ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Apr. 2004, p. 1329–1334 Vol. 48, No.

4
0066-4804/04/$08.00⫹0 DOI: 10.1128/AAC.48.4.1329–1334.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Activities of Artesunate and Primaquine against Asexual- and

Sexual-Stage Parasites in Falciparum Malaria
Sasithon Pukrittayakamee,1 Kesinee Chotivanich,1 Arun Chantra,1 Ralf Clemens,1
Sornchai Looareesuwan,1 and Nicholas J. White1,2*
Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand,1 and
Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University,
Oxford, United Kingdom2
Received 15 September 2003/Returned for modification 5 November 2003/Accepted 9 December 2003

The activities of primaquine in combination with quinine or artesunate against asexual- and sexual-stage

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parasites were assessed in 176 adult Thai patients with uncomplicated Plasmodium falciparum malaria.
Patients were randomized to one of the six following 7-day oral treatment regimens: (i) quinine alone, (ii)
quinine with tetracycline, (iii) quinine with primaquine at 15 mg/day, (iv) quinine with primaquine at 30
mg/day, (v) artesunate alone, or (vi) artesunate with primaquine. Clinical recovery occurred in all patients.
There were no significant differences in fever clearance times, rates of P. falciparum reappearance, or recurrent
vivax malaria between the six treatment groups. Patients treated with artesunate alone or in combination with
primaquine had significantly shorter parasite clearance times (mean ⴞ standard deviation ⴝ 65 ⴞ 18 versus
79 ⴞ 21 h) and lower gametocyte carriage rates (40 versus 62.7%) than those treated with quinine (P < 0.007).
Primaquine did not affect the therapeutic response (P > 0.2). Gametocytemia was detected in 98 patients (56%
[22% before treatment and 34% after treatment]). Artesunate reduced the appearance of gametocytemia
(relative risk [95% confidence interval] ⴝ 0.34 [0.17 to 0.70]), whereas combinations containing primaquine
resulted in shorter gametocyte clearance times (medians of 66 versus 271 h for quinine groups and 73 versus
137 h for artesunate groups; P < 0.038). These results suggest that artesunate predominantly inhibits
gametocyte development whereas primaquine accelerates gametocyte clearance in P. falciparum malaria.

Multidrug-resistant Plasmodium falciparum malaria is of in- aim of the present study was to assess the value of adding
creasing public health concern in tropical countries. Combina- primaquine to artesunate or quinine compared with the stan-
tion regimens of two antimalarial drugs with different targets dard 7-day oral quinine-tetracycline regimen.
of action have been shown to delay the development of drug
resistance and to improve cure rates in falciparum malaria (12, MATERIALS AND METHODS
23). Combination treatments with quinine-tetracycline, artesu- Patients. This prospective study was conducted with adult male patients with
nate-mefloquine, or artemether-lumefantrine are efficacious acute uncomplicated P. falciparum malaria admitted to the Bangkok Hospital for
worldwide, providing cure rates of 90 to 100% (9, 17, 23). In Tropical Diseases, Bangkok, Thailand. Fully informed consent was obtained
children and pregnant women, for whom tetracyclines are con- from each subject. Exclusion criteria were patients with severe malaria (24) or
patients with primary mixed malaria infections. Patients who gave a history of
traindicated, quinine-clindamycin is an effective alternative to
drug hypersensitivity, who had taken any antimalarial drugs within the previous
quinine-tetracycline (10, 16), although adherence to the 7-day 48 h, or whose urine was positive in screening tests for sulfonamides (lignin test)
quinine regimens is often poor. Combination treatments which or 4-aminoquinolines (Wilson-Edeson test) were also excluded. Patients with
include an artemisinin derivative are efficacious in 3-day regi- G6PD deficiency were excluded from treatment with primaquine. The study was
mens and have the additional benefit of reducing gametocyte approved by the Ethics Committee of the Faculty of Tropical Medicine, Mahidol
University, Bangkok, Thailand.
carriage and thus reducing transmission potential (14, 13, 21, Management. After clinical assessment and confirmation of the diagnosis from
22). thick and thin blood smears, baseline blood samples were taken for routine
Primaquine, the only generally available 8-aminoquinoline hematology and biochemistry. Patients were randomized to 7-day treatment with
antimalarial drug, has been used for half a century as a hyp- one of the six following oral regimens: (i) quinine sulfate (Thai Government
Pharmaceutical Organization; 300 mg of salt/tablet) at 10 mg of salt/kg of body
nozoitocidal drug against Plasmodium vivax malaria, as a
weight three times a day for 7 days, (ii) quinine sulfate (10 mg of salt/kg three
causal prophylactic against all malaria species, and as a game- times a day) in combination with tetracycline (Thai Government Pharmaceutical
tocytocidal drug against P. falciparum malaria (3, 6). The Organization; 250 mg/tablet) at 4 mg/kg four times a day for 7 days, (iii) quinine
World Health Organization has recommended for some areas sulfate (10 mg of salt/kg three times a day) in combination with primaquine (Thai
that primaquine, in a single dose, be added to treatment reg- Government Pharmaceutical Organization; 15 mg of base/tablet) at 0.25 mg of
base/kg daily (adult dose, 15 mg of base/day) for 7 days, (iv) quinine sulfate (10
imens for falciparum malaria to reduce the transmissibility of mg of salt/kg three times a day) in combination with primaquine at 0.50 mg of
the infection (25). Primaquine at hypnozoitocidal doses is also base/kg daily for 7 days, (v) artesunate (Guilin No. 1 Factory, Guangxi, People’s
effective against asexual stages of P. vivax malaria (15, 18). The Republic of China; 50 mg of salt/tablet) at 3.3 mg/kg (adult dose, 200 mg) on the
first day and then 1.65 mg/kg (adult dose, 100 mg/day) for a further 6 days, and
(vi) artesunate (3.3 mg/kg on the first day and then 1.65 mg/kg for a further 6
* Corresponding author. Mailing address: Faculty of Tropical Med- days) in combination with primaquine at 0.50 mg of base/kg daily for 7 days.
icine, Mahidol University, 420/6 Rajvithi Rd., Bangkok 10400, Thailand. Oral acetaminophen (0.5 to 1 g every 4 h) was given for fever of ⬎38°C. Vital
Phone: 66-2-354-9172. Fax: 66-2-354-9169. E-mail: nickw@tropmedres signs were recorded every 4 h until resolution of fever and thereafter every 6 to
.ac. 12 h. The fever clearance time (FCT) was defined as the time taken for the body

