Potentiation of antimalarial drug action by chlorpheniramine against multidrug-resistant Plasmodium falciparum in vitro.
ABSTRACT Chlorpheniramine, a histamine H1 receptor antagonist, was assayed for in vitro antimalarial activity against multidrug-resistant Plasmodium falciparum K1 strain and chloroquine-resistant P. falciparum T9/94 clone, by measuring the 3H-hypoxanthine incorporation. Chlorphenirame inhibited P. falciparum K1 and T9/94 growth with IC50 values of 136.0+/-40.2 microM and 102.0+/-22.6 microM respectively. A combination of antimalarial drug and chlorpheniramine was tested against resistant P. falciparum in vitro. Isobologram analysis showed that chlorpheniramine exerts marked synergistic action on chloroquine against P. falciparum K1 and T9/94. Chlorpheniramine also potentiated antimalarial action of mefloquine, quinine or pyronaridine against both of the resistant strains of P. falciparum. However, chlorpheniramine antagonism with artesunate was obtained in both P. falciparum K1 and T9/94. The results in this study indicate that antihistaminic drugs may be promising candidates for potentiating antimalarial drug action against drug resistant malarial parasites.
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ABSTRACT: Plasmodium falciparum, the aetiological agent of human lethal malaria, is responsible for over 2 million deaths per year and malaria episodes may vary considerably in their severity and clinical manifestations. Dysregulated balance of the inflammatory response and a defect in the anti-Plasmodium parasite immune response represent the hallmarks of malaria disease. Among the many possible mechanisms, it is now widely recognized that the production of pro-inflammatory mediators and cytokines and upregulation of endothelial cell adhesion molecules play important roles in malaria pathogenesis. We and others provided evidence that some components of allergic inflammatory response to malaria parasites or elicited by by-products of parasite infection may contribute to malaria pathogenesis. This review provides some clue regarding these mechanisms where mast cells and histamine, an inflammatory mediator generated following IgE-independent or IgE-mediated immune response, were found to play a major role in parasite transmission and malaria pathogenesis, respectively. This article is part of a Special Issue entitled: Mast cells in inflammation.Biochimica et Biophysica Acta 02/2011; 1822(1):49-56. · 4.66 Impact Factor
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ABSTRACT: Members of the ATP-binding cassette (ABC)-type transporter superfamily have been implicated in multidrug resistance in malaria, and various mechanistic models have been postulated to explain their interaction with diverse antimalarial drugs. To gain insight into the pharmacological benefits of inhibiting ABC-type transporters in malaria chemotherapy, we investigated the in vitro chemosensitization potential of various P-glycoprotein inhibitors. A fluorescent chloroquine derivative was synthesized and used to assess the efflux dynamics of chloroquine in MDR and wild type Plasmodium falciparum parasites. This novel BODIPY-based probe accumulated in the digestive vacuole (DV) of CQ-sensitive parasites but less so in MDR cells. Pre-exposure of the MDR parasites to non-cytocidal concentrations of unlabeled chloroquine resulted in a diffused cytoplasmic retention of the probe whereas a similar treatment with the CQR-reversing agent, chlorpheniramine, resulted in DV accumulation. A diffused cytoplasmic distribution of the probe was also obtained following treatment with the P-gp specific inhibitors zosuquidar and tariquidar, whereas treatments with the tyrosine kinase inhibitors gefitinib or imatinib produced a partial accumulation within the DV. Isobologram analyses of the interactions between these inhibitors and the antimalarial drugs chloroquine, mefloquine, and artemisinin revealed distinct patterns of drug synergism, additivity and antagonism. Taken together, the data indicate that competitive tyrosine kinase and noncompetitive P-glycoprotein ATPase-specific inhibitors represent two new classes of chemosensitizing agents in malaria parasites, but caution against the indiscriminate use of these agents in antimalarial drug combinations.Experimental Parasitology 03/2013; · 2.15 Impact Factor
