We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
4-Methylpyrazole Decreases 1,4-Butanediol Toxicity by Blocking Its in Vivo Biotransformation to γ-Hydroxybutyric Acid.
- Authors
QUANG, LAWRENCE S.; DESAI, MALHAR C.; SHANNON, MICHAEL W.; WOOLF, ALAN D.; MAHER, TIMOTHY J.
- Abstract
1,4-Butanediol (1,4-BD), a prodrug converted in vivo to γ- hydroxybutyric acid by alcohol dehydrogenase, has resulted in life-threatening overdoses and deaths. We investigated whether 4-methylpyrazole (4-MP), an alcohol dehydrogenase antagonist, can be used as an antidote in a murine model of 1,4-BD overdose. CD-1 mice were overdosed with 1,4-BD, 600 mg/kg i.p. Mice then received 4-MP, 25 mg/kg i.p., or control injections after 1 min, 5 min, and symptom appearance. Mice were then evaluated for toxicity by the righting reflex and rotarod test every 10 min after intervention. When 4-MP was administered 1 and 5 min after 1,4-BD overdose, mice completely maintained their righting reflex. Conversely, control mice lost their righting reflex for 110 and 130 min, respectively (P < 0.05). When 4-MP was administered after symptomatic 1,4-BD overdose, mice lost their righting reflex but recovered it by 60 min. Conversely, control mice lost their righting reflex and recovered it by 140 min (P < 0.05). When 4-MP was administered at 1 min after 1,4-BD overdose, mice never failed the rotarod test. Conversely, control mice failed the rotarod test for 210 min (P < 0.05). When 4-MP was administered 5 min after 1,4-BD and after symptomatic 1,4-BD overdose, mice failed the rotarod test for 100 and 110 min, respectively. Conversely, control mice failed the rotarod test for 210 and 180 min, respectively (P < 0.05). In addition, treatment of mice with 4- MP significantly attenuated increases in blood γ-hydroxybutyric acid concentrations and prevented loss of the righting reflex and failure of the rotarod test. In this murine model of 1,4-BD overdose, 4-MP conferred antidotal effects by inhibiting alcohol dehydrogenase-mediated biotransformation of 1,4-BD to γ- hydroxybutyric acid.
- Subjects
ALCOHOL dehydrogenase; DRUG abuse; MEDICAL research; LABORATORY mice; MICE behavior
- Publication
Annals of the New York Academy of Sciences, 2004, Vol 1025, Issue 1, p528
- ISSN
0077-8923
- Publication type
Article
- DOI
10.1196/annals.1316.065