Survival Efficacy Evaluation of 3, 4-Diaminopyridine Phosphate in Cynomolgus Monkeys Intoxicated by Botulinum Neurotoxin Serotype A1
Abstract
The purpose of this study was to evaluate the capacity of 3,4-diaminopyridine phosphate(amifampridine phosphate drug substance; 3,4-DAPP) treatment to promote survival in cynomolgus monkeys systemically intoxicated with botulinum neurotoxin serotype A1(BoNT/A1). To accomplish this, male cynomolgus monkeys (of Mauritius origin) were systemically intoxicated with BoNT/A1 by a single intramuscular (IM) injection of a BoNT/A1dosing solution into the right calf muscle at a challenge level of 2.5x the BoNT/A1 median lethal dose (LD50) for IM intoxication in cynomolgus monkeys. Following challenge, animals were observed for toxic signs commonly associated with botulism (e.g., ptosis, muscular weakness, respiratory distress, oral/nasal discharge). Clinical severity scoring was performed based on the presence and/or severity of select toxic signs. A clinical severity score of 1 or greater served as a trigger to initiate subcutaneous (SC) treatments. Animals received SC treatment with either vehicle (saline), or 4.12 mg/kg of 3,4-DAPP. After initial trigger and treatment, repeat treatments were performed at approximately 2-hour intervals thereafter. Endpoints used to evaluate potential reversal of BoNT/A1-induced toxicity with 3,4-DAPP treatment included clinical observations and associated clinical severity scores. Time-to-death calculations were performed based on mortality outcomes.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 13, 2023
- Accession Number
- AD1207295