Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, February 1999, p. 341-346, Vol. 43, No. 2
Shoklo Malaria Research Unit,
Received 22 April 1998/Returned for modification 26 August
1998/Accepted 22 November 1998
Combining artemisinin or a derivative with mefloquine increases
cure rates in falciparum malaria patients, reduces transmission, and
may slow the development of resistance. The combination of artesunate,
given for 3 days, and mefloquine is now the treatment of choice for
uncomplicated multidrug-resistant falciparum malaria acquired on the
western or eastern borders of Thailand. To optimize mefloquine
administration in this combination, a prospective study of mefloquine
pharmacokinetics was conducted with 120 children (4 to 15 years old)
with acute uncomplicated falciparum malaria, who were divided into four
age- and sex-matched groups. The patients all received artesunate (4 mg/kg of body weight/day orally for 3 days and mefloquine as either (i)
a single dose (25 mg/kg) on day 2 with food, (ii) a split dose (15 mg/kg on day 2 and 10 mg/kg on day 3) with food, (iii) a single dose
(25 mg/kg) on day 0 without food, or (iv) a single dose (25 mg/kg) on
day 2 without food. Delaying administration of mefloquine until day 2 was associated with a mean (95% confidence interval) increase in
estimated oral bioavailability of 72% (36 to 109%). On day 2 coadministration with food did not increase mefloquine absorption
significantly, and there were no significant differences between
patients receiving split- and single-dose administration. In
combination with artesunate, mefloquine administration should be
delayed until the second or third day after presentation.
Mefloquine was first introduced for
the treatment of uncomplicated falciparum malaria in Thailand in 1984. It is a quinoline methanol compound available only for oral
administration. Mefloquine is cleared slowly from the body, with an
elimination half-life of ~2 weeks in antimalarial treatment
(6). Although a single dose of 15 mg of base/kg of body
weight initially gave cure rates in excess of 90% on the western and
eastern borders of Thailand, the efficacy of this regimen declined
rapidly after 1990, and the recommended dose was increased to 25 mg/kg
(17). Recent studies have shown that splitting the dose of
mefloquine into 15 and 10 mg/kg (at least 8 h apart) halves the
rate of early vomiting (20), and nearly doubles the mean
blood concentrations on the third day following treatment (which
correspond approximately to peak levels) (18). Since
vomiting and postabsorptive blood levels are major determinants of
treatment outcome (16), these data argue in favor of
splitting the dose of mefloquine when given alone for the treatment of
malaria. In contrast two smaller studies have compared split- and
single-dose mefloquine regimens in healthy volunteers and found no
difference in the overall bioavailability of mefloquine (4,
9). There may also be some benefit in giving mefloquine with
food. Mefloquine is a hydrophobic lipophilic compound. Absorption is
increased by buffering stomach acidity and coadministering fats to
improve solubility. In healthy volunteers mefloquine was absorbed more
rapidly, the peak concentration was 1.7 times higher, and the area
under the plasma concentration-time curve was 1.4 times greater when
mefloquine was taken after food compared to after an overnight fast
(1, 2). The relevance of these observations to the treatment
of malaria is unclear. Furthermore, the majority of pharmacokinetic
data on mefloquine comes from studies in adults, whereas the majority
of antimalarial treatments worldwide are given to children.
By mid-1994 on the Thai-Burmese border cure rates with high-dose
mefloquine alone had fallen to nearly 50%. Mefloquine monotherapy for
uncomplicated falciparum malaria was discontinued and replaced by a
combination of 3 days of artesunate and mefloquine (25 mg/kg) (12). Combinations of artemisinin or a derivative with
mefloquine are associated with more rapid treatment responses,
increased cure rates, and lower transmission potential and may slow the development of mefloquine resistance (13, 21, 22). There is
now increasing acceptance that mefloquine should not be employed alone
and should only be used in combination with artemisinin or one of its
derivatives. Coadministration of an artemisinin derivative has been
reported to alter mefloquine pharmacokinetics (5), although
this is probably a secondary result of the more rapid clinical
improvement rather than a direct interaction. In order to optimize
dosing in the artesunate-mefloquine regimen and define the variance in
blood concentration profiles between patients, we have conducted a
large study of children with acute falciparum malaria to investigate
the pharmacokinetic consequences of splitting the dose, administering
the drug during recovery (compared with on admission), and giving a
small fatty meal with mefloquine.
