Artesunate

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Artesunate
Artesunate.svg
Artesunate 3D balls.png
Clinical data
Pronunciationahr-tez′ŭ-nāt [1]
Trade names many [2]
Other namesSM-804
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Routes of
administration 		By mouth, intravenous, intramuscular
Drug class Artemisinin
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
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UNII
KEGG
ChEBI
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PDB ligand
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ECHA InfoCard 100.106.898 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C19H28O8
Molar mass 384.425 g·mol−1
3D model (JSmol)
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  • InChI=1S/C19H28O8/c1-10-4-5-13-11(2)16(23-15(22)7-6-14(20)21)24-17-19(13)12(10)8-9-18(3,25-17)26-27-19/h10-13,16-17H,4-9H2,1-3H3,(H,20,21)/t10-,11-,12+,13+,16-,17-,18-,19-/m1/s1 X mark.svgN
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Artesunate (AS) is a medication used to treat malaria. [3] [4] [5] The intravenous form is preferred to quinine for severe malaria. [4] Often it is used as part of combination therapy, such as artesunate plus mefloquine. [5] It is not used for the prevention of malaria. [5] Artesunate can be given by injection into a vein, injection into a muscle, by mouth, and by rectum. [5] [6] [7]

Contents

The most common side effects include kidney failure requiring dialysis, hemoglobinuria (the presence of hemoglobin in urine) and jaundice. [8]

Artesunate is generally well tolerated. [6] Side effects may include a slow heartbeat, allergic reaction, dizziness, and low white blood cell levels. [5] During pregnancy it appears to be a safer option, even though animal studies have found harm to the baby. [9] Use is likely fine during breastfeeding. [10] It is in the artemisinin class of medication. [4]

Artesunate was developed by Liu Xu in 1977. [11] It is on the World Health Organization's List of Essential Medicines. [12] It was approved for medical use in the United States in May 2020. [13] It is in the class of medications known as artemisinins, which are derivatives from "qinghao," or sweet wormwood plant ( Artemisia annua ). [14] [4]

Medical uses

Artesunate is the first-line treatment for children or adults with severe malaria, [15] [16] [17] usually in combination with another antimalarial drug. There is moderate-quality evidence that treatment with artesunate plus mefloquine is superior to treatment with artesunate plus amodiaquine or artesunate plus sulfadoxine-pyrimethamine. [18] Artemisinin-based combination therapy may be used by mouth in persons that can tolerate it after 24 hours by injection.[ medical citation needed ]

Artesunate is preferred over parenteral quinine for severe malaria treatment. [4] Artesunate was shown to prevent more deaths from severe malaria than quinine in two large multicentre randomized controlled trials from Africa [19] and Asia. [20] A subsequent systematic review of seven randomized controlled trials found this improvement in survival rates to be consistent across all trials. [21]

Artesunate's efficacy is comparable to that of artemether, another artemisinin derivative, in treating adults for severe malaria caused by Plasmodium falciparum, though artesunate clears more parasites initially. [22] Artesunate combination drugs have a number of advantages over artemether-based drugs in terms of its uptake and administration routes and may be more effective in treatment of severe and complicated malaria in children. [23]

Artesunate is also used to treat less severe forms of malaria when it can be given orally. [15] It has activity against P. ovale , P. malariae , and severe P. knowlesi . [15]

Artesunate + sulfadoxine/pyrimethamine for treatment of P. vivax is not recommended due to high rates of resistance.[ citation needed ]

While artesunate is used primarily as treatment for malaria, there is some evidence that it may also have some beneficial effects in Schistosoma haematobium infection, [24] but has not been evaluated in large randomized trials.

Artesunate is used as the treatment of choice for severe malaria by the World Health Organization (WHO) over quinine. [4] [15]

Pregnancy

When given in the second or third trimesters of pregnancy, no artesunate-related adverse pregnancy outcomes have been reported. [25] However, there is insufficient evidence regarding the safety of artesunate use in the first trimester of pregnancy. The WHO recommends that artesunate use for severe malaria in the first trimester should be based on the individual risks versus benefits. In absence of other viable treatment options, artesunate may be used.[ medical citation needed ]

Children

Artesunate is safe for use in children. Artesunate + sulfadoxine/pyrimethamine should be avoided in the newborns due to sulfadoxine/pyrmethamine effects on bilirubin. [15] Parenteral artesunate dosing for treatment of severe malaria in children less than 20 kg should be higher than that of adults in order to increase exposure. [15] When artesunate cannot be given orally or intramuscularly due to an individual's weakness or inability to swallow, rectal administration may be given as pre-referral treatment as long as parenteral administration is initiated after transfer to a more advanced facility.[ medical citation needed ]

