Susceptibility of Plasmodium falciparum to different

doses of quinine in vivo and to quinine and

quinidine in vitro in relation to chloroquine in
Liberia
A. Bjbrkman,1 M. Willcox,2 N. Marbiah,3 & D. Payne4

Chloroquine-resistant Plasmodium falciparum has been spreading rapidly after its emergence in 1988 in
Yekepa. The in vivo and in vitro susceptibilities to quinine and quinidine, compared to chloroquine, were
studied by investigating the number of treatment days required for radical cure and estimating the quinine
concentrations concomitantly.
The minimal inhibitory concentrations (MIC) for schizont maturation in all successful in vitro tests
were 5.12 x 10-6 mol/l for quinine and 1.28 x 10-6 moll for quinidine, indicating that all 50 isolates were
sensitive to the two drugs. The IC50 and IC90 values were 0.22 and 0.78 x 10-6 mol/l for quinine and
0.07 and 0.26 x 10-6 mol/l for quinidine, respectively. In vitro inhibition of parasites by 1.6 x 10-6 mol/l
of chloroquine was obtained in 31 out of 47 isolates, 16 (34%) being resistant. The IC50, ICgO and
geometrical mean MIC for quinine were all about two times higher for the chloroquine-resistant than for
the chloroquine-sensitive isolates (P = 0.006).
P. falciparum infected children (n = 64) were randomly allocated to four groups and treated with
quinine (10 mg/kg body weight twice daily) for 1 day (3 doses), 2, 4 and 7 days, respectively. All cleared
their parasitaemias by day 4 but 5 out of 15 of those treated with only three doses showed a recurrence
of parasitaemia between days 7 and 14; these were considered to be recrudescences. In the other
groups, recurrent parasitaemias only occurred between days 17 and 28 and were considered to be
reinfections. The mean blood concentrations of quinine in 10 patients on the fourth day of treatment were
17.0, 12.2 and 8.4 x 10-6 mol/l at, respectively, 2, 6 and 12 hours after the last dose. These
concentrations are above the in vitro MIC values.
Quinine remains a highly effective antimalarial drug in Liberia even after the appearance of
chloroquine-resistant P. falciparum strains; the 3-day course appears to be an efficacious regimen in this
semi-immune population.

Introduction required three doses daily for seven days in the

Resistance of Plasmodium falciparum to chloro-
quine is now widespread in sub-Saharan Africa (1).
Quinine, the main drug for severe and complicated
malaria cases, is now an important alternative for
patients with even less severe symptoms; however,
two disadvantages that affect compliance are the
' Associate Professor, Department of Infectious Diseases, Karo-
linska Institute, and Department of Parasitology, National Bacte-
riological Laboratory, Stockholm. Requests for reprints should be
sent to Dr A. Bjorkman, Roslagstull Hospital, Box 5651, S-114 89
Stockholm, Sweden.
2
Microbiologist, Department of Clinical Microbiology, Gavle Hos-
pital, Gavle, Sweden.
3Research Physician, Yekepa Research Unit, Liberian Institute
for Biomedical Research, Robertsfield, Liberia.
4Technical Officer, Malaria Unit, Division of Control of Tropical
Diseases, World Health Organization, Geneva, Switzerland.
Reprint No. 5196
standard regimen and side-effects which are com-
mon but transient.
The high sensitivity to quinine in West Africa
(2, 3) now appears to be decreasing, and resistance
has been reported in in vitro studies in West and
Central Africa (4-6) although differences in
methodology may account for some discrepancies in
these observations. Decreased sensitivity may be
expected to follow the development of resistance to
chloroquine (7, 8) and, indeed, several sentinel
cases of suspected in vivo resistant infections from
Africa have been reported lately (9-14). However,
few clinical trials, especially dose-finding studies
have been performed in Africa, and the re-
commended treatment regimen of quinine is based
largely on experiences in south-east Asia. Further-
more, quinidine, the stereoisomer of quinine, which
has been found to be more active than quinine in
Thailand (15), has been little studied in Africa.

Bulletin of the World Health Organization, 69(4): 459-465 (1991) © World Health Organization 1991 459
A. Bjorkman et al.
Chloroquine-resistant P. falciparum first
emerged in Yekepa, Liberia, in 1988 and is spread-
ing rapidly. We therefore studied the susceptibility
to quinine and quinidine in this area with a
standardized in vitro methodology and performed
an in vivo dose-finding investigation on the number
of treatment days with quinine required for a radical
cure and the drug concentrations thus obtained.
