Curcumin-Artemisinin Combination Therapy for Malaria

Abstract

Artemisinin and curcumin show an additive interaction in killing Plasmodium falciparum in culture. In vivo, 3 oral doses of curcumin following a single injection of ␣,␤-arteether to Plasmodium berghei-infected mice are able to prevent recrudescence due to ␣,␤-arteether monotherapy and ensure almost 100% survival of the animals.Artemisinin derivative-based combination therapy (ACT) has been advocated as the therapy of choice to handle widespread drug resistance in Plasmodium falciparum malaria, at the same time preventing recrudescence due to artemisinin monotherapy. However, most of the combinations are less than ideal because of side effects, pharmacokinetic mismatch, and cost (8,15). Studies in this laboratory have shown that curcumin isolated from the roots of Curcuma longa (turmeric) has antimalarial activity in P. falciparum culture and in Plasmodium berghei-infected mice (10). In this study, we propose a novel artemisinin-curcumin therapy to treat malaria.Artemisinin and curcumin (98% curcuminoid content) were purchased from Sigma Chemicals, Bangalore, India. ␣,␤-Arteether (EMAL, a synthetic derivative of artemisinin) developed by Central Drug Research Institute, Lucknow, India, was a kind gift from IPCA Laboratories Ltd., Mumbai, India. [ 3 H]hypoxanthine was purchased from PerkinElmer, Singapore.The P. falciparum FCK strain, a local chloroquine-resistant isolate, was cultured in human O-positive washed erythrocytes using standard protocols (14). Parasites were synchronized using 5% (wt/vol) D-sorbitol, and the cultures were pooled and the parasites released from the erythrocyte with 0.15% (wt/vol) saponin (3) for further processing. The 50% inhibitory concentrations (IC 50 s) for artemisinin and curcumin were determined in P. falciparum cultures by measuring [3 H]hypoxanthine uptake into the parasite as a measure of viability (2). Fractional inhibitory concentrations (FIC) were calculated using the formulawhere A C and B C are the concentrations of A and B in the combination associated with a particular level of effect, e.g., IC 60 , and A E and B E are the concentrations of A and B when used singly to produce the same level of effect, on the basis that a simple additive interaction should lead to a value of 1 (7). FIC were derived from graphs drawn using GraphPad Prism 4.Means Ϯ standard deviations and Student's t test were analyzed using Microsoft Excel. For in vivo studies, Swiss mice (25 to 28 g) were injected intraperitoneally with P. berghei-infected mouse blood (60 to 70% parasitemia) on day 0, such that the animals developed high parasitemia and died in about 5 to 8 days. The artemisinin derivative ␣,␤-arteether was injected intramuscularly at different doses on day 1. This was followed by oral feeding of curcumin in dimethyl sulfoxide on days 1, 2, and 3 (100 mg/kg of body weight). The mice were observed for external symptoms and mortality when the drugs were given alone or in combination. Blood from the tail vein was analyzed on different days for parasitemia using Giemsa to stain the slides.De...

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