HerbalEGram: Volume 10, Number 6, June 2013

 Artemisinin, an active component in sweet wormwood (Artemisia annua), is used in countries around the world to treat malaria, a global disease transmitted by parasite-hosting mosquitoes that causes hundreds of thousands of deaths every year.^1,2 The World Health Organization (WHO) has considered artemisinin-based combination therapy (ACT) — which includes an artemisinin derivative along with a partner drug — “the best available treatment” for more than 10 years.²

Artemisinin availability and global supplies, however, are low due to several factors, including the six-to-eight month period required to cultivate sweet wormwood, followed by several more months needed for extraction, processing, and manufacturing.¹ Further, malaria-carrying mosquitoes in Cambodia, Myanmar, Thailand, and Vietnam are becoming more resistant to artemisinin. WHO warns that if this resistance were to spread, “the public health consequences could be dire, as no alternative antimalarial medicines will be available for at least five years.”² Interestingly, several recent scientific developments with sweet wormwood and artemisinin present potentially significant options for addressing both problems of drug resistance and limited medication access.


Whole-Plant Rodent Study

In the December 2012 issue of PLoS ONE, a multi-institutional team of researchers from the University of Massachusetts (UM) at Amherst, UM Medical School, and Worcester Polytechnic Institute in Massachusetts published a study that found advantages of using whole-plant sweet wormwood in rodents over the isolated and extracted artemisinin.³ Looking for a way to address the issue of low artemisinin supplies, the researchers thought that employing the whole plant would decrease the amount of post-harvest processing needed for isolating and extracting artemisinin from the plant and converting it to one of the derivatives used in ACTs. Because the researchers had conducted a previous study that found increased levels of the artemisinin compound in the blood of mice fed whole-plant sweet wormwood (compared with those fed the drug artemisinin), they hypothesized that the whole plant might contribute a range of synergistic activities toward improved artemisinin absorption, as well as action against malaria parasites.

With funding from the University of Massachusetts Medical School and a US National Institutes of Health grant, they investigated whether whole-plant sweet wormwood would be efficacious against malaria parasites in a rodent model.³ First they divided the mice into three groups and gave each group either dried sweet wormwood leaves containing 24 mg/kg artemisinin — considered by the researchers to be a low dose for rodents whose metabolism differs from that of humans (WHO recommends 20mg/kg artemisinin for human malaria treatment), low doses of pure artemisinin drug at 24 mg/kg, or placebo. Mice treated with the whole plant exhibited higher numbers of dead parasites at each post-treatment interval, while “mice treated with [drug artemisinin] did not show significant difference in parasitemia from those administered a placebo at any time point.”

When the researchers increased the doses of the whole-plant and drug artemisinin groups, they found that both were equally effective. In comparing all dosages, they found that the low-dose whole plant was more effective than the other therapies within 24 to 30 hours post-treatment and, at three days after the initial treatment, was equally effective as a high dose of artemisinin.³ After that three-day period, however, the high-dose drug was more effective. Therefore, the researchers concluded that “multiple [whole plant] treatments at the [low dose] would be necessary for a curative effect.”

The researchers suggested that the whole plant exhibited such efficacy due to synergism among particular plant flavonoids that have antimalarial activity and artemisinin-enhancing activity, as well as the lower bioavailability of artemisinic compounds in the drug artemisinin as a result of poor solubility and high metabolic breakdown.

According to Andrea Bosman, MD, of WHO’s Global Malaria Programme, the PLoS ONE study has several limitations, including that it used the malaria parasite Plasmodium chabaudi in its animal model. 

“In pre-clinical studies of malaria medicines, P. berghei is more often selected as it is a deadly parasite in the mouse,” he noted. “P. chabaudi is rarely used as model for testing efficacy of antimalarial drugs. On the differences observed, in the absence of blood level measurements to compare the bioavailability of pure artemisinin and that of the whole plant mixture, and determination of flavonoids content in the mixture, the study provides several hypotheses that may serve to guide further studies.” 

