Symptomatic treatment of botulism with a clinically approved small molecule
Autor: | Kathleen T Pagarigan, James B. Machamer, Patrick M. McNutt, Edwin J. Vazquez-Cintron, Brittany M. Winner, Kyle E.M. Kelly, Celinia A. Ondeck, M Ross Pennington, Paige M. Bodner |
---|---|
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Botulinum Toxins Neuromuscular disease Pharmacology Serogroup Respiratory paralysis Lethal Dose 50 Mice 03 medical and health sciences 0302 clinical medicine Potassium Channel Blockers Paralysis medicine Animals Botulism Botulinum Toxins Type A Respiratory system Muscle Skeletal Depression (differential diagnoses) United States Food and Drug Administration business.industry General Medicine medicine.disease United States Disease Models Animal 030104 developmental biology 030220 oncology & carcinogenesis Female Antitoxins Amifampridine medicine.symptom Antitoxin business Ex vivo Research Article |
Zdroj: | JCI Insight. 5 |
ISSN: | 2379-3708 |
Popis: | Botulinum neurotoxins (BoNTs) are potent neuroparalytic toxins that cause mortality through respiratory paralysis. The approved medical countermeasure for BoNT poisoning is infusion of antitoxin immunoglobulins. However, antitoxins have poor therapeutic efficacy in symptomatic patients; thus, there is an urgent need for treatments that reduce the need for artificial ventilation. We report that the US Food and Drug Administration–approved potassium channel blocker 3,4-diaminopyridine (3,4-DAP) reverses respiratory depression and neuromuscular weakness in murine models of acute and chronic botulism. In ex vivo studies, 3,4-DAP restored end-plate potentials and twitch contractions of diaphragms isolated from mice at terminal stages of BoNT serotype A (BoNT/A) botulism. In vivo, human-equivalent doses of 3,4-DAP reversed signs of severe respiratory depression and restored mobility in BoNT/A-intoxicated mice at terminal stages of respiratory collapse. Multiple-dosing administration of 3,4-DAP improved respiration and extended survival at up to 5 LD(50) BoNT/A. Finally, 3,4-DAP reduced gastrocnemius muscle paralysis and reversed respiratory depression in sublethal models of serotype A–, B–, and E–induced botulism. These findings make a compelling argument for repurposing 3,4-DAP to symptomatically treat symptoms of muscle paralysis caused by botulism, independent of serotype. Furthermore, they suggest that 3,4-DAP is effective for a range of botulism symptoms at clinically relevant time points. |
Databáze: | OpenAIRE |
Externí odkaz: |