      Document 0102
 DOCN  DRG0102
 UNIQUE IDENTIFIER        DRG-0145
 NAME OF SUBSTANCE        Cidofovir [USAN 1996]
 REGISTRY NUMBER          149394-66-1
 RELATED REGISTRY NUMBER  113852-37-2 (anhydrous) [USAN 1996]
 STANDARD CHEMICAL NAME   1-[(S)-3-Hydroxy-2-(phosphonylmethoxy)propyl]-
                          cytosine dihydrate [USAN 1996]
 SYNONYMS                 HPMPC [AmFAR Tx Dir 1995;7(4)]
 SYNONYMS                 GS-0504 [USAN 1996]
 SYNONYMS                 Vistide [Gilead Sciences brochure Sept 1995]
 PROTOCOL ID NUMBERS      NIAID 92 I-251
 PROTOCOL ID NUMBERS      FDA 216A
 PROTOCOL ID NUMBERS      FDA 216B
 PROTOCOL ID NUMBERS      FDA 218A
 PROTOCOL ID NUMBERS      FDA 219A
 PROTOCOL ID NUMBERS      NIAID ACTG 281
 SECONDARY SOURCE ID      DRG
 PHARMACOLOGICAL ACTION   MODE OF ACTION: The acycyclic phosphonate
                          analogues (HPMPA, HPMPC, PMEA, FPMPA), seem
                          to be targeted at the viral DNA polymerase,
                          with which they interact, as either
                          competitive inhibitors or alternative
                          substrates (or chain terminators), following
                          their intracellular phosphorylation to the
                          diphosphoryl derivatives. HPMPC penetrates
                          into cells and is then activated to mono-and
                          diphospate derivatives. A third metabolite
                          was obtained in addition to HPMPCp and
                          HPMPCpp (the mono-and diphosphate
                          respectively), which has been tentatively
                          indetified as a phosphate-choline adduct.
                          HPMPC metabolism was unchanged between
                          uninfected and infected cells. The long
                          intracellular half-lives of the HPMPC
                          metabolites suggest that infrequent dosing
                          may be possible due to prolonged antiviral
                          effect. The dose-limiting toxicity of HPMPC
                          appears to be its renal toxicity; the MTD,
                          without renal sparing agents appears to be
                          less than 5 mg/kg IV biw [Int Conf AIDS 1993
                          Jun 6-11;9(1)] [Int J Immunopharm 1991;13
                          Suppl 1] [Ann NY Acad sci 1990;616]
 DISEASES STUDIED/TREATED Treatment of herpes simplex virus and
                          cytomegalovirus ( CMV retinitis ) [AmFAR Tx
                          Dir 1995;7(4)]
 CLASSIFICATION CODE      Antiviral [AmFAR Tx Dir 1995;7(4)]
 ADVERSE EFFECTS          In clinical trials, the dose-limiting
                          toxicity of cidofovir was dose- and
                          schedule-dependent nephrotoxicity [J Infect
                          Dis 1995 Apr;171(4)]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: A nucleotide analog [Int
                          Conf AIDS 1993 Jun 6-11;9(1)]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORM: C8H14N3O6P.2H2O [USAN 1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 319.51 [USAN 1995]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Intravenous [AmFAR Tx Dir
                          1993;6(4)] Intravitreal [Ophthalmology 1995
                          Apr;102(4)]
 MANUFACTURERS            Gilead Sciences Incorporated
 REFERENCES               Polis MA, Spooner KM, Baird BF, Manischewitz
                          JF, Jaffe HS, Fisher PE, Falloon J, Davey RT
                          Jr, Kovacs JA, Walker RE, et al.
                          Anticytomegaloviral activity and safety of
                          cidofovir in patients with human
                          immunodeficiency virus infection and
                          cytomegalovirus viruria. Antimicrob Agents
                          Chemother. 1995 Apr;39(4):882-6.
 REFERENCES               Kirsch LS, Arevalo JF, Chavez de la Paz E,
                          Munguia D, de Clercq E, Freeman WR.
