Keratopathy in rats after treatment with tilorone

  • Renate Lüllmann-Rauch
Original Investigations

Abstract

According to clinical reports, the antitumor drug tilorone induces corneal opacities in patients. The present communication shows that keratopathy can be experimentally reproduced in rats and describes the cellular alterations underlying the corneal opacities. Tilorone was applied either orally (60–90 mg/kg) for several weeks or topically (2%) for a few days. Biomicroscopic examination performed after treatment for 6 weeks or longer revealed fine punctate opacities throughout the corneal stroma. Ultra-structurally, the keratocytes were swollen due to large, optically empty vacuoles in the cytoplasm. Similar, albeit smaller, vacuoles were also numerous in the endothelium and less frequent in the epithelium. Histochemical experiments showed that the cellular alterations represented lysosomal storage of polyanionic substances, most probably sulfated glycosaminoglycans, thus mimicking the cytological picture of mucopolysaccharidosis. Upon discontinuation of drug treatment, the alterations tended not to recede. This keratopathy in rats is part of a generalized mucopoly-saccharidosis-like disorder induced by tilorone.

Keywords

Public Health Sulfated Drug Treatment Glycosaminoglycan Clinical Report 
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References

  1. Aguirre G, Stramm L, Haskins M (1983) Feline mucopolysaccharidosis. VI. General ocular and pigment epithelial pathology. Invest Ophthalmol 24: 991–1007Google Scholar
  2. Balazs EA, Armand G (1982) Glycosaminoglycans and proteoglycans of ocular tissues. In: Varma RS, Varma R (eds) Glycosaminoglycans and proteoglycans in physiological and pathological processes of body systems. Karger, Basel, pp 480–499Google Scholar
  3. Barka T, Anderson PJ (1962) Histochemical methods for acid phosphatase using hexazonium pararosanilin as coupler. J Histochem Cytochem 10: 741–753Google Scholar
  4. Bockhardt H, Drenckhahn D, Lüllmann-Rauch R (1978) Amiodarone-induced lipidosis-like alterations in ocular tissues of rats. Graefes Arch Clin Ophthalmol 207: 91–96Google Scholar
  5. Chew E, Ghosh M, McCulloch C (1982) Amiodarone-induced cornea verticillata. Can J Ophthalmol 17: 96–99PubMedGoogle Scholar
  6. D'Amico DJ, Kenyon KR, Ruskin JN (1981) Amiodarone keratopathy. Drug-induced lipid storage disease. Arch Ophthalmol 99: 257–261PubMedGoogle Scholar
  7. Doty SB, Smith CE, Hand AR, Oliver C (1977) Inorganic trimetaphosphatase as a histochemical marker for lysosomes in light and electron microscopy. J Histochem Cytochem 25: 1381–1384PubMedGoogle Scholar
  8. Drenckhahn D, Jacobi B, Lüllmann-Rauch R (1983) Corneal lipidosis in rats treated with amphiphilic cationic drugs. Arzneimittelforsch 33: 827–831PubMedGoogle Scholar
  9. Gibson JM, Fiedler AR, Garner A, Millac P (1984) Severe ocular side effects of perhexilene maleate: case report. Br J Ophthalmol 68: 553–560PubMedGoogle Scholar
  10. Goldman JN, Benedek GB, Dohlman CH, Kravitt B (1968) Structural alterations affecting transparency in swollen human corneas. Invest Ophthalmol 7: 501–519PubMedGoogle Scholar
  11. Gupta DK, Gieselmann V, Hasilik A, Figura K v (1984) Tilorone acts as a lysosomotropic agent in fibroblasts. Hoppe-Seyler's Z Physiol Chem 365: 859–866PubMedGoogle Scholar
  12. Haskins ME, Aguirre GD, Jezyk PF, Desnick RJ, Patterson DF (1983) The pathology of the feline model of mucopolysaccharidosis I. Am J Pathol 112: 27–36PubMedGoogle Scholar
  13. Horstmann G, Lüllmann-Rauch R (1985) Mucopolysaccharidosislike alterations in cardiac valves of rats treated with tilorone. Virchows Arch [Cell Pathol] 48: 33–45Google Scholar
