PATHOGENESIS OF ANTICONVULSANT HYPERSENSITIVITY SYNDROME

严重的药物不良反应仍然是目前所有临床医生谁使用治疗药物的儿童和成人的关注。“特异性”药物毒性指的是相对罕见但可能危及生命的事件，其中导致事件的因素在很大程度上是未知的，但被认为是个体独有的。这些形式的毒性通常对患者及其家属在身体和情感上都是毁灭性的，并通过延迟诊断、延长住院时间、大量消耗医疗资源、诉讼和对风险的不当概括给社会带来负担，这些往往限制了对大多数患者安全给予的治疗实体的使用。使用芳香抗惊厥药卡马西平的超敏反应作为模型系统，本建议的长期目标是表征可能决定个体对特殊药物毒性敏感性的关键事件。据推测，临床观察到的组织损伤是由个体自身的免疫系统造成的，卡马西平被生物激活为能够不可逆地与细胞蛋白结合的反应性代谢物是导致免疫反应的必要事件。此外，产生反应性代谢物的药物代谢酶，细胞色素P450，本身就是反应性代谢物的靶标。为了确定药物生物活化事件与随后的免疫反应之间的联系，本提案将验证共价修饰的p450在细胞内通过类似于用于抗原加工和提交给免疫系统的途径降解的假设。此外，这一假设表明，患者抗体识别的特定氨基酸序列模仿了类似的感染性肽。因此，环境（感染）、药物代谢（P450和解毒酶基因型或表型）和免疫（HLA单倍型）因素都可能决定对特异事件的易感性。最终目标是利用所有相关的生物活化、解毒和免疫反应因子来构建一个“易感谱”，该易感谱可用于使用特定的基因分型和表型分型方法识别有风险的先验个体。因此，这些基础科学技术可用于有效地解决影响所有年龄段患者的临床问题，从儿科到老年。预计用于这些研究的基本实验范式也可以应用于其他具有可疑药物生物活化和免疫病因的特异性毒性。

Serious adverse drug reactions remain an ever present concern for all clinicians who utilize therapeutic drugs in children and adults. The term "idiosyncratic" drug toxicity refers to relatively rare, but potentially life-threatening events in which the factors predisposing to the event are largely unknown, but are thought to be unique to the individual. These forms of toxicity are frequently devastating, both physically and emotionally, to patients and their families, and also present a burden to society through delayed diagnoses, prolonged hospital- izations with dramatic consumption of healthcare resources, litigation and inappropriate generalizations regarding risk that often restrict the use of therapeutic entities that could be safely given to most patients. Using hypersensitivity reactions to the aromatic anticonvulsant carbamazepine as a model system, the long-term objective of this proposal is to characterize the critical events that may determine individual susceptibility to idiosyncratic drug toxicity. It is hypothesized that the individual's own immune system is responsible for the tissue injury observed clinically, and that bioactivation of carbamazepine to reactive metabolites capable of irreversibly binding to cellular proteins is a necessary event leading to the immune response. Furthermore, the drug metabolizing enzyme generating the reactive metabolite, a cytochrome P450, is itself a target of the reactive metabolite. To identify the link between the drug bioactivation event and the subsequent immune response, this proposal will test the hypothesis that covalently modified P450s are degraded within the cell by pathways similar to those used for antigen processing and presentation to the immune system. Furthermore, this hypothesis implies that the particular amino acid sequences recognized by patient antibodies mimic similar peptides of infectious origin. Thus, environmental (infection), drug metabolism (P450 and detoxification enzyme genotype or phenotype) and immune (HLA haplotype) factors may all determine susceptibility to idiosyncratic events. The ultimate goal is to use all the relevant bioactivation, detoxification and immune response factors to construct a "susceptibility profile" that can be used to identify a priori individuals at risk using specific genotyping and phenotyping methods. Thus, these basic science techniques can be used to effectively address a clinical problem affecting patients of all ages, pediatric to geriatric. It is anticipated that the basic experimental paradigm employed for these studies can also be applied to other idiosyncratic toxicities with suspected drug bioactivation and immune etiologies.