Artemisinin treatment

Both artemisinin and artemether undergo deoxygenation on treatment with zinc in AcOH <96HCA1475>, but Fe(II) salts rupture the peroxy linkage and lead to rearranged products... 

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). 

Since that time, artemisinin has been used successfully in many thousand malaria patients throughout the world including those infected with both cldoroquine-sensitive and chloroquine-resistant strains of P falciparum. Artemisinin has progressively estabhshed itself as one of the most potent and effective antimalarial dmg, and is primarily recommended in the treatment of multidrug-resistant strains of P. falciparum. However, the therapeutic... 

Artemisinin-based regimens are often regarded as safe and effective drugs in the recent years however, clinically relevant artemisinin resistance has been reported both from laboratory and field studies. Some of these studies have shown that P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. This resistance was characterized by a slow parasite clearance in vivo, without corresponding reductions on conventional in vitro susceptibility testing.Although this resistance to artemisinin is still very mild and limited, its emergence would be disastrous because of the lack of alternative treatments. 

Artemisinin ( qinghaosu ) (18), a sesquiterpene lactone antimalarial compound with an endoperoxide group, discovered in the Peoples Republic of China as a constituent of Artemisia annua L., has created great interest in the biomedical community, owing to its unique mechanism of action on the heme complex. Artemisinin serves as an option for the treatment of chloroquine (4l)-resistant malaria and is used in some Asian countries as an antimalarial. However, the use of artemisinin as a single agent anti-malarial is a potential risk since the malaria parasite may become resistant to this compound class. 

Perhaps more significantly they were also able to isolate a polar, water-soluble compound that they believed was 55 in which the cysteine residue had been incorporated into the artemisinin backbone. The broadness of the signals in the proton NMR spectrum made characterization problematic, but treatment of 55 with acetic anhydride afforded 56, which was fully characterized (Scheme 16A). More recently, the same group has isolated and characterized another product from artemether. Adduct 57 was derived from the C4 secondary radical and cysteine (Scheme 16B). 

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. 

Knowledge of local resistance patterns is important to determine the treatment regimen. There is increasing chloroquine and pyrimethamine-sulfado-xine (Fansidar) resistance in Africa and in some areas at the border of Thailand there is resistance for almost all antimalarial drugs including halofantrine, mefloquine and quinine. In these areas only the artemisinin derivatives (artemether, arteether, arte-sunate, dihydroartemisinin) are effective. 

Three currently-used artemisinin based combination therapies (ACT) artesunate-mefloquine, artemether-lumefantrine and dihydroartemisinin-piperaquine, have been proven highly simple, safe and effective in the treatment of multidrug resistant P. falciparum malaria. 

Artemisinin is a natural endoperoxide-containing sesquiterpene, isolated from a plant used in traditional Chinese medicine. Acetalic artemisinin derivatives (arte-mether, artesunate) are very active against chemo-resistant forms of Plasmodium falciparum, and are clinically used for the treatment. However, they suffer from an unfavourable pharmacological profile. They are quickly metabolised by fast oxidative metabolism, hydrolytic cleavage and glucuronidation. 

Various alkylamino-artemisinins 155 were synthesized by the nucleophilic displacement of bromoartemisin 149, which was prepared in situ from 148 (Scheme 19), followed by reaction with alkylamines <2004AGE1381>. A more direct route involved treatment of 29a firstly with a mixture of NaBr and TMSCl and then with the amine <2006AGE2082>. HFIP can be used as an additive in the amination step to increase the yield <2005AGE2060>. Similar aminoartemisinins 155 (where NRR = NHAr) were prepared by reacting 29a with anilines, in the presence of a catalytic amount of pyridinium sulfate in pyridine, in good yields (e.g., Ar = Ph, 93% 72% ... 

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