Reversal of chloroquine resistance in falciparum malaria independent of calcium channels

Ye, Zuguang; Knox, Van Dyke

doi:10.1016/s0006-291x(88)81111-2

Cited by 33 publications

(3 citation statements)

References 22 publications

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“…Several attempts have been undertaken to block CRT with the aim to reverse chloroquine resistance. The calcium channel blocker verapamil (Table 3 ) was shown to inhibit CRT expressed in Xenopus oocytes with an IC 50 of 30 μM (Ye and van Dyke, 1988 , 1994 ; Tanabe et al, 1989 ). In the same system, quinine, a natural product and chloroquine analog, yielded an IC 50 of 48 μM (Martin et al, 2009 ), and the antiretroviral drug saquinavir was effective at 13 μM (Martin et al, 2012 ).…”

Section: Targeting Transport Processes Of Parasites At Different Levementioning

confidence: 99%

“…The resistance reversing effect of verapamil cannot be exploited in humans, because the required dose would be too high to be tolerable (Ye and van Dyke, 1988 ). One approach was to develop a drug-like compound with dual functionality, i.e., blockade of hemozoin formation plus inhibition of CRT (Burgess et al, 2006 ; Kelly et al, 2009 ).…”

Section: Targeting Transport Processes Of Parasites At Different Levementioning

confidence: 99%

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Targeting Channels and Transporters in Protozoan Parasite Infections

2018

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Infectious diseases caused by pathogenic protozoa are among the most significant causes of death in humans. Therapeutic options are scarce and massively challenged by the emergence of resistant parasite strains. Many of the current anti-parasite drugs target soluble enzymes, generate unspecific oxidative stress, or act by an unresolved mechanism within the parasite. In recent years, collections of drug-like compounds derived from large-scale phenotypic screenings, such as the malaria or pathogen box, have been made available to researchers free of charge boosting the identification of novel promising targets. Remarkably, several of the compound hits have been found to inhibit membrane proteins at the periphery of the parasites, i.e., channels and transporters for ions and metabolites. In this review, we will focus on the progress made on targeting channels and transporters at different levels and the potential for use against infections with apicomplexan parasites mainly Plasmodium spp. (malaria) and Toxoplasma gondii (toxoplasmosis), with kinetoplastids Trypanosoma brucei (sleeping sickness), Trypanosoma cruzi (Chagas disease), and Leishmania ssp. (leishmaniasis), and the amoeba Entamoeba histolytica (amoebiasis).

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Section: Targeting Transport Processes Of Parasites At Different Levementioning

confidence: 99%

Section: Targeting Transport Processes Of Parasites At Different Levementioning

confidence: 99%

Targeting Channels and Transporters in Protozoan Parasite Infections

2018

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“…Since then, much work has been focused on reversal of the resistance to CQ by using various compounds, such as calcium channel blockers [3] and their isomers [4-6], antidepressive drugs [7-9], antihistaminics [10-17]. However, most of the above combinations, which reversed the resistance in vitro , have not been successful in vivo either using the Aotus monkey [18] or doing clinical trials [19].…”

Section: Introductionmentioning

confidence: 99%

Effective treatment with a tetrandrine/chloroquine combination for chloroquine-resistant falciparum malaria in Aotus monkeys

Dyke

Rossan

2013

Malar J

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BackgroundIn vitro evidence indicates that tetrandrine (TT) can potentiate the action of chloroquine 40-fold against choloquine-resistant Plasmodium falciparum. The key question emanating from that study is “would tetrandine and chloroquine be highly effective in a live Aotus monkey model with chloroquine-resistant parasites”. This study was designed to closely mimic the pharmacological/anti-malarial activity in man.MethodsThe Vietnam Smith/RE strain of P. falciparum, which is chloroquine-resistant was used in this study. Previous experimental procedures were followed. Panamanian owl monkeys (Aotus) were inoculated with 5×106 erythrocytes parasitized with the CQ-resistant strain of P. falciparum. Oral drug treatment was with CQ (20 mg/kg) and/or tetrandrine at 15 mg/Kg, 30 mg/Kg or 60 mg/Kg or 25 mg/Kg depending on experimental conditions.Results and DiscussionParasitaemia was cleared rapidly with CQ and TT while CQ treatment alone was ineffective. Recrudescence of malaria occurred after seven days post-infection. However, four animals were treated orally with TT and CQ parasites were cleared. It is likely that monkeys were cured via a combination of both drug and host immune responses. A single Aotus monkey infected with P. falciparum and untreated with drugs, died. No side effects were observed with these drug treatments.ConclusionsThis combination of chloroquine and tetrandrine forms the basis of a new attack on chloroquine-resistant malaria - one based upon inhibition of the basis of chloroquine resistance, the multiple drug resistance pump. Previous studies demonstrated that the parasite MDR pump was found on parasite membranes using 3H azidopine photoaffinity labelling.Since MDR-based choloroquine resistance is induced by chloroquine, the basis of the action of tetrandrine is the following: 1) tetrandrine inhibits the MDR pump by stimulating MDR ATPase which limits the energy of the pump by depletion of parasite ATP, 2) tetrandrine blocks the genetic factor which controls the induction of the pump. Therefore, it appears that the parasite cannot outsmart these mechanisms and produce a new mode of resistance. Only time will tell if this is correct.

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