Animal Models in the Development of Antiviral Therapy

  • H. E. Kaufman
Part of the Internationales Symposion der Deutschen Ophthalmologischen Gesellschaft vom 12. bis 14. April 1980 in Freiburg book series (OPH.GES.)

Summary

Virtually all medical laboratory experimentation involves the creation of models of human diseases which can be used in the preliminary evaluation of newly developed modes of therapy. The critical problem with such models is distinguishing between those models that are accurate representations of the human disease and its reaction to treatment and those models that are in some way separate or distinct from the human disease. This problem is clearly illustrated by the various animal models developed in the course of our search for a truly safe and effective treatment for herpesvirus ocular disease.

In the case of epithelial dendritic ulceration, antimetabolite therapy has been tested in the rabbit. The results seen in this animal model have proven highly predictive of actual therapeutic results obtained with antimetabolite drugs in man.

Epithelial disease can also be treated successfully with interferon and with interferon inducers, particularly for the prevention of recurrence of epithelial disease. However, interferon inducers are highly species-specific and, therefore, experimental results obtained in rabbits and rats cannot be usefully extrapolated to man. Thus, primates or even human subjects must be employed to provide relevant data. Actual interferon itself tends to be species-selective, and the quantitative determination of its efficacy in experimental animals, although possibly related to such results in man, may not prove reliable in human therapeutics.

Stromal disease can result from a primary host immune reaction either to viruses and antigen, or to extensive multiplication of virus that causes destructive stromal lesions. Each of these processes can be produced in an animal model on which drug evaluations can be performed; however, the exact relevance to man of these evaluations of immunosuppressive drugs or specific antiviral therapies remains uncertain because the role of each of the two processes in the production of the disease remains uncertain.

The chemical determination of drug penetration has been made more difficult by a lack of knowledge of essential drug concentrations. For example, a virus that multiplies rapidly in the epithelium may require a lower concentration of drug in the stroma where both cellular metabolism and viral multiplication may be different. Several topically administered drugs have been demonstrated to be active in the rabbit against stromal keratitis, but it is uncertain if they are equally active in man. Similar problems are involved in the interpretation of activity of systemically administered drugs on local ocular disease, even though the models for systemic effects such as prevention of death from encephalitis appear to be relevant to man.

Key words

Dendritic keratitis stromal keratitis iritis interferon acyclovir trifluorothymidine vidarabine 

Zusammenfassung

Im Prinzip besteht jegliche Laborforschung in der Entwicklung von Modellen und deren Prüfung. Das Kernproblem dabei ist, wie man klinisch relevante Modelle von solchen unterscheiden kann, die für menschliche Erkrankungen keine Bedeutung haben. Dies sei am Beispiel der Herpeserkrankungen gezeigt. Eine Keratitis dendritica kann man mit Antimetaboliten im Tierversuch behandeln und die Modelle sind sowohl hinsichtlich der Wirksamkeit als auch der relativen Wirkung solcher Substanzen in hohem Maße aussagekräftig.

Interferon-Induktoren vermögen einen epithelialen Herpes günstig zu beeinflussen und können Rezidive verhindern, sie sind aber hochgradig spezies-spezifisch, so daß Versuche mit Kaninchen oder anderen Nagetieren bei solchen Substanzen irrelevant sind. Hierfür muß man Primaten oder eben Menschen selbst benutzen.

Interferon selbst ist ebenfalls in gewissem Maße spezies-spezifisch und das bedeutet, daß eine Prüfung in Tiermodellen ebenfalls nicht sehr viel für die Klinik aussagt, obwohl in diesem Fall die Modelle schon mehr Bedeutung haben.

Ein Stroma-Herpes entwickelt sich entweder durch eine Immunreaktion des Wirtes auf das Virus oder Virusantigene oder auf eine exzessive Virusvermehrung mit ausgedehnter Zellzerstörung im Stroma. Für beide Vorgänge kann man Tiermodelle entwickeln und die Medikamentenwirkung bei ihnen testen; es bleibt aber unklar, inwieweit man den Wert von Immunosuppressiva oder spezifischen Virustatika in solchen Tiermodellen auf die klinische Situation beim Menschen übertragen kann.

Bei der Bestimmung von Virustatikapenetrationen in die Hornhaut oder das Kammerwasser ist es bis jetzt nicht gut möglich gewesen, zu beurteilen, ob die gemessenen Konzentrationen am Ort noch wirksam sind oder nicht. So kann es zum Beispiel sein, daß man im Stroma, wo der Zellstoffwechsel ganz anders als im Epithel ist, sehr viel weniger Virustatikum braucht, um eine Virusvermehrung zu verhindern; auch geht vielleicht die Virusvermehrung im Stroma von Kaninchen anders vor sich als im Stroma von Menschen. So konnte man zum Beispiel zeigen, daß verschiedene lokal applizierte Virustatika bei der Stromakeratitis des Kaninchens wirksam sind; es ist aber völlig unklar, ob dies auch für den Menschen zutrifft. Ähnliche Einschränkungen treffen für die Beurteilung systemisch applizierter Medikamente bei Augenerkrankungen zu, obwohl solche Modelle für die Evaluierung systemischer Defekte gut sind, soweit sie den Schutz vor schweren systemischen Komplikationen wie einer Enzephalitis betreffen.

Schlüsselwörter

Keratitis dendritica Stromaherpes Iritis Interferon Acyclovir Trifluorthymidin Vidarabin 

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Copyright information

© J.F. Bergmann Verlag, München 1981

Authors and Affiliations

  • H. E. Kaufman
    • 1
  1. 1.New OrleansUSA

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