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ABSTRACT: Evidence of emerging Plasmodium falciparum resistance to artemisinin-based combination therapies, documented in western Cambodia, underscores the continuing need to identify new antimalarial combinations. Given recent reports of the resurgence of chloroquine-sensitive P. falciparum parasites in Malawi, after the enforced and prolonged withdrawal of this drug, and indications of a possible synergistic interaction with the macrolide azithromycin, we sought to further characterize chloroquine-azithromycin combinations for their in vitro and in vivo antimalarial properties. In vitro 96-h susceptibility testing of chloroquine-azithromycin combinations showed mostly additive interactions against freshly cultured P. falciparum field isolates obtained from Mali. Some evidence of synergy, however, was apparent at the fractional 90% inhibitory concentration level. Additional in vitro testing highlighted the resistance reversal properties of amlodipine for both chloroquine and quinine. In vivo experiments, using the Peters 4-day suppressive test in a P. yoelii mouse model, revealed up to 99.9% suppression of parasitemia following treatment with chloroquine-azithromycin plus the R enantiomer of amlodipine. This enantiomer was chosen because it does not manifest the cardiac toxicities observed with the racemic mixture. Pharmacokinetic/pharmacodynamic analyses in this rodent model and subsequent extrapolation to a 65-kg adult led to the estimation that 1.8 g daily of R-amlodipine would be required to achieve similar efficacy in humans, for whom this is likely an unsafe dose. While these data discount amlodipine as an additional partner for chloroquine-based combination therapy, our studies continue to support azithromycin as a safe and effective addition to antimalarial combination therapies.Antimicrobial Agents and Chemotherapy 04/2011; 55(7):3115-24. · 4.57 Impact Factor
Potentiation of antimalarial drug action by chlorpheniramine against
multidrug-resistant Plasmodium falciparum in vitro
Sunan Nakornchai⁎, Phattanapong Konthiang
Department of Biochemistry, Faculty of Science, Mahidol University, Rama VI road, Bangkok 10400, Thailand
Received 25 March 2005; received in revised form 6 September 2005; accepted 5 November 2005
Available online 5 June 2006
Chlorpheniramine, a histamine H1 receptor antagonist, was assayed for in vitro antimalarial activity against multidrug-resistant Plasmodium
falciparum K1 strain and chloroquine-resistant P. falciparum T9/94 clone, by measuring the3H-hypoxanthine incorporation. Chlorphenirame
inhibited P. falciparum K1 and T9/94 growth with IC50values of 136.0±40.2μM and 102.0±22.6μM respectively. A combination of antimalarial
drug and chlorpheniramine was tested against resistant P. falciparum in vitro. Isobologram analysis showed that chlorpheniramine exerts marked
synergistic action on chloroquine against P. falciparum K1 and T9/94. Chlorpheniramine also potentiated antimalarial action of mefloquine,
quinine or pyronaridine against both of the resistant strains of P. falciparum. However, chlorpheniramine antagonism with artesunate was obtained
in both P. falciparum K1 and T9/94. The results in this study indicate that antihistaminic drugs may be promising candidates for potentiating
antimalarial drug action against drug resistant malarial parasites.
© 2006 Elsevier Ireland Ltd. All rights reserved.
Keywords: P. falciparum; Antimalarials; Antihistaminic drug; Drug resistance; Drug combination
Multidrug resistance in Plasmodium falciparum malaria
now occurs in most endemic areas. Combination chemother-
apy is a rational approach to the containment of drug
resistance in malaria . Pyrimethamine plus sulfadoxine was
combined with mefloquine. The Chinese drug pyronaridine
has also been occasionally given in conjunction with
pyrimethamine and sulfadoxine . Quinine is most often
combined with tetracycline or doxycycline or clindamycin
. Atovaclone is effective in combination with proguanil for
the treatment of malaria , and in some areas of Southeast
Asia, artesunate is used in combination with mefloquine or
with tetracycline [5–7].
The emergence of chloroquine resistance has led to the
investigation of drugs that modulate chloroquine resistance.
Chloroquine resistance in malaria parasite can be reversed by a
combination of chloroquine and calcium channel blockers,
verapamil or chlorpromazine [8,9]. The tricyclic antidepressant
drug, desipramine, restores the blood schizotocidal action of
chloroquine against chloroquine-resistant strains in vitro .
Antihistamine compounds, cyproheptadine, ketotifen, pizoty-
line and azatadine produce marked reversal of chloroquine
resistance in P. yoelii mice and in P. falciparum in vitro [11,12].
