This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Nyska, A. Articles by Abdo, K. Search for Related Content PubMed PubMed Citation Articles by Nyska, A. Articles by Abdo, K. Social Bookmarking                         What's this?

Lysosomal-Storage Disorder Induced by Elmiron Following 90-Days Gavage Administration in Rats and Mice

Laboratory of Experimental Pathology National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, North Carolina 27709, nyska{at}niehs.nih.gov

James B. Nold

Pathology Associates-A Charles River Company, 4915 D Prospectus Drive, Durham, North Carolina 27713

Jerry D. Johnson

Battelle Columbus Laboratories, 505 King Avenue, Columbus, Ohio 43201

Kamal Abdo

Environmental Toxicology Program, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, North Carolina 27709

Elmiron, a highly sulfated, semisynthetic pentose polysaccharide with properties similar to heparin, is used for the treatment of interstitial cystitis. Thirteen-week gavage studies were conducted by administering the drug in deionized water to F344/N rats and B6C3F₁ mice once daily, 5 days per week for up to 13 consecutive weeks, at doses of 0, 63, 125, 250, 500, and 1,000 mg/kg body weight. No significant drug-related effects were observed in body weight, survival, clinical, and necropsy results. Significant organ weight increases were seen in the liver, lungs, and spleen of both species and the kidneys of rats, mainly in groups treated with 250 mg/kg/day and above. Hematological analysis indicated increases for both species in the white blood cell and lymphocyte counts. Sites of toxicity identified histopathologically were the rectum, liver, mesenteric and mandibular lymph nodes (both sexes), spleen (mice only), and lungs and kidneys (rats only). Lesions consisted mainly of infiltration into multiple tissues of vacuolated histiocytes, which, by histochemical investigation, indicated the presence of neutral and acidic mucins and lipidic material within the vacuoles. Transmission electron microscopy identified these vacuoles as lysosomal structures that exhibited a variety of contents. On the basis of our findings, we propose that Elmiron was absorbed through the focally disrupted rectal mucosa, was deposited in the lamina propria, accumulated within macrophages, and then was distributed by these cells or as a free chemical via the lymphatics and blood, to the various organ sites manifesting histiocytic infi ltration. The cytoplasmic membrane-bound structures within macrophages were lysosomes containing membranous material of cellular origin and, perhaps, remnants of the deposited test material, Elmiron.

Key Words: Sodium pentosan polysulfate • polysaccharide • rodents • rectum • macrophage.

