IMMUNOLOGY AND IMMUNE BASED THERAPY AGENDA

免疫学和基于免疫的治疗议程

• 批准号: 6234715
• 负责人: PETER T FRAME
• 金额: $ 18.62万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 1997-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6234715
• 关键词: AIDS; AIDS related neoplasm /cancer; AIDS therapy; HIV infections; antineoplastics; biomarker; cellular immunity; clinical research; communicable disease control; cooperative study; cytokine; human immunodeficiency virus 1; human subject; human therapy evaluation; humoral immunity; immunization; immunomodulators; immunotherapy; neoplasm /cancer immunotherapy; opportunistic infections; oxidative stress; pathologic process; virus load; virus replication

Plasma concentrations of zidovudine (ZDV) and other nucleoside analog drugs have shown little correlation with clinical events. Because they must be metabolized intracellularly to elicit a biological effect, intracellular concentrations of the phosphorylated metabolites of nucleoside analogs might correlate with drug effects. The studies herein propose to use a sensitive and reproducible radioimmunoassay method, suitable for routine monitoring of total phosphorylated ZDV in peripheral blood mononuclear cells (PBMC), to define the pharmacokinetics of ZDV phosphorylation in PBMC from patients receiving ZDV, and examine the relation between intracellular concentrations and certain prognostic indicators of HIV disease. This includes a two armed study with a total of 40 patients. One arm will examine the rate of ZDV phosphorylation in ZDV-naive patients and the length of time required to reach steady-state concentrations while on standard dose ZDV (500 mg/day). The second arm will investigate the dose-response in patients on an escalating dose regimen. A two-year study combined both patient groups, and investigates the effects of long-term ZDV therapy on intracellular pharmacokinetics, including clearance and phosphorylation upon re-introduction of drug. Concurrent measurements of the prognostic indicators will be made. This study may suggest that longer dosing intervals and/or lower doses of ZDV are adequate to maintain intracellular concentrations. Additionally, an HPLC/RIA method will be validated and used to determine pharmacokinetics of ZDV triphosphate. this 10 patient study will be nested into the larger study because of practical limitations of the method, but the same parameters will be investigated. Similarly, a pilot study investigating the pharmacokinetic differences of ZDV phosphorylation in patients on combination ZDV/dideoxycytidine will also be performed in an effort to investigate synergistic efficacy. This study will be nested in site patients enrolled in ACTG 155. Finally, the development of new assays for measurement of intracellular nucleoside analog metabolites is planned. Eventually, modifications of dose to maximize effect might be possible through routine intracellular monitoring of nucleoside analog metabolites.

Zidovudine（ZDV）和其他核苷类似物的血浆浓度 药物与临床事件几乎没有相关性。 因为他们 必须将细胞内代谢以引起生物学作用， 磷酸化代谢物的细胞内浓度 核苷类似物可能与药物作用相关。 研究 此处建议使用敏感且可重复的放射免疫分子 方法，适合常规监测总磷酸化ZDV 外周血单核细胞（PBMC），以定义 PBMC的ZDV磷酸化的药代动力学来自接受的患者 ZDV，并检查细胞内浓度与 艾滋病毒疾病的某些预后指标。 这包括两个武装 研究总共40名患者。 一只手臂会检查ZDV的速率 ZDV患者的磷酸化以及所需的时间长度 在标准剂量ZDV时达到稳态浓度（500 mg/天）。 第二臂将研究患者的剂量反应 在不断升级的剂量方案中。 一项为期两年的研究结合了两个患者 组，并研究长期ZDV治疗对 细胞内药代动力学，包括清除和磷酸化 重新引入药物。 同时测量预后 将提出指标。 这项研究可能表明更长的给药 间隔和/或较低剂量的ZDV足以维持 细胞内浓度。 此外，HPLC/RIA方法将是 经过验证并用于确定ZDV三磷酸的药代动力学。 这项10个患者研究将嵌套到更大的研究中 该方法的实际限制，但是相同的参数将是 调查。 同样，一项试点研究调查了 ZDV磷酸化患者的药代动力学差异 还将进行ZDV/二氧基胞苷的组合以进行努力 研究协同功效。 这项研究将嵌套在现场 ACTG 155的患者。最后，新测定的发展 用于测量细胞内核苷类似物代谢产物IS 计划。 最终，剂量修改以最大化效果可能是 通过核苷类似物的常规细胞内监测可能 代谢物。