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.