      Document 0215
 DOCN  DRG0215
 UNIQUE IDENTIFIER        DRG-0032
 NAME OF SUBSTANCE        Tumor Necrosis Factor [Drug Evaluations
                          Annual 1995]
 SYNONYMS                 rTNF [NIAID ACTG 025]
 SYNONYMS                 Recombinant Tumor Necrosis Factor [NIAID ACTG
                          025]
 SYNONYMS                 TNF [Merck Index 1989]
 SYNONYMS                 Tumor Necrosis Factor Alpha [Drug Evaluations
                          Annual 1995]
 PROTOCOL ID NUMBERS      NIAID ACTG 025
 PROTOCOL ID NUMBERS      FDA 066A
 IND NUMBER               DRG-0032
 SECONDARY SOURCE ID      DRG
 PHARMACOLOGICAL ACTION   MODE OF ACTION: Tumor necrosis factor induces
                          a variety of biochemical and metabolic
                          alterations in vivo, including decreased
                          expression in adipocytes of genes coding for
                          lipogenic enzymes, stimulation of immune
                          effector cells and secretion of IL-1 and
                          prostaglandin E2, and increased synthesis of
                          collagen. In vitro studies have shown that
                          rTNF acts synergistically with interferon
                          gamma to suppress production of HIV mRNA and
                          p24 antigen, to cause cytotoxicity in
                          HIV-infected cells and to reduce HIV RNA
                          levels in chronically infected cells.
                          [Science 1985;230] Induces hemorrhagic
                          necrosis in tumors; increases viral
                          replication in HIV-infected ACH2 cells; may
                          produce antitumor activity in AIDS patients
                          with Kaposi's sarcoma. In vitro antiviral
                          activity against various RNA and DNA viruses.
                          Is absorbed following intravenous,
                          intramuscular, and subcutaneous injection; is
                          rapidly cleared from blood circulation with a
                          half-life of 15-30 minutes. [Drug Evaluations
                          Annual 1992] [Science 1985;230] [ACTG 025]
 DISEASES STUDIED/TREATED Primary HIV infection; limited effectiveness
                          against Kaposi's sarcoma [J Acquir Immune
                          Defic Syndr. 1989;2(3)]
 CLASSIFICATION CODE      Antiretroviral [Facts and Comparisons 1996]
 CLASSIFICATION CODE      Antineoplastic [Drug Evaluations Annual 1995]
 OTHER MAJOR USES         Treatment of tumors [Drug Evaluations Annual
                          1995]
 SUBSTANCE INTERACTIONS   Acts synergistically with Interferon Gamma to
                          suppress production of HIV mRNA and p24
                          antigen, to cause cytotoxicity in
                          HIV-infected cells, and to reduce HIV RNA
                          levels in chronically infected cells.
                          [Science 1985;230]
 ADVERSE EFFECTS          Fever, chills, and headaches within first 72
                          hours of treatment. Anemia; thrombocytopenia;
                          hypotension; fatigue. [Drug Evaluations
                          Annual 1995]
 CONTRAINDICATIONS        Should not be used by patients with cardiac
                          disease, hemorrhagic diathesis, active
                          bleeding disorders, vascular disease, or
                          lipoprotein disorders, or by pregnant or
                          lactating women. [NIAID ACTG 025]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: A glycoprotein produced by
                          macrophages (lymphokine) [Drug Evaluations
                          Annual 1995]
 CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: Sterile lyophilized
                          powder for parenteral use. [NIAID ACTG 025]
 CHEMICAL/PHYSICAL DATA   STABILITY: The reconstituted injection is
                          subject to shear stress which can cause
                          protein aggregation. Avoid vigorous mixing or
                          handling of the injectable solution. [NIAID
                          ACTG 025]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Sterile liquid solution
                          containing 0.5 mg/ml in 2 ml vials. Smaller
                          doses may be administered by diluting TNF
                          with normal saline. [NIAID ACTG 025]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Intramuscular injection.
