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Daily administration of increasing doses intraperitoneally of 2.5-4.0 mg NaCN/kg to male Wistar rats for 5 weeks produced acute signs of poisoning immediately post-injection but no sign of chronic toxicity except lower final body weights than in control rats. CN-treated rats had less liver copper than controls, but not below the range of normality, and their liver mitochondrial membranes were 24% less able to bind adenine nucleotides than control membranes. No other biochemical or pathological sign of copper deficiency occurred. Liver cytochrome oxidase activity was normal after the 5 weeks of CN-administration, as was the ability of liver mitochondria to synthesize phospholipids. The ultrastructure of hepatocytes was normal without evidence of the enlarged, misshapen mitochondria produced by copper deficiency. Normal cytochrome oxidase activity of liver mitochondria, together with reduced liver copper levels and reduced binding affinity of mitochondrial membranes for adenine nucleotides, indicate that the membrane binding site for adenine nucleotides is not cytochrome oxidase per se but may involve copper, perhaps by virtue of its cationicity. With repeated exposure to CN- rats develop tolerance to acute poisoning. It is suggested that this may be due to the switch in glucose catabolism towards the pentose pathway at the expense of other pathways.

The effects of cyanide on iono- and osmoregulation are soon established and last long after the period of exposure to the toxicant is over. The effects are of the order of 4 to 8 percent changes in blood plasma osmolality and chloride ions, changes which are indicative of serious physiological impairment, having costly energetic implications. The deleterious effects of cyanide were detected at concentrations as low as 0.01 mg/l HCN in water of pH 7.5. Juvenile rainbow trout, Salmo gairdneri, were first exposed to various concentrations of cyanide ranging from 0.01 to 0.037 mg/1 HCN for 28 days in fresh water in flow-through aquaria at 10?C. After this exposure period the fish together with untreated fresh water controls were transferred into 18.9 ppt salt water for 260 hours during which blood plasma osmolality and chloride were monitored. By the end of the salinity tolerance tests the poisoned fish had experienced greater loss of water than the controls but no change of chloride were observed. Upon return to fresh water for 100 hours all the fish lost chloride ions, the effect being much greater in the cyanide exposed fish. When the fish were first adapted to salt water then transferred to fresh water cyanide they also experienced loss of chloride and dilution of plasma greater than the controls did.

Summary A case of accidental poisoning with sodium cyanide is reported. The patient was treated with a new antidote, dicobalt edetate (Kelocyanor). Blood levels of cyanide were shown to fall markedly.

Sheep killed with intramuscular injections of potassium cyanide had high concentrations of cyanide in whole blood. Plasma and serum concentrations were on average 54% lower, but significantly correlated with whole blood concentrations. Cyanide in cerebrospinal fluid was slightly, though not significantly, lower than the concentration in blood plasma, but was significantly higher than the concentration of cyanide in brain white or grey matter. The results are compared with experiments involving the use of small mammals, and the relevance of the findings to the diagnosis of acute cyanide poisoning in man is discussed.

The pyrethrum synergists piperonyl butoxide, sulfoxide, and SKF 525 A (2-diethylaminoethyl 2,2-diphenylpentanoate) were found to give some protection to Sitophilus granarius (L.) against the toxic effects of hydrogen cyanide. This protection was most pronounced with SKF 525 A. These compounds, which are believed to exert their synergistic effect by depressing oxidative metabolism, may protect the insects from cyanide poisoning by a similar process. Studies on the effect of oxygen on insects poisoned with different compounds showed that oxygen enhanced the toxic effects of both parathion and para-oxon but it did not affect the toxicity of pyrethrum. In insects treated with allethrin an increase in the oxygen tension had no significant effect but anoxic conditions caused an increase in mortality.