Study site.
This trial was conducted from May 1994 to
October 1995 in Shoklo, Mae Sod, Thailand, a camp for displaced persons
of the Karen ethnic minority. The camp is situated along the western
border of Thailand in an area of seasonal and low malaria transmission (8).
Patients.
Children between 4 and 15 years with
slide-confirmed falciparum malaria were eligible to be enrolled in the
study if they and their parents gave informed consent. Children who had
received antimalarial medication in the preceding 63 days, had a
parasitemia of >4%, weighed <5 kg, or had signs of severity
(23) or concomitant disease requiring hospital admission
were all excluded. The study was approved by the Ethical Committee of
the Faculty of Tropical Medicine, Mahidol University, Bangkok,
Thailand, and by the Karen Refugee Committee, Mae Sod, Thailand.
Antimalarial drug regimens.
A total of 120 children were
recruited from the outpatient treatment clinic into four sets of 30 age- and sex-matched patients. As each eligible patient presented their
treatment allocation was determined from a randomized sequence. This
resulted in 30 age- and sex-matched quartets, in which each patient
received one of the four drug regimens described below. All patients
received 4 mg of artesunate (Guilin no. 1 factory, Guangxi, People's
Republic of China)/kg/day for 3 days and were allocated to receive
mefloquine (Lariam [250 mg base tablets]; Hoffman-La Roche, Basel,
Switzerland) in one of the four following regimens: (i) group A, a
single dose of mefloquine (25 mg/kg) on day 2 given with food; (ii)
group B, a 15-mg/kg dose of mefloquine on day 2 and a 10-mg/kg dose of
mefloquine on day 3 (both doses given with food); (iii) group C, a
single dose of mefloquine (25 mg/kg) given on day 0 without food; and
(iv) group D, a single dose of mefloquine (25 mg/kg) given on day 2 without food.
Study procedures.
On admission a questionnaire was
completed, recording details of symptoms and their duration and the
history of previous antimalarial medication (since health structures in
the camp are the only source of antimalarial drugs in this area, the
history is usually a reliable guide to pretreatment). A full clinical
examination was made, and blood was taken for blood film, hematocrit,
and leukocyte count procedures. Parasite counts were determined on
Giemsa-stained thick films as the number of parasites per 500 leukocytes. Patients were examined daily thereafter until they became
aparasitemic and then were seen weekly for 9 weeks. At each clinic
appointment, a full physical examination was performed and the symptom
questionnaire was completed, and at the weekly visits, blood was taken
for hematocrit and parasite count procedures. Fever was defined as an
oral temperature of
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Pharmacokinetics of Mefloquine Combined with
Artesunate in Children with Acute Falciparum Malaria
ABSTRACT
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
37.5°C.
20°C locally and
then were transported on dry ice to Bangkok, Thailand, where they were
stored at 70°C until analysis. Whole-blood mefloquine levels are
stable for at least 4 years under these conditions (unpublished observations).
Drug assays. Whole-blood mefloquine levels were determined by high-performance liquid chromatography with UV detection. Quantitation of mefloquine was performed by reversed-phase chromatography with isocratic elution and an internal standard procedure. Mefloquine was extracted by liquid-liquid extraction into a dichloromethane layer, which was separated from the aqueous phase, evaporated to dryness, and reconstituted in mobile phase before injection into the high-performance liquid chromatography column (13). Whole (capillary)-blood samples (0.2 ml) were diluted with distilled water (1:1) before the assay. The assay was linear over 0.05 to 4 µg/ml. The intra- and interassay coefficients of variation for the capillary whole-blood assays were 4.5% for concentrations between 500 and 2,000 ng/ml. The limit of detection was 50 ng/ml. At this study site capillary blood samples have been shown to give equivalent results to larger-volume venous blood samples (19).
