Sex and disease dependent nucleoside analog toxicity

描述（由申请人提供）：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组合延长了HIV患者的生命，但药物毒性是主要的临床问题。女性NRTI毒性的发生率高于男性，并且在晚期与不太晚期的HIV感染中，但这些毒性差异的基础尚不清楚。NRTI通过在宿主细胞中磷酸化为NRTI三磷酸而活化，其中一些可以干扰线粒体DNA复制以引起毒性。我们的实验室已经开发出方法来定量NRTI-三磷酸盐浓度在外周血单核细胞。 在初步研究中，我们发现女性和晚期HIV感染者的NRTITriphosphate浓度分别高于男性和晚期HIV感染者。本申请中提出的工作将前瞻性地回答三个关键问题：NRTI-三磷酸浓度是否依赖于性别？NRTI-三磷酸浓度是否取决于HIV疾病分期？而且，NRTI-三磷酸浓度和NRTI毒性之间是否存在关系？这一领域的研究非常重要，与人类健康相关，因为NRTI毒性可能是痛苦的，毁容和危及生命的。 目前没有足够的临床方法来解决性别和疾病依赖性NRTI毒性。美国Dept。美国卫生与公众服务部警告说，NRTI对女性有毒性，但唯一的建议是在怀孕期间避免使用某些NRTI。需要更全面的战略。 此外，在晚期疾病中增加的NRTI毒性风险尚未在目前关于早期还是晚期开始基于NRTI的治疗的争论中权衡。我们的初步工作提供了一个合理的药理学基础，以评估性别和疾病依赖性的NRTI-三磷酸盐浓度，以及NRTI-毒性的浓度-效应关系。所获得的知识涉及我们的长期目标，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.