The reaction of several aminophenols with hemoglobin and oxygen in vitro and in vivo

Summary p-Methylaminophenol, p-butylaminophenol and o-aminophenol increased the hemiglobin concentration in red cells faster than p-aminophenol did. The activity of p-aminophenol was strongly inhibited by the substitution of an acetyl residue in o-position.Like p-aminophenol, p-methylaminophenol and o-aminophenol reacted faster with dog's hemoglobin than with ox hemoglobin. p-Butylaminophenol raised the concentration of hemoglobin almost equally rapidly in the red cells taken from ox blood and dogs blood.In cats the concentration of hemiglobin produced by o-aminophenol, p-aminophenol, p-methyl- and p-butylaminophenol increased in proportion to the logarithm of the dose. In raising the hemiglobin concentration p-aminophenol was the least, p-butylaminophenol the most effective. Although the p-alkylaminophenols were most toxic when injected intravenously into mice, there was no correlation between the DL₅₀ and the capacity to produce hemiglobin in a series of aminophenols.With 9 Figures in the TextDedicated to Professor Otto Krayer on the occasion of his 65th birthday.The results of this study were briefly reported at a conference held by the New York Academy of Sciences on March 5, 1964.     

几种药物不同部位与不同途径给药对动物LD50的影响

盐酸普魯卡因与硫酸阿託品注射于小白鼠前肢腕部內側正中线深部时其LD₅₀值显著低于同一药物后肢肌內或背部皮下注射.氰化钾注射于小白鼠或大白鼠的上述部位其毒性显著低于后肢肌内注射与背部皮下注射.亚硝酸钠LD₅₀值于小白鼠中未見有上述的差别。实驗論証上述毒性差別主要不是因药物自注射部位吸收差別所致。盐酸普魯卡因不論肌內或腕內侧正中线深部注射都能有效地減低氰化鉀的毒性。大白鼠一側臂神經纵切除后一周,再注射氰化鉀于此側的腕內侧正中线深部,其毒性即显著低于正常动物同部位的給药組,故认为氰化鉀毒性的发生可能与神經机制有关。     

Circulation,respiration, and blood homeostasis in cyanide-poisoned dogs after treatment with 4-dimethylaminophenol or cobalt compounds

The effects of intravenously injected 4-dimethylaminophenol-HCl (DMAP), Co₂EDTA, and Co(histidine)₂ on the survival rate and several physiological parameters were studied on dogs after acute intravenous poisoning with the double lethal dose of potassium cyanide.All dogs survived when the antidotes were administered 1 min after poisoning. When the therapy began 4 min after poisoning more dogs were rescued in the DMAP group than in the cobalt groups. DMAP, Co₂EDTA, and Co(histidine)₂ restored circulation and respiration of the surviving animals in a similar manner.The increase in the plasma concentrations of glucose and lactate was much higher in the Co₂EDTA group than in the DMAP group. The injection of Co₂EDTA produced a sharp rise in the lactate-to-pyruvate ratio. The lactate-to-pyruvate ratio stayed unchanged for some 15 min after injection of DMAP before also rising. The total dose of KCN (4 mg/kg) was bound to the ferrihemoglobin formed by DMAP. The arterial pO₂ increase, caused by liberation of oxygen from oxyhemoglobin during the formation of ferrihemoglobin, was less when the cyanide could act on the tissues for a longer period of time before the therapy with DMAP began.DMAP is more appropriate for the therapy of cyanide poisoning than Co₂EDTA, since the latter adds its inhibitory effects on the metablism to those of cyanide.     