Durch geeignete Dosierung einer Cyanid-Dauerinfusion konnte am in situ arbeitenden Herzen des narkotisierten Hundes eine Glykolyse hervorgerufen und uber einen Zeitraum bis zu 58 min beobachtet werden. Die arteriovenose Milchsauredifferenz betragt unter diesen Bedingungen im Mittel+3,13±0,68 mg/100 ml Blut (n=11). Die Coronardurchblutung last sich unter der Cyanidwirkung auf 320 ml/min·100 g Herz schatzen. Daraus errechnet sich eine Milchsaurebildung im Herzen von etwa 10 mg/min · 100 g. Ungefahr die gleiche Menge Glucose wird standig aufgenommen (Arteriovenose Differenz=−3,62±1,1 mg/100 ml Blut, n=11). 12% des Energiebedarfes des Herzens werden unter den genannten Bedingungen anaerob gedeckt. Unter den Ausgangsbedingungen der Versuche (ohne Cyanidintoxikation) entfallen 58% des Sauerstoffverbrauches auf eine Oxydation der Milchsaure und Glucose, der Rest auf unveresterte Fettsauren. Es werden ferner allgemeine Veranderungen von Stoffwechsel, Kreislauf und Atmung bei Cyanidvergiftung diskutiert.

Ehrlich showed in 1890 that methylene blue, injected in the living animal, stained not only the axons of peripheral nerves, but also some muscle fibres of the arteries. On the basis of the theory that migraine attacks were caused by vascular spasm he decided to try to abort them by injecting methylene blue at their beginning, and was successful in two cases. Many writers have reported f avorably on the intravenous use of methylene blue in cyanide poisoning cases and some have even reported success in carbon monoxide poisoning cases, suggesting to us that it may be used to relieve conditions involving interference with tissue respiration. As local vascular spasm and local relative anoxia in the central nervous system have been demonstrated in both induced and spontaneous convulsions, one of us conceived the idea that this substance might be useful in relieving Status convulsivus. We cannot prove that methylene blue injected intravenously acts as an auxiliary respiratory catalyst, we merely report our experience with its use in severe status. Only those cases in which the patient was completely unconscious (i. e., non-reactive to painful stimuli, with absence of deep reflexes) between attacks were accepted as being status. The treatment was considered entirely successful only when it promptly restored consciousness and terminated the series of convulsions. In contrast to the effect produced by the customary sedative treatments which usually result in longer or shorter periods of continued unconsciousness or sleep and are often followed by severe headache, methylene blue restored consciousness very promptly without these unpleasant after-effects.

The contents of phosphoinositides, ATP, glucose and lactate in leg and claw nerves of the lobster were determined. Nerves were also analysed after cyanide poisoning, after electrical stimulation, and 1 h after removing the leg from the lobster. Cyanide poisoning decreased the levels of ATP and glucose and increased the content of lactate but did not alter the levels of phosphoinositides. Nerves left in situ for 1 h after disconnection from the central nervous system exhibited a decrease in the content of tri-phosphoinositides (TPI) of 50 per cent, without changes in ATP, glucose or lactate. The TPI change was reversed after incubation for 1 h in oxygenated seawater. Nerves labelled in vivo with 32P were removed and stimulated at 50 Hz for 5 min. The turnover of TPI phosphorus increased on stimulation in both normal and cyanide-poisoned nerves. In contrast, turnover of ATP increased after stimulation in normal nerves but not in cyanide-treated nerves. We sought to determine whether polyphosphoinositides play a greater role in resting metabolism of the nerve or in the conducting mechanisms. Our results make more likely the involvement of TPI in permeability changes of neural membranes during excitation.

There are relativcly few reports on the pathologic effects of cyanide poisoning (GREENFIELD et ULE and PRIBILLA~~), despite the frequency of poisoning by cyanide salts or vapor in humans and by cyanogenctic plants in herbivorous animals. There may bc survival without apparent sequelae or rapid death beforc lesions can develop. The characteristic cncephalopathy of cyanide poisoning is seen only in cascs of severe intoxication that have a sufficiently prolongcd survival to permit development of pathologic changes. Instances of this sort are probably even less common among domestic animals than among humans, and we have been unablc to find any specific reference to accidental poisoning of animals by cyanide salts (BLOOD and HENDERSON~ ; JURB and I

Thirteen of the 15 cases of polioencephalomalacia reported in this article are considered to be idiopathic. These cases are compared with two cases of polioencephalomalacia following from cyanide poisoning and all are discussed in relation to similar entities occurring in dogs and in other species.

