1887

Abstract

Summary

The herpesvirus DNA polymerase inhibitor foscarnet, applied topically, and the anti-herpesvirus guanosine analogue buciclovir, given orally, decreased virus replication and disease development in primary skin infections of mice caused by herpes simplex virus type 1 (HSV-1). If the same tissues were infected via sensory nerves, following zosteriform spread of the virus the same treatments showed strongly decreased efficacy, or were inefficacious, when started before development of clinical signs in the infected tissues. These results were obtained in murine models of zosteriform spread of HSV-1 to the ear (following inoculation of the ventral side of the neck) or to the lower flank (following inoculation of the upper flank). In these models the immune system played a dominant role in virus clearance. The topically applied foscarnet could not prevent disease development in these models of recrudescent disease even when applied before the virus was detected in the skin, but a decrease in virus titre was obtained. Orally administered buciclovir lost efficacy when administered at the time of virus entry into the skin, i.e. 1 or 2 days before development of clinical signs. In the flank model, measuring lesion development, orally administered acyclovir also had a strongly decreased efficacy, when compared with its effect during infections in which lesion development did not involve translocation of virus through nerves. In the presence of developing immunity the inhibitors could not accelerate the clearance of virus from infected tissues. Furthermore, all treatments (topical foscarnet and oral buciclovir or acyclovir) were without effect on disease development when treatment was initiated on appearance of the first clinical signs of disease. As disease development following zosteriform spread of HSV resembles that in recurrent herpes in humans, and as the limited efficacy of the inhibitors observed resembles the poor results obtained with inhibitors of herpesvirus DNA synthesis in clinical studies on the treatment of symptomatic recurrent herpes, we suggest the use of animal models of zosteriform spread for pre-clinical evaluation of new antiherpes drugs.

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1988-06-01
2024-12-10
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References

