PHARMACOKINETIC STUDIES OF INTRACELLULAR ZDV IN CHILDREN

齐多夫定(ZDV)的儿科临床试验表明 人类免疫缺陷病毒(HIV)的治疗效果 疾病。表现出临床、病毒学和免疫学特征。 在治疗过程中有所改善。不幸的是，随后的研究 在儿科人群中一直很稀少与 ZDV的血药浓度和临床疗效尚未确定。 这种关系的缺乏可能是因为ZDV需要 代谢成ZDV-三磷酸(ZDV-TP)变得活跃，而 酶过程的激活步骤取决于不同的因素 与ZDV血浆浓度有关。其中一些因素包括， 竞争病毒的内源核苷酸浓度 ZDV-TP的复制形成及ZDV代谢产物的活化 包括目标细胞的激活状态。再说了， 考虑到患者之间酶的可变性的可能性 ZDV和AMT的激活过程，很可能是血浆ZDV 浓度与毒性和/或抗病毒药物关系不大 活动。因此，ZDV代谢物的细胞内测量可能 在临床疗效/毒性方面提供比 血浆ZDV浓度。 细胞内抗逆转录病毒检测方法的发展 核苷酸在儿科临床环境中对 了解这些药物在这方面的药理机制 人口。这一理解将在当前产生重大影响 管理儿童艾滋病毒感染的战略；然而，没有这样的战略 信息是可用的。检测ZDV范围的研究 成年人群中的磷酸化在他们现在是有限的 格式用于儿科研究，因为它们需要15至75毫升 血。如此大的出血量阻碍了进行PK的可能性 在儿科人群中的分析。因此，有必要开发新的 分析程序可以测量细胞内的 齐多夫定和其他抗逆转录病毒药物在儿童人群中的应用 使用少量血液样本。我们的长期目标是了解 与抗逆转录病毒有关的基本药理参数 儿科人群中的治疗。 这项研究项目还将增强以下可能性 代表不足的少数族裔学生在研究领域变得活跃 与艾滋病相关，促进新科学家和 波多黎各的研究人员。 研究项目的具体目标是： 1.建立新的方法以减少抽血量，为 ZDV-磷酸化物种在体内的药代动力学研究 儿科人口。这些方法可以在未来用于 研究其他抗逆转录病毒核苷； 2.建立磷酸化ZDV的药代动力学参数 儿科种群中的物种，如体内ZDV-TP半衰期，以及 开发可用作预测PK的工具的数学模型 配置文件； 3.探讨ZDV与磷酸化之间存在的关系 测定的物种药理参数和抗病毒活性 血浆艾滋病毒RNA-聚合酶链式反应(罗氏)； 4.为本科生、研究生和医学生提供机会 未被充分代表的少数族裔学生将活跃在生物医学领域 将对我们的社会产生影响的研究领域。

Pediatric clinical trials with zidovudine (ZDV) have shown its effectiveness for the treatment of the Human Immunodeficiency Virus (HIV) disease . Clinical, virologic, and immunologic characteristics were shown to improve during the course of therapy. Unfortunately, subsequent studies in the pediatric population have been scarce and a relationship between ZDV plasma concentration and clinical efficacy has not been established. The lack of this relationship may be due to the fact that ZDV needs to be metabolized to ZDV-triphosphate (ZDV-TP) to become active, and the activation steps of the enzymatic processes are dependent on factors not related to ZDV plasma concentrations. Some of these factors include, the concentration of endogenous nucleotides competing for the virus replication with ZDV-TP formation and activation of ZDV metabolites including and the activation state of the target cells. Besides, considering the possibility of interpatient variability in the enzymatic activation processes o ZDV and AMT, it is likely that plasma ZDV concentration has little relationship with toxicity and/or antiviral activity. Therefore, intracellular measurements of ZDV metabolites may provide a better marker with respect to clinical efficacy/toxicity than plasma ZDV concentrations. The development of procedures to measure intracellular antiretroviral nucleotides in a pediatric clinical setting is of utmost importance to understand the pharmacological mechanisms of these drugs in this population. This understanding would have a great impact in the current strategy for management of HIV infection in children; however, no such information is available. Studies examining the extent of ZDV phosphorylation in the adult population are limited in their present format to pediatric studies, since they require between 15 to 75 mL of blood. This large blood volume hinders the possibilities to perform PK analysis in the pediatric population. Thus, there is a need to develop new analytical procedures that could measure intracellular levels of zidovudine and other antiretroviral drugs in the pediatric population using small blood volume samples. Our long term goal is to understand the basic pharmacological parameters that are involved with antiretroviral therapy in the pediatric population. This research project will also enhance the possibilities for underrepresented minority students to become active in a research area related to AIDS, promoting the development of new scientists and researchers in Puerto Rico. The specific aims of the research project are: 1. to establish new methodology to decrease blood sampling volume, for the implementation of pharmacokinetic studies of ZDV-phosphorylated species in the pediatric population. These methods could be used in the future to study other antiretroviral nucleosides; 2. to establish the pharmacokinetic parameters of ZDV phosphorylated species in a pediatric population such as, in vivo ZDV-TP half-life, and develop mathematical models that could be used as tools to predict PK profiles; 3. to probe for the existing relationships between ZDV phosphorylated species pharmacological parameters and anti viral activity as measured by plasma HIV RNA-PCR (Roche); 4. to provide an opportunity for undergraduate, graduate and medical underrepresented minority students to become active in a biomedical research area that will have an impact in our society.