Artemether

ACTs are currently recommended artemether-lume-fantrine, artesunate + amodiaquine, artesunate + mefloquine, artesunate + sulfadoxine-pyrimethamine [1, 5]. In areas with amodiaquine and sulfadoxine-pyrimethamine resistance exceeding 20%, i.e., SE Asia, artesunate + mefloquine or artemether-lumefantrine should be used [1,5]. 

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... 

Anti-infective artemether, saguinavir Antilipemic atorrastatin, lovastatin, simvastatin Cardiovascular carvedilol, cilostazole, felodipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, verapamil... 

Classen, W., Altmann, B., Gretener, P., Souppart, C., Skelton-Stroud, P. and Krinke, G. (1999) Differential effects of orally versus parenterally administered qinghaosu derivative artemether in dogs. Experimental and Toxicologic Pathology, 51, 507-516. 

A new medicine that seems to be promising in this field is artimisinine (19) isolated from Artimisia annua. Extracts of this plant have been known for centuries in Chinese folk medicine under the name of Qinghaosu or Qinghao. For solubility reasons and hydrolysis stability, artimisinine is converted via the dihydro compound into water-soluble artesunate or oil soluble artemether and arteether (Scheme 5.12) [43]. 

Other enzyme-based mechanisms. Furthermore, the epimers of artemether showed nearly equal in vivo activity (1.02 mg/kg of body weight for a epimer versus 1.42 mg/kg of body weight for the P epimer), making the heme-based mechanism preferable over the SERCA-based mechanism for which a greater disparity in the activities would be expected. Whatever the situation may be, we all agree that further studies are necessary to clarify, or to unambiguously determine the real mechanism of action of this family of compounds. 

Li GQ. (1989) Clinical studies on artemisinin suppository and on artesunate and artemether. In S. Jiaxiang (ed.), Antimalarial drug development in China. National Institute of Pharmaceutical Research and Development, Beijing, People s Republic of China, pp. 69-73. 

Brewer TG Grate SJ, Peggins JO, Weina PJ, Petras JM, Levine BS, Heiffer MH, Schuster BG (1994) Fatal neurotoxicity of arteether and artemether. Am J Trop Med Hyg 51 251-259. 

Haynes RK, Vonwiller SC. (1994) Extraction of artemisinin and artemisinic acid Preparation of artemether and new analognes. Trans R Soc Trap Med Hyg 88 23-26. 

Hou et also demonstrated that dihydroartemisinin (39), artemether (40) and artesunate (41) (Fig. 4) were able to inhibit the growth of four human hepatocellular carcinoma cells (HepG2, p53 wild-type Hep3B, p53 null Huh-7, p53 mutant and BEL-7404, p53 mutant). The IC50 values averaged 10.8 /tmol/L (1), 10.6 /tmol/L (39), 21.0 /tmol/L (41), and... 

Singh NP, Panwar VK. (2006) Case report of a pituitary macroadenoma treated with artemether. Integr Cancer Ther 5 391-394. 

Artemisinin (18) is a natural product for which many semisynthetic derivatives have been generated. The major rationale to produce these derivatives was to deal with the low aqueous solubility of artemisinin and its short half-life in plasma. The lipid-soluble arteether (22) and artemether (23), and the water-soluble sodium artesunate (24), were designed for... 

R=Me Artemether Sodium artesunate (25) Ipratropium bromide (26) Tiotropium bromide... 

In addition to artemisinin, other synthetic trioxanes and endoperoxides (fenozan BO-7 4 and arteflene 5 " ) have enjoyed some success arteflene reached Phase II pre-clinical trials. More recently, Vennerstrom and coworkers have reported on the outstanding antimalarial properties of several 1,2,4-trioxolanes, one of which, OZ 277 (6), has entered clinical trials in man . These exciting, easily prepared drugs will be discussed in detail later in this chapter. In order to determine the parasiticidal action of this class of antimalarial, many research groups have focused their efforts on artemisinin and its semi-synthetic derivatives (artemether, arteether and artesunate Ic, Id and le), and this is the point where our discussion will begin. 

