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July 1960, Vol 64, No. 1 >
ARTICLE | July 1960

The Hematologic Toxicity of Pyrimethamine (Daraprim) in Man FREE

HERBERT E. KAUFMAN, M.D.; PHILIP H. GEISLER, M.D.
[+] Author Affiliations

Submitted for publication Feb. 4, 1960.


Arch Ophthalmol. 1960;64(1):140-146. doi:10.1001/archopht.1960.01840010142016
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Pyrimethamine (Daraprim) was first reported therapeutically effective against malaria parasites in 1949.1 In 1952 the efficacy of pyrimethamine in destroying organisms of the genus Toxoplasma was demonstrated, but the toxoplasmacidal dose was found to be larger than the antimalarial dose.2 Although the drug is used with clinical benefit,3,4 little has been reported concerning the toxicity of pyrimethamine in the treatment of toxoplasmosis in man.

Pyrimethamine appears to act primarily as a metabolic antagonist in the folic acid pathway of nucleotide synthesis. Schmidt, in 1953, observed that when massive doses of pyrimethamine were administered to monkeys, an acute toxicity developed with convulsive seizures and death.5 Lower doses produced a chronic toxicity, characterized by granulocytopenia and lymphopenia, and depletion of the myeloid elements of the bone marrow. In rats treated with pyrimethamine both myelopoiesis and erythropoiesis were suppressed, and in dogs a moderate leucopenia developed.6 In an

REFERENCES

1 +
Falio, E. A.; Goodwin, L. G.; Hitchings, G. H.; Rollo, I. M., and Russell, P. B.:  Diaminopyrimidines—A New Study of Antimalarials , Brit. J. Pharmacol. 6:185-200, 1951;.
2 +
Eyles, D. E., and Coleman, N.:  Tests of 2,4-Diaminopyrimidine on Toxoplasmosis , Pub. Health Rep. 67:249-252, 1952;.
3 +
Ryan, R. W.; Hart, W. M.; Culligan, J. J.; Gunkel, R. D.; Jacobs, L., and Cook, M. K.:  Diagnosis and Treatment of Toxoplasmic Uveitis , Tr. Am. Acad. Ophth. 60:548-554, 1958;.
4 +
Perkins, E. S.; Smith, C. H., and Schofield, P. B.:  Treatment of Uveitis with Pyrimethamine (Daraprim) , Brit. J. Ophth. 40:577-586, 1956;.
5 +
Schmidt, L. H.; Hughes, H. B., and Schmidt, I. G.:  The Pharmacological Properties of 2,4-Diamino-5-p-Chlorophenyl-6-Ethyl Primidine (Daraprim) , J. Pharmacol. & Exper. Therap. 107: 92-130, 1953;.
6 +
Hamilton, L.; Philips, F. S.; Sternberg, S. S.; Clarke, D. A., and Hitchings, G. H.:  Hematological Effects of Certain 2,4-Diaminopyrimidines, Antagonists of Folic Acid Metabolism , Blood 9:1062-1081, 1954;.
7 +
Myatt, A. V.; Coatney, G. R.; Hernandez, T., and Burton, H. W.:  A Further Study of the Toxicity of Pyrimethamine (Daraprim) in Man , Am. J. Trop. Med. 2:1000-1001, 1953;.
8 +
Myatt, A. V.; Hernandez, T., and Coatney, G. R.:  Studies in Human Malaria , Am. J. Trop. Med. 2:788-795, 1953;.
9 +
Frenkel, J. K.:  Chorioretinitis Associated with Positive Tests for Toxoplasmosis , Acta XVII Conc. Ophth. 3:1965-1976, 1954;.
10 +
Frenkel, J. K., and Hitchings, G. H.:  Relative Reversal by Vitamins (p-Aminobenzoic, Folic, and Folinic Acids) of the Effects of Sulfadiazone and Pyrimethamine on Toxoplasma , Mouse, and Man, Antibiotics & Chemother. 1:630-638, 1957;.
11 +
King, E. J.; Gilchrist, M., and DeLory, G. E.:  Accuracy of Hemoglobin Methods , Lancet 1:239-243, 1944;.
12 +
Strumia, M. M.; Sample, A. B., and Hart, E. D.:  An Improved Microhematocrit Method , Am. J. Clin. Path. 24:1016-1024, 1954;.
13 +
Brecher, G., and Cronkite, E. P.:  Morphology and Enumeration of Human Blood Platelets , J. Appl. Physiol. 3:365-377, 1950;.
14 +
Brecher, G.:  New Methylene Blue as a Reticulocyte Stain , Am. J. Clin. Path. 19:895-896, 1949;.
15 +
Finland, M.; Strausse, E., and Peterson, O. L.:  Sulfadiazine: Therapeutic Evaluation and Toxic Effects on 446 Patients , J.A.M.A. 116: 2641-2647, 1940;.
16 +
Finland, M.; Peterson, O. L., and Goodwin, R. A., Jr.:  Sulfadiazine: Further Studies of Its Efficacy and Toxic Effects in 460 Patients , Ann. Int. Med. 17:920-934, 1942;.
17 +
Hurd, R. W., and Jacox, R. F.:  Thrombocytopenic Purpura Developing as a Complication of Sulfathiozole and Sulfadiazine Therapy , J.A.M.A. 122:296-298, 1943;.
18 +
Layne, J. A., and Schemm, F. R.:  Acute Macrocytic Hemolytic Anemia Occurring Following Administration of Sulfadiazine , J. Lab. & Clin. Med. 29:347-351, 1944;.
19 +
Denny, H. M., and Menten, M. L.:  Blood Changes Associated with Sulfonamide Therapy: Aplastic Anemia Associated with Sulfonamide Therapy , Am. J.M. Sc. 211:659-665, 1946;.
20 +
Goodman, L. S., and Gilman, A.: The Pharmacological Basis of Therapeutics , Ed. 2, New York, The Macmillan Company, 1956;, p. 1298-1299.
21 +
Wintrobe, M.: Clinical Hematology , Ed. 4, Philadelphia, Lea & Febiger, 1955;, p. 827.
22 +
Kaufman, H. E., and Caldwell, L.:  Pharmacological Studies of Pyrimethamine (Daraprim) in Man , A.M.A. Arch. Ophth. 61:885-890, 1959;.

