Methylene Blue in the Treatment of Poisonings Associated with Methemoglobinemia

Steele, Charles W.; Spink, Wesley W.

doi:10.1056/nejm193306012082205

Cited by 36 publications

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“…Methylene blue stimulation of methemoglobin reduction in human erythrocytes was described 60 years ago by Warburg et al (1), Steele and Spink (2), and Williams and Challis (3). Subsequent work by a number of investigators resulted in preparations of a cytosolic NADPH-dependent reductase that catalyzed the reduction of methylene blue and flavins and, in the presence of redox couplers, catalyzed the reduction of methemoglobin (4)(5)(6)(7)(8)(9).…”

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confidence: 98%

Characterization of NADPH-dependent methemoglobin reductase as a heme-binding protein present in erythrocytes and liver.

Xu¹,

Quandt²,

Hultquist³

1992

Proc. Natl. Acad. Sci. U.S.A.

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An NADPH-dependent reductase, first shown in the 1930s to catalyze the methylene blue-dependent reduction of methemoglobin in erythrocytes, has now been characterized as a high-affinity heme-binding protein and has been detected in liver. Highly purified bovine erythrocyte reductase binds protohemin to form a 1:1 complex with a Kd of 7 nM. Binding of protohemin completely inhibits reductase activity. Other tetrapyrroles and fatty acids also bind to the reductase and inhibit its activity. Protoporphyrin, hematoporphyrin, and coproporphyrin form 1:1 complexes withKd values ranging from 1 to 5 IzM. The inhibition constants for a number of saturated and unsaturated fatty acids range from 6 to 52 ,LM. A protein that is immunologically cross-reactive to the reductase has been detected in the cytosolic fractions of bovine and rat liver and of bovine, rat, rabbit, and human erythrocytes. By immunoblot analysis, the bovine liver and erythrocyte proteins appear identical in size, as do the rat liver and erythrocyte proteins. The concentration of the protein in bovine erythrocytes has been estimated by quantitative immunoblotting to be 10 juM. The detection of this protein in liver cells, the demonstration of its binding properties, and its weak reductase activity bring into question the long-held belief that this is uniquely an erythrocyte protein and that it functions as a reductase.Methylene blue stimulation of methemoglobin reduction in human erythrocytes was described 60 years ago by Warburg et al. (1), Steele and Spink (2), and Williams and Challis (3). Subsequent work by a number of investigators resulted in preparations of a cytosolic NADPH-dependent reductase that catalyzed the reduction of methylene blue and flavins and, in the presence of redox couplers, catalyzed the reduction of methemoglobin (4-9). Whereas this NADPHdependent reductase is believed to contribute very little to methemoglobin reduction under normal conditions (10), its catalysis of methemoglobin reduction in the presence of methylene blue or riboflavin is the basis for the use of these compounds as therapeutic agents in the treatment of congenital and toxic methemoglobinemia (11)(12)(13). The erythrocyte reductase has variously been referred to as NADPH dehydrogenase, diaphorase, methemoglobin reductase, and, most recently, flavin reductase.The reductase has been shown to bind small molecules. Isolation procedures generally yield two forms of the reductase, which exhibit very similar activities but different isoelectric points; one, but not the other, of these forms is reported to possess protein-bound NADP+ and a proteinbound yellow chromophore of unknown structure (7,8,(14)(15)(16). The isolation of the protein in the presence of flavin yields a flavoprotein (17). The protein isolated without the addition of flavin contains no flavin and yet exhibits full reductase activity.Recently (18) Bovine erythrocyte green heme-binding protein was purified as described (19). Antibodies to the green heme-binding protein were raised in young adult ...

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confidence: 98%

Characterization of NADPH-dependent methemoglobin reductase as a heme-binding protein present in erythrocytes and liver.

Xu¹,

Quandt²,

Hultquist³

1992

Proc. Natl. Acad. Sci. U.S.A.

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“…4 Steele and Spink reported using methylene blue (also known as methylthionine chloride) to treat methemoglobinemia in 1933. 5 Ockliz reported a case of methemoglobinemia attributed to a local anesthetic, and its treatment with thionine in 1949. 6 The literature contains numerous cases of local anesthetic-related methemoglobinemia.…”

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Methemoglobinemia Related to Local Anesthetics: A Summary of 242 Episodes

Guay¹

2009

Anesthesia &Amp; Analgesia

263

219

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“…This is essentially the same rate as observed when blood containing methemoglobin from these animals is incubated at body temperature in zitro, and may be looked upon as the rate at which the enzyme systems in the erythrocytes are able to reduce methemoglobin (10). 8 Methemoglobin concentration is expressed in this paper in two ways, as per cent of the total pigment and as volumes per cent, one volume per cent of methemoglobin being that concentration which results from loss of one volume per cent oxygen capacity.…”

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The Control of Methemoglobinemia With Methylene Blue 12

Wendel¹

1939

J. Clin. Invest.

108

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The cyanosis seen in a high percentage of patients receiving sulfanilamide and related drugs has been attributed variously to methemoglobinemia (1, 2), sulfhemoglobinemia (1), an unusual degree of unsaturation of the venous blood (3), and to the presence of aniline black (4) and other colored derivatives of sulfanilamide (5) in the red blood corpuscles. Marshall and Walzl (4) and Chesley (6) consider methemoglobin to be of no importance except perhaps in an occasional patient.The present paper summarizes the results of determinations of methemoglobin in the blood of more than one hundred patients who were receiving sulfanilamide and showing cyanosis. Methemoglobin was found, at least in traces, in over 90 per cent of these. In thirty-five cases the blood contained methemoglobin to the extent of 15 per cent or more of the total pigment. In one instance 40 per cent of the total blood pigment was in the form of methemoglobin Animal experiments are described which confirm and extend the observations of Williams and Challis (7), Steele and Spink (8), and Hauschild (9) that methylene blue hastens disappearance of methemoglobin from the blood. Clinical application of these experiments to patients showing cyanosis from sulfanilamide has shown that intravenous injection of 0.1 to 0.2 cc. of one per cent methylene blue per kilogram body weight reduces 1 A preliminary report of this work was given before the Middle

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Methylene Blue in the Treatment of Poisonings Associated with Methemoglobinemia

Cited by 36 publications

References 0 publications

Characterization of NADPH-dependent methemoglobin reductase as a heme-binding protein present in erythrocytes and liver.

Characterization of NADPH-dependent methemoglobin reductase as a heme-binding protein present in erythrocytes and liver.

Methemoglobinemia Related to Local Anesthetics: A Summary of 242 Episodes

The Control of Methemoglobinemia With Methylene Blue 12

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