HYDROXYUREA IN HIV CHILDREN RECEIVING DIDANOSINE AND/OR STAVUDINE

羟基脲是一种抑制DNA合成的抑制剂。 在体外，羟基脲降低去羟肌苷（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来直接抑制HIV的复制。 在HIV感染的成年人中进行的羟基脲的初步临床试验显示出有希望的结果。 本研究的目的是：（1）评估口服羟基脲加用现有治疗（包括ddI和/或司他夫定（d4 T））治疗HIV感染儿童的稳态药代动力学特征、耐受性和安全性;和（2）评价在现有抗逆转录病毒治疗中加入羟基脲对血浆HIV RNA浓度、总淋巴细胞计数和CD 4+淋巴细胞计数。 这将是一项为期48周的开放性、剂量递增研究，在现有的抗逆转录病毒治疗（包括去羟肌苷和/或司他夫定）中加入羟基脲。 将招募约15名12个月至16岁的艾滋病毒感染儿童。儿童将在筛选、入组和此后每四周进行一次临床和实验室研究评估。 将在研究第1天进行4小时药代动力学研究;随后将在常规临床访视期间采集单次定时血样，用于通过稀疏采样方法测定药代动力学参数。 对于与羟基脲相关的3级毒性，将概述暂时中断给药。 对于药物相关的持续性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.