Pharmacokinetics.
Five main outcome measures were chosen
prospectively to describe the kinetics of mefloquine. These were the
observed maximum whole-blood concentration
(Cmax), which was read directly from the
individual whole-blood concentration-time data; the terminal elimination half-life (t1/2), which was
calculated by dividing ln2 by 
Z (the terminal
elimination rate constant); the area under the whole blood
concentration-time curve extrapolated to infinity
(AUC0-
); the apparent volume of distribution (V/f); and the apparent oral clearance per fraction of drug
absorbed (CL/f). CL/f was estimated from the
ratio of the dose to AUC0-, and V/f was
estimated from CL/f divided by Z.
The terminal elimination rate constant was calculated by fitting the
individual data from the terminal phase of the concentration-time plots
to log-linear regression by using the method of least squares. The AUC0- for each individual was derived from the time of
drug administration to the time of the last measurable concentration by
using the linear trapezoidal rule. Extrapolation to infinity was
determined by dividing the last measurable concentration level by
Z. Each measure was calculated separately for
each subject and calculated from the time of mefloquine administration instead of the day of admission by using noncompartmental
pharmacokinetic analysis (WinNonlin, standard edition version 1.1;
Scientific Consulting Inc., Apex, N.C.). Without day 28 levels the
precision of the estimate of Z is reduced,
and since this parameter is required for the calculation of
V/f, CL/f, t1/2, and
AUC0- it was decided to only calculate these parameters
for patients for whom day 28 levels were available.
Statistical analysis. Data were analyzed by using SPSS for Windows (SPSS Inc., Chicago, Ill.).
Normally distributed data were described by means and 95% confidence intervals (95% CI) and compared by using Student's t test. Abnormally distributed data were described by median, range, and interquartile range, and the four treatment groups were compared by using the Kruskal-Wallis test. For categorical variables, percentages and corresponding 95% CI were calculated, and the
2
test was used for comparison among the four treatment groups. Wilcoxon's test for paired observations was performed to assess the
statistical significance of the differences of the pharmacokinetic parameters for the following three main comparisons: single dose versus
split dose (group A versus group B), giving the drug in the acute phase
of malaria versus during the convalescent phase (group C versus group
D), and giving the drug with food versus without food (group A versus
group D). The association between two continuous variables was assessed
by using Spearman's rank correlation coefficient. A P value
of <0.05 was considered statistically significant.
| |
RESULTS |
|---|
|
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
|
|---|
Clinical and laboratory findings.
Overall, 120 patients were
recruited into the study and received a complete course of treatment.
Of these, 10 were excluded from analysis; 2 were found to have vivax
malaria, 3 had significant pretreatment mefloquine levels (>150 ng/ml)
from an undeclared previous treatment, 1 had only three samples taken,
and for 4 all samples were lost. On admission all of the patients were
symptomatic, and 71 (65%) were febrile. The geometric mean parasitemia
upon presentation was 6,988 (95% CI, 4,763 to 10,251)
µl
1. Baseline characteristics are summarized in Table
1. A total of 728 (91%) samples out of
the 797 planned were collected. There were no significant differences
in baseline characteristics or compliance between groups. For 14 subjects (13%) (1 in group A, 3 in group C, and 5 each in groups B and
D), the sample on day 28 was not collected, which precluded analysis of
the AUC0- and related pharmacokinetic parameters. All
patients responded rapidly to treatment, and none developed
complications. By day 2 only one (1%) patient was still parasitemic,
and five (5%) were still febrile (all with oral temperatures between
37.5 and 38°C). Three patients had recrudescent parasitemia by day 42 of follow-up (one each in groups B, C, and D). All were re-treated
successfully with a 7-day regimen of artesunate.
|
Mefloquine pharmacokinetics.
