Resuscitative treatments on 1,4-butanediol mortality in mice.
OBJECTIVE
Recent reports on fatalities associated with overdoses from 1,4-butanediol (1,4-BD), a precursor of the drug of abuse gamma-hydroxybutyric acid (GHB), pose the need for investigations focusing on possible pharmacologic remedies. Accordingly, the present study investigates whether 4-methylpyrazole (4-MP; also termed fomepizole and Antizol), an inhibitor of alcohol dehydrogenase (the enzyme involved in the first step of the conversion of 1,4-BD into GHB), and the gamma-aminobutyric acid B (GABAB) receptor antagonist (2S)(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911), provides protection against 1,4-BD-induced mortality in CD1 mice.


METHODS
Two sets of experiments were conducted with mortality as the outcome measure. In all experiments, mice were initially treated with a lethal dose of 1,4-BD (3 g/kg, intragastric [i.g.]). In the first set of experiments (dose-response curves), once mice had displayed clear signs of 1,4-BD intoxication, animals were randomly allocated in separate groups (n=10) and treated acutely with either 4-MP (vehicle, 3, 10, 30, and 100 mg/kg, intraperitoneal [i.p.]) or SCH 50911 (vehicle, 75, 150, and 300 mg/kg, i.p.). Mortality was recorded every hour for the first 9 hours and 12, 18, and 24 hours after 1,4-BD injection. In the second set of experiments (time course), mice were randomly allocated in separate groups (n=10). A single dose of either 4-MP (30 mg/kg, i.p.) or SCH 50911 (150 mg/kg, i.p.) was administered 15, 30, 60, 90, or 120 minutes after administration of 3 g/kg 1,4-BD (i.g.). Again, mortality was recorded every hour for the first 9 hours and 12, 18, and 24 hours after 1,4-BD injection.


RESULTS
In the dose-response experiments, the acute administration of 4-MP and SCH 50911 exerted a dose-dependent resuscitative effect in mice acutely intoxicated by 3 g/kg 1,4-BD. Specifically, 30 and 100 mg/kg 4-MP and 150 mg/kg SCH 50911 protected all treated mice against 1,4-BD-induced mortality. Conversely, all mice treated with 4-MP- and SCH 50911-vehicle died. In the time-course experiments, protection induced by 30 mg/kg 4-MP was complete when administered up to 90 minutes after 1,4-BD injection. Vice versa, the complete protection induced by 150 mg/kg SCH 50911 progressively diminished as the time between 1,4-BD and SCH 50911 administration was increased from 15 to 120 minutes.


CONCLUSIONS
These results indicate that both 4-MP and SCH 50911 protected against mortality induced by 1,4-BD. Further, these results suggest that 1,4-BD-induced mortality in mice is a result of conversion of 1,4-BD into GHB and GHB-induced activation of the GABAB receptor. Because both 4-MP and GABAB receptor antagonists are available for human use, clinical studies on their ability to reverse the consequences of 1,4-BD and GHB intoxication, including fatal events, might be considered.
Carai
Mauro A M
MA
Department of Neuroscience, School of Medicine, University of Cagliari, National Research Council, Institute of Neuroscience, Cagliari, Italy. macarai@unica.it
Colombo
Giancarlo
G
Quang
Lawrence S
LS
Maher
Timothy J
TJ
Gessa
Gian Luigi
GL
D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D002072:Butylene Glycols / Q000506:poisoning*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D062787:Drug Overdose / Q000188:drug therapy; D058788:GABA-B Receptor Antagonists; D013287:Illicit Drugs / Q000506:poisoning*; D008297:Male; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011897:Random Allocation; D012151:Resuscitation / Q000379:methods*; D016019:Survival Analysis; D016896:Treatment Outcome
C095804:(+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid; D002072:Butylene Glycols; D058788:GABA-B Receptor Antagonists; D013287:Illicit Drugs; D009025:Morpholines; D010879:Piperazines; C077079:4-methylpiperazine-2,6-dione; C039681:1,4-butanediol; D000426:Alcohol Dehydrogenase