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2017 » 3 » | Latest edition » Archive » Medical field » Fields » Pharmacology and Experimental Toxicology »

Idiosyncratic and Other Type B Reactions: Theoretical Concepts and Clinical Characteristics

 

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A number of drugs have been withdrawn from the market or severely restricted in their use because of unexpected undesirable effects that became apparent only in the post market phase. In spite of the fact that these idiosyncratic drug reactions (IDR) are relatively rare (their incidence is 1 in 10,000–100,000 patients), they can be life-threatening and thus markedly increase the uncertainty of drug development. Type B adverse drug effects, among them also IDRs, can affect virtually any organ, but the skin, liver, and blood cells are the most common targets. Some drugs cause IDRs that are limited to one organ, whereas many others can elicit a multiorgan dysfunction syndrome. Clinical characteristics suggest that almost all IDRs are in some way immune-mediated. Moreover, there is strong evidence that the majority of IDRs are caused by reactive drug metabolites. However, the unpredictable nature of IDR makes prospective studies in humans virtually impossible, and there are few valid animal models which would allow rigorous mechanistic research. In this article, we review the proposed molecular mechanisms of IDR: cell dysfunction due to covalent binding of reactive metabolites to cellular proteins; indirect activation of the immune system by the formation of hapten-protein complexes; direct activation by the pharmacological interaction of the drug or its metabolites with immune receptors; and the role of the so-called danger signals. In the final part, we briefly describe currently used approaches for the evaluation of the bioactivation potential of new compounds.

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