A Bioavailability Solution for the Traditional Chinese Botanical Artemisia Annua

 Artemisia annua, also known as sweet wormwood, or Qinghao, has a long history of use in traditional Chinese medicine primarily as a febrifuge, or an agent to reduce fever. As fever is a symptom of the immune response to infection, the mechanism by which this herb improved upon a fever was likely by reducing the level of infectious microbes and balancing the associated immune response. The primary active moiety artemisinin, a sesquiterpene endoperoxide lactone, is known as Qinghaosu in Chinese medical traditions.1 The plants of the Artemisia genus usually are aromatic with a bitter signature, and thus impact the bitter taste receptors and digestion similarly to other digestive bitters like gentianalutea.2

 

Mechanism of Action. One of the mechanisms by which artemisinin may impact the body is through the production of carbon-centered free radicals via an iron heme-mediated or mitochondrial-activated degradation of endoperoxidase bridges.3,4 Artemisinin is activated in environments with high iron concentration, releasing reactive oxygen species (ROS).5 The generated free radicals have the potential to trigger apoptosis and arrest cell growth, alter enzyme action, and inhibit angiogenesis – actions which may be beneficial in settings of uncontrolled cellular growth and division.

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Sesquiterpene lactones derived from Artemisia annua have been shown to increase prostaglandin levels in the gastric mucosa, and thus it may be protective against gastric ulceration.6 Artemisinin has been shown to inhibit the secretion of tumor necrosis factor (TNF)-α, interleukin- (IL-) 1β, and IL-6 in a dose-dependent manner, as well as LPS-activated production of prostaglandin E2.7,8 Artemisinin may have an immunomodulatory effect in settings of contact and delayed hypersensitivity, suppressing the hypersensitivity response and inducing T regulatory cells.9,10

Broad Antimicrobial Effects. Artemisia annua has a long history of use in parasitic infections such as Plasmodium falciparumLeishmaniaBabesia, and Schistosoma, as well as against wide range of bacteria, fungi, and viruses which cause infection.11,12,13,14 Extracts from Artemisia annua have been shown to have antibacterial action against Campylobacter jejuni and Clostridium perfringens, two bacterium which are common causes of foodborne enteritis.15,16 Artemisinin also has been shown to have strong activity againstHelicobacter pylori.17 Viral action has been demonstrated against cytomegalovirus, herpes simplex virus type 1, Epstein-Barr virus, and hepatitis B and C virus.18

A Bioavailability Dilemma and Solution. Because of the low solubility of artemisinin in both oil and water, the bioavailability of synthetic artemisinin derivatives such as dihydroartemisinin, artemether, arteether, and artesunate or alternate dosing strategies such as liposomes have been investigated.19 First-pass hepatic metabolism of artemisinin and its semisynthetic derivatives artesunate and artemether limit oral bioavailability to 30%. Longer half-lives are achievable with intramuscular and rectal dosing due to the high level of first-pass metabolism with traditional oral dosing.

Screen Shot 2017 12 11 at 1.55.46 PMBecause liposomes are delivered to circulation via the lymphatics, first-pass hepatic metabolism of the substances they contain is avoided.20 As such, liposomal delivery systems are a potential solution for many substances which have limited bioavailability due to a high extent of first-pass liver metabolism. Liposomes also often prolong bioavailability, reducing clearance by the mononuclear phagocytes of the immune system.21,22 For these reasons, they have been investigated for the delivery of artemisinin.

Liposomal artemisinin formulations have been shown to lead to more stable artemisinin plasma concentrations, suggesting they have a continuous release and thereby prolonged systemic effect.23 More immediate effects have also been seen with liposomal dosing than with conventional artemisinin, which took up to 7 days to achieve the desired therapeutic result. In another study, liposomal artemisinin, with a mean diameter of 130 – 140 nm, was shown to stay in circulation significantly longer, with the area under the curve increasing by a factor of six compared with free artemisinin.24 Free artemisinin was hardly detectible after 1 hour of administration, while the liposomal artemisinin was detected for up to 3 hours, and even up to 24 hours when delivered as a pegylated liposome, another technique often used to improve bioavailability.


