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Sweet annie (Artemisia annua)


Sweet annie (Artemisia annua) Image
Synonyms / Common Names / Related Terms
Artemether, Artemisia annua, Artemisia annua essential oil, Artemisia apiacea, artemisia ketone, Artemisia lancea, arteannuin-B, arteether, artemether, artemetin, artemisinic acid, artemisinin, artemotil, artenimol, artesunate, artimesinin, beta-caryophyllene, beta-selinene, camphor, Chinese wormwood, deoxyartemisinin, dihydroartemisinin, dihydroqinghaosu, endoperoxide sesquiterpene lactone artemisinin, friedelan-3 beta-ol, friedelin, germacrene D, oriental wormwood, qing hao (Chinese), qing hao su (Chinese), qinghaosu (Chinese), quercetagetin 6,7,3',4'-tetramethyl ether, quinghao (Chinese), sodium artesunate, stigmasterol, sweet wormwood, thanh hao (Vietnamese), trans-pinocarveol, yin-chen.

Note: This monograph does not include information on (absinthe, Artemisia absinthium) or mugwort (Artemisia vulgaris).

Mechanism of Action

Pharmacology:

  • Constituents: The major active constituent of Artemisia annua, Artemisia apiacea, and Artemisia lancea is artemisinin. Derivatives of this compound include arteether, artemether, artemotil, artenimol, artesunate, and dihydroartemisinin, which, along with artemisin, are currently being used to treat drug-resistant and non-drug resistant malaria.2,3,4,1,5,6,7,8 The aerial parts of Artemisia annua contain 0.01-0.8 % of artemisinin per dry weight.27,9 Other constituents of Artemisia annua include deoxyartemisinin, artemisinic acid, arteannuin-B, stigmasterol, friedelin, friedelan-3 beta-ol, artemetin, and quercetagetin 6,7,3',4'-tetramethyl ether.22,16
  • The essential oil of Artemisia annua aerial parts contains 44% camphor, 16% germacrene D, 11% trans-pinocarveol, 9% beta-selinene, 9% beta-caryophyllene, and 3% artemisia ketone.18
  • Antiangiogenesis effects: In in vivo and in vitro studies, artesunate, a semi-synthetic derivative of artemisinin extracted from Artemisia annua, inhibited angiogenesis.10 In nude mice, artesunate decreased implanted tumor growth and lowered vascular endothelial growth factor expression on tumor cells and KDR/flk-1 expression. The mice showed no toxic effects. Artesunate also dose-dependently inhibited angiogenesis in vitro, and seemed to have a selective inhibitory effect on human umbilical vein endothelial cells.
  • Antimicrobial effects: In vitro, the essential oil of Artemisia annua aerial parts inhibited the growth of Enterococcus hirae and two tested fungi.18
  • Anticancer effects: Artemisinin and quercetagetin 6,7,3',4'-tetramethyl ether, constituents of Artemisia annua, have shown cytotoxic activity for cancer cells.11,16 Two analogs of Artemisia annua constituents have also been found to have anticancer properties in vitro. The artemisinin analog, dihydroartemisinin (DHA), has significantly reduced the number of Molt-4 cells (a human lymphoblastoid leukemia cell line)13,14, but did not significantly affect the number of normal human lymphocytes also in the culture13. When sodium butyrate was added, the combination killed the Molt-4 cells, but did not affect the lymphocytes.13 When artesunate was analyzed for its anti-cancer activity against 55 cell lines of the Developmental Therapeutics Program of the National Cancer Institute, it was most active against leukemia and colon cancer cell lines.12 When compared with standard cytostatic drugs, artesunate's cytotoxicity was comparable. In addition, artesunate induced apoptosis in human umbilical vein endothelial cells in vitro.15
  • Antimalarial effects: According to laboratory tests using NHR spectroscopy, Artemisia annua extracts have antimalarial properties25, which agrees with earlier studies26. In one study in mice infected with Plasmodium berghei, a gelatin capsule of Artemisia annua had a ED50 of 11.9 ± 2.4g (crude drug) for clearance of parasitemia and a therapeutic index of 13.6, which was 3.5 times more than that of artemisinin.23 A combination of Artemisia annua and chloroquine was more effective in fever subsidence and disappearance of malarial symptoms, but the recrudescence rate was still high. This was inhibited by increasing the therapeutic dose or combining with primaquine.
  • Antioxidant activity: According to laboratory tests, the essential oil of Artemisia annua aerial parts has an antioxidant activity equivalent to 18% alpha-tocopherol.18
  • Antiviral activity: In an in vitro study, artemisinin reduced bovine epithelial cell death after the cells were exposed to the flavivirus bovine viral diarrhea virus.17
  • Cardiovascular effects: Based on the toxicities found in a related species (Artemisia composita), Artemisia annua may have potential central nervous system and cardiovascular toxicities.21
  • Immunosuppressive: In in vitro and in vivo studies, a water soluble derivative of artemisinin showed immunosuppressive activity.20
  • Neurologic effects: Based on the toxicities found in a related species (Artemisia composita), Artemisia annua may have potential central nervous system toxicities.21

