Practice of Tiered Testing for Immunosuppression in Rodents
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0092-8615/97 Copyright 0 1997 Dmg Information Association Inc.
PRACTICE OF TIERED TESTING FOR IMMUNOSUPPRESSION IN RODENTS E. J.
DE
WAAL
Preclinical Assessment Group, Medicines Evaluation Board, Laboratory for Medicines and Medical Devices
H.
VAN
LOVEREN AND J. G. Vos
Laboratory for Pathology and Immunobiology National Institute of Public Health and the Environment, Bilthoven, the Netherlands
Zered immunotoxicity testing strategies have been developed in both rats and mice. These tiered systems focus on the detection of compound-induced immunosuppression. Clinical relevance has clearly been demonstrated in the case of pharmaceuticals for which the primary aim is to induce immunosuppression in organ transplant recipients. Validation for pharmaceuticals is still ongoing. Key Wordr: Immunotoxicity; Rodents; Pharmaceuticals
is an important tool in predicting compoundassociated immune disturbance in humans.
INTRODUCTION THE INTERFERENCE OF pharmaceuticals with the immune system may be either the pharmacodynamic activity aimed at (eg, immunosuppressants used in organ transplant recipients), or an undesired event resulting in, an adverse drug reaction. The evaluation of potentially adverse effects on the immune system is an essential part of the risk-benefit assessment of new chemical entities submined to the regulatory authorities to get marketing approval for therapeutic use in humans. During the course of drug development, toxicity testing in laboratory animals
Presented at the DIA Workshop “Immunotoxicity of Pharmaceuticals: Current Knowledge, Testing Strategies, Risk Evaluation, and Consequences for Human Health,” October 2 4 , 1996, Montreux, Switzerland. Reprint address: Dr.E. J. de Waal, Preclinical Assessment Group of the Medicines Evaluation Board, Laboratory for Medicines and Medical Devices, National Institute of Public Health and the Environment, P.O. Box 1, 3720 BA Bilthoven, the Netherlands.
MANIFESTATIONS OF IMMUNOTOXICITY Administration of immunotoxic pharmaceuticals may result in various forms of immunological disturbance (1). Drug-induced hypersensitivity and autoimmunity are generally considered to be the most dangerous manifestations of immunotoxicity. In fact, such immunotoxicities were a major reason for withdrawing pharmaceuticals from the market in the past. Therefore, these adverse events are a matter of great concern for both the pharmaceutical industry and the regulators. At first site, drug-induced immunosuppression seems to be less hazardous to the patient than hypersensitivity and autoimmune responses. Exceptions are cytotoxic antineoplastic agents delivered to cancer patients and pharmaceuticals used in long-term immunosuppressive therapy of organ trans-
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E. J. de Waal, H. van Loveren, and J. G. Vos
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plant recipients (1). Immunosuppression may be relevant, however, if pharmaceuticals are used in already immunocompromised patients or in individuals at risk of immunodeficiency such as
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