the classification and treatment of methemoglobinemia i the
TRANSCRIPT
THE CLASSIFICATION AND TREATMENT
OF METHEMOGLOBINEMIA I
LEROY DOCTOR2
OXIDATION of hemoglobin leads to the formation of methemoglobin, a
compound which contains the same am~)Unt of oxygen as oxyhemoglobin, but ,,,hlch no longer is capable of dissociation wi th release of oxygen in the tissues. Methemoglobin itself has no toxic effects. The symptoms in methemoglobinemia a re due to the anoxia resulting from the lessened oxygen combining and carrying power of the total blood pigment, and the shift to the left of t.he oxygen dissociation curve with the resultant decreased dissociation of the remaining oxyhemoglobin (4, 5, 18, 19, 23).
It is generally agreed (4, 7 8 16 30) that un til 50 to 60 per cent of the h~moglobin has been oxidized to methemoglobin there a re few symptoms other t.han reduced spontaneous activi ty. Above this level there is a progression of ataxia, excess salivation, and vomit ing. Wi th an 80 per cent methemoglobin level t here are prostration and unconsciousness. Levels ahove 90 per cent a re fatal.
C LASSIFICATION
Clinically, methemoglobinemia can be classified into intracellular and extracellular types .
EXTRACELLULAR METHEMOGLOBINEM IA:
Extracellular or plasma methemoglobinemia is associated with diseases in which there is hemolysis, such as eclampsia, black,mter fever, paroxysmal hemoglobinuria, sepsis due to anaerobic organIsms, and hemolytic icterus (3· 14). In these conditions hemoglobin di~solved in the plasma is changed to methemoglobin. Plasma methemoglobinemia is character-
. IThis project \~'as upported in part by a Cancer Teachu:g. Grant provlde~ hy the National Cancer Institute, L ll1!ed States PublIc Health Service.
Received for publication, April 22, 1953. 2Student research assis tant, Department of Patholog\"
,""orthwestern L:niversity Medical School. • ,
ized by cyanosis, icterus, hemolysis and methemoglobinuria. '
INTRACELLU LAR METHEMO GLOBINEMIA:
Intracellular methemoglobinemia may be divided into primary and secondary types.
Primary. Primary or idiopathic methemoglobinemia is believed to be congenital, half of the known cases showing familial tendencies (12, 18, 20, 22, 27). The body normally has mechanisms by which it keeps hemoglobin in its reduced (ferro) form . The principal mechanism, defective in idiopathic methemoglobinemia, is an intracellular process utilizing carbohydrates as substrates (15). This mechanism is usually sufficiently effective to keep the methemoglobin level at 1 per cent or less. In primary methemoglobinemia, however, because this reducing process is defective, an equilibrium is reached at which 40 per cent of the blood pigment is present as methemoglobin. The blood of a person with idiopathic methemoglobinemia has a 10"'er ascorbic acid content than normal. Furthermore, t he methemoglobin is not reconverted to hemoglobin when allowed to stand in a test tube 24 hours (27).
S econdary. Secondary methemeglobinemia has an exogenous origin, generally being caused by chemicals. It may also accompany hemolytic anemias (16) or occur as a primary enterogenous type. The principal chemicals responsible for the formation of methemoglobin are the nit rates, sulfonamides, and aniline derivatives. Nitrates may be inhaled (amyl nitrate), or ingested as food or medicat ion [bismuth sub nitrate (16, 31)], or drink [sodium nitrate in well water (9, 25, 32)] . The administration of su lfonamides may lead to the formation of both methemoglobin and sulfhemoglobin . Aniline dyes are capable of penetrating the skin and producing methemoglobinemia
134
THE CLASSIFICATION AND TREATMENT
OF METHEMOGLOBINEMIA I
LEROY DOCTOR2
OXIDATION of hemoglobin leads to the formation of methemoglobin, a
compound which contains the same am~)Unt of oxygen as oxyhemoglobin, but ,,,hlch no longer is capable of dissociation wi th release of oxygen in the tissues. Methemoglobin itself has no toxic effects. The symptoms in methemoglobinemia a re due to the anoxia resulting from the lessened oxygen combining and carrying power of the total blood pigment, and the shift to the left of t.he oxygen dissociation curve with the resultant decreased dissociation of the remaining oxyhemoglobin (4, 5, 18, 19, 23).
