AMERICAN GINSENG (PANAX QUINQUEFOLIUS) IN INDIVAVIR-INDUCED INSULIN RESISTANCE

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。除化疗外，高效抗逆转录病毒治疗（HAART）的伴随治疗对于成功治疗艾滋病相关恶性肿瘤如卡波西肉瘤（KS）和淋巴瘤至关重要（Bashoff，2000和Hengge，2002）。HAART治疗不仅对已知可引发KS的HIV有直接作用，而且似乎对KS相关疱疹病毒有抗病毒作用（Bashoff，2000和Hengge，2002）。 然而，HAART具有很大的药物相互作用潜力，在某些情况下可能会影响其有效性并危及艾滋病相关恶性肿瘤的治疗。HIV蛋白酶抑制剂通过肝细胞色素P450 3A 4（CYP 3A 4）酶代谢，这是许多常用药物和一些补充和替代药物（CAM）共有的代谢途径，使得这类抗逆转录病毒药物对药物相互作用高度敏感（Flexner，2000）。例如，圣约翰草和大蒜分别降低了HIV蛋白酶抑制剂茚地那韦和沙奎那韦的浓度（Piscitelli，2000）。茚地那韦和沙奎那韦浓度降低30%或更多与治疗失败风险增加相关（Flexner，2000）。由于CAM在HIV和AIDS患者中非常流行，并且AIDS相关恶性肿瘤患者可能正在使用其中一些药物，因此重要的是要确定可能干扰HIV蛋白酶抑制剂代谢并因此损害AIDS相关恶性肿瘤治疗的不必要的药物-草药相互作用。 HIV蛋白酶抑制剂与多种代谢紊乱相关，包括外周消瘦、中枢性肥胖、血脂异常和血糖异常。这些异常的中心特征是胰岛素抵抗，这可能增加心血管疾病和糖尿病的风险。 西洋参（Panax quinquefolius）被发现可以改善II型糖尿病患者和非II型糖尿病患者的葡萄糖耐量（Vuksan，2000）。最近，HIV蛋白酶抑制剂茚地那韦（Crixivan）被证明可诱导健康志愿者的葡萄糖耐受不良（Noor，2002）。因此，西洋参可能是潜在的治疗艾滋病毒/艾滋病患者应对葡萄糖耐受不良的好处。然而，西洋参是否干扰茚地那韦的代谢尚不清楚。我们的目标是研究西洋参-茚地那韦药代动力学药物相互作用，并评估西洋参作为茚地那韦诱导的胰岛素抵抗的治疗。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In addition to chemotherapy, concomitant treatment with highly active antiretroviral therapy (HAART) is essential for the successful treatment of AIDS-related malignancies such as Kaposi's sarcoma (KS) and lymphoma (Bashoff, 2000 and Hengge, 2002). Treatment with HAART not only has a direct action on HIV, known to trigger KS, but also seems to have an antiviral effect on the KS-associated herpes virus (Bashoff, 2000 and Hengge, 2002). However, HAART has a large potential for drug interactions that in some cases could affect its effectiveness and jeopardize the treatment of AIDS-related malignancies. HIV protease inhibitors, are metabolized by the hepatic cytochrome P450 3A4 (CYP3A4) enzyme, a metabolic pathway shared by many commonly used drugs and some complementary and alternative medicine (CAM) agents, making this class of antiretrovirals highly susceptible to drug interactions (Flexner, 2000). For instance, both St. John's wort and garlic, lowered concentrations of the HIV protease inhibitors indinavir and saquinavir, respectively (Piscitelli, 2000). Reducing concentrations of indinavir and saquinavir by 30% or more is associated with an increased risk of treatment failure (Flexner, 2000). Because CAM is very popular among patients with HIV and AIDS, and patients with AIDS-related malignancies could be using some of these agents, it is important to identify unwanted drug-herbal interactions that could interfere with the metabolism of HIV protease inhibitors and consequently compromise the treatment of AIDS-related malignancies. HIV protease inhibitors have been associated with multiple metabolic derangements including peripheral wasting, central adiposity, dyslipedemia, and glucose abnormalities. The central feature of these abnormalities is insulin resistance, which may increase the risk of cardiovascular disease and diabetes mellitus. American ginseng (Panax quinquefolius) was found to improve glucose tolerance in subjects with and without type II diabetes (Vuksan, 2000). Recently, the HIV protease inhibitor indinavir (Crixivan) was shown to induce glucose intolerance in healthy volunteers (Noor, 2002). Thus, American ginseng could be of potential therapeutic benefit for patients with HIV/AIDS coping with glucose intolerance. However, it is unknown whether American ginseng interferes with the metabolism of indinavir. The goal of our proposal is to study American ginseng-indinavir pharmacokinetic drug interaction and to evaluate American ginseng as a treatment for indinavir-induced insulin resistance.