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Artemisinin

Artemisinin

Overview
Artemisinin also known as Qinghaosu (Chinese
Chinese language
The Chinese language is a language or language family consisting of varieties which are mutually intelligible to varying degrees. Originally the indigenous languages spoken by the Han Chinese in China, it forms one of the branches of Sino-Tibetan family of languages...

: 青蒿素) , and its derivatives are a group of drugs
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...

 that possess the most rapid action of all current drugs against falciparum
Plasmodium falciparum
Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by the female Anopheles mosquito. Malaria caused by this species is the most dangerous form of malaria, with the highest rates of complications and mortality...

 malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...

. Treatments containing an artemisinin derivative (artemisinin-combination therapies, ACTs) are now standard treatment worldwide for falciparum malaria. The starting compound artemisinin is isolated from the plant Artemisia annua
Artemisia annua
Artemisia annua, also known as Sweet Wormwood, Sweet Annie, Sweet Sagewort or Annual Wormwood , is a common type of wormwood that is native to temperate Asia, but naturalized throughout the world.-Characteristics:...

, a herb described in Chinese traditional medicine.

Chemically, artemisinin is a sesquiterpene lactone
Sesquiterpene lactone
Sesquiterpene lactones are a class of chemical compounds; they are sesquiterpenoids and contain a lactone ring, hence the name....

 containing an unusual peroxide
Peroxide
A peroxide is a compound containing an oxygen–oxygen single bond or the peroxide anion .The O−O group is called the peroxide group or peroxo group. In contrast to oxide ions, the oxygen atoms in the peroxide ion have an oxidation state of −1.The simplest stable peroxide is hydrogen peroxide...

 bridge.
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Encyclopedia
Artemisinin also known as Qinghaosu (Chinese
Chinese language
The Chinese language is a language or language family consisting of varieties which are mutually intelligible to varying degrees. Originally the indigenous languages spoken by the Han Chinese in China, it forms one of the branches of Sino-Tibetan family of languages...

: 青蒿素) , and its derivatives are a group of drugs
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...

 that possess the most rapid action of all current drugs against falciparum
Plasmodium falciparum
Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by the female Anopheles mosquito. Malaria caused by this species is the most dangerous form of malaria, with the highest rates of complications and mortality...

 malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...

. Treatments containing an artemisinin derivative (artemisinin-combination therapies, ACTs) are now standard treatment worldwide for falciparum malaria. The starting compound artemisinin is isolated from the plant Artemisia annua
Artemisia annua
Artemisia annua, also known as Sweet Wormwood, Sweet Annie, Sweet Sagewort or Annual Wormwood , is a common type of wormwood that is native to temperate Asia, but naturalized throughout the world.-Characteristics:...

, a herb described in Chinese traditional medicine.

Chemically, artemisinin is a sesquiterpene lactone
Sesquiterpene lactone
Sesquiterpene lactones are a class of chemical compounds; they are sesquiterpenoids and contain a lactone ring, hence the name....

 containing an unusual peroxide
Peroxide
A peroxide is a compound containing an oxygen–oxygen single bond or the peroxide anion .The O−O group is called the peroxide group or peroxo group. In contrast to oxide ions, the oxygen atoms in the peroxide ion have an oxidation state of −1.The simplest stable peroxide is hydrogen peroxide...

 bridge. It is believed that this peroxide is responsible for the drug's mechanism of action. No other natural compound with such a peroxide bridge is known.

Use of the drug by itself as a monotherapy is explicitly discouraged by the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...

 as there have been signs that malarial parasites are developing resistance to the drug. Therapies that combine artemisinin with some other anti-malarial drug are the preferred treatment for malaria and are both effective and well tolerated in patients. The drug is also increasingly being used in vivax
Plasmodium vivax
Plasmodium vivax is a protozoal parasite and a human pathogen. The most frequent and widely distributed cause of recurring malaria, P. vivax is one of the four species of malarial parasite that commonly infect humans. It is less virulent than Plasmodium falciparum, which is the deadliest of the...

 malaria as well as being a topic of research in cancer treatment.

