      Document 0220
 DOCN  DRG0220
 UNIQUE IDENTIFIER        DRG-0027
 NAME OF SUBSTANCE        Pyrimethamine [USAN 1995]
 REGISTRY NUMBER          58-14-0
 STANDARD CHEMICAL NAME   5-(4-Chlorophenyl)-6-ethyl-2,4-pyrimidinediam-
                          ine [USAN 1995]
 SYNONYMS                 Daraprim [USP DI 1995]
 SYNONYMS                 Chloridin [Merck Index 1989]
 SYNONYMS                 Malocide [Merck Index 1989]
 SYNONYMS                 Tindurin [Merck Index 1989]
 SYNONYMS                 2,4-Diamino-5-(p-chlorophenyl)-6-ethylpyrimid-
                          ine [USAN 1995]
 SYNONYMS                 Fansidar (Pyrimethamine/Sulfadoxine) [Drug
                          Evaluations Annual 1992]
 PROTOCOL ID NUMBERS      NIAID ACTG 021
 PROTOCOL ID NUMBERS      NIAID ACTG 077 Pilot
 PROTOCOL ID NUMBERS      NIAID ACTG 102
 PROTOCOL ID NUMBERS      NIAID ACTG 154
 PROTOCOL ID NUMBERS      NIAID ACTG 156
 PROTOCOL ID NUMBERS      NIAID 89 CC-02
 PROTOCOL ID NUMBERS      NIAID 89 CC-17
 PROTOCOL ID NUMBERS      NIAID CPCRA 001
 PROTOCOL ID NUMBERS      FDA 021A
 PROTOCOL ID NUMBERS      NIAID ACTG 237
 SECONDARY SOURCE ID      RP 4753 [Merck Index 1989]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: Binds to and reversibly
                          inhibits the protozoal enzyme dihydrofolate
                          reductase, selectively blocking conversion of
                          dihydrofolic acid to its functional form,
                          tetrahydrofolic acid; this depletion of
                          folate, an essential cofactor in the
                          biosynthesis of nucleic acids, results in
                          interference with protozoal nucleic acid and
                          protein synthesis.  The protozoal reductase
                          enzyme is many times more tightly bound to
                          pyrimethamine than the corresponding
                          mammalian enzyme. This drug exerts its effect
                          in folate biosynthesis at a step immediately
                          subsequent to the one at which sulfonamides
                          exert their effect. Pyrimethamine is well
                          absorbed following oral administration, is
                          widely distributed in the body (mainly in red
                          and white blood cells, kidneys, lungs, liver,
                          and spleen), is highly bound to plasma
                          proteins, and undergoes hepatic
                          transformation; peak plasma concentration
                          ranges from 2 to 6 hours. Following a 25 mg
                          dose peak plasma levels range from 0.13 to
                          0.31 mcg/ml in adults. Twenty to 30% of the
                          drug is excreted unchanged in the urine with
                          urinary excretion persisting up to 30 days or
                          longer. [USP DI 1995]
 DISEASES STUDIED/TREATED Used in combination with dapsone for treating
                          Pneumocystis carinii pneumonia (PCP) [AHFS
                          Drug Information 1995]
 DISEASES STUDIED/TREATED Combined with a sulfadiazine for
                          toxoplasmosis treatment [AHFS Drug
                          Information 1995]
 DISEASES STUDIED/TREATED FDA approved for toxoplasmosis [AHFS Drug
                          Information 1995]
 CLASSIFICATION CODE      Antimalarial [USAN 1995]
 CLASSIFICATION CODE      Folic acid antagonist [PDR 1995]
 OTHER MAJOR USES         Malaria due to susceptible strains of
                          plasmodia; toxoplasmosis [PDR 1995]
 SUBSTANCE INTERACTIONS   Synergism occurs when pyrimethamine is
                          administered with sulfonamides in
                          toxoplasmosis therapy. Concomitant use of
                          other antifolic drugs, such as sulfonamides
                          or trimethoprim-sulfamethoxazole combinations
                          may increase the risk of bone marrow
                          suppression. Mild hepatotoxicity has been
                          reported in some patients receiving lorazepam
                          and pyrimethamine. [PDR 1995]
 ADVERSE EFFECTS          Hypersensitivity reactions, occasionally
                          severe, can occur at any dose, particularly
                          when pyrimethamine is administered
                          concomitantly with a sulfonamide. With large
                          doses of pyrimethamine, anorexia and vomiting
                          may occur. Vomiting may be minimized by
                          giving the medication with meals; it usually
                          disappears promptly upon reduction of dosage.
                          Doses used in toxoplasmosis may produce
                          megaloblastic anemia, leukopenia,
                          thrombocytopenia, pancytopenia, atrophic
                          glossitis, hematuria and disorders of cardiac
                          rhythym. Hematologic effects, however, may
                          occur at low doses in certain individuals.
