CAS:63968-64-9 Artemisinin Raw Material for Artemisinin

Description 

Artemisinin and its semisynthetic derivatives are a group of drugs used against malaria due to Plasmodium falciparum. It was discovered in 1972 by Tu Youyou, a Chinese scientist, who was co-recipient of the 2015 Nobel Prize in Medicine for her discovery. Treatments containing an artemisinin derivative (artemisinin-combination therapies, ACTs) are now standard treatment worldwide for P. falciparum malaria. Artemisinin is isolated from the plant Artemisia annua, sweet wormwood, a herb employed in Chinese traditional medicine. A precursor compound can be produced using a genetically-engineered yeast, which is much more efficient than using the plant.

Chemically, artemisinin is a sesquiterpene lactone containing an unusual peroxide bridge. This endoperoxide 1,2,4-trioxane ring is responsible for the drug's mechanism of action. Few other natural compounds with such a peroxide bridge are known.

Artemisinin and its derivatives have been used for the treatment of malarial and parastic worm (helminth) infections. They have the advantage over other drugs in having an ability to kill faster and kill all the life cycle stages of the parasites.^[5] But low bioavailability, poor pharmacokineticproperties and high cost of the drugs are major drawbacks of their use.^[6] Use of the drug by itself as a monotherapy is explicitly discouraged by the World Health Organization,^[7] as there have been signs that malarial parasites are developing resistance to the drug. Therapies that combine artemisinin or its derivatives with some other antimalarial drug are the preferred treatment for malaria.

Medical use

Uncomplicated malaria

Artemisinins can be used alone, but this leads to a high rate of recrudescence (return of parasites) and other drugs are required to clear the body of all parasites and prevent recurrence. The World Health Organization (WHO) is pressuring manufacturers to stop making the uncompounded drug available to the medical community at large, aware of the catastrophe that would result if the malaria parasite developed resistance to artemisinins.

The WHO has recommended artemisinin combination therapies (ACT) be the first-line therapy for P. falciparum malaria worldwide.As short-acting drugs, artemisinin compounds are given with one or two long-acting drugs like amodiaquine, mefloquine, sulfadoxine/pyrimethamine or lumefantrine. Combinations are effective because the artemisinin component kills the majority of parasites at the start of the treatment, while the more slowly eliminated partner drug clears the remaining parasites.

Several fixed-dose ACTs are now available containing an artemisinin component and a partner drug which has a long half-life, such as mefloquine (ASMQ), lumefantrine (Coartem), amodiaquine (ASAQ), piperaquine (Duo-Cotecxin), and pyronaridine (Pyramax). Increasingly, these combinations are being made to GMP standard. A separate issue concerns the quality of some artemisinin-containing products being sold in Africa and Southeast Asia.

Artemisinins are not used for malaria prevention because of the extremely short activity (half-life) of the drug. To be effective, it would have to be administered multiple times each day.

Severe malaria

Artesunate administered by intravenous or intramuscular injection has proven superior to quinine in large, randomised controlled trials in both adults and children. Combining all trials comparing these two drugs, artesunate is associated with a mortality rate that is approximately 30% lower than that of quinine.^[16] Reasons for this difference include reduced incidence of hypoglycaemia, easier administration and more rapid action against circulating and sequestered parasites. Artesunate is now recommended by the WHO for treatment of all cases of severe malaria. Effective treatment with ACT (artemisinin combination therapy) has proven to lower the morbidity and mortality from malaria within two years by around 70%.

Helminthiasis

A serendipitous discovery was made in China in the early 1980s while searching for novel anthelmintics for schistosomiasis that artemisinin was effective against schistosomes,^[18][19][20] the human blood flukes, which are the second-most prevalent parasitic infections, after malaria. Artemisinin and its derivatives are all potent anthelmintics.Artemisinins were later found to possess a broad spectrum of activity against a wide range of trematodes, including Schistosoma japonicum, S. mansoni, S. haematobium, Clonorchis sinensis, Fasciola hepatica, and Opisthorchis viverrini. Clinical trials were also successfully conducted in Africa among patients with schistosomiasis.

Cancer

Artemisinin and its derivatives are under laboratory research for their potential anti-cancer effects. As of 2018, only preliminary clinical research had been conducted using artemisininin derivatives in various cancers, with no approved clinical applications.

Autoimmune disease

Artemisinin derivatives are known for their ability to suppress immune reactions such as inflammation. One derivative, SM934, was approved in 2015 by the China Food and Drug Administration for clinical trial as a drug for systemic lupus erythematosus. Experiments in animal models have given good results. It can regulate T cell subsets, inhibit the activation of B cells, block the production of inflammatory cytokines and NF-κB signal transduction pathway.^[26]

Adverse effects

Artemisinins are generally well tolerated at the doses used to treat malaria.^[ The side effects from the artemisinin class of medications are similar to the symptoms of malaria: nausea, vomiting, loss of appetite, and dizziness. Mild blood abnormalities have also been noted. A rare but serious adverse effect is allergic reaction. One case of significant liver inflammation has been reported in association with prolonged use of a relatively high-dose of artemisinin for an unclear reason (the patient did not have malaria).The drugs used in combination therapies can contribute to the adverse effects experienced by those undergoing treatment. Adverse effects in patients with acute P. falciparum malaria treated with artemisinin derivatives tend to be higher.

Chemistry

An unusual component of the artemisinin molecules is an endoperoxide 1,2,4-trioxane ring. This is the main antimalarial centre of the molecule. Modifications at carbon 10 (C10) position give rise to a variety of derivatives which are more powerful than the original compound. Because the physical properties of artemisinin itself, such as poor bioavailability, limit its effectiveness, semisynthetic derivatives of artemisinin have been developed. Derivatives of dihydroartemisinin were made since 1976. Artesunate, arteether and artemether were synthesised in 1986. Many derivatives have been produced of which artelinic acid, artemotil, artemisone, SM735, SM905, SM933, SM934, and SM1044 are among the most powerful compounds.^[33][34] There are also simplified analogs in preclinical research.Over 120 other derivatives have been prepared, but clinical testing has not been possible due to lack of financial support. 

Artemisinin belongs to a class of sesquiterpene lactones. The solid is poorly soluble in oils and water. Therefore, it is mostly applied through the digestive tract, either by oral or rectal administration. Some chemical modification are suitable for administration by injection. Artesunate is the only artemisinin compound available for all types of administration procedure.A synthetic compound with a similar trioxolane structure (a ring containing three oxygen atoms) named RBx-11160^[37] showed promise in in vitro testing. Phase II testing in patients with malaria was not as successful as hoped, but the manufacturer decided to start Phase III testing anyway.

Packaging and transportation 

Packing: this product is double-packed: the inner layer is sealed with edible polythene plastic bags, and the outer packaging is in cardboard boxes.The net content of each case is 25kg. It can also be packed according to customers' needs.

Transportation: light loading and unloading.Prevent the sun, rain, can not be mixed with toxic, harmful goods, this product is not dangerous goods, can be transported according to the general chemicals.
Storage: it should be stored in a dry, clean and dark environment. It is strictly prohibited to mix with toxic substances to avoid pollution.The shelf life is two years.


Packaging