A New Treatment for Malaria: Artemisinin

Prof. Dr. Talal Aburjai

Overview

• Malaria• Problems associated with the disease• Actions taken in dealing with the

problems• Artemisinin

• Background information• Mechanism of action

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

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

General Symptoms

• Fever and flu-like illness• Shaking chills• Headache• Muscle aches• Tiredness

• Nausea, vomiting and diarrhea may also occur

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)

Classification of Malaria

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

Life Cycle of Malaria Parasite

Conventional Treatment

• Use of insecticide such as DDT• Use of quinoline-based antimalarial

drugs

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

“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

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

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 4th century by a Chinese alchemist

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”

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

Chemical Structure

Structure of Artemisinin

Structure of Artemisinin Derivatives

Sesquiterpene Trioxane Lactone

Key Features

• Rapid onset of actions• Effective against severe malaria

• Rapid clearance rate• Slow development of artemisinin

resistance• Frequent recurrence of infections

Site of Action

Artemisinin

Artemisinin

Conventional Treatment

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

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

Mechanism of Action

Mechanism of Action

• Inhibit homozoin biosynthesis or cause hemozoin degradation

• Inhibit hemoglobin digestion by malaria parasites

• Forms covalent adducts with malarial proteins

Adverse Reactions

• Very few adverse reactions• Common side effects include

– Nausea– Vomiting– Anorexia– dizziness

• Safe for pregnant women

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

Combination Therapy

• Use of artemisinin-based combined therapies would help delay antimalarial drug resistance

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

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?