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  • Carbamate and OP insecticides are still among the

    2019-11-08

    Carbamate and OP insecticides are still among the most widely used pesticides in the world [151]. In 2012, the OP insecticides chlorpyrifos and acephate were ranked 14th and 22nd overall in estimated amounts of agricultural pesticides used in the US. The carbamate insecticide carbaryl and the OP insecticides acephate and malathion were until recently among the most common pesticides for home use. Acephate was also widely used in the industrial sector. Over the last two decades, a number of OP insecticides have been withdrawn from the market, banned, or use-restricted in the US, but others remain a large part of total pesticide use. In 2012, OP insecticides made up roughly 38% of all insecticides used in the US [151]. As of now, multiple regulatory actions in the US have curtailed the use of such pesticides, but certain populations may still be exposed to cholinesterase-inhibiting levels [152]. A seemingly paradoxical pharmacological use of more readily reversible cholinesterase inhibitors is to block the long-term inactivation of AChE by “irreversible” inhibitors, the OP nerve agents [153]. In essence, individuals at risk of exposure to an OP nerve agent can be protected by pre-exposure to pyridostigmine or another carbamate anti-ChE, transiently blocking OP access to the active site of the enzyme. If the agent with short-lived inhibition is given before exposure to the irreversible inhibitor, the latter cannot bind to the enzyme, which will then spontaneously reactivate. In fact this scenario has shown protection against nerve agent intoxication in several animal models [153], [154], [155], [156], [157], [158]. The logic behind this prophylactic approach is based on the concept that cholinergic synapses have “spare” enzyme, so a certain level of AChE inhibition can be tolerated without disrupting the dynamics of cholinergic signaling. This clever prophylactic strategy was implemented in the first Persian Gulf War. Soldiers were given varying doses of pyridostigmine with concern for possible exposure to chemical weapons. For some time, a cloud of suspicion has hovered over this application however because of the potential role of pyridostigmine in the unexplained “Gulf War Illnesses” following the first Persian Gulf War [159]. Those disorders may well have had other contributing causes however, e.g., post-traumatic stress. Even if pyridostigmine had no role in these illnesses, delivering a dose of drug to shield enough enzyme Illumina for 50 ng DNA without excessive inhibition, in a diverse group of people with high variability and exposure to environmental stressors, was a risky approach. But one thing is certain: if one is to use cholinesterase inhibitors for therapy or prophylaxis, there will always be a delicate balance between beneficial and toxic inhibition of AChE. Too little drug will be ineffective, too much will be dangerous.
    First, administering large amounts of purified human BChE has been shown to protect experimental animals against lethal exposures to various OP nerve agents. BChE can sequester or scavenge OP molecules in a stoichiometric manner, inactivating the toxicant molecules before they can inhibit AChE in brain and peripheral tissues to disrupt cholinergic signaling [160]. In fact, both BChE and AChE have been evaluated as bioscavengers for OP nerve agents. In sufficient quantities, administration of these stoichiometric binding proteins can minimize AChE inhibition in target tissues and protect against lethality from OP toxicants in multiple experimental models, including primates. There are obstacles in the prophylactic use of ChEs as OP bioscavengers including a need for large amounts of purified human protein, due in part to their rapid clearance from the circulation. For example, intramuscular (im) administration of human BChE in mice (13 mg/kg, about 0.3 mg) leads to peak blood BChE activities at about 10–12 h, but only ∼ 25% of peak remains at 70 h [161]. Both im and intraperitoneal (ip) administration of 0.1–3 mg of human BChE in mice caused marked elevation of circulating BChE enzyme activity, peaking 12–24 h later, but returning to near baseline by 120 h [162]. Doctor and Saxena [163] and Saxena and coworkers [164] reported on the pharmacokinetics of human BChE in mice and guinea pigs given im and ip administration as well as long-term stability of the lyophilized enzyme (at least 2 years), and complete, sign-free survival in guinea pigs subsequently given an LD50 dosage of the nerve agents VX and soman. Higher im dosages of human BChE (up to 60 mg/kg), led to peak levels of enzyme around 24 h that remained substantial for at least four days [165]. The same investigators reported no overt physiological or behavioral signs after high-dose BChE administration, and no changes in serum chemistry or tissue histopathology. Intravenous administration of 30 mg/kg human BChE in rhesus monkeys led to marked elevation of blood BChE activity that returned to within about 25% of peak levels by 100 h [166]. These and other recent studies illustrate the potential for exogenously administered human BChE to elevate circulating enzyme activity and protect against toxicity from potent OP nerve agents, with little evidence of adverse reaction to high doses of the enzyme.