Pharmacodynamics/Kinetics:

  • In a review, Haynes et al. concluded that artesunate is incompatible with basic quinolines by virtue of proton transfer and has intrinsic chemical instability.22 At pH 1.2, conversion to DHA is rapid, with t1/2 = 26 minutes, and at pH 7.4, t1/2 is about 10 hours. With a pK(a) of 4.6, over 99% of artesunate can be ionized at pH 7.4, and thus uptake by passive diffusion from the intestinal tract is thought to be minimal.
  • In a pharmacokinetic study of 14 healthy male volunteers who ingested 1L of tea prepared from 9g of Artemisia annua leaves, Rath et al. took blood samples and detected the constituent artemisinin by reversed phase high-performance liquid chromatography.19 According to the authors, the mean ± SD maximum plasma concentration of artemisinin was 240 ± 75ng/mL and the mean ± SD area under the plasma concentration-time curve was 336 ± 71ng/mL per hour. Artemisinin was absorbed faster from herbal tea preparations than from oral solid dosage forms, but bioavailability was similar. One liter of an aqueous preparation of 9g of Artemisia annua contained 94.5mg of artemisinin.
  • Chan et al. performed a high-performance liquid chromatography assay for the analysis of artemisinin, the antimalarial drug from Artemisia annua (Asteraceae) in human plasma.28 According to the authors, analysis of plasma samples from eight male volunteers given 10mg/kg of artemisinin orally as an aqueous suspension showed a mean peak plasma concentration (Cmax) of 580.89ng/mL-1 ± 88.64 SD at 2.5 hours ± 0.5 SD after dosing, and the mean area under the plasma concentration-time curve (AUC0-infinity) was 2,227.57ng h/mL-1 ± 677.22 SD. In addition, the elimination rate constant (Ke), elimination half-life (t1/2), and apparent volume of distribution (Vd) were calculated to be 0.2971/h-1 ± 0.0644 SD, 2.42h ± 0.46 SD, and 16.26L/kg-1 ± 3.44 SD, respectively.
  • In another pharmacokinetic study of artemisinin and one of its derivatives, artesunate, Benakis et al. used oral forms of these two compounds in 250mg tablets in two parallel pharmacokinetic studies.24 According to Benakis et al., for artemisinin, the mean pharmacokinetic parameters were maximum drug concentration (Cmax)=0.36mcg/mL; peak time (tmax)=100 minutes; appearance half-life (t1/2 max)=0.62 hour; distribution half-life (t1/2 alpha)=2.61 hour; decline half-life (t1/2 beta)=4.34 hour; and total area under the concentration-time curve (AUC)=1.19mcg.hr/mL. For artesunate, its main metabolite, dihydroartemisinin, was measurable in the plasma. The mean pharmacokinetic parameters for dihydroartemisinin were appearance rate constant (Ka) = 2.11/h; elimination rate constant (Ke)=1.18/h; biotransformation half-life=0.33 hour; elimination half-life=0.65 hour; and AUC = 0.74mcg.hr/mL. Both pharmaceutical forms were well-tolerated and no undesirable side effects were observed in any of the subjects.
  • Qinghaosu (QHS), also known as artemisinin and arteannuin, is a novel type of sesquiterpene with a peroxide linkage isolated from the Chinese herb Artemisia annua L.29 Since its discovery as an antimalarial with low toxicity, hundreds of derivatives have been synthesized; artesunate (ATS), artemether (ATM), and dihydroartemisinin (DHQHS) were found to be more active than QHS itself. A suppository of QHS, a dual-pack dosage form of ATS (artesunic acid to be dissolved in sodium bicarbonate solution just before intravenous injection), and an oil solution of ATM for intramuscular injection had been approved by the Chinese Ministry of Health for clinical use. However, a preparation for oral administration is still not available.
  • According to Zhao et al., when dogs were given artemisinin tablets orally at the dose of 70mg/kg, no drug was detected in the serum, whereas appreciable serum concentration was found by the same method when dogs were given dihydroartemisinin tablets at a dose as low as 10mg/kg.29 When dihydroartemisinin in tablet form was given to human volunteers at doses of 1.1-2.2mg/kg, peak serum levels of 0.13-0.71mcg/mL were obtained in 1.33 hours with MRT of 2.26-2.36 hours. When artemisinin tablets were given at doses as high as 15mg/kg, however, the peak serum level found in 1.5 hour was only 0.09mcg/mL with MRT of 1.33 hour. Therefore, the authors concluded that the bioavailability of artemisinin tablets is only 1.62-10.08% that of dihydroartemisinin.

