Charles L. Rose

Methylene Blue, Nitrites, and Sodium Thiosulphate against Cyanide Poisoning

Following the reports of Sahlin, 1 Eddy, 2 Brooks, 3 Geiger, 4 Hanzlik, 5 Hug, 6 and Wendel, 7 we investigated the comparative antidotal action of methylene blue and amyl nitrite in cyanide poisoning and found that methylene blue detoxified 2 M.L.D.s and amyl nitrite by inhalation 4 M.L.D.s of sodium cyanide. 8 Amyl nitrite is thus twice as effective as methylene blue. To date we have studied other nitrites and sodium thiosulphate. The last compound has been shown to have an antagonistic action against cyanide by several investigators.9-13 The results summarized in Table I were all obtained in dogs. It should be noted that nitroglycerine is ineffective as an antidote; while sodium thiosulphate detoxifies 3 M.L.D.s and sodium nitrite 4 M.L.D.s of sodium cyanide. A more striking antidotal effect is exhibited when amyl or sodium nitrite is supplemented with sodium thiosulphate. The combination of the nitrite and thio-sulphate does not only show synergistic action but surpasses the sum of their individual values. For example, the number of fatal doses detoxified by sodium nitrite and sodium thiosulphate is 13 instead of 7. It is a definite case of potentiation. Compared with methylene blue, the coupling of sodium nitrite and sodium thiosulphate is 6 1/2 times as effective. The following protocol is representative of the experiments: Dog, female, weighing 22 kg., received NaCN subcutaneously at 1:50 p. m., 78 mg. per kg. (13 M.L.D.s); 1:51 p. m., received intravenously NaNO2 22.5 mg. per kg. and Na2S2O3 2 gm. per kg.; 2:00-2:22 p. m. vomited 5 times; 2:23 p. m. drank water; 3:10 p. m. received intravenously NaNO2 10 mg. per kg. and Na2S2O3 0.5 gm. per kg.; 3:16 p. m. vomited; 4:53, 7:57, and 9:50 p. m. received intravenously NaN02 10 mg. per kg. and Na2S2O3 0.5 gm. per kg.; 8:15 a. m. of the next day, completely recovered. To test the crucial efficacy of the nitrite-thiosulphate therapy, dogs were given large amounts of cyanide, say 10 M.L.D.s, and allowed to develop the cardinal signs of cyanide poisoning such as convulsions, loss of corneal reflex, and failing respiration. As long as there was gasping, the intravenous administration of sodium nitrite and sodium thiosulphate enabled the animals to breath briskly at once, stand up within a few minutes, and recover completely in several hours.

Toxicity of Nicotinic Acid

Summary Nicotinic acid is at least several hundred times less toxic in mice, rats, and guinea pigs than nicotine. Nicotinic acid is devoid of action upon the autonomic ganglia. Nevertheless, repeated administration of large doses, 2 gm. daily, in dogs has resulted in poisoning and deaths.

Toxicity of 3,3-Methylenebis (4-hydroxycoumarin)

Summary (1) The median lethal doses of Dicumarol have been determined intravenously or by mouth in mice, rats, and guinea pigs. (2) Death uniformly occurs in rabbits with intravenous injection of daily doses of 1-2 mg per kg; in dogs with oral administration of daily doses of 5-50 mg per kg; and in mice and rats with the feeding of 0.01-1% Dicumarol in food. The majority of rabbits can tolerate daily doses of 0.1-0.5 mg per kg by vein for 6 weeks, and a few mice and rats can survive 30 days on a diet containing 0.005% Dicumarol. (3) Most animals dying from Dicumarol develop hemorrhage into various tissues and organs, and pulmonary edema. Central necrosis of the liver has been observed in about one-half of the rats examined, and occasionally in rabbits, mice, and dogs.

Potentiation of Antidotal Action of Sodium Tetrathionate and Sodium Nitrite in Cyanide Poisoning

