Malaria Site: Artemisinin

Artemisinin or Qinghaosu ("ching-how-soo") is the active principal of the Chinese medicinal herb Artemisia annua. It has been used as treatment of fevers in China for more than 1000 years. The antimalarial value of Artemisia annua was first documented in Zhou Hou Bei Ji Fang (Handbook of prescriptions for emergency treatments) written as early as 340 AD by Ge Hong of the Eastern Jin Dynasty. The active antimalarial constituent of this plant was isolated in 1971 and it was named artemisinin. The WHO accorded high priority to the development of fast acting artemisinin derivatives for the treatment of cerebral malaria as well as for the control of multi-drug resistant P. falciparum malaria. A water soluble ester called artesunate and two oil soluble preparations called artemether and arteether (artemotil) have now been developed.

	Artemisinin
		Reduction
	Dihydroartemisinin


Ethyl Ether	Hemisuccinate	Methyl Ether
Arteether	Artesunate	Artemether

Anti malarial activity: They act by inhibiting a P falciparum-encoded sarcoplasmic-endoplasmic reticulum calcium ATPase, and not by inhibiting the haem metabolic pathway as previously supposed. Most clinically important artemisinins are metabolised to dihydroartemisinin (elimination half-life of about 45 min), in which form they have comparable antimalarial activity. However, their use in monotherapy is associated with high incidences of recrudescent infection, suggesting that combination with other antimalarials might be necessary for maximum efficacy.

It is the fastest acting anti malarial available. It inhibits the development of the trophozoites and thus prevents progression of the disease. Young circulating parasites are killed before they sequester in the deep microvasculature. These drugs starts acting within 12 hours. These properties of the drug are very useful in managing complicated P. falciparum malaria. These drugs are also effective against the chloroquine resistant strains of P. falciparum.

Artesunate and artemether have been shown to clear parasitaemias more effectively than chloroquine and sulfadoxine/pyrimethamine. Meta analysis of mortality in trials indicated that a patient treated with artemether had at least an equal chance of survival as a patient treated with quinine. It has also been reported that artemisinin drugs cleared parasites faster than quinine in patients with severe malaria but fever clearance was similar. Also, parenteral artemether and artesunate are easier to use than quinine and do not induce hypoglycaemia.

Gametocytocidal action: Artemisinin compounds have been reported to reduce gametocytogenesis, thus reducing transmission of malaria, this fact being specially significant in preventing the spread of resistant strains.

These drugs prevent the gametocyte development by their action on the ring stages and on the early (stage I-III) gametocytes.[2] In studies including over 5000 patients in Thailand, it was shown that gametocyte carriage was significantly less frequent after treatment with artemisinin derivatives than after treatment with mefloquine.

Absorption, fate and excretion: Artemisinin derivatives are absorbed well after intra muscular or oral administration. The drug is fully metabolised and the major metabolite is dihydroartemisinin, which also has anti parasite effects. It is rapidly cleared, predominantly through the bile.

Toxicity:[1] Toxic effects have been reported less frequently with the artemisinins than with other antimalarial agents. The most common toxic effects that have been identified are nausea, vomiting, anorexia, and dizziness; these are probably due, in many patients, to acute malaria rather than to the drugs. More serious toxic effects, including neutropenia, anemia, hemolysis, and elevated levels of liver enzymes, have been noted rarely. Two cases of severe allergic reactions to oral artesunate have been reported, with an estimated risk of approximately 1 reaction per 3000 treatments.

Neurotoxicity is the greatest concern regarding artemisinins, since the administration of high doses in laboratory animals has led to severe and irreversible changes in the brain. Extensive studies in many species showed that intramuscular dosing was more toxic than oral dosing and that, by any route, fat-soluble artemisinins were more toxic than artesunate. In humans, an episode of ataxia was reported after treatment with oral artesunate, and one case�control study showed hearing loss after the use of artemether�lumefantrine, but auditory toxic effects were not detected in another case�control study, and reported toxic effects may have been due to underlying malaria or other factors that were independent of artemisinin use. Multiple studies have shown that neurologic findings are fairly common with acute malaria, but there is no convincing evidence of neurotoxic effects resulting from standard oral or intravenous therapy with artemisinins.

Another concern about artemisinins is embryotoxic effects, which have been demonstrated in animals. Studies from Asia and Africa, including treatments during the first trimester, showed similar levels of congenital abnormalities, stillbirths, and abortions in patients who received and those who did not receive artesunate during pregnancy. Limited data are available on the use of intravenous artesunate for severe malaria during pregnancy.

Availability: Artemisinin is available as its derivatives, artemether, artesunate and arteether. The ether derivatives are more soluble in oil and are available as injections for intra muscular use. Artemether is available as injection of 80 mg in 1 ml. Artemether capsules containing 40 mg of the drug are also now available. Arteether is available as injection of 150 mg in 2 ml.

Artesunate is an ester derivative that is more soluble in water. The drug is available as a powder. It should be first dissolved in 1 ml of 5% sodium bicarbonate (usually provided with the vial) and shaken for 2-3 minutes. After it dissolves completely, it is diluted with 5% dextrose or saline (for intravenous use, dilute with 5 ml and for intramuscular use, dilute with 2 ml). Intravenous dose should be injected slowly at a rate of 3-4 ml/minute. It is also available as tablets, each containing 50 mg of the drug.

Injection: 3.2 mg/kg intra muscularly as a loading dose, followed by 1.6 mg/kg daily until oral therapy or a maximum of 7 days.

Artesunate: In India it is available as 50mg tablets and 60mg/ml injection. In China it is also available as 100mg suppository and in Switzerland is available as 200mg rectocap

Oral- 4 mg/kg on the first day followed by 2mg/kg for 6 days. It can also be used in combination; 4mg/kg on the second and third days with mefloquine 15 mg/kg in a single dose on the second day. Oral artesunate is not recommended in pregnancy.

Parenteral- Loading dose of 2.4 mg/kg followed by 2.4mg/kg after 12 hours, 24 hours and once daily thereafter for maximum of 7 days. For children, the recommended dose is 1.2 mg/kg/day for 5-7 days.

Artesunate dosages need not be changed because of hepatic or renal failure or concomitant or previous therapy with other medications, including previous therapy with mefloquine, quinine, or quinidine. There are no known interactions between artesunate and other drugs.[1]

See Rectal artemisinins rapidly eliminate malarial parasites [Full text, Report, Report]

After the acute stage of the illness, artemisinins should be partnered with longer-acting drugs to ensure a high likelihood of cure. Appropriate partner drugs that are available in the United States are a 1-week course of doxycycline or, in children or pregnant women, clindamycin, or full courses of treatment with atovaquone�proguanil or mefloquine (although the neuropsychiatric toxic effects of mefloquine may be increased after cerebral malaria). All of these drugs should be initiated after the patient can tolerate oral medication.[1]

Resistance: The short half-lives of artemisinins limit the possibility of selection for resistance. Nonetheless, recent heavy use of artemisinins, including monotherapy, has created selective pressure.[1] Resistance to artesunate has been recently reported from Cambodia.[4] Some parasites isolated from French Guiana and Senegal recently showed diminished in vitro sensitivity to artemether, and the efficacies of artemisinin-based combination agents have apparently decreased along the Thailand�Cambodia border. However, at present, the likelihood of true artemisinin resistance in malaria parasites is low, and this concern should not prevent the use of intravenous artesunate to treat severe malaria.[1]