Artesunate (AS) is a medication used to treat
malaria
Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. S ...
.
The intravenous form is preferred to
quinine
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 cr ...
for severe malaria.
Often it is used as part of
combination therapy
Combination therapy or polytherapy is therapy that uses more than one medication or modality. Typically, the term refers to using multiple therapies to treat a ''single'' disease, and often all the therapies are pharmaceutical (although it can also ...
, such as artesunate plus
mefloquine
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 ...
.
It is not used for the prevention of malaria.
Artesunate can be given by
injection into a vein
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
,
injection into a muscle
Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles have l ...
, by mouth, and by rectum.
The most common side effects include kidney failure requiring dialysis,
hemoglobinuria
Hemoglobinuria is a condition in which the oxygen transport protein hemoglobin is found in abnormally high concentrations in the urine. The condition is caused by excessive intravascular hemolysis, in which large numbers of red blood cells (RBCs) ...
(the presence of hemoglobin in urine) and
jaundice
Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme meta ...
.
Artesunate is generally well tolerated.
Side effects may include a
slow heartbeat, allergic reaction, dizziness, and
low white blood cell levels.
During
pregnancy
Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins.
Pregnancy usually occurs by sexual intercourse, but ca ...
it appears to be a safer option, even though animal studies have found harm to the baby. Use is likely fine during
breastfeeding
Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that br ...
. It is in the
artemisinin
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 dis ...
class of medication.
Artesunate was developed by
Liu Xu
Liu Xu (; 888–947),'' History of the Five Dynasties'', vol. 89. courtesy name Yaoyuan (), formally the Duke of Qiao (), was a Chinese historian and politician of the Chinese Five Dynasties and Ten Kingdoms Period states Later Tang and Later Ji ...
in 1977. It is on the
World Health Organization's List of Essential Medicines
The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...
.
It was approved for medical use in the United States in May 2020.
It is in the class of medications known as artemisinins, which are derivatives from "qinghao," or
sweet wormwood plant (''
Artemisia annua
''Artemisia annua'', also known as sweet wormwood, sweet annie, sweet sagewort, annual mugwort or annual wormwood (), is a common type of wormwood native to temperate Asia, but naturalized in many countries including scattered parts of North Am ...
'').
Medical uses
Artesunate is the first-line treatment for children or adults with severe malaria,
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.
Artemisinin-based combination therapy
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 c ...
may be used by mouth in persons that can tolerate it after 24 hours by injection.
Artesunate is preferred over parenteral quinine for severe malaria treatment.
Artesunate was shown to prevent more deaths from severe malaria than quinine in two large multicentre randomized controlled trials from Africa and Asia. A subsequent systematic review of seven randomized controlled trials found this improvement in survival rates to be consistent across all trials.
Artesunate's efficacy is comparable to that of
artemether
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 a ...
, another artemisinin derivative, in treating adults for severe malaria caused by ''Plasmodium falciparum'', though artesunate clears more parasites initially. 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.
Artesunate is also used to treat less severe forms of malaria when it can be given orally.
It has activity against ''
P. ovale'', ''
P. malariae'', and severe ''
P. knowlesi''.
Artesunate +
sulfadoxine/pyrimethamine
Sulfadoxine/pyrimethamine, sold under the brand name Fansidar, is a combination medication used to treat malaria. It contains sulfadoxine (a sulfonamide) and pyrimethamine (an antiprotozoal). For the treatment of malaria it is typically used alo ...
for treatment of ''
P. vivax'' is not recommended due to high rates of resistance.
While artesunate is used primarily as treatment for malaria, there is some evidence that it may also have some beneficial effects in ''
Schistosoma haematobium
''Schistosoma haematobium'' (urinary blood fluke) is a species of digenetic trematode, belonging to a group (genus) of blood flukes (''Schistosoma''). It is found in Africa and the Middle East. It is the major agent of schistosomiasis, the most ...
'' infection, 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
The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
(WHO) over
quinine
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 cr ...
.
Pregnancy
When given in the second or third trimesters of pregnancy, no artesunate-related adverse pregnancy outcomes have been reported. 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.
