What Is Artemisinin? Definition, Biological Role, and Applications
Artemisinin is also known as qinghaosu, which is an artemisia (artemisia herb for malaria) antimalarial drug derived from the Artemisia annua, a sweet wormwood plant. Artemisinin is a sesquiterpene lactone (a compound composed of three isoprene units bound to cyclic organic esters) distilled from the flower clusters or dried leaves of Artemisia annua. Chinese physicians, known as the plant qinghao, first recognised the plant's antipyretic (or fever-reducing) properties in the 4th century CE, and recommended a natural remedy in the form of qinghao tea.
Artemisinin Structure
(+)-artemisinin is the sesquiterpene lactone, which is obtained from the sweet wormwood, Artemisia annua. It is used as an artemisia antimalarial (artemisinin and malaria) for multidrug treatment-resistant falciparum malaria strains.
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About Artemisinin and its Effectiveness
In the 19th century, this remedy was commonly prescribed for malaria and hemorrhoids. During the 1970s, the active ingredient, qinghaosu, was isolated from the artemisinin plant, and the compound became known as artemisinin. Today, there are many derivatives of artemisinin, including artemether and artemisinin artesunate, which are used in malaria treatment.
Artemisinin is very effective against all the malaria-causing protozoan organisms which are present in the genus Plasmodium. Particularly, this drug is useful in the treatment of infections involving multidrug-resistant P. falciparum and infections involving the chloroquine-resistant parasites, which is the deadliest of malaria protozoans.
The artemisinin targets the organisms of Plasmodium in the schizont stage of development. Schizonts that mature from sporozoites, which is the form of parasite transmitted to humans in the Anopheles mosquitoes saliva—contain insoluble iron known as hemozoin. Hemozoin can be formed within the schizonts because they feed on hemoglobin present in the cytoplasm of red blood cells of the human. Artemisinin has a peroxide group, which reacts with hemozoin, and this reaction can be suspected to result in the radical production that attacks the parasite proteins, thereby killing organisms.
Uses of Artemisinin
Artemisinin is available as an intramuscular injection, an oral tablet, or a suppository. This drug reaches the peak plasma levels within the hours after administration and acts significantly, rapidly, reducing malaria parasite burden in the first few days of the treatment. Artesunate is the only artemisinin-derived agent that can be administered intravenously, allowing the drug to take effect immediately.
Resultantly, artesunate can be used in the treatment of cerebral malaria, an acute form of the disease characterized by the rapid spread of parasites to the brain and by death within the duration of 72 hours if left untreated. Artemisinin appears to have some side effects in humans. However, high doses have been shown in a few animal studies to cause neurotoxicity symptoms such as unsteady gait and respiratory depression. These particular symptoms are associated with brainstem degeneration, though it remains unclear whether the same neurodegenerative effects take place at high doses in humans.
Because the artemisinin, including its derivatives, contains a short duration of action and targets malaria parasites in a particular stage of their life cycle, there exists a high rate of disease relapse, which is associated with the drugs when they are used alone in the single-agent therapy. Resultantly, they are generally used in combination with other, longer-acting antimalarial drugs.
Some examples of first-line artemisinin-based combination therapies, which are used in malaria treatment, are artemether-lumefantrine, artesunate-mefloquine, and artesunate-amodiaquine. Although all these combination therapies also have proved to be valuable in preventing the emergence of the artemisinin-resistant parasites, the persistent use of a single-agent artemisinin therapy in a few parts of the world has led to resistant parasite development and to the high rates of treatment failure in these particular areas.
In addition to activity against the Plasmodium, artemisinin appears to have a few lethal effects on other protozoal organisms. Also, studies have demonstrated that artemisinin is very effective against the Toxoplasma gondii that causes toxoplasmosis; Leishmania major that causes leishmaniasis; and Babesia species, which causes the diseases resembling anemia in both animals and humans. Artemisinin, including one of its metabolites, dihydroartemisinin, also can be useful as anticancer agents since they have been shown to disrupt various types of cancer cells’ growth in laboratory research.