References

  1. Heide, L. Artemisinin in traditional tea preparations of Artemisia annua. Trans R Soc Trop Med Hyg 2006;100(8):802. 16701762
  2. Hsu, E. The history of qing hao in the Chinese materia medica. Trans R Soc Trop Med Hyg 2006;100(6):505-508. 16566952
  3. Li, Y. and Wu, Y. L. How Chinese scientists discovered qinghaosu (artemisinin) and developed its derivatives? What are the future perspectives? Med Trop (Mars) 1998;58(3 Suppl):9-12. 10212890
  4. Phan, V. T. [Artemisinine and artesunate in the treatment of malaria in Vietnam (1984-1999)]. Bull Soc Pathol Exot 2002;95(2):86-88. 12145966
  5. Lommen, W. J., Schenk, E., Bouwmeester, H. J., and Verstappen, F. W. Trichome dynamics and artemisinin accumulation during development and senescence of Artemisia annua leaves. Planta Med 2006;72(4):336-345. 16557475
  6. Berger, T. G., Dieckmann, D., Efferth, T., Schultz, E. S., Funk, J. O., Baur, A., and Schuler, G. Artesunate in the treatment of metastatic uveal melanoma--first experiences. Oncol Rep 2005;14(6):1599-1603. 16273263
  7. Van der, Meersch H. [Review of the use of artemisinin and its derivatives in the treatment of malaria]. J Pharm Belg 2005;60(1):23-29. 15828489
  8. Bertea, C. M., Freije, J. R., van der, Woude H., Verstappen, F. W., Perk, L., Marquez, V., De Kraker, J. W., Posthumus, M. A., Jansen, B. J., de Groot, A., Franssen, M. C., and Bouwmeester, H. J. Identification of intermediates and enzymes involved in the early steps of artemisinin biosynthesis in Artemisia annua. Planta Med 2005;71(1):40-47. 15678372
  9. Mueller, M. S., Karhagomba, I. B., Hirt, H. M., and Wemakor, E. The potential of Artemisia annua L. as a locally produced remedy for malaria in the tropics: agricultural, chemical and clinical aspects. J Ethnopharmacol 2000;73(3):487-493. 11091003
  10. Chen, H. H., Zhou, H. J., Wu, G. D., and Lou, X. E. Inhibitory effects of artesunate on angiogenesis and on expressions of vascular endothelial growth factor and VEGF receptor KDR/flk-1. Pharmacology 2004;71(1):1-9. 15051917
  11. Efferth, T. Molecular pharmacology and pharmacogenomics of artemisinin and its derivatives in cancer cells. Curr Drug Targets 2006;7(4):407-421. 16611029
  12. Efferth, T., Dunstan, H., Sauerbrey, A., Miyachi, H., and Chitambar, C. R. The anti-malarial artesunate is also active against cancer. Int J Oncol 2001;18(4):767-773. 11251172
  13. Singh, N. P. and Lai, H. C. Synergistic cytotoxicity of artemisinin and sodium butyrate on human cancer cells. Anticancer Res 2005;25(6B):4325-4331. 16309236
  14. Singh, N. P. and Lai, H. C. Artemisinin induces apoptosis in human cancer cells. Anticancer Res 2004;24(4):2277-2280. 15330172
  15. Wu, G. D., Zhou, H. J., and Wu, X. H. Apoptosis of human umbilical vein endothelial cells induced by artesunate. Vascul Pharmacol 2004;41(6):205-212. 15653096
  16. Zheng, G. Q. Cytotoxic terpenoids and flavonoids from Artemisia annua. Planta Med 1994;60(1):54-57. 8134418
