METABOLIC EFFECTS OF PROTEASE INHIBITORS IN HIV DISEASE

描述：（改编自申请人摘要）。报告称， 葡萄糖甘油三酯和胆固醇水平在艾滋病毒感染者的 蛋白酶抑制剂（PI）有更大的推测，这些药物 独特的代谢效应此外，一些艾滋病毒感染者 注意到腹围和布法罗驼峰的增加， 患者使用Pi。在初步研究中， 观察到葡萄糖、胰岛素、TG和总LDL显著升高 一组患者在开始用 PI，而在开始治疗的患者中没有发生这种变化， 拉米夫定或维持不包括拉米夫定的恒定方案 或者私家侦探因为高血糖，高甘油三酯血症， 高胆固醇血症和向心性肥胖与增加的 心血管疾病的风险，这些影响可能会影响长期 预期寿命延长的患者的预后 有效抑制病毒。到目前为止，这些代谢和身体成分 变化没有系统地描述，也不知道是否 这些变化代表一年综合征或为无关的发现。 因此，为了评估这些措施的范围和机制， 碳水化合物和脂质代谢的变化及其关系，如果 任何，身体成分的变化，我们建议进行密集 代谢病房研究中，我们前瞻性地评估 葡萄糖和脂质代谢和身体成分在不同的队列， 艾滋病毒感染的男性和女性在开始Pi治疗之前和之后。这些 研究的目的是：（1）检验PI诱导胰岛素分泌的假设 抵抗（通过口服葡萄糖耐量试验，高胰岛素血症， 正葡萄糖钳夹，肝葡萄糖生成的稳定同位素研究， 2）检验PI的假设， 产生致动脉粥样硬化脂质谱（血浆脂质和脂蛋白 组成，静脉脂肪耐量试验，稳定同位素研究， 全身脂肪分解，从头肝脂肪生成，和 （3）确定患者是否一致 在PI治疗期间发生局部脂肪分布变化， 葡萄糖和脂质代谢的关系（如有）或变化， 身体成分的变化（双能X线吸收测定法，计算 葡萄糖调节激素、肾上腺激素和性腺激素在糖尿病中的作用 还将评估介导这些效应的方法。

DESCRIPTION: (Adapted from applicant's abstract). Reports of increased glucose triglyceride, and cholesterol levels in HIV-infected patients on protease inhibitors (PI) have prompter speculation that these agents have unique metabolic effects. Additionally, some HIV-infected patients have noted increased abdominal girth and buffalo humps that clinicians and patients attribute to the use of Pi's. In preliminary studies, we have observed significant increases in glucose, insulin, TG and total LDL cholesterol in a group of patients following initiation of therapy with a PI, whereas no such changes occurred in patients beginning therapy with lamivudine or maintaining constant regimen that did not include lamivudine or a PI. Because hyperglycemia, hypertriglyceridemia, hypercholesterolemia, and central obesity are associated with increased risk of cardiovascular disease, these effects may impact on the long-term prognosis in patients whose life expectancies are extended due to effective viral suppression. As yet, these metabolic and body composition changes have not been systematically characterized, nor is it known if these changes represent one year syndrome or are unrelated findings. Therefore,, to evaluate the scope of and mechanisms underling these changes in carbohydrate and lipid metabolism and their relationship, if any, to changes in body composition, e propose to perform intensive metabolic ward studies in which we prospectively evaluate changes in glucose and lipid metabolism and body composition in separate cohorts of HIV-infected men and women before and after beginning Pi therapy. These studies are designed to: (1) test the hypothesis that PI's induce insulin resistance (as assessed by oral glucose tolerance test, hyperinsulinemic, euglycemic clamp, stable isotope studies of hepatic glucose production, gluconeogenesis and glycogenesis); 2) test the hypothesis that PI's produce an atherogenic lipid profile (plasma lipids and lipoprotein composition, intravenous fat tolerance test, stable isotope studies of whole body lipolysis, de novo hepatic lipogenesis, and cholesterolgenesis); and (3) to determine whether patients uniformly develop changes in regional fat distribution while on PI therapy and the relationship, if any, or changes in glucose and lipid metabolism to changes in body composition (dual-energy X-ray absorptiometry, computed tomography)> The role of glucoregulatory, adrenal, and gonadal hormones in mediating these effects will also be evaluated.