The antidotal action of sodium nitrite and sodium thiosulfate against cyanide poisoning.

The combination of sodium thiosulfate and sodium nitrite has been used in the United States since the 1930s as the primary antidote for cyanide intoxication. Although this combination was shown to exhibit much greater efficacy than either ingredient alone, the two compounds could not be used prophylactically because each exhibits a number of side effects. This review discusses the pharmacodynamics, pharmacokinetics, and toxicology of the individual agents, and their combination.     

Acute cyanide intoxication treated with a combination of hydroxycobalamin,sodium nitrite,and sodium thiosulfate

An 80-year-old diabetic patient was admitted to the hospital because of sudden unconsciousness and severe metabolic acidosis. His son reported the possibility of cyanide poisoning. Clinical data and the detection of cyanide in blood and gastric material confirmed this possibility. Supportive therapy and the following antidotes--sodium nitrite two doses 300 mg i.v., sodium thiosulfate 3 g i.v., and hydroxocobalamin 4 g in 24 hours--were administered immediately and the patient completely recovered in 48 hours. Our observations suggest that timely and appropriate use of antidotes for cyanide intoxication may prevent death, even in aged diabetic patients.     

The efficiency of aquocobalamine as an antidote in cyanide poisoning when given alone or combined with sodium thiosulfate

The antidotal activities of aquocobalamineacetate 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 Mol/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 guinea 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.Aquocobalamine 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. Its combination with aquocobalamine showed no undesirable change in its antidotal action providing a time interval of 1 min was maintained between the 2 injections.     

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.     

Pharmacokinetics of cyanide in poisoning of dogs,and the effect of 4-dimethylaminophenol or thiosulfate

Cyanide in blood, plasma, and urine of dogs after administration of K¹⁴CN was determined with the isotope dilution technique. The addition of large amounts of inactive KCN as soon as possible to a sample to be analyzed inhibited the decrease of the original cyanide concentration.After administration of several lethal doses of cyanide into the stomach or by slow intravenous infusion a concentration of about 40 M cyanide in plasma was found at the moment of respiratory arrest. Since 60% of the cyanide in plasma was bound to proteins the concentration of free cyanide which stopped respiration was about 16 M.Quick formation of ferrihemoglobin by i.v. injection of 4-dimethylaminophenol after plasma cyanide had risen to or above 40 M decreased the cyanide concentration in plasma and restored respiration, while cyanide was accumulated in red cells by formation of ferrihemoglobin cyanide.Equilibrium constants calculated for the reaction between ferrihemoglobin and cyanide in vivo indicated that the reaction approached equilibrium in a few minutes.Up to 60% of the radioactive cyanide absorbed was found as non-cyanide radioactivity in the urine.Abbreviations Used DMAP 4-Dimethylaminophenol hydrochloride - HbFe²⁺ Ferrohemoglobin - HbFe³⁺ Ferrihemoglobin - HbFe³⁺CN^– Ferrihemoglobin cyanide - C_a Molarity of all radioactive compounds calculated on the assumption that one mole cyanide yields one mole metabolite - NCR Molarity of non-cyanide radioactive compounds calculated on the assumption that one mole cyanide yields one mole of metabolite (C_a-[CN^–])     

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.     

Comparison of nitrite treatment and stroma-free methemoglobin solution as antidotes for cyanide poisoning in a rat model

The standard nitrite/thiosulfate regimen for cyanide poisoning was tested in our rat model. By modifying the treatment regimen and the nitrite solution an effective antidote against an LD90 of cyanide could be produced. However, this treatment was effective against two times the LD90 only when administered ten minutes prior to cyanide injection. These results are in marked contrast to our results with stroma-free methemoglobin solutions (SFMS) which showed SFMS to be a highly effective antidote against four times the LD90 when administered 30 seconds after an intravenous injection of cyanide. SFMS proved to be an effective antidote for two times the LD90 when administered up to sixty seconds after the cessation of respiration.     