Adverse effects

Artesunate may cause serious side effects including hemolytic anemia (a condition in which red blood cells are destroyed), and severe allergic reactions. [8]

Artesunate is generally safe and well tolerated. Artesunate-based regimens are less likely to cause vomiting and tinnitus than quinine plus anti-malarial antibiotic therapy. [26] The best recognised adverse effect of the artemisinins is that they lower reticulocyte counts. [27] This is not usually of clinical relevance.[ medical citation needed ]

With increased use of I.V. artesunate, there have been reports of post-artesunate delayed haemolysis (PADH). [28] Delayed haemolysis (occurring around two weeks after treatment) has been observed in people treated with artesunate for severe malaria. [29]

Contraindications

Artesunate is typically a well tolerated medicine. Known contraindications include a previous severe allergic reaction to artesunate. [30]

Drugs that should be avoided while on artesunate are the drugs that inhibit the liver enzyme CYP2A6. These drugs include amiodarone, desipramine, isoniazid, ketoconazole, letrozole, methoxsalen and tranylcypromine. [31]

Mechanisms of action

The mechanisms of action of artesunate remains unclear and debatable. Artesunate is a prodrug that is rapidly converted to its active form dihydroartemisinin (DHA). This process involves hydrolysis of the 4-carbon ester group via plasma esterase enzyme. [32] It is hypothesized that the cleavage of endoperoxide bridge in the pharmacophore of DHA generates reactive oxygen species (ROS), which increases oxidative stress and causes malarial protein damage via alkylation. [32] In addition, Artesunate potently inhibits the essential Plasmodium falciparum exported protein 1 (EXP1), a membrane glutathione S-transferase. [33] As a result, the amount of glutathione in the parasite is reduced.[ medical citation needed ]

In 2016, artemisinin has been shown to bind to a large number targets, suggesting that it acts in a promiscuous manner. [34] There is evidence suggesting DHA inhibition of calcium-dependent ATPase on endoplasmic membrane, which disrupts protein folding of parasites. [32]

Pharmacokinetics

In infected individuals, the elimination half-life of artesunate is about 0.22 hours. Its active metabolite, DHA, has a slightly longer half-life of 0.34 hours. Overall, the average half-life ranges from 0.5 to 1.5 hours. [35] Because of its short half-life, its use in malaria prevention is limited. [32]

DHA is metabolized to an inactive metabolite by the liver enzymes CYP2B6, CYP2C19, and CYP3A4. [36]

Chemical synthesis

Artesunate is made from dihydroartemisinin (DHA) by reacting it with succinic acid anhydride in a basic medium. It is one of few semi-synthetic derivatives from artemisinin that is water-soluble. [35] [37]

Research

Artesunate is under study for the treatment of COVID-19. [38]

History

In May 2020, artesunate was approved for medical use in United States. [39] [13] Prior to this approval, intravenous (IV) artesunate was only available through the Expanded Access program of the U.S. Food and Drug Administration (FDA), which allowed the Centers for Disease Control and Prevention (CDC) to provide IV artesunate to people in the U.S. with severe malaria and to people with uncomplicated malaria who are unable to take oral medications under an investigational new drug (IND) protocol. [13] There has been no FDA-approved drug for treatment of severe malaria in the United States since the marketing of quinidine was discontinued by the manufacturer in March 2019. [13]

The safety and efficacy of IV artesunate for the treatment of severe malaria was primarily evaluated in a randomized controlled trial in Asia (Trial 1) and a supportive published randomized controlled trial in Africa (Trial 2). [13] [8] Trial 1 was conducted at 10 sites in Myanmar, Bangladesh, India, and Indonesia. [8]

Trial 1 enrolled 1,461 participants who received either IV artesunate or the comparator drug quinine and included 202 pediatric participants younger than 15 years. [13] Trial 2 included 5,425 randomized pediatric participants younger than 15 years of age with severe malaria who were treated with artesunate or quinine. [13] In both trials, the number of participants treated with artesunate who died in the hospital was significantly lower than the number who died in the control group treated with quinine. [13] Trial 2 was conducted during 2005–2010 in nine African countries. [8] A third trial, Trial 3, was conducted during 2007–2008 in Gabon and Malawi. [8]

In Trial 1, the most common adverse reactions in participants with malaria treated with IV artesunate were acute renal failure requiring dialysis, hemoglobinuria and jaundice. [13] The safety profile in Trial 2 was generally similar to Trial 1. [13]