History


Artemisia has been used by Chinese herbalist
Herbalist
An herbalist is:#A person whose life is dedicated to the economic or medicinal uses of plants.#One skilled in the harvesting and collection of medicinal plants ....

s for more than a thousand years in the treatment of many illnesses, such as skin diseases and malaria. The earliest record dates back to 200 BC, in the "Fifty-two Prescriptions
Wushi'er Bingfang
The Wushi'er Bingfang , or Recipes for Fifty-Two Ailments, is an ancient Chinese medical text that was discovered in 1973 in Mawangdui in a tomb that was sealed in 168 BCE under the Han Dynasty. The text was copied in seal script on sheets of silk around 215 BCE, under the Qin Dynasty, but might...

" unearthed from the Mawangdui Han Dynasty Tombs. Its antimalarial
Antimalarial drug
Antimalarial medications, also known as antimalarials, are designed to prevent or cure malaria. Such drugs may be used for some or all of the following:* Treatment of malaria in individuals with suspected or confirmed infection...

 application was first described, in Zhouhou Beiji Fang ("The Handbook of Prescriptions for Emergencies"), edited in the middle of the fourth century by Ge Hong
Ge Hong
Ge Hong , courtesy name Zhichuan , was a minor southern official during the Jìn Dynasty of China, best known for his interest in Daoism, alchemy, and techniques of longevity...

. In that book, 43 malaria treatment methods were recorded.
In the 1960s a research program, under the name Project 523, was set up by the Chinese army
People's Liberation Army
The People's Liberation Army is the unified military organization of all land, sea, strategic missile and air forces of the People's Republic of China. The PLA was established on August 1, 1927 — celebrated annually as "PLA Day" — as the military arm of the Communist Party of China...

 to find an adequate treatment for malaria. In 1972, in the course of this research, Dr. Tu Youyou
Tu Youyou
Tu Youyou , is a Chinese medical scientist, pharmaceutical chemist, and educator. She was awarded the 2011 Lasker Award in Clinical Medicine for discovering artemisinin , used to treat malaria.-Biography:...

 discovered artemisinin in the leaves of Artemisia annua
Artemisia annua
Artemisia annua, also known as Sweet Wormwood, Sweet Annie, Sweet Sagewort or Annual Wormwood , is a common type of wormwood that is native to temperate Asia, but naturalized throughout the world.-Characteristics:...

(annual wormwood). The drug is named Qinghaosu in Chinese. It was one of many candidates then tested by Chinese scientists from a list of nearly 5000 traditional Chinese medicines for treating malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...

. It was the only one that was effective, but it was found that it cleared malaria parasites from their bodies faster than any other drug in history. Artemisia annua is a common herb and has been found in many parts of the world, including along the Potomac River
Potomac River
The Potomac River flows into the Chesapeake Bay, located along the mid-Atlantic coast of the United States. The river is approximately long, with a drainage area of about 14,700 square miles...

, in Washington, D.C.
Washington, D.C.
Washington, D.C., formally the District of Columbia and commonly referred to as Washington, "the District", or simply D.C., is the capital of the United States. On July 16, 1790, the United States Congress approved the creation of a permanent national capital as permitted by the U.S. Constitution....

 Images of the original scientific papers are available online and a book, Zhang Jianfang, "Late Report – Record of Project 523 and the Research and Development of Qinghaosu", Yangcheng Evening News Publisher 2007(張劍方. 遲到的報告五二三項目與青蒿素研發紀實. 羊城晚報出版社, 2007), was published in 2006, which records the history of the discovery.

It remained largely unknown to the rest of the world for about seven years, until results were published in the Chinese Medical Journal in 1979. The report was met with skepticism at first, partly because the chemical structure of artemisinin, particularly the peroxide
Peroxide
A peroxide is a compound containing an oxygen–oxygen single bond or the peroxide anion .The O−O group is called the peroxide group or peroxo group. In contrast to oxide ions, the oxygen atoms in the peroxide ion have an oxidation state of −1.The simplest stable peroxide is hydrogen peroxide...

, appeared to be too unstable to be a viable drug.

