      Document 0142
 DOCN  DRG0142
 UNIQUE IDENTIFIER        DRG-0105
 NAME OF SUBSTANCE        L-697,661 [AmFAR Tx Dir 1993;6(3)]
 SYNONYMS                 Pyridinone [AmFAR Tx Dir 1993;6(4)]
 PROTOCOL ID NUMBERS      NIAID 91 I-74
 PROTOCOL ID NUMBERS      NIAID 91 I-112
 PROTOCOL ID NUMBERS      NIAID ACTG 184
 SECONDARY SOURCE ID      DRG
 PHARMACOLOGICAL ACTION   L-697,661 is a non-nucleoside pyridinone
                          derivative with in vitro activities
                          comparable to other non-nucleoside reverse
                          transcriptase inhibitors (nevirapine, BHAP
                          compounds, and TIBO derivatives). However,
                          all these compounds have unique structures.
                          L-697,661 inhibits HIV-1 reverse
                          transcriptase through direct binding with the
                          enzyme. HIV-1 variants highly resistant to
                          L-697,661 were found to emerge rapidly during
                          treatment. In a 6 week trial, paitents had a
                          rapid dose-related decrease in p24 antigen
                          levels, however, this response virtually
                          disappeared in some patients, coincidentally
                          with the emergence of resistant vruses. This
                          change in susceptibility was more frequent in
                          patients receiving higher doses (500 mg
                          orally every 12 h) and was associated with
                          amino acid substitutions at positions 103 and
                          181 in the HIV-1 reverse transcriptase gene.
                          Researchers have also identified other
                          non-nucleoside RT inhibitors which inhibit
                          virus resistant to L-697,661. [AmFAR Tx Dir
                          1993;6(4)] [N Engl J Med 1993 Oct 7;329(15)]
 DISEASES STUDIED/TREATED Primary HIV infection [AmFAR Tx Dir
                          1993;6(4)]
 CLASSIFICATION CODE      Antiretroviral [AmFAR Tx Dir 1993;6(4)]
 SUBSTANCE INTERACTIONS   The manufacturer suggests that combination
                          treatment with AZT may delay the development
                          of resistance to L-697,661. Possibly
                          interacts with other experimental drugs and
                          antiretroviral drugs. [AmFAR Tx Dir
                          1993;6(4)] [NIAID 91 I-74]
 ADVERSE EFFECTS          Adverse effects include headaches, fatigue,
                          and moderate transaminase elevations. [AmFAR
                          Tx Dir 1993;6(4)]
 CONTRAINDICATIONS        Contraindicated in the presence of a recent
                          history of fever. [NIAID 91 I-74]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Non-nucleoside pyridinone
                          compound [AmFAR Tx Dir 1993;6(4)]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Capsules (100 mg). [NIAID ACTG
                          184]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral. [AmFAR Tx Dir April,
                          1991] [N Engl J Med 1993 Oct 7;329(15)]
 MANUFACTURERS            Merck, Sharpe & Dohme
 REFERENCES               Saag MS, Emini EA, Laskin OL, Douglas J,
                          Lapidus WI, Schleif WA, Whitley RJ,
                          Hildebrand C, Byrnes VW, Kappes JC, et al. A
                          short-term clinical evaluation of L-697,661,
                          a non-nucleoside inhibitor of HIV-1 reverse
                          transcriptase. N Engl J Med. 1993 Oct
                          7;329(15):1065-72.
 REFERENCES               Kuritzkes DR, Curtis S, Rosandich M, Stein
                          DS, Schooley RT. Delayed emergence of
                          resistance to L-697,661 in patients receiving
                          concomitant zidovudine. Int Conf AIDS. 1993
                          Jun 6-11;9(1):467 (abstrract no.
                          PO-B26-1994).
 REFERENCES               Byrne VW et al. Combination therapy with AZT
                          prevents selection of HIV-1 variants that are
                          highly resistant to the nonnucleoside reverse
                          transcriptase inhibitor L-697,661. Intl Conf
                          AIDS. 1993 Jun 6-11: (abstract WS-A19-5).
 REFERENCES               Goldman ME, O'Brien JA, Ruffing TL, Schleif
                          WA, Sardana VV, Byrnes VW, Condra JH, Hoffman
                          JM, Emini EA. A nonnucleoside reverse
                          transcriptase inhibitor active on human
                          immunodeficiency virus type 1 isolates
                          resistant to related inhibitors. Antimicrob
                          Agents Chemother. 1993 May;37(5):947-9.
 REFERENCES               Kappes J, Chopra P, Campbell-Hill S, Conway
                          J, Wang S, Emini E, Saag M, Shaw G. Multiple
                          surrogate marker analyses of Merck L-697,661
                          anti-HIV-1 activity in vivo. Int Conf AIDS.
                          1992 Jul 19-24;8(2):B90 (abstract no. PoB
                          3021).
 ENTRY MONTH              9013
 LAST REVISION DATE       951213
 

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