COMPARISON OF NEW ANALEPTICS IN BARBITURATE-POISONED ANIMALS

¹ Departments of Neurology, University of Washington School of Medicine, Seattle, Washington, and New York Hospital-Cornell Medical Center, New York, N. Y.

Two new analeptics, diethamivan and doxapram, were compared with each other and with bemegride in barbiturate-poisoned animals. Comparable hypoventilation and depth of coma were elicited by giving fractions or multiples of the respiratory arrest dose (RAD) of pentobarbital.

The minimal ventilatory dose and minimal toxic dose were determined. Doxapram had the widest margin of safety, diethamivan the narrowest. Doxapram elicited the most profound and prolonged ventilatory stimulation, diethamivan the least. Diethamivan's effectiveness was improved when given by infusion but this required continuous monitoring. No drug reliably reversed barbiturate induced apnea and behavioral arousal was insignificant in deeply narcotized preparations receiving any of the three stimulants.

The chief toxic manifestation of both bemegride and diethamivan was convulsions; the former always evoked increased EEG activity, the latter did so only during light anesthesia. Doxapram never induced seizures following pentobarbital, 0.8 RAD. It supported the blood pressure of hypotensive animals but produced cardiovascular toxicity in large doses. There was evidence of tachyphylaxis after doxapram.

Doxapram was the superior stimulant in this study although tachyphylaxis limited its repeated effectiveness. Doxapram was never a convulsant under conditions of deep narcosis; its margin of safety was wide, its action was prolonged, and it supported blood pressure in hypotensive animals. These properties justify additional well-controlled studies in clinical drug poisoning.