Efficacy Evaluation of 3,4-Diaminopyridine to Acutely Reverse Toxicity in Cynomolgus Monkeys Intoxicated by Botulinum Neurotoxin Serotype A1
Abstract
The purpose of this study was to evaluate the therapeutic capacity of 3,4-diaminopyridine phosphate (amifampridine phosphate drug substance; 3,4-DAPP) treatment to acutely reverse toxicity in cynomolgus monkeys systemically intoxicated with botulinum neurotoxin serotype Al (BoNT/Al). To accomplish this, male cynomolgus monkeys (of Mauritius origin) were subjected to systemic intoxication with BoNT/Al was achieved in all animals by a single intramuscular (IM) injection of a BoNT/Al dosing solution into the right calf muscle at a a challenge level of 2.5x the BoNT/Al 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 of a clinical sign associated with toxicity from botulinum toxin (ptosis, muscular weakness, respiratory distress, oral or nasal discharge) served as a trigger to initiate subcutaneous (SC) treatments approximately two hours after the initial trigger. As the objective of this study was to show reversal of toxicity, a 2-hour delay from the initial trigger was instituted to ensure sufficient toxicity was present prior to treatment. Animals received SC treatment with either vehicle (saline), 2.06 mg/kg of 3,4-DAPP, or 4.12 mg/kg of 3,4-DAPP. Repeat treatments were performed at approximately 4-hour intervals thereafter. Following IM administration of BoNT/Al at a challenge level of 2.5x LD50, all animals were observed to remain in clinically normal status on average for approximately 48 hours. The time-to-first observation of toxicity following challenge ranged from 35 hours and 21 minutes to 67 hours and 42 minutes.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 30, 2022
- Accession Number
- AD1174623
Entities
People
- Michelle L. Vassar
Organizations
- Battelle Memorial Institute