Artemisinin

Description

Artemisinin, a sesquiterpene isolated from a traditional Chinese remedy (quinghao), is useful in the treatment of Fafciparum malaria, including infections caused by chloroquine resistant strains. It is reported to clear parasitemia quicker than i.v. quinine, and is effective in cerebral malaria.

Description

Artemisinin is isolated from the shrub Artemisia annua and has long been used in traditional Chinese medicine to treat malaria. Current research is investigating more potent derivatives for pharmaceutical use.

Description

Artemisinin is an antimalarial agent with anticancer activity. It is an iron(II) oxide-reactive endoperoxide that generates reactive oxygen species (ROS) upon cleavage of its endoperoxide bridge. It reduces the growth of various P. falciparum strains in vitro (IC₅₀s = 3.98-20.36 nM) and reduces parasitemia in mice infected with P. falciparum with a curative dose (CD₅₀) value of 140 mg/kg. It also reduces P. berghei infection in mice (ED₅₀ = 5.6 mg/kg per day). Artemisinin (100-400 μM) induces cell cycle arrest in the G₀/G₁ phase and apoptosis and inhibits growth of SK-N-AS, BE(2)-C, SK-N-DZ, and SHEP1 neuroblastoma cells in a time- and concentration-dependent manner. It also suppresses BE(2)-C cell colony formation in a soft agar assay and reduces tumor growth in a BE(2)-C mouse xenograft model. Formulations containing artemisinin have been used in combination therapies for the treatment of malaria.

Chemical properties

Crystalline Solid

Physical properties

Appearance: colorless needles or white crystalline powder. Solubility: practically insoluble in water, very soluble in dichloromethane, freely soluble in acetone and ethyl acetate, and soluble in glacial acetic acid, methanol, and ethanol. Melting point: 150–153?°C. Specific optical rotation: +75 to +78°.

Originator

Ping Hau Sau Res. Group (China)

History

The discovery of artemisinin dramatically changes the landscape to combat malaria and leads to a paradigm shift in antimalarial drug development.
However, the discovery of artemisinin is the first stage; the development of artemisinin derivatives and their compound preparations is another important stage. Based on artemisinin, scientists obtained artemisinin ether derivatives by semisynthetic method. After screening of antimalarial activity, artemether was found. To further improve the solubility of artemisinin derivatives, artesunate was also found. The discovery of artesunate makes artemisinin and its derivatives much easier to promote, and more convenient dosage forms to treat malaria enriched the clinic application of artemisinin and its derivatives .

The Uses of Artemisinin

Artemisinin inhibits angiogenesis by down-regulating HIF-1α and VEGF expression in mouse embryonic stem cells. Artemisinin crosses the blood-brain barrier and is an inhibitor of human NOS2 (iNOS).

The Uses of Artemisinin

Active antimalarial constituent of the tradional Chinese medicinal herb Artemisia annua L., Compositae, which has been known for almost 2000 years as Qinghao. Antimalarial

The Uses of Artemisinin

An antimalarial agent that inhibits VEGF expression and NOS2.

What are the applications of Application

Artemisinin is an antimalarial agent that inhibits VEGF expression and NOS2

Definition

ChEBI: A sesquiterpene lactone obtained from sweet wormwood, Artemisia annua, which is used as an antimalarial for the treatment of multi-drug resistant strains of falciparum malaria.

Indications

Clinically, artemisinin is mainly used to treat malaria symptoms, malignant cerebral malaria, uncomplicated malaria, and severe malaria. Combined with different antimalarial can delay and prevent resistance of malaria parasites. In additional, artemisinin can also be used for systemic lupus erythematosus or discoid lupus erythematosus. Currently, artemisinin derivatives and their compound preparations are widely used in clinic.

Antimicrobial activity

Artemisinins are active against the erythrocytic and gametocyte stages of chloroquine-sensitive and chloroquine-resistant strains of P. falciparum and other malaria parasites. Two anomers of artemether are produced on synthesis, α-artemether and β-artemether, of which the latter has higher antimalarial activity. Activity against the protozoa Tox. gondii and Leishmania major and the helminth Schistosoma mansoni has been demonstrated in experimental models.

Acquired resistance

Resistance caused, for example, by changes in the plasmodial endoplasmic reticulum ATPase has been shown in experimental models. There have been clinical reports of reduced susceptibility to treatment with artesunate in Cambodia.