Acute behavioral effects of lorazepam and caffeine, alone and in combination, in humans

The widespread use of benzodiazepines and caffeine makes their combined use inevitable. The purpose of the present experiment was to assess the acute effects of lorazepam (0,2.8 and 5.6mg/70kg) and caffeine (0, 250 and 500mg/70kg), alone and in combination, on human learning, performance and self-reports. Subjects were nine healthy, male volunteers. Subjects received all possible combinations according to a Latin Square design. Lorazepam administered alone dose-dependently disrupted learning and performance on the Repeated Acquisition and Performance procedure and Digit Symbol Substitution Test (DSST), and increased subject ratings of sedation. Caffeine administered alone did not affect learning, performance or subject ratings to a statistically significant degree. Caffeine attenuated lorazepam-induced decrements in learning and performance on the Repeated Acquisition and Performance procedure and DSST. Consistent with the learning and performance measures, caffeine offset lorazepam-induced increases in subject ratings of sedation. These results demonstrate that caffeine generally attenuates the behavioral and self-reported effects of lorazepam on a variety of performance measures. An important extension of these findings would be to test the combined effects of lorazepam and caffeine in other behavioral paradigms such as drug self-administration.     

Acrylonitrile biotransformation in rats,mice, and chinese hamsters as influenced by the route of administration and by phenobarbital,SKF 525-A,cysteine, dimercaprol,or thiosulfate

Female Wistar rats, conventional albino mice, and Chinese hamsters were given a single dose of acrylonitrile, 0.5 or 0.75 mM/kg body weight. The elimination in the urine of thiocyanate, which is the main metabolite of acrylonitrile, indicated a decreasing proportion of biotransformation after oral (over 20 %), intraperitoneal, or subcutaneous (2 to 5 %), and intravenous (1 %) administration in rats. Oral administration of acrylonitrile in hamsters and mice was also followed by higher biotransformation than intraperitoneal administration. Pretreatment of rats with phenobarbital, SKF 525 A, cysteine, or dimercaprol did not significantly influence elimination of thiocyanate in the urine after the administration of acrylonitrile, but simultaneous administration of thiosulfate significantly increased the metabolized portion of acrylonitrile given intraperitoneally in rats (almost twice) and mice (more than three times). Acrylonitrile was found to be strongly bound in blood. The study confirmed the marked effect of distribution (first-pass metabolic phenomenon) on the metabolic fate of foreign compounds. The strong acrylonitrile binding and cyanoethylation are apparently responsible for the unusually high influence of the different routes of administration on the metabolic fate of acrylonitrile. Acrylonitrile was more effectively metabolized to thiocyanate in mice than in rats after oral, intraperitoneal, and intravenous administration. A greater response of acrylonitrile to thiocyanate metabolism and a larger decrease in its acute toxicity after thiosulfate in mice than in rats indicate possible differences in the mechanism of acrylonitrile toxicity in these animals. Cyanide apparently plays a minor role in the acrylonitrile toxicity in rats, but may play quite an important one in mice.     

Chronic effects in mice caused by oral administration of sublethal doses of azaspiracid, a new marine toxin isolated from mussels.

Toxicological effects of orally administered azaspiracid (AZA), a new toxin isolated from mussels, were investigated. First, a total of 25 mice were administered AZA twice at 300-450 microg/kg doses and observed for recovery processes from severe injuries. Slow recoveries from injuries were revealed: erosion and shortened villi persisted in the stomach and small intestine for more than 3 months: edema, bleeding, and infiltration of cells in the alveolar wall of the lung for 56 days; fatty changes in the liver for 20 days; and necrosis of lymphocytes in the thymus and spleen for 10 days. Secondly, low doses of AZA (50, 20, 5 and 1 microg/kg) were administered twice a week up to 40 times to four groups of mice. Many mice, nine out of ten at 50 microg/kg and three out of ten at 20 microg/kg, became so weak that they were sacrificed before completion of 40 injections. All these mice showed interstitial pneumonia and shortened small intestinal villi. Most importantly, lung tumor were observed in four mice, one out of ten (10%) at 50 microg/kg and three out of ten (30%) at 20 microg/kg. Tumors were not observed in 11 mice treated at lower doses and in 19 control mice. Hyperplasia of epithelial cells was also observed in the stomach of six mice out of ten administered at 20 microg/kg.     

Prophylactic treatment with recombinant Eimeria protein, alone or in combination with an agonist cocktail, protects mice from Banzi virus infection

A recombinant Eimeria protozoan protein antigen (rEA) has been shown to have antitumor and antiviral activity. The purpose of this study was to determine the effect of rEA treatment alone or in combination with an agonist cocktail consisting of granulocyte macrophage colony stimulating factor (GM-CSF), interferon gamma (IFN-gamma), interleukin 4 (IL-4), and anti CD-40 antibody, in the treatment of Banzi virus (BV) disease in BALB/c mice. Treatment with rEA resulted in a significant increase in survival, weight gain, and mean day to death in BV-infected mice and resulted in a significant decrease in brain virus titer. Treatment with rEA, in combination with a 4-agonist cocktail, improved disease parameters to a greater degree than rEA treatment alone. The effect of treatment with a reduced concentration of agonist cocktail or fewer components of the agonist cocktail, in combination with rEA, on disease outcome in BV-infected mice was also investigated. Treatment with rEA, alone or in combination with agonist cocktail, 24h after virus challenge did not improve disease. Treatment with rEA, alone or in combination with an agonist cocktail, is efficacious for the prophylaxis of BV infection in mice.     

