      Document 0217
 DOCN  DRG0217
 UNIQUE IDENTIFIER        DRG-0030
 NAME OF SUBSTANCE        Trimethoprim [USAN 1995]
 REGISTRY NUMBER          738-70-5
 STANDARD CHEMICAL NAME   5-((3,4,5-Trimethoxyphenyl)methyl)-2,4-pyrimi-
                          dinediamine [USAN 1995]
 SYNONYMS                 Monotrim [Merck Index 1989]
 SYNONYMS                 Proloprim [USAN 1995]
 SYNONYMS                 Syraprim [Merck Index 1989]
 SYNONYMS                 Tiempe [Merck Index 1989]
 SYNONYMS                 Trimanyl [Merck Index 1989]
 SYNONYMS                 Trimopan [Merck Index 1989]
 SYNONYMS                 Trimpex [USAN 1995]
 SYNONYMS                 Wellcoprim [Merck Index 1989]
 SYNONYMS                 2,4-Diamino-5-(3,4,5-trimethoxybenzyl)pyrimid-
                          ine [Merck Index 1989]
 SYNONYMS                 Co-trimoxazole [USAN 1995]
 SYNONYMS                 Abacin [Merck Index 1989]
 SYNONYMS                 Bactramin [Merck Index 1989]
 SYNONYMS                 Bactrim [Merck Index 1989]
 SYNONYMS                 Baktar [Merck Index 1989]
 SYNONYMS                 Bactromin [Merck Index 1989]
 SYNONYMS                 Drylin [Merck Index 1989]
 SYNONYMS                 Eusaprim [Merck Index 1989]
 SYNONYMS                 Gantaprim [Merck Index 1989]
 SYNONYMS                 Gantrim [Merck Index 1989]
 SYNONYMS                 Kepinol [Merck Index 1989]
 SYNONYMS                 Momentol [Merck Index 1989]
 SYNONYMS                 Nopil [Merck Index 1989]
 SYNONYMS                 Omsat [Merck Index 1989]
 SYNONYMS                 Septra [Merck Index 1989]
 SYNONYMS                 Septrim [Merck Index 1989]
 SYNONYMS                 Sigaprim [Merck Index 1989]
 SYNONYMS                 Sulfotrim [Merck Index 1989]
 SYNONYMS                 Sulfotrimin [Merck Index 1989]
 SYNONYMS                 Sulprim [Merck Index 1989]
 SYNONYMS                 Sumetrolim [Merck Index 1989]
 SYNONYMS                 Tacumil [Merck Index 1989]
 SYNONYMS                 Teleprim [Merck Index 1989]
 SYNONYMS                 TMS 480 [Merck Index 1989]
 SYNONYMS                 Trigonyl [Merck Index 1989]
 SYNONYMS                 Linaris [Merck Index 1989]
 SYNONYMS                 Eltrianyl [Merck Index 1989]
 SYNONYMS                 Microtrim [Merck Index 1989]
 SYNONYMS                 Trimesulf [Merck Index 1989]
 SYNONYMS                 Apo-Sulfatrim [Merck Index 1989]
 SYNONYMS                 Fectrim [Merck Index 1989]
 SYNONYMS                 Trimforte [Merck Index 1989]
 SYNONYMS                 Uro-Septra [Merck Index 1989]
 SYNONYMS                 Trimogal [Merck Index 1989]
 SYNONYMS                 Uretrim [Merck Index 1989]
 SYNONYMS                 Chemotrim [Merck Index 1989]
 SYNONYMS                 Comox [Merck Index 1989]
 SYNONYMS                 Cotrim-Puren [Merck Index 1989]
 SYNONYMS                 Duratrimet [Merck Index 1989]
 SYNONYMS                 Helveprim [Merck Index 1989]
 SYNONYMS                 Imexim [Merck Index 1989]
 SYNONYMS                 Laratrim [Merck Index 1989]
 SYNONYMS                 Supracombin [Merck Index 1989]
 SYNONYMS                 Thiocuran [Merck Index 1989]
 SYNONYMS                 Uroplus [Merck Index 1989]
 SYNONYMS                 TMP [AmFAR Tx Dir 1993;6(3)]
 PROTOCOL ID NUMBERS      NIAID ACTG 021
 PROTOCOL ID NUMBERS      NIAID ACTG 029
 PROTOCOL ID NUMBERS      NIAID ACTG 030
 PROTOCOL ID NUMBERS      NIAID ACTG 031
 PROTOCOL ID NUMBERS      NIAID ACTG 033
 PROTOCOL ID NUMBERS      NIAID ACTG 037
 PROTOCOL ID NUMBERS      NIAID ACTG 040
 PROTOCOL ID NUMBERS      NIAID ACTG 081
 PROTOCOL ID NUMBERS      NIAID ACTG 167
 PROTOCOL ID NUMBERS      NIAID ACTG 108
 PROTOCOL ID NUMBERS      FDA 007A
 PROTOCOL ID NUMBERS      FDA 053A
 PROTOCOL ID NUMBERS      FDA 056A
 PROTOCOL ID NUMBERS      NIAID CPCRA 006
 PROTOCOL ID NUMBERS      NIAID 93 I-36
 PROTOCOL ID NUMBERS      FDA 224A
 PROTOCOL ID NUMBERS      NIAID ACTG 268
 PROTOCOL ID NUMBERS      NIAID ACTG 283
 SECONDARY SOURCE ID      BW 56-72 [USAN 1995]
 SECONDARY SOURCE ID      NSC-106568 [USAN 1995]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: Rapidly and completely
                          absorbed, with plasma level peaking (mean,
                          approximately 1.0 mcg/ml) in 1-4 hours and
                          half life of 8-10 hours following oral
                          administration (dose, 100 mg) with 44 percent
                          bound to protein; following intravenous
                          administration, plasma half-life is 11.3
                          hours, with detectable amounts found in blood
                          24 hours after administration; excretion is
                          chiefly by the kidneys through glomerular
                          filtration and tubular secretion, with urine
                          levels considerably higher than serum levels.