A summary of mefloquine
pharmacokinetics is given in Table 2. The
mean (95% CI) actual times between the first administration of
mefloquine and the subsequent blood samples are shown in Table 3. Whole-blood mefloquine concentrations
during follow-up in each of the treatment groups are shown in Fig.
1. Overall, the median (range)
Cmax of mefloquine was 1,606 (422 to 4,137)
ng/ml, the AUC was 25,589 (6,441 to 73,716) ng/ml · day, the
V/f was 18.1 (5.5 to 60.7) liters/kg, the
t1/2 was 12.5 (6.5 to 33.2) days, and the
CI/f was 0.98 (0.34 to 3.88) liters/kg/day. The Z was always estimated on the basis of at
least three data points. Visual inspection of the individual log-linear
plots of mefloquine levels against time with the fitted regression
equations showed good agreement between the observed and predicted
mefloquine levels. R2 was found to be >80% in
88% (85 of 97) of the cases. The estimates of the
t1/2 were not significantly different among the
four groups. The distribution of values was log normal, with an overall
geometric mean t1/2 value of 13 days (95% CI,
12.2 to 14.0 days; n = 96). Thus, it would be expected that 10%
of patients, similar to those in the present study, would show
t1/2 values of >20.5 days and 10% would show
t1/2 values of <8.4 days.
|
|
|
8
to 18 days; P = 0.002). Assuming that there was no difference in clearance between the groups, delaying the administration of mefloquine until day 2 (48 h after the first dose of artesunate) increased its oral bioavailability (f) by a mean of
1.72-fold (95% CI, 1.36- to 2.09-fold). Mefloquine samples in group B
were taken 24 h after patients received their first dose of
mefloquine (15 mg/kg) but not after their second dose (10 mg/kg). The
derived pharmacokinetic parameters may therefore have underestimated
the actual Cmax and AUC. The median mefloquine
level in group A, 24 h after receiving the 25-mg/kg dose, was
1,614 (range, 704 to 2,881) ng/ml, significantly greater than that in
group B, who had received only 15 mg/kg (1,147 [range, 838 to 2,386]
ng/ml; P = 0.01). By the fifth day after the first dose
of mefloquine had been given to both groups, those patients receiving
the split dose had significantly higher mefloquine levels (median,
1,284 [range, 853 to 2,014] ng/ml versus 1,059 [range, 488 to 2158] ng/ml; P = 0.03), but this difference was no longer
apparent on or after the seventh day. There was no difference between
groups A and B with regard to the time that the concentration was >500 ng/ml, the AUC for concentrations of >500 ng/ml, or the AUC after the
fifth day following mefloquine administration (an estimate of the
postabsorption AUC).
| |
DISCUSSION |
|---|
|
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
|
|---|
Mefloquine has proved to be a simple and highly effective
treatment for adults and children with falciparum malaria infections resistant to both chloroquine and pyrimethamine-sulfadoxine
(17). Therapeutic efficacy is dependent upon adequate drug
absorption and maintenance of parasiticidal blood levels (levels above
the MIC), until all parasites have been eliminated from the body. Since
1994 the standard treatment of choice for uncomplicated falciparum
malaria in the displaced persons on the western border of Thailand has
been a combination regimen of high-dose mefloquine (25 mg/kg) plus 3 days of artesunate (4 mg/kg/day) (11). The artesunate
component acts rapidly, reducing the infecting biomass by a factor of
approximately 108 (21). Although artesunate is
eliminated quickly from the body, after a 3-day course relatively few
parasites (maximum, 106) remain for mefloquine to remove.
