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Document Type

Open Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Entomology

Year Degree Awarded

Summer 2014

First Advisor

Stephen Rich

Second Advisor

Anne Averill

Third Advisor

John Burand

Fourth Advisor

Michele Klingbeil

Subject Categories

Entomology | Medicinal Chemistry and Pharmaceutics | Other Chemicals and Drugs

Abstract

Dried Whole plant Artemisia annua as a novel antimalarial therapy

September 2014

Mostafa Ahmed Elfawal

Ph.D., UNIVERSITY OF MASSACHUSETTS AMHERST

Directed by: Professor Stephen M. Rich

Malaria is one of the worst vector-borne parasitic diseases in the developing world. The World Health Organization (WHO) estimated that 215 million cases of malaria occurred, with >655,000 deaths; half the world’s population is at risk of contracting the disease. Drugs are primary weapons for reducing malaria in human populations. Successful drugs are highly efficacious and inexpensive to manufacture synthetically. However, emergence of resistant parasites has repeatedly curtailed the lifespan of each drug that is developed and deployed. Currently, the most effective anti-malarial is artemisinin, which is extracted from the leaves of Artemisia annua. Due to poor pharmacokinetic properties and prudent efforts to curtail resistance to monotherapies, artemisinin is prescribed only in combination with other anti-malarials composing an Artemisinin Combination Therapy (ACT). Low yield in the plant, and the added cost of secondary anti-malarials in the ACT, make artemisinin costly for the developing world. As an alternative, we compared the efficacy of oral delivery of whole plant (WP) A. annua to a comparable dose of pure artemisinin in a rodent malaria model. We found that WP reduces parasitemia at least five fold more effectively than a comparable dose of purified drug, slows the evolution of malarial drug resistance in Plasmodium chabaudi infected mice, and is effective against already resistant Plasmodium yoelii (ART). This increased efficacy may result from the increase in the bioavailability of artemisinin in the blood of mice fed the whole plant, in comparison to those administered synthetic drug. When accompanied by plant material, more artemisinin enters the blood stream, demonstrating a beneficial effect of the plant matrix on the bioavailability of artemisinin. Increased efficacy and resilience against drug resistance may result from the synergistic benefits of other anti-malarial compounds in A. annua, such as flavonoids and terpenoids. Although effective against Plasmodium, neither WP nor artemisinin and artesunate are effective against Babesia microti. The differential response of B. microti and Plasmodium to artemisinins is likely the result of significant differences in their cell biology and metabolism of hemoglobin. Well-tolerated, and compatible with the public health imperative of forestalling evolution of drug resistance, inexpensive, locally grown and processed whole plant A. annua therapy might prove to be an effective addition to the global effort to reduce malaria morbidity and mortality.

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