Artemisinin Based Combination Therapies ( Acts )

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Artemisinin-based combination therapies (ACTs) are currently considered gold standards in the management of uncomplicated malaria. For the liver stages, primaquine is the only drug approved to eliminate hypnozoites. Resistance against existing antimalarials is well documented, and troubling due to the emerging resistance to artemisinins. Therefore, a rising incidence of drug resistance requires the development new drugs, with novel disease targeting strategies. Moreover, the challenge is to develop innovative drugs that demostrate (i) faster onset and longer duration of drug action, (ii) safe for children and pregnant women, and (iii) ideally be amenable to a single-dose administration. Following are brief descriptions of such innovative…show more content…
2. Ferroquine was found to be active against chloroquine- resistant strains, and is currently undergoing Phase II clinical trials. Ferroquine, unlike chloroquine, accumulates in the digestive vacuole of the chloroquine resistant parasites, enabling P. falciparum chloroquine resistance transporter, PfCRT inhibition.

3. Amodiaquine is also active against most chloroquine resistant strains, however, two reactive metabolites are formed, namely imine and aldehyde, and are the likely cause of the hepatotoxicity and agranulocytosis, respectively.

4. N-tert-Butyl isoquine (GSK369796) was designed to avoid the formation of quinone imines, and entered Phase I studies. It is potent in vitro, including in the chloroquine resistant strain K1 (EC50 = 13 nM) and is active in vivo with an ED50 = 3.8 mg/kg/day, thus being comparable to amodia- quine. In spite of the excellent exposures and near quantita- tive oral bioavailabili ties in animal models, its developmen t was discontinue d due to exposures insufficient to demonstrate drug safety superior to chloroquine.

5. In an effort to select the next generation of quinoline methanol derivatives that could serve as a replacement for mefloquine, the Walter Reed Army Institute of Research screened for analogs with a lower brain penetration, and identified WR621308, which has asubstantially lower permeability across MDCK cell monolayers than mefloquine, suggesting lower brain
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