Resuscitative treatments on 1,4-butanediol mortality in mice

Study objective: Recent reports on fatalities associated with overdoses from 1,4-butanediol (1,4-BD), a precursor of the drug of abuse, ?-hydroxybutyric acid (GHB), pose the need for investigations focusing on possible pharmacological remedies. Accordingly, the present study investigated whether 4-methyl-pyrazole (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 GABAB receptor antagonist, SCH 50911, provided 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, 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, 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 subsequently 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 min after administration of 3 g/kg 1,4-BD (i.g.). Again, mortality was recorded every hour for the first 9 hours and subsequently 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 min 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 min. Conclusion: 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 secondary to (a) conversion of 1,4-BD into GHB and (b) GHB-induced activation of the GABAB receptor. Since both 4-MP and GABAB receptor antagonists are currently 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 to be performed.