Summary1. 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.

The suprarenal vein blood was sampled. in non-anesthetized dogs and the adrenaline in the suprarenal vein blood was. estimated by the rabbit intestine segment method. Potassium cyanide was. injected in a dose of 1.0-2.5mg. per kg. intravenously or 1.5-4.0mg. per kg. subcutaneously. After injection when the symptoms of cyanide poisoning were mani-fested, the secretion of adrenaline accelerated decidedly. An enormously accelerated adrenaline secretion such as 1.9 γ per kg. per minute was able to observe in the cases, in which potassium cyanide was injected in a dose of 2.0mg. or 2.5mg. per kg. intravenously.

Electron-microscopic changes of the heart muscle of rats after administration of cyanide were described in detail with the purpose of demonstrating the direct effects of cyanide on the heart muscle. The most prominent electron-microscopic changes were elongation of the sarcomere, dissociation of the myofibrils at the level of I band, swelling, destruction and disappearance of the mitochondria, enlargement of the vesicles of sarcoplasmic reticulum, margination of chromatin granules in the nucleus, and swelling of the capillary endothelial cells. These findings were most prominent in cases of death in 10 to 15 minutes after injection of 10 mg per kg of potassium cyanide. On the other hand, the above changes were slight in cases of death within 5 minutes after the same dosage, because the rats died rapidly from paralysis of the respiratory center rather than cardiac disturbances. The rats with the dosage of 2 mg per kg of potassium cyanide survived cyanide poisoning, and the ultrastruc-tural changes in 15 minutes after the injection were only slight swelling of mito-chondria and of vesicles of sarcoplasmic reticulum, and these changes were not found in 60 minutes after the injection. These results suggest that the cyanides in a larger dose exert a direct influence nott only on the metabolic systems but also on the contractile elements of the heart, muscle, but those in a smaller dose cause only slight and reversible changes in the metabolic systems.

Intravenous injection of hydroxo-cobalamine tends to delay the onset of toxic signs, prolong the survival time, and occasionally save the life of the non-anesthetized dog following a lethal dose of sodium cyanide administered subcutaneously. It does not seem practical of possible for this antianemic vitamin to detoxify multiple lethal doses of the poison in the dog.

The widely published schedule for the treatment of cyanide poisoning by the nitrite thiosulfate method of Chen is based on adult work and is potentially lethal for children under 25 kg in weight. Unless a dose of sodium nitrite appropriate for the amount of hemoglobin in the child is chosen, lethal methemoglobinemia may result. The dose of NaNO2 for children with a hemoglobin of 12 gm/100 ml is 10 mg/kg per body weight immediately and 5 mg/kg repeated within 30 minutes if necessary.

The rates of decrease in measurable cyanide concentration in various tissues have been experimentally investigated in rabbits killed with potassium cyanide. The study compared the rates of transformation of cyanide in tissues stored for up to 3 weeks following their removal shortly after death, with the rate of decrease of measurable cyanide in similar tissues which were removed from animals at various times after death. The results stress the necessity for early sampling, and prompt analysis, of tissues from suspected cases of acute cyanide poisoning. The importance of analyzing samples of whole blood is stressed, and the practical relevance of the experimental findings to the diagnosis of acute cyanide poisoning in man is discussed.

The respiration rate and intensity of phospholipid metabolism of a rat brain tissue homogenate was studied during incubation at different temperatures (37, 32 and 27°C) in medium with and without cyanide (0.5 and 1 mM). Both these parameters are directly dependent on incubation temperature between 27 and 37°C. The presence of cyanide in the medium inhibits both processes but phospholipid metabolism more so than respiration. The results indicate that phospholipid metabolism during cyanide poisoning is affected both by the toxic action of the cyanide itself directly, and by temperature, the lowering of which potentiates the toxic action.