Enzyme therapy in cyanide poisoning: Effect of rhodanese and sulfur compounds

Crystalline bovine liver rhodanese (thiosulfate: cyanide sulfurtransferase, EC 2.8.1.1) was evaluated as an antidote in combination with different sulfur compounds against cyanide poisoning in mice. The prophylactic antidote effect, when the antidote was injected i.v. 1 min prior to i.p. injection of cyanide, was dependent on both the dose of the enzyme and the dose of the sulfur compound. An optimal dose of the enzyme of about 2,000 U/kg (3 mg/kg of pure enzyme) was found. This enzyme dose combined with 2 mmol/kg of sodium thiosulfate raised the LD₅₀ for potassium cyanide 7.6 times. When thiosulfate was replaced with equimolar doses of ethanethiosulfonate and propanethiosulfonate, the corresponding values were 10.3 and 9.3 times, respectively. Maximum antidote effect was obtained when the doses of ethanethiosulfonate and propanethiosulfonate were raised to 4 mmol/kg, increasing the LD₅₀ for cyanide 20.8 and 15.4 times, respectively. On the other hand, when given without rhodanese, ethanethiosulfonate and propanethiosulfonate were no better antidotes than thiosulfate.Rhodanese and a sulfur compound given therapeutically to mice when symptoms of cyanide poisoning had occurred, also had a very good antidote effect. The prophylactic antidote effect of rhodanese plus thiosulfate rapidly decreased with increasing time interval between injection of the antidote and cyanide. Thus, when rhodanese and thiosulfate were given 20 min prior to cyanide, the antidote effect was of the same order as that of thiosulfate alone. The antidote effect of the latter did not decrease significantly within the same time interval.Enzyme activity in plasma decreased rapidly after i.v. injection of rhodanese, and enzyme activity in urine was detected following injection. No appreciable inactivation occurred when the enzyme was incubated with whole blood in vitro, but a strong and rapid inhibition, about 85%, of the enzyme occurred in fresh mouse urine in vitro.     

The effect of prior treatment with 4-dimethylaminophenol (DMAP) on animals experimentally poisoned with hydrogen cyanide

Six dogs were given sufficient oral 4-dimethylaminophenol (DMAP) to produce a peak methaemoglobin level of 12–15%. Five out of the six dogs then survived an intravenous injection of approximately 2 LD₅₀'s of hydrogen cyanide given when the methaemoglobin had reached 8–10%. The sixth dog died after 44 min. When the same dose of hydrogen cyanide was given to dogs, not previously given DMAP, all three died within 11/2 min. It was concluded that prior treatment with oral DMAP provided a large measure of protection against cyanide poisoning. Comparison of cyanide levels in whole blood and plasma in the two groups of dogs lent support to the hypothesis that methaemoglobin complexed with cyanide in the erythrocytes causing the plasma cyanide to remain lower than it did in unprotected animals.     

Effects of 4-dimethylaminophenol,Co2EDTA,or NaNO2 on cerebral blood flow and sinus blood homeostasis of dogs in connection with acute cyanide poisoning

The effects of the cyanide antidotes DMAP, Co₂EDTA, and NaNO₂ on cerebral blood flow (CBF) and cerebral blood gases were investigated in connection with acute poisoning of dogs by cyanide. The substances were injected intravenously. Local CBF as measured with thermocouples in the cingulum increased by 100–200% after a non-lethal dose of KCN (1 mg/kg) and by 50% after injection of NaNO₂ (15 mg/kg), that oxidized some 20% of the total hemoglobin to ferrihemoglobin. Co₂EDTA (10 mg/kg) induced a decrease in local CBF of 30% and in brain temperature of 0.5°C. The temperature diminished also after poisoning by KCN, but it rose by 0.15°C after the administration of NaNO₂. Local CBF and sinus sagittalis blood flow increased by 60–160% for about 15 min, and the brain temperature decreased by 0.4–0.5°C when DMAP (3.25 mg/kg) or Co₂EDTA (15 mg/kg) was injected 1 min after poisoning by cyanide (4 mg/kg), a dose that always caused respiratory arrest. Immediately after injection of DMAP the brain temperature rose transiently by 0.1–0.2°C. Co₂EDTA did not exert such an effect. In the sinus sagittalis blood of artificially ventilated animals pCO₂ decreased rapidly by 10–20 mmHg after poisoning and approached the initial level after treatment with DMAP or Co₂EDTA. The highest value of pO₂ was about 80 mmHg and 50 mmHg after injection of DMAP and Co₂EDTA, respectively; thereafter pO₂ declined to 20 mmHg or 40 mmHg at 20 min. The lactate concentration increased by 60–70% without tendency to return to normal.     

