Pharmacodynamic interactions of quinolines with other antimalarial compounds in vitro

Chemotherapy remains the most reliable means for the control of Plasmodium falciparum malaria. Unfortunately the parasite has been able to develop resistance to the majority of the antimalarials currently employed. Success in the treatment of resistant infectious diseases such as leprosy, TB and HIV with combination therapy has generated wide interest in its application in malaria. Presently, WHO recommends the deployment of any novel antimalarial regimens for the treatment of P. falciparum only as drug combinations. Artemisinin (ART) combination therapy (ACT) represents the main combination option. Whilst, Quinoline antimalarials are the most important partners in this globally employed chemotherapy strategy. The major objective of this work was to contribute, using the in vitro P.falciparum continuous culture model, the pharmacodynamic interactions between antimalarials as a tool for combination therapy strategies. Special emphasis was conferred on quinoline structures. These include amodiaquine (AQ), its active metabolite desethylamodiaquine (DAQ), quinine (QNN), lumefantrine (LUM), desbutyl-benflumetol (DBB) and pyroniridine (PYRON), with drugs of diverse structure ART, atovaquone (ATQ). Drug susceptibility tests were performed for monocompounds along with drug combinations, according to chequerboard titration designs, of which the raw data obtained were calculated using two evaluation methods, O/E ratios (EC50, EC90, EC99) and isobolograms (sigmaFICs). AQ and DAQ showed high potency against P. falciparum, were superior to most recent antimalarials effective against chloroquine (CQ). Also confirmed was the high potency of DBB over LUM. DBB deserves further and more detailed preclinical/toxicological investigations. AQ and DAQ were able to synergise with such compounds as, quinoline (QNN) and endoperoxide (ART) type of structures. AQ was also shown to synergise markedly with ATQ, a naphthoquinone ATQ. These results discern AQ and DAQ as flexaible partners in the context of combination therapy. In particular, their evident synergism with ART supports its present use in ACT strategies. ART mainly synergised with the two Mannich base-containing quinolines herein tested, AQ and PYRON. Conversely, why ART does not synergise with CQ as much remains an open question, even though this observation could relate to the fact that CQ does not harbour a Mannich base in its structure. AQ exhibited marked synergism with its active metabolite DAQ, even at trace concentrations. We further confirmed that this drug/metabolite phenomenon also occurs between quinoline methanols: LUM and its putative metabolite, DBB. This is the first time it has been shown that some antimalarials can significantly synergise with their own structurally similar active metabolites

Lactate transport and receptor actions in cerebral malaria

Cerebral malaria (CM), caused by Plasmodium falciparum infection, is a prevalent neurological disorder in the tropics. Most of the patients are children, typically with intractable seizures and high mortality. Current treatment is unsatisfactory. Understanding the pathogenesis of CM is required in order to identify therapeutic targets. Here, we argue that cerebral energy metabolic defects are probable etiological factors in CM pathogenesis, because malaria parasites consume large amounts of glucose metabolised mostly to lactate. Monocarboxylate transporters (MCTs) mediate facilitated transfer, which serves to equalize lactate concentrations across cell membranes in the direction of the concentration gradient. The equalizing action of MCTs is the basis for lactate’s role as a volume transmitter of metabolic signals in the brain. Lactate binds to the lactate receptor GPR81, recently discovered on brain cells and cerebral blood vessels, causing inhibition of adenylyl cyclase. High levels of lactate delivered by the parasite at the vascular endothelium may damage the blood-brain barrier, disrupt lactate homeostasis in the brain, and imply MCTs and the lactate receptor as novel therapeutic targets in CM