Antagonism of botulinum toxin A-mediated muscle paralysis by 3, 4-diaminopyridine delivered via osmotic minipumps.
The ability of 3,4-diaminopyridine (3,4-DAP) to antagonize muscle paralysis following local injection of botulinum neurotoxin A (BoNT/A) complex was evaluated in the in situ rat extensor digitorum longus (EDL) preparation. The minipumps were implanted 6 h prior to BoNT/A administration and delivered their contents over a 7-day period producing a steady plasma 3,4-DAP concentration of 27-29 microM. In the absence of 3,4-DAP, a local injection of five mouse LD(50) units of BoNT/A led to total paralysis of EDL muscles within 24 h of application. Recovery from paralysis was slow, remaining at <30% of control 14 days after toxin injection. 3,4-DAP delivery by osmotic minipumps antagonized the actions of BoNT/A on neuromuscular transmission. Seven days after the onset of 3,4-DAP infusion, indirectly elicited twitch and tetanic tensions in BoNT/A-injected EDL muscles were 72.4 and 46.9% of control, respectively. In the absence of 3,4-DAP, twitch and tetanic tensions were only 5.4 and 15. 1% of control. The benefits conferred by 3,4-DAP treatment were not maintained after minipumps were removed. Seven days after cessation of 3,4-DAP infusion, twitch and tetanic tensions were not significantly different from those observed in muscles receiving BoNT/A alone. It is concluded that 3,4-DAP may be useful for treatment of BoNT/A-induced muscle paralysis, but sustained delivery of the drug would be required for the entire period of BoNT intoxication to maintain muscle function.
Adler
M
M
Neurotoxicology Branch, Pharmacology Division, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA. michael.adler@amedd.army.mil
Capacio
B
B
Deshpande
S S
SS
D015761:4-Aminopyridine / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D000077770:Amifampridine; D000818:Animals; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors*; D016503:Drug Delivery Systems; D006614:Hindlimb; D015918:Infusion Pumps, Implantable; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D009929:Organ Size / Q000187:drug effects; D010243:Paralysis / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D026902:Potassium Channel Blockers; D051381:Rats
D026902:Potassium Channel Blockers; D015761:4-Aminopyridine; D019274:Botulinum Toxins, Type A; D000077770:Amifampridine