      Document 0123
 DOCN  DRG0123
 UNIQUE IDENTIFIER        DRG-0124
 NAME OF SUBSTANCE        Pyrazinamide [USAN 1996]
 REGISTRY NUMBER          98-96-4
 STANDARD CHEMICAL NAME   Pyrazinecarboxamide [USAN 1996]
 SYNONYMS                 Pyrazinoic acid amide [Merck Index 1989]
 SYNONYMS                 D-50 [Merck Index 1989]
 SYNONYMS                 Eprazin [Merck Index 1989]
 SYNONYMS                 Pyrafat [Merck Index 1989]
 SYNONYMS                 Piraldina [Merck Index 1989]
 SYNONYMS                 Unipyranamide [Merck Index 1989]
 SYNONYMS                 Pyrazine carboxylamide [Merck Index 1989]
 SYNONYMS                 Aldinamide [Merck Index 1989]
 SYNONYMS                 Pezetamid [Merck Index 1989]
 SYNONYMS                 Pirilene [Merck Index 1989]
 SYNONYMS                 Tebrazid [Merck Index 1989]
 SYNONYMS                 Zinamide [Merck Index 1989]
 PROTOCOL ID NUMBERS      NIAID ACTG 177
 PROTOCOL ID NUMBERS      NIAID ACTG 222
 PROTOCOL ID NUMBERS      NIAID ACTG 238
 PROTOCOL ID NUMBERS      NIAID CPCRA 004
 PROTOCOL ID NUMBERS      NIAID ACTG 309
 SECONDARY SOURCE ID      DRG
 PHARMACOLOGICAL ACTION   MODE OF ACTION:  May be bacteriostatic or
                          bactericidal, depending on the concentration
                          of the drug attained at the site of infection
                          and the susceptibility of the infecting
                          organism. It is a highly specific agent and
                          is active only against Mycobacterium
                          tuberculosis. In vitro and in vivo, the drug
                          is active only at a slightly acid pH. The
                          exact mechanism has not been fully
                          eludicated, but the antimycobacterial
                          activity appears to partly depend on
                          conversion of the drug to pryazinoic acid
                          (POA). Susceptible strains of M. tuberculosis
                          produce pyrazinamidase, an enzyme that
                          deaminates pyrazinamide to POA, and the vitro
                          susceptibility of a given strain of the
                          organism appears to  correspond to its
                          pyrazinamidase activity. In vitro studies
                          indicate that POA has specific
                          antimycobacterial activity against M.
                          tuberculosis.  In addition, the fact that POA
                          lowers the pH of the environment below that
                          which is necessary for growth of M.
                          tuberculosis appears to contribute to the
                          drug's antimycobacterial activity in vitro.
                          Pyrazinamide is well absorbed from the GI
                          tract; it reaches peak plasma concentrations
                          after an oral dose in 2 hours and is widely
                          distributed throughout the body, including in
                          cerebrospinal fluid (100 percent of serum
                          concentrations in normal and inflamed
                          meninges). Half-life is 9-10 hours. It is
                          primarily metabolized by the liver;
                          metabolites and about 3-4% of unchanged drug
                          are excreted in urine. There may be some
                          concentration in the bile. [AHFS Drug
                          Information 1995] [NIAID ACTG 177] [Facts and
                          Comparisons 1995]
 DISEASES STUDIED/TREATED An oral antituberculosis drug used in
                          combination regimens [AHFS Drug Information
                          1995] [NIAID ACTG 177]
 DISEASES STUDIED/TREATED Prophylaxis against Mycobacterium
                          tuberculosis (MTb) in persons dually infected
                          with HIV and MTb (Used in conjunction with
                          rifampin to help overcome drug resistance)
                          [AHFS Drug Information 1995] [NIAID ACTG 177]
 CLASSIFICATION CODE      Antibacterial [USAN 1996]
 OTHER MAJOR USES         Used in conjunction with at least one other
                          anti-tuberculosis agent in the treatment of
                          clinical tuberculosis [AHFS Drug Information
                          1995]
 SUBSTANCE INTERACTIONS   May interact with allopurinol, colchicine,
                          probenecid, or sulfinpyrazone, increasing
                          serum uric acid concentrations. Cyclosporine
                          serum levels may be decreased by concomitant
                          pyrazinamide. [USP DI 1995]
 ADVERSE EFFECTS          Liver injury is the most common adverse
                          effect; it appears to be dose related and may
                          occur at any time during therapy. At doses of
                          40 to 50 mg/kg, signs and symptoms of hepatic
                          disease occur in 15% of patients, with
                          jaundice in 2 to 3%, and rare instances of
                          death due to hepatic necrosis. Current
                          regimens of 20 to 35 mg/kg/day are much
                          safer. Pyrazinamide inhibits excretion of
                          urate, resulting in hyperuricemia in nearly
                          all patients.  Other adverse effects include
                          arthralgias, anorexia, nausea and vomiting,
                          dysuria, malaise and fever, sideroblastic
                          anemia, adverse effects on the blood clotting
                          mechanism or vascular integrity, and
                          hypersensitivity reactions such as urticaria,
                          pruritis and skin rashes. Rarely fever,
                          porphyria, and dysuria have been reported.
