Sodium artesunate

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>. 

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... 

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... 

The pharmaceutical properties of artemisinin are far from optimal it is insoluble in water and only marginally soluble in oil. It has poor oral bioavailability and has been administered for the treatment of Plasmodium falciparum malaria in humans at total doses of about 1 g (over 3 days). Early studies by Chinese scientists in 1979 led to the discovery of dihydroartemisinin 3, artemether 4 (Artenam), and sodium artesunate 5, oil and water soluble derivatives, respectively (Figure 9.1 ).6-7 These drugs are currently in clinical use in Asia in a number of preparations such as suppositories, i.v. injectables, oil depos, to name only a few.8 Capsules containing 0.5 g of artemisinin for oral administration are available in Vietnam. 

Artemisinin (1) can be selectively reduced with NaBH4 to afford dihydroartemisinin (175, DHQHS), which has been shown to be roughly ten times as potent as parent material 1. The lactol DHQHS (175) was converted to various ethers by treatment in alcohols with boron trifluoride (acetal formation conditions). Notably artemether (144) and arteether (145) were prepared in this manner. Alternatively, DHQHS can be acylated to yield esters or carbonates, as shown for sodium artesunate (146) as an example. 

Further support for a hydrophobic binding domain in the southeast quadrant of the artemisinin pharmacophore comes from the carboxylic acid 58 (originally designed as a chemically stable replacement for sodium artesunate), which was found to be nearly devoid of antimalarial activity. Of course, bioavailability of the acid 58 could be poor in contrast to hydrophobic analogues. 

Oil-soluble artemether and water-soluble sodium artesunate were developed and approved as new antimalarial drugs by the Chinese authorities in 1987. After 1992, dihydroartemisinin, Coartem (a combination of artemether and benflumetol), and Artekin (a combination of dihydroartemisinin and piperaquine) were also marketed as new antimalarial dmgs. Since then, over 10 million malaria patients on a global scale have been cured after administration of these drugs. As a result, artemether, artesunate, and Coartem were added by the World Health Organization to the ninth, eleventh, and twelfth Essential Medicine List respectively. 

When artemether and sodium artesunate were successfully used by intramuscular or intravenous administration for treatment of severe malarial patients, their shortcomings, such as short half-life and instability of aqueous solution of sodium artesunate, were cognized. Hence, qinghaosu derivatives and analogs numbering in the thousands were synthesized and evaluated by many research groups worldwide. 

Sodium artesunate is the first water-soluble qinghaosu derivative and used for treatment of the severe malaria patients by intravenous or intramuscular administration. However, the aqueous solution is unstable, and its hydrolysis product,... 

Zhang, X. Yang, X. P. Pan, Q. C. Studies on the antitumor effect and apoptosis induction in human liver cancer cell line (BEL-7402) by sodium artesunate. Chirr Trad. Herb Drug, 1998, 29(7) 467 9. 

Zhang, J. X. Wang, S. X. Zhang, F. G. Zhang, Y. H. Liu, A. H. Effect of sodium artesunate toward antiproliferative activity of human cancer cell (HeLa, SACC-83) in vitro. Chin. Trad. Herb Drug, 2001, 32(4) 345-346. 

Artemether (N2) and arteether (N3) are the most well-studied analogs among many synthetic derivatives and are used in malaria-prone regions, particularly India (131). Artemether and sodium artesunate (a hemisuccinate derivative of dihydroartemisinin) (N4) have been added by the World Health Organization to its Model List of Essential Medicines (132). 

Water solubility can be greatly improved by the standard ploy of esterification with succinic acid and conversion to the sodium salt. Applied to compound (155), this technique gives sodium artesunate (158), a water-soluble prodrug that may be given intravenously (196). It may be assumed that hydrolysis occurs in vivo to give back (155) as the active antimalarial because (156) has been shown to be unstable in aqueous solution and because analogous carboxylic acids with a nonhydro-lyzable ether link are relatively inactive. 

Sodium artesunate inhibits sodium chloride transport in the thick ascending limb of the loop of Henle and therefore has a diuretic effect. 

In two men, aged 16 and 32 years, with falciparum malaria who were given four intravenous doses of sodium artesunate 60 mg, neither of whom had received diuretics or vasoactive drugs, there was a diuresis (6 1/day) accompanied by a natriuresis (31). 

Seguro AC, Campos SB. Diuretic effect of sodium artesunate in patients with malaria. Am J Trop Med Hyg 2002 67(5) 473-4. 

Sodium AmitaR amylobarbitone. sodium artesunate artesunate. sodium ascorbate ascorbic acid, sodium aurothiomalate gold sodium thiomalate. sodium aurotiosulfate [inn] (aurothlosulphate) is a thiogold derivative, and can be used as an ANTIINFLAMMATORY in antiarthritic and antirheumatic treatment. Also a reported ANTIHYPEKTENSIVE, acting as a CYCLOOXYGENASE INHIBITOR. 

B. Because artemisinin is lipophilic it must be formulated as an oily preparation. Various derivatives have been produced which are more water soluble, including an ether called artemether and an ester, sodium artesunate. Quinghao is now extensively cultivated in many areas where malaria is endemic. 

Esters (32 4, R = C(=0)-alkyl or -aryl), of which a-epimers were mainly obtained, were more active than the ethers. Sodium artesunate (32 5, R = C(=0)-CH2CH2C00Na), the half succinic acid half-ester of dihydroartemisinin is water-soluble and shows potent antimalarial activity. Therefore, this can be administered intravenously. However it is uncertain whether this derivative is pharmacologically effective because of its sensitivity to hydrolysis. In considering this result new ether derivatives of dihydroartemisinin, which are stable and water soluble derivatives have been prepared [46]. Dihydroartemisinin was condensed with esters of aliphatic or aromatic carboxylic acids with hydroxy groups to produce mainly ethers with the P-configuration. Ethyl 2-( 10-dihydroartemisininoxy) acetate (31 4, R = CH2COOCH2CH3) and methyl... 

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