Efficacy of various dithiol compounds in acute As2O3 poisoning in mice

The efficacy ofdl-dimercaptopropanol (British Anti-Lewisite, BAL),dl-dimercaptopropanesulfonate (DMPS), and meso-dimercaptosuccinic acid (DMS A) was compared in reducing the acute As₂O₃ toxicity in mice. Mice were treated with a single equimolar dose of a dithiol compound (0.7 mmol/kg i.p.) 0.5 or 30 min after the s.c. injection of various doses of As₂O₃. Both DMPS and DMSA were significantly (p<0.05) more effective in mice treated 0.5 min after the poisoning if compared to BAL on an equimolar level. The highest potency ratio (PR) (LD50 with treatment/LD5o without treatment) was found in animals injected with DMSA (PR=8.6). The corresponding value for DMPS was 4.2, and for BAL 2.1, respectively. In animals treated 30 min after poisoning the efficacy of DMPS (PR = 2.6) was similar to the efficacy of DMSA 2.4, both being only slightly superior to BAL 2.O. DMPS and DMSA were found to be much less toxic than BAL. The LD₅₀ of arsenic was 0.057 mmol/kg. The efficacy of BAL, DMPS, and DMSA in reducing the tissue content of arsenic following acute As₂O₃ poisoning was investigated in mice (n=6/group) and guinea pigs (n=3-4/group). The animals were injected s.c. with 0.043 mmol/kg As₂O₃ (containing a tracer dose of⁷⁴As(III)). Thirty minutes later the antidotes were administered A were more effective in reducing the arsenic content of tissues than BAL. Moreover, BAL caused accumulation of the toxicant in the brain. It is concluded that the recommendation of BAL as drug of choice in acute arsenic poisoning needs to be carefully re-evaluated.     

The role of N,N-dimethylaniline-N-oxide in the formation of hemiglobin following the absorption of N,N-dimethylaniline

Summary Since the concentrations of phenylhydroxylamine and nitrosobenzene in the blood of cats and dogs are too low to produce all the hemiglobin observed following the injection of N,N-dimethylaniline, other meta-bolites were tested for their hemiglobin forming activity.After the intravenous injection of 0.6 mMol N,N-dimethylaniline or N,N-diethylaniline per kg into dogs the hemiglobin concentration rose beyond 0.4 of the total blood pigment, and the N-oxides were found in the blood of dogs in concentrations of about 8 and 6 g/ml. These concentrations of the N-oxides in the blood of dogs, when produced by intravenous infusion of the N-oxides, did not raise the hemiglobin concentration. Therefore, the N-oxides are not the metabolites that form the hemiglobin observed after the absorption of N,N-dialkylanilines.p-Dimethylaminophenol, a metabolite of N,N-dimethylaniline, was found to be highly active in forming hemiglobin in vitro and in vivo. It is likely that it plays an important role in the hemiglobin formation following the absorption of N,N-dimethylaniline.     

