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In vitro and in vivo reversal of chloroquine resistance in plasmodium falciparum with promethazine
Am. J. Trop. Med. Hyg.,
58(5), 1998, pp. 625–629Copyright ᭧ 1998 by The American Society of Tropical Medicine and Hygiene
AND IN VIVO
REVERSAL OF CHLOROQUINE RESISTANCE IN
A. M. J. ODUOLA, A. SOWUNMI, W. K. MILHOUS, T. G. BREWER, D. E. KYLE, L. GERENA, R. N. ROSSAN,
Department of Pharmacology and Therapeutics, Postgraduate Institute for Medical Research and Training, College of Medicine,
University of Ibadan, Ibadan, Nigeria; Division of Experimental Therapeutics, Walter Reed Army Institute of Research,
Washington, District of Columbia; Gorgas Memorial Laboratory, Panama City, Panama
The effect of combining promethazine with chloroquine was examined against Plasmodium falciparum
in the Aotus-P. falciparum
model and in bioassays from volunteers given promethazine. The combination ofchloroquine plus promethazine (1 ϫ 10Ϫ6 M) reversed chloroquine resistance in standard P. falciparum
clones andpatient parasite isolates from Nigeria. The combination reduced the 50% inhibitory concentrations (IC s) for chlo-
roquine against resistant parasites by 32–92%. Coadministration of promethazine with chloroquine also demonstrateda dose-dependent effect in Aotus
monkeys infected with chloroquine-resistant P. falciparum.
Monkeys were given achloroquine dose (20 mg/kg of body weight for seven days), which normally has no effect on parasitemia, plus 10,20, 40, or 80 mg of promethazine/kg of body weight. In one monkey, parasitemia was suppressed at the lowestpromethazine dose, but re-treatment with 20 mg/kg resulted in clearance of parasitemia. Initial treatment with chlo-roquine and 20 or 40 mg/kg of promethazine cleared parasitemia in some animals followed by recrudescence. Re-treatment at higher doses cured one monkey and resulted in initial clearance and delayed recrudescence 28 or 63days after treatment in two monkeys. Recrudescent parasitemia in the two monkeys was low (10 parasites/l of blood)and subsequently cleared without re-treatment. An in vitro
bioassay model was developed to examine the effects ofclinically achievable doses of promethazine on parasites susceptibilities in vitro.
Plasma samples taken at hourlyintervals from patients given a single oral dose of 25 mg of promethazine decreased the IC
by 20–58% with the most significant reductions occurring in plasma obtained from volunteers 3–4 hr after ingestion.
Plasma obtained from two volunteers 6 hr after ingestion of the drug demonstrated no effect on chloroquine suscep-tibility, suggesting that study of the pharmacokinetic disposition and potential interaction is warranted to optimizethe dose regimen in patients for antimalarial efficacy. Historic use of this drug combination for treatment or preventionof chloroquine-associated pruritus or as an antiemetic suggest that the combination is safe and effective when usedat standard dosages. The results from this study demonstrate that promethazine is a potent modulator of chloroquineresistance. Clinical evaluation of therapeutic regimens is required to validate clinical efficacy of this promising com-bination for treatment of uncomplicated chloroquine-resistant malaria.
The reversal of chloroquine resistance by compounds with
little intrinsic antimalarial activity is a well established phe-
Parasites and drug susceptibility testing.
Ten isolates of
notype of drug-resistant Plasmodium falciparum.