The long t1/2 of mefloquine ensures that high
concentrations in blood are present at this time, and provided that
these remain above the MIC until all parasites have been eliminated,
cure will result (22). Previous studies on the
pharmacokinetics of mefloquine have been carried out on relatively
small numbers of subjects, most of whom were healthy adult volunteers.
Following a single oral dose, peak levels are usually reached within 8 to 24 h, and in malaria infections with drug-sensitive parasites,
therapeutic levels are maintained for considerably more than 7 days
(6). Studies in healthy volunteers have shown good oral
bioavailability which is augmented significantly by food; however,
absorption in patients with acute malaria has been found to be erratic,
and there is some evidence that it is dose limited (18).
The present study of mefloquine pharmacokinetics represents the largest series to date of patients acutely infected with P. falciparum. The pharmacokinetic parameters estimated in this study are generally similar to those previously reported in adults (6) and in children (10, 15), although whole-blood concentrations were lower and thus estimates of apparent V/f were slightly higher. Estimates of t1/2 were similar in the four large groups studied. The distribution of values in this large series was log normal, with an overall geometric mean t1/2 of 13 days. Thus, 10% of children would be expected to show t1/2 values of >20.5 days, and 10% would be expected to show t1/2 values of <8.4 days. This estimate is similar to that in adults (6). The mean t1/2 of mefloquine in younger children (<2 years) (15) is slightly shorter than that in the older children studied here and in adults with acute malaria (11 versus 13 days, respectively), although there is considerable interindividual variance.
In this large and carefully matched series it is unlikely that there
were significant differences in true V/f or clearance capacity between the patient groups. Assuming no capacity limitation in
clearance, the apparent differences in pharmacokinetic parameters resulted therefore from differences in oral bioavailability. The present study shows that although delaying the administration of
mefloquine until the third day after admission (day 2) rather than
giving it on admission (day 0) did not increase the peak mefloquine
levels obtained, it did increase the overall bioavailability by 72%
(minimum, 1.4-fold), and this resulted, on average, in an additional 8 days of therapeutic blood mefloquine levels. Delaying the
administration of mefloquine until day 2 in the combination regimen
(i.e., once the patient is aparasitemic and afebrile), has also been
shown to reduce the risk of vomiting by a third (14). The in
vivo consequences of this are apparent in patients presenting with high
parasite counts (>40,000 µl1). These patients are
three times less likely to recrudesce during follow-up when mefloquine
is given during recovery (14). The considerable
interindividual variation in mefloquine absorption, distribution,
and elimination has important therapeutic consequences, as
inadequate concentrations in blood lead to treatment failure and
provide a powerful selective pressure for the development of resistance
(22). Peak concentrations varied between four- and sevenfold
in this series. The high dose of mefloquine currently used is
required to reduce the number of patients with inadequate drug levels,
but this is costly and risks toxicity in those with the higher
drug concentrations. If bioavailability could be improved, then
variability might be reduced. Administration of mefloquine in
convalescence improved bioavailability, presumably because by this time
patients were generally afebrile and eating normally, and their
gastrointestinal functions had returned to normal, but it did not
reduce interindividual variability. This suggests that even with
delayed administration bioavailability is still far from complete.
A single dose of mefloquine (25 mg/kg) is easy to administer and convenient, but early vomiting of the drug is a common problem, occurring in up to 8% of patients. The risk has been shown to be greatest in children less than 5 years old and febrile patients and following the administration of a high dose of mefloquine (25 mg/kg) compared with a lower dose (15 mg/kg) (20). Previous pharmacokinetic studies with mefloquine monotherapy have shown that a split-dose regimen might result in higher bioavailability (19). In the present study there was no significant difference between patients receiving split and single dosing, when mefloquine was administered during recovery, but our sampling may have failed to capture the peak levels after the administration of the split-dose regimen and for this reason may have underestimated the Cmax and bioavailability with this regimen. When comparing mefloquine levels 72 h after starting mefloquine treatment, there was a 21% increase for patients receiving the split dose compared to those receiving the single dose. However, this difference was no longer apparent after 120 h and therefore did not increase the time that mefloquine levels were above the MIC for P. falciparum. These data suggest that the higher apparent bioavailability observed in our previous study with split dosing may have resulted from the delay in administering the second part of the dose. Acute malaria is associated with reduced absorption of oral mefloquine. Vomiting is also more likely if mefloquine is administered in the acute phase. Readministration of mefloquine after vomiting does not necessarily ensure adequate subsequent drug levels (19). In the present study, any patient vomiting the mefloquine medication was excluded. Since lower doses of mefloquine are better tolerated, if compliance can be achieved, a split-dose regimen would result in therapeutic blood concentrations being reached more reliably.