Acute behavioral and cardiac effects of alcohol and caffeine, alone and in combination, in humans

The acute behavioral and cardiac effects of alcohol (0, 0.5 and 1.0g/kg) and caffeine (0,250 and 500mg/70kg), administered alone and in combination, were assessed in eight adult humans. Subjects received all possible combinations twice. Alcohol administered alone disrupted responding in the Digit-Symbol Substitution Test and the Repeated Acquisition and Performance Procedure, increased heart rate, decreased blood pressure, and increased subject ratings of drunkenness. Caffeine administered alone offset performance decrements that emerged across the test session on the Digit-Symbol Substitution Test performance and accuracy of responding in the Repeated Acquisition and Performance Procedure, but never actually enhanced performance and learning. Caffeine administered alone increased blood pressure and increased subjective ratings of drug strength. The most notable effect of the drug combination was that caffeine partially attenuated the disruptive behavioral effects of alcohol. Combining alcohol and caffeine generally offset the presser effects observed with the drugs administered alone. By contrast, alcohol-caffeine combinations did not significantly alter breath alcohol levels, heart rate or subject-rated drug effects, relative to the effects of the drugs alone. Across all measures except heart rate, these effects are qualitatively similar to those observed previously with cocaine and d-amphetamine in combination with alcohol, documenting a high degree of consistency in the behavioral pharmacology of alcohol-stimulant combinations in humans.     

Acute and residual effects of alcohol and marijuana,alone and in combination,on mood and performance

The duration of behavioral impairment after marijuana smoking remains a matter of some debate. Alcohol and marijuana are frequently used together, but there has been little study of the effects of this drug combination on mood and behavior the day after use. The present study was designed to address these issues. Fourteen male and female subjects were each studied under four conditions: alcohol alone, marijuana alone, alcohol and marijuana in combination, and no active treatment. Mood and performance assessments were made during acute intoxication and twice the following day (morning and mid-afternoon). Acutely, each drug alone produced moderate levels of subjective intoxication and some degree of behavioral impairment. The drug combination produced the greatest level of impairment on most tasks and strong overall subjective ratings. There were few significant interactions between the two drugs, indicating that their effects tended to be additive. Only weak evidence was obtained for subjective or behavioral effects the day after active drug treatments, although consistent time-of-day effects (morning versus afternoon) were observed on several subjective and behavioral measures. In sum, this study provided little evidence that moderate doses of alcohol and marijuana, consumed either alone or in combination, produce behavioral or subjective impairment the following day.     

Acute performance-impairing and subject-rated effects of triazolam and temazepam, alone and in combination with ethanol, in humans

The acute behavioural effects of triazolam (0.125 and 0.25 mg), temazepam (15 and 30 mg), and placebo, alone and in combination with ethanol (0 and 0.5 g/kg), were assessed in 10 volunteers. Ethanol alone did not impair performance and produced only a few subject-rated drug effects. Triazolam and temazepam alone produced some performance impairment and a few subject-rated drug effects. These effects tended to be dose-dependent and were comparable for the two drugs across the range of doses tested. The triazolam-ethanol and temazepam-ethanol combinations produced robust performance impairment and sedative-like subject-rated drug effects that were similar in magnitude. The findings of the present study suggest that even a moderate amount of ethanol in combination with a clinical dose of triazolam or temazepam can cause performance impairment that might diminish an individual's ability to respond adequately to unexpected demands (e.g. smoke alarms or middle-of-the-night child care).     