For many years after the discovery, access to the purified drug and the plant it was extracted from were restricted by the Chinese government. It was not until the late 1970s and early 80s that news of the discovery reached scientists outside China. The World Health Organisation (WHO) tried to contact Chinese scientists and officials to find out more, but drew a blank. Dr Ying Lee, one of the scientists involved in the research into artemisinin, said the Chinese distrusted the West. The Chinese suspected the West just wanted to exploit the drug and sell it around the world slightly altered and repatented. The fact that there were several Americans on the WHO's steering board on malaria and that some were from the military did not help clear the distrust. It can be noted Americans had just invested a lot into mefloquine
Mefloquine
Mefloquine hydrochloride is an orally administered medication used in the prevention and treatment of malaria. Mefloquine was developed in the 1970s at the United States Department of Defense's Walter Reed Army Institute of Research as a synthetic analogue of quinine...

, an analogue of quinine
Quinine
Quinine is a natural white crystalline alkaloid having antipyretic , antimalarial, analgesic , anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine which, unlike quinine, is an anti-arrhythmic...

.

In 2006, after artemisinin had become the treatment of choice for malaria, the WHO called for an immediate halt to single-drug artemisinin preparations in favor of medications that combine artemisinin with another malaria drug, in order to reduce the risk of parasites developing resistance.

In 2011, Dr. Tu was awarded the prestigious Lasker-DeBakey Clinical Medical Research Award for her discovery.

Project 523 developed, in addition to artemisinin, a number of products that are used in combination with artemisinin, including lumefantrine
Lumefantrine
Lumefantrine is an antimalarial drug. It is only used in combination with artemether. The term "co-artemether" is sometimes used to describe this combination....

, piperaquine
Piperaquine
Piperaquine is an antimalarial drug, a bisquinoline first synthesised in the 1960s, and used extensively in China and Indochina as prophylaxis and treatment during the next 20 years. Usage declined in the 1980s as piperaquine-resistant strains of P. falciparum arose and artemisinin-based...

, and pyronaridine
Pyronaridine
Pyronaridine is an antimalarial drug. It was first synthesized in 1970 and has been in clinical use in China since the 1980s....

.

Artemisinin derivatives


Because artemisinin itself has physical properties such as poor bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...

 that limit its effectiveness, semi-synthetic derivative
Derivative
In calculus, a branch of mathematics, the derivative is a measure of how a function changes as its input changes. Loosely speaking, a derivative can be thought of as how much one quantity is changing in response to changes in some other quantity; for example, the derivative of the position of a...

s of artemisinin have been developed. These include:
  • Artesunate
    Artesunate
    Artesunate is part of the artemisinin group of drugs that treat malaria. It is a semi-synthetic derivative of artemisinin that is water-soluble and may therefore be given by injection...

     (water-soluble: for oral, rectal, intramuscular, or intravenous use)
  • Artemether
    Artemether
    Artemether is an antimalarial for the treatment of multi-drug resistant strains of falciparum malaria. It is combined with Lumefantrine and sold by Novartis under the brand names Riamet and Co-Artem.-Chemical nature:...

     (lipid-soluble: for oral, rectal or intramuscular use)
  • Dihydroartemisinin
    Dihydroartemisinin
    Dihydroartemisinin is a drug used to treat malaria. Dihydroartemisinin is the active metabolite of all artemisinin compounds and is also available as a drug in itself...

  • Artelinic acid
    Artelinic acid
    Artelinic acid is an experimental drug that is being investigated as a treatment for malaria. It is a semi-synthetic derivative of the natural compound artemisinin. Artelinic acid has a lower rate of neurotoxicity than the related artemisin derivatives arteether and artemether, but is three...

  • Artenimol
  • Artemotil
    Artemotil
    Artemotil , is a fast acting blood schizonticide specifically indicated for the treatment of chloroquine-resistant Plasmodium falciparum malaria and cerebral malaria cases. It is a semi-synthetic derivative of artemisinin, a natural product of the Chinese plant Artemisia annua...



There are also simplified analogs in preclinical research.

A synthetic compound with a similar trioxolane structure (ring containing three oxygen atoms) named arterolane
Arterolane
Arterolane, also known as OZ277 or RBx 11160, is a substance being tested for antimalarial activity by Ranbaxy Laboratories. Its molecular structure is uncommon for pharmacological compounds in that it has both an ozonide group and an adamantane substituent.Phase III clinical trials of arterolane,...