The formation in vivo of p-hydroxylaminopropiophenone from p-aminopropiophenone and its action in vivo and in vitro

Summary The N-hydroxylation of p-aminopropiophenone in dogs was demonstrated by the spectrum of p-nitrosopropiophenone in carbon tetrachloride extracts taken from the blood of dogs after injecting p-aminopropiophenone.The N-hydroxylation of p-aminopropiophenone proceeded rather rapidly. The p-hydroxylaminopropiophenone proved to be more active than phenylhydroxylamine in the enzymic cycle of hemiglobin formation in the red cell.By comparing the velocity of hemiglobin formation and the concentration of p-hydroxylamino- and p-nitrosopropiophenone in the blood of dogs following the injection of p-aminopropiophenone or the slow infusion of p-hydroxylaminopropiophenone it was ascertained that the hemiglobin formation following the injection of p-aminopropiophenone was mainly due to p-hydroxylaminopropiophenone.With 4 Figures in the Text     

Formation of cyanide from o-chlorobenzylidene malononitrile and its toxicological significance

Mice received o-chlorobenzylidene malononitrile (CS) by i.p. injection (0.5 LD₅₀) or by aerosol exposure (20,000 mg min^–1 m^–3). Increased excretion of thiocyanate in the urine was observed, indicating a transformation of CS to cyanide in vivo. Determinations of cyanide in whole blood after i.p. administration of CS verified a rapid transformation of the agent to cyanide. A correlation between the time course of cyanide levels and symptoms was observed. Toxicity of injected CS was significantly reduced by pretreatment with thiosulfate, slightly reduced by nitrite and not affected by Co₂EDTA.Thiocyanate excretion, blood cyanide levels and protective effect of antidotes were also evaluated after administration of 0.5 LD₅₀ of malononitrile and potassium cyanide. The importance of cyanide formation for the toxicity of CS is discussed.     

大苞雪莲有效成分的抗缺氧药效学研究

目的 研究大苞雪莲有效成分（石油醚活性部位及其主要单体成分二十八烷）的抗缺氧药效学。方法 首先采用常压密闭缺氧耐受力实验和急性减压缺氧耐受力实验联合评价大苞雪莲石油醚部位和二十八烷的抗缺氧活性,然后采用3种化学中毒缺氧模型（氰化钾、亚硝酸钠、盐酸异丙肾上腺素）进行其抗化学中毒缺氧活性的药效学评估。结果 大苞雪莲石油醚部位和二十八烷可以有效延长常压密闭缺氧小鼠的存活时间（P<0.01）,降低急性减压缺氧小鼠的死亡率（P<0.01）,且具有剂量依赖关系;化学中毒缺氧药效学研究表明,石油醚部位和二十八烷在化学中毒缺氧实验中的小鼠存活时间均明显大于乙酰唑胺（P<0.05）。结论 大苞雪莲石油醚部位和二十八烷具有良好的抗缺氧活性。     

Comparison of hydroxylamine, 4-dimethylaminophenol and nitrite protection against cyanide poisoning in mice

Intraperitoneal doses of 4-dimethylaminophenol hydrochloride (DMAP), hydroxylamine hydrochloride (H₂NOH) and sodium nitrite (NaNO₂) were found where each converted a maximum of about 37% of the total circulating hemoglobin in mice to methemoglobin. Those doses in mmol/kg were: 0.29 for DMAP, 1.1 for H₂NOH, and 1.1 for NaNO₂. For DMAP and H₂NOH the peak was sharp and at about 7 min after injection whereas for NaNO₂ the peak was much broader and at about 40 min. The i.p. LD₅₀'s in mmol/kg were: 0.48 for DMAP, 1.8 for H₂NOH and 2.3 for NaNO₂. When mice pretreated with each of the methemoglobin-generating agents were challenged with sodium cyanide, the ratios of the LD₅₀'s in protected mice to those in control mice (protection index, PI) were 1.5 for H₂NOH, 2.0 for DMAP and 3.1 for NaNO₂. When sodium thiosulfate was also given in combination with each of the three methemoglobin-generating agents, the protective effect was at least additive. The PI against sodium sulfide was also significantly greater in mice pretreated with NaNO₂ than in mice given H₂NOH. Methemoglobins generated from human and mouse hemoglobins by either NaNO₂ or by H₂NOH had identical binding affinities (dissociation constants) for cyanide. When human red cells containing methemoglobin generated by exposure to either NaNO₂ or H₂NOH were injected into the peritoneal cavity of mice and then followed by cyanide challenges, there was no difference in the PI for the two kinds of methemoglobin. Not only was the PI the same in each case with human cells, but it was also identical with that in mice given NaNO₂ systemically to generate the same total amount of methemoglobin. The difference in PI between NaNO₂ and H₂NOH (or DMAP) in mice appears to be related to the high rate of methemoglobin reductase activity in mouse RBC. It appears likely that cyanmethemoglobin is a substrate for mouse methemoglobin reductase activity, and that NaNO₂ is an inhibitor of mouse methemoglobin reductase. No differences in cyanide antagonism between NaNO₂ and H₂NOH would be anticipated in humans because of the slow rates of methemoglobin reduction in human red cells.     

