Qinghaosu and Artemisinin derivatives

Qinghaosu (“essence of qinghao”) originates from a Chinese plant, Artemisia annua (sweet wormwood). This is a plant with composite flowers related to absinthe and tarragon. As the name suggests it is an annual plant, from which seeds need to be collected each year for the next cultivation. The leaves and flower heads contain the highest concentration of drug and are harvested. The variant which grows in South China and North Vietnam contains a high concentration of active constituents (up to 1.5% dry weight), unlike the variants which grow outside this zone (Europe, Virginia). From it are produced artemisinin and the derivatives artesunate (the hemisuccinate), arteether (the ethyl ether) and artemether (the methyl ether). (A reminder: an ether has the formula R-O-R’). Artelininic acid is a more water-soluble derivative (artelinate). The products are rapidly converted after ingestion to the equally active dihydro-artemisinin. Inhibitors of the cytochrome P450 (CYP 3A 4/5) such as grapefruit juice, increase the plasma levels of artemether to a significant extent (e.g. double). After oral administration there is a significant first-pass effect in the liver. The plasma half-life of artemether and its active metabolite is very short: both 1 hour.

The active molecule is a sesquiterpene lactone with a peroxide bridge [sesquiterpene = a molecule formed from 3 isoprene units; a lactone = a cyclical ester, R-COO-R’]. The endoperoxyde bridge (-O-O-) is important to the activity of the molecule. Nevertheless the mechanism of action is more complicated than purely aspecific oxidative damage to the parasite by free radicals.

The substance is not active upon liver stages, but upon both the immature sexual and the early-stage asexual blood forms. It does not kill mature gametocytes of P. falciparum. Since it reduces the number of gametocyte carriers, it helps to prevent malaria transmission. These drugs are used chiefly in Asia (including China, Thailand and Vietnam). They are also available at present in many African countries. One important advantage of artemisinin derivatives is the very rapid action (faster than quinine). Artemisinin and artesunate may be administered as suppositories if the patient is too ill to take oral medication (e.g. Plasmotrim Rectocaps®). The bio-availability of the drug via this route is approximately equal to that of the oral form. Artemisinin induces an enzyme which strongly promotes its own breakdown. In monotherapy relapse is frequently seen (depending on the dose and duration of therapy). Should these products be used wrongly, swift appearance of artemisinin-resistant falciparum strains can be expected. Neurotoxicity has been observed in animal trials (selective damage to certain brain stem nuclei and to the auditory nuclei in rats, dogs and Rhesus monkeys treated with IM artemether and arteether). Apparently no ototoxicity or neurotoxicity occurs in humans. The drugs also suppress reticulocytosis, but the clinical importance is still unclear. During treatment with artemether a transitory bradycardia and prolonged QT-interval was observed in approximately 1% of cases, but with no direct clinical repercussions. Artemether and dihydroartemisinin reduce the number of parasites by approximately 10,000 for each asexual cycle. After two cycles (3 days’ treatment) there is a 10⁸-fold reduction of the parasitaemia. Five days’ treatment can result in a 10¹²-fold reduction in the parasitic biomass. In functional asplenia artemether is less effective. People who are heterozygous for haemoglobin E have a swifter parasite clearance with artemisinin derivatives than those without this haemoglobin variant.

Artemisinin is poorly soluble in water and oil, but can be given as suppositories.

The derivative artemether (Paluther®, Arteminth®, Cotexcin®, Artenam®) is oil-soluble and can be used for IM administration (e.g. 600 mg/day x 5 days; recommended dose 3.2 mg/kg IV on day 1 followed by 1.6 mg/kg per day x 5 days). It should be protected from light during storage. The ampoule must be clear (there is sometimes a cloudy precipitate). There is also an oral form. Absorption improves considerably with concurrent ingestion of grapefruit juice (possible role of intestinal CYP3A4). The fixed combination of artemether with mefloquine produced good results in Southeast Asia.

Artesunate (Artenam®, Artesunate®, Arsumax®, Artemax®, Arinate®, Plasmotrim®) is the fastest-acting artemisinin derivative. It can be administered parenterally (IV, IM), rectally or orally. The dose for adults is 200 to 400 mg on day 1, 100-200 mg/day once daily on the following days to a total of 5 days. Since the molecule is not stable in water, the dry powder (60 mg) should be dissolved just before the injection with 0.6 ml sodium bicarbonate and 5.4 ml dextrose or dextrose/physiological fluid.

Arteether (Artecef®, a mixture of α- and β-enantiomers; beta-arteether is also known as artemotil) is at present only available in the Netherlands for IM administration. For children 2.4 mg/kg IV is given on day 1, then 1.2 mg/kg per day from day 2 to day 5 inclusive.

The combination of dihydroartemisinin and piperaquine, a chemical related to chloroquine, is known as Artekin in China. Dihydroartemisinin-piperaquine is believed to be one of the most effective drug combinations to treat malaria.

Category: Medicine Notes