It is generally agreed (4, 7 8 16 30) that un til 50 to 60 per cent of the h~moglobin has been oxidized to methemoglobin there a re few symptoms other t.han reduced spontaneous activi ty. Above this level there is a progression of ataxia, excess salivation, and vomit ing. Wi th an 80 per cent methemoglobin level t here are prostration and unconsciousness. Levels ahove 90 per cent a re fatal.
C LASSIFICATION
Clinically, methemoglobinemia can be classified into intracellular and extracellular types .
EXTRACELLULAR METHEMOGLOBINEM IA:
Extracellular or plasma methemoglobinemia is associated with diseases in which there is hemolysis, such as eclampsia, black,mter fever, paroxysmal hemoglobinuria, sepsis due to anaerobic organIsms, and hemolytic icterus (3· 14). In these conditions hemoglobin di~solved in the plasma is changed to methemoglobin. Plasma methemoglobinemia is character-
. IThis project \~'as upported in part by a Cancer Teachu:g. Grant provlde~ hy the National Cancer Institute, L ll1!ed States PublIc Health Service.
Received for publication, April 22, 1953. 2Student research assis tant, Department of Patholog\"
,""orthwestern L:niversity Medical School. • ,
ized by cyanosis, icterus, hemolysis and methemoglobinuria. '
INTRACELLU LAR METHEMO GLOBINEMIA:
Intracellular methemoglobinemia may be divided into primary and secondary types.
Primary. Primary or idiopathic methemoglobinemia is believed to be congenital, half of the known cases showing familial tendencies (12, 18, 20, 22, 27). The body normally has mechanisms by which it keeps hemoglobin in its reduced (ferro) form . The principal mechanism, defective in idiopathic methemoglobinemia, is an intracellular process utilizing carbohydrates as substrates (15). This mechanism is usually sufficiently effective to keep the methemoglobin level at 1 per cent or less. In primary methemoglobinemia, however, because this reducing process is defective, an equilibrium is reached at which 40 per cent of the blood pigment is present as methemoglobin. The blood of a person with idiopathic methemoglobinemia has a 10"'er ascorbic acid content than normal. Furthermore, t he methemoglobin is not reconverted to hemoglobin when allowed to stand in a test tube 24 hours (27).
S econdary. Secondary methemeglobinemia has an exogenous origin, generally being caused by chemicals. It may also accompany hemolytic anemias (16) or occur as a primary enterogenous type. The principal chemicals responsible for the formation of methemoglobin are the nit rates, sulfonamides, and aniline derivatives. Nitrates may be inhaled (amyl nitrate), or ingested as food or medicat ion [bismuth sub nitrate (16, 31)], or drink [sodium nitrate in well water (9, 25, 32)] . The administration of su lfonamides may lead to the formation of both methemoglobin and sulfhemoglobin . Aniline dyes are capable of penetrating the skin and producing methemoglobinemia
134
DOCTOR-METHEMOGLOBINEMIA 135
by action of their breakdO\m products, phenylhydroxlamine and aminophenol.
Enterogenous methemoglobinemia may be found in patients with gastrointestinal upsets, more commonly diarrhea than constipation (6, 16). Often there is abdominal pain, headache, cyanosis, dyspnea, dizziness, collapse, syncope, and anemia. Normally, ingested nitrates are changed to nitrites which are further broken down to ammonia and excreted without being absorbed. However, when a gastrointestinal disturbance is present, the process proceeds only as far as nitrate formation , and the nitrates are absorbed through the damaged intestinal mucosa (14).
Methemoglobemia from ingested nitrates occurs without gastrointestinal disturbance in cases where E. coli and A. aerogenes are found in the upper gastrointestinal tract due to a high pH of gastric juice (10). This occurs most frequently in the neonatal period (25).
