INVESTIGATION OF A SCREENING BATTERY FOR IMMUNOTOXICITY OF PHARMACEUTICALS WITHIN A 28-DAY ORAL TOXICITY STUDY USING AZATHIOPRINE AND CYCLOSPORINE-A AS MODEL COMPOUNDS
Ej. Dewaal et al., INVESTIGATION OF A SCREENING BATTERY FOR IMMUNOTOXICITY OF PHARMACEUTICALS WITHIN A 28-DAY ORAL TOXICITY STUDY USING AZATHIOPRINE AND CYCLOSPORINE-A AS MODEL COMPOUNDS, Regulatory toxicology and pharmacology, 21(3), 1995, pp. 327-338
The authors have investigated a panel of parameters for immunotoxicity
that may be incorporated in routine screening for toxicity of pharmac
euticals. This panel comprises serum immunoglobulin concentrations, ce
llularity of bone marrow, weights and histopathology of thymus, spleen
, and lymph nodes, histopathology of Peyers' patches, and FACScan anal
ysis of lymphocyte subpopulations in the spleen, in addition to parame
ters of toxicity to other systems. To study the value of these assays
for pharmaceuticals, the authors used the immunosuppressants azathiopr
ine (AZP) and cyclosporin A (CsA) as model compounds with known immuno
toxic activity. In two separate experiments, rats were treated by dail
y 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 histopatholog
y of the thymus and the spleen were valuable parameters of immunotoxic
ity, since these organs showed microscopic alterations at relatively l
ow dose levels. In the CsA experiment, both the histopathology of the
thymus and the data provided by FACScan analysis were sensitive indica
tors of immunotoxicity detecting effects at the lowest dose level empl
oyed, The data indicate that the lymphoid system is the most sensitive
target of toxicity after AZP or CsA administration. The authors concl
ude that their test battery yielded immunotoxicity profiles of AZP and
CsA in rats that were consistent with published findings in the liter
ature, indicating the usefulness of the test battery employed. (C) 199
5 Academic Press, Inc.