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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


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


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

460 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

Quinine
(x 10 -6 mol/I)
Chloroquine MICa Quinine MlCa
Isolates (x 10-6 mol/1) (x 10-6 mol!) IC50 IC90
CQ sensitive (n = 31) 0.6 ± 0.3 (0.4-0.8)b 0.64 ± 0.04 (0.16-5.12) 0.18 0.61
CQ resistant (n = 16) 10.4 ± 0.4 (1.6-25.6) 1.23 ± 0.03 (0.64-2.56) 0.35 1.13
a
Figures are means ± standard deviations.
b Figures in parentheses are the ranges.

to cinchonism were tested for their drug concentra- with chloroquine (19), which also corresponds to the
tions; both had high peak levels, 20.2 and inoculation rate observed in this village (20).
26.8 x 10-6 mol/l. As the study was performed in children, many
of them significantly semi-immune, the results have
Discussion to be treated with caution as regards individuals with
low immunity and should not be interpreted as a
In vivo results recommendation for non-immunes. In two previous
The in vivo results suggest that even two days of studies with quinine in Zaire (21) and Quinimax
quinine treatment may be satisfactory, whereas (quinine-quinidine-chinonine) in Madagascar (22),
three doses during 24 hours may only be partly three days of treatment gave 100% clearance of
curative with a high rate of RI responses although all parasitaemia after 60 and 52 hours, respectively,
parasitaemias were reduced to subpatent levels by similar to the parasitic clearance of 2.2 to 2.4 days in
day 4 (Table 2). The parasitaemias from day 17 our study. However, follow-up was for only seven
onwards in the groups treated for two, four and days and failures would have been missed as RI
seven days were considered as reinfections, as the responses around day 14 represented the major part
rates of recurrences in the groups treated for two of therapeutic failures in previous studies with
and four days were similar to the rate in the group quinine treatment in Thailand (23) and Cambodia
treated for seven days, except for a minor shift of (24).
about three days corresponding to clearance of the There are a few sentinel reports of in vivo
drug about three days later in the group treated for quinine failures in Africa (1) among patients not
seven days. Furthermore, the rate of reinfection was taking the complete seven-day standard treatment,
similar to that previously observed after radical cure 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
Fig. 1. In vitro susceptibility to quinine (concentrations in individuals may achieve abnormally low quinine
blood) of chloroquine-sensitive (1) and chloroquine-resistant
(2) P. falciparum isolates from Yekepa area, Liberia, in 1988. 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
99. antagonism between quinine and chloroquine. has
been reported in vitro (25). In the most recent
report of quinine failure (14) two patients from
90.

E (1)
Table5: Concentrations of quinine in whole blood in 10
C Liberian children on third day of treatment (10 mg/kg body
o. weight twice daily) 2, 6 and 12 hours after the last dose
0
Hours after in- No. of children Quinine concentrationsa
X 10. take of last dose (x 10 -6 molA)
2 10 17.0 ± 5.6 (9.9-26.8)b
1. 6 10 12.2 ± 3.7 (7.3-17.2)
12 10 8.4 ± 2.2 (4.9-11.8)

0.1 1i0
a
Figures are means ± standard deviations.
Concentration (X 10o6mol/l) bFigures in parentheses are the ranges.