The analogous adducts of artemether Ic and fenozan 4 were also obtained and characterized in each case porphyrin adducts were isolated in 20-30% yield. When artemisinin was treated with manganese(II) TPP in the presence of cyclohexene, Robert and Meu-nier also failed to observe any of the corresponding epoxide. The authors suggest that the Dewar benzene rearrangement and the oxidation reactions observed by Posner... 

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). 

The first generation CIO acetal derivatives artemether (Ic) and arteether (Id) both have a short half-life as a consequence of cytochrome P450 catalysed transformation to DTLA (lb), which in turn is an efficient substrate for Phase II clearance through... 

Recently, a CIO carba analogue (TDR 40292) 70 has been compared with artemether . This compound cannot form DHA as a metabolite and contains a side-chain that can be formulated as a water-soluble salt. In addition, this compound has superior activity to artemether and artesunate, both in vitro and in vivo. From initial pharmacokinetic data, 70 has a higher volume of distribution than artemether and is considerably more orally bioavailable (16% versus 1.5% for artemether) . 

An alternative approach to preventing the formation of dihydroartemisinin by simple P450 metabolism is to replace the methyl function in artemether with an aryl function. Phenoxy analogues of DHA can easily be prepared in a one-step synthesis from dihydroartemisinin in a manner similar to the preparation of Ic and Id. In addition to having superior in vivo activity to artesunate and artemether, analogues substituted with a p-fluoro (71a) or trifluoromethyl group (71b), in the phenoxy ring, resist metabolism to DHA . ... 

Woerdenbag and coworkers reported on the cytotoxicity of artemisinin endoperoxides to Ehrlich ascites tumour cells . Artemisinin had an IC50 of 29.8 p.M, whereas arteether, artemether, artelininc acid and sodium artesunate all had more potent activities, ranging from 12.2 to 19.9 p.M. It was found that opening of the lactone ring of artemisinin dramatically reduced the cytotoxicity. An ether dimer of dihydroartemisinin 106, prepared by... 

Artemisinin is very poorly soluble in water or oil and can thus only be administered orally. Active derivatives have been synthesized such as artemether, arteether and beta-arteether (Artemotil), artelinic acid and artesunate, which are used for oral, intramuscular, rectal and intravenous administration. Dihydroartemisinin is the active metabolite of all artemisinin compounds and is also available as a drug in itself (see Fig. 2). 

Oral formulations of artemisinin and its derivatives are absorbed rapidly but incompletely. Peak plasma concentrations are reached in 1-2 h. A relative bioavailability of 43% was found for oral artemether compared to intramuscular administration. The absolute bioavailability of artesunate, the only derivative for which an intravenous formulation exists, was about 15%. Artesunate is extensively hydrolyzed to dihydroartemisinin in the gastro-intestinal lumen before first-pass metabolism in the gut wall and liver takes place. Artesunate acts like a prodrug with fast transformation into... 

Artemisinin DihydroartemIsinIn Artemether Arteether Artelinic acid Artesunic acid... 

Halofantrine is usually well tolerated. Gastrointestinal complaints as well as pruritus and skin rashes may occur. It can prolong the QTc interval which can result in ventricular dysrythmias. Lume-fantrine has many similarities to halofantrine but seems not to prolong QTc. It is thus far only used in a fixed dose combination with artemether (see Section VI.a.2.5). 

Mutabingwa TK, Anthony D, Heller A, Hallett R, Ahmed J, Drakeley C et al. Amodiaquine alone, amodiaquine-i-sulfadoxine-pyrimethamine, amodi-aquine-i-artesunate, and artemether-lumefantrine for outpatient treatment of malaria in Tanzanian children a four-arm randomised effectiveness trial. Lancet 2005 365(9469) 1474-80. 

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