Medical Aspects of Chemical Warfare (2008) - The Black Vault

Medical Aspects of Chemical Warfaredose of enzyme could protect against 3.3 times theLD 50of soman or 2.1 times the LD 50of VX in rhesusmonkeys. 19 They also reported substantial protectionagainst soman-induced behavioral deficits using aspatial discrimination task.Wolfe et al assessed the ability of FBS AChE or EqBChE pretreatment to protect rhesus monkeys againstmultiple LD 50of soman. 20 Survival and the ability toperform the primate equilibrium platform behavioraltask were concurrently assessed. Animals pretreatedwith FBS AChE were protected against a cumulativeexposure of 5 times the LD 50of soman and showedno decrement in the primate equilibrium platformtask. Two of the four monkeys that received purifiedEq BChE showed a transient decrement in the primateequilibrium platform task performance whenthe cumulative dose of soman exceeded 4 times theLD 50. All experimental animals were observed foran additional 6 weeks and none displayed residualor delayed performance decrements, suggesting noresidual adverse effects.CaE is another enzyme with potential as a goodanti-OP scavenger molecule. CaE can be distinguishedfrom ChEs because while ChEs react with positivelycharged carboxylesters, such as acetylcholine and butyrylcholine,and are readily inhibited by carbamates,CaE does not react with positively charged substratesand is inhibited by carbamates only at high concentrations.21 These differences in substrate specificity alsoextend to the reaction of CaE with OP compounds.Positively charged OP compounds, such as VX, reactpoorly with CaE, while neutral OP compounds suchas soman, sarin, and paraoxon, react rapidly. CaE issynthesized in the liver and secreted into circulation. 22The levels of circulating CaE vary between mammalianspecies, and animals that have high levels of plasmaCaE require much larger doses of OP compounds toproduce toxicity than do species with low levels ofplasma CaE. 23 For example, the LD 50for soman in ratsis 10-fold higher than the LD 50in nonhuman primates,which correlates with the differences in the plasma concentrationsof CaE found in these species. Like nonhumanprimates, humans do not express CaE in plasma. 24The primary evidence supporting the hypothesisthat CaE can function as a stoichiometric scavengeragainst OPs (especially sarin and soman) but not forV agents was obtained by comparing LD 50s of OPs inanimals possessing high endogenous plasma levels ofCaE to LD 50in the same animal species following inhibitionof plasma CaE with chemicals (Figure 7-1). 25 Forexample, inhibition of plasma CaE reduced the LD 50ofsoman in rats approximately 8-fold, suggesting that circulatingCaE can be an effective bioscavenger againstOPs. Furthermore, investigations of the reactivationof OP-inhibited CaE have suggested that it may bepossible to increase its potential as an OP scavenger byexploiting its turnover of OPs. Maxwell et al observedthat OP-inhibited CaE did not undergo aging thatprevented oxime reactivation of OP-inhibited ChEs, 26while Jokanovic et al found that OP-inhibited plasmaCaE in rats underwent spontaneous reactivation witha half time of 1 to 2 hours. 27 Extensive investigationsneed to be carried out before considering using CaE asa bioscavenger for humans. Although human CaE hasbeen cloned and expressed, 22 there is no commercialsource of highly purified CaE for use in in-vivo testingof protective efficacy.The absence of immunological or physiological sideeffects following transfusions of plasma in humans andthe lack of adverse reaction to the administration ofpartially purified pHu BChE suggest that this enzymewould be the most promising prophylactic antidotefor human use. 28,29 As an exogenously administeredprophylactic, pHu BChE has several advantages forhuman use. 30 First, it reacts rapidly with all highlytoxic OPs, offering a broad range of protection fornerve agents, including soman, sarin, tabun, and VX.Second, its retention time in human circulation is long CaE: carboxylesteraseLD 50: median lethal doseFig. 7-1. Effect of plasma carboxylesterase concentration onsoman median lethal dose (administered subcutaneously)in different species. Data points (from lower left to upperright of graph) for species were monkey, rabbit, guinea pig,rat, and mouse.Reproduced with permission from: Maxwell DM, Wolfe AD,Ashani Y, Doctor BP. Cholinesterase and carboxylesteraseas scavengers for organophosphorus agents, In: MassoulieJ, Bacou F, Bernard E, Chatonnet A, Doctor BP, Quinn DM,eds. Cholinesterases: Structure, Function, Mechanism, Genetics,and Cell Biology. Washington, DC: American ChemicalSociety; 1991: 206.246