                           It exists in the blood as unbound,
                          protein-bound, and metabolized forms; 10-20
                          percent is metabolized, primarily in the
                          liver, with the remainder excreted unchanged
                          in the urine; the principal metabolites are
                          the 1- and 3-oxides and the 3'- and
                          4'-hydroxy derivatives. It binds to and
                          reversibly inhibits the bacterial enzyme
                          dihydrofolate reductase, selectively blocking
                          conversion of dihydrofolic acid to its
                          functional form, tetrahydrofolic acid; this
                          action depletes folate, resulting in
                          interference with bacterial nucleic acid and
                          protein production.  It exerts its effect at
                          a step in the folate biosynthesis immediately
                          subsequent to the one in which sulfonamides
                          exert their effect. [PDR 1995]
 DISEASES STUDIED/TREATED Used in combination with sulfamethoxazole or
                          dapsone for treatment of Pneumocystis carinii
                          pneumonia (PCP) [AHFS Drug Information 1995]
 DISEASES STUDIED/TREATED FDA approved Bactrim and Septra 6/23/81 for
                          PCP treatment and approved 1/7/94 for PCP
                          prophylaxis [AHFS Drug Information 1995]
 CLASSIFICATION CODE      Antibacterial [USAN 1995]
 OTHER MAJOR USES         Treatment of initial episodes of
                          uncomplicated urinary tract infections due to
                          susceptible strains of E. coli, P. mirabilis,
                          K. pneumoniae, and Enterobacter species and
                          coagulase-negative Staphylococcus species,
                          including S. saprophyticus [PDR 1995]
 SUBSTANCE INTERACTIONS   Trimethoprim may inhibit the hepatic
                          metabolism of phenytoin, increasing the
                          half-life and decreasing its metabolic
                          clearance rate by 51 percent and 30 percent,
                          respectively. Drug interactions have been
                          observed in concurrent use of trimethoprim
                          with bone marrow depressants (may increase
                          leukopenic/thrombocytopenic effects), folate
                          antagonists (may cause megablastic anemia),
                          and rifampim (may significantly increase the
                          elimination and shorten the elimination
                          half-life of trimethoprim. Warfarin
                          anticoagulant activity may be potentiated.
                          Procainamide renal clearance may be decreased
                          and cyclosporine nephrotoxicity may be
                          increased. [USP DI 1995]
 ADVERSE EFFECTS          Adverse effects most often encountered with
                          trimethoprim are rash and pruritis. The
                          incidence of aseptic meningitis,
                          hypersensitivity, methemoglobinemia, and
                          Stevens-Johnson syndrome is rare.
                          Gastrointestinal disturbances include
                          diarrhea, nausea or vomiting, stomach cramps
                          or pain. Hematologic effects include
                          thrombocytopenia, leukopenia, and
                          megaloblastic anemia. Fever and increase in
                          BUN and serum creatinine levels have also
                          been reported. [PDR 1995]
 CONTRAINDICATIONS        Because trimethoprim may interfere with folic
                          acid metabolism, it should be used during
                          pregnancy only if the potential benefit
                          justifies the potential risk. Contraindicated
                          in those with documented megaloblastic anemia
                          due to folate deficiency. [PDR 1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION:
                          Trimethoxybenzyl-substituted pyrimidine
                          diamine; bacteriostatic lipophilic weak base
                          structurally related to pyrimethamine [USP DI
                          1989]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C14H18N4O3 [USAN 1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 290.32 [USAN 1995]
 CHEMICAL/PHYSICAL DATA   PERCENT ELEMENTAL COMPOSITION: C57.92%;
                          H6.25%; N19.30%; O16.52% [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   MELTING POINT: 199-203 degrees C [Merck Index
                          1989]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: (g/100 ml; 25 C): DMAC, 13.86;
                          benzyl alcohol, 7.29; propylene glycol, 2.57;
                          chloroform, 1.82; methanol, 1.21; water,
                          0.04; ether, 0.003; benzene, 0.002 [Merck
                          Index 1989]
 CHEMICAL/PHYSICAL DATA   PHYSICAL COMMENT: pKa: 6.6 [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: White to cream, bitter
                          crystalline powder [Merck Index 1989]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Tablets (100 mg and 200 mg).
