Effects of Antiretroviral Drugs on Metabolism

抗逆转录病毒药物对代谢的影响

• 批准号: 7558268
• 负责人: Carl Grunfeld
• 金额: $ 36.25万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7558268
• 关键词: Acute; Anti-Retroviral Agents; Antiatherogenic; Apolipoprotein A-I; Arts; Atherosclerosis; Blood Circulation; Cells; Chronic; Counseling; Data; Doctor of Medicine; Doctor of Philosophy; Dose; Drug toxicity; GLUT4 gene; Glucose; Glucose Transporter; Grant; HIV; HIV Infections; HIV Protease Inhibitors; HIV therapy; Health; Hepatic; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Highly Active Antiretroviral Therapy; Human; Hypertriglyceridemia; Immune; Insulin; Insulin Resistance; Link; Mediating; Metabolic; Metabolism; Methods; Mus; Patients; Pharmaceutical Preparations; Production; Property; Protease Inhibitor; Ritonavir; Techniques; Time; Toxic effect; Treatment Protocols; Triglyceride Metabolism; Triglycerides; Vasodilation; Very low density lipoprotein; adiponectin; atheroprotective; base; design; efavirenz; glucose disposal; glucose metabolism; glucose production; healthy volunteer; improved; insulin secretion; low density lipoprotein inhibitor; non-nucleoside reverse transcriptase inhibitors; particle; reconstitution; restoration; stable isotope; treatment strategy; very low density lipoprotein triglyceride; volunteer

DESCRIPTION (provided by applicant): To define the direct toxicities of antiretroviral drugs (ARV) and separate those changes from their effects on HIV infection, we gave single ARV to healthy volunteers and compared results to studies in HIV infected patients on those ARV. We now propose to resolve controversies with currently used ARV. 1) The mechanism(s) by which ritonavir increases triglycerides is unknown, but have significant implications for atherosclerosis. Hypothesis 1: Ritonavir-based regimens increase triglycerides and VLDL by both increasing VLDL production and decreasing VLDL clearance. Specific Aim 1A: To quantify the effect of ritonavir on VLDL production and clearance using stable isotope turnover and other clearance methods. Specific Aim 2B: To determine the composition of the triglyceride rich particles 2) NNRTI increase HDL cholesterol, but the mechanism is unknown and NNRTI may not generate HDL particles that have strong anti-atherogenic effects. Hypothesis 2: NNRTI drugs do not increase HDL by increasing apo AI production, but by decreasing apo AI clearance, prolonging time in circulation and producing particles with limited anti-atherogenic properties. Specific Aim 2A: To determine the composition of HDL before and after NNRTI and assess its function. Specific Aim 2B: To quantify the effect of NNRTI on apo AI production & clearance using stable isotopes. Specific Aim 2C: To determine if the efavirenz induced increase in HDL is accompanied by improvement in flow mediated vasodilation and circulating markers of endothelial function 3) The effects of PI on glucose metabolism cannot be solely explained by their effects on insulin resistance. PIs may impair insulin secretion, which has important implications for design of safer PI. Hypothesis 3: Ritonavir-based PIs impair insulin secretion. Specific Aim 3: To determine which ritonavir-based PI regimens alter insulin secretion. The results from these studies will define the direct toxicities of ARV, which provide essential information for rationally evaluating treatment strategies and counseling patients.Carl Grunfeld, MD, PhD.

描述（由申请人提供）：定义抗逆转录病毒药物（ARV）的直接毒性，并将这些变化与对HIV感染的影响分开，我们将单个ARV与健康的志愿者分开，并将结果与​​HIV感染患者的研究结果进行了比较。现在，我们建议使用当前使用的ARV解决争议。 1）利托那韦增加甘油三酸酯的机制尚不清楚，但对动脉粥样硬化具有重要意义。假设1：基于利托那韦的方案通过增加VLDL的产生和降低VLDL清除率来增加甘油三酸酯和VLDL。特定目标1a：使用稳定的同位素转让和其他清除方法来量化利托那韦对VLDL生产和清除的影响。特定目标2B：确定富含甘油三酸酯颗粒的组成2）NNRTI增加HDL胆固醇，但该机制尚不清楚，NNRTI可能不会产生具有强大抗动脉本体作用的HDL颗粒。假设2：NNRTI药物不会通过增加APO AI的产生而增加HDL，而是通过降低APO AI清除率，延长循环时间和具有有限的抗动脉本体特性的颗粒。特定目标2a：确定NNRTI前后HDL的组成并评估其功能。特定目标2B：使用稳定的同位素量化NNRTI对APO AI生产和清除的影响。特定目标2C：确定efavirenz诱导的HDL诱导的增加是否伴随着流动介导的血管舒张的改善和内皮功能的循环标记3）PI对葡萄糖代谢的影响不能完全通过其对胰岛素耐药的作用而纯粹解释。 PI可能会损害胰岛素分泌，这对更安全的PI设计具有重要意义。假设3：基于Ritonavir的PIS损害胰岛素分泌。特定目的3：确定哪种基于利托纳维尔的PI方案改变了胰岛素分泌。这些研究的结果将定义ARV的直接毒性，这为理性评估治疗策略和咨询患者提供了重要信息。CarlGrunfeld，MD，PhD。