1 Bilia AR, Santomauro F, Sacco C, et al. Essential Oil of Artemisia annua L.: An Extraordinary Component with Numerous Antimicrobial Properties. Evid Based Complement Alternat Med. 2014;2014:159819. View Full Paper

2 Brockhoff A, Behrens M, Massarotti A, Appendino G, Meyerhof W. Broad tuning of the human bitter taste receptor hTAS2R46 to various sesquiterpene lactones, clerodane and labdane diterpenoids, strychnine, and denatonium. J Agric Food Chem. 2007 Jul 25;55(15):6236-43. View Abstract

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7 Wang Y, Huang ZQ, Wang CQ, et al. Artemisinin inhibits extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase-9 expression via a protein kinase Cδ/p38/extracellular signal-regulated kinase pathway in phorbol myristate acetate-induced THP-1 macrophages. Clin Exp Pharmacol Physiol. 2011 Jan;38(1):11-8. View Abstract

8 Zhu XX, Yang L, Li YJ, et al. Effects of sesquiterpene, flavonoid and coumarin types of compounds from Artemisia annua L. on production of mediators of angiogenesis. Pharmacol Rep. 2013;65(2):410-20. View Abstract

9 Li T, Chen H, Wei N, et al. Anti-inflammatory and immunomodulatory mechanisms of artemisinin on contact hypersensitivity. Int Immunopharmacol. 2012 Jan;12(1):144-50.View Abstract

10 Noori S, Naderi GA, Hassan ZM, et al. Immunosuppressive activity of a molecule isolated from Artemisia annua on DTH responses compared with cyclosporin A. Int Immunopharmacol. 2004 Oct;4(10-11):1301-6. View Abstract

11 Klayman DL. Qinghaosu (artemisinin): an antimalarial drug from China. Science. 1985 May 31;228(4703):1049-55. View Abstract

12 Tariq A, et al. Ethnomedicines and anti-parasitic activities of Pakistani medicinal plants against Plasmodia and Leishmania parasites. Ann Clin Microbiol Antimicrob. 2016 Sep 20;15(1):52. View Full Paper

13 Goo YK, et al. Artesunate, a potential drug for treatment of Babesia infection. Parasitol Int. 2010 Sep;59(3):481-6. View Abstract

14 Xiao SH. Development of antischistosomal drugs in China, with particular consideration to praziquantel and the artemisinins. Acta Trop. 2005 Nov-Dec;96(2-3):153-67. View Abstract

15 Militaru D, et al. In vitro evaluation of the potential antibacterial effect of artemisinin on Campylobacter jejuni. Rom Biotech Let. 2015 Mar 1;20(2):10221-7. View Full Paper

16 Engberg RM, et al. The effect of Artemisia annua on broiler performance, on intestinal microbiota and on the course of a Clostridium perfringens infection applying a necrotic enteritis disease model. Avian Pathology. 2012 Aug 1;41(4):369-76. View Abstract

17 Goswami S, Bhakuni RS, Chinniah A, et al. Anti-Helicobacter pylori potential of artemisinin and its derivatives. Antimicrob Agents Chemother. 2012 Sep;56(9):4594-607.View Full Paper

18 Efferth T, et al. The antiviral activities of artemisinin and artesunate. Clin Infect Dis. 2008 Sep 15;47(6):804-11. View Abstract

19 Medhi B, Patyar S, Rao RS, et al. Pharmacokinetic and toxicological profile of artemisinin compounds: an update. Pharmacology. 2009;84(6):323-32. View Full Paper

20 Ahn H, Park JH. Liposomal delivery systems for intestinal lymphatic drug transport. Biomater Res. 2016 Nov 23;20:36. View Full Paper

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22 Allen TM, Cullis PR. Liposomal drug delivery systems: from concept to clinical applications. Adv Drug Deliv Rev. 2013 Jan;65(1):36-48. View Abstract

23 Isacchi B, Bergonzi MC, Grazioso M, et al. Artemisinin and artemisinin plus curcumin liposomal formulations: enhanced antimalarial efficacy against Plasmodium berghei-infected mice. Eur J Pharm Biopharm. 2012 Apr;80(3):528-34. View Abstract

24 Isacchi B, Arrigucci S, la Marca G, et al. Conventional and long-circulating liposomes of artemisinin: preparation, characterization, and pharmacokinetic profile in mice. J Liposome Res. 2011 Sep;21(3):237-44. View Abstract