Acute, sublethal cyanide poisoning in mice is ameliorated by nitrite alone: complications arising from concomitant administration of nitrite and thiosulfate as an antidotal combination

Sodium nitrite alone is shown to ameliorate sublethal cyanide toxicity in mice when given from ～1 h before until 20 min after the toxic dose as demonstrated by the recovery of righting ability. An optimum dose (12 mg/kg) was determined to significantly relieve cyanide toxicity (5.0 mg/kg) when administered to mice intraperitoneally. Nitrite so administered was shown to rapidly produce NO in the bloodsteam as judged by the dose-dependent appearance of EPR signals attributable to nitrosylhemoglobin and methemoglobin. It is argued that antagonism of cyanide inhibition of cytochrome c oxidase by NO is the crucial antidotal activity rather than the methemoglobin-forming action of nitrite. Concomitant addition of sodium thiosulfate to nitrite-treated blood resulted in the detection of sulfidomethemoblobin by EPR spectroscopy. Sulfide is a product of thiosulfate hydrolysis and, like cyanide, is known to be a potent inhibitor of cytochrome c oxidase, the effects of the two inhibitors being essentially additive under standard assay conditions rather than dominated by either one. The findings afford a plausible explanation for an observed detrimental effect in mice associated with the use of the standard nitrite-thiosulfate combination therapy at sublethal levels of cyanide intoxication.     

Effects of 4-dimethylaminophenol and Co2EDTA on circulation,respiration, and blood homeostasis in dogs

The effects of intravenously injected 4-dimethylaminophenol and Co₂EDTA on peripheral circulation, respiration, acid-base balance, and several other physiological and biochemical parameters were studied on dogs. DMAP increased the respiratory minute volume and mean arterial pressure, diminished the lactate-to-pyruvate ratio, and induced an increase in arterial oxygen pressure caused by liberation of oxygen from oxyhemoglobin during the formation of ferrihemoglobin.A study in vitro of the fate of the oxygen during the reaction between DMAP and oxyhemoglobin showed that only 30–40% of the oxygen released by the formation of ferrihemoglobin appeared in the gas phase.Co₂EDTA caused circulatory depression, hyperventilation, and metabolic acidosis resulting in a decrease in base-excess and pH. The concentrations of lactate, pyruvate, potassium, and urea nitrogen and the hemoglobin content were increased by Co₂EDTA. The side effects of Co₂EDTA in therapeutic doses were more serious than those of DMAP. Thus the latter is superior in the therapy of cyanide poisoning, all the more since it detoxifies more cyanide.     

对二甲氨基酚治疗急性失血合并氰中毒对血液动力学及血液内环境的影响

本实验用犬制备了轻(10％)、中(15％)、重度(20％)急性失血合并ⅳ NaCN 2.5 mg/kg中毒的动物模型,观察了ⅳ DMAP 2.5mg/kg治疗时血液动力学及血液内环境的变化。结果发现,DMAP治疗轻度急性失血合并氰中毒能使心血管功能迅速恢复正常并维持稳定,随失血程度加重DMAP对心血管功能兴奋作用减弱;血气分析及HbFe~(3+)测定结果表明,DMAP治疗急性失血合并氰中毒可造成机体严重缺氧及代谢性酸中毒,并随失血程度的加重而加剧。     