TREATMENT
The normal reconversion mechanisms convert methemoglobin to hemoglobin at a rate of 0.5 gm. of methemoglobin per hour (15). This is accomplished by an enzymatic process using triosephosphate and lactate as substrates. This oxidationreduction system requires coenzyme factor I in addition to coenzyme I (DPN) and specific enzymes. In normal erythrocytes the coenzyme II system is not active in methemoglobin reduction. The following reactions are thought to occur:
globin . However, in primary methemoglobinemia, where these conversion mechanisms are reduced, and in secondary methemoglobinemia \\'here one wishes to speed up these conversion mechanisms, certain drugs are employed.
Ascorbic Acid: J n primary methemoglobinemia, methemoglobin is not reduced with appreciable speed in the presence of triosephosphate (or glucose) or lactate. The erythrocytes in primary methemoglobinemia contain a lower conconcentration of coenzyme factor I than normal cells, causing a slo\\'er rate of reconversion and thus a higher concentration of methemoglobin (17). The methemoglobin level , however, does not continue to rise without limitat ion because as its concentration increases, its rate of reaction \\'ith nonspecific reducing agents in the blood also ri ses, and an equilibrium is thus established. Ascorbic acid is the most important of the nonspecific reducing substances in the blood. It reacts with methemoglobi n yielding hemoglobin and dehydroascorbic acid . The latter is then reduced to ascorbic acid by glutathione.
Ascorbic acid, the most important reducing substance normally found in blood , has a reconversion rate of 0.1 to 0.3 gm. of methemoglobin per hour (15), an amount less than the normal reconversion rate of over 0.3 gm. per hour (27) . It thus finds its application in the primary methemoglohinemias, where, in do es of 100 to 500 mg. per Kg. per day (22) , it effectively redu ces methemoglobin
(1) Glucose glycolysis Lactate + 2 MHb dehydrogenase
coenzyme I
2 Hb + pyruvate. coenzyme factor J
(2) Glucose glycolysis Triose phosphate + 2 MHb
dehydrogenase coenzyme I --------------~
coenzyme factor I 2 Hb + phosphoglycerate.
After removal of the offending substance in secondary methemoglobinemia, the normal cell conversion mechanisms will reconvert methemoglobin to hemo-
levels from 40 per cent to 7 to 10 per cent of the total blood pigment (22) in the absence of the normal reducing mechanism. It is especially useful in primary
DOCTOR-METHEMOGLOBINEMIA 135
by action of their breakdO\m products, phenylhydroxlamine and aminophenol.
Enterogenous methemoglobinemia may be found in patients with gastrointestinal upsets, more commonly diarrhea than constipation (6, 16). Often there is abdominal pain, headache, cyanosis, dyspnea, dizziness, collapse, syncope, and anemia. Normally, ingested nitrates are changed to nitrites which are further broken down to ammonia and excreted without being absorbed. However, when a gastrointestinal disturbance is present, the process proceeds only as far as nitrate formation , and the nitrates are absorbed through the damaged intestinal mucosa (14).
Methemoglobemia from ingested nitrates occurs without gastrointestinal disturbance in cases where E. coli and A. aerogenes are found in the upper gastrointestinal tract due to a high pH of gastric juice (10). This occurs most frequently in the neonatal period (25).
TREATMENT
The normal reconversion mechanisms convert methemoglobin to hemoglobin at a rate of 0.5 gm. of methemoglobin per hour (15). This is accomplished by an enzymatic process using triosephosphate and lactate as substrates. This oxidationreduction system requires coenzyme factor I in addition to coenzyme I (DPN) and specific enzymes. In normal erythrocytes the coenzyme II system is not active in methemoglobin reduction. The following reactions are thought to occur:
globin . However, in primary methemoglobinemia, where these conversion mechanisms are reduced, and in secondary methemoglobinemia \\'here one wishes to speed up these conversion mechanisms, certain drugs are employed.
