Artemisia annua, from which

artemisinin is derived

Credit: Jorge Ferreira

Preclinical research suggests that using the whole plant Artemesia annua, from which the drug artemisinin is extracted, may treat malaria more effectively than artemisinin itself.

Whole-plant treatment withstood the evolution of resistance and remained effective for up to 3 times longer than pure artemisinin.

Whole-plant therapy was also more effective in killing rodent parasites that have previously evolved resistance to pure artemisinin.

Stephen Rich, PhD, of the University of Massachusetts Amherst, and his colleagues reported these findings in PNAS.

The team previously showed that the whole-plant approach is more effective at killing rodent malaria than purified artemisinin.

In the present study, the investigators conducted a series of experiments to determine the rates at which parasites become resistant to whole-plant treatment compared to the rate with pure artemisinin, and if the whole-plant treatment can overcome resistance to pharmaceutical artemisinin.

The team chose 2 rodent malaria species for particular characteristics. They chose Plasmodium yoelii because an artemisinin-resistant strain exists and could be used to test whether the whole plant can overcome that resistance.

And they chose Plasmodium chabaudi because, among several species of rodent malaria, it most closely biologically resembles the deadliest of the 5 human malaria parasites, Plasmodium falciparum.

“Conducting these experiments in different rodent malaria species also provides a robust test of the therapy,” Dr Rich noted.

To determine the respective evolutionary rates of resistance to whole-plant therapy and artemisinin, Dr Rich and his colleagues conducted artificial evolution experiments. The goal was to compare the rates at which resistance to these two treatments arises in serial passage among wild-type parasite lines.

In this technique, parasite proliferation rates determine resistance. Resistant parasites are expected to reach a certain target level at the same time, whether treatment is present or absent. Sensitive parasite strains will grow more slowly in the presence of treatment and reach the target later than untreated strains.

The investigators found that artemisinin-treated parasites achieved stable resistance to low-dose (100 mg/kg) therapy on passage 16. Those parasites were then treated with a doubled artemisinin dose, and they became resistant to this after an additional 24 passages.

By comparison, parasites did not become resistant to even the low dose of whole-plant therapy (100 mg/kg) after 49 passages.

From this, the investigators concluded that the whole-plant therapy lasts at least 3 times longer than its artemisinin counterpart, and at least twice as long as the doubled dose of pure artemisinin.

“This is especially important given the recent reports of resistance to artemisinin in malaria-endemic regions of the world,” Dr Rich said.

He and his colleagues also tested whether dried, whole-plant therapy can overcome existing resistance to pharmaceutical artemisinin.

They fed groups of mice infected with artemisinin-resistant malaria either the whole-plant therapy or artemisinin mixed with water. Single treatments were given in low (40 mg) and high (200 mg) doses. Control groups received a mouse chow placebo.

The investigators then measured the parasite levels in the rodents’ bloodstream at 9 points after treatment began.

Mice given either the low or high dose of whole-plant therapy showed a significantly greater reduction in parasitemia than those in their respective artemisinin groups. As expected for these resistant parasites, parasitemia in mice in the low-dose artemisinin group did not differ from controls.

The investigators said consuming the whole plant may be more effective than the single purified drug because the whole plant “may constitute a naturally occurring combination therapy that augments artemisinin delivery and synergizes the drug’s activity.”

Dr Rich did note that the exact mechanisms of whole-plant therapy’s effectiveness still need to be identified. But he also said the antimalarial activity of whole-plant therapy against artemisinin-resistant parasites provides “compelling reasons to further explore the role of non-pharmaceutical forms of artemisinin to treat human malaria.”

Whole plant treats malaria better