  14. Kaufman HE, Centifanto YM, Ellison ED, Brown DC (1971) Tilorone hydrochloride: human toxicity and interferon stimulation. Proc Soc Exp Biol Med 137: 357–360PubMedGoogle Scholar
  15. Kenyon KR (1976) Ocular manifestations and pathology of systemic mucopolysaccharidoses. Birth Defects 12: 133–153Google Scholar
  16. Klintworth GK (1982) Disorders of glycosaminoglycans (mucopolysaccharides) and proteoglycans. In: Garner A, Klintworth GK (eds) Pathobiology of ocular disease, part B. Marcel Dekker, New York, pp 863–895Google Scholar
  17. Lagunoff D, Ross R, Benditt EP (1962) Histochemical and electron microscopic study in a case of Hurler's disease. Am J Pathol 41: 273–286PubMedGoogle Scholar
  18. Lüllmann-Rauch R (1979) Drug-induced lysosomal storage disorders. In: Dingle JT, Jacques PJ, Shaw IH (eds) Lysosomes in applied biology and therapeutics, vol 6. North Holland, Amsterdam, pp 49–130Google Scholar
  19. Lüllmann-Rauch R (1981) Experimentally induced lipidosis in rat retinal pigment epithelium. Graefe's Arch Clin Exp Ophthalmol 215: 297–303CrossRefGoogle Scholar
  20. Lüllmann-Rauch R (1982) Histochemical evidence for lysosomal storage of acid glycosaminoglycans in splenic cells of rats treated with tilorone. Histochemistry 76: 71–87CrossRefPubMedGoogle Scholar
  21. Lüllmann-Rauch R (1983) Tilorone-induced lysosomal storage mimicking the features of mucopolysaccharidosis and of lipidosis in rat liver. Virchows Arch [Cell Pathol] 44: 355–368Google Scholar
  22. Pearse AGE (1968) Histochemistry — theoretical and applied, 3rd edn, vol 1. Little, Brown & Co, BostonGoogle Scholar
  23. Pülhorn G, Thiel HJ (1976) Das ultrastrukturelle Bild der Chloroquin-Keratopathie. Graefe's Arch Clin Exp Ophthalmol 201: 89–99CrossRefGoogle Scholar
  24. Regelson W (1981) The biological activity of the synthetic polyanion, pyran copolymer (diveema, MVE, 46015) and the heterocyclicbis DEAE fluorenone derivative, tilorone and congeners: clinical and laboratory effects of these agents as modulators of host resistance. Pharmacol Ther 15: 1–44CrossRefPubMedGoogle Scholar
  25. Scheie HG, Hambrick GW, Barness LA (1962) A newly recognizedforme fruste of Hurler's disease (gargoylism) Am J Ophthalmol 53: 753–769PubMedGoogle Scholar
  26. Shull RM, Munger RJ, Spellacy E, Hall CW, Constantopoulos G, Neufeld EF (1982) Canine α-l-iduronidase deficiency. A model of mucopolysaccharidosis I. Am J Pathol 109: 244–248PubMedGoogle Scholar
  27. Spicer SS, Hardin JH, Setser ME (1978) Ultrastructural visualization of sulphated complex carbohydrates in blood and epithelial cells with high iron diamine procedure. Histochem J 10: 435–452CrossRefPubMedGoogle Scholar
  28. Toussaint D, Pohl S (1969) Aspect histologique et ultrastructure des depots corneens dus au chlorhydrate d'amiodarone. Bull Soc Beige Ophthalmol 153: 675–686Google Scholar
  29. Weiss JN, Weinberg RS, Regelson W (1980a) Keratopathy after oral administration of tilorone hydrochloride. Am J Ophthalmol 89: 46–53Google Scholar
  30. Weiss JN, Ochs AL, Abedi S, Selhorst JB (1980b) Retinopathy after tilorone hydrochloride. Am J Ophthalmol 90: 846–853Google Scholar
  31. Wolfe HJ, Blennerhasset JB, Young GF, Cohen RB (1964) Hurler's syndrome. A histochemical study. New techniques for localization of very water-soluble acid mucopolysaccharides. Am J Pathol 45: 1007–1027PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1986

Authors and Affiliations

  • Renate Lüllmann-Rauch
    • 1
  1. 1.Department of AnatomyUniversity of KielKielFederal Republic of Germany

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