Physostigmine does not effect arousal but produces toxicity in an animal model of severe gamma-hydroxybutyrate intoxication.
OBJECTIVE
Physostigmine is an acetylcholinesterase inhibitor and can produce fasciculations, seizures, bradycardia, and asystole. gamma-hydroxybutyrate (GHB) increases acetylcholine levels in the central nervous system and can decrease heart rate. Despite this, physostigmine has been proposed as an arousal agent to treat coma from overdoses of GHB. The authors hypothesized that in the setting of severe GHB intoxication, physostigmine would reverse sedation without producing adverse effects such as a decrease in heart rate, seizures, and fasciculations.


METHODS
GHB intoxication was induced in 20 rats by intraperitoneal injection of 700 mg/kg of the GHB precursor gamma-butyrolactone. One hour later, rats were randomly assigned to receive either physostigmine (0.06 mg/kg) intraperitoneally or an equivalent volume of saline. After administration of physostigmine, rats were continuously monitored by a blinded observer for arousal (return of righting reflex), fasciculations, and seizures. Heart rate and respiratory rate were recorded at 0, 5, 15, and 60 minutes after administration of physostigmine. Data were analyzed using repeated-measures analysis of variance and chi-square test. A pretest sample size calculation determined that 10 rats per group would detect a change in arousal from 0% to 50% and a 10% change in heart rate.


RESULTS
No rats in either group had arousal within one hour (p = 1.0); however, ten of ten physostigmine-treated rats developed signs of physostigmine toxicity (fasciculations, 7; seizures, 3), while no controls developed signs of physostigmine toxicity (p = 0.00). The authors were unable to detect a decrease in heart rate.


CONCLUSIONS
Physostigmine did not produce a 50% change in arousal as measured by a return of righting reflex but did produce physostigmine toxicity (fasciculations and seizures) in this rat model of severe GHB intoxication.
Bania
Theodore C
TC
St. Luke's-Roosevelt Hospital Center, 1000 10th Avenue, Room GE01, New York, NY 10019, USA. toxtod@aol.com
Chu
Jason
J
D000818:Animals; D001143:Arousal / Q000187:drug effects*; D002800:Cholinesterase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D003128:Coma / Q000139:chemically induced / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D062787:Drug Overdose; D005207:Fasciculation / Q000139:chemically induced; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D010830:Physostigmine / Q000009:adverse effects / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects; D015656:Respiratory Mechanics / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced; D012978:Sodium Oxybate / Q000506:poisoning*
D002800:Cholinesterase Inhibitors; D012978:Sodium Oxybate; D010830:Physostigmine