Pharmacy World and Science

, Volume 18, Issue 1, pp 30–34 | Cite as

Safety of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) in patients with human immunodeficiency virus infection

A pilot study
  • S. Arends
  • E. van Halteren
  • W. Kamp
  • J. Schokker


The compound 9-(2-phosphonylmethoxyethyl)adenine (PMEA) is a potent inhibitor of a number of viruses in vitro, such as human immunodeficiency virus types 1 and 2, herpes simplex virus types 1 and 2, hepatitis B virus, cytomegalovirus, and Epstein-Barr virus. PMEA also proved to be effective in vivo against feline immunodeficiency virus in cats and simian immunodeficiency virus in rhesus monkeys. In an open, non-placebo-controlled trial, the safety of weekly doses of PMEA in 10 patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex was studied for a period of 11 weeks. CD4+ T-Cell counts at baseline were between 10 and 450/mm3. The drug was administered intravenously at a dose of 1000 mg. No serious side-effects were seen. On one occasion one patient showed alanine aminotransferase and aspartate aminotransferase levels 5 times higher than the upper limit of normal and another patient showed on one occasion aspartate aminotransferase levels 5 times higher than the upper limit of normal. In another patient serum amalyse levels increased, on one occasion 1.5 times above the upper limit of normal. An improvement in general well-being was reported by all patients. For patients with a CD4+ T-cell count > 100/mm3 at baseline, the CD4+ T-cell count increased from a mean of 283/mm3 at baseline to a mean of 448/mm3 at the end of the study. Repeat infusions of PMEA at a dose of 1000 mg were safe and well tolerated. Our results suggest that PMEA, administrated according to this treatment schedule, may be effective in treating patients with human immunodeficiency virus infection.


Acquired immunodeficiency syndrome Adverse effects AIDS-related complex CD4-positive T-lymphocytes Clinical trials Human immunodeficiency virus 9-(2-Phosphonylmethoxyethyl)adenine 


