Synergistic interaction of 4-aminopyridine with neostigmine at the neuromuscular junction.
The pre- and postsynaptic events at the neuromuscular junction were studied in vitro in rat skeletal muscle exposed to clinically significant concentrations of 4-aminopyridine (4-AP), neostigmine or combinations of the two drugs. Simultaneous application of 4-AP and neostigmine produced increases in the amplitudes of nerve-evoked end-plate potentials which were significantly greater than the summed effects of the drugs applied individually. Such synergism was present at the junctions where transmission was blocked either postsynaptically by d-tubocurarine or presynaptically by low [Ca2+]0 and high [Mg2+]0. Quantal content analysis in the latter preparation indicated that the evoked release of acetylcholine was potentiated significantly more than the amplitude of spontaneous miniature end-plate potentials, suggesting that the site of synergism is predominantly presynaptic. For symptomatic relief and long-term management of the neuromuscular junction disorders, we propose a combined medication of aminopyridine and anticholinesterase at reduced dosages. Such therapy would minimize adverse effects and be particularly effective in the treatment of such presynaptic disorders as the Lambert-Eaton myasthenic syndrome and botulism.
D015761:4-Aminopyridine; D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D066298:In Vitro Techniques; D008274:Magnesium / Q000494:pharmacology; D009045:Motor Endplate / Q000187:drug effects; D009388:Neostigmine / Q000494:pharmacology*; D009469:Neuromuscular Junction / Q000187:drug effects*; D051381:Rats; D011917:Rats, Inbred Lew; D014403:Tubocurarine / Q000494:pharmacology
D000631:Aminopyridines; D002800:Cholinesterase Inhibitors; D009388:Neostigmine; D015761:4-Aminopyridine; D008274:Magnesium; D002118:Calcium; D014403:Tubocurarine