PATHOGENESIS OF ANTICONVULSANT HYPERSENSITIVITY SYNDROME

严重的药物不良反应仍然是所有在儿童和成人中使用治疗药物的临床医生一直关注的问题。 术语“特异质”药物毒性是指相对罕见但可能危及生命的事件，其中诱发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人在身体和情感上都是毁灭性的，并且还通过延迟诊断、延长住院时间以及大量消耗医疗保健资源、诉讼和关于风险的不适当概括而给社会带来负担，这些风险通常限制了可以安全地给予大多数患者的治疗实体的使用。 使用超敏反应的芳香族抗惊厥药卡马西平作为一个模型系统，本提案的长期目标是表征的关键事件，可能会决定个人敏感性特异质药物毒性。 据推测，个体自身的免疫系统是临床观察到的组织损伤的原因，并且卡马西平生物活化为能够不可逆地结合细胞蛋白的反应性代谢物是导致免疫应答的必要事件。 此外，产生反应性代谢物的药物代谢酶细胞色素P450本身是反应性代谢物的靶标。 为了确定药物生物活化事件和随后的免疫应答之间的联系，该提案将测试以下假设：共价修饰的P450在细胞内通过与用于抗原加工和呈递给免疫系统的途径相似的途径降解。 此外，该假设意味着患者抗体识别的特定氨基酸序列模拟感染源的类似肽。 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质事件的易感性。 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构建“易感性谱”，利用特定的基因分型和表型分型方法，可用于识别先验的高危个体。 因此，这些基础科学技术可以用来有效地解决影响所有年龄段患者的临床问题，从儿科到老年人。预计这些研究采用的基本实验范式也可应用于其他疑似药物生物活化和免疫病因的特异质毒性。

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.