Material and methods
Study area and population
Yekepa town with about 15 000 inhabitants is
situated in the north-east of Liberia and surrounded
by villages. James Dolo's Farm (JDF), one of these
villages, is about 10 km from Yekepa. Malaria is
hypoendemic to mesoendemic in Yekepa town and
holoendemic in JDF (16).
In December 1988, at the end of the rainy
season, blood films were taken from 78 children in
JDF (age 1 to 12) and from 100 schoolchildren in
Yekepa (area T). All asymptomatic children with
pure P. falciparum infections with a parasite density
between 1000 and 100000 asexual parasites per ,ul
and with no history of drug intake for the previous
two weeks were included in the study. Fully in-
formed consent was obtained from the patients
and/or their parents before inclusion in the study.
In vivo tests
Sixty-four children from JDF who fulfilled the
inclusion criteria for the study were, after age
stratification, randomly divided in four groups.
Group I received 10 mg quinine per kg body weight
three times every 12 hours for 24 hours; groups II,
III and IV received the same dose of quinine twice
daily for 2, 4, and 7 days, respectively. Quinine was
given as tablets of 100 mg and 250 mg quinine
hydrochloride, divided into halves and quarters
when required. The drug was administered under
close supervision. Every day the children were asked
about any symptoms possibly related to malaria or
the drug taken.
Thick blood films were made daily from days 0
to 5 and then on days 7, 10, 14, 17, 21, 24 and 28.
The films stained with Giemsa were considered as
negative if no asexual parasite was found after 10
minutes of examination under light microscopy;
parasite counts were determined by counting the
parasites against 1000 leukocytes, assuming an
average leukocyte count of 8000 per ,ul of blood.
In vitro tests
Isolates from 33 children in JDF and 25 schoolchild-
ren in Yekepa were included in a study on the in
460
vitro susceptibility of P. falciparum to quinine and
chloroquine. Isolates from 24 children in JDF were
also tested for their susceptibility to quinidine.
A modified Rieckmann's in vitro microtest (17)
was used to determine the sensitivity of P. falci-
parum isolates to chloroquine and quinine. A
standard procedurea was followed using RPMI
culture medium and microtitration plates provided
by WHO. Drug concentrations were expressed as
amounts of chloroquine per volume of blood and
amounts of quinine or quinidine per volume of
blood-medium mixture, in accord with previous
practices described in the literature. Isolates show-
ing schizont maturation at 1.6 x 10-6molA chloro-
quine or at 5.12 x 10-6 molA quinine/quinidine
were considered resistant to the respective drug
(18).a A probit analysis of the log dose-response
was performed to estimate the effective drug con-
centrations for 50% (EC50), 90% (EC90) and 99%
(EC99) inhibition of schizont maturation. b
Drug concentrations
Samples of fingerprick whole blood (100 ,l) were
taken from twelve children while still on treatment
on the fourth day, at 2, 6 and 12 hours after intake of
the repeated standard dose of 10 mg quinine per kg
body weight. The blood was transferred into plastic
Eppendorf tubes and kept frozen at -20 °C before
determination of quinine concentrations by HPLC.
Results
In vivo tests
All 64 children from JDF in the in vivo study had
pure P. falciparum infections with a geometrical
mean of 4895 parasites per ,ul (range, 1000 to 68 000
parasites per ,l). Five of them were excluded from
the study because they did not take their stipulated
course of quinine or attend the follow-up according
to schedule. They were not excluded because of lack
of efficacy or side-effects from the treatment., The
remaining 59 children had cleared their parasitaemia
by day 4 (Tables 1 and 2). Between days 7 and 14,
five in group 1, however, showed a recurrence
(considered as recrudescence of parasitaemia)
whereas recurrent parasitaemia (considered as rein-
a
In vitro microtest (Mark /I) for the assessment of the response
of Plasmodium falciparum to chloroquine, mefloquine, quinine,
sulfadoxine/pyrimethamine and amodiaquine. Unpublished WHO
document MAP/87.2, 1987.
bGrab, B. & Wernsdorfer, W.H. Evaluation of in vitro tests for
drug sensitivity in Plasmodium falciparum: probit analysis of log
dose/response test from 3-8 points assay. Unpublished docu-
ment WHO/MAL/83.990.