 

Sweet Wormwood Tea

Some communities in malaria-prone areas drink sweet wormwood tea because ACTs are often expensive and/or difficult to obtain. According to a clinical trial published in the June 2012 issue of the Tropical Journal of Pharmaceutical Research, sweet wormwood tea ingested by workers on a flower farm in Uganda was shown to be a successful preventive option.^4,5 In this study, 132 workers who previously had not ingested sweet wormwood were given either the tea (A. annua 250 ml infusion containing 5 g dried leaf powder) or placebo once a week for nine months.⁵ Of the tea group, just 17.9% of participants experienced more than one episode of malaria compared to 40% in the placebo group. In addition to this significant reduction in multiple malaria episodes, the tea group had no major adverse effects other than complaints about the tea’s bitter flavor.

Despite the interesting findings of Ogwang et al., in April 2013, Slate magazine reported that “when Ogwang tried to publish the results in Malaria Journal, a reviewer largely praised the quality of the science but nixed publication out of concern that use of the tea could render ACTs ineffective.”⁴ The anonymous peer reviewer noted that in order to protect against resistance WHO recommends combination therapy of an artemisinin derivative (artemether, artesunate, or dihydroartemisinin), and not whole plants or monotherapies, which consist of a single malaria treatment such as artemisinin without the presence of additional combination drugs.⁶

Indeed, WHO actively encourages local governments of malaria-prone regions to implement and enforce bans against the sale and marketing of such whole-plant products and monotherapies.⁷ WHO’s statement, released the same month as the Ogwang et al. article, stressed its position against “the use A. annua plant material, in any form, including tea, for the treatment or the prevention of malaria.”⁸ According to WHO, whole-plant therapies are discouraged largely because of the following:

- They lack consistent artemisinin content due to chemical variations resulting from differing practices of harvesting, drying, storing, and processing of sweet wormwood leaves;

- Sweet wormwood tea would need to be ingested in amounts of five liters per day for at least seven days in order to ensure adequate artemisinin intake, but the tea’s bitter taste results in most people drinking only one liter and thus ingesting too little artemisinin, which does not completely eliminate the parasite and could increase resistance;  

- Studies investigating one liter of tea per day for seven days found unacceptable rates of malaria reoccurrence.⁸

“In conclusion,” WHO continues, “extensive fundamental and clinical research would be required to demonstrate that non-pharmaceutical forms of A. annua, including tea bag, are safe and effective to treat malaria and that their dissemination would not promote the development of artemisinin-resistant parasites.”⁸

Advocates of the whole-plant therapy, however, have argued that the presence of many non-artemisinin active antimalarial ingredients within A. annua suggest that it is a natural ACT. A recent in vitro study published in the journal Transactions of the Royal Society of Tropical Medicine and Hygiene, for example, found that the tea exhibited antimalarial activity, which the researchers suggested was indicative of the synergistic interactions among the variety of compounds in the tea.⁹

“It has also been suggested that although herbal medicines may not be as perfect as the exact dosages administered in industrially produced formulations, [they] may be better than no treatment,” said Professor Maurice Iwu, president of the Nigeria-based Bioresources Development and Conservation Program (email, May 30, 2013). “Given the seriousness of the disease, local cultivation of high-artemisinin variety and preparation of A. annua [in] combination with other antimalarial herbs could be considered part of a malaria control strategy, especially in remote areas with poor access to health facilities and poor availability of effective industrially manufactured antimalarial drugs.”

Likely to address WHO’s concerns with sweet wormwood tea, the authors of the PLoS ONE study underscored the differences between the product used in their study — whole-plant sweet wormwood leaves — and the tea. They note in the article that these teas “have major shortcomings,” including the large amount required to ingest adequate levels of artemisinin, the tea’s bitter flavor, and the tea production process’s failure to extract key flavonoids that “reportedly synergize with artemisinin.”³

In its position paper (although published prior to the aforementioned PLoS ONE article), WHO does recognize the encouraging findings of two prior studies on non-tea preparations. But, it concludes that “the high recrudescence [recurrence] rate observed in clinical studies suggests that even if these constituents do act synergistically with artemisinin, these interactions are insufficient to eliminate Plasmodium parasites and cure malaria.”⁸ The studies it cites for the unacceptable recrudescence rate and insufficient parasite elimination, however, both investigated sweet wormwood tea, not non-tea whole-plant therapies, such as that which was used in the PLoS ONE study.

