NEWER DRUGS FOR MYASTHENIA GRAVIS; A MICROPHYSIOLOGIC STUDY OF EFFECTS

¹ Laboratory of Clinical Neurophysiology, Department of Neurology, Veterans Administration Hospital, and Division of Neurology, Stanford University School of Medicine, Palo Alto, California

Veratrine, germine diacetate (GDA) and guanidine have been applied to myasthenic neuromuscular junctions in vitro in order to clarify their mode of action in improving the force of muscular contraction and to see whether any of the agents could be expected to be useful in long-term treatment of the disease. The data suggest that the effect of the veratrum alkaloids on the twitches of myasthenic preparations is chiefly postsynaptic and the result of the conversion of single muscle action potentials to short tetani. For these drug effects to be observed, the endplate response must be suprathreshold to begin with. With direct end-plate recording no evidence has been found that the veratrum alkaloids cause repetitive motor nerve discharges in myasthenic preparations in vitro. Both GDA and veratrine appear to enhance the amount of transmitter liberated per nerve impulse during short trains of stimuli at 20/sec. However, the same concentrations of veratrine produce nerve conduction failures at many junctions, and the facilitatory effects on transmitter release are not reflected in an improved mechanical response. It seems likely that the presynaptic effects of GDA would be similar at sufficient concentration. Guanidine also increased slightly the amount of transmitter liberated by a train of stimuli, but the effect was of short duration. The improved twitch and tetanic responses after guarndine are presumed to reflect the temporary recruitment of those fibers whose end-plate potentials were previously just subthreshold. The evidence indicates that, with the veratrum alkaloids as a class, the drug concentrations required for potentially beneficial or harmful effects may be dangerously close. Guanidine, though lacking some of the posteynaptic effects of veratrine and GDA, appears to have a wider margin of safety at the neuromuscular junction. None of the tested drugs produced any more than a small fraction of the improvement seen with neostigmine in vitro.