1 In the past
obtained from patients in Nigeria were tested
decade, numerous compounds have been shown to reverse
for susceptibilities to chloroquine, desethylchloro-
resistance in vitro
to chloroquine in parasite isolates from
quine, quinine, mefloquine, and halofantrine alone and in
various geographic areas;2–9 some of these compounds also
combination with promethazine or verapamil. The chloro-
reverse chloroquine resistance in animal models.3, 10–12 Al-
quine-susceptible west African clone D6 and the multidrug-
though limited clinical studies have failed to demonstrate a
resistant Indochina clone W215 were used as reference par-
reversal of chloroquine resistance in human infections,7, 13
asites. Parasites obtained from patients at the University Col-
potential clinical application of the phenomenon remains
lege Hospital in Ibadan, Nigeria were adapted to continuous
valid and provides a potentially innovative strategy to treat
culture using standard techniques at the Walter Reed Army
Institute of Research where these tests were conducted.15 The
Promethazine is an antihistamine that acts by competing
parasites were cultured in human erythrocytes (type Aϩ,
with histamine for H-1 receptor sites on effector cells. This
6.0% hematocrit) in vitro
in RPMI 1640 culture medium
H-1 antagonist is also used as adjunct therapy in the treat-
supplemented with 10% human plasma.16, 17 Each culture was
ment of malaria in English-speaking west African countries.
maintained in 50-ml sealed culture flasks (Corning Glass
The drug is given as an antiemetic with chloroquine to pre-
Works, Corning, NY) at 37ЊC in an atmosphere of 3–5% O ,
2.5–4.0% CO , and 90% N (premixed bottled gas; Potomac
vent or alleviate chloroquine-associated pruritus.14 Common-
Airgas, Hyattsville, MD). A modification of the semiauto-
ly, a dose of 5.0–10 mg is given simultaneously, or just prior
mated microdilution technique in which the hematocrit was
to administration of chloroquine in children with falciparum
1.5% and the initial parasitemia was 0.5–0.8% was used to
malaria in Nigeria; in adults, daily doses of 25 mg are well
test the parasites’ susceptibilities to drugs. Suspensions of
tolerated. In this report, the in vitro
and in vivo
parasites, drug(s), and 3H-hypoxanthine were incubated in
promethazine on chloroquine-resistant P. falciparum
microtitration plates for 42–46 hr at 37ЊC as described pre-
evaluated. The data from both in vitro
and in vivo
viously.4, 5, 18 Inhibition of 3H-hypoxanthine incorporation by
ments demonstrate that promethazine is a potent modulator
50% (IC ) was determined using a nonlinear regression
of chloroquine resistance in falciparum malaria.
analysis of the concentration-response curve.
Evaluation of in vitro enhancing activities of prometh-
Quantitative analysis of the increased activity of the
quinoline-containing antimalarial drug when combined with
promethazine was done by comparing concentration-re-
sponse curves for chloroquine alone and in the presence of
several fixed, subinhibitory concentrations of promethazine.
Effects of each fixed concentration of promethazine on the
response of the parasites (IC ) to the antimalarial drugs were
expressed as the response modification index (RMI).5 TheRMI was calculated by the following formula: RMI ϭIC
, where drug A is a quinoline-containing an-
timalarial and B is promethazine. An RMI of 1.0 representsno change in the IC
combined with promethazine. The RMI values Ͻ 1.0 rep-resent the degree of potentiation or synergism.
Determination of biologic activity.
A bioassay was used
at the University of Ibadan to measure the enhancing effectof promethazine in plasma from volunteers that had receivedpromethazine. Three volunteers 19–25 years old were given25 mg of promethazine each as a single oral dose (equal toa total daily dose for an adult). Similar blood samples wereobtained from two additional volunteers who did not takeany drug and used as controls. Blood samples (5 ml) were
Effects of serial concentrations of promethazine on
obtained from each volunteer prior to ingestion of the drug
the susceptibility of chloroquine-sensitive (clone D6 -Ⅵ-), resistant-
(if any) and every hour for 6 hr after ingestion of the drug.
(clone W2 -ⅷ-), and Nigerian isolates (NIG-82 -᭡-) and (NIG-60
The volunteers were observed for tolerance and any reaction
-ࡗ-) of Plasmodium falciparum
to chloroquine in vitro.
