The effect of pyridostigmine pretreatment on oxime efficacy against intoxication by soman or VX in rats.
This study was done to assess the effects of pyridostigmine (PYR) on a) the accumulation of labelled VX and soman within the brain, b) the therapeutic efficacy of atropine and oxime (2-PAM or HI-6) against intoxication by VX and soman and c) oxime-induced reactivation of inhibited acetylcholinesterase (AChE). In all experiments, rats were given PYR (131 micrograms/kg, im; I70 dose for whole blood AChE) or vehicle 30 min prior to nerve agent. In estimating 3H-agent the accumulation in the brain or estimating blood AChE activity, sufficient soman (47 micrograms/kg, iv) or VX (21.3 micrograms/kg, iv) was given to inhibit 50% of brain AChE activity. In assessing therapeutic efficacy and oxime-induced reactivation of blood AChE, rats were pretreated with PYR, challenged with agent and treated with atropine (16 mg/kg, im) and HI-6 or 2-PAM (100 umoles/kg, im) 30 sec post agent. Whole blood was collected by tail bleeding to monitor peripheral AChE activity at various time points before and after PYR and challenge. Pyridostigmine failed to alter covalent binding of labelled VX or soman in the brain. The 24-hr survival data showed that PYR reduced the therapeutic benefit of atropine and oxime against VX intoxication (but not soman). Protective ratios in VX-challenged rats given vehicle or PYR and treated with atropine + 2-PAM decreased slightly from 2.5 to 2.1 (p > .05), whereas with atropine + HI-6 they decreased significantly from 3.8 to 2.4. Also, AChE reactivation by HI-6 in VX-challenged rats was greater (p < .05) in vehicle- than in PYR-pretreated rats. HI-6 significantly reactivated AChE activity in both pretreatment groups (PYR or vehicle) given soman. The data suggest that PYR decreases the overall recovery of inhibited AChE in VX-challenged rats given HI-6; under the conditions used, this adverse effect decreases atropine+oxime efficacy against VX-induced lethality.
Anderson
D R
DR
U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5425.
Harris
L W
LW
Woodard
C L
CL
Lennox
W J
WJ
D000818:Animals; D000931:Antidotes / Q000627:therapeutic use*; D002800:Cholinesterase Inhibitors / Q000506:poisoning*; D008297:Male; D009946:Organothiophosphorus Compounds / Q000493:pharmacokinetics / Q000506:poisoning*; D010091:Oximes; D011041:Poisoning / Q000188:drug therapy; D011220:Pralidoxime Compounds / Q000627:therapeutic use*; D011726:Pyridinium Compounds / Q000627:therapeutic use*; D011729:Pyridostigmine Bromide / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012999:Soman / Q000493:pharmacokinetics / Q000506:poisoning*
D000931:Antidotes; D002800:Cholinesterase Inhibitors; D009946:Organothiophosphorus Compounds; D010091:Oximes; D011220:Pralidoxime Compounds; D011726:Pyridinium Compounds; D011729:Pyridostigmine Bromide; D012999:Soman; C009680:VX-agent; C022870:asoxime chloride; C028797:pralidoxime