Ascorbic Acid: J n primary methemoglobinemia, methemoglobin is not reduced with appreciable speed in the presence of triosephosphate (or glucose) or lactate. The erythrocytes in primary methemoglobinemia contain a lower conconcentration of coenzyme factor I than normal cells, causing a slo\\'er rate of reconversion and thus a higher concentration of methemoglobin (17). The methemoglobin level , however, does not continue to rise without limitat ion because as its concentration increases, its rate of reaction \\'ith nonspecific reducing agents in the blood also ri ses, and an equilibrium is thus established. Ascorbic acid is the most important of the nonspecific reducing substances in the blood. It reacts with methemoglobi n yielding hemoglobin and dehydroascorbic acid . The latter is then reduced to ascorbic acid by glutathione.
Ascorbic acid, the most important reducing substance normally found in blood , has a reconversion rate of 0.1 to 0.3 gm. of methemoglobin per hour (15), an amount less than the normal reconversion rate of over 0.3 gm. per hour (27) . It thus finds its application in the primary methemoglohinemias, where, in do es of 100 to 500 mg. per Kg. per day (22) , it effectively redu ces methemoglobin
(1) Glucose glycolysis Lactate + 2 MHb dehydrogenase
coenzyme I
2 Hb + pyruvate. coenzyme factor J
(2) Glucose glycolysis Triose phosphate + 2 MHb
dehydrogenase coenzyme I --------------~
coenzyme factor I 2 Hb + phosphoglycerate.
After removal of the offending substance in secondary methemoglobinemia, the normal cell conversion mechanisms will reconvert methemoglobin to hemo-
levels from 40 per cent to 7 to 10 per cent of the total blood pigment (22) in the absence of the normal reducing mechanism. It is especially useful in primary
136 QUARTERLY BULLETIN, N.U.M.S.
met.hemoglobinemia because of its lasting, non-transitory nature (1, 18). Ascorbic acid has little use in the treatment of secondary methemoglobinemia, where the usual reconversion process is maintained.
Methylene blue: Methylene blue opens a ne\\" reduction pathway within the erythrocyte, in addition to accelerating the usual mechanism of conversion (16, 31 , 33). With methylene blue, coenzyne II (TPN) and its associated system become effective; without methylene blue, only coenzyme I (DPN) is active. The following scheme is thought to represent the mechanism of action :
Glucose phosphorylation
dehydrogenase coenzyme II
coenzvme factor II methylene blue
The phosphorylation mechanism must change glucose to hexo ephosphate, which in turn is oxidized, reducing the methemoglobin.
In idiopathic methemoglobinemia, methylene blue causes increased methemoglobin reduction by incorporating the coenzyme II- coenzyme factor II system, in \\'hich the erythrocytes a re not deficient. In this mechanism lactate causes no increased reduction, as glucose and hexosephosphate must be used as substrates (17).
Methylene blue has been the most widely used and the most effective agent in the treatment of methemoglobinemia, both primary and secondary . The quantities used are 1 mg. per Kg. of body weight in adults and 2 mg. per Kg. of body weight in children injected intravenously over a 5-minute period. Alternately 3 to 5 mg. per Kg. of body \\"eight may be given orally. If methylene blue is used in excess (7 mg. pel' Kg.), toxic symptoms such as dyspnea, precordial pain, restlessne s, a sense of oppression, apprehension, and fibrillating tremors occur( 4, 14, 24, 28). There may also be a depressant action on circulatory and respiratory centers.
BAL: British Anti-Lewisite has been
reported to be useful in diminishing secondary methemoglobinemia in animals (4, 11). It must be given, however, in near toxic intravenous doses to be as effective as methylene blue. The dosage suggested is 10 mg. (4 ml. of a 1 :400 suspension) of BAL intravenously. Occasionally the effects are only transient and a second injection is needed to avoid a return of methemoglobinemia.
Sodium Thiosulfate: Experimentally, sodium thiosulfate (0.8 mg. per Kg. of body weight) has been found effective in lowering p-aminopropiophenone induced methemoglobin levels in dogs. This
hexose phosphate + MHb
Hb.
dosage is believed to be as effective as 0.1 mg. per Kg. of methylene blue (29).