WHO Bulletin OMS. Vol 69 1991.
 Susceptibility of P. falciparum to quinine in Liberia

Table 1: P. falciparum clearance in 59 children after treat- Table 3: Inhibition of schizont development in in vitro tests
ment with quinine (10 mg/kg body weight orally twice daily) of P. falciparum susceptibility to quinine (n = 50) and to
for 1, 2, 4 or 7 days in JDF village, 1988 quinidine (n = 23) in Yekepa area, 1988
No. of days of treatment Drug concentra- No. of tests inhibited No. of tests inhibited
tion (x 10 -6 by quinine by quinidine
1 2 4 7 mol/l)
No. of children 15 14 15 15 0.08 0 (0) 0 (0)
Mean age (years) 5.3 5.4 5.4 5.0 0.16 1 (2) 9 (39)
(1-11)a (2-10) (1-10) (1-10) 0.32 10 (20) 17 (74)
Mean parasite 0.64 29 (38) 21 (91)
density on day 0 4510 5890 4530 5240 1.28 45 (90) 23 (100)
Mean time for 2.56 49 (98) 23 (100)
parasite clear- 2.2 2.4 2.3 2.2 5.12 50 (100) 23 (100)
ance (days)
a
Figures in parentheses are percentages.
a Figures in parentheses are the age range in years.

5.12 x 10-6 molA) were successfully treated with

fections) occurred in the other three groups between four and seven days of quinine, respectively. When
days 17 and 28 (Table 2). all isolates were added, the calculated mean IC50
No serious adverse drug reactions were re- and IC90 were 0.22 and 0.78 x 10-6 mol/l, respect-
ported, except that 4 of the 15 children over 4 years ively. The individual IC50 values varied between a
of age who took quinine for four or seven days, lowest value of less than 0.1 x 10-6 molA and a
when questioned specifically on the third day, highest value of 1.8 x 10-6 molA; 15/50 isolates
reported transient symptoms: two reported nausea, (30%) had IC50 values >0.3 x 10-6 molA. Quini-
one had stomach ache, and two had tinnitus. dine inhibited all isolates at 1.28 x 10-6 molA
(Table 3) with a mean MIC of 0.31 x 10-6 mol/l
In vitro tests (range, 0.16 to 1.28 x 10-6 molA) and with calcul-
For quinine, the in vitro microtest was attempted on ated mean IC5o and IC90 of 0.07 and 0.26 x 10-6
58 isolates with interpretable results from 50 (86%) mol/l, respectively.
tests for quinine (30 from JDF and 20 from Yekepa) Chloroquine inhibited 31/47 isolates at a con-
and 47 tests (81%) for chloroquine. For quinidine, centration of 1.6 x 10-6 molA indicating that 16
23 of 24 (96%) isolates from JDF gave interpretable (34%) isolates were resistant. One out of the 16
results. resistant isolates showed schizont maturation even
Schizont maturation was inhibited in all 50 tests at the highest concentration tested, 12.8 x 10-6
by 5.12 x 10-6 molA quinine (Table 3). This indi- mol/l. In Table 4 and Fig. 1 the results of quinine in
cated full sensitivity (MIC of --25.6 x 10-6 molA) in vitro tests are presented separately for chloroquine-
all isolates. The geometrical mean MIC was sensitive and resistant isolates. The IC50, IC90 and
0.80 x 10-6 mol/l (range 0.16 to 5.12 x 10-6 molIA). geometric mean MIC for quinine were all about two
The two isolates with highest MICs (2.56 and times higher for the chloroquine-resistant than for
the chloroquine-sensitive isolates. This relationship
Table 2: Cumulative incidence of parasitaemia in 59 children
between chloroquine resistance and decreased sus-
after treatment with quinine (10 mg/kg body weight orally ceptibility to quinine was highly significant for th(
twice daily) for 1, 2, 4 or 7 days in JDF village, 1988 IC50 and IC90 values (P = 0.006) according to the
Mann-Whitney non-parametric test.