Children
Artesunate is safe for use in children. Artesunate + sulfadoxine/pyrimethamine should be avoided in the newborns due to sulfadoxine/pyrmethamine effects on bilirubin.
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.
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.
Adverse effects
Artesunate may cause serious side effects including hemolytic anemia (a condition in which red blood cells are destroyed), and severe allergic reactions.
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. The best recognised adverse effect of the artemisinins is that they lower
reticulocyte
Reticulocytes are immature red blood cells (RBCs). In the process of erythropoiesis (red blood cell formation), reticulocytes develop and mature in the bone marrow and then circulatory system, circulate for about a day in the blood stream before ...
counts. This is not usually of clinical relevance.
With increased use of I.V. artesunate, there have been reports of post-artesunate delayed
haemolysis
Hemolysis or haemolysis (), also known by several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid (e.g. blood plasma). Hemolysis may occur in vivo o ...
(PADH). Delayed haemolysis (occurring around two weeks after treatment) has been observed in people treated with artesunate for severe malaria.
Contraindications
Artesunate is typically a well tolerated medicine. Known contraindications include a previous severe allergic reaction to artesunate.
Drugs that should be avoided while on artesunate are the drugs that inhibit the liver enzyme
CYP2A6. These drugs include
amiodarone
Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia (VT), ventricular fibrillation (VF), and wide complex tachycardia, as well as atrial fibrilla ...
,
desipramine
Desipramine, sold under the brand name Norpramin among others, is a tricyclic antidepressant (TCA) used in the treatment of depression. It acts as a relatively selective norepinephrine reuptake inhibitor, though it does also have other activiti ...
,
isoniazid
Isoniazid, also known as isonicotinic acid hydrazide (INH), is an antibiotic used for the treatment of tuberculosis. For active tuberculosis it is often used together with rifampicin, pyrazinamide, and either streptomycin or ethambutol. For l ...
,
ketoconazole
Ketoconazole, sold under the brand name Nizoral among others, is an antiandrogen and antifungal medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin infections such as tinea, cutaneous candid ...
,
letrozole
Letrozole, sold under the brand name Femara among others, is an aromatase inhibitor medication that is used in the treatment of breast cancer.
It was patented in 1986 and approved for medical use in 1996. In 2020, it was the 257th most common ...
,
methoxsalen
Methoxsalen, sold under the brand name Oxsoralen among others, is a medication used to treat psoriasis, eczema, vitiligo, and some cutaneous lymphomas in conjunction with exposing the skin to ultraviolet (UVA) light from lamps or sunlight. Methox ...
and
tranylcypromine
Tranylcypromine, sold under the brand name Parnate among others,Drugs.co Page accessed April 17, 2016 is a monoamine oxidase inhibitor (MAOI). More specifically, tranylcypromine acts as nonselective and irreversible inhibitor of the enzyme mono ...
.
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
Dihydroartemisinin (also known as dihydroqinghaosu, artenimol or DHA) is a drug used to treat malaria. Dihydroartemisinin is the active metabolite of all artemisinin compounds (artemisinin, artesunate, artemether, etc.) and is also available as ...
(DHA). This process involves
hydrolysis
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...
of the 4-carbon ester group via plasma
esterase
An esterase is a hydrolase enzyme that splits esters into an acid and an alcohol in a chemical reaction with water called hydrolysis.
A wide range of different esterases exist that differ in their substrate specificity, their protein structure, ...
enzyme.
It is hypothesized that the cleavage of endoperoxide bridge in the
pharmacophore
300px, An example of a pharmacophore model.
A pharmacophore is an abstract description of molecular features that are necessary for molecular recognition of a ligand by a biological macromolecule. IUPAC defines a pharmacophore to be "an ensemble o ...
of DHA generates
reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
(ROS), which increases oxidative stress and causes malarial protein damage via
alkylation
Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecting ...
.
In addition, Artesunate potently inhibits the essential ''
Plasmodium falciparum
''Plasmodium falciparum'' is a Unicellular organism, unicellular protozoan parasite of humans, and the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female ''Anopheles'' mosqu ...