The re-sponse modification index (RMI) is the ratio of the 50% inhibitory
to the drug. Plasma from each volunteer was collected and
concentrations (IC s) for chloroquine plus the concentration of pro-
used in the bioassay to determine the ability of promethazine
methazine, and chloroquine. An RMI of 1.0 represents no change in
in the volunteer plasma to reverse chloroquine resistance in
for chloroquine when combined with promethazine. The
clones of P. falciparum in vitro.
The effect of promethazine
RMI values Ͻ 1.0 represent the degree of potentiation or synergism.
in plasma from volunteers was evaluated by using a modi-fication of the semiautomated microdilution technique.18 TheIC
for chloroquine versus chloroquine-resistant clone W2
asite inoculation in each monkey when parasitemia ranged
was measured in the presence of plasma routinely used for
from 0.1 to 5.0ϫ 103 parasites/ml. Additional treatment was
continuous culture of P. falciparum
in the laboratory. Sim-
initiated if there was recrudescence of infection during the
ilar data were obtained for plasma obtained from volunteers
100 days of follow-up. Each treatment consisted of daily oral
before taking promethazine. Reduction of the IC
administration of a combination of chloroquine and pro-
used as an index of promethazine concentration in the plas-
methazine. Doses of promethazine (10 mg/kg, 20 mg/kg, 40
ma and its biological activity for reversing resistance to chlo-
mg/kg, or 80 mg/kg) were combined with the standard dose
roquine in vitro.
The protocol for the studies in the volun-
of chloroquine (20 mg/kg) daily for seven days. Two of the
teers and patients was reviewed and approved by the Joint
monkeys treated with chloroquine (20 mg/kg) alone were
University College Hospital/University of Ibadan Ethical
Committee. Potential volunteers were given both oral andwritten explanations of the study and their informed consent
was obtained prior to enrollment in the study.
Evaluation of in vitro activities in a monkey model.
Potentiation of chloroquine in vitro.
effect of promethazine plus chloroquine on infection with
posure of isolates and cloned strains of P. falciparum
the chloroquine-resistant Vietnam Smith/RE strain of P. fal-
chloroquine plus subinhibitory concentrations of prometha-
in owl monkeys (Aotus lemurinus lemurinus
zine increased the intrinsic schizontocidal activities of chlo-
evaluated at the Gorgas Memorial Laboratory as described
roquine against the resistant parasites. This enhanced effect
previously.3, 11 Six monkeys were each inoculated intrave-
on chloroquine occurred in the presence of 17.8–284 ng/ml
nously with 5.0ϫ 106 trophozoites of the parasite. The mon-
of promethazine and increased the intrinsic schizonticidal
keys were maintained following procedures and husbandry
activity of chloroquine against the resistant isolates by 32–
practices outlined in the Guide for the Care and Use of Lab-
92% (Figure 1 and Table 1). Identical concentrations of pro-
as described previously.19 Infection in each
methazine increased intrinsic activities of desethylchloro-
monkey was monitored by microscopic examination of
quine and quinine against the same parasites by 49–89%,
Giemsa-stained blood smears prepared daily for 15 consec-
and 29–79%, respectively. The IC s for desethylchloroquine
utive days after inoculation; enumeration of parasitemia was
against the isolates ranged from 7.08 ng/ml to 56.89 ng/ml
done using the Earle-Perez method.20 Response of infection
and were reduced to 6.3–35 ng/ml in the presence of 284
to treatment regimen was followed for 100 days in each
monkey. Primary treatment was initiated five days after par-
against the parasites ranged from 20.38 ng/ml to 57.73
REVERSAL OF CHLOROQUINE RESISTANCE WITH PROMETHAZINE
Reversal of chlorquine resistance with promenthazine or verapamil
Susceptibility of chloroquine-resistant reference clone W2 of Plas-
in Nigerian isolates and reference cloned strains of Plasmodium
to chloroquine in the presence of plasma from
human volunteers given 25 mg of promethazine and a controlvolunteer that did not take any drug*
ϭ 50% inhibitory concentration. Values in parentheses are the percent reductions
† Plasma obtained from volunteer at designated time interval. The plasma was not heat
inactivated to maintain drug integrity. Variation in IC
is probably due to the lack of heat inactivation and antiparasitic activities in the semi-
‡ NA ϭ not available (sample was contaminated with bacteria).