                          [PDR 1995]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral. [PDR 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: Store below 40 C (104 F), preferably
                          between 15-30 C (59-86 F) in a tight,
                          light-resistant container. [USP DI 1995]
 MANUFACTURERS            Glaxo Wellcome
 MANUFACTURERS            Hoffmann-La Roche
 REFERENCES               Saah AJ, Hoover DR, Peng Y, Phair JP,
                          Visscher B, Kingsley LA, Schrager LK.
                          Predictors for failure of Pneumocystis
                          carinii pneumonia prophylaxis. JAMA. 1995 Apr
                          19;273(15):1197-202.
 REFERENCES               Bozzette SA, Forthal D, Sattler FR, Kemper C,
                          Richman DD, Tilles JG, Leedom J, McCutchan
                          JA. The tolerance for zidovudine plus thrice
                          weekly or daily trimethoprim-sulfamethoxazole
                          with and without leucovorin for primary
                          prophylaxis in advanced HIV disease. Am J
                          Med. 1995 Feb;98(2):177-82.
 REFERENCES               Bozzette SA, Finkelstein DM, Spector SA,
                          Frame P, Powderly WG, He W, Phillips L,
                          Craven D, van der Horst C, Feinberg J. A
                          randomized trial of three antipneumocystis
                          agents in patients with advanced human
                          immunodeficiency virus infection. N Engl J
                          Med. 1995 Mar 16;332(11):693-9.
 REFERENCES               May T, Beuscart C, Reynes H, Marchou B,
                          Leclercq P, Borsa Lebas F, Saba J, Micoub M,
                          Mouton Y, Canton P.
                          Trimethoprim-sulfamethoxazole versus
                          aerosolized pentamidine for primary
                          prophylaxis of Pneumocystis carinii
                          pneumonia: a prospective, randomized,
                          controlled clinical trial. J Acquired Immune
                          Defic Syndr. 1994 May;7(5):457-62.
 REFERENCES               Sattler FR, Frame P, Davis R, Nichols L,
                          Shelton B, Akil B, Baughman R, Hughlett C,
                          Weiss W, Boylen CT, et al. Trimetrexate with
                          leucovorin versus
                          trimethoprim-sulfamethoxazole for moderate to
                          severe episodes of Pneumocystis carinii
                          pneumonia in patients with AIDS: a
                          prospective, controlled mulicenter
                          investigation of the AIDS Clinical Trial
                          Group Protocol 029/031. J Infect Dis. 1994
                          Jul;170(1):165-72.
 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               Reynes J, Brunschwig C, Atoui N, Fabre J,
                          Siffert M, Janbon F. Folate deficiency and
                          cotrimoxazole prophylaxis during HIV
                          infection. Int Conf AIDS. 1993 Jun
                          6-11;9(1):387 (abstract no. PO-B10-1512).
 REFERENCES               Podzamczer D, Santin M, Jimenez J, Casanova
                          A, Bolao F, Gudiol GR. Thrice-weekly
                          cotrimoxazole 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               Hardy WD, Feinberg J, Finkelstein DM, Power
                          ME, He W, Kaczka C, Frame PT, Holmes M,
                          Waskin H, Fass RJ, et al. A controlled trial
                          of trimethoprim-sulfamethoxazole or
                          aerosolized pentamidine for secondary
                          prophylaxis of Pneumocytis carinii pneumonia
                          in patients with the acquired
                          immunodeficiency syndrome. N Engl J Med. 1992
                          Dec 24;327(26):1842-8.
 REFERENCES               Klein NC, Ducanson FP, Lenox TH, Forszpaniak
                          C, Sherer CB, Quentzel H, Nunez M, Suarez M,
                          Kawwaff O, Pitta-Alvarez A, et al.
                          Trimethoprim-sulfamethoxazole versus
                          pentamidine for Pneymocystis carinii
                          pneumonia in AIDS patients: results of a
                          large prospective randomized treatment trial.
                          AIDS. 1992 Mar;6(3):301-5.
 ENTRY MONTH              8906
 LAST REVISION DATE       960612
 

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