The action of methylene blue in restoring the respiration of cyanide inhibited tissues (Gerard1) has led to the clinical and apparently successful use of the dye as an antidote for cyanide poisoning (Brooks2). It has been urged that methylene blue acts in the intact organism not directly by substituting in the cells for the inactivated respiratory enzymes, but indirectly by removing the cyanide and releasing the enzyme. Cyanide would thus be removed by the formation of the stable cyanmethemoglobin, from it and methemoglobin; formed in turn from the blood pigment by methylene blue (Wendel3). An antagonism of methemoglobin and cyanide has been demonstrated on rat tissues (Rosenthal and Voegtlin4).It seemed of interest, in this connection, to determine the action of methemoglobin and methylene blue, with cyanide, on isolated invertebrate tissues. Ciliated gill tissue of the quahog (Venus mercenaria) was isolated in sea water and its oxygen consumption followed at 22°C. in Warburg manometers. Alkali in the in...

SummaryMercuric cyanide has a dual mechanism of poisoning. In dogs receiving this poison intramuscularly, the cyanide radicle may be detoxified by intravenous injection of sodium nitrite and sodium thiosul-fate, one after the other; and the mercury radicle, by prompt injection of BAL. The latter can be given first by intravenous injection, and repeated by intramuscular injection. The LD50 of mercuric cyanide in dogs without treatment is 2.71 ± 0.17 mg per kg; and that with nitrite-thiosulfate therapy and BAL injections, 8.66 ± 0.66 mg per kg.

The prophylactic intraperitoneal administration of sodium nitrite (80 mg./Kg.) thirty minutes prior to the subcutaneous injection of one LD 95 of sodium cyanide protected 80 per cent of the mice. Under similar circumstances, sodium cobaltinitrite (60 mg./Kg.) afforded optimal protection to 97 per cent. Both sodium nitrite and sodium cobaltinitrite, administered thirty seconds after the injection of 1 LD 95 of sodium cyanide, required lower doses and were more effective than when given prophylactically. The most effective therapeutic dose of sodium nitrite was 50 mg./Kg. which produced 90 per cent survival, while sodium cobaltinitrite was most effective at a dose of 30 mg./Kg., which produced a 96 per cent survival. Sodium cobaltinitrite–sodium thiosulfate combinations, when antidoting 4 LD 95 's of sodium cyanide, achieved percentage results that were similar to those attained with sodium nitrite–sodium thiosulfate combinations in antidoting 3 LD 95 's of the poison.

Since the work of Warburg (1) on the respiration of tumor cells several studies have been made of the influence of various reducing and oxidizing agents on tumor growth. Thus Brooks (2) studied the effect of methylene blue injections on tumor growth in rats and mice and the present authors (3) investigated the effect of sodium formaldehydesulfoxylate on rat sarcoma. In 1929 Karczag (4) showed that potassium cyanide inhibited the growth of transplanted adenocarcinoma in mice and in some instances caused regression. Later Maxwell and Bischoff (5), and Perry (6) studied the effect of the powerful reducing agent, hydrogen cyanide, on tumor growth. Perry observed that inhalation of hydrogen cyanide brought about regression in growing tumors and diminution in capacity to transplant. In all instances the effective dose closely approached the toxic dose. Chen et al. (7 and 8) recently developed an effective antidote against cyanide poisoning. It was observed that injections of sodium nitrite and sodium thiosulfate solutions would protect against 10 fatal doses of cyanide. It occurred to the authors to investigate the action of potassium cyanide on rat sarcoma, using this antidote to protect the animal, thus making it possible to administer many times the fatal dose. Materials and Methods Freshly prepared solutions of reagent sodium nitrite and sodium thiosulfate were injected subcutaneously; the cyanide solutions were injected intraperitoneally. Implantations of Walker sarcoma 319 (9) were made by mincing small pieces of tumor tissue, taken from the wall of a well developed tumor, with the animal under light surgical anesthesia. The cells were implanted subcutaneously in the anterior axillary region, aseptically, by means of a trocar. In Series 1, male rats weighing between 100 and 150 grams were used. In Series 2, young male rats weighing between 50 and 100 grams were employed. In Series 1 injections were made on alternate days and in Series 2 the injections were made daily. In each instance the rats were injected immediately after the tumor implantation. The lethal dose of potassium cyanide on intraperitoneal injection was found to be 0.44 mg. per 100 gram of rat. The results of the experiment were as shown in Tables I and II.