462 WHO Bulletin OMS. Vol 69 1991.


Susceptibility of P. falciparum to quinine in Liberia

Ghana and Nigeria were unsuccessfully treated for Senegal (4) and Guinea (5) have been interpreted as
seven days in the United Kingdom but no informa- indicating the existence of several resistant strains.
tion was given on possible previous chloroquine In our study, 15 individual isolates (30%) also had
prophylaxis, or quinine concentrations during IC50 values above 0.3 x 10-6 molA and yet were
therapy, or the in vitro susceptibility of the para- successfully treated with even shorter courses of
sites. 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
In vitro results least when evaluated according to the standardized
All isolates were considered as highly sensitive to 24-hour test.
quinine and even the isolate with the highest MIC
(5.12 x 10-6 molA) was successfully treated with Drug concentrations
quinine (7-day treatment). This supports the WHO
criteria for the standardized 24-hour test, with a The concentrations of quinine showed up to
cut-off MIC of >5.12 x 10-6 mol/l for resistance.C threefold individual variation which is in accord with
The mean MIC was 0.75 x 10-6 molA compared to previous studies (28, 29). The quinine concentra-
0.37 x 10-6 molA in 1983 (2). Similarly the EC50, tions were measured in whole blood as compared to
EC90 and ECg9 were about twice those recorded in plasma in previous studies. Considering that the
1983. Although the previous study was based on ratio of red cell to plasma concentrations in one
only seven isolates, this may suggest a partial previous study varied between 0.49 and 0.26 (30),
decrease in sensitivity between 1983 and 1988. This the values obtained in our study are as expected
is supported by the fact that the isolates with from data in previous studies both on patients and
chloroquine-resistant parasites, not present in 1983, volunteers (29).
were less sensitive to quinine than the sensitive All peak concentrations during the third day of
isolates (Table 4, Fig. 1). treatment were well above MIC values in the in vitro
A correlation between decreased sensitivities to test and even the trough concentrations were above
chloroquine and quinine has previously been sug- the MICs. From previous pharmacokinetic studies it
gested (6-8) and chloroquine resistance has been may be assumed that the concentrations during the
considered a prerequisite for the development of first day of treatment were also above these MIC
quinine resistance in south-east Asia. levels (31). This supports the efficacy of the treat-
Comparisons of in vitro results with those from ment, although effective drug concentrations in vivo
other studies is difficult because of differences in the in whole blood or plasma may not necessarily
in vitro methodology (1). The expressions of inhibi- correspond exactly to effective drug concentations
tion, e.g., MIC or IC50, and drug concentrations, in vitro in the blood-medicine mixture because of
e.g., blood or blood-medium, also vary. When the different conditions such as plasma binding, etc.
compared with studies using the same methodology, That two of the older children with side-effects
equivalent results were found in Zaire (7, 21) and had high peak concentrations confirms previous
Nigeria (3), whereas significantly more resistance studies where plasma concentrations above 5 mgA
was found in Cambodia where many individual (= 12.5 x 10-6 molA) were associated with cinchon-
MICs were over 5.12 x 10-6 molA (24) together ism (32, 33) and were reported more often in older
with a 60% failure rate in vivo, and in Thailand than younger children (23). To avoid transient
where the mean MIC was 3.0 x 10-6 molA (23) with side-effects such as cinchonism, a lower dosage of
a 15% failure rate in vivo. Previous results from quinine might be considered because doses of
Thailand in 1984 (26) showed an IC50 of 0.24 x 10-6 10 mg/kg body weight produce concentrations well
molA, similar to the IC50 from Liberia in 1988. above that needed to inhibit the in vitro growth of
In francophone countries, the hypoxanthine P. falciparum parasites. However, this may not be
method for evaluating 48-hour growth (27) has suitable in areas where quinine resistance is increas-
mostly been used and the susceptibilities are usually ing, as in south-east Asia, and might even enhance
expressed as IC50 values. An individual IC50 value the development of quinine resistance in the African
for quinine of 0.3 x 10-6 molA has been considered situation.
as indicative of resistance (4-6). Thus, although the
mean IC50 values have been similar to that obtained Quinidine. Quinidine had three- to fourfold higher
in our study, the individual results in Cameroon (6), 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
c See footnote a on page 460. quinine in equivalent doses (23, 28). In areas like

