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性药物的临床医生始终关注的问题。“特殊”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，但被认为是个人独有的。这些形式的毒性往往对患者及其家人的身体和情感都是毁灭性的，也给社会带来了负担，因为诊断延误、长期住院导致医疗资源的急剧消耗、诉讼和对风险的不适当概括，这些风险往往限制了可以安全地给予大多数患者的治疗实体的使用。使用对芳香族抗惊厥剂卡马西平的超敏反应作为模型系统，这项建议的长期目标是表征可能决定个体对特殊药物毒性的敏感性的关键事件。据推测，临床上观察到的组织损伤是由个人自身的免疫系统造成的，卡马西平对能够与细胞蛋白不可逆结合的反应性代谢产物的生物激活是导致免疫反应的必要事件。此外，产生反应代谢物的药物代谢酶细胞色素P450本身就是反应代谢物的靶标。为了确定药物生物激活事件和随后的免疫反应之间的联系，这一提议将检验这样的假设，即共价修饰的P450在细胞内通过类似于用于抗原处理和呈递给免疫系统的途径降解。此外，这一假设意味着，患者抗体识别的特定氨基酸序列模仿了类似的感染源多肽。因此，环境(感染)、药物代谢(P450和解毒酶基因或表型)和免疫(HLA单倍型)因素都可能决定特异性事件的易感性。最终的目标是使用所有相关的生物激活、解毒和免疫反应因素来构建一个“易感图谱”，该图谱可以用来通过特定的基因分型和表型方法来识别先验的风险个体。因此，这些基础科学技术可以有效地解决影响所有年龄段的患者的临床问题，从儿科到老年病。预计用于这些研究的基本实验范式也可以应用于其他可疑药物生物激活和免疫病因的特殊毒性。

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.