      Document 0091
 DOCN  DRG0091
 UNIQUE IDENTIFIER        DRG-0156
 NAME OF SUBSTANCE        PMEA [Facts and Comparisons 1995]
 REGISTRY NUMBER          106941-25-7
 STANDARD CHEMICAL NAME   9-(2-phosphonylmethoxyethyl)adenine [AmFAR Tx
                          Dir 1995;7(4)]
 SYNONYMS                 9-PMEA [MeSH]
 PROTOCOL ID NUMBERS      FDA 217A
 PROTOCOL ID NUMBERS      FDA 217B
 PROTOCOL ID NUMBERS      NIAID 93 I-29
 SECONDARY SOURCE ID      GS-393 [Facts and Comparisons 1995]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: PMEA,like the other
                          nucleoside analogues, inhibits HIV
                          replication by inducing premature viral DNA
                          chain termination through inhibition of the
                          viral enzyme reverse transcriptase. PMEA is
                          converted to the mono- and diphosphorylated
                          metabolites (PMEAp and PMEApp). Being an
                          alternative substrate to dATP, PMEApp acts as
                          a potent DNA chain terminator, and this may
                          explain its anti-retrovirus activity. Active
                          in vitro against many human and animal
                          viruses, including HIV-1 and HIV-2, as well
                          as human herpes viruses. PMEA inhibits HIV
                          induced cytopathogenicity in MT-4 cells and
                          HIV expression in H9 cells at a concentration
                          of 1.6-2 microM. PMEA has been shown to be
                          effective in delaying or preventing the
                          development of retrovirus-induced diseases in
                          mice, cats, and monkeys. Some in vitro
                          results suggest that PMEA may be more
                          effective at inhibiting HIV replication when
                          administered on an intermittent schedule. In
                          vivo PMEA was more effective at preventing
                          Moloney murine sarcoma virus (MSV)-induced
                          tumors in mice when given as a single dose at
                          the time of viral inoculation rather than
                          divided over several administrations. [AmFAR
                          Tx Dir 1995;7(4)] [Proc Natl Acad Sci USA
                          1991 Feb 15;88(4)] [Int J Cancer 1995
                          Mar;61(1)]
 DISEASES STUDIED/TREATED HIV infection [AmFAR Tx Dir 1995;7(4)] [Int J
                          Cancer 1995 Mar;61(1)]
 CLASSIFICATION CODE      Antiretroviral [Facts and Comparisons 1995]
 ADVERSE EFFECTS          Adverse effects include reversible elevated
                          liver enzymes and neutropenia following IV
                          PMEA. [AmFAR Tx Dir 1995;7(4)]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: An acyclic nucleoside
                          phosphonate. [AmFar Tx Dir 1995;7(4)] [Int J
                          Cancer 1995 Mar;61(1)]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C8H12N5O4P [CHEMLINE]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Intravenous, subcutaneous.
                          [AmFAR Tx Dir 1995;7(4)]
 MANUFACTURERS            Gilead Sciences Incorporated
 REFERENCES               Serafinowska HT, Ashton RJ, Bailey S, Harnden
                          MR, Jackson SM, Sutton D. Synthesis and in
                          vivo evaluation of prodrugs of
                          9-[2-(phosphonomethoxy)ethoxy]adenine. J Med
                          Chem. 1995 Apr 14;38(8):1372-9.
 REFERENCES               Balzarini J, Verstuyf A, Hatse S, Goebels J,
                          Sobis H, Vandeputte M, De Clercq E. The human
                          immunodeficiency virus (HIV) inhibitor
                          9-(2-phosphonylmethoxyethyl)adenine (PMEA) is
                          a strong inducer of differentiation of
                          several tumor cell lines. Int J Cancer. 1995
                          Mar 29;61(1):130-7.
 REFERENCES               Robbins BL, Connelly MC, Marshall DR,
                          Srinivas RV, Fridland A. A human T lymphoid
                          cell variant resistant to the acyclic
                          nucleoside phosphonate
                          9-(2-phosphonylmethoxyethyladenine shows a
                          unique combination of a phosphorylation
                          defect and increased efflux of the agent. Mol
                          Pharmacol. 1995 Feb;47(2):391-7.
 REFERENCES               Villani N, Calio R, Balestra E, Balzarini J,
                          De Clercq E, Fabrizi E, Perno CF, Del Gobbo
                          V. 9-(2-Phosphonylmethoxyethyl) adenine
                          increases the survival of influenza
                          virus-infected mice by an enhancement of the
                          immune system. Antiviral Res. 1994
                          Oct;25(2):81-9.
 REFERENCES               Gong YF, Marshall DR, Srinivas RV, Fridland
                          A. Susceptibilities of zidovudine-resistant
                          variants of human immunodeficiency virus type
                          1 to inhibition by acyclic nucleoside
                          phosphonates. Antimicrob Agents Chemother.
                          1994 Jul;38(7):1683-7.
 REFERENCES               Starrett JE Jr, Tortolani DR, Russell J,
                          Hitchcock MJ, Whiterock V, Martin JC, Mansuri
                          MM. Synthesis, oral bioavailability
                          determination, and in vitro evaluation of
                          prodrugs of antiviral agent
                          9-[2-(phosphonomethoxy)ethyl]adenine (PMEA).
                          J Med Chem. 1994 Jun 10;37(12):1857-64.
 REFERENCES               Marec F, Gelbic I. High recombinagenic
                          activities of three antiviral agents, adenine
                          derivatives, in the drosophila wing spot
                          test. Mutat Res. 1994 Dec 1;311(2):305-17.
 REFERENCES               Neyts J, De Clercq E. Mechanism of action of
                          acyclic nucleoside phosphonates against
                          herpes virus replication. Biochem Pharmacol.
                          1994 Jan 13;47(1):39-41.
 REFERENCES               Calio R, Villani N, Balestra E, Sesa F, Holy
                          A, Balzarini J, De Clercq E, Perno CF, Del
                          Gobbo V. Enhancement of natural killer
                          activity and interferon induction by
                          different acyclic nucleoside phosphonates.
                          Antiviral Res. 1994 Jan;23(1):77-89.
 REFERENCES               Tsai CC, Follis KE, Grant R, Sabo A, Nolte R,
                          Bartz C, Bischofberger N, Benveniste R.
                          Comparison of the efficacy of AZT and PMEA
                          treatment on acute SIVMNE infection in
                          macaques. Symp Nonhum Primate Models AIDS.
                          1993 Sep 19-22;11:abstract no. 43.
 ENTRY MONTH              9212
 LAST REVISION DATE       960612
 

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