  1. ALENIUS S., BERG M., BROBERG F., EKLIND K., LINDBORG B., ÖBERG B. 1982; Therapeutic effects of foscarnet sodium and acyclovir on cutaneous infections due to herpes simplex virus type 1 in guinea pigs. Journal of Infectious Diseases 145:569–573
    [Google Scholar]
  2. BARTON S. E., MUNDAY P. E., KINGHORN G. R., VAN DER MEIJDEN W. I., STOLZ E., NOTOWICZ A., RASHID S., SCHULLER J. L., ESSEX-CATER A. J., KUIIPERS M. H. M., CHANAS A. C. 1986; Topical treatment of recurrent genital herpes simplex virus infections with trisodium phosphonoformate (foscarnet): double blind, placebo controlled, multicentre study. Genitourinary Medicine 62:247–250
    [Google Scholar]
  3. BERNSTEIN D. I., STANBERRV L. R. 1986; Zosteriform spread of herpes simplex virus type 2 genital infection in the guinea-pig. Journal of General Virology 67:1851–1857
    [Google Scholar]
  4. BLYTH W. A., HARBOUR D. A., HILL T. J. 1984; Pathogenesis of zosteriform spread of herpes simplex virus in the mouse. Journal of General Virology 65:1477–1486
    [Google Scholar]
  5. BRYSON Y. J., DILLON M., LOVETT M., ACUNA G., TAYLOR S., CHERRY J. D., JOHNSON B. L., WIESMEIER E., GROWDON W., CREAGH-KIRK T., KEENEY R. 1983; Treatment of first episodes of genital herpes simplex virus infection with oral acyclovir. A randomized double-blind controlled trial in normal subjects. New England Journal of Medicine 308:916–921
    [Google Scholar]
  6. COREY L., NAHMIAS A. J., GUINAN M. E., BENEDETTI J. K., CRITCHLOW C. W., HOLMES K. K. 1982; A trial of topical acyclovir in genital herpes simplex virus infections. New England Journal of Medicine 306:1313–1319
    [Google Scholar]
  7. DATEMA R., ERICSON A.-C, FIELD H. J., LARSSON A., STENBERG K. 1987; Critical determinants of antiherpes efficacy of buciclovir and related acyclic guanosine analogs. Antiviral Research 7:303–316
    [Google Scholar]
  8. DOUGLAS J. M., CRITCHLOW C, BENEDETTI J., MERTZ G. J., CONNOR J. D., HINTZ M. A., FAHNLANDER A., REMINGTON M., WINTER C., COREY L. 1984; A double-blind study of oral acyclovir for suppression of recurrences of genital herpes simplex virus infection. New England Journal of Medicine 310:1551–1556
    [Google Scholar]
  9. ERICSON A. C, LARSSON A., AOKI F. Y., YISAK W. A., JOHANSSON N. G., ÖBERG B., DATEMA R. 1985; Antiherpes effects and pharmacokinetic properties of 9-(4-hydroxybutyl)guanine and the (i?)- and (S)- enantiomers of 9-(3,4-dihydroxybutyl)guanine. Antimicrobial Agents and Chemotherapy 27:753–759
    [Google Scholar]
  10. HALSOS A. M., SALO O. P., LASSUS A., TJØTTA E. A. L., HOVI T., GABRIELSEN B. O., FIDDIAN A. P. 1985; Oral acyclovir suppression of recurrent genital herpes: a double-blind placebo-controlled crossover study. Acta dermato-venereologica 65:59–63
    [Google Scholar]
  11. HELGSTRAND E., FLODH H., LERNESTEDT J.-O., LUNDSTRÖM J., ÖBERG B. 1980 Trisodium phosphonoformate: antiviral activities, safety evaluation and preliminary clinical results. Developments in Antiviral Therapy63–83 Edited by Collier L. H., Oxford J. New York & London: Academic Press;
    [Google Scholar]
  12. HILL T. J. 1985 Herpes simplex virus latency. The Herpesviruses 3175–240 Edited by Roizman B. New York & London: Plenum Press;
    [Google Scholar]
  13. HILL T. J., BLYTH W. A., HARBOUR D. A., TULLO A. B., EASTY D. L., SHIMELD C. 1984 Antiviral agents, antiinflammatory agents and models of herpes simplex in the mouse. Herpesvirus601–615 Edited by Rapp F. New York: Alan R. Liss;
    [Google Scholar]
  14. HSIUNG C. D., MAYO D. R., LUCIA H. L., LANDRY M. L. 1984; Genital herpes: pathogenesis and chemotherapy in the guinea pig model. Reviews of Infectious Diseases 6:33–50
    [Google Scholar]
  15. KERN E. R. 1982; Acyclovir treatment of experimental genital herpes simplex virus infections. American Journal of Medicine 73:100–108
    [Google Scholar]
  16. KLEIN R. J. 1985; Initiation and maintenance of latent herpes simplex virus infections: the paradox of perpetual immobility and continuous movement. Reviews of Infectious Diseases 7:21–30
    [Google Scholar]
  17. LARSSON A., STENBERG K., ERICSON A.-C, HAGLUND U., YISAK W.-A., JOHANSSON N. G., ÖBERG B., DATEMA R. 1986a; Mode of action, toxicity, pharmacokinetics, and efficacy of some new antiherpes virus guanosine analogs related to buciclovir. Antimicrobial Agents and Chemotherapy 30:598–605
    [Google Scholar]
  18. LARSSON A., SUNDQVIST A., PARNERUD A.-M. 1986b; Inhibition of herpes simplex virus-induced DNA polymerases and cellular DNA polymerase a by triphosphates of acyclic guanosine analogs. Molecular Pharmacology 29:614–621
    [Google Scholar]
