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

描述（由申请人提供）：本申请的目的是研究西洋参（AG）治疗HIV相关疲劳的安全性、有效性和作用机制，HIV相关疲劳是HIV/AIDS患者的一种普遍症状，与功能和心理疾病以及生活质量差相关。HIV相关疲劳的机制还不清楚;然而，已经提出了促炎细胞因子浓度增加的作用。很少有药物干预措施可用于减少HIV感染患者的疲劳，大多数的临床试验也很有限。癌症患者的初步数据表明，AG可以改善疲劳。因此，AG也可能对应对HIV相关疲劳的患者有治疗益处。AG已经被艾滋病毒/艾滋病患者广泛使用，单独使用或与抗逆转录病毒（ARV）药物联合使用。然而，尽管其广泛使用，AG治疗HIV相关疲劳的安全性和有效性尚未得到正式评估。特别是，AG和ARV药物之间的草药药物相互作用尚未得到充分研究。中草药与抗逆转录病毒药物的相互作用主要涉及抗逆转录病毒药物代谢细胞色素P450（CYP 450）同工酶的调节，这反过来又可以改变药物的疗效和/或毒性。初步数据表明，AG不会显著影响CYP 3A 4活性，这是大多数ARV药物的主要代谢途径。然而，缺乏另一种重要同工酶CYP 2B 6的数据。以下具体目标将检验标准化AG制剂可以改善HIV相关疲劳而不引起显著的草药-药物相互作用的假设：测定健康志愿者接受AG联合治疗14天前后CYP 2B 6底物依法韦仑的稳态血药浓度。目标2.在一项为期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。还将定量促炎细胞因子，以阐明HIV相关疲劳的机制和AG对这些标志物的影响。这项申请将使申请人能够严格研究一种治疗艾滋病毒相关疲劳的新方法，并扩大目前对草药-抗逆转录病毒相互作用的了解。 公共卫生相关性：疲劳是艾滋病毒感染者的一种衰弱症状。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.