Whole-plant Artemisia May Curtail Malaria Drug Resistance

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Artemisia Malaria Red Blood Cells

Artemisia superimposed on a slide of malaria infected red blood cells. A University of Massachusetts research team reports a promising new, low-cost combined therapy for treating the most deadly form of malaria that offers a much higher chance of outwitting the parasite than current modes. (Image courtesy of University of Massachusetts Amherst.)

Malaria affects millions of people in the developing world each year, and fighting the disease can be difficult, because the  mosquito-borne parasite Plasmodium falciparum, which causes the deadliest form of malaria, has developed resistance to every anti-malaria drug.

Molecular parasitologist Stephen Rich at the University of Massachusetts Amherst is leading a research team that has found a promising new low-cost combined therapy with a much higher chance of outwitting P. falciparum than current modes. He and plant biochemist Pamela Weathers at the Worcester Polytechnic Institute (WPI), with research physician Doug Golenbock at the UMass Medical School, also in Worcester, have designed an approach for treating malaria based on a new use of Artemisia annua, a plant employed for thousands of years in Asia to treat fever.

“The emergence of resistant parasites has repeatedly curtailed the lifespan of each drug that is developed and deployed,” says UMass Amherst graduate student and lead author Mostafa Elfawal. Rich, an expert in the malaria parasite and how it evolves, adds, “We no sooner get the upper hand than the parasite mutates to become drug resistant again. This cycle of resistance to anti-malarial drugs is one of the great health problems facing the world today. We’re hoping that our approach may provide an inexpensive, locally grown and processed option for fighting malaria in the developing world.”

Currently the most effective malaria treatment uses purified extracts from the Artemisia plant as part of an Artemisinin Combined Therapy (ACT) regime with other drugs such as doxycycline and/or chloroquine, a prescription far too costly for wide use in the developing world. Also, because Artemisia yields low levels of pure artemisinin, there is a persistent worldwide shortage, they add.

The teams’s thesis, first proposed by Weathers of WPI, is that locally grown and dried leaves of the whole plant, rich in hundreds of phytochemicals not contained in the purified drug, might be effective against disease at the same time limiting post-production steps, perhaps substantially reducing treatment cost. She says, “Whole-plant Artemisia has hundreds of compounds, some of them not even known yet. These may outsmart the parasites by delivering a more complex drug than the purified form.”

Rich adds, “The plant may be its own complex combination therapy. Because of the combination of parasite-killing substances normally present in the plant (artemisinin and flavonoids), a synergism among these constituent compounds might render whole plant consumption as a form of artemisinin-based combination therapy, or what we’re calling a ‘pACT,’ for plant Artemisinin Combination Therapy.”

Rich’s group conducted experiments in rodents to explore whether feeding them the whole plant was effective. They found that animals treated with low-dose whole-plant Artemisia showed significantly lower parasite loads than those treated with much higher doses of the purified artemisinin drug or placebo.

Further, in their most recent experiments in a rodent malaria model, Elfawal and colleagues confirmed Weathers’ earlier results showing that animals fed dry, whole-plant Artemisia had about 40 times more of the effective compound in their bloodstream than mice fed a corresponding amount of the purified drug. This is eight times the minimum concentration required to kill P. falciparum. In dose-response experiments, treatment with whole-plant Artemisia was just as effective at reducing parasitemia as the purified form for the first 72 hours, and faster reduction of symptoms thereafter compared to other groups.

These results, if they translate to humans with further research, could solve two problems with the current drug strategy, Rich says. First, parasites may be less able to evolve resistance to the whole plant because the makeup is far more complex. Second, it could drastically reduce the high cost associated with malaria treatment by allowing for low cost, locally sustainable production of whole plant therapy.

“It’s a local agriculture solution to a global health problem,” says Rich. Preliminary findings from dose-response experiments suggest that whole plant therapy would require a far smaller dose of dried plant than the corresponding amount of purified artemisinin, perhaps as much as a five-fold increased potency for the whole plant.

This work was funded by UMass Medical School’s Center for Clinical and Translational Science. Findings appear in the current issue of the journal PLOS ONE.

Source: University of Massachusetts Amherst

Traditional Methods for Malaria Treatment and Prevention

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QUESTION

What are the traditional methods on treating and preventing malaria?