A component of the Green-Williamson preparation (35) is active in the reduction of methemoglobin when t reated with sodium thiosulphate (N a2S204) . It has been suggested (21) that this component is coenzyme factor I (DPN), which, when reduced by sodium thiosulfate, takes an active part in methemoglobin reduction . This suggests a method by which sodium thiosulfate acts as reconverter of methemoglobin. If sodium thiosulfate acts solely with coenzyme I , it would not be effective in primary methemoglobinemia.
SUMMARY
1. The various types of methemoglobinemia are defined, and their causes discussed. Methemoglobinemia may be classified as extracellular or intracellular types, the latter occurring either on a congeni tal or acquired basis.
2. The biochemical phenomena in the formation of methemoglobin are summarized, and treatment considered on this basis. Ascorbic acid, or a combination of ascorbic acid and methylene blue, are satisfactory in the t reatment of primary methemoglobinemia; methylene blue alone is effective in the secondary types.
136 QUARTERLY BULLETIN, N.U.M.S.
met.hemoglobinemia because of its lasting, non-transitory nature (1, 18). Ascorbic acid has little use in the treatment of secondary methemoglobinemia, where the usual reconversion process is maintained.
Methylene blue: Methylene blue opens a ne\\" reduction pathway within the erythrocyte, in addition to accelerating the usual mechanism of conversion (16, 31 , 33). With methylene blue, coenzyne II (TPN) and its associated system become effective; without methylene blue, only coenzyme I (DPN) is active. The following scheme is thought to represent the mechanism of action :
Glucose phosphorylation
dehydrogenase coenzyme II
coenzvme factor II methylene blue
The phosphorylation mechanism must change glucose to hexo ephosphate, which in turn is oxidized, reducing the methemoglobin.
In idiopathic methemoglobinemia, methylene blue causes increased methemoglobin reduction by incorporating the coenzyme II- coenzyme factor II system, in \\'hich the erythrocytes a re not deficient. In this mechanism lactate causes no increased reduction, as glucose and hexosephosphate must be used as substrates (17).
Methylene blue has been the most widely used and the most effective agent in the treatment of methemoglobinemia, both primary and secondary . The quantities used are 1 mg. per Kg. of body weight in adults and 2 mg. per Kg. of body weight in children injected intravenously over a 5-minute period. Alternately 3 to 5 mg. per Kg. of body \\"eight may be given orally. If methylene blue is used in excess (7 mg. pel' Kg.), toxic symptoms such as dyspnea, precordial pain, restlessne s, a sense of oppression, apprehension, and fibrillating tremors occur( 4, 14, 24, 28). There may also be a depressant action on circulatory and respiratory centers.
BAL: British Anti-Lewisite has been
reported to be useful in diminishing secondary methemoglobinemia in animals (4, 11). It must be given, however, in near toxic intravenous doses to be as effective as methylene blue. The dosage suggested is 10 mg. (4 ml. of a 1 :400 suspension) of BAL intravenously. Occasionally the effects are only transient and a second injection is needed to avoid a return of methemoglobinemia.
Sodium Thiosulfate: Experimentally, sodium thiosulfate (0.8 mg. per Kg. of body weight) has been found effective in lowering p-aminopropiophenone induced methemoglobin levels in dogs. This
hexose phosphate + MHb
Hb.
dosage is believed to be as effective as 0.1 mg. per Kg. of methylene blue (29).
A component of the Green-Williamson preparation (35) is active in the reduction of methemoglobin when t reated with sodium thiosulphate (N a2S204) . It has been suggested (21) that this component is coenzyme factor I (DPN), which, when reduced by sodium thiosulfate, takes an active part in methemoglobin reduction . This suggests a method by which sodium thiosulfate acts as reconverter of methemoglobin. If sodium thiosulfate acts solely with coenzyme I , it would not be effective in primary methemoglobinemia.