The antidotal activities of aquocobalamineacetates and sodium thiosulfate were tested in guinea pigs and cats. The animals were attached to artificial respirators throughout the experiment and were poisoned with a continuous infusion of sodium cyanide solution (4.1 muMol/kg.min NaCN). The rate of action of each antidote was determined from the time taken for the HCN exhalation to drop below the level of 100 nMol/kg.min in quinea pigs, and to values below 25 nMol/kg.min in cats; the detoxifying capacity of each antidote was determined from the time taken for the HCN exhalation to rise above the said values and the time interval for normal function of heart activity to be restored. Aquobalamine was characterized by its rapid rate of reaction in both the animal species; its detoxifying capacity showed, however, according to our expectations, variations corresponding to the applied doses. The combination of the antidotes aquocobalamine (100 mg/kg) and thiosulfate (500 mg/kg) proved to possess high rate of reaction and a large detoxifying capacity in guinea pigs. Similar results were obtained in cats with antidote doses of 200 mg/kg aquocobalamine combined with 500 mg/kg thiosulfate. The slow rate of reaction and large detoxifying capacity of thiosulfate were confirmed in our experiments. It combination with aquocobalamine showed no undesirable change in its antidotal action providing a time interval of 1 min was maintained between the 2 injections.

The original scope of this investigation was the study of the passage of hydrocyanic acid vapour through the skin. We have partly repeated and confirmed the results of Walton and Witherspoon (1926). In view of the extensive use of hydrocyanic acid vapour in the destruction of vermin in ships the subject is of considerable practical interest. In the course of our work certain other matters were considered and these are referred to in the text.

Es wurde der Einflus von Cyanid in verschiedener Dosierung auf den Plasmaspiegel von freiem Cholin der A. femoralis, V. femoralis und V. hepatica des Hundes untersucht. Die Abtrennung des Cholin erfolgte mittels eines Ionenaustauschers, die quantitative Bestimmung durch Fallung als Reineckat und nachfolgende spektrophotometrische Messung.

The oxidation-reduction potential of cytochrome-c has been studied by Paul (1) and by Rodkey & Ball (2). Whereas previous investigations were confined to a narrow pH range around 7, these new measurements extend over a much wider range, designed to reveal any dissociation constants due to heme-linked groups in the molecule. The results are in fairly good agreement, though differing in detail. Ferricytochrome-c has a dissociation constant of nearly 10-7 [pK = 6.86 according to Paul (1); 7.70 according to Rodkey & Ball (2) J. The Eo' = pH curve has a slope of 0.0 between pH 1.75 and 7.70 (Eo' = +0.254 v.) and of 0.060 between pH 7.70 and 10.0. There is some indication that below pH 1. 75 the slope is 0.120 (2). Light absorption measurements reveal for ferrocytochrome-c a pK value of 9.28 (1). Azide, like cyanide (3), forms a well-defined complex with fer­ ricytochrome-c, though not with the ferrous form (4). The com­ pound is characterized by a shift of the absorption maximum from 5300 A to 5400 A, by the appearance of a faint new band at 5750 A and, again in analogy to the cyanide compound, by the disappear­ rance of the band at 6925 A. The azide complex differs from the cyanide complex by the fact that it is highly dissociated and that its formation is almost instantaneous. Whereas cytochrome-c, like methemoglobin, reacts only with the cyanide or azide ions, cyto­ chrome oxidase combines with the undissociated acids. This con­ clusion is based on an analysis of the inhibition as a function of pH (5). Michel & Scheinberg (6) did not observe any beneficial effects of intravenous injections of cytochrome-c on anoxic or cyanide­ poisoned rats, as claimed by Proger et al. (7). Since Albaum et al. (8) had shown that "after cyanide poisoning 50 per cent of rat brain cytochrome oxidase was still functional, an increased supply of cytochrome-c might conceivably have increased the efficiency of

