Edward E. Swanson

Ultra-short-acting thiobarbituric acids.

Summary Four N-methyl thiobarbituric acids have been studied and compared with sodium 5-allyl-5-(1-methylbutyl) thiobarbitu-rate and thiopental in rats, rabbits, cats, and dogs. They are all potent anesthetics by intravenous injection. The N-methylated derivatives, in an observed AD60 duration of anesthetic and hypnotic action than the 2 non-methylated compounds. When one-half of AD50 is intravenously injected at hourly intervals, all 4 N-methyl-substituted barbiturates show less cumulative action than sodium 5-allyl-5-(1-methylbutyl) thiobarbiturate and still less than thiopental. In anesthetized cats, 2 of the N-methyl barbiturates produce less hiccup, sneezing, and coughing than sodium 5-allyl-5-(1-methylbutyl) thiobarbiturate and thiopental, while the 2 others are free from such effects. Like all barbiturates, the 4 N-methylated compounds, when injected intravenously in anesthetized dogs, lower the blood pressure and depress respiration. They do not inhibit the vagal response in these preparations. They induce slight hypothermia and tachycardia in dogs following an AD50 of each product. The authors are indebted to Misses Eva Sommermeyer and Marion Ellaby, and to Messrs. William R. Gibson. Wallace C. Wood, James E. Waddell, E. Brown Robbins, and Lester Le Compte for their invaluable assistance in this work.

Anticonvulsant Activity of Some Substituted Ethylene Glycols

Summary 1. A series of substituted ethylene glycols has been studied for anticonvulsant activity by both the maximal electroshock seizure and subcutaneous Metrazol seizure tests. 2. Fully substituted ethylene glycols are more potent anticonvulsant agents than mono-, di-, or trisubstituted analogues. 2-p-Chlorophenyl − 3 - methyl-2, 3-butanediol (phenaglycodol) has been selected for clinical trial since it has high potency and long duration of action. It is suggested that the long duration of action may be related to full substitution of the ethylene glycol nucleus which should reduce the probability of oxidative detoxification.

Short Acting Barbituric Acid Derivatives

In a previous communication, 1 it was pointed out that there is obvious relationship between the pharmacological action and the chemical structure of certain barbituric acid derivatives, and that compounds with long alkyl groups have a shorter duration of action. The present report deals with the evaluation of 12 such compounds, all of which were prepared by Shonle, Waldo, Keltch, and Coles. 2 Typical hypnotic and anesthetic properties were observed with all the substances except one, injected intraperitoneally, in albino rats. Their minimal hypnotic doses (M.H.D.), minimal anesthetic doses (M.A.D.), and minimal lethal doses (M.L.D.) were determined, and their therapeutic indices calculated as shown in Table I. Compounds numbered 1, 2, 3, and 7 were also tested in dogs, being effective either by vein or by mouth. It is curious that compound numbered 12, 1, 3-dimethyl-butyl-ethyl barbituric acid, is devoid of any hypnotic or anesthetic action, but on the contrary, produces convulsions. The substance is also highly toxic.

Relationship Between Pharmacological Action and Chemical Structure of Barbituric Acid Derivatives

To elucidate the relationship between the chemical structure and the pharmacological action in the barbital series, over 50 derivatives were investigated. These compounds were all 5, 5-substituted barbituric acids, having the general formula: wherein R-alkyl radical (normal or secondary with 2 to 9 C-atoms). Several of them were new compounds synthesized for the first time. 1 Albino rats weighing from 71 to 126 gm. (average 96 gm.) were employed in this study. Solutions of the sodium salts of the compounds were injected intraperitoneally. The minimal anesthetic dose (M.A.D.), the duration of action, and the minimal lethal dose (M.L.D) were determined by using 5 animals for each dose level. Since space does not permit a presentation of detailed results, only a few salient points will be discussed here. In Figs. 1 and 2, the “primary alkyls” refer to those compounds having a normal alkyl group. It should be noticed from Fig. 1 that with the increase in number of C-atoms in the alkyl group, either normal or secondary, both the M.A.D. and M.L.D. grow relatively smaller, but when the alkyl radical is longer than 5 C-atoms, the amount required to anesthetize or kill rats again increases. The therapeutic index, or the ratio between the M.L.D. and M.A.D., appears to be gradually greater as the alkyl chain lengthens. In general, the duration of action shows similar features; that is, it is shorter when the alkyl group becomes lengthened (Fig. 2). In the series of normal alkyl derivatives, the critical compound is the one that possesses 6 C-atoms at R; and in the series of secondary alkyl derivatives, the critical compound is the one having 7 C-atoms at R, beyond which the duration of action begins to increase.