In a previous communication we 1 reported the synergism and potentiation of the antidotal action of sodium or amyl nitrite and sodium thiosulphate against cyanide poisoning. The combination of sodium thiosulphate with sodium nitrite proves to be better than with amyl nitrite. It becomes interesting to ascertain whether or not sodium tetrathionate will similarly potentiate the detoxifying action of sodium nitrite, since the tetrathionate has been shown to reduce the toxicity of hydrocyanic acid by Foresti 2 and Draize. 3 In a series of experiments with dogs our results reveal exactly the same synergism and potentiation that occur with sodium thiosulphate. With the combination of sodium nitrite and sodium tetrathionate,∗ at least 3 dogs out of groups of 5 survived 13 or less M.L.D.s of sodium cyanide; whereas, with sodium nitrite alone only 4 M.L.Ds and with sodium tetrathionate alone 3 M.L.D.s of NaCN were detoxified. The antidotal effect of sodium nitrite and sodium tetrathionate given together thus exceeds the sum of those contributed individually by sodium nitrite and sodium tetrathionate. It is therefore another case of potentiation of action. The nitrite-tetrathionate combination is apparently efficacious in the late stages of cyanide poisoning. Dogs receiving large doses of NaCN have completely recovered at the point of respiratory failure. The following protocol can be taken as an example of our experiments: We have also studied the combination of methylene blue and sodium tetrathionate or thiosulphate in cyanide poisoning, and observed a synergistic action. The results are, however, much less striking.

Effect of Cyanide Poisoning on the Central Nervous System of Rats and Dogs.

Summary 1. Prolonged cyanide poisoning in rats may cause cerebral changes in 10% of the animals. 2. Daily injection of potassium thiocyanate similarly results in brain injury in 10% of rats. 3. In the rat continuous administration of sodium nitrite does not produce lesions in the central nervous system. 4. In dogs cyanide poisoning with or without the nitrite-thiosulfate therapy does not induce abnormal behavior. When they die from the poisoning, their brains usually show a normal appearance.

Relative Susceptibility of Warm Blooded Animals to Ouabain, Cymarin, and Coumingine Hydrochloride

Summary 1. The acute toxicity of ouabain, cymarin, and coumingine hydrochloride has been compared by subcutaneous injection in cats, rabbits, guinea pigs, rats, and mice. 2. Both mice and rats are much more tolerant to ouabain and cymarin than cats in the ratios of 62:1 to 671:1. Regarding the alkaloid, coumingine HCI, which also has a digitalis-like action, their resistance is not so marked, being in the ratios of 13:1 to 29:1. 3. Guinea pigs and rabbits, like cats, are highly susceptible to ouabain, cymarin, and coumingine HCI.

Detoxification of Dendrobine by ‘Sodium Amytal’

Summary ‘Sodium Amytal’ detoxifies dendrobine. In rabbits it can antidote 5 minimal lethal doses of the alkaloid after definite signs of intoxication have been observed.

Effect of beta-sitosterol on regression of hyperlipemia and increased plasma coagulability in the chicken.

Summary 1. A cholesterol-induced hyperlipemia was fully counteracted (reduced to normal levels) by feeding beta-sitosterol. 2. The decreased plasma clotting times associated with a hyperlipemia returned to control values when a normal lipid level was attained. 3. An inverse relationship was demonstrated between plasma clotting time in presence of Russells viper venom and degree of lipemia; i.e., a hyperlipemia resulted in decreased plasma clotting time, and vice versa. 4. Addition of 4% beta-sitosterol to the diet prevented or reversed an increased lipid and cholesterol concentration in liver and aorta.

Detoxification of Amidopyrine by Sodium Amytal

The antidotal action of sodium amytal against convulsant drugs has been demonstrated in both animals and men. 1 , 2 , 3 , 4 In view of the fact that large doses of amidopyrine cause convulsions of central origin, 5 it appears interesting to ascertain whether or not sodium amytal will similarly reduce its toxicity. Evidence of antagonism between amidopyrine and other barbituric acid derivatives has already been observed by several European workers. 6 , 7 White mice numbering 272 and rats numbering 221 were employed in the present investigation. They were all starved over night prior to medication. The drugs were injected by the tail vein. It is a coincidence that amidopyrine and sodium amytal when given alone have the same toxicity. The M.L.D. (minimal lethal dose) of each was found to be 150 mg. per kg. in mice and 135 in rats—using dose increments of 5 mg., and groups of 5 animals. The determined dose killed at least 3 animals out of an injected group of 5. In the next series of experiments, sodium amytal was added and injected together with amidopyrine, various amounts of both drugs being used. As shown in Table I, the toxicity of amidopyrine is reduced approximately 2/3 when an optimal dose of sodium amytal was employed (which was 40% of the M.L.D. in mice, and 50% in rats). It may be interesting to mention that in a group of 5 rabbits which was given by mouth 100 mg. of amytal and 227 mg. of amidopyrine daily, except Saturdays and Sundays, for 4 1/2 weeks, there was no decrease in either the total white blood cell or the granulocyte counts.