Chlorpheniramine, a histamine H1 receptor antagonist, has been
shown to reverse chloroquine resistance in vitro in the African
isolate of P. falciparum [13,14]. Chlorpheniramine enhances the
efficacy of chloroquine in treating acute uncomplicated P.
falciparum in children from an endemic area of Nigeria . In
further clinical trials, Sowunmi et al. [16,17] found that a higher
dosage of chlorpheniramine produced a more significant and
beneficial action. Antihistamines are widely available at low
cost in malaria endemic zones. They have been prescribed often
in children above 2 years of ages . Chlorpheniramine
produces drowsiness as a side effect . The relative safety of
these drugs prompted us to study the in vitro activity of standard
antimalarial drugs (Fig. 1) in combination with chlorphenir-
amine against multidrug-resistant or chloroquine-resistant P.
falciparum. The results from this study demonstrate that
chlorpheniramine showed synergistic effect with chloroquine,
mefloquine, quinine or pyronaridine against both P. falciparum
Parasitology International 55 (2006) 195–199
⁎Corresponding author. Fax: +66 2 354 7174.
E-mail address: email@example.com (S. Nakornchai).
1383-5769/$ - see front matter © 2006 Elsevier Ireland Ltd. All rights reserved.
K1 and T9/94. In contrast, chlorpheniramine combined with
artesunate showed antagonistic effect.
2. Materials and methods
Multidrug-resistant P. falciparum K1 strain was obtained
from an infected individual in Kanchanaburi province, Thai-
land. They can be routinely maintained in human group O red
blood cells in a medium containing RPMI 1640 supplemented
with 10% human serum using the candle jar method .
Isolate T9 of chloroquine-resistant P. falciparum was obtained
from a patient at Tak province, Thailand and T9/94 clone was
prepared by limiting dilution. The isolation and characterization
of P. falciparum T9/94 clone have been previously described
. Antimalarial drugs (Fig. 1) in combination with
antihistaminic drug were tested by using
incorporation . An aliquot of 25μl of drug solution
dissolved in culture medium and 200μl of the parasitized
erythrocyte suspension, in which red blood cells were
suspended at 3% hematocrit concentration, were placed in 96
well plates in triplicate. At the start of the experiment, 0.5% red
blood cells were infected with K1 or T9/94 strain. After
incubation at 37°C for 48h, 25μl of
added to a final concentration 1μCi/ml, followed by further
incubation at 37°C for 48h. Red blood cells were harvested
using an automated sample harvester and counted for
radioactivity incorporated into the parasites with a Beckman
liquid scintillation counter, model LS-1801 (Beckman Instru-
presence of both a single drug and a combination of antimalarial
drug with antihistaminic drug, and was expressed as percentage
of control. The 50% inhibitory concentration (IC50) values,
defined as the drug concentration required for 50% reduction of
the3H uptake by parasites as compared to control (without the
drugs), were determined from the dose–response curve. The
antimalarial drug IC50for various antihistamine concentrations
3H-hypoxanthine uptake was assayed in the
ANTIMALARIAL AND ANTIHISTAMINIC DRUGS
Fig. 1. Structure of antimalarial and antihistaminic drugs.
Chlorpheniramine (µ µM)
Chlorpheniramine (µ µM)
Fig. 2. (a) Isobologram of chlorpheniramine in combination with chloroquine against P. falciparum K1 strain. (b) Isobologram of chlorpheniramine in combination
with chloroquine against P. falciparum T9/94 clone.
196S. Nakornchai, P. Konthiang / Parasitology International 55 (2006) 195–199
and the antihistamine IC50 for various antimalarial drug
concentrations were determined and used to construct the
Chlorpheniramine was assayed for in vitro antimalarial
activity against multidrug-rersistant P. falciparum K1 strain and
chloroquine-resistant P. falciparum T9/94 clone. P. falciparum
K1 and T9/94 growth were inhibited by chlorpheniramine with
IC50values of 136.0±40.2μM and 102.0±22.6μM, respec-
tively. Combinations of antimalarial drugs with chlorphenir-
amine were tested against P. falciparumd K1 strain and T9/94
clone. The isobologram of an additive combination of two
agents lies on straight line. The isobologram of synergistic
agents is concave. With antagonistic agents, the isobologram is
convex. Chlorpheniramine showed synergistic effects with
chloroquine both in P. faciparum K1 and T9/94 (Fig. 2a,b).