  19. LUBY J. P., GNANN J. W. JR, ALEXANDER W. J., HATCHER V. A., FRIEDMAN-KIEN A. E., KLEIN R. J., KEYSERLING H., NAHMIAS A., MILLS J., SCHACHTER J., DOUGLAS I. M., COREY L., SACKS S. L. 1984; A collaborative study of patient-initiated treatment of recurrent genital herpes with topical acyclovir or placebo. Journal of Infectious Diseases 150:1–6
    [Google Scholar]
  20. LUNDGREN B., ERICSON A.-C, BERG M., DATEMA R. 1986; Efficacy of the acyclic guanosine analog buciclovir [(Ä)-9-(3,4-dihydroxybutyl)guanine] in experimental genital herpes. Antimicrobial Agents and Chemotherapy 29:294–297
    [Google Scholar]
  21. MERTZ G. J., CRITCHLOW C W., BENEDETTI J., REICHMAN R. C, DOLIN R., CONNOR J., REDFIELD D. C, SAVOIA M. C, RICHMAN D. D., TYRRELL D. L., MIEDSINSKI L., PORTNOY J., KEENEY R. E., COREY L. 1984; Double-blind placebo-controlled trial of oral acyclovir in first-episode genital herpes simplex virus infection. Journal of the American Medical Association 252:1147–1151
    [Google Scholar]
  22. MINDEL A., WELLER I. V. D., FAHERTY A., SUTHERLAND S., HINDLEY D., FIDDIAN A. P., ADLER M. W. 1984; Prophylactic oral acyclovir in recurrent genital herpes. Lancet ii:57–59
    [Google Scholar]
  23. NAGAFUCHI S., ODA H., MORI R., TANIGUCHI T. 1979; Mechanism of acquired resistance to herpes simplex virus infection as studied in nude mice. Journal of General Virology 44:715–723
    [Google Scholar]
  24. NILSEN A. E., AASEN T., HALSOS A. M., KINGE B. R., TJØTTA E. A. L., WIKSTRÖM K., FIDDIAN A. P. 1982; Efficacy of oral acyclovir in the treatment of initial and recurrent genital herpes. Lancet ii:571–573
    [Google Scholar]
  25. ÖBERG B. 1983; Antiviral effects of phosphonoformate (PFA, foscarnet sodium). Pharmacology and Therapeutics 19:387–415
    [Google Scholar]
  26. REICHMAN R. C, BADGER G. J., GUINAN M. E., NAHMIAS A. J., KEENEY R. E., DAVIS L. G., ASHIKAGA T., DOLIN R. 1983; Topically administered acyclovir in the treatment of recurrent herpes simplex genitalis: a controlled trial. Journal of Infectious Diseases 147:336–340
    [Google Scholar]
  27. REICHMAN R. C, BADGER G. J., MERTZ G. J., COREY L., RICHMAN D. D., CONNOR J. D., REDFIELD D., SAVOIA M. C, OXMAN M. N., BRYSON Y., TYRRELL D. L., PORTNOY J., CREAGH-KIRK T., KEENEY R. E., ASHIKAGA T., DOLIN R. 1984; Treatment of recurrent genital herpes simplex infections with oral acyclovir. A controlled trial. Journal of the American Medical Association 251:2103–2107
    [Google Scholar]
  28. SACKS S. L., PORTNOY J., LAWEE D., SLECH W., AOKI F. Y., TYRRELL D. L., POISSON M., BRIGHT C, KALUSKI J.THE CANADIAN COOPERATIVE STUDY GROUP 1987; Clinical course of recurrent genital herpes and treatment with foscarnet cream: results of a Canadian multicenter trial. Journal of Infectious Diseases 155:178–186
    [Google Scholar]
  29. SIMMONS A., NASH A. A. 1984; Zosteriform spread of herpes simplex virus as a model of recrudescence and its use to investigate the role of immune cells in prevention of recurrent disease. Journal of Virology 52:816–821
    [Google Scholar]
  30. SPRUANCE S. L., CRUMPACKER C. S. 1982; Topical 5 percent acyclovir in polyethylene glycol for herpes simplex labialis: antiviral effect without clinical benefit. American Journal of Medicine 73:315–319
    [Google Scholar]
  31. SPRUANCE S. L., FREEMAN D. J., SETH N. V. 1986; Comparison of foscarnet cream, acyclovir cream, and acyclovir ointment in the topical treatment of experimental cutaneous herpes simplex virus type 1 infection. Antimicrobial Agents and Chemotherapy 30:196–198
    [Google Scholar]
  32. STANBERRY L. R. 1986; Herpesvirus latency and recurrence. Progress in Medical Virology 33:61–77
    [Google Scholar]
  33. STENBERG K., LARSSON A., DATEMA R. 1986; Metabolism and mode of action of (R)-9-(3,4-dihydroxybutyl)guanine in herpes simplex virus-infected Vero cells. Journal of Biological Chemistry 261:2134–2139
    [Google Scholar]
  34. STRAUS S. E., TARIFF H. E., SEIDLIN M., BACHRACH S., LININGER L., DIGIOVANNA J. J., WESTERN K. A., SMITH H. A., LEHRMAN S. N., CREAGH-KIRK T., ALLING D. W. 1984; Suppression of frequently recurring genital herpes. A placebo-controlled double-blind trial of oral acyclovir. New England Journal of Medicine 310:1545–1550
    [Google Scholar]
  35. VAN GENDEREN J., WOLTHUIS O. L., ARIENS A. T., ERICSON A.-C., DATEMA R. 1987; The effects of topical foscarnet in a new model of herpes simplex skin infection. Journal of Antimicrobial Chemotherapy 20:547–556
    [Google Scholar]
  36. WALLIN J., LERNESTEDT J.-O., OGENSTAD S., LYCKE E. 1985; Topical treatment of recurrent genital herpes infections with foscarnet. Scandinavian Journal of Infectious Diseases 17:165–172
    [Google Scholar]
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