Artesunate

384.42

384.42

1312995-182-4

712571

DTXSID3042681

Fine white crystalline powder

P - Antiparasitic products, insecticides and repellents

29419090

101

log Kow = 2.61 (est)

white to off-white

1.2076 (rough estimate)

140-142 °C

502.1°C at 760 mmHg

173.5ºC

1.543

acetone: soluble 33.4mg/mL

room temp

3.2X10-9 mm Hg at 25 °C (est)

Henry's Law constant = 3.8X10-15 atm cu m/mol at 25 °C (est)

pKa = 4.35 (est)

Poor stability in aqueous solutions /Artesunate sodium salt/|Hydroxyl radical reaction rate constant = 5.6X10-11 cu cm/molec-sec at 25 °C (est)

3

20/21/22

24/25

Xn

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 (95.35%): Harmful if swallowed [Warning Acute toxicity, oral]|P261, P264, P270, P271, P280, P301+P312, P302+P352, P304+P312, P304+P340, P312, P322, P330, P363, and P501|Aggregated GHS information provided by 43 companies from 4 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]|P235+P410, P261, P272, P280, P302+P352, P321, P333+P313, P363, P407, P413, P420, and P501|Aggregated GHS information provided by 3 companies from 1 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

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.

Treatment of severe malaria caused by Plasmodium falciparum|Treatment of malaria

Therap Cat: Antimalarial|Artesunate Rectal Capsules is indicated for the initial management of acute malaria in patients who cannot take medication by mouth and for whom parenteral treatment is not available.|To counter the threat of resistance of P. falciparum to monotherapies, and to improve treatment outcome, combinations of antimalarials are now recommended by WHO for the treatment of falciparum malaria. The following ACTs are currently recommended (alphabetical order): AS+AQ artesunate + amodiaquine combination, AS+MQ artesunate + mefloquine combination, AS+SP artesunate + sulfadoxine-pyrimethamine combination.|Artemisinin and its derivatives (artesunate, artemether, artemotil, dihydroartemisinin) produce rapid clearance of parasitaemia and rapid resolution of symptoms. They reduce parasite numbers by a factor of approximately 10,000 in each asexual cycle, which is more than other current antimalarials (which reduce parasite numbers 100- to 1000-fold per cycle). Artemisinin and its derivatives are eliminated rapidly. When given in combination with rapidly eliminated compounds (tetracyclines, clindamycin), a 7-day course of treatment with an artemisinin compound is required; but when given in combination with slowly eliminated antimalarials, shorter courses of treatment (3 days) are effective. The evidence of their superiority in comparison to monotherapies has been clearly documented.|For more Therapeutic Uses (Complete) data for ARTESUNIC ACID (14 total), please visit the HSDB record page.

Artemisinin congeners should not be given to patients with a previous history of an allergic reaction following their consumption or if an urticarial rash develops during treatment. Patient with a history of hypersensitivity reaction to one of the artemsinins should be advised not to take any of the derivatives again.|Artesunate rectal capsules have not been evaluated as sole therapy for malaria; consequently all patient who are initially treated with artesunate rectal capsules should be promptly referred and evaluated at the nearest health care facility able to provide a full curative course of treatment for malaria.|Adverse events described /following artesunate/ included bitter taste, mild pain at the injection site, bradycardia, paroxysmal ventricular premature beat, incomplete right bundle branch block, first-degree atrio-ventricular block, and urticaria.|... The most commonly reported adverse events (in the order of <1%) to be mild gastrointestinal (nausea, vomiting, diarrhea, abdominal pain) events.|For more Drug Warnings (Complete) data for ARTESUNIC ACID (25 total), please visit the HSDB record page.

