PATHOGENESIS OF ANTICONVULSANT HYPERSENSITIVITY SYNDROME

抗惊厥药过敏综合征的发病机制

基本信息

批准号：
6636276
负责人：
JAMES STEVEN LEEDER
金额：
$ 36.27万
依托单位：
CHILDREN'S MERCY HOSP (KANSAS CITY, MO)
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-05-01 至 2005-12-31
项目状态：
已结题

项目摘要

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.

对于所有利用儿童和成人治疗药物的临床医生来说，严重的不良药物反应仍然是一个关注的问题。 “特殊”药物毒性一词是指相对较少的，但可能威胁生命的事件，其中易感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。这些形式的毒性经常在身体和情感上，对患者及其家人都具有毁灭性，并且还通过延迟诊断，长期延长医院的医院消费，诉讼和不当概括的概括，这些风险通常限制了可能会限制大多数患者的治疗实体的使用，从而给社会带来负担。使用对芳族抗惊厥药carbamazepine作为模型系统的超敏反应，该提案的长期目标是表征可能确定个人对特殊药物毒性易感性的关键事件。假设个体自身的免疫系统负责临床观察到的组织损伤，并且卡马西平生物激活能够使能够不可逆地结合细胞蛋白的反应性代谢产物生物活化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，一种细胞色素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，该建议将检验以下假设：通过类似于用于抗原加工的途径和呈现给免疫系统的途径，共价修改的P450在细胞内降解。此外，该假设意味着患者抗体识别的特定氨基酸序列模仿了传染性的相似肽。因此，环境（感染），药物代谢（P450和排毒酶基因型或表型）和免疫（HLA单倍型）因子可能都决定了对特质事件的敏感性。最终目标是使用所有相关的生物活化，排毒和免疫反应因素来构建“易感性概况”，可用于使用特定的基因分型和表型方法来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解决影响各个年龄段患者的临床问题，即小儿至老年。预计这些研究所采用的基本实验范式也可以应用于具有可疑的药物生物活化和免疫病因的其他特质毒性。