“Specific” Drug Antagonists to Barbiturates, Morphine and Hallucinogens.
Compound 2 (succinic acid) was and still is puzzling in both its clinical effects and mode of action. One of its basic effects was as an analeptic in a variety of cases of CNS depressant induced drug effects and in different comas and confusional states. It demonstrated meaningful arousal in all cases and complete restoration of clear consciousness and normal motor activity in some. We did not proceed further because we had no lead to follow; looking back, this is a sorry admission as succinic acid produced some remarkable clinical effects without side effects in our dose range. So we studied a group of more specific drug antagonists, because we had a better idea of their actions as well as a source for the compounds and their analogues.
Bemegride was the first compound in this series we studied. Its structure and development suggested it would be a specific antagonist against barbiturates. We published three studies in barbiturate poisoning, the first in several animal species (Trautner, Shaw & Gershon, 1956), the next in the treatment of barbiturate overdose in humans (Trautner, Shaw & Gershon, 1957 a) and the third an overall summary of the experiments in animals and the study in human overdose. (Trautner, Shaw & Gershon, 1957 b). In the 1950’s and 1960’s barbiturate poisoning was very common in suicide attempts and accidental overdoses, often causing death. We also noted in animals that pretreatment with Bemegride prior to barbiturate dosage would shorten sleeping time, the opposite of the effect seen with succinate.
Our results led to preparing a pill containing both barbiturate and Bemegride designed to diminish the lethality of barbiturate overdose. The pill was manufactured by a small pharmaceutical company and entered into animal studies followed by small clinical trials. These demonstrated a clear effect, diminishing the depth and duration of coma in animals and humans while reducing the death rate in animals. With the advent of the benzodiazepines public health policy strongly discouraged prescribing barbiturates for insomnia so manufacture of the combination pill and marketing ceased.
Bemegride was a lifesaving drug but when safer alternatives to barbiturates were available it became irrelevant. My future as a pharmaceutical tycoon took a turn for the worse!
Trautner EM, Shaw FH, Gershon S. Bemegride in barbiturate poisoning. Lancet 1956; 2: 514.
Trautner EM, Shaw FH, Gershon S. Treatment of barbiturate poisoning. Brit med J 1957 a; 1: 231.
Trautner EM, Shaw FH, Gershon S. Effects of Bemegride in barbiturate overdosage in humans. Brit med J 1957 b; 2: 1509-14.
July 9, 2015