Safety, Efficacy, and Mechanisms in American Ginseng in HIV-Related Fatigue

描述(申请人提供)：本申请的目的是调查美国人参(AG)治疗艾滋病毒相关性疲劳的安全性、有效性和作用机制。艾滋病毒相关性疲劳是艾滋病毒/艾滋病患者的一种普遍症状，与功能和心理障碍以及较差的生活质量有关。HIV相关疲劳的机制还不是很清楚，然而，已经提出了增加促炎细胞因子浓度的作用。几乎没有可用的药物干预措施来减轻艾滋病毒感染患者的疲劳，而且大多数的临床试验都是有限的。癌症患者的初步数据表明，AG可以改善疲劳。因此，AG对应对艾滋病毒相关疲劳的患者也有治疗作用。AG已经被艾滋病毒/艾滋病患者广泛使用，无论是单独使用还是与抗逆转录病毒(ARV)药物联合使用。然而，尽管AG被广泛使用，但其在治疗艾滋病毒相关疲劳方面的安全性和有效性尚未得到正式评估。特别是，AG和ARV药物之间的草药相互作用还没有得到充分的研究。草药与ARV的相互作用主要涉及ARV代谢细胞色素P450(CYP450)同工酶的调节，进而改变药物的疗效和/或毒性。初步数据表明，AG不会显著影响大多数ARV药物的主要代谢途径--细胞色素P3A4的活性。然而，另一种重要的同工酶--CYP2B6的数据却很缺乏。以下特定目标将检验这样一个假设，即标准化的AG配方可以改善HIV相关的疲劳，而不会引起显著的药物-药物相互作用：目标1.确定健康志愿者在同时使用AG治疗14天之前和之后的CYP2B6底物efavirenz的稳态血浆浓度。目的2.在为期6周的随机、安慰剂对照、剂量递增(1000、2000和3000 mg/天)临床试验中，确定AG对HIV感染患者疲劳的影响。促炎症细胞因子也将被量化，以阐明HIV相关疲劳的机制以及AG对这些标志物的影响。这项申请将允许申请者严格研究一种治疗艾滋病毒相关疲劳的新方法，并扩大目前关于草药与抗逆转录病毒相互作用的知识。 与公共卫生相关：疲倦是艾滋病毒感染的一种衰弱症状。HIV感染患者疲劳的病因尚不清楚，但可能的潜在机制可能包括全身炎症的变化。我们的目标是确定西洋参治疗HIV感染疲劳的安全性、有效性和作用机制。

DESCRIPTION (provided by applicant): The goal of this application is to investigate the safety, efficacy, and mechanisms of action of American ginseng (AG) in the treatment of HIV-related fatigue, a widespread symptom in patients with HIV/AIDS that is associated with functional and psychological morbidity and poor quality of life. The mechanisms of HIV-related fatigue are not well understood; however, a role for increased concentrations of pro-inflammatory cytokines has been proposed. Few pharmacologic interventions are available to decrease fatigue in HIV-infected patients, and clinical trials of most have been limited. Preliminary data in cancer patients suggest that AG can improve fatigue. Thus, AG could also have therapeutic benefits for patients coping with HIV-related fatigue. AG is already widely used by patients with HIV/AIDS, alone or in combination with antiretroviral (ARV) drugs. However, despite its widespread use, the safety and efficacy of AG in treating HIV-related fatigue have not been formally evaluated. In particular, the herb-drug interactions between AG and ARV drugs have not been fully investigated. Herb-ARV interactions primarily involve the modulation of ARV-metabolizing cytochrome P450 (CYP450) isoenzymes, which in turn can alter drug efficacy and/or toxicity. Preliminary data indicate that AG does not significantly affect CYP3A4 activity, the major metabolic pathway for most ARV drugs. However, data are lacking for CYP2B6, another important isoenzyme. The following specific aims will test the hypothesis that a standardized AG formulation can improve HIV-related fatigue without causing significant herb-drug interactions: Aim 1. To determine the steady-state plasma concentrations of the CYP2B6 substrate, efavirenz, in healthy volunteers, before and after 14 days of concurrent treatment with AG. Aim 2. To determine the impact of AG on fatigue in HIV-infected patients in a randomized, placebo-controlled, dose-escalating (1000, 2000, and 3000 mg/day) clinical trial over 6 weeks. Pro-inflammatory cytokines will also be quantified in order to elucidate the mechanism of HIV-related fatigue and the effects of AG on these markers. This application will allow the applicants to rigorously investigate a novel treatment for HIV-related fatigue and expand the current knowledge of herbal-ARV interactions. PUBLIC HEALTH RELEVANCE: Fatigue is a debilitating symptom in HIV-infection. The etiology of fatigue in HIV-infected patients is unknown, but possible underlying mechanisms may include changes in systemic inflammation. Our goal is to determine the safety, efficacy, and mechanisms of action of American ginseng for treatment of fatigue in HIV infection.