Chlorpheniramine also potentiated antimalarial action of
mefloquine, quinine or pyronaridine against both resistant
strains of P. falciparum (Figs. 3a,b, 4a,b, and 5a,b). Our results
demonstrate that chlorpheniramine potentiates in vitro antima-
larial action of chloroquine, mefloquine, quinine or pyronar-
idine which are quinoline-containing drugs (Fig. 1). However,
chlorpheniramine showed antagonism with artesunate for both
P. falciparum K1 and T9/94 (Fig. 6a,b).
In a previous study, Martin et al.  found that the blood
schizontocidal action of chloroquine against chloroquine-
resistant strain of P. falciparum could be reversed in vitro by
exposing the parasitized red cells to a combination of
chloroquine and verapamil. The resistance-reversing activity
of verapamil is associated with the increased accumulation of
chloroquine by resistant parasite . The mechanism of
reversal by calcium channel blockers is independent of the
calcium channel . The use of combination therapy with
chloroquine and calcium antagonists is probably unsuitable for
human malaria because of the high doses of antagonists needed
to reverse chloroquine resistance. Other agents that reverse
chloroquine resistance are chlorpromazine, fluoxetin and
cyproheptadine [25–27]. Sowunmi and Oduola  reported
that a chloroquine and chlorpheniramine combination produced
a significantly higher cure rate than chloroquine alone in
African children with acute symptomatic uncomplicated
falciparum malaria. Chlorpheniramine plasma concentration
collected 4h after the oral dose of 10mg. chlorpheniramine to a
normal subject is 15.4ng/ml . In this study, we demonstrat-
ed the marked reversal effect of chlorpheniramine on chloro-
quine or multidrug-resistant P. falciparum. At the present time,
the antimalarial activity of chlorpheniramine is still unknown,
as is the way in which the chloroquine resistance of parasites is
0 20 4060
0 2040 60 80100
Chlorpheniramine (µ µM)
Chlorpheniramine (µ µM)
Fig.3.(a)Isobologram ofchlorpheniramine incombinationwithmefloquine againstP. falciparumK1strain.(b) Isobologram ofchlorpheniramine incombinationwith
mefloquine against P. falciparum T9/94 clone.
0 20 40 6080
0100200 300 400
Chlorpheniramine (µ µM)
Chlorpheniramine (µ µM)
Fig. 4. (a) Isobologram showing effect of chlorpheniramine in combination with quinine against P. falciparum K1 strain. (b) Isobologram showing effect of
chlorpheniramine in combination with quinine against P. falciparum T9/94 clone.
197 S. Nakornchai, P. Konthiang / Parasitology International 55 (2006) 195–199
reversed. The original hypothesis that they act as calcium
channel blockers is no longer accepted . Scheibel et al. 
have indicated the possibility that such action is linked to the
inhibition of parasite calmodulin functions rather than to a more
direct action on calcium transport.
When a combination of chlorpheniramine and mefloquine
was tested, chlorpheniramine could potentiate mefloquine
action. Mefloquine resistance in P. falciparum from Nigeria
can also be reversed by the neuroleptic drug, penfluridol, in
vitro . Synergism between chlorpheniramine and quinine
was also observed in our study. A chlorpheniramine and quinine
combination may offer an advantage over the current drug
combination, tetracycline and quinine, in that chlorpheniramine
can be prescribed in children above 2 years of age , while
tetracycline should not be given to pregnant women and
children . Synergism between chlorpheniramine and
pyronaridine indicates that this may be a promising combination
against drug resistant malaria parasites. Pyronaridine has good
antimalarial activity with little evidence for cross-resistance
with other widely used drug . Field tests in China reported
that pyronaridine was well tolerated with few major adverse
effects. Antagonism between chlorpheniramine and artersunate
indicated that these two drugs cannot be used together. Our
results demonstrate that chlorpheniramine potentiates in vitro
antimalarial action of quinoline-containing antimalarial com-
pounds. Because chlorpheniramine is a safe therapeutic drug,
the clinical use of chlorpheniramine as a cheap and highly
effective combination with quinoline-containing antimalarial
drugs holds great promise against multidrug-resistant falci-
This work was supported by The Thailand Research Fund
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