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

Nerve Agentsfor comparison was not included. 247 Clinical expertsfrom all countries have concluded from these data thatpyridostigmine isan essential pretreatment adjunct fornerve agent threats under combat conditions, wherethe identity of threat agents is uncertain.The effectiveness of pyridostigmine pretreatmentmay not provide conclusive evidence of the importanceof central mechanisms in respiratory arrest;it appears that there is at least partial permeabilityof the blood-brain barrier to polar compounds suchas pyridostigmine, specifically in the regions of thefourth ventricle and brainstem, where respiratorycenters are located. In addition, an increase in bloodbrainbarrier permeability occurs rapidly after somanadministration. 251,252 The key observation remains thatanimals pretreated with pyridostigmine and promptlyreceive atropine and oxime therapy after an otherwiselethal soman exposure are able to maintain adequaterespiration and survive.SafetyPyridostigmine maintains a good safety recordfollowing its administration to myasthenia gravis patients.Known adverse reactions have been limited toinfrequent drug rashes after oral administration and theconstellation of signs of peripheral cholinergic excess,which have been seen only when the dosage in patientswith myasthenia gravis was increased to AChE inhibitionlevels well beyond the 20% to 40% range desiredfor nerve agent pretreatment. The recommended dosefor nerve agent pretreatment, based upon non-humanprimate studies and human pharmacokinetic studies,is only half of the starting myasthenic dose of 60 mgorally every 8 hours, 30 mg orally every 8 hours. Whenthis recommended adult dose regimen has been followed,no significant decrements have been found inthe performance of a variety of military tasks. A reviewof British studies reported that pyridostigmine causedno changes in memory, manual dexterity, vigilance,day and night driving ability, or in psychological testsfor cognitive and psychomotor skills. 253 No significantchanges in sensory, motor, or cognitive functioning atground level, at 800 ft, and at 13,000 ft were noted in12 subjects in another study after their fourth 30-mgdose of pyridostigmine. 254The flight performance of subjects taking pyridostigminein two studies was not affected, 255,256 and noimpairment in neuromuscular function was noted inanother study in which subjects took pyridostigminefor 8 days. 257 Cardiovascular and pulmonary functionwere normal at high altitudes in pyridostigmine-treated subjects in another study. 258 However, onestudy noted a slight decrement in performance insubjects taking pyridostigmine when they performedtwo tasks simultaneously; these subjects also had aslight decrement on a visual probability monitoringtask. 259 Two studies found an increase in sweating anda decrease in skin blood flow in pyridostigmine-treatedsubjects subjected to heat/work stress. 260,261Although there has been wide experience withlong-term administration of pyridostigmine to patientswith myasthenia gravis, until recently, there was nocomparable body of safety data in healthy youngadults. Short-term pyridostigmine administration(on or two doses of 30 mg each) has been conductedin peacetime in some countries, including the UnitedStates, to screen critical personnel, such as aircrew, forunusual or idiosyncratic reactions, such as drug rash.The occurrence of such reactions has been well belowthe 0.1% level. Currently no military populations areroutinely screened with administration of a test doseof pyridostigmine.A limited number of animal studies of toxicologicalabnormalities and teratogenicity and mutagenicityin animals that were given pyridostigmine havehad negative results (Hoffman-LaRoche, proprietaryinformation). 262 In a study 263 in which pyridostigminewas administered to rats, either acutely or chronically,in doses sufficient to cause an average 60% AChE inhibition,ultrastructural alteration of a portion of thepresynaptic mitochondria at the neuromuscular junctionresulted, as well as alterations of nerve terminalbranches, postsynaptic mitochondria, and sarcomeres.These morphological findings, which occurred at twicethe AChE inhibition level desired in humans, havenot been correlated with any evidence of functionalimpairment at lower doses, but they emphasize theneed to limit enzyme inhibition to the target range of20% to 40%. Pyridostigmine has been used by pregnantwomen with myasthenia gravis at higher dosesand for much longer periods than it was used duringthe Persian Gulf War and has not been linked to fetalmalformations. 264 Because safety in pregnancy hasnot been completely established, the FDA considerspyridostigmine a Class C drug (ie, the risk cannot beruled out).Several studies have sought information on pyridostigmineuse under certain conditions: soldiersin combat who frequently take other medications;wounding and blood loss; and use while undergoinganesthesia. The possible interaction of pyridostigminewith other commonly used battlefield medications wasreviewed by Keeler. 265 There appears to be no pharmacologicalbasis for expecting adverse interactionsbetween pyridostigmine and commonly used antibiotics,anesthetics, and analgesic agents. In a study 266of pyridostigmine-treated swine, for example, theautonomic circulatory responses to hemorrhagic shockand resuscitation appeared normal. One potentially201