Investigation of a Screening Battery for Immunotoxicity of Pharmaceuticals Within a 28-Day Oral Toxicity Study Using Azathioprine and Cyclosporin A as Model Compounds

The authors have investigated a panel of parameters for immunotoxicity that may be incorporated in routine screening for toxicity of pharmaceuticals. This panel comprises serum immunoglobulin concentrations, cellularity of bone marrow, weights and histopathology of thymus, spleen, and lymph nodes, h...

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Published in:	Regulatory toxicology and pharmacology Vol. 21; no. 3; pp. 327 - 338
Main Authors:	Dewaal, E.J., Timmerman, H.H., Dortant, P.M., Kranjc, M.A.M., Vanloveren, H.
Format:	Journal Article
Language:	English
Published:	San Diego, CA Elsevier Inc 01-06-1995 Elsevier
Subjects:	Administration, Oral Animals Azathioprine - toxicity Biological and medical sciences Blood Cell Count - drug effects Body Weight - drug effects Bone Marrow - drug effects Bone Marrow Cells Cyclosporine - toxicity Dose-Response Relationship, Drug Drug Administration Schedule Drug Evaluation, Preclinical - methods Drug toxicity and drugs side effects treatment Immunoglobulins - blood Immunosuppressive Agents - administration & dosage Immunosuppressive Agents - toxicity Lymphocyte Count Male Medical sciences Miscellaneous (drug allergy, mutagens, teratogens...) Organ Size - drug effects Organ Specificity - drug effects Pharmacology. Drug treatments Rats Rats, Wistar T-Lymphocyte Subsets - drug effects Drug Spleen Immunopathology Thymus gland Rat Toxicity Rodentia Oral administration Intragastric administration Vertebrata Mammalia Histopathology Investigation method Animal Detection
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Summary:	The authors have investigated a panel of parameters for immunotoxicity that may be incorporated in routine screening for toxicity of pharmaceuticals. This panel comprises serum immunoglobulin concentrations, cellularity of bone marrow, weights and histopathology of thymus, spleen, and lymph nodes, histopathology of Peyers′ patches, and FACScan analysis of lymphocyte subpopulations in the spleen, in addition to parameters of toxicity to other systems. To study the value of these assays for pharmaceuticals, the authors used the immunosuppressants azathioprine (AZP) and cyclosporin A (CsA) as model compounds with known immunotoxic activity. In two separate experiments, rats were treated by daily gastric intubation with 0, 5, 12.5, and 25 mg AZP/kg body wt or 0, 1.25, 5, and 20 mg CsA/ kg body wt. In the AZP study, the histopathology of the thymus and the spleen were valuable parameters of immunotoxicity, since these organs showed microscopic alterations at relatively low dose levels. In the CsA experiment, both the histopathology of the thymus and the data provided by FACScan analysis were sensitive indicators of immunotoxicity detecting effects at the lowest dose level employed, The data indicate that the lymphoid system is the most sensitive target of toxicity after AZP or CsA administration. The authors conclude that their test battery yielded immunotoxicity profiles of AZP and CsA in rats that were consistent with published findings in the literature, indicating the usefulness of the test battery employed.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0273-2300 1096-0295
DOI:	10.1006/rtph.1995.1047