Effects of Antiretroviral Drugs on Metabolism

抗逆转录病毒药物对代谢的影响

• 批准号: 7419141
• 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/7419141
• 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; 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）：为了确定抗逆转录病毒药物（ARV）的直接毒性，并将这些变化与其对艾滋病毒感染的影响区分开来，我们给健康志愿者服用单一抗逆转录病毒药物，并将结果与艾滋病毒感染患者服用这种抗逆转录病毒药物的研究结果进行比较。我们现在建议用目前使用的ARV解决争议。1)利托那韦增加甘油三酯的机制尚不清楚，但对动脉粥样硬化有重要意义。假设1：以利托那韦为基础的方案通过增加VLDL产生和降低VLDL清除来增加甘油三酯和VLDL。特定目的1A：利用稳定同位素转换和其他清除方法，量化利托那韦对VLDL产生和清除的影响。特异性目的2B：确定富甘油三酯颗粒的组成2)NNRTI增加HDL胆固醇，但其机制尚不清楚，NNRTI可能不会产生具有强抗动脉粥样硬化作用的HDL颗粒。假设2:NNRTI药物不是通过增加载脂蛋白AI产生来增加HDL，而是通过降低载脂蛋白AI清除率、延长循环时间和产生具有有限抗动脉粥样硬化特性的颗粒来增加HDL。具体目的2A：确定NNRTI前后HDL的组成并评估其功能。特定目标2B：使用稳定同位素量化NNRTI对载脂蛋白AI产生和清除的影响。特异性目的2C：确定依非韦伦诱导的HDL升高是否伴随着血流介导的血管舒张和内皮功能循环标志物的改善3)PI对葡萄糖代谢的影响不能仅仅通过其对胰岛素抵抗的影响来解释。PI可能影响胰岛素分泌，这对设计更安全的PI具有重要意义。假设3：利托那韦类PIs损害胰岛素分泌。特异性目的3：确定以利托那韦为基础的PI方案改变胰岛素分泌。这些研究结果将明确ARV的直接毒性，为合理评估治疗策略和为患者提供咨询提供重要信息。卡尔·格伦菲尔德，医学博士。