Cholinesterase reactivators

Therapeutic Function Cholinesterase reactivator (antidote for nerve gas) Chemical Name 2-[(Hydroxyimino)methyl] -1-methylpyridinium chloride Common Name 2-PAM chloride Structural Formula ... 

Use antidote (against anticholinesterase-alkylphosphate), cholinesterase reactivator... 

Hunt, K.A., M.J. Hooper, and E.E. Littrell. 1995. Carbofuran poisoning in herons diagnosis using cholinesterase reactivation techniques. Jour. Wildl. Dis. 31 186-192. 

The specific therapy consists in concurrent use of two antidotes differing by mechanism of action cholinolytics eliminating anticholinesterase effects on CNS, and cholinesterase reactivators (ChR) ensuring the restoration of inhibited enzymatic activity. 

Aging is of clinical interest in the treatment of poisoning because cholinesterase reactivators such as pralidoxime (2-PAM, Protopam) chloride are ineffective after aging has occurred. Measurement of metabolites of methyl parathion, p ra-nitrophenol, and dimethylphosphate in the urine has been used to monitor exposure to workers. ... 

Treatment of intoxication of organophosphorons componnds inclndes artificial respiration, administration of atropine—an antagonist of mnscarinic receptors, and administration of pralidoxime, which is a cholinesterase reactivator. 

Atropine does not counter muscle weakness and respiratory failure. To overcome this, pralidoxime (P2AM), a cholinesterase reactivator, is used in many countries, in an initial dose of 30 mg/kg intravenously followed by 8 mg/kg/h until clinical recovery. Oximes have to be given before the irreversible aging of the enzyme-organophosphorus... 

Panel on Cholinesterase Reactivator Chemicals Panel on Psychochemicals Panel on Irritants and Vesicants... 

Jean E. Dent, Secretary, Panel on Cholinesterase Reactivator Chemicals, Panel on Psychochemicals, and Panel on Irritants and Vesicants Norman Grossblatt, Editor... 

After completion of Volume 1, three new panels were established to Identify and assess evidence on the possible long-term health effects or delayed sequelae of the three chemical classes tested. This was done over a period of a year, during which each panel met three times. Pertinent material was examined to evaluate the possibility that experimental exposure of soldiers may have resulted in untoward health effects. The three panels were separately concerned with four cholinesterase reactivator chemicals (oximes) two types of psychochemicals (phencyclidine and dlmethylheptylpyran and congeners), administered In pure form, as opposed to street drugs and mustard gas and several lacrlmatory and respiratory irritants (such as CN, CS, CR, and CA). 

On the basis of an examination of toxicologic literature, case reports from Edgewood volunteers, and a review of mortality data conducted by the National Research Council Medical Follow-up Agency, the Committee found no evidence of chronic disease in animals or humans associated with single or repeated doses of the cholinesterase reactivators (oximes). 

The adverse effects of cholinesterase reactivating chemicals on the human cardiovascular system are shown in Tables 2-2 through 2-7. These effects may be classified as hypertension characterized by moderate Increased systolic and diastolic pressure with hypertension followed by hypotension, and ECG changes.20,61,97,102,107 The... 

Appendix B reviews some important animal studies of cholinesterase reactivator chemicals. The extensive literature reviewed offers little definitive information with which to project possible long-term effects or delayed sequelae in human subjects tested at Edgewood. These compounds have a short biologic half-life of 1 to 3 h. However, no chronic studies were found. Consequently, the carcinogenic potential of cholinesterase reactivators remains... 

The medical records of the volunteers who received cholinesterase-reactivating chemicals consisted of the test protocol, physicians orders, nursing notes (Including clinical observations), a checklist of symptoms, and laboratory and performance test results. The reports of physicians examinations and physical findings were generally not Included. Volunteers were identified by number. The Committee on Toxicology s assessment was based on records and summaries provided by the Department of the Army and NRC staff. The procedures were described fully in Volume 1. In most cases, the analysis was based on summaries of drug administrations prepared by a consultant to the Panel. 

In summary, with the possible exception of those two cases, the records contained no evidence of delayed or persistent effects after administration of the cholinesterase reactivators. Such data cannot, however, address the issue of long-term effects or delayed sequelae. 

Possible Ixtng-Tcrm Health Effects of Short-Term Exposure To Chemical Agents, Volume 2 Cholinesterase Reactivators, Psychochcmicals and Irritants and Vcsi..,... 

Because atropine has never been found to have reactivating activity in vitro, the reactivation that occurred in the rats treated with atropine sulfate is assumed to be spontaneous. It is apparent from Table 3 that addition of 2-PAM I to atropine increased cholinesterase reactivation by 40.5% in the parotid gland, by 127.8% in the gastrocnemius muscle, and by 8.2% in the brain. The especially large change in cholinesterase activity in skeletal muscle suggests that this may be the principal site at which 2-PAM I antagonizes inhibition of cholinesterase. 

Albanus, L., Jarplid, B., Sundwall, A. 1964 The toxicity of some cholinesterase reactivating oximes. Brit. J. Exp. Path. 45 120-127. 

De La Manche, I.S., Verge, D.E., Bouchaud, C., Coq, H., Sentenac-Roumanou, H. 1979. Penetration of oximes across the blood-brain barrier. A histochemical study of the cerebral cholinesterases reactivation. Experlentia 35 531-532. 

Landauer, W. 1977. Cholinomimetic teratogens. V. The effect of oximes and related cholinesterase reactivators. Teratology 15 33-42. 

The present report evaluates toxicologic and epidemiologic data relevant to the testing of approximately 750 subjects exposed to cholinesterase reactivators, about 260 exposed to psychochemicals, and 1,500 exposed to irritants or vesicants. A remaining group of subjects used largely In tests involving placebo or Innocuous chemicals or conditions is available for comparison and will be discussed In Volume 3. 

This report is the work of three panels of scientists—the Panel on Cholinesterase Reactivator Chemicals, the Panel on Psychochemicals, and the Panel on Irritants and Vesicants. The chairman of each panel was selected from the Committee on Toxicology, and the members were selected on the basis of their knowledge of the compounds in question or because they represented required disciplines. 

Rapid advances in chemistry during the nineteenth and twentieth centuries, coupled with the success of mustard gas as a toxic weapon in World War I, attracted attention to the warfare potential of chemical agents. This led to support for research on lethal nerve agents during and immediately after World War II. The research was followed by the development of treatment methods, and prominent among these was the use of cholinesterase reactivators to reverse the lethal effects of anticholinesterase nerve gases. 

Structural formulas of cholinesterase reactivators tested at Edgewood... 

All four cholinesterase reactivator compounds are pralidoxlmes. The first two are monoquatemary oximes the last two are bisquatemary oximes. 

Two features of the cholinesterase reactivating agents are critical for their pharmacokinetics ... 

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