アルテスナート

Breast Feeding; Lactation; Milk, Human; Anti-infective Agents; Antiparasitic Agents; Antimalarials; Antiprotozoal Agents

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine (Orphan designations)

FDA approved drugs -> Active ingredient

Antimalarial medicines > Medicines for curative treatment

Artesunate is the sodium salt of the hemisuccinate ester of artemisinin. It is soluble in water but has poor stability in aqueous solutions at neutral or acid pH. In the injectable form, artesunic acid is drawn up in sodium bicarbonate to form sodium artesunate immediately before injection.

Warning

H302 (95.7%): Harmful if swallowed [Warning Acute toxicity, oral]

P261, P264, P270, P271, P280, P301+P317, P302+P352, P304+P340, P317, P321, P330, P362+P364, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 46 reports by companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Danger

H251 (100%): Self-heating; may catch fire [Danger Self-heating substances and mixtures]

Acute Tox. 4 (95.7%)

Self-heat. 1 (100%)

The activity of artemisinin in combination with other antimalarial drugs against P. falciparum was measured in vitro and against P. berghei in vivo. A combination of artemisinin with mefloquine was synergistic whereas that with pyrimethamine was antagonistic in vitro and in vivo. A combination of artemisinin with other antimalarials (sulfadiazine, sulfadoxine, sulfadoxine-pyrimethamine, cycloguanil, and dapsone) was also shown to be antagonistic in vivo.

There has been some concern that antipyretics might attenuate the host defense against malaria, as their use is associated with delayed parasite clearance. However, this appears to result from delaying cytoadherence, which is likely to be beneficial. There is no reason to withhold antipyretics in malaria. ...Paracetamol (acetaminophen) and ibuprofen are the preferred options for reducing fever.

In an open label study of severe malaria in 104 patients in the United States, elevations in ALT occurred in 27% of subjects, AST in 49%, and bilirubin in 17%. These abnormalities, however, were attributable to the hemolysis and liver involvement that are common in patients with acute, severe malaria. None of the elevations were attributed to drug induced liver injury. Since licensure of artesunate for injection and its more widescale clinical use in the United States, there have been no reports of acute liver injury attributed to its use.

A 2025 systematic review discusses how treatment with Artesunate can produce liver and kidney damage in specific scenarios, i.e., when patients receive doses that are too high or receive extended periods of therapy. This hepatic and renal damage involves free-radical damage, cellular respiration failure, and inflammatory reaction pathways. The authors note that a combination of antioxidants, natural compounds, and optimized doses is an effective strategy to help protect the liver and kidneys.

/CASE REPORTS/ A total of 83 pregnant women with Plasmodium falciparum malaria, administered artesunate or artemether, often followed by quinine or mefloquine, were followed weekly until delivery. Overall 73 pregnancies (88%) resulted in live births, 3 (4%) in abortions, and 2 (3%) in still births. There were no congenital abnormalities and the 46 children followed for more than a year all developed normally

/CASE REPORTS/ A 33-year-old man presented with acute uncomplicated falciparum malaria. Eleven hours after receiving artesunate 4 mg/kg, he was admitted to the inpatient department with agitation, generalized pruritus, leftsided chest pain, and dyspnea. He was apyrexial with pulse 96/min, BP 150/110 mmHg, wheezes over both lung fields, and a widespread urticarial rash over the limbs and abdomen. Parenteral chlorpheniramine and dexamethasone were given. He improved over 2 hr; the vital signs returned to normal, the rash faded, and chest auscultation revealed only a few wheezes, but then the rash reappeared suddenly and the patient became clammy and sweaty and collapsed to the floor, unconscious with impalpable pulses. Adrenaline and dexamethasone were given. He regained consciousness after 1-2 min, vomited, and became extremely agitated. The following morning he was well with only a fading urticarial rash. Antimalarial treatment was completed with quinine and doxycycline. On questioning further, he remembered that 2 years previously he had been treated for malaria with /artesunate-melfoquine/ (MAS3), and had been admitted to hospital because of a generalized rash. Unfortunately his records were untraceable. He denied previous allergic reactions or asthma.