One trial was used to evaluate both, safety and benefits of artesunate. [8] The trial enrolled participants with severe malaria who needed hospitalization because of their condition. [8] Participants received at random either artesunate or a medicine used to treat malaria (quinine). [8] Participants and the health care providers knew which treatment was being given. [8]

The benefit of artesunate in comparison to quinine was evaluated by comparing the number of participants who died while in the hospital (in-hospital mortality). [8]

The benefit of artesunate was supported by the data from Trial 2 in which pediatric participants younger than 15 years of age with severe malaria were randomly assigned treatment with artesunate or quinine. [8]

The application for IV artesunate was granted priority review and orphan drug designations. [13] [40] The FDA granted approval of artesunate for injection to Amivas. [13]

Related Research Articles

<span class="mw-page-title-main">Malaria</span> Mosquito-borne infectious disease

Malaria is a mosquito-borne infectious disease that affects humans and other vertebrates. Human malaria causes symptoms that typically include fever, fatigue, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. Symptoms usually begin 10 to 15 days after being bitten by an infected Anopheles mosquito. If not properly treated, people may have recurrences of the disease months later. In those who have recently survived an infection, reinfection usually causes milder symptoms. This partial resistance disappears over months to years if the person has no continuing exposure to malaria.

<span class="mw-page-title-main">Quinine</span> Medication used to treat malaria and babesiosis

Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to Plasmodium falciparum that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal leg cramps, quinine is not recommended for this purpose due to the risk of serious side effects. It can be taken by mouth or intravenously. Malaria resistance to quinine occurs in certain areas of the world. Quinine is also used as an ingredient in tonic water to impart a bitter taste.

<span class="mw-page-title-main">Mefloquine</span> Pharmaceutical drug

Mefloquine, sold under the brand name Lariam among others, is a medication used to prevent or treat malaria. When used for prevention it is typically started before potential exposure and continued for several weeks after potential exposure. It can be used to treat mild or moderate malaria but is not recommended for severe malaria. It is taken by mouth.

Antimalarial medications or simply antimalarials are a type of antiparasitic chemical agent, often naturally derived, that can be used to treat or to prevent malaria, in the latter case, most often aiming at two susceptible target groups, young children and pregnant women. As of 2018, modern treatments, including for severe malaria, continued to depend on therapies deriving historically from quinine and artesunate, both parenteral (injectable) drugs, expanding from there into the many classes of available modern drugs. Incidence and distribution of the disease is expected to remain high, globally, for many years to come; moreover, known antimalarial drugs have repeatedly been observed to elicit resistance in the malaria parasite—including for combination therapies featuring artemisinin, a drug of last resort, where resistance has now been observed in Southeast Asia. As such, the needs for new antimalarial agents and new strategies of treatment remain important priorities in tropical medicine. As well, despite very positive outcomes from many modern treatments, serious side effects can impact some individuals taking standard doses.

<span class="mw-page-title-main">Quinidine</span> Antiarrythmic medication

Quinidine is a class IA antiarrhythmic agent used to treat heart rhythm disturbances. It is a diastereomer of antimalarial agent quinine, originally derived from the bark of the cinchona tree. The drug causes increased action potential duration, as well as a prolonged QT interval. As of 2019, its IV formulation is no longer being manufactured for use in the United States.

<span class="mw-page-title-main">Artemisinin</span> Group of drugs used against malaria

Artemisinin and its semisynthetic derivatives are a group of drugs used in the treatment of malaria due to Plasmodium falciparum. It was discovered in 1972 by Tu Youyou, who shared the 2015 Nobel Prize in Physiology or Medicine for her discovery. Artemisinin-based combination therapies (ACTs) are now standard treatment worldwide for P. falciparum malaria as well as malaria due to other species of Plasmodium. Artemisinin is extracted from the plant Artemisia annua a herb employed in Chinese traditional medicine. A precursor compound can be produced using a genetically engineered yeast, which is much more efficient than using the plant.

<span class="mw-page-title-main">Artemether</span> Chemical compound

Artemether is a medication used for the treatment of malaria. The injectable form is specifically used for severe malaria rather than quinine. In adults, it may not be as effective as artesunate. It is given by injection in a muscle. It is also available by mouth in combination with lumefantrine, known as artemether/lumefantrine.

<span class="mw-page-title-main">Dihydroartemisinin</span> Drug used to treat malaria

Dihydroartemisinin is a drug used to treat malaria. Dihydroartemisinin is the active metabolite of all artemisinin compounds and is also available as a drug in itself. It is a semi-synthetic derivative of artemisinin and is widely used as an intermediate in the preparation of other artemisinin-derived antimalarial drugs. It is sold commercially in combination with piperaquine and has been shown to be equivalent to artemether/lumefantrine.

