HYDROXYUREA IN HIV CHILDREN RECEIVING DIDANOSINE AND/OR STAVUDINE

羟基脲是一种抑制DNA合成的抗肿瘤药物。在体外，羟基脲降低了二腺苷（ddI）的细胞竞争对手的水平，并协同药物的抗逆转录病毒作用。羟基脲还通过降低病毒DNA合成所必需的细胞内脱氧核苷酸的浓度直接抑制HIV的复制。羟基脲在hiv感染成人中的初步临床试验显示出令人鼓舞的结果。本研究的目的是：(1)评估在现有的包括ddI和/或司他夫定（d4T）的治疗中，口服羟脲对hiv感染儿童的稳态药代动力学特征、耐受性和安全性；(2)评估羟脲加入现有抗逆转录病毒治疗后，血浆HIV RNA浓度、总淋巴细胞计数和CD4+淋巴细胞计数与基线相比的变化。这将是一项为期48周的开放、剂量递增研究，将羟脲添加到现有的抗逆转录病毒治疗中，包括二腺苷和/或司他夫定。大约15名12个月至16岁感染艾滋病毒的儿童将被招募。儿童将在筛查、入组和此后每四周进行临床和实验室研究评估。研究第一天将进行4小时的药代动力学研究；随后在常规门诊就诊时采集单次定时血样，采用稀疏抽样法测定药代动力学参数。对于羟基脲相关的3级毒性，将概述暂时中断给药。对于药物相关的持续3级或4级毒性，将规定永久停药。

Hydroxyurea is an antineoplastic agent which inhibits DNA synthesis. In vitro hydroxyurea decreases levels of a cellular competitor of didanosine (ddI) and synergizes the antiretroviral effect of the drug. Hydroxyurea also directly inhibits replication of HIV by lowering concentrations of intracellular deoxynucleotides essential for viral DNA synthesis. Initial clinical trials of hydroxyurea in HIV-infected adults have shown promising results. The objectives of the present study are: (1) to assess the steady-state pharmacokinetic features, tolerance, and safety of orally administered hydroxyurea, added to existing therapy which includes ddI and/or stavudine (d4T), in HIV-infected children; and (2) to evaluate addition of hydroxyurea to existing antiretroviral therapy, with respect to changes from baseline in plasma HIV RNA concentrations, total lymphocyte counts, and CD4+ lymphocyte counts. This will be a 48-week open, dose-escalating study of hydroxyurea added to existing antiretroviral therapy which includes didanosine and/or stavudine. Approximately 15 HIV-infected children aged 12 months to 16 years will be enrolled. Children will be evaluated clinically and with laboratory studies at screening, entry, and every four weeks thereafter. A four-hour pharmacokinetic study will be conducted on study day one; single timed blood samples will be collected subsequently during routine clinic visits for determination of pharmacokinetic parameters by sparse sampling methodology. Temporary interruption of dosing will be outlined for hydroxyurea-associated grade 3 toxicities. Permanent discontinuation of dosing will be prescribed for drug-associated persistent grade 3 or grade 4 toxicities.