1. A New Treatment for Malaria: Artemisinin Prof. Dr. Talal Aburjai

2. Overview Malaria Problems associated with the disease Actions taken in dealing with the problems Artemisinin Background information Mechanism of action

3. Introduction on Malaria ~40% of population at risk India, Indonesia, Latin America and Africa ~500 million cases of malarial illness per year ~1.5 million deaths Total cost of malaria is approximately $1,800 million US dollars

4. What is the Cause of Malaria? Malaria caused by four major Plasmodium parasites: Plasmodium vivax Plasmodium malariae Plasmodium ovale Plasmodium falciparum Plasmodium falciparum is the most prevalent parasite species

5. General Symptoms Fever and flu-like illness Shaking chills Headache Muscle aches Tiredness Nausea, vomiting and diarrhea may also occur

6. Classification of Malaria Uncomplicated Malaria Cold stage (sensation of cold, shivering) Hot stage (fever, headaches, vomiting; seizures in young children) Sweating stage (sweats, return to normal temperature, tiredness)

7. Classification of Malaria Severe Malaria –Cerebral malaria (seizures, coma) –Severe anemia –Hemoglobinuria –Abnormalities in blood coagulation –Cardiovascular collapse and shock

8. Life Cycle of Malaria Parasite

9. Conventional Treatment Use of insecticide such as DDT Use of quinoline-based antimalarial drugs

10. Malaria Parasite Resistance Mechanism of resistance is due to genetic mutations in malaria parasite Resistance Delayed Response Recurrence of Infection Increased GametocyteIncrease Transmission Increased Clinical Cases More Drug Used

11. “Roll Back Malaria” Currently courses of actions being explored: Development of drug combinations Search for effective vaccine Genomic approach Search for new antimalarial drugs ARTEMISININ

12. Artemisia annua Also known as sweet wormwood Origin from northern parts of China Artemisinin present in leaves and flower of the plant in 0.01-0.08% dry weight

13. Artemisia annua Used in Traditional Chinese Medicine for more than 2000 years Earliest record found in the “Fifty Two Prescription” First antimalarial application described in “The Handbook of Prescriptions for Emergencies” in the 4 th century by a Chinese alchemist

14. Artemsia annua Li Shizhen, a great Chinese herbalist Use of wormwood is also recorded in the “Great Compendium of Herbs” in 1596 “take a handful of sweet wormwood, soak it in a sheng (liter) of water, and squeeze out the juice and drink it all”

15. Artemisinin One of the most novel discoveries in recent medicinal plant research 1967- extracts of Artemisia was found to have antimalarial activity 1972- artemisinin isolated from the plant 1979- structure of artemisinin determined by X-ray analysis

16. Chemical Structure Structure of Artemisinin Structure of Artemisinin Derivatives Sesquiterpene Trioxane Lactone

17. Key Features Rapid onset of actions Effective against severe malaria Rapid clearance rate Slow development of artemisinin resistance Frequent recurrence of infections

18. Site of Action Artemisinin Conventional Treatment

19. Mechanism of Action Killing of malaria parasite is mediated by production free radicals –Artemisinin derivatives lacking endoperoxide bridge are devoid of antimalarial activity –Addition of free radical generating compounds enhances antimalarial activity –Antioxidants block antimalarial activity

20. Mechanism of Action Heme/iron mediates breakage of endoperoxide bridge –Chloroquine antagonizes the antimalarial activity –Iron chelators antagonize antiparasitic effect of artemisinin Artemisinin-derived free radicals bind to protein through alkylation

21. Mechanism of Action

22. Inhibit homozoin biosynthesis or cause hemozoin degradation Inhibit hemoglobin digestion by malaria parasites Forms covalent adducts with malarial proteins

23. Adverse Reactions Very few adverse reactions Common side effects include –Nausea –Vomiting –Anorexia –dizziness Safe for pregnant women

24. Resistance Currently no evidence for clinically relevant artemisinin resistance Reasons for delay of artemisinin resistance: –Short half-life –Reduces transmission potential –Used in combination with other antimalarial drugs

25. Combination Therapy Use of artemisinin-based combined therapies would help delay antimalarial drug resistance

26. Summary Artemisinin induce rapid killing of parasites Fast clearance rate Very few side effects Artemsinin-resistant parasites have not been identified Should be used in combination with other antimalarial drugs

27. Discussion What is your opinion about integration of Complementary and Alternative Medicine with Western Medical Practices? –Do you think this integration process will benefit the patients? –What would be your concerns if you’re asked to take Traditional Chinese Medicine?