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  1. 1.
    Fischl M, Richman D, Grieco M, Gottlieb M, Volberding P, Laskin O, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. N Engl J Med 1987;317:185–91.Google Scholar
  2. 2.
    Lambert JS, Seidlin M, Reichman R, Plank C, Laverty M, Morse G, et al. 2′,3′-Dideoxyinosine (ddl) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. N Engl J Med 1990;322:1340–5.Google Scholar
  3. 3.
    Collier A, Coombs R, Fischl M, Skolnik P, Northfelt D, Boutin P, et al. Combination therapy with zidovudine and didanosine compared with zidovudine alone in HIV-1 infection. Ann Intern Med 1993;119:786–93.Google Scholar
  4. 4.
    Meng T, Fischl M, Boota A, Spector SA, Bennett D, Bassiakos Y, et al. Combination therapy with zidovudine and dide-oxycytidine in patients with advanced human immuno-deficiency virus infection: a phase I/II study. Ann Intern Med 1992;116:13–20.Google Scholar
  5. 5.
    Richman D, Fisch M, Grieco M, Gottlieb M, Volberding P, Loskin O, et al. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. N Engl J Med 1987;317:192–7.Google Scholar
  6. 6.
    De Clercq E, Holý A, Rosenberg I, Sakuma T, Balzarini J, Maudgal PC. A novel selective broad-spectrum anti-DNA virus agent. Nature 1986;323:464–7.Google Scholar
  7. 7.
    Balzarini J, Perno C-F, Schols D, de Clercq E. Activity of acyclic nucleoside phosphonates analogues against human immunodeficiency virus in monocyte/macrophages and peripheral blood lymphocytes. Biochem Biophys Res Commun 1991;178:329–35.Google Scholar
  8. 8.
    Pauwels R, Balzarini J, Schols D, Baba M, Desmyter J, Rosenberg I, et al. Phosphonylmethoxyethyl purine derivatives a new class of anti-human immunodeficiency virus agents. Antimicrob Agents Chemother 1988;32:1025–30.Google Scholar
  9. 9.
    Balzarini J, Naesens L, Herdewijn P, Rosenberg I, Holý A, Pauwels R, et al. Marked in vivo antiretrovirus activity of 9-(2-phosphonylmethoxyethyl)adenine, a selective anti-human immunodeficiency virus agent. Proc Natl Acad Sci USA 1989;86:332–6.Google Scholar
  10. 10.
    Heijtink R, de Wilde G, Kruining J, Berk L, Balzarini J, De Clercq E, et al. Inhibitory effect of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) on human and duck hepatitis B virus infection. Antiviral Res 21:141–53.Google Scholar
  11. 11.
    Heijtink R, Kruining J, de Wilde G, Balzarini J, de Clercq E, Schalm S. Inhibitory effects of acyclic nucleoside phosphonates on human hepatitis B virus and duck hepatitis B virus infections in tissue culture. Antimicrob Agents Chemother 1994;38:2180–2.Google Scholar
  12. 12.
    Yokota T, Mochizuki S, Konno K, Mori S, Shigeta S, de Clercq E. Inhibitory effects of selected antiviral compounds on human hepatitis B virus DNA synthesis. Antimicrob Agents Chemother 1991;35:394–7.Google Scholar
  13. 13.
    Cerny J, Foster S, Cheng Y. Cell-protecting effect against herpes simplex virus-1 and cellular metabolism of 9-(2-phosphonylmethoxyethyl)adenine in HeLa S3 cells. Mol Pharmacol 1991;42:537–44.Google Scholar
  14. 14.
    De Clercq E, Holý A, Rosenberg I. Efficacy of phosphonyl-methoxyalkyl derivatives of adenine in experimental herpes simplex virus and vaccinia virus infections in vivo. Antimicrob Agents Chemother 1989;33:185–91.Google Scholar
  15. 15.
    Gangemi J, Cozens RM, de Clercq E, Balzarini J, Hochkeppel H. 9-(2-Phosphonylmethoxyethyl)adenine in the treatment of murine acquired immunodeficiency disease and opportunistic herpes simplex virus infections. Antimicrob Agents Chemother 1989;33:1864–8.Google Scholar
  16. 16.
    Vonka V, Anisimova E, Cerny J, Holý A, Rosenberg I, Votruba I. Properties of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) resistant herpes simplex type 1 virus. Antiviral Res 1990;14:117–21.Google Scholar
  17. 17.
    Lin J, de Clercq E, Pagano JS. Novel acyclic adenosine analogs inhibit Epstein-Barr virus replication. Antimicrob Agents Chemother 1987;31:1431–3.Google Scholar
  18. 18.
    De Castro L, Kern E, de Clercq E, Ghaffar A, Mayer E, Vogt P, et al. Phosphonylmethoxyalkyl purine and pyrimidine derivatives for treatment of opportunistic cytomegalovirus and herpes simplex virus infections in murine AIDS. Antiviral Res 1991;16:101–14.Google Scholar
  19. 19.