Zur Beurteilung der Blausäure-Antidote

The effect of various antidotes on the exhalation of hydrocyanic acid has been measured in guinea pigs and cats poisoned with cyanide. This procedure permits evaluation of both the speed of action and the capacity of the agents tested to detoxify hydrocyanic acid, and therefore allows an exact judgement as to therapeutic value of various antidotes to cyanide poisoning. The results were as follows:

1. Cobaltous histidine at a dose of 20 mg/kg was distinguished among the compounds tested by its rapid action in both species. Its detoxifying capacity was not adequate however. Treatment of severe cyanide poisoning in man with Co (his)₂ would appear to be reasonable, but only when combined with sodium thiosulfate.
2. The same rapid action as with cobaltous histidine was achieved in cats by intravenous injection of 2.25 mg/kg p-dimethylaminophenole (DMAP) leading to a methemoglobin formation of 30%. A dose of 0.75 mg/kg DMAP forming 10% methemoglobin reduced HCN-exhalation by an equivalent amount only after a 2.4 min delay. The capacity of DMAP to detoxify hydrocyanic acid was considerably greater than that of cobaltous histidine but still was far inferior to that of sodium thiosulfate.
3. The high capacity of sodium thiosulfate to detoxify hydrocyanic acid was likewise demonstrated by the new method employed here in both animal species. However, the onset of its effect was always very delayed. In clinical practice, this agent should never be omitted, but in treatment of severe poisonings it will only be successful when combined with a more rapid-acting antidote such as cobaltous histidine or DMAP.
4. Sodium nitrite, even when applied in relatively high doses, did not act rapidly enough nor did it demonstrate a satisfactory capacity to detoxify hydrocyanic acid. Therefore, it no longer fulfills the requirements that presently should be demanded of an antidote to hydrocyanic acid.

     

苍耳子的有毒成分及其药理作用

蒼耳(Xanthium strumarium L.)是菊科植物,别名野茄子、敞子、老蒼子(东北)及刺儿棵(河南)等,我国各地都有野生。蒼耳的果实名蒼耳子,是一味常用中药,內含油約39％,蒼耳甙(xanthostrumarin)1.27％,此外尚含树脂、生物碱和丙种維生素等。儿童与家畜誤食蒼耳的果实或幼苗可以中毒死亡。为了寻找蒼耳子的毒性成分,我所植物化学室侯翠英等将蒼耳子仁脫脂,制成水浸剂,并从中提出一种蛋白貭及一种黃白色結晶状具有甙类性貭的物貭(含葡萄糖及鼠李糖),后者暫名为AA_2。我們比較了蒼耳子油、蒼耳子水浸剂、蒼耳子蛋白及AA_2的毒性,并观察了AA_2的一些药理作用。     

荭草苷对缺氧模型小鼠的抗缺氧作用研究

目的:研究荭草苷对缺氧模型小鼠的抗缺氧作用。方法:通过常压耐缺氧、亚硝酸钠中毒、氰化钾中毒、利多卡因中毒、夹闭气管及断头等建立小鼠缺氧模型,于造模前20min给予相应药物,观察药物的抗缺氧作用。结果:与生理盐水空白对照组比较,荭草苷可明显延长模型小鼠在常压缺氧、亚硝酸钠中毒、氰化钾中毒、利多卡因中毒时的存活时间,延长夹闭气管后的心电图消失时间及断头后的喘气时间。结论:荭草苷对缺氧模型小鼠具有抗缺氧作用。     

Effects of amyl nitrite on circulation,respiration and blood homoeostasis in cyanide poisoning