The Action of Ergometrinine

Ergometrinine is one of the newer alkaloids of ergot isolated by Smith and Timmis. 1 It decomposes at about 195° and has an optical rotation of [α]20 5461 + 598°. Its empirical formula is the same as that for ergometrine, that is, C19H23O2N2. Raymond-Hamet 2 reported that in the dog ergometrinine caused a rise of blood pressure and vasoconstriction, and that with a dose of 24.5 mg. per kg., it abolished the vasoconstricting action of adrenalin. He concluded that ergometrinine was weaker than ergometrine. With the aid of Mr. Howard B. Fonda, Experimental Research Laboratories, Burroughs Wellcome and Company, Tuckahoe, we were able to secure 50 mg. of ergometrinine nitrate. The material is easily soluble in water and exhibits a blue fluorescence in aqueous solution. Unlike ergotoxine or ergotamine, ergometrinine does not inhibit the adrenalin response on the isolated rabbits uterus in a concentration as strong as 1:27,777 (the Broom-Clark test 3 ), but on the contrary, it exerts a weak stimulating action itself. When assayed by the method described previously, 4 ergometrinine HNO3 was shown to be 1/100 as active as ergotocin maleate in 6 observations (Fig. 1A).

Sodium Propyl-methyl-carbinyl Allyl Barbiturate, a Short Acting Hypnotic

Fitch, Waters, and Tatum 1 in their extensive work on barbituric acid hypnotics emphasized the importance of employing short acting members for surgical procedures. Among the different derivatives synthesized by Shonle and his associates, 2 , 3 , 4 the sodium salt of propyl-methyl-carbinyl allyl barbituric acid appears to have the desirable promptness and brevity of action. The same compound has been prepared by Tabern and Volwiler. 5 By following Eddys scheme of recording results, 6 it was found that in rats by intraperitoneal injection the minimal anesthetic dose (M.A.D.) was 40 mg. and the minimal lethal dose (M.L.D.) 110 mg., per kg. Twenty mg. per kg. by the same route of administration were sufficient to induce sleep. These animals, 220 in number, weighed on the average 94 gm. In dogs by intravenous injection of a 5% solution at the rate of 1 cc. per minute, the M.A.D. was ascertained to be 25 mg. and the M.L.D. 50 mg., per kg. By mouth in the same species of animal the M.A.D. was determined to be 35 mg. and the M.L.D. 90 mg., per kg. A total of 83 dogs were used. A comparison of the onset and duration of action of sodium propyl-methyl-carbinyl allyl barbiturate in dogs with those of sodium amytal and pentobarbital sodium is shown in Table I. It will be noted that when given by mouth the appearance of ataxia occurred slightly sooner with the new barbituric acid derivative. Its duration of anesthesia was, on the average, longer than that with pentobarbital sodium and comparable to that with sodium amytal. However, the time for complete recovery after the administration of sodium propyl-methyl-carbinyl allyl barbiturate was approximately half that with sodium amytal, and slightly shorter than that with pentobarbital sodium. Similar to sodium amytal and pentobarbital sodium, the new compound by intravenous injection proved to protect rabbits from 4 but not 5 M.L.D.s of strychnine or cocaine—34 animals being employed for this purpose.