In vitro assessment of drug resistance in Plasmodium falciparum in five States of India.

Background & objectives: In vitro assays are an important tool to assess baseline sensitivity and monitor the drug response of Plasmodium falciparum over time and place and, therefore, can provide background information for the development and evaluation of drug policies. This study was aimed at determining the in vitro sensitivity of P. falciparum isolates to antimalarials. Methods: The in vitro activity of 108 P. falciparum isolates obtained from five States of India was evaluated using WHO microtest (Mark III) to chloroquine, monodesethylamodiaquine, dihydroartesunate and mefloquine. Samples were collected from the States of Orissa, Jharkhand, Karnataka, Goa and Chhattisgarh from September 2007 to August 2009. In addition, representative samples from different States of India cryopreserved and culture adapted in the Malaria Parasite Bank of National Institute of Malaria Research, New Delhi, were also evaluated. Results: The proportion of isolates resistant to chloroquine and monodesethylamodiaquine was 44.4 and 25 per cent, respectively. Of the 27 isolates resistant to monodesethylamodiaquine, 16 (59.3%) were cross-resistant to chloroquine. No isolate showed resistance to dihydroartesunate and mefloquine. Isolates from Orissa showed the highest degree of resistance to chloroquine and amodiaquine followed by Jharkhand. Forty two isolates were genotyped for pfcrt T76K chloroquine resistant mutation; mutations were seen in 38 (90.47%) isolates. Interpretation & conclusions: The Indian P. falciparum isolates showed a high degree of resistance to chloroquine followed by monodesethylamodiaquine. No resistance was recorded to mefloquine and dihydroartesunate.

[Synthesis and evaluation of 4-fleuroamodiaquine, a novel antimalarial drug against sensitive and resistant strains of plasmodium falciparum]

Resistance to chloroquine [CQ] in Plasmodium falciparum malaria has become a major health concern in the developing countries. This problem has prompted investigators for finding alternative antimalarials that may be effective against resistant strains. Amodiaquine [AQ] is an antimalarial which is effective against many choloroquine-resistant strains of P. falciparum. However, clinical use of AQ has severely been restricted because of its hepatotoxicity and agranulocytosis side effects. The aim of this study was to design and examine the effects of new analogues of amodiaquine. A successful four-step synthesis of a new series of 4-fluoro analogues was designed and applied to the synthesis of an array of 10 analogues. Antimalarial activity of these agents was assessed against chloroquine-resistant [TM6] and sensitive strains [3D7] of P. falciparum. Several analogues have shown potent antimalarial activity against sensitive 3D7 strain of the parasite. The 6h analogue was superior to the pyrollidino analogue 6b against all of the strains examined. The N-tert butyl analogue 6b was potent against choloroquine resistant strains, though it was not quite as active as amodiaquine [AQ] against both chloroquine sensitive and resistant parasites. From the different analogues made, it was shown that the analogue 6h was more potent than the others. However, this analogue has equal or slightly less potent than amodiaquine and chloroquine against P. falciparum. Further studies on the metabolism and pharmacokinetics of 6h are recommended

Investigation of the anti-acetylcholinesterase activities of the antimalarial agent, amodiaquine, and related compounds.

The antimalarial agent, amodiaquine, is a potent inhibitor of AChE (Ki = 1.50 x 10(-9) M, pH 7.4, 25 degrees C). Both the protonated diethylamino and phenolic hydroxyl functions of amodiaquine are necessary for interaction with AChE. This suggests that the inhibition of AChE by amodiaquine may involve binding of the protonated diethylamino and phenolic hydroxyl functions to the anionic and esteric sites of the enzyme respectively. The anti-AChE property of amodiaquine may be related in some way to the gastrointestinal and central nervous system disturbances frequently encountered when large doses of amodiaquine are used for the treatment of malaria.