Malaria, a disease caused by parasites of the Plasmodium genus, infects over 220 million people annually, resulting in over 400,000 deaths. Most of these deaths occur in Africa in children < 5 years of age. Artemisia annua L., an ancient Chinese medicinal herb, is known for its foremost phytochemical constituent, artemisinin (AN). Semisynthetic derivatives of AN form the primary component of artemisinin combination therapies (ACTs), the frontline treatment for malaria worldwide. However, ACTs have several drawbacks including cost and availability. Thus, cheaper, more readily available antimalarials are needed. Recent clinical data suggested dried leaves of A. annua (DLA) administered orally as a tea infusion may be as efficacious as ACTs despite a significantly lower AN dose delivered. In mice, AN plasma concentration was improved when administered as DLA compared to pure AN. I therefore hypothesized that phytochemicals within DLA enhanced the oral bioavailability of AN. To investigate this hypothesis, here I examined the effects of DLA on the underlying mechanisms that govern oral bioavailability. Using an in vitro human digestion model, I showed that AN solubility was greater when delivered as DLA, largely due to essential oil in the plant. Furthermore, AN intestinal permeability was enhanced in a Caco-2 cell model of the intestinal epithelium. Extracts, teas, and phytochemicals produced by Artemisia also inhibited the activity of CYP2B6 and CYP3A4, the enzymes responsible for first-pass AN metabolism in the liver. Additionally, AN tissue distribution was improved when delivered as DLA and AN accumulation in tissues was higher in female vs. male rats. Finally, I showed that DLA was a more efficacious anti-inflammatory than pure AN in rats, potentially due to enhanced AN bioavailability. Taken together, these results shed light on the mechanisms behind enhanced oral bioavailability afforded by DLA and demonstrate the potential for DLA to be used as a therapeutic for malaria and other diseases.
| Identifer | oai:union.ndltd.org:wpi.edu/oai:digitalcommons.wpi.edu:etd-dissertations-1611 |
| Date | 05 May 2020 |
| Creators | Desrosiers, Matthew R. |
| Contributors | Pamela Weathers, Advisor, Scarlet Shell, Committee Member, Jose Arguello, Committee Member, Jagan Srinivasan, Committee Member |
| Publisher | Digital WPI |
| Source Sets | Worcester Polytechnic Institute |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Doctoral Dissertations (All Dissertations, All Years) |
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