Dihydroartemisinin (also known as dihydroqinghaosu, artenimol or DHA) is a drug used to treat

malaria Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. S ...

. Dihydroartemisinin is the active metabolite of all

artemisinin Artemisinin () and its semisynthetic derivatives are a group of drugs used in the treatment of malaria due to '' Plasmodium falciparum''. It was discovered in 1972 by Tu Youyou, who shared the 2015 Nobel Prize in Physiology or Medicine for her ...

compounds (artemisinin,

artesunate Artesunate (AS) is a medication used to treat malaria. The intravenous form is preferred to quinine for severe malaria. Often it is used as part of combination therapy, such as artesunate plus mefloquine. It is not used for the prevention of ma ...

artemether Artemether is a medication used for the treatment of malaria. The injectable form is specifically used for severe malaria rather than quinine. In adults, it may not be as effective as artesunate. It is given by injection in a muscle. It is also ...

, etc.) and is also available as a drug in itself. It is a semi-synthetic derivative of

and is widely used as an intermediate in the preparation of other artemisinin-derived antimalarial drugs. It is sold commercially in combination with piperaquine and has been shown to be equivalent to

artemether/lumefantrine Artemether/lumefantrine, sold under the trade name Coartem among others, is a combination of the two medications artemether and lumefantrine. It is used to treat malaria caused by ''Plasmodium falciparum'' that is not treatable with chloroquine. ...

Medical use

Dihydroartemisinin is used to treat

, generally as a

combination drug A combination drug or a fixed-dose combination (FDC) is a medicine that includes two or more active ingredients combined in a single dosage form. Terms like "combination drug" or "combination drug product" can be common shorthand for a FDC prod ...

with piperaquine. In a systematic review of randomized controlled trials, both dihydroartemisinin-piperaquine and artemether-lumefantrine are very effective at treating

(high quality evidence). However, dihydroartemisinin-piperaquine cures slightly more patients than artemether-lumefantrine, and it also prevents further malaria infections for longer after treatment (high quality evidence). Dihydroartemisinin-piperaquine and artemether-lumefantrine probably have similar side effects (moderate quality evidence). The studies were all conducted in Africa. In studies of people living in Asia, dihydroartemisinin-piperaquine is as effective as artesunate plus mefloquine at treating malaria (moderate quality evidence). Artesunate plus mefloquine probably causes more nausea, vomiting, dizziness, sleeplessness, and palpitations than dihydroartemisinin-piperaquine (moderate quality evidence).

Pharmacology and mechanism

The proposed

mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targ ...

of artemisinin involves cleavage of endoperoxide bridges by iron, producing free radicals (

hypervalent In chemistry, a hypervalent molecule (the phenomenon is sometimes colloquially known as expanded octet) is a molecule that contains one or more main group elements apparently bearing more than eight electrons in their valence shells. Phosphorus pe ...

iron-oxo species,

epoxides In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale f ...

aldehydes In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...

, and

dicarbonyl In organic chemistry Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain ...

compounds) which damage biological macromolecules causing

oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...

in the cells of the parasite. Malaria is caused by apicomplexans, primarily '' Plasmodium falciparum'', which largely reside in red blood cells and itself contains iron-rich

heme Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver. In biochemical terms, heme is a coordination complex "consis ...

-groups (in the form of

hemozoin Haemozoin is a disposal product formed from the digestion of blood by some blood-feeding parasites. These hematophagous organisms such as malaria parasites (''Plasmodium spp.''), ''Rhodnius'' and ''Schistosoma'' digest haemoglobin and release high ...

). In 2015 artemisinin was shown to bind to a large number targets suggesting that it acts in a promiscuous manner. Recent mechanism research discovered that artemisinin targets a broad spectrum of proteins in the human cancer cell proteome through heme-activated radical alkylation.

Chemistry

Dihydroartemisinin has a low solubility in water of less than 0.1 g/L. Consequently, its use may results in side effects caused by minor, yet much more soluble, additives (

excipient An excipient is a substance formulated alongside the active ingredient of a medication, included for the purpose of long-term stabilization, bulking up solid formulations that contain potent active ingredients in small amounts (thus often referred ...

s) such as Cremophor EL. The lactone of artemisinin could selectively be reduced with mild hydride-reducing agents, such as

sodium borohydride Sodium borohydride, also known as sodium tetrahydridoborate and sodium tetrahydroborate, is an inorganic compound with the formula Na BH4. This white solid, usually encountered as an aqueous basic solution, is a reducing agent that finds applica ...

, potassium borohydride, and

lithium borohydride Lithium borohydride (LiBH4) is a borohydride and known in organic synthesis as a reducing agent for esters. Although less common than the related sodium borohydride, the lithium salt offers some advantages, being a stronger reducing agent and ...

to dihydroartemisinin (a lactol) in over 90% yield. It is a novel reduction, because normally lactones cannot be reduced with sodium borohydride under the same reaction conditions (0–5 ˚C in methanol). Reduction with LiAlH₄ leads to some rearranged products. It was surprising to find that the lactone was reduced, but that the peroxy group survived. However, the lactone of deoxyartemisinin resisted reduction with

and could only be reduced with

diisobutylaluminium hydride Diisobutylaluminium hydride (DIBALH, DIBAL, DIBAL-H or DIBAH) is a reducing agent with the formula (''i''-Bu2AlH)2, where ''i''-Bu represents isobutyl (-CH2CH(CH3)2). This organoaluminium compound is a reagent in organic synthesis. Properties Lik ...

to the lactol deoxydihydroartimisinin. These results show that the peroxy group assists the reduction of lactone with sodium borohydride to a lactol, but not to the alcohol which is the over-reduction product. No clear evidence for this reduction process exists.

Society and culture

In combination with piperaquine, brands include: * D-Artepp (GPSC) * Artekin (Holleykin) * Diphos ( Genix Pharma) * TimeQuin ( Sami Pharma ) * Eurartesim (Sigma Tau; by Good Manufacturing Practices) * Duocotecxin (Holley Pharm) Alone (not recommended by WHO due to risk of resistance development): *Cotecxin (Zhejiang Holley Nanhu Pharmaceutical Co.)

Research

Accumulative research suggests that dihydroartemisinin and other artemisinin-based endoperoxide compounds may display activity as experimental cancer chemotherapeutics. Recent pharmacological evidence demonstrates that dihydroartemisinin targets human metastatic melanoma cells with induction of NOXA-dependent mitochondrial apoptosis that occurs downstream of iron-dependent generation of cytotoxic oxidative stress.

References

External links

* {{Portal bar , Medicine Antimalarial agents Organic peroxides Trioxanes Chinese discoveries Oxygen heterocycles Heterocyclic compounds with 4 rings Tetracyclic compounds Lactols