                          Insomnia, diarrhea, headache,
                          light-headedness, dryness of the mouth or
                          throat, fever, malaise, dermatitis, abnormal
                          skin pigmentation, depression, seizures,
                          pulmonary eosinophilia, and
                          hyperphenylalaninemia have been reported
                          rarely. [PDR 1995]
 CONTRAINDICATIONS        Contraindicated in patients with known
                          hypersensitivity to pyrimethamine.  It should
                          be used by pregnant women only if the
                          potential benefit justifies the potential
                          risk to the fetus.  The drug is also
                          contraindicated in patients with documented
                          megaloblastic anemia due to folate
                          deficiency. [PDR 1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Pyrimethamine is a
                          synthetic, aminopyrimidine derivative
                          structurally related to trimethoprim [AHFS
                          Drug Information 1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C12H13ClN4 [USAN 1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 248.72 [USAN 1995]
 CHEMICAL/PHYSICAL DATA   PERCENT ELEMENTAL COMPOSITION: C57.94%;
                          H5.27%; Cl14.25%; N22.53% [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   MELTING POINT: 233-234 C [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY (g/l): ethanol (about 9); dilute
                          HCl (about 5); boiling ethanol (about 25).
                          Very sparingly soluble in propylene glycol
                          and dimethylacetamide at 70 C; practically
                          insoluble in water [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: White crystalline
                          powder [AHFS Drug Information 1995]
 CHEMICAL/PHYSICAL DATA   STABILITY: Tablets should be stored at 15 C
                          to 25 C in a tight, light-resistant container
                          [USP DI 1995]
 CHEMICAL/PHYSICAL DATA   STABILITY: Oral suspensions prepared from the
                          tablets are stable at room temperature for 5
                          to 7 days [USP DI 1995]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: 25 mg tablets. [PDR 1995]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral. [PDR 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: Store at 15 C to 30 C in a tight,
                          light-resistant container. Suspensions
                          prepared from crushed tablets should be used
                          immediately. [USP DI 1995]
 MANUFACTURERS            Glaxo Wellcome
 REFERENCES               Jacobson MA, Besch CL, Child C, Hafner R,
                          Matts JP, Muth K, Wentworth DN, Neaton JD,
                          Abrams D, Rimland D, et al. Primary
                          prophylaxis with pyrimethamine for
                          toxoplasmic encephalitis in patients with
                          advanced human immunodeficiency virus
                          disease: results of a randomized trial. J
                          Infect Dis. 1994 Feb;169(2):384-94.
 REFERENCES               Gregoire NE. Prevention of cerebral
                          toxoplasmosis in severely depressed patients
                          with AIDS. Int Conf AIDS. 1994 Aug
                          7-12;10(2):154 (abstract no. PBO629).
 REFERENCES               Podzamczer D, Santin M, Jimenez J, Casanova
                          A, Bolao F, Gudiol GR. Thrice-weekly
                          cotrimazole is better than weekly
                          dapsone-pyrimethamine for the primary
                          prevention of Pneumocystis carinii pneumonia
                          in HIV-infected patients. AIDS. 1993
                          Apr;7(4):501-6.
 REFERENCES               Opravil M, Heald A, Lazzarin A, Hirschel B,
                          Luthy R. Dapsone-pyrimethamine (DP) vs.
                          aerosolized pentamidine (AP) for combined
                          prophylaxis of PCP and toxoplasmic
                          encephalitis (TE). Int Conf AIDS. 1993 Jun
                          6-11;9(1):373 (abstract no. PO-B10-1429).
 REFERENCES               Mallolas J, Zamora L, Gatell JM, Miro JM,
                          Vernet E, Valls ME, Soriano E, SanMiguel JG.
                          Primary prophylaxis for Pneumocystis carinii
                          pneumonia: a randomized trial comparing
                          cotrimoxazole, aerosolized pentamidine and
                          dapsone plus pyrimethamine. AIDS. 1993
                          Jan;7(1):59-64.
 REFERENCES               Grunewald T, Bergamnn F, Eljaschewitsch J,
                          Pohle HD Ruf B. Antiprotozoal prophylaxis in
                          AIDS patients--results of a prospective
                          randomized study comparing
                          Dapson/pyrimethamine and
                          sulfadoxine/pyrimethamine. Int Conf AIDS.
                          1993 Jun 6-11;9(1):56 (abstract no.
                          WS-B13-3).
 REFERENCES               Saba J, Morlat P, Raffi F, Hazebroucq V, Joly
                          V, Leport C. Vilde JL. Pyrimethamine plus
                          azithromycin for treatment of acute
                          toxoplasmic encephalitis in patients with
                          AIDS. Eur J Clin Microbiol Infect Dis. 1993
                          Nov;12(11):853-6.
 REFERENCES               de Gans J, Portegies P, Reiss P, Troost D,
                          van Gool T, Lange JM. Pyrimethamine alone as
                          maintenance therapy for central nervous
                          system toxoplasmosis in 38 patients with
                          AIDS. J Acquir Immune Defic Syndr.
                          1992;5(2):137-42.
 REFERENCES               Koppen S, Grunewald T, Jautzke G, Gottschalk
                          J, Pohle HD, Ruf B. Prevention of
                          Pneumocystis carinii pneumonia and
                          toxoplasmic encephalitis in human
                          immunodeficiency virus infected patients: a
                          clinical approach comparing aerosolized
                          pentamidine and pyrimethamine/sulfadoxine.
                          Clin Investig. 1992 Jun;70(6):508-12.
 REFERENCES               Jacobson MA, Besch CL, Child C, Hafner R,
                          Muth K, Wentworth DN, Deyton L. Toxicity of
                          clindamycin as prophylaxis for
                          AIDS-associated toxoplasmic encephalitis.
                          Lancet. 1992 Feb 8;339(8789):333-4.
 ENTRY MONTH              8906
 LAST REVISION DATE       960612
 

SOURCE: National Library of Medicine, Bethesda, MD.  Distributed by AEGIS.