SUMMARY
1. The various types of methemoglobinemia are defined, and their causes discussed. Methemoglobinemia may be classified as extracellular or intracellular types, the latter occurring either on a congeni tal or acquired basis.
2. The biochemical phenomena in the formation of methemoglobin are summarized, and treatment considered on this basis. Ascorbic acid, or a combination of ascorbic acid and methylene blue, are satisfactory in the t reatment of primary methemoglobinemia; methylene blue alone is effective in the secondary types.
DOCTOR-METHEMOGLOBINEMIA 137
REFEREN CES
l. Albaum, H. G., Tepperman, J . and Bodansky, 0.: A Spectrophotometric Study of the Competition of Methemoglobin and Cytochrome Oxidase for Cyanide in vitl·0, J. BioI. Chem., 163:641-647, 1946.
2. Bass, A. D., Frost, L. H. and Salter, W. T .: 2-Anileothanol-an Industrial Hazard. Production of Methemoglobinemia, J .A.M.A., 123: 761-763, 1943.
3. Bensley, E. H., Rhea, L. J . and Mills, E. S. : Familial Idiopathic Methaemoglobinaemia, Quart. J . Med. , 7:325-330, 1938. .
4. Bodansky, O. and Gutmann, H .: Treatment of Methemoglobinemia, .T. Pharm. & Exper. Therap., 90:46-56, 1947.
5. Brooks, J.: The Oxidation of Haemoglobin to Methaemoglobin by Oxygen, J. Physiol. , 107 :332-335, 1948.
6. Carnick, M., Polis, B. D. and Klein, T. , Methemoglobinemia. Treatment with Ascorbic Acid, Arch. Int. Med. , 78:296-302, 1946.
7. Clark, B. B. and Van Loon, E. J .: The Acute Effects of Hypoxia Resulting from Methemoglobin Produced by Aniline, Federation Proc., 1 :147, 1942.
8. Clark, B. B., Van Loon, E. J. and Morrissey, R. W.: Acute Experimental Aniline Intoxication, J. Indust. Hyg. & Toxicol, 15:1-12, 1943.
9. Comly, H. H .: Cyanosis in Infants Caused by Nitrates in Well Water, J.A.M.A., 129:112-116, 1945.
10. Cornblath, M. and Hartman n, A. F.: Methemoglobinemia in Young Infant , J . Pediat. , 33:421-425, 1948.
11. Derobert, L. , Hadengue, A., LeBreton, R., et al: Action in vivo du B.A.L. dans les intoxications par poisons methemoglobinisants, Ann. de Med. Legale, 30:51-52, 1950.
12. Diekmann, W. J.: Methemoglobinemia, Arch. Int. Med., 50:574-578, 1932.
13. Earle, D. P. , Jr. , Bigelow, F. S., Zubrod, C. G. and Kane, C. A.: Studies on the Chemotherapy of the Human Malarias. IX. Effect of Pamaquine on the Blood Cells of Man, J. Clin. Investigation, 27:121-129, 1948.
14. Ferrant, M.: Methemoglobinemia. Two Cases in Xewborn Infants Caused by Nitrates in Well Water, J. Pediat. , 29:585-592, 1946.
15. Finch, C. A.: Treatment of Intracellular Methemoglobinemia, Bull. J'lew England M. Center, 9:241-245, 1947.
16. Finch, C. A.: Methemoglobinemia and Sulfhemoglobinemia, New England.T. Med., 239: 470-478, 1948.
17. Gibson, Q. H.: The Reduction of Methaemoglobin in Red Blood Cells and Studies on the Cause of Idiopathic Methaemoglobinaemia, Riochem. J. , 42:13-23, 1948.
18. Gibson, Q. H. and Harrison, D. C.: Familial Idiopathic Methaemoglobinaemia. Five
Cases in One Family, Lancet, 2:941-943, 1947.
