Artemisinin bioavailability via an orally consumed dry leaf herbal therapeutic.

青蒿素通过口服干叶草药治疗的生物利用度。

• 批准号: 8689557
• 负责人: PAMELA J WEATHERS
• 金额: $ 42.02万
• 依托单位: WORCESTER POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8689557
• 关键词: Affect; American; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apical; Artemisia annua; Artemisinins; Bioavailable; Biological; Biological Availability; Blood Circulation; Chemicals; Combined Modality Therapy; Consumption; Development; Digestion; Disease; Drug resistance; Falciparum Malaria; Flavonoids; Freezing; Goals; Hand; Healed; Health; Human; In Vitro; Incidence; Individual; Intestines; Lactones; Malaria; Marketing; Measures; Medicinal Herbs; Modeling; Mus; Parasitemia; Parasites; Permeability; Pharmaceutical Preparations; Plant Leaves; Plants; Plasmodium falciparum; Play; Reporting; Resistance; Role; Sampling; Serum; Sesquiterpenes; Side; System; Tablets; Tea; Terpenes; Testing; Therapeutic; Time; artemisinine; comparative; feeding; healing; improved; interest; mutant; prevent; prophylactic; public health relevance; research study; response; small molecule; synergism

DESCRIPTION (provided by applicant): Artemisinin (AN), produced by the plant Artemisia annua L. and delivered as ACT (Artemisinin Combination Therapy), is a proven sesquiterpene lactone therapeutic for treating malaria and shows promise against many other diseases. This important medicinal herb is also becoming of interest to the N. American market, particularly to promote general health and healing via its anti-inflammatory effects. Recently we reported that whole plant A. annua (pACT) is at least fivefold more effective against parasitemia, >40-fold more bioavailable, and much more resilient to development of drug resistance than pure AN. Together these results suggest the native chemical complexity of pACT is facilitating these responses. Some endogenous small molecules produced by the plant have shown antiplasmodial activity; some also show therapeutic synergism with AN vs. falciparum malaria. However, little is known about the effect of these assistive compounds (ACs), mainly flavonoids and terpenes, on bioavailability of AN. Their passage through the intestinal wall into the serum is also not clear. Our fundamental studies will help explain how the plant matrix and its endogenous small molecules affect bioavailability of AN, important to improving overall understanding of pACT efficacy. Aim 1 The target ACs, verified to be present in the A. annua cultivar (SAM) used in pACT, may enhance bioavailability of AN as observed in our animal studies. To determine if the ACs enhance transport through the intestinal wall, we will use the in vitro digestion model, Caco-2, with pure AN + combinations of the pure test ACs to measure AN and AC permeability. This will tell us how the pure ACs affect AN intestinal passage and indicate if any of the ACs also pass through the intestinal wall, but absent the background plant matrix. Aim 2 To determine how the plant matrix of pACT affects bioavailability of AN, we will measure the Caco-2 permeability of AN from ex vitro intestinal digestion of the pACT plant matrix produced from SAM (contains ACs). We will also measure the level of passaged ACs. This tells us how much AN and ACs move from the apical to basolateral side of the Caco-2 systems and becomes our comparative control against which results of Aim 3 will be measured. Aim 3 Using intestinal digestate of the GLS plant matrix we will systematically add AN along with individual ACs known to be absent (or nearly so) in GLS, but present in SAM (the pACT plant), to determine which is effective in improving the passage of AN. This will tell us which of the ACs is effective in assisting the passage of AN, but with a null plant matrix. Aim 4 Using serum already on hand from pACT-fed mice, we will also extract and measure ACs for their presence in the bloodstream. We already have on hand frozen serum extracts from our recent PK experiment (see Sec. 3.3.3). While we have now measured AN in those extracts, we have waited until we have accumulated relavant AC standards to quantify their levels in these serum samples. This will tell us if any ACs actually appears in the serum.

描述（由申请人提供）：青蒿素 (AN) 由植物黄花蒿 (Artemisia annua L.) 产生，并以 ACT（青蒿素联合疗法）形式提供，是一种经过验证的倍半萜内酯疗法，可用于治疗疟疾，并显示出对抗许多其他疾病的前景。这种重要的药草也引起了北美市场的兴趣，特别是通过其抗炎作用促进整体健康和愈合。最近我们报道，与纯 AN 相比，全株青蒿 (pACT) 对抗寄生虫血症的效果至少高出五倍，生物利用度高出 40 倍以上，并且对耐药性发展的抵抗力更强。这些结果共同表明 pACT 的天然化学复杂性正在促进这些反应。植物产生的一些内源性小分子具有抗疟原虫活性；有些还表现出与 AN 相对于恶性疟疾的治疗协同作用。然而，人们对这些辅助化合物（AC）（主要是类黄酮和萜烯）对 AN 生物利用度的影响知之甚少。它们通过肠壁进入血清的通道也不清楚。我们的基础研究将有助于解释植物基质及其内源性小分子如何影响 AN 的生物利用度，这对于提高对 pACT 功效的整体了解非常重要。目标 1 经证实，pACT 中使用的青蒿品种 (SAM) 中存在目标 AC，如我们的动物研究中所观察到的，可能会增强 AN 的生物利用度。为了确定 AC 是否增强通过肠壁的转运，我们将使用体外消化模型 Caco-2，使用纯 AN + 纯测试 AC 的组合来测量 AN 和 AC 渗透性。这将告诉我们纯 AC 如何影响 AN 肠道，并表明是否有任何 AC 也穿过肠壁，但不存在背景植物基质。目标 2 为了确定 pACT 植物基质如何影响 AN 的生物利用度，我们将通过对 SAM（包含 AC）产生的 pACT 植物基质进行体外肠道消化来测量 AN 的 Caco-2 渗透性。我们还将测量传代的 AC 的水平。这告诉我们有多少 AN 和 AC 从 Caco-2 系统的顶端移动到基底外侧，并成为我们衡量 Aim 3 结果的比较控制。目标 3 使用 GLS 植物基质的肠道消化物，我们将系统地添加 AN 以及已知在 GLS 中不存在（或几乎不存在）但存在于 SAM（pACT 植物）中的单个 AC，以确定哪一种可有效改善传代AN 的。这将告诉我们哪种 AC 可有效协助 AN 通过，但植物基质为零。目标 4 使用 pACT 喂养小鼠现有的血清，我们还将提取并测量 AC 在血液中的存在情况。我们手头上已经有最近 PK 实验中的冷冻血清提取物（参见第 3.3.3 节）。虽然我们现在已经测量了这些提取物中的 AN，但我们一直等到积累了相关的 AC 标准来量化这些血清样本中的 AN 水平。这将告诉我们血清中是否确实出现了 AC。