/CASE REPORTS/ A 26-year-old previously well man presented to the Research Unit's malaria clinic with acute uncomplicated falciparum malaria. Four years previously he had received artesunate-mefloquine (MAS3) antimalarial treatment without adverse reactions. About 15-20 min after receiving oral artesunate 4 mg/kg, he developed generalized pruritus and a widespread urticarial rash. He was given chlorpheniramine (8 mg) orally. After 1 hr he felt dizzy, and was found to be hypotensive (blood pressure, BP, 80/40 mmHg), but the chest was clear and other vital signs remained normal. After 2 hr the hypotension, rash, and dizziness had resolved. Following the Unit's previously satisfactory experience with rechallenge, artesunate was given again the next day. The patient received chlorpheniramine orally 30 min before this second dose, as pretreatment. Mefloquine was not given. One hour later, he developed pruritus, periorbital, lip, and forearm swelling, tachycardia (140/min), hypotension (90/30 mmHg), a widespread urticarial rash and labored breathing, although the chest remained clear. He was given dexamethasone, chlorpheniramine, and adrenaline twice and recovered rapidly. He was kept under observation for the afternoon and then discharged home. The third dose of artesunate was withheld and he was given mefloquine alone under supervision without further problems.

/CASE REPORTS/ In July 1996, a 36-year-old American geologist in Ghana had fever and chills without associated neurologic symptoms. His blood smear revealed P. falciparum. ... He took two /artesunate/ tablets on day 1, followed by one tablet daily for the next four days. He became afebrile on day 2. A blood smear on day 5 contained no malaria parasites. Two days after completing the artesunate treatment, the patient noted that his gait was unsteady. His electroencephalogram was normal. Over the next week, worsening ataxia and slurred speech developed. Three weeks later, he was evacuated to a London hospital. Magnetic resonance imaging of the brain and a lumbar puncture revealed no abnormalities. In September 1996, the patient was admitted to a southern California hospital with persistent neurologic symptoms. He had slurred speech; a wide-based, ataxic gait; and impaired heel-to-shin and rapid alternating movements. A peripheral smear was again positive for plasmodium species, but the parasites were too scant to speciate. He was re-treated with oral quinine and doxycycline. In October 1996 he began rehabilitation therapy. One month later, his ataxia was moderately improved, and his speech was nearly normal. ... Our patient had neurologic sequelae over a four-month period immediately after treatment with artesunate for P. falciparum. Since cerebellar dysfunction would be a highly unusual complication of malaria, this case serves as a warning of the need for further attentiveness to the neurotoxic side effects of artemisinin compounds.

For more Human Toxicity Excerpts (Complete) data for ARTESUNIC ACID (7 total), please visit the HSDB record page.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Artesunate

Ambiguous-DILI-concern

5

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Acute Exposure/ Many animal studies suggest that systemic artesunate has immunoregulatory activity. /The authors/ investigated the effect of topical artesunate on contact sensitivity in guinea pigs sensitized with dinitrochlorobenzene (DNCB). Female hairless guinea pigs were used and the contact reaction graded by visual (5 point) score and erythema measured with a color analyzer. Topical artesunate inhibited the elicitation reaction of contact hypersensitivity when given at the 1st and 12th hr after challenge (p < 0.05), but showed no effect when given from day 3 to day 1 before challenge (p > 0.05). Artesunate had no effect on toxic (irritant) contact dermatitis from 20% croton oil (p > 0.05). The results indicate that topical application of artesunate may offer a novel treatment of allergic contact dermatitis and other cutaneous immune-mediated disorders.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In the present investigation, artesunate (ART) was found also to inhibit angiogenesis in vivo and in vitro. The anti-angiogenic effect in vivo was evaluated in nude mice by means of human ovarian cancer HO-8910 implantation and immunohistochemical stainings for microvessel (CD31), vascular endothelial growth factor (VEGF) and VEGF receptor KDR/flk-1. Tumor growth was decreased and microvessel density was reduced following drug treatment with no apparent toxicity to the animals. ART also remarkably lowered VEGF expression on tumor cells and KDR/flk-1 expression on endothelial cells as well as tumor cells. The in vitro effect of ART was tested on models of angiogenesis, namely, proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVEC). The results showed that ART significantly inhibited angiogenesis in a dose-dependent form in the range of 0.5-50 umol/L. Additionally, the inhibitory effect of ART on HVUEC proliferation was stronger than that on Hela, JAR, HO-8910 cancer cells, NIH-3T3 fibroblast cells and human endometrial cells, indicating that ART was selectively against HUVEC. These findings and the known low toxicity of ART are clues that ART may be a promising angiogenesis inhibitor.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Reproductive studies performed in rats and rabbits have show dose-dependent loss of implantation without major congenital abnormalities with artemisinin, including artesunate. Dose within the therapeutic range have abortive effects. The dose, and presumably exposure, of the artemisinin that cause reduced fetal survival and increased abortion rates in experimental animals are similar to the proposed human dose. ... Despite the consistent finding of impaired fetal survival following exposure to artemisinin in the first trimester in animals, none of the studies in any animal species has shown teratogenicity.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In experiments carried out in mice, hamsters, guinea pigs and rabbits both dihydroartemisinin and artesunate showed contragestational effect. In mice and rabbits they caused embryo absorption whereas in hamsters and guinea pigs they induced abortion. The contragestational ED50 of dihydroartemisinin given sc on d 7 of pregnancy in mice and d 5 of pregnancy in hamsters were 32.8(27.7-38.9) mg.kg-1 and 6.1(5.6-6.7) mg.kg-1 respectively. The ED50 of this drug given im on d 18 of pregnancy in guinea pigs was 18.3(13.9-24.2) mg.kg-1. Dihydroartemisinin also showed mid-pregnancy terminating effect in hamsters. The contragestational ED50 of artesunate given sc on d 5 of pregnancy in hamsters and the ED50 of sodium artesunate given sc on d 5-8 of pregnancy in hamsters were 12.2(10.3-14.4) mg.kg-1 and 1.0(0.9-1.2) mg.kg-1 daily respectively. Results of light microscopic examination revealed that dihydroartemisinin was selectively toxic to embryo sac. At dose levels sufficient to induce embryo sac necrosis, dihydroartemisinin did not injure the uterus and ovary of the maternal animals. On the ground of the foregoing observations we consider that dihydroartemisinin, artesunate and their analogous drugs should not be used to treat malaria in pregnant women and there is the possibility to exploit intentional abortion agents from artemisinin derivatives.