Acute comparison of clovoxamine and mianserin, alone and in combination with ethanol, on human psychomotor performance

Objective and subjective effects on human performance of clovoxamine and mianserin were measured in 12 student volunteers who participated in 12 test sessions and received single doses of clovoxamine 50 mg, 100 mg and 150 mg, mianserin 20 mg, and placebo in a double-blind and cross-over manner. Each test drug was given twice, both in combination with alcohol 0.8 g/kg and with a non-alcoholic drink. The tests included tracking, body balance, flicker fusion, horizontal nystagmus, digit symbol substitution, recall memory, and subjective assessments on visual analogue scales. Mianserin and alcohol impaired objective performance in most tests, and their combination showed at least an additive effect. Alcohol counteracted rather than increased mianserin-induced subjective sedation. Clovoxamine neither differed significantly from placebo nor increased alcohol effects. On the contrary, clovoxamine 150 mg reduced significantly alcohol-induced body sway. No evidence of pharmacokinetic interactions were found between the study drugs and alcohol.     

Changes in rat liver monooxygenase activities after administration of atenolol, nifedipine and diltiazem alone and in combination

The effects of the Ca2+ antagonists nifedipine (NF) and diltiazem (DL) and of the cardioselective beta 1-adrenergic blocking agent atenolol (AT) on the hexobarbital (HB) sleeping time and on the activity of some liver drug-metabolizing enzyme systems in male Wistar rats were studied. Two hours after single oral administration, atenolol (150 mg/kg) did not change hexobarbital sleeping time, while nifedipine (50 mg/kg) and diltiazem (30 mg/kg) prolonged it by 171.2 and 99.6%, respectively. Coadministration of atenolol with diltiazem or with nifedipine significantly prolonged hexobarbital sleep by 205 and 283%, respectively. Administered alone, atenolol decreased the ethylmorphine-N-demethylase (EMND) activity, but the amidopyrine-N-demethylase (APND) activity was not changed in any of the treated groups. Atenolol and nifedipine significantly increased aniline-4-hydroxylase (AH) activity and this effect was also observed with the combinations AT + NF and AT + DL. The NADPH cytochrome P-450 reductase activity was significantly decreased by nifedipine and diltiazem. Only nifedipine increased the total content of cytochrome P-450 (by 23.8%). Atenolol and diltiazem tended to increase the content of cytochrome b5 which was increased by nifedipine by 97.6%. The same effect was observed with the combinations AT + NF and AT + DL. The results suggest that NF, AT + NF and AT + DL produced the manifested changes in hepatic oxidative metabolism. The decreased EMND activity by atenolol, however, and the prolongation of hexobarbital sleeping time by nifedipine, diltiazem and their coadministration with atenolol did not correlate with enhanced microsomal P-450 and b5 content.     

Efficacy of administration of dexfenfluramine and phentermine, alone and in combination, on ingestive behavior and body weight in rats

 Cocaine, which non-selectively blocks the reuptake of the monoamines serotonin, dopamine and norepinephrine, produces weak antinociceptive effects and increases the antinociceptive effects of low- to intermediate-efficacy mu opioid agonists in rhesus monkeys. In the present study, the antinociceptive effects of more selective monoamine reuptake inhibitors administered alone and in combination with mu opioid agonists were evaluated in rhesus monkeys using a warm-water tail-withdrawal assay of thermal nociception. Like cocaine, the selective serotonin reuptake inhibitors clomipramine (0.01–3.2 mg/kg) and fluoxetine (0.1–10 mg/kg) produced weak antinociceptive effects. Pretreatment with the serotonin receptor antagonist mianserin (0.032–0.32 mg/kg) produced rightward and downward shifts in the clomipramine dose-effect curve, suggesting that the effects of clomipramine were mediated by serotonin receptors. Combination of clomipramine with the low efficacy mu agonist nalbuphine or the intermediate efficacy mu agonist morphine produced more antinociception than did the mu agonists alone. Fluoxetine also produced a small leftward shift in the morphine dose-effect curve. The selective norepinephrine reuptake inhibitors nisoxetine (0.1–10 mg/kg) and tomoxetine (0.1–10 mg/kg) and the selective dopamine reuptake inhibitors bupropion (0.032–3.2 mg/kg) and GBR 12909 (0.1–10 mg/kg) did not produce antinociception or increase antinociception induced by nalbuphine or morphine. In fact, GBR 12909 produced dose-dependent allodynia and reduced the maximal antinociceptive effects of morphine. These results suggest that inhibition of serotonin reuptake is sufficient to produce weak antinociceptive effects and enhance the antinociceptive effects of low efficacy mu opioid agonists. These results also suggest that the effects of cocaine on serotonin reuptake may contribute to cocaine’s antinociceptive effects in rhesus monkeys. Received: 5 May 1997 / Final version: 30 July 1997