 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. A combination with piperaquine
Piperaquine
Piperaquine is an antimalarial drug, a bisquinoline first synthesised in the 1960s, and used extensively in China and Indochina as prophylaxis and treatment during the next 20 years. Usage declined in the 1980s as piperaquine-resistant strains of P. falciparum arose and artemisinin-based...

 is also in development.

Uncomplicated Malaria


Artemisinins can be used alone, but this leads to a high rate of recrudescence
Recrudescence
Recrudescence1. Revival of material or behavior that had previously quiesced.2. A recurrence of symptoms in a patient whose blood stream infection has previously been at such a low level as not to be clinically demonstrable or cause symptoms....

 (return of parasites) and other drugs are required to clear the body of all parasites and prevent recurrence. The World Health Organization 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 World Health Organisation has recommended that artemisinin combination therapies (ACT) be first-line therapy for P. falciparum malaria worldwide. 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
Mefloquine
Mefloquine hydrochloride is an orally administered medication used in the prevention and treatment of malaria. Mefloquine was developed in the 1970s at the United States Department of Defense's Walter Reed Army Institute of Research as a synthetic analogue of quinine...

 (ASMQ), lumefantrine
Lumefantrine
Lumefantrine is an antimalarial drug. It is only used in combination with artemether. The term "co-artemether" is sometimes used to describe this combination....

 (Coartem
Coartem
The combination artemether/lumefantrine is an artemisinin-based combination therapy indicated for the treatment of acute uncomplicated plasmodium falciparum malaria. Coartem is produced by the Swiss pharmaceutical company, Novartis.Artemether is a derivative of artemisinin, and lumefantrine is...

), amodiaquine
Amodiaquine
Amodiaquine is a 4-aminoquinoline compound related to chloroquine, used as an antimalarial and anti-inflammatory agent....

 (ASAQ
ASAQ
ASAQ is a medication launched in 2007-03-01 which is a pharmaceutical formula combining artesunate and amodiaquine for an affordable treatment of malaria, devised by DNDi in partnership with Sanofi-Aventis. The drug is patent free as well....

), piperaquine
Piperaquine
Piperaquine is an antimalarial drug, a bisquinoline first synthesised in the 1960s, and used extensively in China and Indochina as prophylaxis and treatment during the next 20 years. Usage declined in the 1980s as piperaquine-resistant strains of P. falciparum arose and artemisinin-based...

 (Duo-Cotecxin) and pyronaridine
Pyronaridine
Pyronaridine is an antimalarial drug. It was first synthesized in 1970 and has been in clinical use in China since the 1980s....

 (Pyramax). Increasingly these combinations are being made to GMP
Good Manufacturing Practice
"Good manufacturing practice" or "GMP" are practices and the systems required to be adapted in pharmaceutical manufacturing, quality control, quality system covering the manufacture and testing of pharmaceuticals or drugs including active pharmaceutical ingredients, diagnostics, foods,...

 standard. A separate issue concerns the quality of some artemisinin-containing products being sold in Africa and South-East Asia.

Artemisinins are not used for malaria prophylaxis (prevention) because of the extremely short activity (half-life
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...

) 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
Quinine
Quinine is a natural white crystalline alkaloid having antipyretic , antimalarial, analgesic , anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine which, unlike quinine, is an anti-arrhythmic...

 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. Reasons for this difference include reduced incidence of hypoglycaemia, easier administration and more rapid action against circulating and sequestered parasites.

Cancer treatment


Artemisinin is undergoing early research and testing for the treatment
Experimental cancer treatment
Experimental cancer treatments are medical therapies intended or claimed to treat cancer by improving on, supplementing or replacing conventional methods ....

 of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

, primarily by researchers at the University of Washington. Chinese scientists have shown artemisinin has significant anticancer effects against human hepatoma cells. Artemisinin has a peroxide
Organic peroxide
Organic peroxides are organic compounds containing the peroxide functional group . If the R' is hydrogen, the compound is called an organic hydroperoxide. Peresters have general structure RCOOR. The O-O bond easily breaks and forms free radicals of the form RO·...

 lactone
Lactone
In chemistry, a lactone is a cyclic ester which can be seen as the condensation product of an alcohol group -OH and a carboxylic acid group -COOH in the same molecule...

 group in its structure, and it is thought that when the peroxide comes into contact with high iron concentrations (common in cancerous cells), the molecule becomes unstable and releases reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....