ANSWER

Many different cultures have had their own traditional ways of treating malaria. Perhaps the two best known come from the native tribes in the Western Amazon basin and the ancient Chinese.

Tribes in the Amazon used the bark of a shrub called Cinchona to treat fevers and shivering; Spanish priests in this region observed traditional Quechua healers using this bark and started using it themselves to treat the fevers associated with malaria. Many centuries later, the active ingredient from this bark was isolated and called quinine, which is still used in the treatment of malaria today.

In ancient China, traditional healers would use the plant sweet wormwood (Artemisia annua, to give it its full Latin name), also to treat fevers and the symptoms of malaria. For many hundreds of years, this traditional cure was forgotten about, until the 1970s when a concerted effort led by Mao Tse-Tung began to search for new anti-malarial compounds as part of their Vietnam war effort. Their scientists, led by Dr Youyou, re-discovered sweet wormwood and extracted a potent anti-malarial compound from it, called artemisinin. This compound and and its many derivatives, in the form of artemisinin-based combination therapies (ACTs), are now the mainstay of the World Health Organization’s first-line recommended treatment against uncomplicated malaria.

New Treatment for Malaria

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QUESTION

New treatment for malaria?

ANSWER

The most recently developed type of treatment for malaria actually has very ancient origins. The herb wormwood (Artemisia annua) has been used in ancient Chinese medicine for hundreds, even thousands, of years to cure certain fevers.

In the 1970s, a Chinese research program intensively sought new medications against malaria, as part of their Vietnam war effort. They re-discovered wormwood, and from it isolated the compound artemisinin, which is highly effective against malaria parasites in the blood, and kills them very quickly. Due to its quick action against malaria, there was concern that use of artemisinin alone would lead to resistance developing rapidly in the malaria parasite, as was seen with chloroquine in many parts of the world. As such, the World Health Organisation recommended that artemisinin should only be used in combination with another anti-malarial drug with a longer lasting action, to prevent resistance.

A number of such compounds, containing artemisinin derivatives and a second anti-malarial, have now been developed. These are collectively called “artemisinin-based combination therapies,” or ACTs. Some of the main artemisinin compounds used in these drugs are artemether, artesunate and dihydroartemisinin, and the brand names of the drugs as they are marketed (in combination with other compounds, such as lumefantrine, piperaquine and pyronaridine) include Coartem, Pyramax and Duo-Cotecxin.

In which country did malaria start?

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QUESTION:

In which country did malaria start?

ANSWER:

That’s an interesting question! In terms of the evolution of the disease, the different types of malaria probably evolved in different places; it is hypothesised for example, that P. falciparum evolved from a related strain of malaria that is found in gorillas in central Africa, so the human form also probably originates from that area. Although an exact date for the origin of P. falciparum is still under debate, it was probably sometime around 10,000 years ago,  long before modern countries existed in the region!

As for when malaria was first recorded in human populations, it was known in ancient China, as long ago as 2700 BCE, when the ancient Chinese medical text, Nei Ching, was written. Two and a half thousand years later, in around 200 BCE, there are descriptions of the use of Artemisia annua for the treatment of malarial-type fevers; extracts from this plant, known as artemisinins, are still used for the treatment of malaria today.

Malaria was also known from Europe by the 4th century BCE when it was described by ancient Greek writers. The Romans too were aware of malaria and the risks it posed; they even associated the disease with stagnant water (required by mosquitoes to breed, though it is unclear whether they actively understood the association between mosquito bites and the fevers), which led to extensive public drainage works in order to eliminate bodies of standing water.

Given the lack of written histories, it is more difficult to determine the earliest understanding of malaria in the Americas. However, when the Spanish arrived in the 15th century, they learned of local remedies that the indigenous populations had for various fevers; one of these natural medicines was the bark of a tree of the genus Chichona. More commonly called quinine, this compound is still used as an anti-malarial in modern times.

Nowadays, vector control measures, efficient health monitoring systems and treatment availability has much reduced and in some cases even eradicated the transmission of malaria from most of the United States, Europe and even large parts of China. The greatest burden of the disease continues to be in the tropical regions of the world, and in particular, in sub-Saharan Africa.