'' exported protein 1 (EXP1), a membrane
glutathione S-transferase
Glutathione ''S''-transferases (GSTs), previously known as ligandins, are a family of eukaryotic and prokaryotic phase II metabolic isozymes best known for their ability to catalyze the conjugation of the reduced form of glutathione (GSH) to x ...
. As a result, the amount of
glutathione
Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pero ...
in the parasite is reduced.
In 2016, artemisinin has been shown to bind to a large number targets, suggesting that it acts in a promiscuous manner. There is evidence suggesting DHA inhibition of calcium-dependent ATPase on endoplasmic membrane, which disrupts protein folding of parasites.
Pharmacokinetics
In infected individuals, the
elimination half-life
Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...
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.
Because of its short half-life, its use in malaria prevention is limited.
DHA is metabolized to an inactive metabolite by the liver enzymes
CYP2B6
Cytochrome P450 2B6 is an enzyme that in humans is encoded by the ''CYP2B6'' gene. CYP2B6 is a member of the cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances.
Funct ...
,
CYP2C19
Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some pr ...
, and
CYP3A4
Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...
.
Chemical synthesis
Artesunate is made from
dihydroartemisinin
Dihydroartemisinin (also known as dihydroqinghaosu, artenimol or DHA) is a drug used to treat malaria. Dihydroartemisinin is the active metabolite of all artemisinin compounds (artemisinin, artesunate, artemether, etc.) and is also available as ...
(DHA) by reacting it with
succinic acid anhydride in a basic medium. It is one of few
semi-synthetic
Semisynthesis, or partial chemical synthesis, is a type of chemical synthesis that uses chemical compounds isolated from natural sources (such as microbial cell cultures or plant material) as the starting materials to produce novel compounds with ...
derivatives
The derivative of a function is the rate of change of the function's output relative to its input value.
Derivative may also refer to:
In mathematics and economics
* Brzozowski derivative in the theory of formal languages
* Formal derivative, an ...
from
artemisinin
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 dis ...
that is water-soluble.
Research
In 2007, the FDA approved an
Investigational New Drug (IND) protocol for intravenous artesunate.
Artesunate is under study for the treatment of cancer and COVID-19.
History
In May 2020, artesunate was approved for medical use in United States.
Prior to this approval, intravenous (IV) artesunate was only available through the Expanded Access program of the U.S.
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA), which allowed the
Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...
(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.
There has been no FDA-approved drug for treatment of severe malaria in the United States since the marketing of
quinidine
Quinidine is a class IA antiarrhythmic agent used to treat heart rhythm disturbances. It is the enantiomer of antimalarial agent quinine, originally derived from the bark of the cinchona tree. The drug causes increased action potential duratio ...
was discontinued by the manufacturer in March 2019.
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).
Trial 1 was conducted at 10 sites in Myanmar, Bangladesh, India, and Indonesia.
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.
Trial 2 included 5,425 randomized pediatric participants younger than 15 years of age with severe malaria who were treated with artesunate or quinine.
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.
Trial 2 was conducted during 2005–2010 in nine African countries.
A third trial, Trial 3, was conducted during 2007–2008 in Gabon and Malawi.
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.
The safety profile in Trial 2 was generally similar to Trial 1.
One trial was used to evaluate both, safety and benefits of artesunate.
The trial enrolled participants with severe malaria who needed hospitalization because of their condition.
Participants received at random either artesunate or a medicine used to treat malaria (quinine).
Participants and the health care providers knew which treatment was being given.
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).
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.
The application for IV artesunate was granted priority review and orphan drug designations.
The FDA granted approval of artesunate for injection to Amivas.
References
External links
*
{{Portal bar, Medicine
Antimalarial agents
Carboxylate esters
Organic peroxides
Orphan drugs
Sesquiterpenes
Trioxanes
World Health Organization essential medicines
Wikipedia medicine articles ready to translate
Heterocyclic compounds with 4 rings
Succinate esters