      Document 0149
 DOCN  DRG0149
 UNIQUE IDENTIFIER        DRG-0098
 NAME OF SUBSTANCE        Fialuridine [USAN 1996]
 REGISTRY NUMBER          69123-98-4
 STANDARD CHEMICAL NAME   1-(2-deoxy-2-fluoro-beta-arabinofuranosyl)-5--
                          iodouracil [MeSH]
 SYNONYMS                 FIAU [USP DI 1995]
 SYNONYMS                 2'-Fluoro-5-iodouracil [MeSH]
 SYNONYMS                 1-(2'Fluoro-2'-deoxyarabinofuranosyl)-5-iodou-
                          racil [MeSH]
 PROTOCOL ID NUMBERS      NIAID ACTG 122 FIAU
 IND NUMBER               34,973
 SECONDARY SOURCE ID      R90-001-01 [NIAID ACTG 122 FIAU]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: The pyrimidine nucleoside
                          analog FIAC and its primary deaminated uracil
                          metabolite FIAU are highly and specifically
                          active compounds in vitro against several
                          herpes group viruses, particularly herpes
                          simplex virus (HSV) types 1 and 2, varicella
                          zoster (VZV), cytomegalovirus (CMV) and
                          hepatitis B virus (HBV). While the specific
                          mechanism of action of FIAC/FIAU is unknown,
                          it appears to exert its effect by serving as
                          substrate for viral DNA polymerase. A single
                          dose study of FIAC in man documented a
                          conversion of a majority of the compound to
                          FIAU, which was then eliminated by renal
                          excretion and further biotransformation
                          (deiodinization and glucuronic conjugation).
                          After IV administration of 50 or 100 mg/m2
                          (approx 1.2 or 2.5 mg/kg) the plasma T 1/2
                          values for FIAC and FIAU were 1.3 and 4.2
                          hours, respectively. After oral dosing with
                          either 50 or 100 mg/m2, peak concentrations
                          of FIAC and FIAU were noted at one to two
                          hours and eight hour plasma levels averaged
                          more than twice those observed after IV
                          administration (1.16 mcm versus 0.44 mcm,
                          respectively). [Int Conf AIDS 1991 Jun
                          16-21;7(2):(abstract no. W.B. 2290] [NIAID
                          ACTG 122 FIAU]
 DISEASES STUDIED/TREATED Cytomegalovirus infections [AmFAR Tx Dir
                          1993;6(3)]
 CLASSIFICATION CODE      Antiviral [USAN 1996]
 OTHER MAJOR USES         Demonstrated along with its parent compound,
                          FIAC, to be a highly and specifically active
                          compound in vitro against several herpes
                          group viruses, particularly herpes simplex
                          virus (HSV) types 1 and 2, varicella zoster
                          (VZV) and hepatitis B virus (HBV) [Int Conf
                          AIDS 1991 Jun 16-21;7(2):(abstract no. W.B.
                          2290)] [USP DI 1995]
 ADVERSE EFFECTS          Although short term studies reported minor
                          side effects, longer term hepatitis B trials
                          (3 months) resulted in 4 fatalities in 20
                          patients and resulted in discontinuance of
                          human studies. In addition, other fatalities
                          due to hepatotoxicity have been reported.
                          FIAU toxicity was due to marked mitochondrial
                          dysfunction as shown by disturbances in
                          cellular energy metabolism and micro- and
                          macrovesicular steatosis in liver cells.
                          [Lancet 1994 June 11;343] [J Clin Invest 1995
                          Feb;95(2)] [J NIH Res 1995 Sep;5(9)]
 CONTRAINDICATIONS        Contraindicated in patients exhibiting HIV
                          wasting syndrome; presenting clinical or
                          x-ray evidence of bronchitis, pneumonitis,
                          pulmonary edema, effusion, or suspected
                          active tuberculosis; or having any unstable
                          medical condition (including serious
                          infections or cardiovascular, oncologic,
                          renal or hepatic conditions) or any
                          cytomegalovirus end organ disease.  [NIAID
                          ACTG 122 FIAU]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Primary deaminated uracil
                          metabolite of the pyrimidine nucleoside
                          analog
                          1-(2'deoxy-2'fluoro-1-B-D-arabinofuranosyl)-5-
                          -iodocytosine (FIAC) [NIAID ACTG 122 FIAU]
                          [AmFAR Tx Dir 1993;6(3)]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: Soluble in water (Parent
                          compound) [NIAID ACTG 122 FIAU]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Oral syrup. [NIAID ACTG 122
                          FIAU]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral. [Int Conf AIDS 1991
                          Jun 16-21;7(2): (abstract no. W.B. 2290)]
 SUBSTANCE DELIVERY DATA  STORAGE: Store between 15-30 C (59-86 F).
                          [NIAID ACTG 122 FIAU]
 MANUFACTURERS            Oclassen
 REFERENCES               Dusheiko GM. Treatment and prevention of
                          chronic viral hepatitis. Pharmacol Ther. 1995
                          Jan;65(1):47-73.
 REFERENCES               Brahams D. Deaths in US fialuridine trial
                          [news]. Lancet. 1994 Jun 11;343(8911):1494-5.
 REFERENCES               Pottage JC, Kessler HA, Kapell K, Benson CA.
                          Acyclovir resistant (ACV-R) herpes simplex:
                          susceptibility to alternative antiviral
                          agents. Int Conf AIDS. 1992 Jul
                          19-24;8(2):B126 (abstract no. PoB 3238).
 REFERENCES               Tartaglione T, Hooton TM, Jones T, Smiles K,
                          Corey L. Actg 122: phase II tolerance study
                          of oral FIAU in HIV-infected persons. Int
                          Conf AIDS. 1991 Jun 16-21;7(2):254 (abstract
                          no. W.B.2290).
 REFERENCES               Drew WL, Miner R, King D, Antiviral activity
                          of FIAU.
                          (1-[2'deoxy-2'-fluoro-1-beta-D-arabinofuranos-
                          yl]-5-iodo-uri dine) on strains of
                          cytomegalovirus sensitive and resistant to
                          ganciclovir [letter]. J Infect Dis. 1991
                          Jun;163(6):1388-9.
 ENTRY MONTH              9012
 LAST REVISION DATE       951128
 

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