Overall, these results suggest that, when given in combination with artesunate, mefloquine should be administered during recovery. Splitting the dose into 15- and 10-mg/kg doses at least 8 h apart decreases the rate of vomiting of mefloquine, and this may further ensure that adequate levels of mefloquine are reached more reliably. The addition of a fatty meal does not appear to be warranted.
| |
ACKNOWLEDGMENTS |
|---|
We are grateful to the Karen staff of the Shoklo Malaria Research Unit for support and technical assistance. We thank Feiko ter Kuile for his help in setting up this study.
Mefloquine assays were supported by the U.S. Army Medical Research and Material Command. This study was part of the Wellcome-Mahidol University Oxford Tropical Medicine Research Programme, supported by the Wellcome Trust of Great Britain.
| |
FOOTNOTES |
|---|
* Corresponding author. Mailing address: Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand. Phone: (66 2) 246 0832. Fax: (66 2) 246 7795. E-mail: fnnjw{at}diamond.mahidol.ac.th.
Present address: Division of Communicable Diseases and
Immunology, Walter Reed Army Institute of Research, Washington, DC 20307.
| |
REFERENCES |
|---|
|
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
|
|---|
| 1. | Crevoisier, C., and J. Barre. 1992. Food increases the bioavailability of mefloquine, p. 268. In 13th International Congress for Tropical Medicine and Malaria. Pattaya, Thailand. |
| 2. | Crevoisier, C., J. Handschin, J. Barre, D. Roumenov, and C. Kleinbloesem. 1997. Food increases the bioavailability of mefloquine. Eur. J. Clin. Pharmacol. 53:135-139[Medline]. |
| 3. | Edstein, M. D., I. D. Lika, T. Chongsuphajaisiddhi, A. Sabcharoen, and H. K. Webster. 1991. Quantitation of fansimef components (mefloquine + sulfadoxine + pyrimethamine) in human plasma by two high performance liquid chromatographic methods. Ther. Drug Monit. 13:146-151[Medline]. |
| 4. | Franssen, G., B. Rouveix, J. Lebras, J. Bauchet, F. Verdier, C. Michon, and F. Ricaire. 1989. Divided-dose kinetics of mefloquine in man. Br. J. Clin. Pharmacol. 28:179-184[Medline]. |
| 5. | Karbwang, J., K. Na-Banchang, A. Thanavibul, D. J. Back, D. Bunnag, and T. Harinasuta. 1994. Pharmacokinetics of mefloquine alone or in combination with artesunate. Bull. W. H. O. 72:83-87[Medline]. |
| 6. | Karbwang, J., and N. J. White. 1990. Clinical pharmacokinetics of mefloquine. Clin. Pharmacokinet. 19:264-279[Medline]. |
| 7. | Looareesuwan, S., C. Viravan, S. Vanijanonta, P. Wilairatana, P. Suntharasamai, P. Charoenlarp, K. Arnold, D. Kyle, C. Canfield, and H. K. Webster. 1992. A randomised trial of mefloquine, artesunate, and artesunate followed by mefloquine in acute uncomplicated falciparum malaria. Lancet 339:821-824[Medline]. |
| 8. | Luxemburger, C., K. L. Thew, H. K. Webster, N. J. White, D. E. Kyle, L. Maelankirri, T. Chongsuphajaisiddhi, and F. Nosten. 1996. The epidemiology of malaria in a Karen population on the western border of Thailand. Trans. R. Soc. Trop. Med. Hyg. 90:105-111[Medline]. |
