ART PHARMACOKINETICS IN SEVERELY MALNOURISHED HIV-INFECTED CHILDREN

严重营养不良的艾滋病毒感染儿童的 ART 药代动力学

• 批准号: 7692872
• 负责人: Ericka Hayes
• 金额: $ 6.3万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7692872
• 关键词: Affect; Africa South of the Sahara; Age-Months; Alanine Transaminase; Albumins; Anthropometry; Anti-Retroviral Agents; Antioxidants; Area Under Curve; Arts; Aspartate Transaminase; Body fat; CD4 Lymphocyte Count; Characteristics; Child; Childhood; Control Groups; Data; Deuterium Oxide; Dose; Drug Kinetics; Drug resistance; Edema; Enrollment; Erythrocytes; Glomerular Filtration Rate; Glutathione; Goals; HIV; Half-Life; Height; Hepatic; Highly Active Antiretroviral Therapy; Immunologics; Kidney; Kinetics; Kwashiorkor; Lamivudine; Lead; Living Wills; Lymphocyte Subset; Malnutrition; Marasmus; Measurement; Measures; Metabolism; Methods; Mitochondria; Mitochondrial DNA; Nevirapine; Nutritional; Nutritional Support; Nutritional status; Observational Study; Patients; Pharmaceutical Preparations; Physiological; Recruitment Activity; Renal function; Research Design; Research Proposals; Resistance; Role; Sample Size; Serum; Serum Proteins; Stavudine; Stress; Superoxide Dismutase; Toxic effect; Virus Diseases; Weight; Whole Blood; age group; aged; base; cohort; combat; drug metabolism; glutathione peroxidase; immune function; liver function; monocyte; post gamma-globulins; primary outcome; public health relevance; secondary outcome; wasting

DESCRIPTION (provided by applicant): The objective of this project is to understand how severe malnutrition affects the pharmacokinetics of highly active antiretroviral therapy (HAART) as well as antioxidant capacity and mitochondrial integrity in HIV infected children started on HAART and nutritional therapy. Pediatric dosing and kinetics for HAART drugs are based on data obtained in well nourished or only mildly malnourished children which may not be accurate for a severely malnourished child. Severely malnourished children have decreased lean body mass, decreased body fat and likely alterations in liver function, kidney function, and mitochondrial integrity that would affect drug metabolism and clearance. An observational study of a cohort of 117 HIV-infected children 6 to 24 months of age will be performed with 1/3 recovering from marasmus, 1/3 recovering from kwashiorkor and 1/3 a control group of well-nourished HIV-infected children all of whom are being started on HAART. Parameters to be studied at baseline and 2 and 8 weeks after starting HAART include lean body mass (calculated by deuterium oxide dilution method), mitochondrial integrity (measured by lactate and copy numbers of mitochondrial DNA/RNA in monocytes), antioxidant capacity (assessed by whole blood glutathione, red cell superoxide dismutase, glutathione peroxidase, and oxidized serum proteins), hepatic function and integrity (quantified by albumin, alanine transaminase and aspartate transaminase), renal function (measured by serum cystatin C) and immunologic function (characterized by lymphocyte subpopulations). Area under the curve pharmacokinetic measurements will be done for stavudine, lamivudine and nevirapine after 2 and 8 weeks of HAART. Primary outcomes will be the relationship between nutritional status and antioxidant capacity/mitochondrial toxicity and total drug dose and pharmacokinetics correlated with lean body mass. This project will help establish appropriate dosing for HAART in the severely malnourished child and decrease toxicity as well as minimize subtherapeutic dosing and the emergence of resistance. The project will also characterize mitochondrial damage and antioxidant stress which may lead to further therapies to decrease the toxicities of these therapies in these children. PUBLIC HEALTH RELEVANCE: This research proposal will study the appropriate dosing of HIV medications in severely malnourished HIV infected children in sub-Saharan Africa in order to decrease toxicities and minimize the emergence of drug resistant HIV infection in these children. We will also evaluate cellular damage in severely malnourished HIV infected children and the role of HIV medications in increasing this damage to hopefully lead to the discovery of ways to combat this toxicity.

描述（由申请人提供）：该项目的目的是了解严重的营养不良如何影响高度活跃的抗逆转录病毒疗法（HAART）的药代动力学以及HIV感染儿童的抗氧化能力和线粒体完整性，而HAART和营养治疗开始于HAART和营养治疗。 HAART药物的儿科剂量和动力学是基于在养育或温和营养不良的儿童中获得的数据，这对于严重营养不良的儿童可能不准确。严重营养不良的儿童减少了体重，体内脂肪降低，肝功能，肾功能和线粒体完整性的可能改变，这会影响药物代谢和清除率。对117名HIV感染儿童6至24个月大的人群的观察性研究将进行，从Marasmus中恢复1/3，从Kwashiorkor中恢复1/3，而1/3恢复了1/3的对照组，一组良好的HIV艾滋病儿童在Haart上都在Haart上开始。启动HAART时要研究的参数包括瘦体重（通过氧化氘稀释法计算），线粒体完整性（通过单核​​细胞中乳酸和线粒体DNA/RNA的拷贝数测量），单核细胞中的副本数量），抗氧化能力（通过全血细胞氧化剂，红细胞超级氧化氧化物，红细胞的氧化氧化剂，红细胞的氧化氧化物，氧化和氧化血清蛋白），肝功能和完整性（由白蛋白，丙氨酸转氨酶和天冬氨酸转氨酶定量），肾功能（通过血清胱抑素C）和免疫功能（由淋巴细胞亚群测量）。 HAART 2和8周后，将针对Stavudine，Lamivudine和Nevirapine进行曲线药代动力学测量的面积。主要结果将是营养状况与抗氧化能力/线粒体毒性与总药物剂量和药代动力学与瘦体重相关的关系。该项目将有助于在严重营养不良的儿童中为Haart建立适当的剂量，并降低毒性，并最大程度地减少亚治疗剂量和抗药性的出现。该项目还将表征线粒体损伤和抗氧化应激，这可能会导致进一步的疗法降低这些儿童这些疗法的毒性。 公共卫生相关性：这项研究建议将研究撒哈拉以南非洲的严重营养不良的艾滋病毒感染儿童的适当给药，以降低毒性并最大程度地减少这些儿童中耐药性HIV感染的出现。我们还将评估严重营养不良的HIV感染儿童的细胞损害，以及HIV药物在增加这种损害方面的作用，希望发现能够发现对抗这种毒性的方法。

项目成果

Plantar soft tissues and Achilles tendon thickness and stiffness in people with diabetes: a systematic review.

• DOI: 10.1186/s13047-021-00475-7
• 发表时间: 2021-04-28
• 期刊: Journal of foot and ankle research
• 影响因子: 2.9
• 作者: Khor BYC;Woodburn J;Newcombe L;Barn R
• 通讯作者: Barn R