A potential for resistance development by Plasmodium species to artesunate was examined in vitro and in vivo. In a preliminary study, the erythrocytic forms of the FCR3 strain of P. falciparum were passaged by exposure to increasing concentrations of artesunate (starting with 4 ng/mL) for 48 hours each, followed by growth in drug-free medium for 18 days (equivalent to 9 life cycles). The artesunate IC50 value increased by 3-fold after 6 to 7 passages over a period of 130 days. Such an effect was reversible when the parasites were grown in drug free medium for 5 weeks.|There is no convincing evidence yet of clinically relevant, stable, parasite resistance having developed to artesunate, or to other artemisinins. Resistant strains of fresh P. flaciparum have been established although not sustained in vitro.|With the exception of artemether-lumefantrine, the partner medicines of all other Antimalarial Combination Therapies (ACTs) have been previously used as monotherapies, and still continue to be available as such in many countries. Their continued use as monotherapies can potentially compromise the value of Antimalarial Combination Therapies (ACTs) by selecting for drug resistance. The withdrawal of artemisinins and other monotherapies is recommended.

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) (See all compounds classified as Antimalarials.)|Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)|Agents that act systemically to kill adult schistosomes. (See all compounds classified as Schistosomicides.)|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. (See all compounds classified as Antiviral Agents.)

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 .|The pharmacokinetics of oral dihydroartemisinin (DHA) following the dose of 2 and 4 mg/ kg body weight dihydroartemisinin and 4 mg/kg body weight oral artesunate (AS) were investigated in 20 healthy Thai volunteers (10 males, 10 females). All formulations were generally well tolerated. Oral DHA was rapidly absorbed from gastrointestinal tract with marked inter-individual variation. The pharmacokinetics of DHA following the two dose levels were similar and linearity in its kinetics was observed. Based on the model-independent pharmacokinetic analysis, median (95% CI) values for Cmax of 181 (120-306) and 360 (181-658) ng/ml were achieved at 1.5 hours following 2 and 4 mg/kg body weight dose, respectively. The corresponding values for AUC0-infinity, t1/2z, CL/f and Vz/f were 377 (199-1,128) vs 907 (324-2,289) ng.hr/mL, 0.96 (0.70-1.81) vs 1.2 (0.75-1.44) hours, 7.7 (4.3-12.3) vs 6.6 (3.1-10.1) L/kg, and 90.5 (28.6-178.2) vs 6.6 (3.1-10.1) mL/min/kg, respectively (2 vs 4 mg/kg dose). Oral AS was rapidly biotransformed to DHA, which was detectable in plasma as early as 15 minutes of AS dosing. Following 4 mg/kg dose, median (95% CI) value for Cmax of 519 (236-284) ng/mL was achieved at 0.7 (0.25-1.5) hours. AUC0-infinity, and t1/2z were 657 (362-2,079) ng.hr/mL, 0.74 (0.34-1.42) hours, respectively. Cmax of DHA following oral AS were significantly higher, but total systemic exposure was greater following oral DHA at the same dose level (4 mg/kg body weight). There was no significant sex difference in pharmacokinetics of DHA|The aims of this study were to determine the pharmacokinetic parameters of a single dose of 200 mg oral and rectal artesunate in healthy volunteers, and to suggest a rational dosage regimen for rectal administration. The study design was a randomized open cross-over study of 12 healthy volunteers... Pharmacokinetic parameters were derived from the main metabolite alpha-dihydroartemisinin data due to the rapid disappearance of artesunate from the plasma. Dihydroartemisinin following oral administration of artesunate had a significantly higher AUC(0-infinity) (P<0.05 95% confidence interval (CI) -1168.73, -667.61 ng x hr/mL(-1)) and Cmax (P<0.05; 95% CI -419.73, -171.44 ng/mL(-1)), and had shorter tmax (P<0.05; 95% CI -0.97, -0.10 hr) than that following rectal artesunate. There was no statistically significant difference in the elimination half-life between both routes of administration (P>0.05; 95% CI -0.14, 0.53 hr). The relative bioavailability of rectal artesunate was [mean (coefficient of variation %) 54.9 (24.8%) %].|For more Absorption, Distribution and Excretion (Complete) data for ARTESUNIC ACID (8 total), please visit the HSDB record page.

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.

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.

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.

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/

/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.

artesunate|artesunic acid

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.

Derivative of artemisinin

Analyte: artesunate; matrix: blood (plasma); procedure: high-performance liquid chromatography with ultraviolet detection at 290 nm

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