| 9. | Na Bangchang, K., J. Karbwang, V. Banmairuroi, D. Bunnag, and T. Harinasuta. 1993. Mefloquine monitoring in acute uncomplicated malaria treated with Fansimef and Lariam. Southeast Asian J. Trop. Med. Public Health 24:221-225[Medline]. |
| 10. | Nosten, F., F. ter Kuile, T. Chongsuphajaisiddhi, K. Na Bangchang, J. Karbwang, and N. J. White. 1991. Mefloquine pharmacokinetics and resistance in children with acute falciparum malaria. Br. J. Clin. Pharmacol. 31:556-559[Medline]. |
| 11. | Nosten, F., C. Luxemburger, F. O. ter Kuile, C. Woodrow, J. P. Eh, T. Chongsuphajaisiddhi, and N. J. White. 1994. Treatment of multi-drug resistant Plasmodium falciparum malaria with 3-day artesunate-mefloquine combination. J. Infect. Dis. 170:971-977[Medline]. |
| 12. | Price, R. N., F. Nosten, C. Luxemburger, A. Kham, A. Brockman, T. Chongsuphajaisiddhi, and N. J. White. 1995. Artesunate versus artemether in combination with mefloquine for the treatment of multidrug resistant falciparum malaria. Trans. R. Soc. Trop. Med. Hyg. 89:523-527[Medline]. |
| 13. | Price, R. N., F. Nosten, C. Luxemburger, F. O. ter Kuile, L. Paiphun, T. Chongsuphajaisiddhi, and N. J. White. 1996. Effects of artemisinin derivatives on malaria transmissibility. Lancet 347:1654-1658[Medline]. |
| 14. | Price, R. N., F. Nosten, C. Luxemburger, M. van Vugt, L. Phaipun, T. Chongsuphajaisiddhi, and N. J. White. 1997. Artesunate/mefloquine treatment of multi-drug resistant falciparum malaria. Trans. R. Soc. Trop. Med. Hyg. 91:574-577[Medline]. |
| 15. | Singhasivanon, V., T. Chongsuphajaisiddhi, A. Sabcharoen, P. Attanath, H. K. Webster, W. H. Wernsdorfer, U. K. Sheth, and I. D. Lika. 1992. Pharmacokinetics of mefloquine in children aged 6 to 24 months. Eur. J. Drug Metab. Pharmacokinet. 17:275-279[Medline]. |
| 16. | ter Kuile, F., C. Luxemburger, F. Nosten, L. Phaipun, T. Chongsuphajaisiddhi, and N. J. White. 1995. Predictors of mefloquine treatment failure: a prospective study in 1590 patients with uncomplicated falciparum malaria. Trans. R. Soc. Trop. Med. Hyg. 89:660-664[Medline]. |
| 17. | ter Kuile, F. O., F. Nosten, M. Thieren, C. Luxemburger, M. D. Edstein, T. Chongsuphajaisiddhi, L. Phaipun, H. K. Webster, and N. J. White. 1992. High dose mefloquine in the treatment of multidrug resistant falciparum malaria. J. Infect. Dis. 166:1393-1400[Medline]. |
| 18. | ter Kuile, F. O. 1994. Mefloquine, halofantrine and artesunate in the treatment of uncomplicated falciparum malaria in a multidrug resistant area. Doctoral thesis. University of Amsterdam, Amsterdam, The Netherlands. |
| 19. | ter Kuile, F. O., P. Teja-Isavatharm, M. D. Edstein, D. Keeratithakul, G. Dolan, F. Nosten, L. Phaipun, H. K. Webster, and N. J. White. 1994. Comparison of capillary whole blood, venous whole blood, and plasma concentrations of mefloquine, halofantrine, and desbutyl-halofantrine measured by high-performance liquid chromatography. Am. J. Trop. Med. Hyg. 51:778-784. |
