sodium-nitrite and 4-dimethylaminophenol

Cyanide toxicity can be reduced by the use of methemoglobin (MetHb) formers, and antidotal dosage is based on the extent of MetHb formation. Hemoglobin and ferrihemoglobin (MetHb, hemimethemoglobins alpha3+beta2+ and alpha2+beta3+, tetracyanmethemoglobin, and dicyanmethemoglobin) concentrations in human, pig, and mouse blood were determined after separation by isoelectric focusing with an octyl-bonded capillary. The predominant species formed in blood when MetHb formers, such as potassium ferricyanide, hydroxylamine, sodium nitrite, and 4-dimethylaminophenol (DMAP), added at molar ratios ranging from 1:10 to 1:1 to hemoglobin, are the valency hybrid intermediates alpha3+beta2+ and alpha2+beta3+. In the detoxication of cyanide with methemoglobin, an intermediate dicyanhemimethemoglobin was demonstrated to be the predominant species in the formation of tetracyanmethemoglobin. Complex mixtures of hemoglobin derivatives were observed with DMAP at 1:1 or greater molar ratio to hemoglobin. Comparison of the MetHb values obtained with a hemoxometer indicated that the valency hybrids were measured as MetHb and the values of oxidized hemoglobin were overestimated. In cyanide poisoning, incorrect dosages of MetHb formers could be calculated, and misinterpretation of MetHb data would result from methods that fail to discriminate among the various species of MetHb.

Topics: Aminophenols; Animals; Antidotes; Cyanides; Ferricyanides; Hemoglobins; Humans; Hydroxylamine; Hydroxylamines; Isoelectric Focusing; Male; Methemoglobin; Mice; Sensitivity and Specificity; Sodium Nitrite; Swine

1. The therapeutic efficacy of combined treatment of sodium nitrite (NaNO2) and 4-dimethylaminophenol (DMAP) or hydroxylamine (H2NOH) was investigated in potassium cyanide (KCN) intoxication in male rats. 2. Therapy with NaNO2 (0.27 mmol kg-1) + DMAP (0.09 mmol kg-1) or NaNO2 + H2NOH (0.09 mmol kg-1, produced a protection index (ratio of LD50 of KCN in rats receiving therapy to an LD50 of KCN in rats given only 0.9% saline) of 2.5 and 2.0 respectively. 3. Both the regimens exhibited a beneficial effect in terms of improving the survival time and postural defects in rats exposed to 2 LD50 KCN. 4. NaNO2 + DMAP showed a significant protective effect in the disposition of the plasma cyanide level at different time intervals. 5. The NaNO2 + DMAP regimen was superior to NaNO2 + N2NOH in terms of reactivating the inhibited brain cytochrome oxidase enzyme. 6. The addition of sodium thiosulphate (Na2S2O3) in both the regimens increased the degree of protection. 7. The results suggest that combined therapy with NaNO2 + DMAP could significantly reduce the toxic effects of cyanide, compared with NaNO2+H2NOH treatment.

Topics: Aminophenols; Animals; Brain; Cyanides; Electron Transport Complex IV; Hemoglobins; Hydroxylamine; Hydroxylamines; Male; Rats; Rats, Wistar; Sodium Nitrite

The in vivo effects of sodium cyanide and its antidotes, sodium nitrite, sodium thiosulfate and 4-dimethylaminophenol (DMAP), as well as the alpha-adrenergic blocking agent phentolamine, on rat brain cytochrome oxidase were studied. The course of inhibition was time-dependent and a peak of 40% was attained between 15 and 20 min after the s.c. injection of 1.3 LD50 (12 mg/kg) of cyanide. Pronounced dose-dependence was observed in the inhibition of the enzyme, at this relatively low, but lethal dose. Further observation was impossible because of rapidly lethal effects of cyanide. In animals artificially ventilated with room air, observation was possible up to 60 min. However, maximum inhibition was also 40%. When antidotes were applied 30 min after 20 mg/kg of cyanide, marked reactivation of cytochrome oxidase activity was observed with all antidotes (particularly with thiosulfate) except for phentolamine which had no effect. Prevention of methemoglobin forming with toluidine blue did not affect the reactivating ability of nitrite or DMAP, thus suggesting more complex protective mechanisms then simple methemoglobin formation. The high efficacy of thiosulfate may be attributed to its rhodanese catalyzed, direct binding to free blood cyanide, leading thus to its dissociation from cytochrome oxidase. The theory that cytochrome oxidase inhibition is a basic mechanism of cyanide toxicity could not be disproved.

Topics: Aminophenols; Animals; Antidotes; Brain; Electron Transport Complex IV; Male; Phentolamine; Rats; Rats, Wistar; Sodium Cyanide; Sodium Nitrite; Thiosulfates

Clinical efficacy of two pretreatment regimens, sodium nitrite (SN) + hydroxylamine (HA) and SN + 4-dimethylaminophenol (DMAP) were evaluated in rats by studying various biochemical variables at different time intervals. Animals given single subcutaneous (s.c.) co-administration of SN+HA or SN+DMAP showed significantly elevated levels of blood bilirubin indicating hemolytic anemia. Increased levels of blood creatine phosphokinase (CPK), lactate dehydrogenase (LDH) and glutamic oxaloacetic transaminase (GOT) were indicative of aseptic necrosis at the injection site. On account of low methemoglobin reductase activity in human erythrocytes, a reduced sub-clinical dose of HA or DMAP is envisaged in humans.