ϭ 50% inhibitory concentration. Values in parentheses are the percent reductions
† 1 ϫ 10Ϫ6 M promethazine.
‡ 1 ϫ 10Ϫ6 M verapamil.
were reduced by 45%, 54.7%, and 58%, respectively (Table3). Combination of plasma samples obtained from the con-trol volunteers at identical times did not reduce the IC
ng/ml, and were reduced to 5.9–26.5 ng/ml in the presence
ues for chloroquine against the parasites.
of promethazine (284 ng/ml). Similar combinations did not
Activities in a monkey model.
Response of infection in
have significant effect on susceptibilities of sensitive para-
monkeys treated with chloroquine alone or a combi-
sites to chloroquine, desethylchloroquine, or quinine. Incu-
nation of chloroquine and promethazine showed that primary
bation of parasites with identical concentrations of prometh-
treatment with the combination ameliorated infection while
azine alone reduced growth of both chloroquine-resistant and
chloroquine alone had no effect on parasitemia (Table 4).
-sensitive parasites by 10% or less. Combination of pro-
Additional treatment with higher doses of promethazine re-
methazine with mefloquine or halofantrine did not have any
sulted in cure of two monkeys with an infection that is nor-
significant effects on the parasites susceptibilities to the an-
mally chloroquine resistant. Parasitemia was cleared in three
of the four monkeys treated initially with the standard dose
either chloroquine-sensitive or -resistant parasites ranged
of chloroquine combined with either 10 mg/kg (one monkey)
from 443 ng/ml to 2,500 ng/ml (Table 2), confirming that
or 20 mg/kg (two monkeys) of promethazine. Infection in
the drug is not a potent antimalarial drug when used alone.
one monkey receiving chloroquine plus 10 mg/kg of pro-
In vivo/in vitro biologic activities.
The effects of plasma
methazine was only suppressed. This monkey was cured fol-
obtained from human volunteers who took promethazine on
lowing treatment with chloroquine and 20 mg/kg of pro-
susceptibilities of the chloroquine-resistant W2 clone in a
methazine. Infections in the other three monkeys recru-
bioassay for determining reversal of chloroquine resistance
desced between seven and 17 days after completing the ini-
tial treatment (Table 4). Subsequent treatment in these
resistant clone was reduced by 20–58% when the antima-
monkeys resulted in cure of the infection in one monkey
larial drug was combined with plasma samples obtained at
given 20 mg/kg of chloroquine and 80 mg/kg of prometha-
specific time intervals after the volunteers ingested prometh-
zine. Infection in the other two monkeys was again cleared
azine. The most significant reduction in the IC
but recrudescence occurred 28 and 63 days after completing
curred 3–4 hr after ingestion of the drug. The IC
for chloroquine when combined with plasma obtained fromthe three volunteers 3 or 4 hr after ingestion of promethazine
Response of chloroquine-resistant infection of the Plasmodium fal-
Smith/RE strain in Aotus
monkeys (Aotus lemurinus le-
) to treatment with chloroquine and promethazine
Comparative susceptibilities of Nigerian isolates and reference
cloned strains of Plasmadium falciparum
to chloroquine, meflo-
* Chloroquine, 20 mg/kg/day for seven days.
† Promethazine (mg/kg) given twice a day for seven days.
‡ Promethazine (mg/kg) given daily for seven days.
¶ CD ϭ animal was cured of drug-resistant infection with the combination.
# CL ( )
ϭ parasitemia was cleared but infection recrudesced in (8) days.