19. Gibson, Q. H. and Harrison, D. C.: Haemoglobin-Methaemoglobin Mixtures, X ature. 162:258-259, 1948.
20. Graybiel, A., Lilienthal, J. L., Jr. and Riley, R. L.: The Report of a Case of Idiopath ic Congenital (and Probably Familial) Methemoglobinemia, Bull. Johns Hopkins Hosp. , 76:155-162, 1945.
21. Gutmann, H. R., Jandorf, J. B. and Bodansky, 0.: The Role of Pyridine Nucleotide in the Reduction of Methemoglobin, J . BioI. Chern., 169: 145-152, 1947.
22. Kin!!;, E. .T ., White, J . C. and Gilchrist, M.: A Case of Idiopathic Methaemoglobinaemia Treated by A cOl·bic Acid and Methylene Blue, J. Path. & Bact., 59:181-188, 1947.
23. Lester, D. and Greenberg, L. A.: The Comparative Anoxemic Effects from Carbon Monoxide Hemoglobin and Methemoglobin , J. Pharmacol. & Expel". Therap. , 81 :182-188, 1944.
24. Macht, D. I. and Harden, W. C.: Toxicology and Assay of Methylene Blue, Ann. Int. Med., 71 :738-745, 1933.
25. Medovy, H.: Well-water Methemoglobinemia in Infan ts, Journal Lancet, 68:194-196. 1948.
26. Scott, E. P.: Cyanosis Cau ed by Methemog~obinemia, Am. J. Dis. Cild., 78:77-79, 1~49.
27. SIevers, R. F. and Ryon, J. B.: Congellltal Idiopathic Methemoglobinemia. Favorable Response to Ascorbic Acid Therapy, Arch. Int. Med., 78:299-307, 1945.
28. Spicer, S. S.: Effect of para-Aminobenzoic Acid on the in vi/Jo Oxidation of Hemoglobin J. Indust. Hyg. & Toxicol., 31: 204-205, 1949.
29. Stevenson, G. F. and Doctor, L.: l:npubIi shed data.
30. Vandenbelt, J. M. , Pfeiffer, C., Kaiser, M. and Sibert, M.: Methemoglobinemia after Administration of p-Aminoacetophenone and p-Aminopropiophenone, J . Pharmacol. & Exper. Therap., 80:31-38, 1944.
31. Wallace, W. M.: Methemoglobinemia in an Infant as a Result of the Administration of Bismuth Subnitrate, J .A.M.A., 13:J:1280-1281, 1947.
32. Weart, J . G.: Effect of Nitrates in Rural Water Supplies on Infant Health , Illinois M. J ., 93:131-132, 1948-
33. Wendel, W. B.: The Control of Methemoglobinemia with Methylene Blue, J. Olin. Investigation, 18 :179-185, 1939.
34. Wendel, W. B.: Methemoglobinemia: Significance and Treatment, Memphis M. J. , 14 :3-5, 1939.
35. Williamson, S. and Green, D. E. : The Preparation of Coenzyme I from Yeast, J . BioI. Chem., 135:345-346, 1940.
DOCTOR-METHEMOGLOBINEMIA 137
REFEREN CES
l. Albaum, H. G., Tepperman, J . and Bodansky, 0.: A Spectrophotometric Study of the Competition of Methemoglobin and Cytochrome Oxidase for Cyanide in vitl·0, J. BioI. Chem., 163:641-647, 1946.
2. Bass, A. D., Frost, L. H. and Salter, W. T .: 2-Anileothanol-an Industrial Hazard. Production of Methemoglobinemia, J .A.M.A., 123: 761-763, 1943.
3. Bensley, E. H., Rhea, L. J . and Mills, E. S. : Familial Idiopathic Methaemoglobinaemia, Quart. J . Med. , 7:325-330, 1938. .
4. Bodansky, O. and Gutmann, H .: Treatment of Methemoglobinemia, .T. Pharm. & Exper. Therap., 90:46-56, 1947.
5. Brooks, J.: The Oxidation of Haemoglobin to Methaemoglobin by Oxygen, J. Physiol. , 107 :332-335, 1948.
6. Carnick, M., Polis, B. D. and Klein, T. , Methemoglobinemia. Treatment with Ascorbic Acid, Arch. Int. Med. , 78:296-302, 1946.