Topics: Aminophenols; Anemia, Hemolytic; Animals; Antidotes; Cyanides; Drug Evaluation, Preclinical; Hydroxylamine; Hydroxylamines; Male; Methemoglobinemia; Rats; Rats, Inbred Strains; Sodium Nitrite

Topics: Aminophenols; Animals; Cyanides; Disease Models, Animal; Lethal Dose 50; Male; Methemoglobin; Methemoglobinemia; Rats; Rats, Inbred Strains; Sodium Nitrite

By measuring the methemoglobin formation, the permeabilities of some cyanide antidotes passing through mouse erythrocyte membrane were studied. K3Fe(CN)6(0.1 mol/L) did not permeate the red cell and no methemoglobin formed. To the red cell suspension, adding PAPP 0.07 mmol/L, an useful cyanide antidote, no methemoglobin was found. On the contrary, PHAPP, the metabolite of PAPP, transported into the cell readily and reacted with hemoglobin to form methemoglobin quickly. DMAP and NaNO2 passed through the red cell membrane easily. With comparable amount of methemoglobin formation, the concentration of NaNO2 was about 200 times as much as that of DMAP. A comparison of the anticyanide potency of DMAP and NaNO2, the permeability rate constant, the half time and activation energy were measured as: 0.217 and 0.0506/min; 3.2 and 13.7 min; 17.1 and 50.2 kJ/mol, respectively. Owing to its ready permeability and formation of methemoglobin, DMAP is a better antidote than NaNO2 against cyanide poisoning.

Topics: Aminophenols; Animals; Cell Membrane Permeability; Erythrocyte Membrane; Ferricyanides; Male; Methemoglobin; Mice; Propiophenones; Sodium Nitrite

In three patients with severe acute cyanide poisoning, a cyanosis was observed instead of the bright pink skin coloration often mentioned as a sign in textbooks. Treatment of cardiopulmonary insufficiency is as essential as antidotal therapy and the use of sodium nitrite and 4-DMAP is not without risk as, in practice, the methemoglobin-level induced is difficult to control.

Topics: Adult; Aminophenols; Coma; Cyanides; Humans; Male; Methemoglobinemia; Methylene Blue; Nitrites; Respiration, Artificial; Sodium Nitrite; Suicide, Attempted; Thiosulfates

A coincubation system composed of hepatocytes in primary monolayer culture and erythrocytes suspended in the culture medium was developed and used as a model for investigations of mechanisms of cyanide antidote action at the cellular level. Hepatocyte ATP was used as the cytotoxicity indicator. Treatment of rat hepatocytes in the coincubation system with KCN (1.0 mM) for 10 min at 37 degrees C selectively reduced hepatocyte ATP levels to 33 +/- 15% of control (no KCN added) levels. 4-dimethylaminophenol (DMAP), cobalt(II) chloride, sodium nitrite, sodium thiosulfate, or a combination of the last two antidotes added to the KCN-containing medium significantly reversed ATP depression and the response was concentration dependent. The relative effectiveness, on a molar basis, was estimated to be DMAP greater than CoCl2 much greater than NaNO2 congruent to Na2S2O3. NaNO2 and DMAP induced methemoglobin formation in the absence of cyanide and cyanmethemoglobin formation in its presence; erythrocytes were required in the medium for effectiveness. CoCl2 produced neither cyanmethemoglobin nor thiocyanate in appreciable quantities nor required erythrocytes for antagonism. Na2S2O3 converted cyanide to thiocyanate and reversed ATP depression without erythrocytes in the medium. The addition of erythrocytes increased these rates significantly and to a greater extent than albumin. The overall results are consistent with previously proposed modes of action for these antidotes. However, the enhancement in cyanide metabolism and ATP recovery with Na2S2O3 and erythrocytes in the system was unexpected and raises the possibility that erythrocytes may contribute to cyanide disposition and antagonism in vivo when this antidote is administered.

Topics: Adenosine Triphosphate; Aminophenols; Animals; Antidotes; Cell Survival; Cobalt; Cyanides; Erythrocytes; In Vitro Techniques; Liver; Male; Potassium Cyanide; Rats; Rats, Inbred Strains; Sodium Nitrite; Thiosulfates

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 degree C. The temperature diminished also after poisoning by KCN, but it rose by 0.15 degree 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 degree 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 degree 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.

Topics: Aminophenols; Animals; Blood Gas Analysis; Blood Pressure; Body Temperature; Cerebrovascular Circulation; Cranial Sinuses; Cyanides; Dogs; Edetic Acid; Hydrogen-Ion Concentration; Male; Nitrites; Potassium Cyanide; Respiration, Artificial; Sodium Nitrite

Topics: Aminophenols; Animals; Antibodies; Cyanides; Cytochrome-B(5) Reductase; Humans; Hydroxylamine; Hydroxylamines; Lethal Dose 50; Male; Methemoglobinemia; Mice; Nitrites; Sodium Nitrite; Species Specificity; Thiosulfate Sulfurtransferase