  17. Romero, M. R., Serrano, M. A., Vallejo, M., Efferth, T., Alvarez, M., and Marin, J. J. Antiviral effect of artemisinin from Artemisia annua against a model member of the Flaviviridae family, the bovine viral diarrhoea virus (BVDV). Planta Med 2006;72(13):1169-1174. 16902856
  18. Juteau, F., Masotti, V., Bessiere, J. M., Dherbomez, M., and Viano, J. Antibacterial and antioxidant activities of Artemisia annua essential oil. Fitoterapia 2002;73(6):532-535. 12385883
  19. Rath, K., Taxis, K., Walz, G., Gleiter, C. H., Li, S. M., and Heide, L. Pharmacokinetic study of artemisinin after oral intake of a traditional preparation of Artemisia annua L. (annual wormwood). Am J Trop Med Hyg 2004;70(2):128-132. 14993622
  20. Shen, M., Ge, H. L., He, Y. X., Song, Q. L., and Zhang, H. Z. Immunosuppressive action of Qinghaosu. Sci Sin [B] 1984;27(4):398-406. 6379875
  21. Ho, N. K. Traditional Chinese medicine and treatment of neonatal jaundice. Singapore Med J 1996;37(6):645-651. 9104069
  22. Haynes, R. K. From artemisinin to new artemisinin antimalarials: biosynthesis, extraction, old and new derivatives, stereochemistry and medicinal chemistry requirements. Curr Top Med Chem 2006;6(5):509-537. 16719805
  23. Wan, Y. D., Zang, Q. Z., and Wang, J. S. [Studies on the antimalarial action of gelatin capsule of Artemisia annua]. Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi 1992;10(4):290-294. 1303339
  24. Benakis, A., Paris, M., Loutan, L., Plessas, C. T., and Plessas, S. T. Pharmacokinetics of artemisinin and artesunate after oral administration in healthy volunteers. Am J Trop Med Hyg 1997;56(1):17-23. 9063354
  25. Bailey, N. J., Wang, Y., Sampson, J., Davis, W., Whitcombe, I., Hylands, P. J., Croft, S. L., and Holmes, E. Prediction of anti-plasmodial activity of Artemisia annua extracts: application of 1H NMR spectroscopy and chemometrics. J Pharm Biomed Anal 4-1-2004;35(1):117-126. 15030886
  26. Fattorusso, E., Parapini, S., Campagnuolo, C., Basilico, N., Taglialatela-Scafati, O., and Taramelli, D. Activity against Plasmodium falciparum of cycloperoxide compounds obtained from the sponge Plakortis simplex. J Antimicrob Chemother 2002;50(6):883-888. 12461008
  27. Abdin, M. Z., Israr, M., Rehman, R. U., and Jain, S. K. Artemisinin, a novel antimalarial drug: biochemical and molecular approaches for enhanced production. Planta Med 2003;69(4):289-299. 12709893
  28. Chan, K. L., Yuen, K. H., Jinadasa, S., Peh, K. K., and Toh, W. T. A high-performance liquid chromatography analysis of plasma artemisinin using a glassy carbon electrode for reductive electrochemical detection. Planta Med 1997;63(1):66-69. 9063097
  29. Zhao, K. C. and Song, Z. Y. [Pharmacokinetics of dihydroqinghaosu in human volunteers and comparison with qinghaosu]. Yao Xue Xue Bao 1993;28(5):342-346. 8237378




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