      Document 0083
 DOCN  DRG0083
 UNIQUE IDENTIFIER        DRG-0164
 NAME OF SUBSTANCE        Saquinavir mesylate [USAN 1996]
 REGISTRY NUMBER          127779-20-8
 STANDARD CHEMICAL NAME   Butanediamide,
                          N(1)-(3-(3-(((1,1-dimethylethyl)amino)
                          carbonyl)octahydro-2(1H)-isoquinolinyl)
                          -2-hydroxy-1-(phenylmethyl)propyl)-2-
                          ((2-quinolinylcarbonyl)amino)-,
                          (3S-(2(1R*(R*),2S*),3alpha,4abeta,8aalpha))-,
                          monomethanesulfonate [USAN 1996]
 SYNONYMS                 Ro 31-8959 [USAN 1996]
 SYNONYMS                 Invirase [USAN 1996]
 SYNONYMS                 Fortovase [USAN 1996]
 PROTOCOL ID NUMBERS      NIAID ACTG 229
 PROTOCOL ID NUMBERS      FDA 212A
 PROTOCOL ID NUMBERS      FDA 229B
 PROTOCOL ID NUMBERS      FDA 229A
 PROTOCOL ID NUMBERS      FDA 229C
 SECONDARY SOURCE ID      DRG
 PHARMACOLOGICAL ACTION   MODE OF ACTION: HIV-infected cells produce
                          large polyproteins which are precursors to
                          the individual components of HIV. Protease,
                          which is also produced by HIV infected cells,
                          cleaves the large precursor proteins, thereby
                          separating the final viral elements (such as
                          p24 and reverse transcriptase) in preparation
                          for viral assembly. If the precursor proteins
                          are not processed by the protease enzyme,
                          nonfunctional, non-infectious virions are
                          formed. In vitro, there is synergistic
                          anti-HIV activity of saquinavir when combined
                          with AZT, ddC or alpha interferon in acutely
                          infect PBMC (peripheral blood mononuclear
                          cells). A clinical trial of 302 subjects with
                          advanced HIV disease and CD4 counts between
                          50-300 cubic mm, were given saquinavir/AZT,
                          saquinavir/AZT/ddC or AZT/ddC. CD4 counts in
                          all groups rose during the first 8 weeks but
                          then declined gradually. CD4 increase was
                          greatest in the triple combination group,
                          which also showed significantly greater - but
                          temporary - reductions in viral burden (in
                          HIV PBMC co-cultures). [AmFAR Tx Dir
                          1995;7(4)]
 DISEASES STUDIED/TREATED HIV infection [AmFAR Tx Dir 1995;7(4)]
 DISEASES STUDIED/TREATED FDA approved 12/7/95 in combination with
                          nucleoside analogues for advanced HIV
                          infection [FDA press release]
 CLASSIFICATION CODE      Antiretroviral [AmFAR Tx Dir 1995;7(4)]
 CLASSIFICATION CODE      Protease inhibitor [AmFAR Tx Dir 1995;7(4)]
 SUBSTANCE INTERACTIONS   Ro 31-8959 should be taken within 2 hours
                          after a meal. Oral administration of Ro
                          31-8959 within 30 minutes of food has been
                          shown to increase bioavailability by
                          approximately 1800% compared to dosing in the
                          fasted state. [Int Conf AIDS 1993 Jun
                          6-11;9(1):abstract no PO-B30-2199)]
 ADVERSE EFFECTS          Adverse effects include headache,
                          gastrointestinal disturbances, and muscle
                          fatigue. [AmFAR Tx Dir 1993 Apr;6(3)]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Peptide based protease
                          inhibitor [AmFAR Tx Dir 1995;7(4)]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C38H50N6O5 [CHEMLINE]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: 600 mg three times daily. [AmFAR
                          Tx Dir 1995;7(4)]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral. [AmFAR Tx Dir
                          1995;7(4)]
 MANUFACTURERS            Hoffman-La Roche Incorporated
 REFERENCES               Gulnik SV, Suvorov LI, Liu B, Yu B, Anderson
                          B, Mitsuya H, Erickson JW. Kinetic
                          characterization and cross-resistance
                          patterns of HIV-1 protease mutants selected
                          under drug pressure. Biochemistry; VOL 34,
                          ISS 29, 1995, P9282-7.
 REFERENCES               Kitchen VS, Skinner C, Ariyoshi K, Lane EA,
                          Duncan IB, Burckhardt J, Burger HU, Bragman
                          K, Pinching AJ, Weber JN. Safety and activity
                          of saquinavir in HIV infection. Lancet; VOL
                          345, ISS 8955, 1995, P952-5.
 REFERENCES               Brennan TM, Taylor DL, Bridges CG, Leyda JP,
                          Tyms AS. The inhibition of human
                          immunodeficiency virus type 1 in vitro by a
                          non-nucleoside reverse transcriptase
                          inhibitor MKC-442, alone and in combination
                          with other anti-HIV compounds. Antiviral Res;
                          VOL 26, ISS 2, 1995, P173-87.
 REFERENCES               Ridky T, Leis J. Development of drug
                          resistance to HIV-1 protease inhibitors. J
                          Biol Chem. 1995 Dec 15;270(50):29621-3.
 REFERENCES               Eberle J, Bechowsky B, Rose D, Hauser U, von
                          der Helm K, Gurtler L, Nitschko H. Resistance
                          of HIV type 1 to proteinase inhibitor Ro
                          31-8959. AIDS Res Hum Retroviruses. 1995
                          Jun;11(6):671-6.
 REFERENCES               Collier AC, Coombs RW, Timpone J, Schoenfeld
                          DA, Bassett R, Baruch A, Corey L. Comparative
                          study of Ro 31-8959 and zidovudine (ZDV) vs.
                          ZDV and zalcitabine (ddC) vs. Ro 31-8959,
                          ZDV, and ddC. Int Conf AIDS. 1994 Aug
                          7-12;10(1):21 (abstract no. 058B).
 REFERENCES               Mous J, Brun-Vezinet F, Duncan IB, Hanggi M,
                          Jacobsen H, Vella S. Characterisation of in
                          vivo selected HIV-1 variants with reduced
                          sensitivity to proteinase inhibitor
                          Saquinavir. Int Conf AIDS. 1994 Aug
                          7-12;10(2):60 (abstract no. 515B).
 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               Delfraissy JF, Sereni D, Brun-Vezinet F,
                          Dussaix E, Krivine A, Dormont J, Bragman K. A
                          phase I-II dose ranging study of the safety
                          and activity of Ro 31-8959 (HIV-proteinase
                          inhibitor) in previously zidovudine (ZDV)
                          treated HIV infected individuals. Int Conf
                          AIDS. 1993 Jun 6-11;9(1):69 (abstract no.
                          WS-B26-3).
 REFERENCES               Kitchen V, Skinner C, Sedgwick A, Bragman K,
                          Pinching AJ, Weber J. A phase I-II dose
                          ranging study of the safety and activity of
                          Ro 31-8959 (HIV-proteinase inhibitor) in
                          asymptomatic or mildly symptomatic
                          HIV-infection. Int Conf AIDS. 1993 Jun
                          6-11;9(1):474 (abstract no. PO-B26-2033).
 ENTRY MONTH              9303
 LAST REVISION DATE       960310
 

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