No. of days of treatment
1 2 4 7 Drug concentrations
No. of children 15 14 15 15 The whole blood quinine concentrations of 10
No. of children with parasites on: patients are shown in Table 5. The mean 2-hour
Day4 0 0 0 0 ("peak") concentration, 17.0 x 10-6 molA, was well
Day7 2 0 0 0
Day 10 3 0 0 0 above the mean MIC, about 1.0 x 10-6 molA, or the
Day 14 5 0 0 0 highest MIC, 5.12 x 10-6 mol/l, found for one
Day 17 6 2 4 1 isolate. Even the trough concentrations at 12 hours,
Day21 10 7 6 4 ranging from 4.9 to 11.8 x 10-6 molA, were at or
Day 24 11 10 9 7
Day 28 12 11 10 9 above the concentrations required to inhibit parasite
growth in vitro. Two children with symptoms related
WHO Bulletin OMS. Vol 69 1991. 461
A. Bjorkman et al.
Table 4: Minimal inhibitory concentrations (MIC), IC50 and IC90 of quinine in relation to susceptibility to chloroquine (CQ) of 47
isolates in children from Yekepa area, 1988
Chloroquine MICa
Isolates (x 10-6 mol/1)
CQ sensitive (n = 31) 0.6 ± 0.3 (0.4-0.8)b
CQ resistant (n = 16) 10.4 ± 0.4 (1.6-25.6)
a
Figures are means ± standard deviations.
b Figures in parentheses are the ranges.
to cinchonism were tested for their drug concentra-
tions; both had high peak levels, 20.2 and
26.8 x 10-6 mol/l.
Discussion
In vivo results
The in vivo results suggest that even two days of
quinine treatment may be satisfactory, whereas
three doses during 24 hours may only be partly
curative with a high rate of RI responses although all
parasitaemias were reduced to subpatent levels by
day 4 (Table 2). The parasitaemias from day 17
onwards in the groups treated for two, four and
seven days were considered as reinfections, as the
rates of recurrences in the groups treated for two
and four days were similar to the rate in the group
treated for seven days, except for a minor shift of
about three days corresponding to clearance of the
drug about three days later in the group treated for
seven days. Furthermore, the rate of reinfection was
similar to that previously observed after radical cure
Fig. 1. In vitro susceptibility to quinine (concentrations in
blood) of chloroquine-sensitive (1) and chloroquine-resistant
(2) P. falciparum isolates from Yekepa area, Liberia, in 1988.
99.
90.
E (1)
C Liberian children on third day of treatment (10 mg/kg body
o.
0
X 10.
1.
0.1 1i0
Concentration (X 10o6mol/l)
462
Quinine
(x 10 -6 mol/I)
Quinine MlCa
(x 10-6 mol!) IC50 IC90
0.64 ± 0.04 (0.16-5.12) 0.18 0.61
1.23 ± 0.03 (0.64-2.56) 0.35 1.13
with chloroquine (19), which also corresponds to the
inoculation rate observed in this village (20).
As the study was performed in children, many
of them significantly semi-immune, the results have
to be treated with caution as regards individuals with
low immunity and should not be interpreted as a
recommendation for non-immunes. In two previous
studies with quinine in Zaire (21) and Quinimax
(quinine-quinidine-chinonine) in Madagascar (22),
three days of treatment gave 100% clearance of
parasitaemia after 60 and 52 hours, respectively,
similar to the parasitic clearance of 2.2 to 2.4 days in
our study. However, follow-up was for only seven
days and failures would have been missed as RI
responses around day 14 represented the major part
of therapeutic failures in previous studies with
quinine treatment in Thailand (23) and Cambodia
(24).
There are a few sentinel reports of in vivo
quinine failures in Africa (1) among patients not
taking the complete seven-day standard treatment,
indicating that seven days may be required for a
100% cure rate, or that odd marginally resistant
strains may be present in Africa, or that some
individuals may achieve abnormally low quinine
values in the blood. It may be noted, however, that
they all had high residual levels of chloroquine from
either previous prophylaxis or treatment and that
antagonism between quinine and chloroquine. has
been reported in vitro (25). In the most recent
report of quinine failure (14) two patients from
Table5: Concentrations of quinine in whole blood in 10
weight twice daily) 2, 6 and 12 hours after the last dose
Hours after in- No. of children Quinine concentrationsa
take of last dose (x 10 -6 molA)
2 10 17.0 ± 5.6 (9.9-26.8)b
6 10 12.2 ± 3.7 (7.3-17.2)
12 10 8.4 ± 2.2 (4.9-11.8)
a
Figures are means ± standard deviations.
bFigures in parentheses are the ranges.
