Anticholinesterase compounds

Costa LG, Schwab BW, Murphy SD. 1982. Tolerance to anticholinesterase compounds in mammals. Toxicology 25 79-97. 

A growing number of other diverse compounds have also been shown to bind to an allosteric site on the muscarinic receptors. Among them are pirenzepine (highly selective for Mi receptor), lidocaine and verapamil (ion channel blockers), tacrine (anticholinesterase compound), batrachotoxin, and strychnine (glycine receptor antagonist) [25,31-35],... 

Altstein, M., Segev, G., Aharonson, N., Ben-Aziz, O., Turniansky, A. and Avnir, D. (1998) Sol-gel-entrapped cholinesterases A microtiter plate method for monitoring anticholinesterase compounds. Journal of Agricultural and Food Chemistry, 46, 3318-3324. 

MODERN APPROACHES TO MEDICAL TREATMENT OF POISONING CAUSED BY NEUROPARALITIC ANTICHOLINESTERASE COMPOUNDS... 

Keywords anticholinesterase compounds ChE reactivators delayed polineuropathy ... 

A principle of the therapy for acute poisonings with anticholinesterase compounds (OPC, carbamates) lies in the complex performance of specific antidotic therapy including methods for poison excretion and intensive resuscitation measures. 

The number of subjects tested with each compound, the number of records examined, routes of administration, and doses are shown in Tables 2-8 through 2-11. In some instances, the compounds were given before or after anticholinesterase compounds or in conjunction with other drugs thus, some of the results shown here were also presented in Volume 1. 

Hopff and Waser have listed mechanisms whereby reactivators of Inhibited cholinesterase could be harmful to persons to whom they are administered In treatment of intoxication by anticholinesterase compounds. The following is a slightly modified version of their list ... 

McNamara, B.P. 1976. Oximes as antidotes In poisoning by anticholinesterase compounds. EB-SP-76004. 

The major action resulting from human exposure to diazinon is the inhibition of cholinesterase activity (refer to Section 2.4 for discussion). Two pools of cholinesterases are present in human blood acetylcholinesterase in erythrocytes and serum cholinesterase (sometimes referred to as pseudocholinesterase or butyrlcholinesterase) in plasma. Acetylcholinesterase, present in human erythrocytes, is identical to the enzyme present in neural tissue (the target of diazinon action) while serum cholinesterase has no known physiological function. Inhibition of both forms of cholinesterase have been associated with exposure to diazinon in humans and animals (Coye et al. 1987 Edson and Noakes 1960 Soliman et al. 1982). Inhibition of erythrocyte, serum, or whole blood cholinesterase may be used as a marker of exposure to diazinon. However, cholinesterase inhibition is a common action of anticholinesterase compounds such as organophosphates (which include diazinon) and carbamates. In addition, a wide variation in normal cholinesterase values exists in the general population, and there are no studies which report a quantitative... 

Development of Highly Sensitive Monitors for the Detection of Anticholinesterase Compounds... 

Elhn, R.I. 1981. Anomalies in Theories and Therapy of Intoxication by Potent Organophosphorus Anticholinesterase Compounds. Special Publication USA-BML-SP-81-003. DTIC AD-A101364. U.S. Army Medical Research and Development Command, Biomedical Laboratory, Aberdeen Proving Ground, Edgewood, Md. 

Grob, D., and J.C. Harvey. 1958. Effects in man of the anticholinesterase compound Sarin (isopropyl methyl phosphonofluoridate). J. CUn. Invest. 37 350-368. 

The use of a rat study for developing an RfD for GA is complicated by the fact that rodents have a much lower RBC-AChE activity level compared to humans (Ellin, 1981). By itself, this could cause rats to be relatively more sensitive than humans to anticholinesterase compounds however, the lower RBC-AChE activity may be offset by the presence of ahesterases in the blood of rats. Aliesterases, which are not found in human blood plasma, are known to bind to and, therefore, reduce the toxicity of GB, and a similar mechanism may operate in the case of GA. Other species differences, such as in the rates of aging of the GA-ChE complex, in the rates of synthesis of plasma-ChE in the liver, and in the levels of AChE in the nervous system (see Ivanov et al., 1993) may also result in difference between species in sensitivity to GA. Data are insufficient to more fuUy evaluate these possibihties. There is httle human acute toxicity data that can be compared with the available rat data however, acute toxicity data for primates in general (see Table 2) suggests that humans are likely to be more sensitive than rats. Therefore, for the purpose of this assessment, the standard EPA method will be followed which assumes that humans can be as much as ten times more sensitive to a chemical than laboratory animals. 

An uncertainty factor of 10 for sensitive subpopulations is considered necessary because some individuals have a genetic defect causing their blood cholinesterase activity to be abnormally low (Evans et al., 1952 Harris and Whittaker, 1962). For homozygous individuals, the activity can be as low as 8-821% of the normal mean (Bonderman and Bonderman, 1971). These individuals may be unusually sensitive to organophosphate anticholinesterase compounds (Morgan, 1989). 

Holmstedt, B. 1951. Synthesis and pharmacology of dimethylamidoethoxyphosphoryl cyanide (Tabun) together widi a description of some allied anticholinesterase compounds containing the NP bond. Acta Physiol. Scand. 25 (Suppl. 90) 1-120. 

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