Nerve agents cholinesterase inhibition

The potency of nerve agents can also be expressed in terms of the dose necessary to produce 50% inhibition of cholinesterase (ChEso). In humans, RBC-CI1E50 values for GB are 0.003 mg/kg and 0.01 mg/kg, respectively, for i.v. and oral doses (Grob and Harvey, 1958). The relative effectiveness of nerve agents in inhibiting cholinesterase is closely correlated with their acute toxicity (see Appendix A). 

The primary mechanism of conventional OP-containiiig chemical nerve agents is inhibition of cholinesterase and the concomitant accumulation of ACh. Logically, vascular smooth muscle contractility will be altered if substantially high levels of circulating ACh remain. Freeman et al. (1986) reported that the disruption of ACh signaling... 

Possibly the earliest recorded use of a substance that works, like nerve agents, by inhibiting cholinesterase (ChE) is by native tribesmen of western Africa who used the Calabar bean as an ordeal poison in witchcraft trials.1,2 An extract, the elixir of the Calabar bean, was later used medicinally,3 and in 1864, the active principle was isolated by Jobst and Hesse and called physostigmine.1 Vee and Leven independently isolated this same substance in 1865 and named it eserine,1 hence its dual nomenclature. 

Although the organophosphate insecticides are similar to nerve agents in inhibiting cholinesterase, they differ in other characteristics. For example, the cholinergic crisis caused by acute, severe intoxication with the insecticides is generally much longer... 

DF and its precursor, methylphosphonic dichloride (DC), are organophos-phonic acids. They will react with alcohols to form crude lethal nerve agents, such as crude GB. High overexposure may cause inhibition of cholinesterase activity. Although much less toxic than GB, DF and DC are toxic and corrosive materials. 

DF and its precursor, DC are organophosphonic acids. They will react with alcohols to form crude lethal nerve agents, such as crude GB. High overexposure may cause inhibition of cholinesterase activity. Although much less toxic than GB, DF and DC are toxic and corrosive materials. Because DF and DC are relatively volatile compounds, the primary route of exposure is expected to be the respiratory system. However, ingestion also results from inhalation exposures in animals and could occur in humans. DF and DC vapors have a pungent odor and may cause severe and painful irritation of the eyes, nose, throat, and lungs. Data provided is for DF only, DC has similar properties. 

Although bicyclophosphates do not inhibit acetylcholinesterase, they exhibit a synergistic toxic effect with materials that do. Individuals who have had previous exposure to cholinesterase inhibitors such as nerve agents and commercial organophosphate or carbamate pesticides may be at a greater risk from exposure to bicyclophosphates. 

Presently available methods to diagnose and biomonitor exposure to anticholinesterases, e.g., nerve agents, rely mostly on measurement of residual enzyme activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in blood. More specific methods involve analysis of the intact poison or its degradation products in blood and/or urine. These approaches have serious drawbacks. Measurement of cholinesterase inhibition in blood does not identify the anticholinesterase and does not provide reliable evidence for exposure at inhibition levels less than 20 %. The intact poison and its degradation products can only be measured shortly after exposure. Moreover, the degradation products of pesticides may enter the body as such upon ingestion of food products containing these products. 

In addition to battlefield trauma, there is also the risk of exposure to chemical weapons such as the nerve agents, notably the organophosphorus gases (soman, sarin, VX, tabun) [6]. Organophosphorus toxicity arises largely from their ability to irreversibly inhibit acetyl-cholinesterases, leading to effects associated with peripheral acetyl-choline accumulation (muscarinic syndrome) such as meiosis, profuse sweating, bradychardia, bronchioconstriction, hypotension, and diarrhoea. Central nervous system effects include anxiety, restlessness, confusion, ataxia, tremors. 

Two basic types of chemical agents comprise the stockpile cholinesterase-inhibiting (nerve) agents and blister (mustard and Lewisite) agents. Both types are frequently, and erroneously, referred to as gases even though they are liquids at normal temperature and pressure.1... 

Although there is the potential for nerve agents to have direct toxic effects on the nervous system, there is no evidence that such effects occur in humans at doses lower than those causing cholinesterase inhibition. For the purpose of evaluating potential health effects, inhibition of blood cholinesterase is generally considered the most useful biological endpoint. 

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