Survey of drug therapies against acute oral tetramethylenedisulfotetramine poisoning in a rat voluntary consumption model

• Published in: Neurotoxicology (Park Forest South) 2019-09, Vol.74, p.264-271
• Main Authors: Moffett, Mark C., Rauscher, Noah A., Rice, Nathaniel C., Myers, Todd M.
• Format: Article
• Language: English
• Subjects: Allosteric properties; Animals; Anticonvulsant; Avoidance Learning - drug effects; Barbiturates; Barbiturates - therapeutic use; Behavior, Animal - drug effects; Benzodiazepines; Benzodiazepines - therapeutic use; Body weight loss; Bridged-Ring Compounds - poisoning; Convulsions; Diazepam; Dose-Response Relationship, Drug; Drug abuse; Drug dosages; Drug therapy; Drugs; Epilepsy; Ethanol; Fuel consumption; GABA Modulators - therapeutic use; Ingestion; Ketamine; Lorazepam; Male; Midazolam; Pentobarbital; Phenobarbital; Poisoning - drug therapy; Polls & surveys; Pregnanolone; Rats; Rats, Sprague-Dawley; Rodenticides - poisoning; Survival; Survival Analysis; Tetramethylenedisulfotetramine; Weight loss; Weight Loss - drug effects; γ-Aminobutyric acid A receptors
• ISSN: 0161-813X; 1872-9711
• DOI: 10.1016/j.neuro.2019.08.004

•Tetramethylenedisulfotetramine intoxication is rapid following ingestion.•A single high dose of a benzodiazepine or phenobarbital improves survival.•Survivors were in poor health and showed signs of intoxication at 24 h. Ingestion of the noncompetitive GABAA receptor antagonist tetramethylenedisulfotetramine (TETS) results in arrhythmias, respiratory depression, and life-threatening convulsive status epilepticus. We have previously developed a realistic model of voluntary TETS consumption, in which rats promptly consumed a piece of cereal containing a dose of TETS that led to rapid progression of toxic signs (including convulsions) and profound and enduring behavioral suppression. Recently, this model was used to survey nine different drugs from distinct drug classes over a large range of doses to identify possible therapeutics. The drugs included three benzodiazepines (diazepam, midazolam, and lorazepam), two barbiturates (phenobarbital and pentobarbital), the GABAA allosteric modulator allopregnanolone, and three non-traditional therapeutics (dexmedetomidine, ketamine, and ethanol). Treatment was administered intraperitoneally 10 min after consumption of the cereal morsel containing TETS (600 μg/kg). This exposure model resulted in a survival rate of 30% in vehicle-treated rats. Diazepam (12.5 mg/kg) and midazolam (25 mg/kg), compared to vehicle, significantly increased survival (75 and 100% respectively) but at only one of the three doses tested. Lorazepam increased survival across a wide range of doses (1.56–25 mg/kg) with survival rates between 80–100%. Phenobarbital (100 mg/kg) was the only other drug and non-benzodiazepine to improve survival rates (80%). Although the four aforementioned therapeutics increased survival, TETS-induced weight loss, food wastage, and behavioral deficits remained in survivors.