    Balzarini J, Naesens L, Slachmuylders J, Niphuis H, Rosenberg I, Holý A, et al. 9-(2-Phosphonomethoxyethyl)adenine (PMEA) effectively inhibits retrovirus replication in vitro and simian immunodeficiency virus infection in rhesus monkeys. AIDS 1991;5:21–8.Google Scholar
  20. 20.
    Egberink H, Borst M, Niphuis H, Balzarini J, Neu H, Schellekens H, et al. Suppression of feline immunodeficiency virus infection in vivo by 9-(2-phosphonomethoxyethyl)adenine. Proc Natl Acad Sci USA 1990;87:3087–91.Google Scholar
  21. 21.
    Hartmann K, Donath A, Beer B, Egberink H, Horzenik M, Lutz H, et al. Use of two virustacia (AZT, PMEA) in treatment of FIV and of FeLV seropositive cats with clinical symptoms. Vet Immunol Immunopathol 1992;35:167–75.Google Scholar
  22. 22.
    Tsai C, Follis K, Grant R, Sabo A, Nolte R, Bartz C, et al. Comparison of the efficacy of AZT and PMEA treatment against acute SIVmne infection in macaques. J Med Primatol 1994;23:175–83.Google Scholar
  23. 23.
    Merta A, Vesely I, Votruba I, Rosenberg I, Holý A. Phosphorylation of acyclic nucleotide analogues HPMPA and PMEA in L210 mouse leukemic cell extracts. Neoplasma 1990;37:111–20.Google Scholar
  24. 24.
    Balzarini J, Hao Z, Herdewijn P, Johns DG, de Clercq E. Intracellular metabolism and mechanism of anti-retrovirus action of 9-(2-phosphonylmethoxy)ethyladenine, a potent anti-human immunodeficiency virus compound. Proc Natl Acad Sci USA 1991;88:1499–503.Google Scholar
  25. 25.
    Naessens L, Balzarini J, de Clercq E. Acyclic adenine nucleoside phosphonates in plasma determined by high-performance liquid with fluorescence detection. Clin Chem 1992;38:480–5.Google Scholar
  26. 26.
    Russell JW, Marrero D, Whiterock VJ, Klunk LJ, Starrett JE. Determination of 9-(2-phosphonylmethoxy)ethyladenine in rat urine by high-performance liquid chromatography with fluorescence detection. J Chromatogr 1991;572:321–6.Google Scholar
  27. 27.
    Del Gobbo V, Foli A, Balzarini J, de Clercq E, Balestra E, Viliani N, et al. Immunomodulatory activity of 9-(2-phosphonylmethoxyethyl)adenine (PMEA), a potent anti-HIV nucleotide analogue, on in vivo murine models. Antiviral Res 1991;16:65–75.Google Scholar
  28. 28.
    Caliò R, Viliani N, Balestra E, Sesa F, Holý A, Balzarini J, et al. Enhancement of natural killer activity and interferon induction by different acyclic nucleoside phosphonates. Antiviral Res 1994;23:77–89.Google Scholar
  29. 29.
    Villani N, Caliò R, Balestra E, Balzarini J, de Clercq E, Fabrizi E, et al. 9-(2-Phosphonomethoxyethyl)adenine increases the survival of influenza virus-infected mice by an enhancement of the immune system. Antiviral Res 1994;25:81–9.Google Scholar
  30. 30.
    Yang H, Datema R. Prolonged and potent therapeutic and prophylactic effects of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine against herpes simplex virus type 2 infections in mice. Antimicrob Agents Chemother 1991;35:1596–600.Google Scholar
  31. 31.
    Neyts J, Balzarini J, Naesens L, de Clercq E. Efficacy of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine and 9-(1,3-dihydroxy-2-propoxymethyl)guanine for the treatment of murine cytomegalovirus infection in severe combined immunodeficiency mice. J Med Virol 1992;37:61–71.Google Scholar
  32. 32.
    Soike K, Huang J-Y, Bohm R, Hitchcock M, Martin JC. Evaluation of infrequent dosing regimens with (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (S-HPMPC) on simian varicella infection in monkeys. Antiviral Res 1991;16:17–28.Google Scholar
  33. 33.
    Balzarini J, Naesens L, de Clercq E. Anti-retrovirus activity of 9-(2-phosphonylmethoxyethyl)adenine in vivo increases when it is less frequently administered. Int J Cancer 1990;46:337–40.Google Scholar
  34. 34.
    Naessens L, Balzarini J, de Clercq E. Single dose administration of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEADAP) in the prophylaxis of retrovirus infection in vivo. Antiviral Res 1991;16:53–64.Google Scholar
  35. 35.
    Holý A, Rosenberg I. Synthesis of 9-(2-phosphonylmethoxyethyl)adenine and related compounds. Collect Czech Chem Commun 1987;2:2801–9.Google Scholar

Copyright information

© Kluwer Academic Publishers 1996

Authors and Affiliations

  • S. Arends
    • 1
  • E. van Halteren
    • 1
  • W. Kamp
    • 1
  • J. Schokker
    • 1
  1. 1.‘Fight for Life’Amsterdamthe Netherlands

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