Multiple centrally acting antidotes protect against severe organophosphate toxicity.
BACKGROUND
Accumulation of acetylcholine in the central nervous system is believed to account for the rapid lethality of organophosphate pesticides and chemical nerve agents. Diazepam is known to supplement atropine therapy, but its specific mechanism of action is uncertain.


OBJECTIVE
To test four centrally acting agents for early antidotal efficacy in severe dichlorvos poisoning in the murine model.


METHODS
The up-and-down method was used to dose four candidate antidotes: diazepam, xylazine, morphine, and ketamine. Antidotes were administered subcutaneously to unsedated adult Sprague-Dawley rats who were pretreated with 3 mg/kg intraperitoneal glycopyrrolate. All animals received 20 mg/kg of dichlorvos subcutaneously 5 minutes later. A blinded observer adjudicated the outcomes of 10-minute mortality and survival time.


RESULTS
All animals pretreated with either no antidote (8/8 deaths) or glycopyrrolate alone (8/8) died within 10 minutes of dichlorvos injection. Pretreatment with diazepam (3/9 deaths), or xylazine (3/9), decreased lethality substantially (Fisher p = 0.007; median effective doses, 0.12 mg/kg and 3.0 mg/kg, respectively). Intermediate doses of morphine (3.1 to 5.5 mg/kg) resulted in survival, but higher doses did not, presumably because of excessive respiratory depression (7/11 deaths; p = 0.09). Ketamine (7/8 deaths) was ineffective as an antidote. Survival times also were prolonged in the diazepam and xylazine groups (log-rank p < 0.001) and, to a lesser degree, the morphine group (p = 0.07).


CONCLUSIONS
Doses of diazepam, xylazine, and morphine below those used for deep sedation protect against severe dichlorvos poisoning, implying that several distinct central mechanisms are each sufficient to avert lethality. These findings suggest new possibilities for prophylaxis or therapy.
Department of Emergency Medicine, Queen's University, Kingston, Ontario, Canada. sivilotm@meds.queensu.ca
Marco L A
ML
Sivilotti
Steven B
SB
Bird
Jean C Y
JC
Lo
Eric W
EW
Dickson
D000818:Animals; D000931:Antidotes / Q000627:therapeutic use*; D003975:Diazepam / Q000627:therapeutic use*; D004006:Dichlorvos / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006024:Glycopyrrolate / Q000627:therapeutic use; D007306:Insecticides / Q000633:toxicity*; D007649:Ketamine / Q000627:therapeutic use*; D009020:Morphine / Q000627:therapeutic use*; D011041:Poisoning / Q000188:drug therapy; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014991:Xylazine / Q000627:therapeutic use*
D000931:Antidotes; D007306:Insecticides; D014991:Xylazine; D007649:Ketamine; D009020:Morphine; D004006:Dichlorvos; D003975:Diazepam; D006024:Glycopyrrolate