METABOLIC EFFECTS OF PROTEASE INHIBITORS IN HIV DISEASE

描述：(改编自申请人的摘要)。有报道称， HIV感染者的血糖、甘油三酯和胆固醇水平 蛋白水解酶抑制剂(PI)有更强的推测性，认为这些试剂具有 独特的新陈代谢作用。此外，一些感染艾滋病毒的患者 注意到腹围和水牛驼峰的增加，临床医生和 患者归因于PI的使用。在初步研究中，我们有 观察到血糖、胰岛素、甘油三酯和总低密度脂蛋白显著增加 一组患者在开始治疗后的胆固醇水平 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， 高胆固醇血症和中心性肥胖与 心血管疾病的风险，这些影响可能会对长期 因高血压而延长预期寿命患者的预后 有效的病毒抑制。到目前为止，这些代谢和身体成分 变化还没有得到系统的描述，也不知道是否 这些变化代表了一年综合症，或者是无关的发现。 因此，为了评估这些措施的范围和机制 糖脂代谢的变化及其相互关系 任何，对于身体成分的变化，我们建议进行强化训练 代谢病房研究，在这些研究中，我们前瞻性地评估 糖脂代谢和身体成分的不同队列 HIV感染的男性和女性开始PI治疗前后。这些 研究的目的是：(1)检验派诱导胰岛素的假设 抵抗力(以口服葡萄糖耐量试验、高胰岛素血症、 正常血糖钳夹，肝脏葡萄糖产生的稳定同位素研究， 糖异生和糖异生)；2)检验派的假设 产生致动脉粥样硬化的血脂谱(血浆脂类和脂蛋白 组成、静脉脂肪耐量试验、稳定同位素研究 全身脂肪分解，新生肝脏脂肪生成，以及 胆固醇生成)；以及(3)确定患者是否一致 PI治疗期间局部脂肪分布的变化 与糖脂代谢的关系(如果有)或变化 身体成分的变化(计算的双能X射线吸收测量法 糖调节激素、肾上腺激素和性腺激素在 调解这些影响也将得到评估。

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.