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Drug-induced hypersensitivity: role in drug development.

机译：药物引起的超敏反应：在药物开发中的作用。

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Drug-induced hypersensitivity is an adverse reaction, characterised by damaging immune-mediated responses, initiated by medicine given at therapeutic doses for prevention, diagnosis or treatment. Immune-mediated drug hypersensitivity accounts for 6-10% of the adverse drug reactions, which rank between the fourth and sixth leading causes of death in the US. With <10% of all adverse drug reactions reported, the magnitude of the problem is significant, with estimates of costs >Dollars US30 billion annually in the US (1995 value). In addition, the costs of not determining the potential of a drug to produce hypersensitivity in the pre-clinical phase of drug development can be substantial. It has been estimated that the pre-clinical phase and clinical phase I, phase II and phase III costs are approximately Dollars US6 million, Dollars US12 million, Dollars US12 million and Dollars US100 million per drug, respectively (1999 values). It is important that investigational drugs with the potential to produce hypersensitivity reactions be identified as early in the development process as possible. Some adverse reactions to drugs can be avoided if drug-drug interactions are known or if there is a structure-activity relationship established. However, these methods are inadequate. Appropriate animal models of drug-induced hypersensitivity are needed, especially because hypersensitivity has been cited as the leading reason for taking drugs off the market.It is of critical importance to be able to predict hypersensitivity reactions to drugs. Most anaphylactic reactions occur in atopic individuals. Similarly, patients who have experienced other hypersensitivity reactions are more likely to have recurrent reactions. Therefore, animal models should be considered that predispose the animal to the reaction, such as the use of appropriate adjuvants and species. Using known positive controls of varying strengths, the investigator can rank the reaction against the positive controls as standards. This approach might yield greater results in a shorter period of time than using novel models. For the greatest safety, use of well understood models that have been thoroughly validated is imperative.
机译：药物引起的超敏反应是一种不良反应，其特征在于破坏性免疫介导的反应，是由治疗剂量的药物预防，诊断或治疗引起的。免疫介导的药物超敏反应占药物不良反应的6-10％，在美国居第四位和第六位。报告的所有药物不良反应均不到10％，问题的严重性很大，据估计，美国每年的成本超过300亿美元（1995年价值）。另外，在药物开发的临床前阶段未确定药物产生超敏反应的潜力的成本可能很大。据估计，每种药物的临床前阶段和临床阶段I，阶段II和阶段III的费用分别约为600万美元，1200万美元，1200万美元和1亿美元（1999年价值）。重要的是，应在开发过程中尽早识别出可能产生超敏反应的研究药物。如果已知药物相互作用或建立了结构-活性关系，则可以避免对药物的某些不良反应。但是，这些方法是不够的。需要适当的药物引起的超敏反应的动物模型，尤其是因为超敏反应被认为是将药物撤出市场的主要原因。能够预测对药物的超敏反应至关重要。大多数过敏反应发生在特应性个体中。同样，经历过其他超敏反应的患者更有可能复发反应。因此，应考虑使动物易于发生反应的动物模型，例如使用适当的佐剂和物种。使用已知的各种强度的阳性对照，研究人员可以将针对阳性对照的反应分级为标准。与使用新颖的模型相比，该方法可能在较短的时间内产生更好的结果。为了最大的安全，必须使用经过充分验证的广为人知的模型。

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