Contraindications
WHO recommends avoiding the ACT for women in their first trimester of pregnancy because of a lack of research on the safety of artemisinins in early pregnancy. Instead, WHO recommends a seven-day course of quinine and clindamycin. For pregnant women, either in their second or third trimesters, WHO recommends a general treatment course with an ACT. For a few other groups, certain ACTs are avoided because of the side effects of the partner drug: which is - sulfadoxine-pyrimethamine - is avoided at the time of the 1st few weeks of life because it interferes with the bilirubin action and may worsen neonatal jaundice.
In people having HIV-positive, the combination of trimethoprim or the sulfamethoxazole, zidovudine-containing antiretroviral treatments, including the ASAQ, is associated with neutropenia. The combination of ASAQ and the HIV drug efavirenz has been linked to liver toxicity.
Adverse Effects
Generally, artemisinins are well tolerated at the doses that are used in malaria treatment. The artemisinin class of drugs has the same side effects as malaria: vomiting, nausea, appetite loss, and dizziness. Also, mild blood abnormalities have been noticed. A serious but rare adverse effect is an allergic reaction.
FAQs on Artemisinin: Key Features, Benefits, and Mechanism of Action
1. What is Artemisinin and from which organism is it sourced?
Artemisinin is a powerful antimalarial compound, specifically a sesquiterpene lactone containing a unique endoperoxide bridge, which is crucial for its medicinal activity. It is naturally derived from the leaves and flowers of the plant Artemisia annua, commonly known as sweet wormwood or 'qinghao' in traditional Chinese medicine.
2. What is the primary medical importance of Artemisinin?
The primary medical importance of artemisinin and its derivatives is the treatment of malaria, particularly infections caused by the drug-resistant Plasmodium falciparum parasite. It is known for its rapid action in clearing parasites from the bloodstream, making it a frontline treatment for both uncomplicated and severe cases of malaria worldwide.
3. How does Artemisinin work to kill the malaria parasite inside the human body?
Artemisinin's mechanism of action involves its unique endoperoxide bridge. Inside the parasite, this bridge reacts with heme iron, which is abundant due to the parasite's digestion of haemoglobin. This reaction generates a burst of highly reactive free radicals. These free radicals damage the parasite's proteins and membranes, leading to oxidative stress and ultimately killing the parasite.
4. Why is Artemisinin usually given as a combination therapy (ACT) and not as a single drug?
Artemisinin is administered as an Artemisinin-based Combination Therapy (ACT) to combat and prevent the development of drug resistance. Artemisinin acts very quickly but has a short half-life, meaning it is eliminated from the body rapidly. Using it alone could allow some parasites to survive and develop resistance. By combining it with a longer-acting partner drug, the combination ensures that any residual parasites are eliminated, significantly reducing the chances of treatment failure and resistance.
5. What are some examples of Artemisinin-based drugs used in medicine?
Artemisinin itself is not very soluble, so more effective semi-synthetic derivatives have been developed. Common examples used in ACTs include:
- Artesunate: Water-soluble and can be administered orally, intravenously, or rectally.
- Artemether: Lipid-soluble and often combined with lumefantrine (e.g., Coartem).
- Dihydroartemisinin (DHA): The active metabolite of both artesunate and artemether.
6. What are the known side effects of using Artemisinin-based therapies?
Artemisinin and its derivatives are generally well-tolerated. However, some potential side effects can occur, which are often difficult to distinguish from the symptoms of malaria itself. These can include:
- Nausea and vomiting
- Dizziness
- Headache
- Rarely, neurotoxicity (at very high doses) or liver inflammation with prolonged use.
7. How does the commercial production of Artemisinin cater to global demand?
Due to the high demand for ACTs, relying solely on extracting artemisinin from Artemisia annua is insufficient and costly. Therefore, a semisynthetic production method has been developed. This process involves genetically engineering yeast (Saccharomyces cerevisiae) to produce artemisinic acid, a precursor to artemisinin. This artemisinic acid is then harvested and converted into artemisinin through a simple chemical process, ensuring a stable and affordable supply for medical use.
8. Is Artemisinin effective against all stages of the malaria parasite's life cycle?
Artemisinin and its derivatives are highly effective against the asexual erythrocytic stages of the *Plasmodium* life cycle, which are responsible for the clinical symptoms of malaria. They rapidly reduce the parasite biomass in the blood. However, they are generally less effective against the dormant liver stage (hypnozoites) of *Plasmodium vivax* and *P. ovale*, and have limited activity against the mature sexual stages (gametocytes) that transmit the disease to mosquitoes.