For more Non-Human Toxicity Excerpts (Complete) data for ARTESUNIC ACID (14 total), please visit the HSDB record page.

Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

P - Antiparasitic products, insecticides and repellents

P01BE03

Artesunate is an artemisinin derivative that is metabolized to DHA, which generates free radicals to inhibit normal function of _Plasmodium_ parasites. It has a short duration of action due to its short half life, and a moderate therapeutic index. Patients should be counselled regarding the risk of post treatment hemolytic anemia and hypersenstivity.

Artesunate is metabolized to the active DHA. the endoperoxide bridge of DHA reacts with heme, generating free radicals which inhibit protein and nucleic acid synthesis of the _Plasmodium_ parasites during all erythrocytic stages. Reactions with these free radicals can also lead to alkylation of parasitic proteins such as a calcium adenosine triphosphatase and EXP1, a glutathione S-transferase.

Two theories have been put forward for the mode of antimalarial action of the artemisinin antimalarials, in accodance with the known properties of peroxides with medicinal activity. The first assumes that the artemisinins must be activated by contact with either reduced haem (ferrous haem, Fe(ll)PPIX) or non-haem ferrous iron (exogenous iron), causing cleavage of the peroxide to generate oxygen-centered radicals (alkoxy radicals') which are the presumed to be converted into carbon-centered radicals by transfer of proximate hydrogen atoms from the periphery of the peroxide molecule. These carbon-centered radicals are then thought to alkylate sensitive, yet unspecified, biomolecules in the parasite. A second theory argues for a process in which the intact artemisinin binds to a site within a vital protein in the parasite. The act of binding causes the peroxide to be converted to hydroperoxide or similar open peroxide, which in accordance with known properties of such compounds, generates one or more active chemical entities, either oxidizing agents or oxygen transfer agents per se, or oxygen-centered free radicals. This would be associated with the binding process. In such a way, the artemisinins might act as (irreversibile) inhibitors. Iron may, or may not, be associated with the activation process. No specific biological target in the parasite has yet been identified in support of this theory, but it may be membrane-bound proteins.

Artesunate is a water soluble derivative of artemisinin, an antimalarial compound isolated from the Chinese herb Qinghao (Artemisia annua). Artesunate is rapidly metabolized to dihydroartemisinin (DHA) in the body. Chemically, artesunate, and its active metabolite, DHA, are sesquiterpene lactones with a trioxane ring containing a peroxide bridge. The peroxide bridge appears to be essential for the antimalarial activity of artesunate. Structure-activity relationship studies show that the deoxy derivative of DHA (that lack the peroxide bridge) was 277-fold less active than DHA. The activity of deoxyartesunate was not measured. Deoxy derivatives of other artemisinin analogs were 10- to 1000-fold less active compared to the parent compounds. Artesunate increases superoxide anion production and lipid peroxidation in falciparum-infected erythrocytes in vitro. However, artesunate does not suppress the activity of antioxidant enzymes (superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase) in infected or uninfected erythrocytes. Erythrocytes infected with the ring or trophozoite forms in vitro accumulate 100- and 180- fold higher concentrations of DHA (12 nM ie, 3.40 ng/mL), respectively, compared to uninfected erythrocytes. These experiments were performed in a medium containing 10% human serum. The relevance of these findings to the uptake in vivo is unclear. The precise mechanism by which artesunate exhibits antiplasmodial activity is not understood.

