药物致过敏:在药物开发中的作用。

Helen V Ratajczak
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引用次数: 13

摘要

药物性超敏反应是一种不良反应,其特征是免疫介导的破坏性反应,由为预防、诊断或治疗而给予治疗剂量的药物引起。免疫介导的药物超敏反应占药物不良反应的6-10%,在美国排名第四至第六位。在美国每年有300亿美元(1995年的价值)。此外,在药物开发的临床前阶段不确定药物产生超敏反应的可能性的代价可能是巨大的。据估计,每种药物的临床前阶段和临床I期、II期和III期成本分别约为600万美元、1200万美元、1200万美元和1亿美元(1999年的价值)。重要的是,在开发过程中尽可能早地确定可能产生超敏反应的研究药物。如果已知药物与药物之间的相互作用或建立了构效关系,则可以避免某些药物的不良反应。然而,这些方法是不够的。需要适当的药物性超敏反应的动物模型,特别是因为超敏反应被认为是药物从市场上撤下的主要原因。能够预测对药物的过敏反应是至关重要的。大多数过敏反应发生在特应性个体。同样,经历过其他过敏反应的患者更有可能出现复发性反应。因此,应考虑动物模型使动物易发生反应,例如使用适当的佐剂和种类。使用已知的不同强度的阳性对照,研究者可以将反应与阳性对照作为标准进行排序。与使用新的模型相比,这种方法可能在更短的时间内产生更大的结果。为了最大程度的安全,必须使用经过彻底验证的易于理解的模型。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Drug-induced hypersensitivity: role in drug development.

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 >$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 $US6 million, $US12 million, $US12 million and $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.

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