Still, WHO told the American Botanical Council that neither of the studies changes its position on whole-plant therapies.

“The PLoS ONE study published in December 2012 does not change the findings of other studies already quoted in WHO position statement…,” said Dr. Bosman (email, May 28, 2013). “The wormwood tea study … was a very small-scale study, with over 35 percent lost to follow-up in both study arms and a significantly higher use of [insecticide-treated nets], which protect from malaria, in the same group that received the wormwood tea once weekly (and had less episodes of malaria…). This study has not altered the WHO position on malaria treatment.” [Editor’s note: the authors of the wormwood tea study wrote that the bed nets had a non-statistically significant effect on outcome and that farmers who drank the tea and went without bed nets still had improvement in malaria episodes.]


Announcement of Semi-Synthetic Artemisinin Production

A significant development contrary to the whole-plant strategy occurred in April of 2013, when France’s Sanofi Pharmaceuticals announced that it would begin large-scale production of semi-synthetic (s-s) artemisinin.¹⁰

According to a press release from Sanofi’s partnering organization OneWorld Health, “Because the existing botanical supply of artemisinin — derived from the sweet wormwood plant — is inconsistent, having multiple sources of high-quality artemisinin will strengthen the artemisinin supply chain, contribute to a more stable price, and ultimately ensure greater availability of treatment to people suffering from malaria.”¹⁰

Sanofi had been working since 2004 on the synthesis of artemisinin with an international team consisting of Jay Keasling, PhD, at the University of California at Berkeley, his company Amyris, Inc., and OneWorld Health, as well as funding from the Bill and Melinda Gates Foundation.¹⁰ Dr. Keasling and his lab engineered a specific yeast strain that produced artemisinic acid. Dr. Keasling then founded Amyris to optimize the technology, and then OneWorld Health helped transition the remaining tasks to Sanofi for licensing, further optimizing (including the conversion of artemisinic acid to pure artemisinin), and up-scaling of production. “Sanofi plans to produce 35 tons of artemisinin in 2013 and, on average, 50 to 60 tons a year by 2014, which corresponds to between 80 and 150 million ACT treatments,” the press release stated.¹⁰

On May 8, 2013, the Prequalification of Medicines Programme (PQP), a program of the United Nations that WHO manages, announced its acceptance of the usage of synthetic or semi-synthetic artemisinin in the manufacture of pharmaceutical ingredients or products.¹¹ Manufacturers that wish to use the new form of artemisinin in their malaria drugs must first submit a variation or amendment in order to notify the regulator of changes to the drug’s dossier details — in this case, the introduction of a new supplier of the key raw material.

“This is required for each API [active pharmaceutical ingredient] manufacturer who wishes to use this material in order that the details of their suppliers remains up-to-date,” said Antony Fake, PhD, API assessment focal point for PQP (email, May 16, 2013). “In addition, as part of their submission they will provide data to confirm that the quality of the API remains unaffected. This validation information is a standard requirement for most changes in manufacture to ensure consistency and is not unique to the introduction of a supplier of semi-synthetic artemisinin.”

Dr. Fake noted that the artemisinin derivatives artemether and artesunate — used in the ACTs — are the same molecules regardless of origin and that “this is, of course, confirmed by the drug substance manufacturer. For this reason there is no change to the efficacy and safety profile.” 

In regards to parasite resistance, he noted, “There is no reason to believe that the semi-synthetic artemisinin will be in any way different to the artemisinin extracted from Artemisia annua dry leaves, in terms of response to P. falciparum resistance.”

