Dihydroartemisinin
Encyclopedia
Dihydroartemisinin is a drug used to treat malaria
. Dihydroartemisinin is the active metabolite of all artemisinin
compounds (artemisinin, artesunate
, artemether
, etc.) and is also available as a drug in itself. It is a semi-synthetic derivative of artemisinin
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.
, potassium borohydride, and lithium borohydride
to dihydroartemisinin (a lactol) in over 90% yield. It is a novel reduction, because normally lactone 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 sodium borohydride
and could only be reduced with diisobutylaluminium hydride
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.
(each tablet contains 40 mg of dihydroartemisinin and 320 mg of piperaquine; trade name Artekin, manufactured by Holleykin Pharmaceuticals).
The adult dose is 1.6/12.8 mg/kg per dose (rounded up or down to the nearest half tablet) given at 0 h, 8 h, 24 h, and 48 h. Alternatively, the same total dose may be given once daily for three days.
Dihydroartemisinin is also sold in Africa as Cotecxin in 60 mg tablets, which is manufactured by Zhejiang Holley Nanhu Pharmaceutical Co., Ltd., in China.
:
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...
. Dihydroartemisinin is the active metabolite of all artemisinin
Artemisinin
Artemisinin , also known as Qinghaosu , and its derivatives are a group of drugs that possess the most rapid action of all current drugs against falciparum malaria. Treatments containing an artemisinin derivative are now standard treatment worldwide for falciparum malaria...
compounds (artemisinin, 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...
, 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:...
, etc.) and is also available as a drug in itself. It is a semi-synthetic derivative of artemisinin
Artemisinin
Artemisinin , also known as Qinghaosu , and its derivatives are a group of drugs that possess the most rapid action of all current drugs against falciparum malaria. Treatments containing an artemisinin derivative are now standard treatment worldwide for falciparum malaria...
and is widely used as an intermediate in the preparation of other artemisinin-derived antimalarial drugs.It is sold commercially in 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...
and has been shown to be equivalent to artemether/lumefantrine.
Chemistry
The lactone of artemisinin could selectively be reduced with mild hydride-reducing agents, such as sodium borohydrideSodium borohydride
Sodium borohydride, also known as sodium tetrahydridoborate, is an inorganic compound with the formula NaBH4. This white solid, usually encountered as a powder, is a versatile reducing agent that finds wide application in chemistry, both in the laboratory and on a technical scale. Large amounts are...
, potassium borohydride, and lithium borohydride
Lithium borohydride
Lithium borohydride is a tetrahydroborate 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 of being highly soluble in ethers and being a stronger reducing agent but still safer to...
to dihydroartemisinin (a lactol) in over 90% yield. It is a novel reduction, because normally lactone 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 sodium borohydride
Sodium borohydride
Sodium borohydride, also known as sodium tetrahydridoborate, is an inorganic compound with the formula NaBH4. This white solid, usually encountered as a powder, is a versatile reducing agent that finds wide application in chemistry, both in the laboratory and on a technical scale. Large amounts are...
and could only be reduced with diisobutylaluminium hydride
Diisobutylaluminium hydride
Diisobutylaluminium hydride, DIBAL, DIBAL-H or DIBAH, is a reducing agent with the formula 2, where i-Bu represents isobutyl...
to the lactol
Lactol
In organic chemistry, a lactol is the cyclic equivalent of a hemiacetal or a hemiketal.The compound is formed by the intramolecular nucleophilic addition of a hydroxyl group to the carbonyl group of an aldehyde or a ketone....
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.
Dosing
Dihydroartemisinin is available as a fixed drug combination with piperaquinePiperaquine
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...
(each tablet contains 40 mg of dihydroartemisinin and 320 mg of piperaquine; trade name Artekin, manufactured by Holleykin Pharmaceuticals).
The adult dose is 1.6/12.8 mg/kg per dose (rounded up or down to the nearest half tablet) given at 0 h, 8 h, 24 h, and 48 h. Alternatively, the same total dose may be given once daily for three days.
Dihydroartemisinin is also sold in Africa as Cotecxin in 60 mg tablets, which is manufactured by Zhejiang Holley Nanhu Pharmaceutical Co., Ltd., in China.
Activity as experimental cancer chemotherapeutic
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.Commercial preparations
In combination with piperaquinePiperaquine
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...
:
- Duocotecxin (Holley Pharm)
- Artekin (Holleykin)