Selective Antagonism of Central Nervous System Depressants by DH-524; A Comparative Study with Bemegride

Abstract

Widespread use and abuse of barbiturates has resulted in numerous cases of barbiturate poisoning. Usually victims of barbiturate overdose are given supportive care while diuresis, dialysis, and gastrointestinal adsorption are used to lower barbiturate blood levels. Unfortunately, there is no specific antagonist for use in barbiturate poisoning, although some investigators have advocated the use of powerful analeptic agents ( 1 , 2) for shortening narcosis. Present knowledge views the antagonistic action of analeptics as the result of nonspecific central nervous system stimulation. In deep coma the difference between the lowest dose of analeptic producing a discernible effect and that producing convulsions may be very small (3). Also, at high doses the analeptics often produce vomiting and cardiac arrhythmias (5, 6).This report deals with 2 (3,4-dichlorophenoxy) methyl-2-imidazoline (DH-524) 11 an agent which shares with known analeptics the property of dramatically shortening barbiturate narcosis.2 However, several important differences between DH-524 and a typical analeptic, bemegride, were discovered in these studies.Materials and Methods. Male albino mice (Spartan strain Swiss Webster) from Spartan Research Animals, Inc. (Haslett, MI) were used in all studies. Animals of approximately the same age and weight were used in each experiment. Sleeping times were defined as the time from the ip injection of depressant until the animal was able to right him-1The details of the preparation and purification of the DH-524 used in this study are reported in U S . Pat. No. 3449355. 2Unpublishjed data, A. D. Rudzik and J. H. Mennear in this hboratary.self twice. In each experiment narcosis was allowed to develop for 10 min after injection of the depressant, and then iv injections of Krebs buffer or test drugs dissolved in Krebs were given. Animals which were not asleep at the time of iv injection were eliminated from the experiment. Because there was considerable day to day variation in sleeping times, each experiment contained a control group which received only depressant and iv Krebs. Drug groups were then compared to their own controls by use of Student's t test.Spontaneous motor activity measurements were obtained from individual animals with an electronic activity monitor (Stoelting Co.).Mice were placed in plastic cages ( 1 1 X 13x 8 cm) for a 30 min acclimitization period during which no measurements were made. Subsequently pretreatment activity was recorded for 30 min and then drugs were administered. Recording of activity was continued for three 30 min periods. Since these experiments extended over a period of days in order to accumulate sufficient data, the effect of diurnal variation was distributed equally among the treatment groups (10 mice/group) by simultaneously testing one member from each group at each session.Convulsant activity was determined by continuous iv infusion of 5 mg/ml solutions of drug. Ten mice were used for each group, with a weight range of 27-34 g. All animals received the drug solutions...