Evaluation of a human in vitro skin test for predicting drug hypersensitivity reactions.

The occurrence of drug hypersensitivity reactions (DHRs) following administration of low molecular weight (LMW) drugs is an important health concern. However, in vivo animal models which could be used as tools for the prediction of DHRs are lacking. As a result, research has focused on development of in vitro tools for predicting DHRs. In this study a novel human in vitro pre-clinical skin explant test was used to predict T cell-mediated hypersensitivity responses induced by LMW drugs. Responses in the skin explant test for 12 LMW drugs associated with T cell-mediated hypersensitivity in the clinic (abacavir, amoxicillin, carbamazepine, diclofenac, lamotrigine, lapatinib, lumiracoxib, nevirapine, ofloxacin, phenytoin, propranolol, sulfamethoxazole) were compared with responses for 5 drugs with few/no reports of T cell-mediated hypersensitivity reactions (acetaminophen, cimetidine, flecainide, metformin, verapamil). Changes in skin histology following in vitro exposure to the drugs as well as T cell proliferation and interferon gamma (IFNγ) production were studied. The results of the skin explant assays showed a good positive correlation (r = 0.77, p < .001) between the test outcome (prediction of positive or negative) and the clinical classification of the tested drugs. The T cell proliferation assay showed a correlation of r = 0.60 (p < .01) and the IFNγ assay r = 0.51 (p < .04). The data suggest that the skin explant model could be a useful tool to predict the potential of LMW drugs to induce DHRs.

Nonclinical Tools to Assess Risk of Drug Hypersensitivity Reactions.

The term drug hypersensitivity refers to a category of adverse drug reactions mediated by various immunological and nonimmunological mechanisms. Small-molecule drugs and biotherapeutics have been associated with drug hypersensitivity reactions (DHRs), and the mechanisms driving the responses vary. Depending on the mechanism, some DHRs may be detected in nonclinical toxicology studies, and there may be tools and models in place that can be used as part of a risk assessment strategy. In contrast, for other mechanisms, particularly those that are not readily detected during nonclinical development, predictive tools and strategies for risk assessment are not well defined. This chapter provides an overview of the nonclinical tools currently available to assess the risk for developing DHRs.

Relationship between serotonin and the immune system in a teleost model.

An immunomodulatory role for serotonin (5-HT) has been demonstrated in mammals and evidence for a similar role for 5-HT has recently emerged in fish. However, as limited studies are available, discrepancies often exist regarding the role of 5-HT in the teleost immune response. Therefore, studies were undertaken to help clarify this relationship. Lymphocyte proliferation and extracellular superoxide (O2.-) production were examined in cells from bluegill sunfish injected with either 5-HTP (the immediate precursor to 5-HT) or pCPA (an inhibitor of the rate-limiting enzyme in 5-HT synthesis), or, in vitro following exposure of immune cells to either 5-HT, the 5-HT(1A) receptor agonist, 8-OH-DPAT, or the receptor antagonist, NAN-190. Exposure of fish to 5-HTP increased whole brain 5-HT levels, while pCPA exposure decreased whole brain and splenic 5-HT. In vivo exposure of fish to pCPA depressed T- and B-lymphocyte proliferation; exposure to 5-HTP failed to alter either immune endpoint. In vitro exposure of bluegill splenocytes to 5-HT or 8-OH-DPAT inhibited lymphoproliferation; treatment with NAN-190 had no effect on immune function. Results suggest a link in bluegill between immune function and the serotonergic system. The disparity observed following in vivo- and in vitro-induced serotonergic alterations indicates the complexity of this neuro-immune relationship and emphasizes the need for further studies in this regard.