WHO Bulletin OMS. Vol 69 1991.

Ghana and Nigeria were unsuccessfully treated for
seven days in the United Kingdom but no informa-
tion was given on possible previous chloroquine
prophylaxis, or quinine concentrations during
therapy, or the in vitro susceptibility of the para-
sites.
In vitro results
All isolates were considered as highly sensitive to
quinine and even the isolate with the highest MIC
(5.12 x 10-6 molA) was successfully treated with
quinine (7-day treatment). This supports the WHO
criteria for the standardized 24-hour test, with a
cut-off MIC of >5.12 x 10-6 mol/l for resistance.C
The mean MIC was 0.75 x 10-6 molA compared to
0.37 x 10-6 molA in 1983 (2). Similarly the EC50,
EC90 and ECg9 were about twice those recorded in
1983. Although the previous study was based on
only seven isolates, this may suggest a partial
decrease in sensitivity between 1983 and 1988. This
is supported by the fact that the isolates with
chloroquine-resistant parasites, not present in 1983,
were less sensitive to quinine than the sensitive
isolates (Table 4, Fig. 1).
A correlation between decreased sensitivities to
chloroquine and quinine has previously been sug-
gested (6-8) and chloroquine resistance has been
considered a prerequisite for the development of
quinine resistance in south-east Asia.
Comparisons of in vitro results with those from
other studies is difficult because of differences in the
in vitro methodology (1). The expressions of inhibi-
tion, e.g., MIC or IC50, and drug concentrations,
e.g., blood or blood-medium, also vary. When
compared with studies using the same methodology,
equivalent results were found in Zaire (7, 21) and
Nigeria (3), whereas significantly more resistance
was found in Cambodia where many individual
MICs were over 5.12 x 10-6 molA (24) together
with a 60% failure rate in vivo, and in Thailand
where the mean MIC was 3.0 x 10-6 molA (23) with
a 15% failure rate in vivo. Previous results from
Thailand in 1984 (26) showed an IC50 of 0.24 x 10-6
molA, similar to the IC50 from Liberia in 1988.
In francophone countries, the hypoxanthine
method for evaluating 48-hour growth (27) has
mostly been used and the susceptibilities are usually
expressed as IC50 values. An individual IC50 value
for quinine of 0.3 x 10-6 molA has been considered
as indicative of resistance (4-6). Thus, although the
mean IC50 values have been similar to that obtained
in our study, the individual results in Cameroon (6),
c See footnote a on page 460.
WHO Bulletin OMS. Vol 691991.
Susceptibility of P. falciparum to quinine in Liberia
Senegal (4) and Guinea (5) have been interpreted as
indicating the existence of several resistant strains.
In our study, 15 individual isolates (30%) also had
IC50 values above 0.3 x 10-6 molA and yet were
successfully treated with even shorter courses of
quinine than the standardized seven days. This
indicates that a higher IC50 value than 0.3 x 10-6
mol! is a more accurate cut-off for resistance, at
least when evaluated according to the standardized
24-hour test.
Drug concentrations
The concentrations of quinine showed up to
threefold individual variation which is in accord with
previous studies (28, 29). The quinine concentra-
tions were measured in whole blood as compared to
plasma in previous studies. Considering that the
ratio of red cell to plasma concentrations in one
previous study varied between 0.49 and 0.26 (30),
the values obtained in our study are as expected
from data in previous studies both on patients and
volunteers (29).
All peak concentrations during the third day of
treatment were well above MIC values in the in vitro
test and even the trough concentrations were above
the MICs. From previous pharmacokinetic studies it
may be assumed that the concentrations during the
first day of treatment were also above these MIC
levels (31). This supports the efficacy of the treat-
ment, although effective drug concentrations in vivo
in whole blood or plasma may not necessarily
correspond exactly to effective drug concentations
in vitro in the blood-medicine mixture because of
the different conditions such as plasma binding, etc.