A 2025 systematic review notes Artesunate's pharmacological activities (antimalarial, antiparasite,antitumor, antivirus, antiinflammation, and antibacterial),and that it is a highly effective antimalarial agent with the potential to induce organ toxicity under certain conditions. The authors note that mechanisms of Artesunate-induced toxicity include oxidative stress, inflammation, and apoptotic signaling patthhways.They also note that Artesunate ameliorates MASH (Metabolic Dysfunction-Associated Steatohepatitis) by reducing

The elimination half life of artesunate is 0.3h with a range of 0.1-1.8h. The elimination half life of DHA is 1.3h with a range of 0.9-2.9h. Half life after intramuscular administration is 48 min in children and 41 min in adults.

In volunteer studies, artsunate was cleared very rapidly (within minutes) by biotransformation to dihydroartemisinin, which was eliminated by with a half-life of approximately 45 minutes.

Artesunate is rapidly metabolized to dihydroartemisinin (DHA) by plasma esterases. DHA is glucuronidated by UGT1A9 and UGT2B7 to DHA-glucuronide. DHA-glucuronide can undergo a minor metabolic pathway to for a furano acetate derivative of DHA-glucuronide. CYP2A6 may minorly contribute to the metabolism of artesunate.

Following administration to humans, artesunate is rapidly hydrolyzed to its principle active metabolite, dihydroartemisinin. Data from in vitro studies with human liver microsomes and from clinical studies suggest that DHA-glucoronide (10-position) is the principal Phase II metabolite of DHA and that uridine diphosphate glucuronyl transferase isoforms 1A1, 1A8-9, or 2B7 may be the main conjugating enzyme.

Artemisinin is completely and rapidly absorbed after oral administration in rats. However, a very low plasma level was obtained even after a dose of 300 mg/kg. Liver was found to be the chief site of inactivation. When artemisinin was given i.m., significant and more persistent plasma levels were detected. Artemisinin was shown to pass the blood-brain and blood-placenta barriers after i.v. injection. Very little unchanged artemisinin was found in the urine or feces in 48 hours regardless of the route of administration. Metabolites identified after administration to humans include deoxyartemisinin, deoxydihydroartemisinin, and 9,10-dihydroxydeoxyartemisinin.

Artesunate has known human metabolites that include (1S,4S,5R,8S,9R,10R,12R,13R)-1,5,9-Trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.04,13.08,13]hexadecan-10-ol.

Agents used in the treatment of malaria. They are usually classified on the basis of their action against plasmodia at different stages in their life cycle in the human. (From AMA, Drug Evaluations Annual, 1992, p1585)

Substances that inhibit or prevent the proliferation of NEOPLASMS.

Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly.

Agents that act systemically to kill adult schistosomes.

The Cmax of artesunate is 3.3µg/mL while the Cmax of the active metabolite DHA is 3.1µg/mL. The AUC of artesunate is 0.7µg\*h/mL while the AUC of DHA is 3.5µg\*h/mL. After intravenous artesunate, DHA has a Tmax of 0.5-15 minutes in adult patients and 21-64 minutes in pediatric patients. Intramuscular artesunate has a Tmax of 8-12 minutes. Infants less than 6 months old will have a higher AUC due to an undeveloped UGT metabolic pathway.

The main route of elimination in humans is unknown. In rats, a dose of artesunate is 56.1% eliminated in the urine and 38.5% in the feces.

The volume of distribution of artesunate is 68.5L while the volume of distribution of DHA is 59.7L.

The clearance of artesunate is 180L/h while the clearance of DHA is 32.3L/h.

Following administration to humans, artesunate is rapidly hydrolyzed to its principal active metabolite, dihydroartemisinin. The pharmacokinetics of artesunate are characterized by marked inter-subject variability, differing significantly between healthy volunteers and infected patients, and among patients with different disease severity.

The pharmacokinetic of artesunate and dihydroartemisin are characterized by marked inter-subject variability. The pharmacokinetic parameters of artesunate and dihydroartemisinin differ significantly between healthy volunteers and infected patients, and among patients with different disease severity. Pharmacokinetic data from unbound plasma concentrations of artesunate or dihydroartemisinin should be interpreted with caution because the drug accumulates selectively in parasitized RBC's In in vitro experiments, accumulation of dihydroartemisinin in infected RBC's is in concentrations approximately 300-fold higher than those in plasma .

Artesunate is dispensed as a powder of artesunic acid. This is dissolved in sodium bicarbonate (5%) to form sodium artesunate. The solution is then diluted in approximately 5 ml of 5% dextrose and given by intravenous injection or by intramuscular injection to the anterior thigh. The solution should be prepared freshly for each administration and should not be stored.