Artesunate

Artemisinin and its derivatives, artesunate and arthemether, kill both asexual and sexual blood stages (Fig. 2). However, artemisinins are quickly eliminated from the body, resulting in parasite recrudescence, and are therefore combined with schizontocides that have a longer biological half-life, such as amodiaquine,... 

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). 

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]. 

Deoxoartemisinin and carboxypropyldeoxoartimisinin have also been shown to have anti-tumour activity and, NMR studies on solution conformations have been reported <00BBR359>. One of the problems with artemisinin use is its poor water solubility characteristics. An attempt to rectify this, and to overcome stability problems associated with sodium artesunate in solution, has involved the introduction of amino group functionality as in 127 (eg. R = 0(CH2)3NR r2 where NR r2 = morpholine). The maleate salt of this compound has reasonable water solubility and aqueous solutions are stable at room temperature for an extended time. However activity against Plasmodium knowlesi in rhesus monkeys after oral administration was poorer compared with artesunic acid <00JMC1635>. 

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]. 

A number of chemometric tools have been employed for these classifications, including partial least squares - hierarchical cluster analysis (PLS-HCA) for Viagra tablets [98] and antimalarial artesunate tablets [99]. de Peinder et al. used partial least squares discriminant analysis (PLS-DA) models to distinguish genuine from counterfeit Lipitor tablets even when the real API was present [100]. The counterfeit samples also were found to have poorer API distribution than the genuine ones based on spectra collected in a cross pattern on the tablet. 

C. Ricci, C. Eliasson, N.A. MacLeod, P.N. Newton, P. Matousek and S.G. Kazarian, Characterization of genuine and fake artesunate anti-malarial tablets using Fourier transform infrared imaging and spatially offset Raman spectroscopy through blister packs. Anal. Bioanal. Chem., 389, 1525-1532 (2007). 

C. Ricci, L. Nyadong, F. Yang, F.M. Fernandez, C.D. Brown, P.N. Newton and S.G. Kazarian, Assessment of hand-held Raman instrumentation for in situ screening for potentially counterfeit artesunate antimalarial tablets by FT-Raman spectroscopy and direct ionization mass spectrometry. Anal. Chim. Acta, 623, 178-186... 

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. 

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. 

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... 

Efferth T, Romero MR, Wolf DG Stamminger T, Marin JJ, Marschall M. (2008) The antiviral activities of artemisinin and artesunate. Clin Infect Dis 47 804-811. 

Singh NP, Verma KB. (2002) Case report of a laryngeal squamous cell carcinoma treated with artesunate. Arch Oncol 10 279-280. 

Berger TG, Dieckmann D, Efferth T, Schultz ES, Funk JO, Baur A, Schuler G. (2005) Artesunate in the treatment of metastatic uveal melanoma-first experiences. Oncol Rep 14 1599-1603. 

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. 

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... 

Newton PN, Dondorp A, Green M, Mayxay M, White NJ. Counterfeit artesunate antimalarials in Southeast Asia. Lancet 2003 362 9. 

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... 

Jones KL, Donegan S, Lalloo DG. Artesunate versus quinine for treating severe malaria. Cochrane Database Syst Rev 2007. 

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. 

In complicated falciparum malaria exchange transfusion can be considered if high parasitemia s (>5%) is present, although the benefit has not been proven with a randomised controlled trial. In these severe cases i.v. quinine (with loading dose) is gradually being replaced by artesunate, wich has proven less mortality and less side effects than good old ... 

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. 

Artesunate x 3 days + mefloquine has been used in several Asian countries for MDR falciparum malaria. Artesunate 4 mg/kg/day x 3 day and mefloquine 25 mg/kg single splitting into 2 dose 6-8 hours apart (15 mg/kg then 10 mg/kg). 

Bukirwa H, Critchley J. Sulfadoxine-pyrimethamine plus artesunate versus sulfadoxine-pyrimethamine plus amodiaquine for treating uncomplicated malaria. Cochrane Database Syst Rev 2006. 

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