Times are changing for sweet Annie, an herb that has been used in traditional Chinese medicine and noted for its compounds that can effectively treat malaria. Sweet Annie (Artemisia annua L., Asteraceae), also called sweet wormwood, is sometimes referred to by its Chinese name qing hao (green herb). Artemisinin, and some of the related compounds derived directly from the herb, are sometimes referred to as quinghaosu (extract of green herb). These compounds, and their synthetic derivatives, have been described in The New York Times as “strikingly effective against malaria.”¹

The antimalarial artemisinin-derived compounds include, but are not limited to, artesunate, artemether, and dihydroartemisinin. Artemisinin, used in the semi-synthesis of related compounds in Artemisinin-based Combination Therapies (ACT), are found mainly in the leaves and flowers of sweet Annie (little artemisinin is found in the stems, and none is found in seeds or roots).²

Drug manufacturers utilize the dried aerial part of sweet Annie, divested of the older stems,³ to create the useful artemisinin compounds. It takes a minimum of six months to cultivate the sweet Annie plants, and depending on the intended product formulation, it can take an additional two to five months of extraction, processing, and manufacturing phases to create the pharmaceutical grade artemisinin compounds.⁴

Artemisinin was first isolated in 1972 by scientists working for the Chinese Military (People’s Liberation Army). The herb qing hao (sweet Annie) has been used in Traditional Chinese Medicine for more than 2000 years to treat fevers. The Pharmacopoeia of the People’s Republic of China states that quing hao (Herba Artemisiae Annuae, its pharmacopeial name in the Pharmacopoeia monograph) is indicated to treat malaria with chills and fever.³ Because of the plant’s traditional use, it has not been a surprise for the herb and medicinal plant research community to learn that, when used in ACT, artemisinin and its synthetic derivatives are finally gaining international acceptance and recognition as an effective alternative in eliminating susceptible and multi-drug resistant Plasmodium falciparum malaria.

The need for an effective treatment for malaria in Africa is great. Malaria infects more than 500 million people and kills more than a million people each year. Ninety percent of malaria deaths occur in Africa, where the disease accounts for one in five of all childhood deaths. In addition, the illness contributes to anemia, which affects growth and development in children, contributes to low birth weight in babies, and causes maternal illness and anemia in pregnant women.⁵

“Malaria, in tandem with HIV/AIDS, stands in the way of social progress and better standards of life at every level, from children’s intellectual and physical development to the growth of national economies,” states Carol Bellamy, Executive Director of UNICEF.⁵

The name malaria (from the Italian words mala and aria ) literally means “bad air,” and derives from a time when people mistakenly believed that the disease was caused by “bad air” in marshy areas.⁶ Incidentally, the name for the disease in French ( paludisme ) and in Spanish ( paludismo ) are derived from the Latin palus , meaning swamp. The term malaria entered the English medical literature in the first half of the nineteenth century.²

Malaria is caused by four species of Plasmodium . The two most common forms are Plasmodium vivax and P. falciparum , the latter being the most deadly form. The illness is transmitted from infected to uninfected humans through the bite of an infected female Anopheles mosquito.⁷

The malaria parasite’s complex life cycle eludes detection and destruction by the body’s immune system. The parasite takes 10-14 days to fully mature in its host’s liver; then it is able to transmit the illness to another host via another mosquito. About 9 to 14 days after an infectious mosquito bite, malaria symptoms appear, including fever, headache, vomiting, and other flu-like symptoms. If malaria is left untreated or the parasites are resistant to the antimalarial drug used, the infection can progress rapidly and become life threatening. Malaria can kill by infecting and destroying hemoglobin in red blood cells, leading to severe anemia, and by clogging the capillaries that carry blood to the brain (cerebral malaria) or other vital organs.⁷

The malaria epidemic is not new. Global campaigns to eradicate the illness have been in place since the 1950s. These early initiatives used anti-malarial drugs to treat the illness and eliminate the parasite in humans and used the highly controversial pesticide DDT against mosquitoes. By 1967, the campaign succeeded in eradicating endemic malaria in all developed countries and parts of tropical Asia and Latin America. However, success was not universal. These campaigns were unable to sustain and achieve these same results using DDT and anti-malarial drugs on a global scale in undeveloped and underdeveloped countries.⁸

