Artemisinin drugs

Thus far no major adverse effects have been reported for artemisinin and its derivatives. Although neurotoxicity can occur in animals, it has never been reported in humans. However, subclinical cumulative neurotoxicity could occur with each treatment course for separate episodes of malaria. This possible risk prohibits the use of artemisinin drugs for malaria prophylaxis. 

Van Agtmael MA. Eggelte TA, Van Boxtel CJ. Artemisinin drugs in the treatment of malaria from medicinal herb to registered medication. Trends Pharmacol Sci 1999 20(2) 199-205. 

Fig. 6 Mechanism of the action of artemisinin drugs. Active metabolites and formation of reactive epoxide intermediates...

Burk, O., Arnold, K. A., Nussler, A. K., Schaeffeler, E., Efimova, E., Avery, B. A., Avery, M. A., Fromm M. F., and Eichelbaum, M. (2005) Antimalarial artemisinin drugs induce cytochrome P450 and MDR1 expression by activation of xenosensors pregnane X receptor and constitutive androstane receptor. Mol. Pharmacol. 67,1954-1964. 

Prospects. Other indications for malaria for the artemisinin drugs are currently under investigations. Without a final proof, other erythrocyte persisting parasites like Babesia are maybe another interesting target parasite. But also Toxoplasma gondii, Pneumocystis carinii infections in mice have been treated successfully with artemisinin drugs [157-159],... 

Price, R. N. 2000. Artemisinin drugs novel antimalarial agents . Expert Opin Investig Drugs. P(8) 1815-27. 

Leskovac, V. Theoharides, A.D. Hepatic metabolism of artemisinin drugs -1. Drag metabolism in rat liver microsomes, Comp.Biochem.Physiol.C, 1991, 99, 383-390. [arteether dihydroartemisinin]... 

Antimalarial drug artemisinine, sesquiterpenic 8-lactone with 1,2,5-trioxane (endoperoxide) fragment 98CSR273. 

Trioxane 210 has been used as a model system by Gu and coworkers to study the antimalarial drug artemisinin 211 (Scheme 137) [97CPL234, 99JST103]. It is the boat/twist form rather than the chair conformer of 210 that describes the subunit in 211. Moreover, geometric parameters and vibrational frequencies can only reliably be computed at the DFT level and by post-Hartree-Fock methods. B3-LYP/6-31G calculations on the conformers of 3,3,6,6-tetramethyl-1,2,4,5-tetroxane show that the chair conformer is stabilized with respect to the twisted conformer by about -2.8 kcal/mol [00JST85]. No corresponding boat conformer was found. 

Antiprotozoal Drugs. Figure 5 Artemisinin combination therapy (ACT) Adding a 3-days artesunate course to mefloquine cleats the parasitaemia much more rapidly (A — A). The remaining parasites are exposed to higher mefloquine levels in ACT (B) compared to mefloquine monotherapy (B (with permission White, 1997 Antimicrob Agents Chemother 41 1413-1422). 

There is an expanding body of evidence to suggest that sesquiterpene lactones inhibit the synthesis NO synthetase. One such compound is an ambrosanolides-type sesquiterpene known as cumanin characterized from Ambrosia psilostachya. This sesquiterpene inhibit the enzymatic activity of NO synthetase with an IC50 value of 9.38 xM (49). Another example is the well-known artemisinin, a sesquiterpene used as an alternative drug in the treatment of severe and multidrug-resistant malaria, which inhibits NO synthesis in cytokine-stimulated human astrocytoma T67 cells (50). 

How do traditional remedies fare in such trials Some perform quite well and prove to be highly effective, but others are no better than placebos. One striking success is an extract of sweet wormwood (Artemisia annua), which Chinese physicians have prescribed for the chills and fevers of malaria for more than two thousand years. About twenty-five years ago, Chinese chemists obtained from sweet wormwood its principal active component, a compound now called artemisinin. Clinical trials on malaria patients in Southeast Asia agreed with Chinese tradition on the value of artemisinin and also identified a few even more useful drugs prepared from it in the laboratory. These compounds are effective against the deadliest form of malaria and are now frequently the therapies of choice for treating it. 

The Plasmodium falciparum malaria PD model successfully described the antimalarial effect of artemisinin, mefloquine, and a combination of the two drugs... 

WaUaart TE, Bouwmeester HJ, Hille J, Poppinga L, Maijers NCA (2001) Amorpha-4, 11-diene synthase cloning and functional expression of a key enzyme in the biosynthetic pathway of the novel antimalarial drug artemisinin. Planta 212 460-465... 

Other derivatives of artemisinin are in various stages of clinical development as antimalarial drugs in Europe. 

Jefford CW. (2007) New developments in synthetic peroxidic drugs as artemisinin mimics. Drug Discovery Today 12 487 95. 

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