Pharmacological Studies of Some Organic Thiocyanates
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PHARMACOLOGICAL STUDIES OF SOME ORGANIC THIOCYANATES YASUO YOKOI Department of Pharmacology, Faculty of Medicine, University of Tokyo and the National Hygienic Laboratory, Tokyo Received for publication October 19, 1953 Strikingly rapid toxic symptoms of organic thiocyanates were repeatedly ob served in various kinds of animals by Traubmann (1930)(1), von Oettingen et al. (1936)(2), Cameron et al. (1939)(3), Ohashi and Kimizuka (1947)(4), though not confirmed by Moriki (1936)(5). Such a violent action as above, however, can not be expected in regard to inorganic thiocyanates, such as KSCN, clinically available as a sedative or a blood pressure depressant. The SCN radical has a close similarity in its chemical property to halogens, which may be named "pseudohalogen". Then, Traubmann naturally presupposed an ethyl chloride C2H5Cl-like narcotic action as a pharmacological property of alkyl thiocyanates, i.e. methyl thiocyanate CH3SCN, ethyl thiocyanate C2H5SCN, or propyl thiocyanate C3H7SCN. But it was found that the animals poisoned either by these alkyl thiocyanates or by aromatic thiocyanates (phenyl thiocyanate C6H5SCN and aniline thiocyanate NH2C6H4SCN) caused respiratory excitement and convulsions. Thus he came to a postulation for the toxic particularity of organic thiocyanates. Von Oettingen and others noticed the following phenomena : hyperemia, hemor rhage and edema in internal organs, when animals succumbed to the acute poison ing by lower alkyl thiocyanates, respiratory excitement and a rise in blood pres sure when methyl or ethyl thiocyanate was administered subcutaneously ; appear ance of a AgNO3-consuming substance in vitro when these thiocyanates were placed for 48 hours with pieces of liver. These observations gave the impression that hydrocyanic acid might be liberated from methyl and ethyl thiocyanates in living animals. In order to scrutinize more carefully the above-mentioned assumption, the present study was designed with six compounds of organic thiocyanates* as listed in Table 1. *The author owes the preparation of these compounds to Dr . T. Itai in the National Hygienic Laboratory, Tokyo TABLE 1. Organic thiocyanates adopted for experiments METHODS AND RESULTS Distilled water was used to solve inorganic cyanides and ethyl thiocyano acetate, and olive oil or 50 per cent ethylenglycol monoethyl ether to the other compounds. Their respective solubilities are shown in Table 1. Lethal doses were expressed in gram per kilogram and also in millimol per kilogram. From the figures of the molecular lethal dose of various compounds in question, their lethal effect was calculated, as expressed by the ratio of the molecular lethal dose of each substance divided by that of HCN. I. Systemic symptoms and taxi ci ti es Toxic symptoms : When ethyl thiocyanoacetate or potassium cyanide was ad ministered through three routes to hundreds of mice and some rabbits and pige ons, no particular difference was noticed between the toxic symptoms developed respectively by them: marked respiratory stimulation, heavy convulsions and then respiratory failure along with general paresis. With other organic thiocyanates, especially when administered intraperitoneally, the symptoms yielded were nearly same as mentioned above, although the convulsive manifestations were less mar ked in most cases when administered subcutaneously. In regard to the halogenated organic compounds, in which SCN radical of the mother thiocyanates was substituted with a halogen, the toxic symptoms became different losing a cyanide-like symptom : chloro-, bromo or iodobenzene appeared to have some toxic resemblances in their symptoms to carbolic acid, and ethyl iodide yielded such narcotic effect as alchol or ether, and thymol chloride caused a toxic symptom like that of thymol itself. Ethyl monochloroacetate was excep tional, because it resembled to cyanide in toxic symptom, when administered in much larger dose than that of ethyl thiocyanoacetate. Lethal dose : The molecular lethal doses of organic thiocyanates, indeed, varied with species of animal or method of administration, but they tended to approach to one in their ratios to that of hydrocyanic acid, especially when they were ad ministered intraperitoneally as shown in Table 2. On the contrary, the halogena ted corresponding compounds were much larger in their ratios to cyanide, although they had many physical properties common to their mother compounds and were prepared for testing in a solvent common to the mother ones. IL Respiratory movement and blood pressure Organic thiocyanates and sodium cyanide were administered into ear vein of rabbit, about 2 Kg. of body weight, anesthetized with urethane. Kymographic tracings of respiratory