That two of the older children with side-effects
had high peak concentrations confirms previous
studies where plasma concentrations above 5 mgA
(= 12.5 x 10-6 molA) were associated with cinchon-
ism (32, 33) and were reported more often in older
than younger children (23). To avoid transient
side-effects such as cinchonism, a lower dosage of
quinine might be considered because doses of
10 mg/kg body weight produce concentrations well
above that needed to inhibit the in vitro growth of
P. falciparum parasites. However, this may not be
suitable in areas where quinine resistance is increas-
ing, as in south-east Asia, and might even enhance
the development of quinine resistance in the African
situation.
Quinidine. Quinidine had three- to fourfold higher
activity than quinine. This is probably not equivalent
to a higher degree of efficacy in vivo as quinidine
gives about three times lower concentrations than
quinine in equivalent doses (23, 28). In areas like
463
A. Bj6rkman et al.
Liberia where quinine has retained sufficient activ-
ity, it is probably to be preferred for antimalarial
therapy as it has less cardiotropic affinity and
therefore possibly fewer side-effects on the heart
than quinidine.
Conclusion
Quinine remains a highly efficient antimalarial drug
in Liberia even after the appearance of chloroquine-
resistant P. falciparum strains and changes in the
susceptibility to quinine. As short as two days of
therapy with quinine (10 mg/kg body weight twice
daily) appeared to be efficacious in 15 children
tested. A 3-day course may therefore be expected to
safely provide radical cures in a larger sample and
may be an alternative treatment for semi-immune
individuals in endemic areas with a certain degree of
chloroquine resistance. This dosage represents a
60% cost reduction compared with the 7-day course
and is expected to have a higher rate of compliance.
That chloroquine-resistant parasites are less
susceptible to quinine, although not to the point of
showing a resistance pattern, may be an indication
of a further development towards P. falciparum
resistance to quinine in Africa. It is therefore
essential to continuously monitor the susceptibility
of P. falciparum to quinine in different parts of
Africa, preferably using both standardized in vivo
and in vitro tests.
Acknowledgements
This study was supported by LAMCO Joint Venture, and by
grants from the UNDP/World Bank/WHO Special Pro-
gramme for Research and Training in Tropical Diseases, the
Swedish Agency for Research Cooperation with Developing
Countries (SAREC), and the Swedish Medical Research
Council.
We thank Dr 0. Ericson for analysis of quinine con-
centrations in blood samples, J. Enego and Monica Friden
for valuable laboratory technical assistance, Professor A.P.
Hanson (Liberian Institute for Biomedical Research) for
general support, and Christina Karlsson for secretarial as-
sistance.
Resume
Sensibilite de Plasmodium falciparum a dif-
ferentes doses de quinine in vivo, et a la
quinine et la quinidine in vitro, par rapport a la
chloroquine, au Lib6ria
Plasmodium falciparum chloroquinoresistant s'est ra-
pidement etendu a Yekepa apres son apparition en
1988. Les sensibilites in vivo et in vitro a la quinine
et a la quinidine, comparees a la sensibilite & la
chloroquine, ont ete etudiees en recherchant le nom-
464
bre de jours de traitement n6cessaires pour une
gu6rison radicale, et en mesurant, en meme temps,
les concentrations de quinine.
Les concentrations minimales inhibitrices (CMI)
pour la maturation des schizontes, dans tous les
tests in vitro reussis, etaient de 5,12 x 10-6 mol/!
pour la quinine et de 1,28 x 10-6 molA pour la quini-
dine, montrant que les 50 isolats etudies etaient
sensibles aux deux medicaments. La C150 et la Clgo
etaient de 0,22 et de 0,78 x 10-6 mol/! pour la
quinine, et de 0,07 et 0,26 x 10-6 mol/! pour la
quinidine. L'inhibition in vitro de parasites par
1,6 x 10-6 mol/A de chloroquine etait obtenue pour
31 isolats sur 47, 16 (34%) etant r6sistants. La Cl50,
la Clgo et la CMI moyenne geom6trique pour la
quinine etaient environ deux fois superieures pour les
isolats chloroquinoresistants que pour ceux qui
etaient sensibles a la chloroquine (P = 0,006).
