Sex and disease dependent nucleoside analog toxicity

描述(申请人提供)：包括核苷类似物-逆转录酶抑制剂(NRTI)在内的抗逆转录病毒药物的组合延长了艾滋病毒患者的生命，但药物毒性是主要的临床问题。NRTI毒性在女性中的发生率高于男性，在晚期与非晚期艾滋病毒感染中的发生率更高，但这些毒性差异的基础尚不清楚。NRTI是通过宿主细胞对NRTI的磷酸化而激活的，其中一些NRTI可以干扰线粒体DNA复制而引起毒性。我们实验室已经开发出定量测定外周血单核细胞中NRTI-三磷酸浓度的方法。在初步研究中，我们发现，患有晚期艾滋病毒感染的女性和受试者的NRTI三磷酸浓度分别高于男性和那些感染艾滋病毒程度较低的患者。本申请中提出的工作将前瞻性地回答三个关键问题：NRTI-三磷酸浓度是否与性别有关？NRTI-三磷酸浓度与HIV疾病分期有关吗？而且，NRTI-三磷酸浓度和NRTI毒性之间是否存在关系？这一领域的研究对人类健康非常重要，因为NRTI的毒性可能是痛苦的、毁容的，并危及生命。目前还没有足够的临床方法来解决与性别和疾病相关的NRTI毒性。美国部门。卫生与公众服务部警告NRTI对女性的毒性，但唯一的建议是在怀孕期间避免某些NRTI。需要更全面的战略。此外，晚期疾病中增加的NRTI毒性风险还没有在目前关于早或晚开始基于NRTI的治疗的辩论中权衡。我们的初步工作为评估性别和疾病依赖的NRTI-三磷酸浓度以及NRTI毒性的浓度-效应关系提供了合理的药理学基础。将获得的知识解决了我们的长期目标，即发现药物反应的决定因素，并利用这些信息来提高药物安全性。

DESCRIPTION (provided by applicant): Combinations of antiretroviral drugs that include nucleoside analog-reverse transcriptase inhibitors (NRTI) have prolonged the lives of patients with HIV, but drug-toxicities are major clinical issues. The rate of NRTI toxicities is higher in women than men, and in advanced versus less-advanced HIV infection, but the basis for these differences in toxicities is unknown. NRTIs are activated by phosphorylation in host cells to NRTItriphosphates, some of which can interfere with rnitochondrial DNA replication to elicit toxicity. Our laboratory has developed methods to quantify NRTI-triphosphate concentrations in peripheral blood mononuclear cells. In preliminary studies, we found that women and subjects with advanced HIV-infection had higher NRTItriphosphate concentrations than men and those with less-advanced HIV-infection, respectively. The work proposed in this application will prospectively answer three critical questions: Are NRTI-triphosphate concentrations sex-dependent? Are NRTI-triphosphate concentrations dependent on HIV disease stage? And, is there a relationship between NRTI-triphosphate concentrations and NRTI toxicity? Research in this area is important and relevant to human health because NRTI-toxicities can be painful, disfiguring, and life-threatening. There is currently no adequate clinical approach to address sex- and disease-dependent NRTI-toxicity. The US Dept. of Health and Human Services warns of NRTI-toxicity in women, but the only recommendation is to avoid certain NRTIs during pregnancy. More comprehensive strategies are needed. Also, the increased NRTI-toxicity risk in advanced disease is not yet weighed in the current debate of early versus late initiation of NRTI-based treatments. Our preliminary work provides a rational pharmacologic basis to evaluate sex- and disease-dependent NRTI-triphosphate concentrations, and the concentration-effect relationship to NRTI-toxicity. The knowledge to be gained addresses our long-term objective to discover the determinants of drug responses and to utilize the information to improve drug safety.