      Document 0093
 DOCN  DRG0093
 UNIQUE IDENTIFIER        DRG-0154
 NAME OF SUBSTANCE        Ro 24-7429 [AmFAR Tx Dir 1993,6(4)]
 SYNONYMS                 Ro-24-7429 [MeSH]
 PROTOCOL ID NUMBERS      NIAID ACTG 213
 PROTOCOL ID NUMBERS      FDA 128A
 SECONDARY SOURCE ID      DRG
 PHARMACOLOGICAL ACTION   MODE OF ACTION: Ro 24-7429 inhibits HIV-1
                          through direct binding with the HIV-1 tat
                          protein. Tat is a viral protein which
                          upregulates viral gene expression and
                          replication through interaction with the TAR
                          sequence of the HIV-1 long terminal repeat
                          (LTR). It is not clear if tat is essential
                          for HIV replication. Ro 24-7429 exhibits
                          broad activity in vitro against a wide
                          variety of viral isolates in both acutely and
                          chronically infected cells. The compound is
                          extensively bound to plasma proteins; binding
                          in human serum is estimated to be 98.7
                          percent. In a study of Kaposi's sarcoma
                          patients 13 out of 23 discontinued treatment
                          due to side effects. Due to these results the
                          manufacturer has discontinued development of
                          Ro 24-7429. [AmFAR Tx Dir 1993;6(4)] [NIAID
                          ACTG 213]
 DISEASES STUDIED/TREATED HIV infection [AmFAR Tx Dir 1993;6(4)]
 CLASSIFICATION CODE      Antiretroviral [AmFAR Tx Dir 1993;6(4)]
 CLASSIFICATION CODE      Tat inhibitor [AmFAR Tx Dir 1993;6(4)]
 ADVERSE EFFECTS          Rash, headaches, and discolored urine were
                          the most frequently reported side effects of
                          Ro 24-7429. Other adverse effects include
                          headaches, gastrointestinal problems,
                          abnormal EKG, mild neurologic changes, and
                          possible elevation in serum creatinine.
                          [AmFAR Tx Dir 1993;6(4)] [NIAID ACTG 213]
 CONTRAINDICATIONS        Contraindicated in persons with
                          hypersensitivity to benzodiazepines. [NIAID
                          ACTG 213]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: A benzodiazepine
                          derivative; structural analog of Ro 5-3335
                          [AmFAR Tx Dir 1993;6(4)] [NIAID ACTG 213]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Tablets. [NIAID ACTG 213]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral. [AmFAR Tx Dir
                          1993;6(4)]
 MANUFACTURERS            Hoffmann-La Roche Incorporated
 REFERENCES               Haubrich RH, Flexner C, Lederman MM, Hirsch
                          M, Pettinelli CP, Ginsberg R, Lietman P,
                          Hamzeh FM, Spector SA, Richman DD. A
                          randomized trial of the activity and safety
                          of Ro 24-7429 (Tat antagonist) versus
                          nucleoside for human immunodeficiency virus
                          infection. The AIDS Clinical Trials Group 213
                          Team. J Infect Dis 1995 Nov;172(5):1246-52.
 REFERENCES               Georges DL, Hsu MC, Connell E, Tam S,
                          Lederman MM. The HIV-1 Tat antagonist Ro
                          24-7429 is highly protein bound and
                          relatively inactive at physiologic serum
                          concentrations. Natl Conf Hum Retroviruses
                          Relat Infect (2nd). 1995 Jan 29-Feb 2;:144.
 REFERENCES               Patki AH, Lederman MM. HIV-1 Tat and its
                          inhibitor Ro 24-7429 induce apoptosis and
                          inhibit lymphocyte proliferation in
                          peripheral blood mononuclear cells of HIV-1
                          seronegative subjects. Natl Conf Hum
                          Retroviruses Relat Infect (2nd). 1995 Jan
                          29-Feb 2;:135
 REFERENCES               Haubrich RH, Flexner C, Lederman M, Hirsch M,
                          Herman S, Studlack M, Wang J, Dreyer K,
                          Richman DD. Quantitative HIV RNA measured by
                          reverse transciption PCR (RT PCR) as a marker
                          of activity of antiviral therapy. Natl Conf
                          Hum Retroviruses Relat Infect (2nd). 1995 Jan
                          29-Feb 2;:117.
 REFERENCES               Luznik L, Kraus G, Guatelli J, Richman D,
                          Wong-Staal F. Tat-independent replication of
                          human immunodeficiency viruses. J Clin
                          Invest. 1995 Jan;95(1):328-32.
 REFERENCES               Dunne AL, Siregar H, Mills J, Crown SM. HIV
                          replication in chronically infected
                          marcrophages is not inhibited by the Tat
                          inhibitors Ro-5-3335 and Ro-24-7429. J Leukoc
                          Biol. 1994 Sep;56(3):369-73.
 REFERENCES               Connell EV, Hsu MC, Richman DD. Combinative
                          interactions of a human immunodeficiency
                          virus (HIV) Tat antagonist with HIV reverse
                          transcriptase inhibitors and an HIV protease
                          inhibitor. Antimicrob Agents Chemother. 1994
                          Feb;38(2):348-52.
 REFERENCES               Petty B, Ginsberg R, Noe D, Barditch-Crovo P,
                          Flexner C, Lietman P. RO 24-7429 (TAT
                          antagonist) safety, tolerance, and
                          pharmacokinetics in HIV-infected subjects.
                          Int Conf AIDS 1993 Jun 6-11;9(1):476
                          (abstract no. PO-B26-2045).
 REFERENCES               Hsu MC, Dhingra U, Earley JV, Holly M, Keith
                          D, Nalin CM, Richou AR, Schutt AD, Tam SY,
                          Potash MJ, et al. Inhibition of type 1 human
                          immunodeficiency virus replication by a tat
                          antagonist to which the virus remains
                          sensitive after prolonged exposure in vitro.
                          Proc Natl Acad Sci USA. 1993 Jul
                          15;90(14):6395-9.
 REFERENCES               Lange JM. Antiretroviral treatment. Int Conf
                          AIDS. 1993 Jun 6-11;9(1):10 (abstract no.
                          PS-03-2).
 ENTRY MONTH              9212
 LAST REVISION DATE       960404
 

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