Des enfants infectes par P. falciparum (n = 64)
ont ete r6partis au hasard dans quatre groupes et
traites par la quinine (10 mg/kg de poids corporel,
deux fois par jour), pendant 1 jour (3 doses), 2 jours,
4 jours et 7 jours respectivement. Les 59 enfants qui
ont tous termin6 I'etude n'avaient plus de para-
sitemie au jour 4, mais 5 sur 15 de ceux traites avec
seulement trois doses ont pr6sente une recidive de
parasitemie entre le jour 7 et le jour 14, qui a e
consideree comme une recrudescence. Dans les
autres groupes, des recidives de parasitemie n'ont
eu lieu qu'entre les jours 17 et 28, et ont ete
considerees comme des reinfections. Les concentra-
tions sanguines moyennes de quinine chez 12 mala-
des le quatrieme jour du traitement etaient de 17,0,
12,2 et 8,4 x 10-6 mol/l, 2, 6 et 12 heures respecti-
vement apres la dernibre dose. Ces concentrations
6taient bien superieures aux valeurs de la CMI in
vitro.
La quinine reste un antipaludeen extremement
efficace au Lib6ria, meme apres I'apparition de sou-
ches de P. falciparum chloroquinoresistantes; le trai-
tement de 3 jours, qui semble un schema efficace
dans une population semi-immune, repr6sente, une
reduction de coOt de 60% par rapport au traitement
de 7 jours, et il est vraisemblable que son taux
d'observance sera plus eIeve. Le fait que des para-
sites chloroquinoresistants soient moins sensibles a
la quinine, mais pas au point de faire preuve d'une
r6elle resistance, peut etre l'indication d'une nouvelle
extension de la resistance de P. falciparum a la
quinine en Afrique. II est de ce fait indispensable de
surveiller continuellement la sensibilite de P. falcipa-
rum a la quinine dans differentes parties d'Afrique.
References
1. Bjorkman, A. & Phillips-Howard, P.A. The epide-
miology of drug resistant malaria. Trans. Roy. Soc.
WHO Bulletin OMS. Vol 691991.

Trop. Med. Hyg., 84: 177-180 (1990).
2. Bjorkman, A. & Willcox, M. In vitro susceptibility of
Plasmodium falciparum to amodiaquine, mefloquine,
quinine and chloroquine in Liberia, West Africa. Trans.
Roy. Soc. Trop. Med. Hyg., 80: 761-762 (1986).
3. Salako, A. et al. Evaluation of the sensitivity in vivo and
in vitro of Plasmodium falciparum malaria to quinine in
an area of full sensitivity to chloroquine. Trans. Roy.
Soc. Trop. Med. Hyg., 82: 366-368 (1988).
4. Brandicourt, 0. et al. Decreased sensitivity to chloro-
quine and quinine of some Plasmodium falciparum
strains from Senegal in September 1984. Am. j. trop.
med. hyg., 35: 717-721 (1986).
5. Brasseur, P. et al. Low sensitivity to chloroquine and
quinine of Plasmodium falciparum isolates from Guinea
in March 1986. Am. j. trop. med. hyg., 37: 452-454
(1987).
6. Brasseur, P. et al. Patterns of in vitro resistance to
chloroquine, quinine and mefloquine of Plasmodium
falciparum in Cameroon, 1985-1986. Am. j. trop. med.
hyg., 39: 166-172 (1988).
7. Wery, M. et al. Evolution de la sensibilite de P. falci-
parum a la chloroquine, a la quinine et a la mefloquine
entre 1983 et 1985 au Zaire. Ann. Soc. Beige Med.
Trop., 66: 309-324 (1988).
8. Knowles, G. et al. The relationship between the in vitro
response of Plasmodium falciparum to chloroquine, qui-
nine and mefloquine. Trans. Roy. Soc. Trop. Med. Hyg.,
78:146-150 (1984).
9. Nguyen, C. et al. Falciparum malaria resistant to
chloroquine, quinine and Fansidar®) in a non-immune
patient infected in Ghana. Trans. Roy. Soc. Trop. Med.
Hyg., 83: 485-486 (1989).
10. Simon, F. et al. Severe chloroquine-resistant falciparum
malaria in Gabon with decreased sensitivity to quinine.
Trans. Roy. Soc. Trop. Med. Hyg., 80: 996-997 (1986).
11. Warhurst, D.C. et al. RI quinine-fansidar resistant
falciparum malaria from Malawi. Lancet, 2: 330 (1985).
12. Bisseru, B. Quinine-resistant Plasmodium falciparum in
Zambia. Centr. Afr. j. med., 34: 17-18 (1988).