. It has been shown to reduce angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...

 and the expression of vascular endothelial growth factor
Vascular endothelial growth factor
Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....

 in some tissue cultures. Recent pharmacological evidence demonstrates that the artemisinin-derivative dihydroartemisinin targets human metastatic melanoma cells with induction of NOXA (Phorbol-12-myristate-13-acetate-induced protein 1)-dependent mitochondrial apoptosis that occurs downstream of iron-dependent generation of cytotoxic oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...

.

Helminth parasites


Serendipitous discovery was made in China while searching for novel anthelmintics for schistosomiasis
Schistosomiasis
Schistosomiasis is a parasitic disease caused by several species of trematodes , a parasitic worm of the genus Schistosoma. Snails often act as an intermediary agent for the infectious diseases until a new human host is found...

. Artemisinin was effective against schistosomes
Schistosoma
A genus of trematodes, Schistosoma, commonly known as blood-flukes and bilharzia, includes flatworms which are responsible for a highly significant parasitic infection of humans by causing the disease schistosomiasis, and are considered by the World Health Organization as the second most...

, 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
Schistosoma japonicum
Schistosoma japonicum is an important parasite and one of the major infectious agents of schistosomiasis.This parasite has a very wide host range, infecting at least 31 species of wild mammals, including 9 carnivores, 16 rodents, one primate , two insectivores and three artiodactyls and therefore...

, S. mansoni
Schistosoma mansoni
Schistosoma mansoni is a significant parasite of humans, a trematode that is one of the major agents of the disease schistosomiasis. The schistosomiasis caused by Schistosoma mansoni is intestinal schistosomiasis....

, S. haematobium
Schistosoma haematobium
Schistosoma haematobium is an important digenetic trematode, and is found in the Middle East, India, Portugal and Africa. It is a major agent of schistosomiasis; more specifically, it is associated with urinary schistosomiasis....

, Clonorchis sinensis
Clonorchis sinensis
Clonorchis sinensis, the Chinese liver fluke, is a human liver fluke in the class Trematoda, Phylum Platyhelminthes. This parasite lives in the liver of humans, and is found mainly in the common bile duct and gall bladder, feeding on bile...

, Fasciola hepatica
Fasciola hepatica
Fasciola hepatica, also known as the common liver fluke or sheep liver fluke, is a parasitic flatworm of the class Trematoda, phylum Platyhelminthes that infects the livers of various mammals, including humans. The disease caused by the fluke is called fascioliasis . F...

and Opisthorchis viverrini
Opisthorchis viverrini
Opisthorchis viverrini, common name Southeast Asian liver fluke, is a trematode parasite from the family Opisthorchiidae that attacks the area of the bile duct. Infection is acquired when people ingest raw or undercooked fish. It causes the disease opisthorchiasis...

. Clinical trials were also successfully conducted in Africa among patients with schistosomiasis. A randomized, double-blind placebo-controlled trial also revealed the efficacy against schistosome infection in Côte d'Ivoire and China.

Resistance


A 2008 study suggests a consensus among researchers that artemisinin is losing its potency in Cambodia and increased efforts are required to prevent drug-resistant malaria from spreading across the globe. These findings were subsequently supported by a detailed study from Western Cambodia.

In April 2011 the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...

 stated that resistance to the most effective anti-malarial drug, artemisinin, could unravel national (India) malaria control programs, which have achieved significant progress in the last decade. WHO advocates the rational use of anti-malarial drugs and acknowledges the crucial role of community health workers in reducing malaria in the region.

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, anorexia, and dizziness. Mild blood abnormalities have also been noted. A rare but serious adverse effect is allergic reaction. One case of significant liver inflammation
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "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 that are used in combination therapies can contribute to the adverse effects that are experienced by those undergoing treatment. Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives tend to be higher.

Mechanism of action


There is no consensus regarding the mechanism through which artemisinin derivatives kill the parasites. Their site of action within the parasite also remains controversial.

All artemisinins used today are prodrugs of the biologically active metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...

 dihydroartemisinin
Dihydroartemisinin
Dihydroartemisinin is a drug used to treat malaria. Dihydroartemisinin is the active metabolite of all artemisinin compounds and is also available as a drug in itself...

