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Modification of the local lymph node assay to evaluate the potential for adverse immunologically-mediated drug reactions.
Toxicologist 2004 Mar; 78(S-1):195
There is no generally accepted preclinical method to predict the potential for drug allergy to systemically administered drugs. A collaborative research project, involving members of industry, government and academia, was initiated to evaluate an assay which uses the basic protocol of the Local Lymph Node Assay (LLNA, an assay accepted by regulatory agencies for hazard identification of skin sensitizers) modified by administration of test article by subcutaneous injections between the ears, rather than the prescribed topical exposure. Test compounds were selected from marketed drugs known to cause human drug allergy. Selection of active drugs was based on reports of adverse events found in at least two independent data sources including FDA postmarketing data, drug labeling, clinical trial data, and publications. The following drugs associated with adverse reactions were tested by at least three laboratories: streptozotocin, hydralazine, sulfamethoxazole, diphenhy-dramine, procainamide, clonidine, ofloxacin, chlorpromazine, nevirapine, abacavir, lamotrigine, and zomepirac. Clinically negative drugs tested were Phenobarbital and metformin. The pure compound was used if available; otherwise the marketed drug formulation was used. Range finding studies in mice were performed to allow selection of the highest dose that did not produce systemic toxicity. Both clinically negative drugs tested negative in the assay. Six of the 12 clinically positive drugs were positive in the modified LLNA (mLLNA). For a limited set of drugs, a con-current Popliteal Lymph Node Assay was performed and the results were comparable to those obtained in the mLLNA. Evaluation of the lymph node cell phenotypes by flow cytometry showed population changes in general agreement with the mLLNA data. These results suggest that the mLLNA holds promise as a screen for systemic hypersensitivity inducing drugs and the use of concurrent flow cytometry may provide insight into the underlying mechanisms.
Lymph-nodes; Immunology; Allergies; Laboratory-testing; Drugs; Hypersensitivity; Bioassays
The Toxicologist. Society of Toxicology 43nd Annual Meeting and ToxExpo, March 21-25, 2004, Baltimore, Maryland
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