                          Intravitreal cidofovir (HPMPC) treatment of
                          cytomegalovirus retinitis in patients with
                          acquired immune deficiency syndrome
                          [published erratum appears in Ophthalmology
                          1995 May;102(5):702]. Ophthalmology. 1995
                          Apr;102(4):533-42; discussion 542-3.
 REFERENCES               Kirsch LS, Arevalo JF, De Clercq E, Chavez de
                          la Paz E, Munguia D, Garcia R, Freeman WR.
                          Phase I/II study of intravitreal cidofovir
                          for the treatment of cytomegalovirus
                          retinitis in patients with the acquired
                          immunodeficiency syndrome. Am J Ophthalmol.
                          1995 Apr;119(4):466-76.
 REFERENCES               Lalezari JP, Drew WL, Glutzer E, James C,
                          Miner D, Flaherty J, Fisher PE, Cundy K,
                          Hannigan J, Martin JC, et al.
                          (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]
                          cytosine (cidofovir): results of a phase I/II
                          study of a novel antiviral nucleotide
                          analogue. J Infect Dis. 1995
                          Apr;171(4):788-96.
 REFERENCES               Lalezari J, Stagg R, Kuppermann B, Kramer F,
                          Holland G, Ives D, Youle M, Robinson M,
                          Northfelt D, Eron J, et al. A phase II/III
                          randomized study of immediate versus deferred
                          intravenous (IV) cidofovir (CDV, HPMPC) for
                          the treatment of peripheral CMV retinitis
                          (CMV-R) in patients with AIDS. Natl Conf Hum
                          Retroviruses Relat Infect (2nd). 1995 Jan
                          29-Feb 2;:170.
 REFERENCES               Miner R, Drew WL, Lalezari J, Cherrington JM,
                          Chen MS, Hitchcock MJM, Jaffe HS. Human
                          cytomegalovirus (HCMV) does not develop
                          resistance following treatment with
                          cidofovir. Natl Conf Hum Retroviruses Relat
                          Infect (2nd). 1995 Jan 29-Feb 2;:107.
 REFERENCES               Lalezari JP, Drew WL, Glutzer E, Miner D,
                          Safrin S, Owen WF Jr, Davidson JM, Fisher PE,
                          Jaffe HS. Treatment with intravenous
                          (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]-
                          -cytosine of acyclovir-resistant
                          mucocutaneous infection with herpes simplex
                          virus in a patient with AIDS. J Infect Dis.
                          1994 Sep;170(3):570-2.
 REFERENCES               Snoeck R, Gerard M, Sadzot-Delvaux C, Andrei
                          G, Balzarini J, Reymen D, Ahadi N, De Bruyn
                          JM, Piette J, Rentier B, et al.
                          Meningoradiculoneuritis due to
                          acyclovir-resistant varicella zoster virus in
                          an acquired immune deficiency syndrome
                          patient. J Med Virol 1994 Apr;42(4):338-47.
 REFERENCES               Snoeck R, Andrei G, Gerard M, Silverman A,
                          Hedderman A, Balzarini J, Sadzot-Delvaux C,
                          Tricot G, Clumeck N, De Clercq E. Successful
                          treatment of progressive mucocutaneous
                          infection due to acyclovir- and
                          foscarnet-resistant herpes simplex virus with
                          (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cy-
                          tosine (HPMPC). Clin Infect Dis. 1994
                          Apr:18(4):570-8.
 REFERENCES               Snoeck R, Gerard M, Sadzot-Delvaux C, Andrei
                          G, Balzarini J, Reymen D, Ahadi N, De Bruyn
                          JM, Piette J, Rentier B, et al.
                          Meningoradiculoneuritis due to
                          acyclovir-resistant varicella zoster virus in
                          an acquired immune deficiency syndrome
                          patient. J Med Virol. 1994 Apr;42(4):338-47.
 ENTRY MONTH              9209
 LAST REVISION DATE       960129
 

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