                          [NIAID ACTG 025]
 SUBSTANCE DELIVERY DATA  STORAGE: Ship frozen (dry ice).
                          Unreconstituted vials should be stored under
                          refrigeration at 2-8 C. Store reconstituted
                          vials under refrigeration at 2-8 C and use
                          within 24 h. Do not freeze. [NIAID A
 MANUFACTURERS            Genentech
 REFERENCES               Beutler B, Grau GE. Tumor necrosis factor in
                          the pathogenesis of infectious diseases. Crit
                          Care Med. 1993 Oct;21(10 Suppl):S423-35.
 REFERENCES               Agosti JM, Coombs RW, Collier AC, Paradise
                          MA, Benedetti JK, Jaffe HS, Corey L. A
                          randomized, double-blind, phase I/II trial of
                          tumor necrosis factor and interferon-gamma
                          for treatment of AIDS-related complex
                          (Protocol 025 from the AIDS Clinical Trials
                          Group). AIDS Res Hum Retroviruses. 1992
                          May;8(5):581-7.
 REFERENCES               Brinchmann JE, Gaudernack G, Vartdal F. In
                          vitro replication of HIV-1 in naturally
                          infected CD4+ T cells is inhibited by rIFN
                          alpha 2 and by a soluble factor secreted by
                          activated CD8+ T cells, but not by rIFN beta,
                          rIFN gamma, or recombinant tumor necrosis
                          factor-alpha. J Acquir Immune Defic Syndr.
                          1991;4(5):480-8.
 REFERENCES               Mellors JW, Griffith BP, Ortiz MA, Landry ML,
                          Ryan JL. Tumor necrosis
                          factor-alpha/cachectin enhances human
                          immunodeficiency virus type 1 replication in
                          primary macrophages. J Infect Dis. 1991
                          Jan;163(1):78-82.
 REFERENCES               Moro D, Goy A, Nagy-Mignotte H, Brambilla C.
                          [Immunotherapy of cancer using cytokinins.
                          Use and poerspectives in lung oncology]. Rev
                          Mal Respir. 1990;7(3)195-201.
 REFERENCES               Kaplan LD, Abrams DI, Sherwin SA, Kahn J,
                          Volberding PA. A phase I/II study of
                          recombinant tumor necrosis factor and
                          recombinant interferon gamma in patients with
                          AIDS-related complex. Biotechnol Ther.
                          1989-90;1(3):229-36.
 REFERENCES               Agosti JM, Coombs R, Kidd PG, Paradise M,
                          Sherwin S, Corey L. Randomized phase II trial
                          of recombinant tumor necrosis factor (rTNF)
                          and recombinant interferon-gamma (rIFN-gamma)
                          in patients with ARC. Int Conf AIDS. 1989 Jun
                          4-9;5:558 (abstract no. M.C.P.101).
 REFERENCES               Kahn JO, Kaplan LD, Volberding PA, Ziegler
                          JL, Crowe S, Saks SR, Abrams DI.
                          Intralesional recombinant tumor necrosis
                          factor-alpha for AIDS-associated Kaposi's
                          sarcoma: a randomized, double-blind trial. J
                          Acquir Immune Defic Syndr. 1989;2(3):217-23.
 REFERENCES               Aboulafia D, Miles SA, Saks SR, Mitsuyasu RT.
                          Intravenous recombinant tumor necrosis factor
                          in the treatment of AIDS-related Kaposi's
                          sarcoma. J Acquir Immune Defic Syndr.
                          1989;2(1):54-8.
 REFERENCES               Israel N, Hazan U, Alcami J, Munier A,
                          Arenzana-Seisdedos F, Bachelerie F, Israel A,
                          Virelizier JL. Tumor necrosis factor
                          stimulates transcription of HIV-1 in human T
                          lymphocytes, independently and
                          synergistically with mitogens. J Immunol.
                          1989 Dec 15;143(12):3956-60.
 ENTRY MONTH              8906
 LAST REVISION DATE       960310
 

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