** Parasitemia at recrudescence was low (10 parasites/l of blood) and cleared without
additional treatment (after 60 and 40 days in #89022 and #86040, respectively).
treatment. Parasitemia in the two monkeys at recrudescence
a good candidate for further studies. Unlike cyprohepta-
was low, less than 10 parasites/l of blood. The recrudescent
dine,21 promethazine retained detectable reversing activities
infection cleared without re-treatment in the two animals
in human plasma after oral administration of drug to human
volunteers. In addition, both chloroquine and promethazineare commonly used in combination in anglophone countriesof west Africa (for other reasons) and appear to be safe and
well tolerated. Data on pharmacokinetic interactions of the
The results of this study demonstrate that promethazine,
two drugs are warranted to optimize dosage regimens of pro-
an H-1 antagonist, is a potent modulator of chloroquine re-
methazine plus chloroquine for a combination therapy in
sistance in P. falciparum
isolates and clones. Promethazine
enhanced the activity of chloroquine against resistant para-sites in vitro
and in vivo.
Perhaps most importantly, potent
Acknowledgments: We thank Dr. James Peggins and Dr. R. Keith
chloroquine reversal activity was demonstrated in a bioassay
Martin for critical review of the manuscript. We are grateful to Drs.
of plasma from volunteers that had taken promethazine.
O. A. T. Ogundahunsi and G. O. Omitowoju for contributions to this
The costs of a complete dosage of mefloquine, halofan-
study, and to Margaret Bell for secretarial assistance.
trine, or the derivatives of qinghaosu (artemether and arte-
Financial support: This investigation received financial support from
sunate) are prohibitively high for most residents of the poor
the UNDP/World Bank/WHO Special Program for Research and
malaria-endemic countries. This economic reality makes it
Training in Tropical Diseases and the Rockefeller Foundation Bio-
imperative that cheaper alternatives be available for treat-
technology Career Fellowship Program.
ment of malaria. The phenomenon of reversal of chloroquine
Authors’ addresses: A. M. J. Oduola, A. Sowunmi, and L. A. Salako,
resistance could play an important role in efforts to control
Department of Pharmacology and Therapeutics, Postgraduate Insti-
drug-resistant malaria at economically feasible costs, es-
tute for Medical Research and Training, College of Medicine, Uni-versity of Ibadan, Ilbadan, Nigeria. W. K. Milhous, T. G. Brewer, D.
pecially in Africa. A combination of chloroquine with pro-
E. Kyle, L. Gerena, and B. G. Schuster, Division of Experimental
methazine, or some other resistance modulator drugs, would
Therapeutics, Walter Reed Army Institute of Research, Washington,
be substantially cheaper than any of the currently available
DC 20307-5100. R. N. Rossan, 9122 W. Viking Road, Las Vegas,
antimalarial drugs. Unfortunately, a decade has elapsed since
the description of the reversal phenomenon1 without a clearchoice among the potential resistance reversal agents or sig-
nificant preclinical studies leading to development of a novelresistance modulator drug. Results of the present studies sug-
1. Martin SK, Oduola AMJ, Milhous WK, 1987. Reversal of chlo-
gest that promethazine has potential to fill this need in the
roquine resistance in Plasmodium falciparum
by verapamil.Science 235:
2. Peters W, Ekong R, Robinson BL, Warhurst DC, Pan X, 1989.
The limited success among compounds tested in a monkey
Antihistaminic drugs that reverse chloroquine resistance in
model3, 11 and the failure in human volunteers7, 13, 21 has been
Plasmodium falciparum. Lancet i:
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3. Bitonti AJ, Sjoerdsma A, McCann PP, Kyle DE, Oduola AMJ,
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.21 The discrepancies between these in vitro
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and in vivo
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International Journal for Parasitology 29 (1999) 619±625The eect of chloroquine treatment on the infectivity ofInstitute of Cell, Animal and Population Biology, Division of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JT, UKReceived 19 October 1998; received in revised form 3 December 1998; accepted 3 December 1998The antimalarial drug chloroquine has been reported to in