, which is active during the stage when the parasite is located inside red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...

s.

When the parasite that causes malaria infects a red blood cell, it consumes hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...

 within its digestive vacuole, liberating free heme
Heme
A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are...

, an iron-porphyrin complex. According to one theory about the action of artemisinin, the iron of the heme reduces
Redox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....

 the peroxide
Peroxide
A peroxide is a compound containing an oxygen–oxygen single bond or the peroxide anion .The O−O group is called the peroxide group or peroxo group. In contrast to oxide ions, the oxygen atoms in the peroxide ion have an oxidation state of −1.The simplest stable peroxide is hydrogen peroxide...

 bond in artemisinin, generating high-valent iron-oxo species and resulting in a cascade of reactions that produce reactive oxygen radicals
Radical (chemistry)
Radicals are atoms, molecules, or ions with unpaired electrons on an open shell configuration. Free radicals may have positive, negative, or zero charge...

 which damage the parasite and lead to its death.

Numerous studies have investigated the type of damage that oxygen radicals may induce. For example, Pandey et al. have observed inhibition of digestive vacuole cysteine protease
Cysteine protease
Proteases are enzymes that degrade polypeptides. Cysteine proteases have a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic dyad. The first step is deprotonation of a thiol in the enzyme's active site by an adjacent amino acid with a basic side chain, usually a...

 activity of malarial parasite by artemisinin. These observations were supported by ex vivo experiments showing accumulation of hemoglobin in the parasites treated with artemisinin and inhibition of hemozoin
Hemozoin
Hemozoin is a disposal product formed from the digestion of blood by some blood-feeding parasites. These hematophagous organisms such as Malaria parasites , Rhodnius and Schistosoma digest hemoglobin and release high quantities of free heme, which is the non-protein component of hemoglobin...

 formation by malaria parasites. Electron microscopic evidence linking artemisinin action to the parasite's digestive vacuole has been obtained showing that the digestive vacuole membrane suffers damage soon after parasites are exposed to artemisinin. This would also be consistent with data showing that the digestive vacuole is already established by the mid-ring stage of the parasite's blood cycle, a stage that is sensitive to artemisinins but not other antimalarials.

A commonly cited theory that the parasite's SERCA
SERCA
SERCA, or sarco/endoplasmic reticulum Ca2+-ATPase, or SR Ca2+-ATPase, is a calcium ATPase-type P-ATPase.-Function:SERCA resides in the sarcoplasmic reticulum within muscle cells...

 pump (PfATP6) is a key target of artemisinins now appears highly questionable. Artemisinins do not inhibit this protein when it is expressed in yeast and transfection
Transfection
Transfection is the process of deliberately introducing nucleic acids into cells. The term is used notably for non-viral methods in eukaryotic cells...

 studies show no significant effect of PfATP6 genotype on artemisinin phenotype. Although a single field study identified a mutation in PfATP6 that was associated with resistance to artemether, this mutation has not achieved a meaningful prevalence in any location and the phenotypic association is not replicated elsewhere. There is no role for PfSERCA in the artemisinin resistance that appears to be emerging in Cambodia.

A 2005 study investigating the mode of action of artemisinin using a yeast model demonstrated that the drug acts on the electron transport chain
Electron transport chain
An electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...

, generates local reactive oxygen species, and causes the depolarization of the mitochondrial membrane.

Dosing


Artemisinin and its derivatives have half-lives in the order of a few hours and therefore require at least daily dosing, usually for three days. For example the WHO approved adult dose of co-artemether (artemether-lumefantrine) is
4 tablets at 0, 8, 24, 36, 48 and 60 hours (six doses). This regimen has been proven to be superior to regimens based on amodiaquine
Amodiaquine
Amodiaquine is a 4-aminoquinoline compound related to chloroquine, used as an antimalarial and anti-inflammatory agent....

.

Artemisinin is not soluble in water and therefore Artemisia annua
Artemisia annua
Artemisia annua, also known as Sweet Wormwood, Sweet Annie, Sweet Sagewort or Annual Wormwood , is a common type of wormwood that is native to temperate Asia, but naturalized throughout the world.-Characteristics:...

tea was postulated not to contain pharmacologically significant amounts of artemesinin. However, this conclusion was rebuked by several experts who stated that hot water (85 oC), and not boiling water, should be used to prepare the tea. Although Artemisia tea is not recommended as a substitute for the ACT (artemisinin combination therapies) more clinical studies on artemisia tea preparation have been suggested.