In fact, recent WHO documents suggest that more accessible, dependable supplies of ACTs might actually help stem resistance. According to the April 2013 WHO report Emergency Response to Artemisinin Resistance in the Greater Mekong Subregion, “A patient who has the experience of being unable to get treatment at a formal health facility is less likely to return, and may revert to substandard medicines or artemisinin-based monotherapies purchased through informal drug vendors. Stock-outs can thus hinder progress towards artemisinin resistance containment and elimination.”⁷

At the same time, if s-s artemisinin is molecularly equal to the artemisinin currently used in ACTs, one could assume that the semi-synthetic would be no less susceptible to drug-resistant malaria parasites. And, if the level of widespread usage of ACTs increases with the production of the s-s artemisinin, the pace of resistance development might only speed up as the parasites will have increased exposure to the drug.

“The determinants of artemisinin resistance are not fully understood,” said WHO’s Dr. Bosman, “but there is a correlation with the time and extent of exposure to artemisinin monotherapies, as well as with large availability in the private sector and consumption of artemisinin-based substandard products generating sub-therapeutic drug levels.” 

Historically, malaria parasites eventually have developed resistance after long-term exposure to several previously used anti-malarials, such as chloroquine and sulfadoxine pyrimethamine. Perhaps as a result of these past experiences, WHO recommends that the research strategies of the Global Plan for Artemisinin Resistance Containment primarily focus on discovering and developing new non-artemisinin medicines.¹²

—Lindsay Stafford Mader

References

1. Sawyer E. Artemisia annua: a vital partner in the global fight against malaria. Scitable blog. Nature Education. May 2, 2012. Available here. Accessed May 13, 2013.

2. Malaria. Fact Sheet number 94; last reviewed March 2013. World Health Organization website. Available here. Accessed May 13, 2013.

3. Elfawal MA, Towler MJ, Reich NG, Golenbock D, Weathers PJ, et al. Dried whole plant Artemisia annua as an antimalarial therapy. PLoS ONE. 2012;7(12):e52746. doi:10.1371/journal.pone.0052746. Available here. Accessed May 13, 2013.

4. Borrell B. The WHO vs. the tea doctor. Slate. April 4, 2013. Available here. Accessed May 14, 2013.

5. Ogwang P, Ogwal J, Kasasa S, et al. Artemisia annua L. infusion consumed once a week reduces risk of multiple episodes of malaria: a randomised trial in a Ugandan community. Tropical Journal of Pharmaceutical Research. 2012; 11(3): 445-453. Available here. Accessed May 14, 2013.

6. Anon. Reviewer’s report: Artemisia annua L. 'herbal tea' shows prophylactic effect against malaria: a community use study in Uganda. November 3, 2010. Malaria Journal. Available here. Accessed May 16, 2013.

7. Emergency Response to Artemisinin Resistance in the Greater Mekong Subregion: Regional Framework for Action 2013-2015. World Health Organization, Drug Resistance and Containment Unit of the Global Malaria Programme. 2013. Available here. Accessed May 16, 2013.

8. WHO position statement: Effectiveness of Non-Pharmaceutical Forms of Artemisia annua L. against malaria. World Health Organization Global Malaria Programme. June 2012. Available here. Accessed May 14, 2013.

9. De Donno A, Grassi T, Idolo A,  et al.  First-time comparison of the in vitro antimalarial activity of Artemisia annua herbal tea and artemisinin. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2012;106(11):696-700.

10. Sanofi and PATH announce the launch of large-scale production of semisynthetic artemisinin against malaria [press release]. San Francisco, CA: OneWorld Health; April 11, 2013. Available here. Accessed May 14, 2013.

11. Prequalification of Medicines Programme. Acceptance of non-plant-derived-artemisinin offers potential to increase access to malaria treatment. World Health Organization, United Nations. May 8, 2013. Available here. Accessed May 14, 2013. 

12. Global Plan for Artemisinin-Resistance Containment. Drug Resistance and Containment Unit, Global Malaria Programme. World Health Organization. 2011.