Antagonism of botulinum toxin A-mediated muscle paralysis by 3, 4-diaminopyridine delivered via osmotic minipumps.

Abstract

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.

• Authors: M Adler, B Capacio, S S Deshpande
• Journal: Toxicon : official journal of the International Society on Toxinology (Toxicon) Vol. 38 Issue 10 Pg. 1381-8 (Oct 2000) ISSN: 0041-0101 [Print] England
• PMID: 10758273 (Publication Type: Journal Article)

Chemical References

• Potassium Channel Blockers
• 4-Aminopyridine
• Botulinum Toxins, Type A
• Amifampridine

Topics

• 4-Aminopyridine (analogs & derivatives, blood, therapeutic use)
• Amifampridine
• Animals
• Botulinum Toxins, Type A (antagonists & inhibitors)
• Drug Delivery Systems
• Hindlimb
• Infusion Pumps, Implantable
• Male
• Muscle Contraction (drug effects, physiology)
• Muscle, Skeletal (drug effects, pathology, physiopathology)
• Organ Size (drug effects)
• Paralysis (chemically induced, drug therapy, physiopathology)
• Potassium Channel Blockers
• Rats