References

• Baba M., Nakajima M., Schols D., Pauwels R., Balzarini J., De ClercqE. (1988). Pentosan polysulfate, a sulfated oligosaccharide, is a potent and selective anti-HIV agent in vitro. Antiviral Res 9: 335—343.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Bispinck F., Fischer J., Lullmann-Rauch R., von Witzendorff B. (1998). Lysosomal glycosaminoglycan storage as induced by dicationic amphiphilic drugs: Investigation into the mechanisms underlying the slow reversibility. Toxicology 128: 91—100.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Castagnaro M., Alroy J., Ucci AA, Glew RH (1987). Lectin histochemistry and ultrastructure of feline kidneys from six different storage diseases. Virchows Arch B Cell Pathol 54: 16—26.[Web of Science][Medline] [Order article via Infotrieve]
• Chhabra RS, Huff JE, Schwetz BS, Selkirk J. (1990). An overview of prechronic and chronic toxicity/carcinogenicity experimental study designs and criteria used by the National Toxicology Program. Environ Health Perspect 86: 313—321.[Web of Science][Medline] [Order article via Infotrieve]
• Cotran RS, Kumar V., Collins T. (1999). Genetic disorders. In: Pathologic Basis of Disease, Cotran RS, Kumar V, Collins T (eds). WB Saunders Company, Philadelphia, pp 139—187.
• Danielson B., Fellstrom B., Lindsjo M., Ljunghall S., Wikstrom B. (1990). New Drugs to Prevent Recurrence of Renal Stone Disease. Proceedings of the 11th International Congress of Nephrology, Tokyo.
• Dencker L., Tengblad A., Odlind B. (1985). Preferential localization of 3H-pentosan polysulfate to the urinary tract in rats. Acta Physiol Scand 124 (Supplement 542): 351.[Web of Science]
• Faaij RA, Srivastava N., van Griensen JMT, Schoemaker RC, Kluft C., Burggraaf J., Cohen AF (1999). The oral bioavailability of pentosan polysulphate sodium in healthy volunteers. Eur J Clin Pharmacol 54: 929— 935.
• Fischer AM, Merton RE, Marsh NA, Williams S., Gaffney PJ, Barrowcliffe TW, Thomas DP (1982). A comparison of pentosan polysulphate and heparin II: Effects of subcutaneous injection. Thromb Haemost 47: 109—113.[Web of Science][Medline] [Order article via Infotrieve]
• Ghadially FN (1997). Lysosomes. In: Ultrastructural Pathology of the Cell and Matrix. Butterworth-Heinemann, Boston, pp 619—802.
• Grossblatt N. (1996). Guide for the Care and Use of Laboratory Animals. National Academy Press, Washington, DC.
• Halliwell WH (1997). Cationic amphiphilic drug-induced phospholipidosis. Toxicol Pathol 25: 53—60.[Abstract/Free Full Text]
• Kacew S., Reasor MJ, Ruben Z. (1997). Cationic lipophilic drugs: Mechanisms of action, potential consequences, and reversibility. Drug Metab Rev 29: 355—368.[Web of Science][Medline] [Order article via Infotrieve]
• Losonczy H., Nagy I., David M. (1988). Effects of various doses of SP54 on fibrinolytic activity in patients with thrombotic diseases. Folia Haematol 115:388—393.
• Marshall JL, Wellstein A., Rae J., DeLap RJ, Phipps K., Hanfelt J., Yunmbam MK, Sun JX, Duchin KL, Hawkins MJ (1997). Phase I trial of orally administered pentosan polysulfate in patients with advanced cancer. Clin Cancer Res 3: 2347—2354.[Abstract/Free Full Text]
• McDowell EM, Trump BF (1976). Histologic fi xatives suitable for diagnostic light and electron microscopy. Arch Pathol Lab Med 100: 405— 414.
• National Toxicology Program (2001). Toxicology and Carcinogenesis Studies of Elmiron (Cas No. 37319-17-8) in F344/N Rats and B6C3F1 Mice (Gavage Studies). Public Health Service, US Department of Health and Human Services, Bethesda, Maryland.
• Prasad A., Kaye EM, Alroy J. (1996). Electron microscopic examination of skin biopsy as a cost-effective tool in the diagnosis of lysosomal storage diseases. J Child Neurol 11: 301—308.[Abstract/Free Full Text]
• Rees S., Constantopoulos G., Barranger JA, Brady RO (1982). Organomegaly and histopathology in an animal model of mucopolysaccharidosi s induced by suramin. Naunyn Schmiedeberg s Arch Pharmacol 319: 262—270.[CrossRef]
• Ruben Z., Dodd DC, Rorig KJ, Anderson SN (1989). Disobutamide: A model agent for investigating intracellular drug storage. Toxicol Appl Pharmacol 97: 57—71.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Ruben Z., Anderson SN, Kacew S. (1991). Changes in saccharide and phospholipid content associated with drug storage in cultured rabbit aorta muscle cells. Lab Invest 64: 574—584.[Web of Science][Medline] [Order article via Infotrieve]
• Schneider P. (1992). Drug-induced lysosomal disorders in laboratory animals: New substances acting on lysosomes. Arch Tox 66: 23—33.[CrossRef]
• Ruben Z., Dodd DC, Rorig KJ, Anderson SN (1989). Disobutamide: A model agent for investigating intracellular drug storage. Toxicol Appl Pharmacol 97: 57—71.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Windholz M. (1983). The Merck Index. An Encyclopedia of Chemicals, Drugs, and Biologicals, 10th ed, Merck & Co, Rahway, NJ.

Toxicologic Pathology, Vol. 30, No. 2, 178-187 (2002)
DOI: 10.1080/019262302753559515


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				A. R. Boobis, S. M. Cohen, N. G. Doerrer, S. M. Galloway, P. J. Haley, G. C. Hard, F. G. Hess, J. S. Macdonald, S. Thibault, D. C. Wolf, et al. A Data-Based Assessment of Alternative Strategies for Identification of Potential Human Cancer Hazards Toxicol Pathol, October 1, 2009; 37(6): 714 - 732. [Abstract] [Full Text] [PDF]

				D. M. Sells, A. E. Brix, A. Nyska, M. P. Jokinen, D. P. Orzech, and N. J. Walker Respiratory Tract Lesions in Noninhalation Studies Toxicol Pathol, January 1, 2007; 35(1): 170 - 177. [Abstract] [Full Text] [PDF]

This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Nyska, A. Articles by Abdo, K. Search for Related Content PubMed PubMed Citation Articles by Nyska, A. Articles by Abdo, K. Social Bookmarking                         What's this?