The effects of intravenously (i.v.) administered or inhaled amyl nitrite (AN) were followed under chloralose anaesthesia in intact and cyanide-poisoned, spontaneously breathing beagles. The i.v. doses of AN were 0.03 and 0.15 mmol/kg and the i.v. dose of KCN was 0.06 mmol/kg. AN was inhaled in a closed system at 0.15 mmol/kg without previous poisoning and, in addition, at 0.074 mmol/kg (two ampoules at 0.3 ml AN) during artificial ventilation after poisoning with 0.045 mmol KCN/kg i.v., Mean arterial pressure decreased by 15 and 40 mmHg, respectively, after i.v. injection of AN, associated with bradycardia and lowered peripheral blood flow. Respiratory minute volume rose by 65% with the higher dose. Arterial pO₂ decreased by 20 mmHg while pCO₂ rose by 6 mmHg. Within 30 min of injection, these changes were only partially reversible. Similar results were obtained following inhalation of AN in a closed system. Lactic acidosis and lowering of pH were produced by the i.v. route, but not by inhalation. Total haemoglobin increased. The lethality of KCN was abolished with AN doses that produced 10–30% ferrihaemoglobin. Artificial ventilation and simultaneous inhalation of AN after poisoning with lethal doses of KCN turned out to be ineffective therapeutic measures. The findings are compared with those of other papers dealing with cyanide poisoning and AN. It is pointed out that, for the present, there is no experimental proof for another antidotal mechanism of action of AN than ferrihaemoglobin formation.     

Die Bedeutung der Wirkungsgeschwindigkeit von Antidoten bei der Behandlung der BlausÄurevergiftung

Zusammenfassung Am isolierten HerzvorhofprÄparat der Ratte und an narkotisierten Meerschweinchen, beide in definierter Weise mit Cyanid vergiftet, wurde die Wirkungsgeschwindigkeit verschiedener Antidote verglichen.Am isolierten Organ waren die Ergebnisse mit Aquocobalamin und Kobalt-Desferrioxamin erheblich besser als mit Co₂-EDTA und Kobaltchlorid.An Meerschweinchen (280 Versuche) konnte gezeigt werden, da\ die Kobaltverbindungen Aquocobalamin, Co₂-EDTA und Co-Desferrioxamin den traditionellen Antidoten Natriumnitrit und Natriumthiosulfat weit überlegen sind.Untereinander unterschieden sich diese Kobaltkomplexe in optimaler Dosierung in ihrer Wirksamkeit kaum. Im Hinblick auf die ToxicitÄt konnte Co-Desferrioxamin günstiger beurteilt werden als Co₂-EDTA.Aquocobalamin mu\ den anderen Kobaltverbindungen grundsÄtzlich vorgezogen werden, weil diese Substanz völlig ungiftig ist. Es steht aber bisher nicht in ausreichenden Mengen zur Verfügung.

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Summary The time required by various antidotes to counteract cyanide poisoning has been investigated in isolated atria of rat hearts and on anaesthetised guinea pigs. Cyanide poisoning was induced in a defined and reproducible way. In the isolated organ aquocobalamine and cobalt desferrioxamine were considerably more effective than Co₂-EDTA and cobalt chloride. It could be demonstrated in guinea pigs (280 experiments) that cobaltous compounds as aquocobalamine, Co₂-EDTA and cobalt desferrioxamine are by far superior to traditional antidotes as sodium nitrite and sodium thiosulfate. In an optimal dose range there was hardly a difference in the efficiency of these complex cobaltous compounds. With regard to toxicity cobalt desferrioxamine was more favourable than Co₂-EDTA. Aquocobalamine is in principle preferable to other cobaltous compounds as it is entirely untoxic. For the time being, however, it is not available in sufficient amounts.

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Herrn Prof. Dr. phil. Dr. med.Friedrich Timm, Göttingen, zum 70. Geburtstag gewidmet.

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Ein Teil der hier mitgeteilten Ergebnisse wurde im Oktober 1964 in Bad Nauheim auf der 28. Tagung der Deutschen Pharmakologischen Gesellschaft vorgetragen (vgl.Grützmacher u.Friedberg, 1965).