Mosquitoes are one of the most powerful forces in the world. Widespread diseases caused by mosquito bites, including malaria, helped change human history.
Malaria is caused by infection of red blood cells by protozoan parasites of the genus Plasmodium, which are transmitted through the bites of infected female Anopheles mosquitoes. There were an estimated 241 million cases and 627,000 deaths from malaria worldwide in 2020, most of which occurred in tropical and subtropical regions where malaria is often endemic, including most of Africa and parts of South America and Asia . Of the five Plasmodium species known to infect humans, P. falciparum is the dominant species and P. vivax is the second most common threat.
Timely treatment of malaria can be challenging. People usually don’t have any symptoms for the first few weeks after being bitten. Infections were classified as either “simple” or “severe” depending on the severity of symptoms and target organ dysfunction, the Plasmodium species infected, and the level of parasitemia. The distinction between the two forms of malaria infection is important because this decision can influence the choice of treatment. Artemisinin derivatives are the main drugs for the treatment of malaria, and intravenous artesunate is the antimalarial drug of choice for severe forms of the disease.
Artemisinin is obtained from the leaves of Chinese sweet wormwood (Artemisia annua). Extracts from these leaves have been used in China for over 1500 years, where they are reported to have antipyretic properties. However, the artemisinin molecule was not discovered until recently.
Quinine and its derivative chloroquine were successfully used to treat malaria several years before the discovery of artemisinin. However, the effectiveness of these drugs declined as resistance developed, due in part to their widespread use during the Vietnam War. In search of new antimalarial drugs, Vietnam turned to China, and in 1967 the Chinese government launched an organized research program in China to help with this effort. In 1971, the active ingredient in wormwood was discovered and identified as artemisinin. Since then, several artemisinin derivatives have been developed and are used in modern malaria treatment.
Artemisinin derivatives have a similar mechanism of action against Plasmodium. They interact with the heme iron of the parasite, causing the rupture of peroxide bridges in the artemisinin molecule, which leads to the formation of free radicals that damage the proteins of the parasite. Artemisinin derivatives have the fastest parasite clearance time of all antimalarials due to their preferred position in therapy. Oral variants of artemisinin derivatives are combined with other antimalarials in the form of so-called “artemisinin-based combination therapies” (ACTs). Artesunate is the only intravenous artemisinin derivative used to treat malaria.
Before the discovery of artemisinin and its derivatives, intravenous administration of quinidine was the mainstay of treatment for severe malaria. In 2019, Lilly stopped making quinidine and intravenous artesunate became the first line treatment for severe malaria. Numerous studies have shown that intravenous artesunate reduces mortality compared to intravenous quinidine. In an open randomized controlled trial (RCT) involving 1461 patients with severe malaria, mortality was 15% in patients treated with intravenous artesunate compared with 22% in patients treated with intravenous quinine. Another open-label RCT in 5425 African children with severe malaria showed similar results, with a mortality rate of 8.5% in the artesunate intravenous group compared to 10.9% in the quinine intravenous group. These findings, along with better tolerability and ease of administration, make artesunate a first-line treatment for severe malaria.
The recommended starting dose of intravenous artesunate for severe malaria is 2.4 mg/kg at 0, 12, and 24 hours. After the first three doses of intravenous treatment, if the patient has a parasitemia rate of 1% or less and is able to take oral medications, the patient may switch to subsequent oral regimens to complete the course of treatment. If these two criteria were not met, patients could continue to receive intravenous artesunate daily for up to 6 days. Artesunate does not require dose adjustment in renal or hepatic impairment. A serious adverse reaction that may occur is hemolytic anemia caused by artesunate. This response is usually delayed and occurs after parasite clearance in about 15% of patients. The average hemoglobin nadir observed was 6.2 g/dl. It is recommended that every patient receiving intravenous artesunate have weekly laboratory checks for hemolysis for 4 weeks after starting treatment. Otherwise, artesunate is generally well tolerated.
On May 26, 2020, the FDA approved intravenous artesunate for the treatment of severe malaria in adults and children. Prior to FDA approval and commercial availability, intravenous artesunate is only available in the United States under the CDC-managed Expanded Access to Investigation of New Drugs (IND) program. Artesunate is now available from drug distributors Amerisource Bergen, Cardinal, and McKesson. Despite these recent changes, there may still be some delays in getting the product and starting treatment because malaria is still relatively uncommon in the United States, and given the high cost of artesunate (approximately $5,000 for a 110 mg vial), not all hospitals are able to keep stocks. artesunate. If a hospital does not have intravenous artesunate in stock and needs to treat a patient with severe malaria, the hospital pharmacy should contact the drug distributor to request an urgent purchase of this product. If artesunate is not available from distributors or cannot be borrowed from the nearest hospital, hospital pharmacies can still obtain intravenous artesunate from the CDC according to IND protocols. Given the importance of timely initiation of antimalarial treatment for severe malaria, it is recommended, if possible, that oral antimalarial drugs be initiated while waiting for intravenous artesunate.
Several oral antimalarial drugs are available for the follow-up treatment of uncomplicated illness and severe illness after intravenous artesunate. However, due to the high efficacy, rapid onset of action, and good tolerability of artemisinin derivatives, ACT is the treatment of choice in most countries.
ACT is a combination of a short-acting artemisinin derivative and another long-acting antimalarial drug. This combination helps prevent resistance to artemisinin derivatives and should therefore not be used as monotherapy. There are currently five WHO-approved first-line ACT options available to countries. In many trials, they have shown a PCR-adjusted treatment failure rate of less than 5%. Artemether-lumefantrine is an AST used in the US.
Artemether-benzoxanthraquinone was approved by the FDA in 2009 for the treatment of uncomplicated P. falciparum malaria, but more recently it has been recommended for the treatment of severe malaria infections, as follow-up after intravenous therapy, or as interim therapy for A. drugs at that time how succinate anticipates availability. It comes as fixed-dose oral tablets and is given in a six-dose regimen over 3 days. Tablets should be taken with food and crushed if necessary. In renal or hepatic insufficiency, dose adjustment is not recommended. Like intravenous artesunate, artemether-benzoxanthraquinone is generally well tolerated.
Mosquitoes and malaria have been here for a long time. Artemisinin derivatives have become first-line drugs for the treatment of uncomplicated and severe malaria with low mortality, side effects, and affordability. However, these basic treatments are still only a partial solution to the problem of mosquito eradication. Medication, including vaccination, and non-drug approaches must continue.
Post time: Feb-24-2023