<span class="mw-page-title-main">Amodiaquine</span> Chemical compound

Amodiaquine (ADQ) is a medication used to treat malaria, including Plasmodium falciparum malaria when uncomplicated. It is recommended to be given with artesunate to reduce the risk of resistance. Due to the risk of rare but serious side effects, it is not generally recommended to prevent malaria. Though, the World Health Organization (WHO) in 2013 recommended use for seasonal preventive in children at high risk in combination with sulfadoxine and pyrimethamine.

<span class="mw-page-title-main">Mass drug administration</span>

The administration of drugs to whole populations irrespective of disease status is referred to as mass drug administration (MDA) or mass dispensing.

Intermittent preventive therapy or intermittent preventive treatment (IPT) is a public health intervention aimed at treating and preventing malaria episodes in infants (IPTi), children (IPTc), schoolchildren (IPTsc) and pregnant women (IPTp). The intervention builds on two tested malaria control strategies to clear existing parasites and to prevent new infections (prophylaxis).

<span class="mw-page-title-main">Piperaquine</span> Chemical compound

Piperaquine is an antiparasitic drug used in combination with dihydroartemisinin to treat malaria. Piperaquine was developed under the Chinese National Malaria Elimination Programme in the 1960s and was adopted throughout China as a replacement for the structurally similar antimalarial drug chloroquine. Due to widespread parasite resistance to piperaquine, the drug fell out of use as a monotherapy, and is instead used as a partner drug for artemisinin combination therapy. Piperaquine kills parasites by disrupting the detoxification of host heme.

Project 523 is a code name for a 1967 secret military project of the People's Republic of China to find antimalarial medications. Named after the date the project launched, 23 May, it addressed malaria, an important threat in the Vietnam War. At the behest of Ho Chi Minh, Prime Minister of North Vietnam, Zhou Enlai, the Premier of the People's Republic of China, convinced Mao Zedong, Chairman of the Chinese Communist Party, to start the mass project "to keep [the] allies' troops combat-ready", as the meeting minutes put it. More than 500 Chinese scientists were recruited. The project was divided into three streams. The one for investigating traditional Chinese medicine discovered and led to the development of a class of new antimalarial drugs called artemisinins. Launched during and lasting throughout the Cultural Revolution, Project 523 was officially terminated in 1981.

Sulfadoxine/pyrimethamine, sold under the brand name Fansidar, is a combination medication used to treat malaria. It contains sulfadoxine and pyrimethamine. For the treatment of malaria it is typically used along with other antimalarial medication such as artesunate. In areas of Africa with moderate to high rates of malaria, three doses are recommended during the second and third trimester of pregnancy.

Artesunate/sulfadoxine/pyrimethamine is an artesunate-based oral medication used to treat malaria. It consists of artesunate and sulfadoxine/pyrimethamine.

Piperaquine/dihydroartemisinin (DHA/PPQ), sold under the brand name Eurartesim among others, is a fixed dose combination medication used in the treatment of malaria. It is a combination of piperaquine and dihydroartemisinin. Specifically it is used for malaria of the P. falciparum and P. vivax types. It is taken by mouth.

Risankizumab, sold under the brand name Skyrizi, is a humanized monoclonal antibody used for the treatment of plaque psoriasis, psoriatic arthritis, and Crohn's disease. It is designed to target interleukin 23A (IL-23A). It is given by subcutaneous injection.

Artesunate/pyronaridine, sold under the brand name Pyramax, is a fixed-dose combination medication for the treatment of malaria. It can be used for malaria of both the P. falciparum and P. vivax types. It combines artesunate and pyronaridine. It is taken by mouth.

Liu Xu was a Chinese pharmaceutical chemist known for the discovery of artesunate, a novel antimalarial drug. The discovery of artesunate solves the problem that artemisinin is nearly insoluble in water. Artesunate can be given by intravenous injection, intramuscular injection, by mouth, and by rectum.

Sanjeev Krishna,, is a British physician and parasitologist whose research focuses on affordable diagnosis and treatment of diseases such as COVID-19, malaria, Ebola, African trypanosomiasis, leishmaniasis, and colorectal cancer. Krishna is Professor of Medicine and Molecular Parasitology at St George's, University of London and St George's Hospital.

References

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  39. ↑ "Drug Approval Package: Artesunate". U.S. Food and Drug Administration (FDA). 25 June 2020. Retrieved 24 September 2020.
  40. ↑ "Artesunate Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). 5 September 2017. Retrieved 27 May 2020.
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