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A comparison of the antagonisms by neostigmine and diaminopyridine against the neuromuscular block caused by cobrotoxin and (+)‐tubocurarine

Cobrotoxin was about 11‐fold more potent than (+)‐tubocurarine on a weight basis in blocking neuromuscular transmission in mouse isolated phrenic nerve‐diaphragm preparations. Neostigmine and diaminopyridine increased the concentrations of cobrotoxin for 70% inhibition of indirect contraction by 290 and 320%, and increased those of (+)‐tubocurarine by 180 and 230%, respectively. More than additive increases were obtained when neostigmine and diaminopyridine were used simultaneously. Cobrotoxin, however, was only 6‐fold more toxic than (+)‐tubocurarine after intraperitoneal injection in mice. The lethal dose of (+)‐tubocurarine was increased by 80% when both antidotes were used together, but only by 15–20% when used alone. In contrast, the lethality of cobrotoxin was not decreased by these drugs. Unexpectedly, the time to death after treatment with cobrotoxin was shortened when mice were pretreated with these antidotes.