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

Nerve Agentssible for binding nerve agent molecules. Functionally,sufficient excess AChE activity is normally present insynapses so that carbamoylation of 20% to 40% of theenzyme with pyridostigmine does not significantlyimpair neurotransmission.Additionally, it must be recognized that the normalhuman carries excess ChE. Thus, temporary inhibitionof a small portion of ChE is well tolerated by humans,with minimal side effect profiles, as detailed below.When animals are challenged with a lethal doseof nerve agent, AChE activity normally decreasesrapidly, becoming too low to measure. In pyridostigmine-pretreatedanimals with a sufficient quantityof protected, carbamoylated enzyme, spontaneousdecarbamoylation of the enzyme regenerates enoughAChE activity to sustain vital functions, such asneuromuscular transmission to support respiration.Prompt postexposure administration of atropine isstill needed to antagonize ACh excess, and an oximereactivator must also be administered if an excess ofnerve agent remains to attack the newly uncoveredAChE active sites that were protected by pyridostigmine.EfficacyBecause it is impossible to test the rationale inhumans exposed to nerve agents, the US military embarkedupon a series of studies in animal models. Table5-9 summarizes one study using male rhesus monkeys.73 Pretreatment with orally administered, pyridostigmine-inhibitedcirculating red blood cell AChE(RBC-AChE) by 20% to 45%. (Inhibition of RBC-AChEby pyridostigmine is a useful index of its inhibition ofAChE in peripheral synapses). Monkeys that had nopyridostigmine pretreatment were not well protectedfrom soman by the prompt administration of atropineand 2-PAM Cl. The PR of 1.64 in these monkeys is typicalof the most effective known postexposure antidotetherapy in animals not given pretreatment to a somanchallenge. In contrast to this low level of protection,however, the combination of pyridostigmine pretreatmentand prompt postchallenge administration ofatropine and 2-PAM Cl resulted in greatly improvedprotection (PR > 40 when compared with the controlgroup; PR = 24 when compared with the group givenatropine and 2-PAM Cl).Because the number of animals available for somanchallenge at extremely high doses was limited,accurate calculation of a PR was indeterminate in thisexperiment. The PR was well in excess of 40, clearlymeeting the requirement for effectiveness of 5-foldimproved protection. In a later study, four of five rhesusmonkeys receiving pyridostigmine pretreatmentTABLE 5-9EFFECT OF THERAPY ON Median LethalDose IN MONKEYS EXPOSED TO SOMANGroup Mean LD 50(µg/kg) [95% CL]Control (no treatment)Postexposure atropine+ 2-PAM ClPyridostigminepretreatment +postexposureatropine +2-PAM ClMean ProtectiveRatio [95% CL]15.3 [13.7–17.1] NA25.1 [22.0–28.8] 1.64 [1.38–19.5]> 617 > 40**Indeterminate because of small number of subjects; PR relative tothe atropine plus 2-PAM Cl group > 24 (617 ÷ 25.1)2-PAM Cl: 2-pyridine aldoxime methyl chlorideCL: confidence limit (based on a separate slopes model)LD 50: median lethal doseNA: not applicablePR: factor by which the LD 50of a nerve agent challenge is raised(in this experiment, the LD 50for group given therapy divided bythe LD 50for control group)Adapted from: Kluwe WM. Efficacy of pyridostigmine againstsoman intoxication in a primate model. In: Proceedings of the SixthMedical Chemical Defense Bioscience Review. Aberdeen ProvingGround, Md: US Army Medical Research Institute of ChemicalDefense; 1987: 233.and postexposure therapy of atropine and 2-PAM Clsurvived for 48 hours after being challenged with GFat a level 5-fold higher than its LD 50. 247Pyridostigmine pretreatment shows its strongestbenefit, compared with atropine and oxime therapyalone, in animals challenged with soman and tabun,and provides little additional benefit against challengeby sarin or VX. 248–250 Table 5-10 shows the PRs obtainedin animals given atropine and oxime therapy afterchallenge with the five nerve agents with and withoutpyridostigmine pretreatment. As shown, pyridostigminepretreatment is essential for improved survivalafter soman and tabun challenge. With sarin or VX,depending on the animal system studied, pyridostigminecauses either no change or a minor decrease inPRs, which still indicate strong efficacy of atropineand oxime therapy for exposure to these agents. Thedata for GF show no benefit from pyridostigminepretreatment for mice and a small benefit for guineapigs. The only published data on protection of primatesfrom GF show a PR of more than 5 with pyridostigminepretreatment and atropine/oxime therapy, buta control group treated with atropine/oxime alone199