アルテミシニン 化学特性,用途語,生産方法
外観
白色～ほとんど白色粉末～結晶
用途
アルテミシニン（Artemisinin、アーテミシニンとも）は、抗マラリア活性を有するセスキテルペンラクトンのひとつで、多薬剤耐性をもつ熱帯熱マラリアにも効果的である。
効能
抗マラリア薬
説明
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.
化学的特性
Crystalline Solid
物理的性質
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°.
来歴
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 .
使用
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).
適応症
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.
定義
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.
抗菌性
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.
獲得抵抗性
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.
一般的な説明
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.
応用例（製薬）
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.
生物活性
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.
薬物動態学
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).
薬理学
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.
臨床応用
Malaria (including cerebral malaria), in combination with other antimalarials.
副作用
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.
安全性プロファイル
Moderately toxic by ingestion,intramuscular, and intraperitoneal routes. When heated todecomposition it emits acrid smoke and fumes.
アルテミシニン 上流と下流の製品情報
原材料
準備製品
(3R,5aα,8aα,12aR)-デカヒドロ-3,6α,9β-トリメチル-3β,12α-エポキシピラノ[4,3-j]-1,2-ベンゾジオキセピン-10β-オール
(3R,5aα,8aα,12aR)-10α-エトキシデカヒドロ-3,6α,9β-トリメチル-3β,12α-エポキシピラノ[4,3-j]-1,2-ベンゾジオキセピン
アルテモチル
アルテニモール
Deoxy Arteether