| 20. | ter Kuile, F. O., F. Nosten, C. Luxemburger, D. Kyle, P. Teja-Isavatharm, L. Phaipun, R. N. Price, T. Chongsuphajaisiddhi, and N. J. White. 1995. Mefloquine treatment of acute falciparum malaria: a prospective study of non-serious adverse effects in 3673 patients. Bull. W. H. O. 73:631-642[Medline]. |
| 21. | White, N. J. 1997. Assessment of the pharmacodynamic properties of antimalarial drugs in vivo. Antimicrob. Agents Chemother. 41:1413-1422[Medline]. |
| 22. | White, N. J. 1998. Preventing antimalarial drug resistance through combinations. Drug Resist. Updates 1:3-9. |
| 23. | World Health Organization. 1990. Control of tropical diseases. Severe and complicated malaria. Trans R. Soc. Trop. Med. Hyg. 84(Suppl. 2):1-65. |
Antimicrobial Agents and Chemotherapy, February 1999, p. 341-346, Vol. 43, No. 2
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
This article has been cited by other articles:
-
Ramharter, M., Kurth, F. M., Belard, S., Bouyou-Akotet, M. K., Mamfoumbi, M. M., Agnandji, S. T., Missinou, M. A., Adegnika, A. A., Issifou, S., Cambon, N., Heidecker, J. L., Kombila, M., Kremsner, P. G.
(2007). Pharmacokinetics of two paediatric artesunate mefloquine drug formulations in the treatment of uncomplicated falciparum malaria in Gabon. J Antimicrob Chemother
60: 1091-1096
[Abstract] [Full Text] -
Humphreys, G. S., Merinopoulos, I., Ahmed, J., Whitty, C. J. M., Mutabingwa, T. K., Sutherland, C. J., Hallett, R. L.
(2007). Amodiaquine and Artemether-Lumefantrine Select Distinct Alleles of the Plasmodium falciparum mdr1 Gene in Tanzanian Children Treated for Uncomplicated Malaria. Antimicrob. Agents Chemother.
51: 991-997
[Abstract] [Full Text] -
Davis, T. M. E., England, M., Dunlop, A.-M., Page-Sharp, M., Cambon, N., Keller, T. G., Heidecker, J. L., Ilett, K. F.
(2007). Assessment of the Effect of Mefloquine on Artesunate Pharmacokinetics in Healthy Male Volunteers. Antimicrob. Agents Chemother.
51: 1099-1101
[Abstract] [Full Text] -
Ashley, E. A., Stepniewska, K., Lindegardh, N., McGready, R., Hutagalung, R., Hae, R., Singhasivanon, P., White, N. J., Nosten, F.
(2006). Population pharmacokinetic assessment of a new regimen of mefloquine used in combination treatment of uncomplicated falciparum malaria.. Antimicrob. Agents Chemother.
50: 2281-2285
[Abstract] [Full Text] -
Dow, G., Bauman, R., Caridha, D., Cabezas, M., Du, F., Gomez-Lobo, R., Park, M., Smith, K., Cannard, K.
(2006). Mefloquine Induces Dose-Related Neurological Effects in a Rat Model. Antimicrob. Agents Chemother.
50: 1045-1053
[Abstract] [Full Text] -
HUNG, L. Q., DE VRIES, P. J., BINH, T. Q., GIAO, P. T., NAM, N. V., HOLMAN, R., KAGER, P. A.
(2004). ARTESUNATE WITH MEFLOQUINE AT VARIOUS INTERVALS FOR NON-SEVERE PLASMODIUM FALCIPARUM MALARIA. Am J Trop Med Hyg
71: 160-166
[Abstract] [Full Text]
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Copyright © 2009 by the American Society for Microbiology. For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»