During the 1990s, malaria deaths and illnesses escalated in Africa because of increased resistance to conventional malaria drugs like amodiaquine and the less-expensive monotherapies like chloroquine and sulfadoxine-pyrimethamine.⁴

Certain factors have compounded the resistance problem in the population. “Antimalarial drugs were deployed on a large scale, always as monotherapies, introduced in sequence, and were generally poorly managed in that their use was continued despite unacceptably high levels of resistance. In addition, there has been over-reliance on both quinoline compounds…and antifolate drugs…with consequent encouragement of cross-resistance among these compounds.”⁴

As a result, the health organizations realized that they needed a new strategy focused on the disease rather than parasite control. The goal was to make a program that could be adapted to suit local conditions and meet local needs.⁸

The ACT drugs offer new hope because they have a rapid therapeutic effect in reducing the parasite and diminishing symptoms, they are active against the multi-drug resistant strain of malaria, they are thus far well tolerated in patients, and they have the potential to reduce transmission of the illness.⁴

The United Nations’ Roll Back Malaria (RBM) initiative reports another key benefit: “To date, no parasitic resistance has been detected…Furthermore, there is some evidence that use of such combinations can greatly retard development of resistance to the partner drug.”⁴

As a result, world health organizations like the WHO and the United Nations Children’s Fund (UNICEF) have begun to consider using the purified bioactive substances from this herbal remedy as a first-line treatment for malaria in Africa.

This is a significant change in policy. In previous years, health officials were opposed to using ACTs to treat malaria in Africa for the following reasons: (1) due to the potential for the public to misuse the artemisinin derivatives (like some of the previous and now ineffective drugs) in treating severe malaria, (2) because of the potential for the public to create and use non co-formulated combinations (i.e., unapproved combinations) of the drugs, (3) the greater expense of using ACTs instead of the cheaper conventional first-line treatments, and (4) because the side effects and efficacy of ACTs were under-tested on children.^{2, 9}

The health organizations were also concerned with lack of evidence for the ACT drugs’ ability to delay resistance in areas of higher transmission and because of the increased effort and high cost of changing existing policy. Finally, they were hesitant to change because some of the existing conventional medications were still effective in treating the illness for some people, in some areas.^2,9 The bias against ACTs began to change when the efficacy of the front-line treatments began to fade and, consequently, resistance to standard treatments continued to develop.

The current commercial ACT is Coartem^®, a combination of artemether, a derivative of artemisinin and a synthetic substance, lumefantrine. The drug was developed by the pharmaceutical giant Novartis with the Institute for Microbiology and Epidemiology in Beijing,¹⁰ and it is recommended by WHO. Out of 13 African countries that have changed their national policies to require more effective antimalarial treatment, four (South Africa, Tanzania, Zambia and Burundi) have adopted ACTs as first-line treatment.¹¹

The International Federation of Pharmaceutical Manufacturers Association (IFPMA) Web site describes a recent health initiative using Coartem: “The resulting oral, fixed-dose artemisinin based combination therapy (ACT) is the fastest acting anti-malaria medicine—destroying parasites in 48 hours—with highly documented cure rates.”¹⁰

“KwaZulu Natal was the first Department of Health in Africa to agree upon a malaria treatment policy with artemether/lumefantrine as the first-level drug…The result was a dramatic 78% reduction in the total malaria cases by the end of 2001 (41,786 cases in 2000 and 9443 cases in 2001). During this period, the number of malaria deaths decreased by 87%.”¹² The WHO estimates that it will need at least 30,000,000 adult ACT treatment courses in 2004, and 132,000,000 treatment courses by the end of 2005.⁴