Production and price


Artemisinin is the only high-volume drug that continues to be produced from a plant-based source. China and Vietnam provide 70% and East Africa 20% of the raw material. Seedlings are grown in nurseries and then transplanted into fields. It takes about 8 months for them to reach full size. The plants are harvested, the leaves are dried and sent to facilities where the artemisinin is extracted using solvent, typically hexane
Hexane
Hexane is a hydrocarbon with the chemical formula C6H14; that is, an alkane with six carbon atoms.The term may refer to any of four other structural isomers with that formula, or to a mixture of them. In the IUPAC nomenclature, however, hexane is the unbranched isomer ; the other four structures...

. The market price for artemisinin has fluctuated widely, between $120 and $1200 per kilogram from 2005 to 2008.

After negotiation with the WHO, Novartis
Novartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...

 and Sanofi-Aventis
Sanofi-Aventis
Sanofi S.A. is a multinational pharmaceutical company headquartered in Paris, France, the world's fourth-largest by prescription sales. Sanofi engages in the research and development, manufacturing and marketing of pharmaceutical products for sale principally in the prescription market, but the...

 provide ACT (artemisinin combination therapy) drugs at cost on a non-profit basis; however, these drugs are still more expensive than other malaria treatments.

High-yield varieties of Artemisia are being produced by the Centre
for Novel Agricultural Products at the University of York
University of York
The University of York , is an academic institution located in the city of York, England. Established in 1963, the campus university has expanded to more than thirty departments and centres, covering a wide range of subjects...

 using molecular breeding techniques.

Using seed supplied by Action for Natural Medicine (ANAMED), the World Agroforestry Centre (ICRAF) has developed a hybrid, dubbed A3, which can grow to a height of 3 m and which produces 20 times more artemisinin than wild varieties. In northwestern Mozambique
Mozambique
Mozambique, officially the Republic of Mozambique , is a country in southeastern Africa bordered by the Indian Ocean to the east, Tanzania to the north, Malawi and Zambia to the northwest, Zimbabwe to the west and Swaziland and South Africa to the southwest...

, ICRAF is working together with a medical organisation, Médecins sans frontières
Médecins Sans Frontières
' , or Doctors Without Borders, is a secular humanitarian-aid non-governmental organization best known for its projects in war-torn regions and developing countries facing endemic diseases. Its headquarters are in Geneva, Switzerland...

, ANAMED and the Ministry of Agriculture and Rural Development to train farmers on how to grow the shrub from cuttings, and to harvest and dry the leaves to make artemisia tea.

A research group from the Philippines have published a work on the extraction of artemisinin from its plant source, Artemisia annua. They produced a synthetic polymer that was imprinted with artemisinin and showed a selective recognition to said compound.

Biosynthesis in A. annua


The biosynthesis of artemisinin is expected to involve the mevalonate pathway (MVA) and the cyclization of FDP (farnesyl diphosphate). Although it is not clear whether the DXP (deoxyxylulose phosphate)pathway can also contribute 5-carbon precursors (IPP or/and DMAPP), as occurs in other sesquiterpene biosynthetic systems. The routes from artemisinic alcohol to artemisinin remain controversial and they differ mainly in when the reduction step takes place. Both routes suggested dihydroartemisinic acid as the final precursor to artemisinin. Dihydroartemisinic acid then undergoes photo-oxidation to produce dihydroartemisinic acid hydroperoxide. Ring expansion by the cleavage of hydroperoxide and a second oxygen-mediated hydroperoxidation furnish the biosynthesis of artemisinin.



Figure 1. Biosynthesis of Artemisinin.

