title: Comparing the response surfaces of two cholinolytics when used in combination with physostigmine as a pretreatment against organophosphate challenge.
abstract: Physostigmine (PHY) is currently being evaluated as a potential pretreatment against nerve agent challenge. Although it might provide increased protection against nerve agent-induced incapacitation, it is nonetheless behaviorally toxic itself. Addition of a cholinolytic adjunct is expected to significantly reduce this behavioral toxicity. The efficacy of pretreatment regimens (PRG) (composed of PHY in combination with either scopolamine (SCP) or trihexyphenidyl (artane; ART] was evaluated in guinea pigs challenged with soman (98 ug/kg, sc; 3.5 LD50) to determine the dose of PHY and adjunct required for optimal efficacy as well as the better of the two adjuncts. Three different endpoints were measured on each animal: (1) whether or not the animal survived up to 24 hours post challenge, (2) severity of incapacitation, and (3) time to recovery. The survival data revealed no significant differences between the two adjuncts and PHY against soman, but the data suggests that a pretreatment combination of PHY and ART is likely to give a greater therapeutic index than one containing SCP. Furthermore, since ART is less toxic behaviorally, it would most likely be better tolerated as a pretreatment with PHY in non-agent exposed subjects. The findings in this report are not to be construed as an official Department of the Army position unless so designated by other authorized documents. In conducting the work described in this report, the investigators adhered to the "Guide for the Care and Use of Laboratory Animals" as promulgated by the Committee on Revision of the Guide for Laboratory Animal Facilities and Care of the Institute of Laboratory Animal Resources, National Research Council.
authors.affiliation: US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5425.
authors.forename: R P
authors.initials: RP
authors.lastname: Solana
authors.forename: C
authors.initials: C
authors.lastname: Gennings
authors.forename: D
authors.initials: D
authors.lastname: Anderson
authors.forename: W H
authors.initials: WH
authors.lastname: Carter
authors.forename: R A
authors.initials: RA
authors.lastname: Carchman
authors.forename: L W
authors.initials: LW
authors.lastname: Harris
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004359:Drug Therapy, Combination; D005260:Female; D006168:Guinea Pigs; D008297:Male; D008722:Methods; D051379:Mice; D008954:Models, Biological; D010830:Physostigmine / Q000627:therapeutic use*; D012044:Regression Analysis; D012601:Scopolamine / Q000627:therapeutic use*; D012999:Soman / Q000506:poisoning*; D014282:Trihexyphenidyl / Q000627:therapeutic use*
chemical_list: D014282:Trihexyphenidyl; D012999:Soman; D010830:Physostigmine; D012601:Scopolamine