WHO Bulletin OMS. Vol 691991. 463


A. Bj6rkman et al.

Liberia where quinine has retained sufficient activ- bre de jours de traitement n6cessaires pour une
ity, it is probably to be preferred for antimalarial gu6rison radicale, et en mesurant, en meme temps,
therapy as it has less cardiotropic affinity and les concentrations de quinine.
therefore possibly fewer side-effects on the heart Les concentrations minimales inhibitrices (CMI)
than quinidine. pour la maturation des schizontes, dans tous les
tests in vitro reussis, etaient de 5,12 x 10-6 mol/!
Conclusion pour la quinine et de 1,28 x 10-6 molA pour la quini-
dine, montrant que les 50 isolats etudies etaient
Quinine remains a highly efficient antimalarial drug sensibles aux deux medicaments. La C150 et la Clgo
in Liberia even after the appearance of chloroquine- etaient de 0,22 et de 0,78 x 10-6 mol/! pour la
resistant P. falciparum strains and changes in the quinine, et de 0,07 et 0,26 x 10-6 mol/! pour la
susceptibility to quinine. As short as two days of quinidine. L'inhibition in vitro de parasites par
therapy with quinine (10 mg/kg body weight twice 1,6 x 10-6 mol/A de chloroquine etait obtenue pour
daily) appeared to be efficacious in 15 children 31 isolats sur 47, 16 (34%) etant r6sistants. La Cl50,
tested. A 3-day course may therefore be expected to la Clgo et la CMI moyenne geom6trique pour la
safely provide radical cures in a larger sample and quinine etaient environ deux fois superieures pour les
may be an alternative treatment for semi-immune isolats chloroquinoresistants que pour ceux qui
individuals in endemic areas with a certain degree of etaient sensibles a la chloroquine (P = 0,006).
chloroquine resistance. This dosage represents a Des enfants infectes par P. falciparum (n = 64)
60% cost reduction compared with the 7-day course ont ete r6partis au hasard dans quatre groupes et
and is expected to have a higher rate of compliance. traites par la quinine (10 mg/kg de poids corporel,
That chloroquine-resistant parasites are less deux fois par jour), pendant 1 jour (3 doses), 2 jours,
susceptible to quinine, although not to the point of 4 jours et 7 jours respectivement. Les 59 enfants qui
showing a resistance pattern, may be an indication ont tous termin6 I'etude n'avaient plus de para-
of a further development towards P. falciparum sitemie au jour 4, mais 5 sur 15 de ceux traites avec
resistance to quinine in Africa. It is therefore seulement trois doses ont pr6sente une recidive de
essential to continuously monitor the susceptibility parasitemie entre le jour 7 et le jour 14, qui a e
of P. falciparum to quinine in different parts of consideree comme une recrudescence. Dans les
Africa, preferably using both standardized in vivo autres groupes, des recidives de parasitemie n'ont
and in vitro tests. eu lieu qu'entre les jours 17 et 28, et ont ete
considerees comme des reinfections. Les concentra-
Acknowledgements tions sanguines moyennes de quinine chez 12 mala-
This study was supported by LAMCO Joint Venture, and by des le quatrieme jour du traitement etaient de 17,0,
grants from the UNDP/World Bank/WHO Special Pro- 12,2 et 8,4 x 10-6 mol/l, 2, 6 et 12 heures respecti-
gramme for Research and Training in Tropical Diseases, the vement apres la dernibre dose. Ces concentrations
Swedish Agency for Research Cooperation with Developing 6taient bien superieures aux valeurs de la CMI in
Countries (SAREC), and the Swedish Medical Research vitro.
Council. La quinine reste un antipaludeen extremement
We thank Dr 0. Ericson for analysis of quinine con- efficace au Lib6ria, meme apres I'apparition de sou-
centrations in blood samples, J. Enego and Monica Friden ches de P. falciparum chloroquinoresistantes; le trai-
for valuable laboratory technical assistance, Professor A.P.
Hanson (Liberian Institute for Biomedical Research) for tement de 3 jours, qui semble un schema efficace
general support, and Christina Karlsson for secretarial as- dans une population semi-immune, repr6sente, une
sistance. reduction de coOt de 60% par rapport au traitement
de 7 jours, et il est vraisemblable que son taux
Resume d'observance sera plus eIeve. Le fait que des para-
sites chloroquinoresistants soient moins sensibles a
Sensibilite de Plasmodium falciparum a dif- la quinine, mais pas au point de faire preuve d'une
ferentes doses de quinine in vivo, et a la r6elle resistance, peut etre l'indication d'une nouvelle
quinine et la quinidine in vitro, par rapport a la extension de la resistance de P. falciparum a la
chloroquine, au Lib6ria quinine en Afrique. II est de ce fait indispensable de
surveiller continuellement la sensibilite de P. falcipa-
Plasmodium falciparum chloroquinoresistant s'est ra- rum a la quinine dans differentes parties d'Afrique.
pidement etendu a Yekepa apres son apparition en
1988. Les sensibilites in vivo et in vitro a la quinine References
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464 WHO Bulletin OMS. Vol 691991.


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