General Description

The artemisinin series are the newest of the antimalarialdrugs and are structurally unique when comparedwith the compounds previously and currently used. Theparent compound, artemisinin, is a natural product extractedfrom the dry leaves of Artemisia Annua (sweetwormwood). The plant has to be grown each year fromseed because mature plants may lack the active drug. The growing conditions are critical to maximize artemisininyield. Thus far, the best yields have been obtained fromplants grown in North Vietnam, Chongqing province inChina, and Tanzania.

Pharmaceutical Applications

Artemisinin (qinghaosu), a compound derived from a plant used in traditional Chinese medicine, Artemisia annua, has been used extensively in East Asia and Africa for the treatment of malaria. This drug, and derivatives that have higher intrinsic antimalarial activity (artesunate, artemether and arteether), have replaced quinine as a treatment of falciparum malaria in many countries, normally in combination with other antimalarials. A semisynthetic derivative, artemisone, which has higher efficacy than artesunate and lower toxicity potential, is in development. Artemisinin and its derivatives also show broad antiprotozoal, anthelmintic and antiviral activities.
The novel structure, containing an endoperoxide bridge, has stimulated the development of semisynthetic and synthetic dioxane, trioxane and tetroxane compounds with activity against Plasmodium spp. and Schistosoma spp. Some of these synthetic trioxalanes are now in clinical development with Medicines for Malaria Venture and other organizations.

Biological Activity

Antimalarial agent; interacts with heme to produce carbon-centred free radicals, causes protein alkylation and damages parasite microorganelles and membranes. Also selectively inhibits the P-type ATPase (PfATP6) of Plasmodium falciparum (K i ~ 150 nM). Displays antiangiogenic effects in mouse embryonic stem cell-derived embryoid bodies.

Biochem/physiol Actions

Artemisinin (Qinghaosu), a sesquiterpene lactone, is a highly active anti-malarial (falciparum malaria) drug. Artemisinin is also an anthelmintic (parasitic worm) effective against the blood fluke, schistosomiasis.

Pharmacokinetics

Oral absorption: Incomplete
C_max 500 mg oral: 0.4 mg/L after 1.8 h
Plasma half-life (dihydroartemisinin): 40–60 min
Volume of distribution: c. 0.25 L/kg
Plasma protein binding (artemether): 77%
Artemisinins are concentrated by erythrocytes and are rapidly hydrolyzed to dihydroartemisinin. They are hydroxylated by cytochromes 2B6, 2C19 and 3A4; the derivatives induce this metabolism. After injection, peak plasma concentrations are reached within 1–3 h, when levels of dihydroartemisinin are included. The elimination half-life of intravenous artesunate is <30 min; artemether appears to have a much longer half-life (4–11 h).

Pharmacology

The mechanism of artemisinins is not known, but the most widely accepted theory is that they are first activated through cleavage after reacting with haem and iron(II) oxide, which results in the generation of free radicals that in turn damage susceptible proteins, resulting in the death of the parasite .
Artemisinin and its derivatives also show a good antitumor effect , which is mainly via (1) apoptosis, ferroptosis, or necrosis; (2) anti-angiogenesis; (3) oxidative stress; (4) tumor suppressor genes; and (5) protein targeting. In addition, artemisinin can exhibit antiarrhythmic, anti-fibrotic, and immunomodulating effects.

Clinical Use

Malaria (including cerebral malaria), in combination with other antimalarials.

Side Effects

A few toxic effects in addition to drug-induced fever and a reversible decrease in reticulocyte counts have been reported. High-dose studies in animal models show neurotoxicity and reproducible dose-related neuropathic lesions; dihydroartemisinin is a toxic metabolite but the precise causes of neurotoxicity are not clear. Embryotoxicity of artemisinin and derivatives has been reported in rodent and primate models, probably due to depletion of erythroblasts.

Safety Profile

Moderately toxic by ingestion,intramuscular, and intraperitoneal routes. When heated todecomposition it emits acrid smoke and fumes.

Synthesis

Quinghaosu, octahydro-3,6,9-trimethyl-3,12-epoxy-12Hpyrano-(4,3-di)-1,2-benzodioxepin-10-(3H)-one (37.1.1.57), is isolated from the plant Artemisia annua. It also has been made synthetically.

storage

+4°C