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: firstname.lastname@example.org (S. Nakornchai).
1383-5769/$ - see front matter © 2006 Elsevier Ireland Ltd. All rights reserved.