† Two cases of acute poisoning by the inhalation of hydrogen cyanide are described. The first patient regained consciousness 40 minutes after his collapse; in the interval he was treated with inhalations of amyl nitrite and intravenous injections of 0.3 gm. of sodium nitrite and 12.5 gm. of sodium thiosulfate. The second patient remained stuporous during the five hours that followed her collapse; during that interval she received inhalations of oxygen and carbon dioxide and of amyl nitrite as well as an intravenous injection of 0.6 gm. of sodium thiosulfate. Much improvement followed the intravenous injection of 50 cc. of a 1 % solution of methylene blue. No dramatic effects were obtained from alternating injections of sodium nitrite and sodium thiosulfate in her case. Both patients made complete recoveries.

Nigerian nutritional ataxic neuropathy comprises panmyelopathy, bilateral optic atrophy, sensorineural deafness and polyneuropathy. In a third of the patients, mucocutaneous evidence of malnutrition is present. The disease occurs in high prevalence in the areas of Nigeria where cassava is most intensely cultivated. Cassava contains a cyanogenetic glycoside, from which hydrocyanic acid is released on hydrolysis. The sex incidence is equal. It is a disease of the poor who subsist entirely on culinary derivatives of cassava. It has a peak prevalence in the 4th to 6th decades. In 41% of 320 patients studied, a positive history that someone else in the household or family suffered from the disease was obtained. In familial cases, 50% are conjugal. There is biochemical evidence of increased exposure to cyanide in ataxic families. There is no evidence so far of a genetically determined predisposition to the disease. Field surveys in 2 villages in an endemic area, and one village in a non-endemic area, showed a positive correlation between the prevalence of the disease and consumption of cassava meals and biochemical evidence of chronic cyanide intoxication. The prevalence rate of the disease in the endemic foci is 18 to 26 per thousand of the population, with a peak prevalence rate of 80 per 1000 in the 6th decade. Cassava processors and farmers who grow and handle cassava may be at special risk. Goitre is not uncommon in patients and may be related to inhibition of iodine uptake by the thyroid due to high concentration of plasma thiocyanate (a detoxication product of cyanide). The epidemiological data support the hypothesis that in Nigerians, chronic cyanide intoxication of dietary origin is the most important factor in the aetiology of ataxic neuropathy. The main source of the cyanide is cassava.

Wurden Katzen in flacher Chloralose-Narkose 4 bzw. 8 mg KCN/kg in 2 min i.v. infundiert, so fielen Atemfrequenz, Blutdruck, Pulsfrequenz und Stromung in der A. femoralis rasch ab. In der A. carotis stieg die Stromung zunachst uber den Ausgangswert an und sank danach schnell ab.

Summary. The LD50 for rapidly intravenously injected HCN was increased about 15 to 20 times by a previous intravenous injection of rhodanese and ethanethiosulfonate. The therapeutic effect in cyanide poisoning of this combination was also demonstrated.

Cyanide poisoning in mice can be antagonized by the administration of hyperbaric oxygen (OHP) when it is administered in combination with the conventional cyanide antidotes, sodium nitrite and sodium thiosulfate. Potency ratios derived from LD50 values were compared in groups of mice treated with sodium thiosulfate, sodium nitrite, oxygen and OHP, either alone or in various combinations. These results indicate that the administration of OHP alone provides no protection against the lethal effects of cyanide poisoning. Furthermore, OHP does not enhance the effect of sodium nitrite or sodium thiosulfate. Hyperbaric oxygen does strikingly potentiate the antidotal effect of sodium thiosulfate in combination with sodium nitrite; however, this synergistic effect of OHP is no greater than that of oxygen under normal atmospheric conditions. Therefore, the use of OHP rather than oxygen under atmospheric conditions incyanide poisoning is not warranted.