A WHO Policy Implication sheet outlines the dosage and recommended treatment of artemether-lumefantrine, the same ACT combination used in Coartem. The artemether-lumefantrine-based combination therapy treatment course consists of tablets containing 20 mg of artemether plus 120 mg of lumefantrine (blenflumetol).¹³

The policy sheet states that, “Artemether-lumefantrine can be used for the treatment of uncomplicated infections with P. falciparum, including strains from multi-drug resistant areas.” The policy goes on to recommend treatment: “In semi-immune patients, the manufacturer recommends the 4-dose regimen, consisting of 1, 2, 3, or 4 tablets taken at 0 h, 8 h, 24 h and 48 hours. The total course for an adult is 16 tablets, which gives a total dose of 320 mg of artemether plus 1920 mg of lumefantrine.”¹³

WHO’s policy sheet offers recommendations for areas with multi-drug resistance, non-immune patients, and children. It recommends that artemether-lumefantrine should not be used to treat malaria in pregnant women because the safety of the ACT chemotherapy is still a concern. It also indicates that the drug combination should not be used for chemoprophylaxis (prevention), and it gives the specifics of the drug disposition, adverse effects, and contraindications.¹³

An agreement between WHO and Novartis stipulates that Coartem will be available at a cost price of $0.90 per child and $2.40 per adult, per treatment course, for use in the public sector in malaria-endemic countries.⁴

References:

1. McNeil DG Jr. Herbal Drug is Embraced in Treating Malaria. The New York Times . May 10, 2004. Available at: www.nytimes.com. Accessed July 16, 2004.

2. Ferreira JFS, Simon JE, Janick J. Artemisia annua: botany, horticulture, pharmacology. Horticultural Reviews. 1997;19:319-371.

3. Guoshi T, Chen C, Fang Q, Jiang H, et al., eds; Cheng S, Feng M, Guo J, trans. Pharmacopoeia of the People’s Republic of China. English Ed. Beijing, China: The People’s Medical Publishing House; 1988:63.

4. The World Health Organization. Roll Back Malaria Infosheet. Facts on ACTs (Artemisinin-based Combination Therapies), An update on recent Progress in Policy and Access to Treatment. Available at: http://www.rbm.who.int/cmc_upload/0/000/015/364/RBMInfosheet_9.htm. Accessed July 20, 2004.

5. UNICEF. Malaria. Available at: http://www.unicef.org/health/index_malaria.html. Accessed July 20, 2004.

6. Harper D. Malaria. Online Etymology Dictionary. Available at: http://www.etymonline.com/index.php?search=malaria&searchmode=none. Accessed September 15, 2004.

7. World Health Organization. Roll Back Malaria Infosheet. What is Malaria? Available at: http://www.rbm.who.int/cmc_upload/0/000/015/372/RBMInfosheet_1.htm. Accessed July 20, 2004.

8. Trigg PI, Kondrachine AV. Commentary: malaria control in the 1990s. Bulletin of the World Health Organization . 1998;76(1):11-16.

9. Olumese P. Antimalarial combination therapy in Africa. Africa Health . September 2001. Available at: http://mosquito.who.int/cmc_upload/0/000/015/270/ah_therapy_ po.htm. Accessed September 17, 2004.

10. The International Federation of Pharmaceuticals Manufactures Associations (IFPMA). Novartis Coartem. Available at: http://www.ifpma.org/Health/malaria/health_coartem_mal.aspx. Accessed July 20, 2004.

11. World Health Organization. Africa Malaria Report 2003. Available at: http://www.rbm.who.int/amd2003/amr2003/amr_toc.htm. Accessed September 24, 2004.

12. World Health Organization. Review of Application for Inclusion of a Drug in the WHO Essential Drug List. Fixed combination of artemether and lumefantrine (Coartem®). Available at: http://www.who.int/medicines/organization/par/edl/coartem.doc. Accessed September 24, 2004.

13. World Health Organization. Part II: 1.3 Artemether-Lumefantrine. The Use of Antimalarial Drugs. Available at: http://mosquito.who.int/cmc_upload/0/000/014/923/am2_1-13.htm. Accessed September 17, 2004.