Chemical synthesis


The total synthesis of artemisinin, while expensive, can be performed using basic organic reagents. In 1982, G. Schmid and W. Hofheinz published a paper showing the complete synthesis of artemisinin. Their starting material was (-)-Isopulegol (2) which as converted to methoxymethyl ether (3). The ether was hydroborated and then underwent oxidative workup to give (4). The primary hydroxyl group was then benzylated and the methoxymethyl ether was cleaved resulting in (5) which would be oxidized to (6). Next, the compound was protonated and treated with (E)-(3-iodo-1-methyl-1-propenyl)-trimethylsilane to give (7). This resulting ketone was reacted with lithium methoxy(trimethylsily)methylide to obtain two diastereomeric alcohols, (8a) and (8b). 8a was then debenzylated using (Li) to give lactone (9). The vinylsilane was then oxidized to ketone (10). The ketone was then reacted with fluoride ion that caused it to undergo desilylation, enol ether formation and carboxylic acid formation to give (11). An introduction of a hydroperoxide function at C(3) of 11 gives rise to (12). Finally, this underwent photooxygenation
Photooxygenation
A photooxygenation is a light-induced oxidation reaction in which molecular oxygen is incorporated into the product. Initial research interest in photooxygenation reactions arose from Oscar Raab's observations in 1900 that the combination of light, oxygen and photosensitizers is highly toxic to cells...

 and then treated with acid to produce artemisinin.

Synthesis in engineered organisms


In 2006 a team from UC Berkeley reported that they had engineered Saccharomyces cerevisiae
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...

yeast to produce the precursor artemisinic acid. The synthesized artemisinic acid can then be transported out, purified and chemically converted into artemisinin that they claim will cost roughly 0.25 cents per dose. In this effort of synthetic biology
Synthetic biology
Synthetic biology is a new area of biological research that combines science and engineering. It encompasses a variety of different approaches, methodologies, and disciplines with a variety of definitions...

, a modified mevalonate pathway was used and the yeast were engineered to express the enzyme amorphadiene synthase
Amorpha-4,11-diene synthase
In enzymology, an amorpha-4,11-diene synthase is an enzyme that catalyzes the chemical reactionHence, this enzyme has one substrate, 2-trans,6-trans-farnesyl diphosphate, and two products, amorpha-4,11-diene and diphosphate....

 and a cytochrome P450 monooxygenase
Monooxygenase
Monooxygenases are enzymes that incorporate one hydroxyl group into substrates in many metabolic pathways. In this reaction, two atoms of dioxygen are reduced to one hydroxyl group and one H2O molecule by the concomitant oxidation of NADH.-Classification:...

 (CYP71AV1), both from A. annua. A three-step oxidation of amorpha-4,11-diene
Amorpha-4,11-diene
Amorpha-4,11-diene is a precursor to artemisinin....

 gives the resulting artemisinic acid. Amyris Inc. collaborated with UC Berkeley and the Institute for One World Health to further develop this technology. The collaboration, known as the Artemisinin Project, is supported by funding from the Bill & Melinda Gates Foundation
Bill & Melinda Gates Foundation
The Bill & Melinda Gates Foundation is the largest transparently operated private foundation in the world, founded by Bill and Melinda Gates. It is "driven by the interests and passions of the Gates family"...

, and aims to create a source of non-seasonal, high-quality and affordable artemisinin to supplement the botanical supply, with the objective of making ACTs more accessible. The technology is based on inventions licensed from UC Berkeley and the National Research Council (NRC) Plant Biotechnology Institute of Canada. In 2011, OneWorld Health announced that the project has entered the "production and distribution" phase. Integration of semisynthetic artemisinin into the supply chain is planned for 2012.

According to the WHO World Malaria Report 2010, semisynthetic artemisinin from yeast will not become available on the market until 2012 at which time it will supplement botanical sources.

In 2010 a team from Wageningen University
Wageningen University
Wageningen University and Research Centre is a Dutch public university in Wageningen, The Netherlands. It consists of Wageningen University, the Van Hall-Larenstein School of Higher Professional Education, and the former agricultural research institutes of the Dutch Ministry of Agriculture...

 reported that they had engineered a close relative of tobacco, Nicotiana benthamiana
Nicotiana benthamiana
Nicotiana benthamiana is a close relative of tobacco and species of Nicotiana indigenous to Australia.The herbaceous plant is found amongst rocks on hills and cliffs throughout the northern regions of Australia. Variable in height and habit, the species may be erect and up to 1.5 metres or...

, that can also produce the precursor artemisinic acid.

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