movement were recorded by a Marey's tambour connected to tracheal canula, and blood pressure by an ordinary mercury manometer at common carotid artery. TABLE 3. Effects of cyanide and organic thiocyanates on respiratory movement of rabbit Ethyl thiocyanoacetate for testing was dissolved in distilled water, and other organic thiocyanates were all in 50 per cent ethyl o.nglycol monoethyl ether. The effect of organic thiocyanates was proved quite similar to that of sodium cyanide (Fig. 1). As to the respiratory movement, the only finding with smaller dose was of excitatory one and the movement ceased transiently for several minutes when used in more dose, resulting in its standstill in a final large dose (Table 3 and Fig. 1, A). FIG. 1 A. Effect of intravenous phenyl thiocyanate on respiration of urethanized rabbits. There was no marked dfference between the toxicity of sodium cyanide and that of organic thiocyanate ; the doses causing the transient cessation of the movement were determined by intravenous administration as shown in Table 4: 0.02 millimol per Kg. of body weight for ethyl thiocyanoacetate, phenyl, benzyl, and thymol thiocyanates as well as sodium cyanide respectively , and 0.04 millimol for ethyl thiocyanate. Regarding the blood pressure, the effects appeared more complicated than the above and yet there was no remarkable difference between sodium cyanide and organic thiocyanates. With smaller dose, in the above-mentioned stage o respira tory excitement, an initial rise in blood pressure was mostly followed by a tran sient fall even below the starting level and then a second rise in the pressure . When used in larger dose, blood pressure fell rapidly and respiration stopped long before the heart did (Fig. 1, B). TABLE 4. Intravenous millimol doses causing transient cessation of respiration* FIG. 1 B. Effect of intravenous phenyl thiocyanate on blood pressure of urethanized rabbits It was thus revealed that organic thiocyanates and sodium cyanide acted alike qualitatively upon respiration and blood pressure and also quantitatively upon the former. As for halogen compounds, ethyl monochloroacetate was adopted for testing in place of ethyl thiocyanoacetate, chlorobenzene for phenyl thiocyanate and thymol chloride for thymol thio;yanate. These compounds caused no remarkable change in respiratory movement but only a transient fall in blood pressure, when administered to rabbits intravenously even in the dose with which thiocyanates would cause noticeable effects. III. Gas metabolism fin order to analize the air expired from rabbit under the influence of organic thiocyanates or potassium cyanide, in a rabbit, comparatively deeply anesthetized with urethane, one end of a T-shaped glass-tube was inserted into the trachea. This T-canula was provided with an inflow valve at one of the other ends to conduct fresh air into lungs and an outflow valve at another end letting expired air out. The expired air was caught in a Douglass' bag with every 10 minutes frac TABLE 5. VoI ime of oxygen consumption and expired air of rabbits intoxicated by cyanide and organic thiocyanates tion ; its volume was measured by a gas-meter (Table 5) and the percentages of its components were obtained by a modified Haldane's gas-analyser(6) and then calculation showed the volumes of oxygen consumed (Table 5) and of carbon dio xide produced. When organic thiocyanates and potassium cyanide were given in the doses listed in Table 5, a rapid and marked decrease of oxygen consumed and a decre ase of carbon dioxide produced were both proved in all samples, and the expired air did not change pararell to them; in fact, it increased mostly very much, resul ting in a consequent hyperpnea and in some cases convulsions too. All changes in volume as observed above were recovered as the poisoning subsided. The organic thiocyanates' doses causing actually such an impressive phenomenon were nearly same as in case of cyanide : 0.07 millimol per kilogram with KCN, ethyl thiocyanoacetate and benzyl thiocyanate, respectively, 0.07 to 0.11 millimol with phenyl thiocyanate and 0.19 millimol with ethyl thiocyanate. IV. Antidotes Sodium thiosulfate and nitrite, well-known antidotes against cyanide poison ing, were tried respectively as a treatment to the poisoning of organic thiocyanates. TABLE 6 A. Effect of sodium thiosulfate pretreatment on de-ith-rate of mice h poisoning of organic thioz yanates and other chemicals (1) Sodium thiosulfate The experimental method for the organic thiocyanates was designed in accor dance with the R. Hunt's antidotal experiment(7) in which sodium thiosulfate was used against "cyanide" poisoning: first, 10 per cent sodium thiosulfate solution, 0.5 cc. per animal, was administered subcutaneously on the ventral part of a mouse, and then, about 10 minutes later, a certain dose of one of