The Formation of Methemoglobin and Sulfhemoglobin During Sulfanilamide Therapy

Harris, Jerome S.; Michel, Harry O.

doi:10.1172/jci101064

Cited by 22 publications

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“…Clinical methemoglobemia has been noted to depend upon the concentration of sulfanilamide in the blood, and to reach a peak several hours after the sulfanilamide concentration of the blood had reached its peak (5). The methemoglobinemia of patients was also found to depend slightly upon the concentration of circulating hemoglobin.…”

Section: Discussionmentioning

confidence: 99%

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“…From the clinical statistics on methemoglobinemia it has been deduced that sulfanilamide is partially converted by the body into some active agent which can function as an oxidant (5). It is the purpose of this paper to determine whether the oxidation of hemoglobin is performed by sulfanilamide itself or whether the active agent is produced through the interaction of tissues and sulfanilamide.…”

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The in Vitro Formation of an Oxidizing Agent by Surviving Tissues and Sulfanilamide

Harris¹

1939

J. Clin. Invest.

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Methemoglobin formation generally occurs during sulfanilamide therapy in humans (1,2,3,4,5). From the clinical statistics on methemoglobinemia it has been deduced that sulfanilamide is partially converted by the body into some active agent which can function as an oxidant (5). It is the purpose of this paper to determine whether the oxidation of hemoglobin is performed by sulfanilamide itself or whether the active agent is produced through the interaction of tissues and sulfanilamide. METHODSNormal animals were killed by a blow on the head followed by decapitation. The tissues were removed and slices of 0.2 to 0.4 mm. thickness were immediately prepared. These were suspended in 5 ml. Ringer-phosphate solution of pH 7.4 (6) containing 0.1 gram per cent glucose, varying concentrations of sulfanilamide, and the saline-washed erythrocytes from approximately 0.5 ml. of normal human blood. The mixtures were placed in 50 ml. Erlenmeyer flasks and were shaken constantly in a water bath at 37.50 C. for approximately 2 hours. The tissue slices were removed, dried, and weighed. The dry weight was generally between 30 and 50 mgm. The red cells were centrifuged, washed with physiological saline, hemolyzed with saponin, and diluted to 10 ml. with 1/20 M pH 7.4 phosphate buffer. Methemoglobin and total hemoglobin were determined spectrophotometrically by the change in extinction at 634 m,u upon conversion to cyanmethemoglobin (7). The presence of methemoglobin was confirmed by the disappearance of the alpha band upon the addition of cyanide, hydrosulfite, and ammonium hydroxide. Furthermore, the percentage of methemoglobin in the mixture as determined from the ratio of the extinctions at 575 m,u to 560 m,u (8) checked with the quantity as previously determined. Only methemoglobin could give these results. The bands of pigments other than met-521 hemoglobin and oxyhemoglobin were not detected with the hand spectroscope.EXPERIMENTAL DATAThe incubation of erythrocytes with Ringerphosphate solution containing from 0 to 250 mgm. per cent of sulfanilamide never caused the conversion of more than 1 per cent of the total hemoglobin to methemoglobin. The incubation of erythrocytes with tissue slices of the liver, kidney, muscle, spleen of the mouse, rabbit, rat, cat, and guinea pig, was likewise without appreciable effect on the hemoglobin. However, when liver slices were incubated with sulfanilamide and red cells, the formation of methemoglobin invariably occurred. A sample protocol is shown in Table I. Similar results were obtained with the livers of the cat, guinea pig, and rabbit. Other animals were not tried. These results are shown in Figure TABLE I

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The in Vitro Formation of an Oxidizing Agent by Surviving Tissues and Sulfanilamide

Harris¹

1939

J. Clin. Invest.

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“…Inasmuch as methemoglobin is formed from hemoglobin only by oxidizing agents (e.g., ferricyanide), the uniform occurrence of some methemoglobin in the red cells of all patients treated with the sulfonamide drugs (3,14) is excellent evidence that the body produces oxidizing agents from these drugs (15). Furthermore, one such oxidant, hydroxylaminobenzene sulfonamide, unlike ferricyanide, can penetrate the erythrocyte membrane and is detectable in the urine during sulfanilamnide therapy (16).…”

Section: Methodsmentioning

confidence: 99%

“…This is not the case. Most patients receiving huge doses over long periods of time with correspondingly large amounts of methemoglobin in their cells (up to 40 per cent in man (14), 75 per cent in monkeys (17)), do not develop hemolysis. On the other hand, when hemolytic anemia occurs, it appears early-within 2 to 5 days from the start of administration, and after only moderate doses of the drug (only 12 grams in one of the present cases).…”

Section: Methodsmentioning

confidence: 99%