13. Mutabingwa, T.K. et al. Response of Plasmodium
falciparum to chloroquine in hospital patients at Muheza,
Tanzania. East Afr. med. j., 62: 161-171 (1985).
14. Malin, A.S. & Hall, A.P. Falciparum malaria resistant to
quinine and pyrimethamine-sulfadoxine successfully
treated with mefloquine. Brit. med. j., 300: 1175 (1990).
15. White, N.J. et al. Quinidine in falciparum malaria.
Lancet, 2: 1069-1071 (1981).
16. Bjorkman, A. et al. Different malaria control activities in
an area of Liberia-effects on malariometric parameters.
Ann. trop. med. parasitol., 79: 239-246 (1985).
17. Rieckman, K.H. et al. Drug sensitivity of Plasmodium
falciparum. An in vitro micro technique. Lancet, 1:
22-23 (1978).
18. Kremsner, P.G. et al. In vitro drug sensitivity of Plas-
WHO Bulletin OMS. Vol 691991.
Susceptibility of P. falciparum to quinine in Liberia
modium falciparum in Acre, Brazil. Bull. Wrld Hlth Org.,
67: 289-293 (1989).
19. Bjorkman, A. et al. In vivo response of Plasmodium
falciparum in semi-immune children to different doses of
chloroquine in Liberia, West Africa. Ann. trop. med.
parasitol., 80: 1-6 (1986).
20. Petersen, E. et al. A longitudinal study of antibodies to
the Plasmodium falciparum antigen Pf1 55/RESA and
immunity to malaria infection in adult Liberians. Trans.
Roy. Soc. Trop. Med. Hyg., 84: 339-345 (1990).
21. Greenberg, A.E. et al. Intravenous quinine therapy of
hospitalized children with Plasmodium falciparum mal-
aria in Kinshasa, Zaire. Am. j. trop. med. hyg., 40:
360-364 (1989).
22. Deloron, P. et al. Efficacy of 3-day oral regimen of a
quinine-quinidine-cinchonine association (Quinimax®)
for treatment of falciparum malaria in Madagascar.
Trans. Roy. Soc. Trop. Med. Hyg., 83: 751-754 (1989).
23. Sabchareon, A. et al. In vivo and in vitro responses to
quinine and quinidine of Plasmodium falciparum. Bull.
Wrld Hlth Org., 66: 347-352 (1988).
24. Giboda, M. & Denis, M.B. Response of Kampuchean
strains of Plasmodium falciparum to antimalarials: in
vivo assessment of quinine and quinine plus tetracy-
cline; multiple drug resistance in vitro. J. trop. med.
hyg., 91: 205-211 (1988).
25. Stahel, E. et al. Antagonism of chloroquine with other
antimalarials. Trans. Roy. Soc. Trop. Med. Hyg., 82:
221 (1988).
26. Suebsaeng, L. et al. Sensitivity to quinine and meflo-
quine of Plasmodium falciparum in Thailand. Bull. Wrld
Hlth Org., 64: 759-765 (1986).
27. Brasseur, P. et al. High level of sensitivity to chloro-
quine of 72 Plasmodium falciparum isolates from south-
ern Cameroon in January 1985. Am. I. trop. med. hyg.,
35: 711-716 (1986).
28. Jamaludin, A. et al. Single-dose comparative kinetics
and bioavailability study of quinine hydrochloride, quini-
dine sulfate and quinidine bisulfate sustained-release in
healthy male volunteers. Acta Leidensia, 57: 39-46
(1988).
29. White, N.J. The pharmacokinetics of quinine and quini-
dine in malaria. Acta Leidensia, 55: 65-76 (1987).
30. White, N.J. et al. Red-cell quinine concentrations in
falciparum malaria. Am. j. trop. med. hyg., 31: 456-460
(1982).
31. Chongsuphajaisiddhi, T. et al. In vivo and in vitro
sensitivity of falciparum malaria to quinine in Thai child-
ren. Ann. trop. paed., 1: 21-26 (1981).
32. White, N.J. et al. Quinine pharmacokinetics and toxicity
in cerebral and uncomplicated falciparum malaria. Am. j.
med., 73: 564-572 (1982).
33. Powell, R.D. & McNamara, J.V. Quinine: side-effects
and plasma levels. Proc. Helminthol. Soc. Washington,
39: 331-338 (1972).
465