                          [PDR 1995] [AHFS Drug Information 1995]
                          [NIAID ACTG 177]
 CONTRAINDICATIONS        Contraindicated in persons with severe
                          hepatic damage, those who have shown
                          hypersensitivity to the drug, and those with
                          acute gout. Should be used with caution in
                          patients with renal failure, history of gout,
                          or diabetes. [PDR 1995] [AHFS Drug
                          Information 1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: The pyrazine analogue of
                          nicotinamide [PDR 1995]
 CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: Drug occurs as a white
                          to practically white, odorless or practically
                          odorless, crystalline powder [AHFS Drug
                          Information 1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C5H5N3O [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 123.11 [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   MELTING POINT: 189-191 C [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   ELEMENTAL COMPOSITION: C 48.78%, H 4.09%, N
                          34.14%, O 13.00% [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: Sparingly soluble in water and
                          slightly soluble in alcohol [AHFS Drug
                          Information 1995]
 CHEMICAL/PHYSICAL DATA   PHYSICAL COMMENT: pka = 0.5. Aqueous
                          solutions are neutral [Merck Index 1989]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Tablets (300 mg). [AHFS Drug
                          Information 1995]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral. [AHFS Drug
                          Information 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: Store in a well-closed container at
                          controlled room temperature of 15-30 C. [AHFS
                          Drug Information 1995]
 MANUFACTURERS            Lederle Laboratories / American Cyanamid
                          Company
 REFERENCES               Paramasivan CN, Herbert D, Prabhakar R.
                          Bactericidal action of pulsed exposure to
                          rifampicin, ethambutol, isoniazid &
                          pyrazinamide on Mycobacterium tuberculosis in
                          vitro. Indian J Med Res. 1993 Jul;97:145-50.
 REFERENCES               Singh V, Choudhury P, Puri RK. Pyrazinamide.
                          Indian Pediatr. 1993 Feb;30(2):233-6.
 REFERENCES               Jain A, Mehta VL, Kulshrestha S. Effect of
                          pyrazinamide on rifampicin kinetics in
                          patients with tuberculosis. Tuber Lung Dis.
                          1993 Apr;74(2):87-90.
 REFERENCES               Mwinga A, Pobee J, Luo N, Porter J, McAdam
                          KP. Chemoprophylaxis in the prevention of HIV
                          related tuberculosis in Zambia. Int Conf AIDS
                          1993 Jun 6-11;9(1):334 (abstract no.
                          PO-B07-1191).
 REFERENCES               Coberly J, Halsey N, Johnson M, Desormeaux J,
                          et al. Acceptability of twice weekly short
                          course rifampin and pyrazinamide for TB
                          preventive therapy in HIV infected adults.
                          Int Conf AIDS 1993 Jun 6-11;9(1):328
                          (abstract no. PO-B07-1158).
 REFERENCES               Gatell JM. Tuberculosis (TBC) in HIV infected
                          patients (P): a multicentric, randomized
                          comparative study of a three versus a four
                          drug regimen. European Tuberculosis Study
                          Group. ENTA and EEC-Tuberculosis Concerted
                          Actions. Int Conf AIDS. 1992 Jul
                          19-24;8(2):B99 (abstract no. PoB 3077).
 REFERENCES               Mukadi Y, St. Louis M, Perriens J, Kaboto M,
                          Portael F, Prignot J, Piot P, Alingi E.
                          Maintenance chemotherapy after short course
                          treatment of tuberculosis in HIV-infected
                          persons: is it needed and is it effective?
                          Int Conf AIDS. 1992 Jul 19-24;8(2):B144
                          (abstract no. PoB 3347).
 REFERENCES               Pust RE. Tuberculosis in the 1990's:
                          resurgence, regimens, and resources. South
                          Med J. 1992 Jun;85(6):584-93.
 REFERENCES               Mukadi Y, Perriens J, Kaboto M, Roscigno G,
                          Prignot J, Portaels F, Ngamboli K, Williame
                          J, Piot P, St Louis M. Prolonged chemotherapy
                          for tuberculosis following standard short
                          course treatment among HIV-infected persons
                          in Zaire. Int Conf AIDS. 1991 Jun
                          16-21;7(1):226 (abstract no. M.B.2176).
 REFERENCES               Nunn P, Wasunna K, Kwanyah G, Gathua S,
                          Imalingat A, Lucas S, Gilks C, Brindle R,
                          Omwega M, Were J, et al. Cutaneous
                          hypersensitivity reactions (CHR) to
                          thiacetazone among HIV-1 seropositive
                          tuberculosis (TB) patients, Nairobi. Int Conf
                          AIDS. 1991 Jun 16-21;7(1):224 (abstract no.
                          M.B.2170).
 ENTRY MONTH              9111
 LAST REVISION DATE       960131
 

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