning. Some progress has resulted from better use of existing drugs, better management of chemical casualties (Myhrer and Aas, 2016 ; Rice et al, 2016 ), and encapsulation of quaternary oximes in nanoparticles (Pashirova et al, 2017 ). However, new potential drugs such as anti-Alzheimer inhibitors of AChE, non-quaternary oximes, anti-nicotinic drugs, and neuroprotectants like ketamine are still under evaluation (Masson, 2016b ).…”