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1 +
Falio, E. A.; Goodwin, L. G.; Hitchings, G. H.; Rollo, I. M., and Russell, P. B.:  Diaminopyrimidines—A New Study of Antimalarials , Brit. J. Pharmacol. 6:185-200, 1951;.
2 +
Eyles, D. E., and Coleman, N.:  Tests of 2,4-Diaminopyrimidine on Toxoplasmosis , Pub. Health Rep. 67:249-252, 1952;.
3 +
Ryan, R. W.; Hart, W. M.; Culligan, J. J.; Gunkel, R. D.; Jacobs, L., and Cook, M. K.:  Diagnosis and Treatment of Toxoplasmic Uveitis , Tr. Am. Acad. Ophth. 60:548-554, 1958;.
4 +
Perkins, E. S.; Smith, C. H., and Schofield, P. B.:  Treatment of Uveitis with Pyrimethamine (Daraprim) , Brit. J. Ophth. 40:577-586, 1956;.
5 +
Schmidt, L. H.; Hughes, H. B., and Schmidt, I. G.:  The Pharmacological Properties of 2,4-Diamino-5-p-Chlorophenyl-6-Ethyl Primidine (Daraprim) , J. Pharmacol. & Exper. Therap. 107: 92-130, 1953;.
6 +
Hamilton, L.; Philips, F. S.; Sternberg, S. S.; Clarke, D. A., and Hitchings, G. H.:  Hematological Effects of Certain 2,4-Diaminopyrimidines, Antagonists of Folic Acid Metabolism , Blood 9:1062-1081, 1954;.
7 +
Myatt, A. V.; Coatney, G. R.; Hernandez, T., and Burton, H. W.:  A Further Study of the Toxicity of Pyrimethamine (Daraprim) in Man , Am. J. Trop. Med. 2:1000-1001, 1953;.
8 +
Myatt, A. V.; Hernandez, T., and Coatney, G. R.:  Studies in Human Malaria , Am. J. Trop. Med. 2:788-795, 1953;.
9 +
Frenkel, J. K.:  Chorioretinitis Associated with Positive Tests for Toxoplasmosis , Acta XVII Conc. Ophth. 3:1965-1976, 1954;.
10 +
Frenkel, J. K., and Hitchings, G. H.:  Relative Reversal by Vitamins (p-Aminobenzoic, Folic, and Folinic Acids) of the Effects of Sulfadiazone and Pyrimethamine on Toxoplasma , Mouse, and Man, Antibiotics & Chemother. 1:630-638, 1957;.
11 +
King, E. J.; Gilchrist, M., and DeLory, G. E.:  Accuracy of Hemoglobin Methods , Lancet 1:239-243, 1944;.
12 +
Strumia, M. M.; Sample, A. B., and Hart, E. D.:  An Improved Microhematocrit Method , Am. J. Clin. Path. 24:1016-1024, 1954;.
13 +
Brecher, G., and Cronkite, E. P.:  Morphology and Enumeration of Human Blood Platelets , J. Appl. Physiol. 3:365-377, 1950;.
14 +
Brecher, G.:  New Methylene Blue as a Reticulocyte Stain , Am. J. Clin. Path. 19:895-896, 1949;.
15 +
Finland, M.; Strausse, E., and Peterson, O. L.:  Sulfadiazine: Therapeutic Evaluation and Toxic Effects on 446 Patients , J.A.M.A. 116: 2641-2647, 1940;.
16 +
Finland, M.; Peterson, O. L., and Goodwin, R. A., Jr.:  Sulfadiazine: Further Studies of Its Efficacy and Toxic Effects in 460 Patients , Ann. Int. Med. 17:920-934, 1942;.
17 +
Hurd, R. W., and Jacox, R. F.:  Thrombocytopenic Purpura Developing as a Complication of Sulfathiozole and Sulfadiazine Therapy , J.A.M.A. 122:296-298, 1943;.
18 +
Layne, J. A., and Schemm, F. R.:  Acute Macrocytic Hemolytic Anemia Occurring Following Administration of Sulfadiazine , J. Lab. & Clin. Med. 29:347-351, 1944;.
19 +
Denny, H. M., and Menten, M. L.:  Blood Changes Associated with Sulfonamide Therapy: Aplastic Anemia Associated with Sulfonamide Therapy , Am. J.M. Sc. 211:659-665, 1946;.
20 +
Goodman, L. S., and Gilman, A.: The Pharmacological Basis of Therapeutics , Ed. 2, New York, The Macmillan Company, 1956;, p. 1298-1299.
21 +
Wintrobe, M.: Clinical Hematology , Ed. 4, Philadelphia, Lea & Febiger, 1955;, p. 827.
22 +
Kaufman, H. E., and Caldwell, L.:  Pharmacological Studies of Pyrimethamine (Daraprim) in Man , A.M.A. Arch. Ophth. 61:885-890, 1959;.

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