7. Clark, B. B. and Van Loon, E. J .: The Acute Effects of Hypoxia Resulting from Methemoglobin Produced by Aniline, Federation Proc., 1 :147, 1942.
8. Clark, B. B., Van Loon, E. J. and Morrissey, R. W.: Acute Experimental Aniline Intoxication, J. Indust. Hyg. & Toxicol, 15:1-12, 1943.
9. Comly, H. H .: Cyanosis in Infants Caused by Nitrates in Well Water, J.A.M.A., 129:112-116, 1945.
10. Cornblath, M. and Hartman n, A. F.: Methemoglobinemia in Young Infant , J . Pediat. , 33:421-425, 1948.
11. Derobert, L. , Hadengue, A., LeBreton, R., et al: Action in vivo du B.A.L. dans les intoxications par poisons methemoglobinisants, Ann. de Med. Legale, 30:51-52, 1950.
12. Diekmann, W. J.: Methemoglobinemia, Arch. Int. Med., 50:574-578, 1932.
13. Earle, D. P. , Jr. , Bigelow, F. S., Zubrod, C. G. and Kane, C. A.: Studies on the Chemotherapy of the Human Malarias. IX. Effect of Pamaquine on the Blood Cells of Man, J. Clin. Investigation, 27:121-129, 1948.
14. Ferrant, M.: Methemoglobinemia. Two Cases in Xewborn Infants Caused by Nitrates in Well Water, J. Pediat. , 29:585-592, 1946.
15. Finch, C. A.: Treatment of Intracellular Methemoglobinemia, Bull. J'lew England M. Center, 9:241-245, 1947.
16. Finch, C. A.: Methemoglobinemia and Sulfhemoglobinemia, New England.T. Med., 239: 470-478, 1948.
17. Gibson, Q. H.: The Reduction of Methaemoglobin in Red Blood Cells and Studies on the Cause of Idiopathic Methaemoglobinaemia, Riochem. J. , 42:13-23, 1948.
18. Gibson, Q. H. and Harrison, D. C.: Familial Idiopathic Methaemoglobinaemia. Five
Cases in One Family, Lancet, 2:941-943, 1947.
19. Gibson, Q. H. and Harrison, D. C.: Haemoglobin-Methaemoglobin Mixtures, X ature. 162:258-259, 1948.
20. Graybiel, A., Lilienthal, J. L., Jr. and Riley, R. L.: The Report of a Case of Idiopath ic Congenital (and Probably Familial) Methemoglobinemia, Bull. Johns Hopkins Hosp. , 76:155-162, 1945.
21. Gutmann, H. R., Jandorf, J. B. and Bodansky, 0.: The Role of Pyridine Nucleotide in the Reduction of Methemoglobin, J . BioI. Chern., 169: 145-152, 1947.
22. Kin!!;, E. .T ., White, J . C. and Gilchrist, M.: A Case of Idiopathic Methaemoglobinaemia Treated by A cOl·bic Acid and Methylene Blue, J. Path. & Bact., 59:181-188, 1947.
23. Lester, D. and Greenberg, L. A.: The Comparative Anoxemic Effects from Carbon Monoxide Hemoglobin and Methemoglobin , J. Pharmacol. & Expel". Therap. , 81 :182-188, 1944.
24. Macht, D. I. and Harden, W. C.: Toxicology and Assay of Methylene Blue, Ann. Int. Med., 71 :738-745, 1933.
25. Medovy, H.: Well-water Methemoglobinemia in Infan ts, Journal Lancet, 68:194-196. 1948.
26. Scott, E. P.: Cyanosis Cau ed by Methemog~obinemia, Am. J. Dis. Cild., 78:77-79, 1~49.
27. SIevers, R. F. and Ryon, J. B.: Congellltal Idiopathic Methemoglobinemia. Favorable Response to Ascorbic Acid Therapy, Arch. Int. Med., 78:299-307, 1945.
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