1329
1330 PUKRITTAYAKAMEE ET AL. ANTIMICROB. AGENTS CHEMOTHER.

temperature to fall below 37.5°C and remain below this value for ⬎48 h. Patients

26,566 (800–350,173)

1,374 (108–12,521)
who were unable subsequently to stay in the hospital until clearance of both fever

Artesunate ⫹
and parasites were excluded from the study. Reappearance of infection was

primaquinec

32 (8–164)
63 ⫾ 18
24 ⫾ 8
assessed for patients who remained in Bangkok either in the hospital or at home

27
(i.e., outside the malaria transmission area) for at least 28 days. Patients with
recrudescences were retreated with a 7-day course of quinine (10 mg of salt/kg
three times a day) combined with tetracycline (4 mg/kg four times a day), and
those who had late vivax appearances (relapses) were subsequently treated with
the standard doses of chloroquine and primaquine.
Laboratory investigations. Parasite and gametocyte counts were measured
every 12 h in thin films or thick films until clearance and thereafter daily for 28
days. Parasite density was expressed as the number of parasites per microliter of

64,449 (321–569,722)ⴱ
blood, which was derived from number of parasites per 1,000 red blood cells in
a thin film stained with Giemsa or Field stain or calculated from the white cell

759 (59–5,801)
count and the number of parasites per 200 white blood cells in a thick film. The

Artesunate

69 ⫾ 19
34 (7–180)
23 ⫾ 8
parasite clearance time (PCT) was the interval from the start of antimalarial

23
TABLE 1. Demographic data and immediate therapeutic responses for patients with P. falciparum malaria
treatment until the asexual malaria parasite count fell below detectable levels in
a peripheral blood smear. The gametocyte clearance time (GCT) was the interval

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from the first detection to the last detection of gametocytes in a peripheral blood

Data are shown as mean ⫾ SD or median (range); the parasite count is the geometric mean. ⴱ, value is significantly different from that for the other groups.
smear. Gametocyte carriage was described as the total number of hours for each
patient during which gametocytemia was detectable; this differed slightly from
the GCT in that if gametocytemia was intermittent, then intervals without ga-
metocytes were subtracted from the GCT. Routine biochemical and hematolog-
ical tests were repeated on days 7, 14, 21, and 28 after admission.

17,637 (405–200,458)
Quinine ⫹ primaquinec
Statistical analysis. The quantitative data from each treatment group were

221 (⬍1–2,052)
compared by one-way analysis of variance with post hoc adjustment for multiple

Valuea for the following treatment group:

comparisons using the Bonferroni correction. Nonparametric data were com-

60 (7–154)
24 ⫾ 10

79 ⫾ 19
pared by the Kruskal-Wallis test. Categorical data were compared by Fisher’s

37
exact test or the chi-square test with Yates’ correction. The cumulative cure rates
were calculated by Kaplan-Meier survival analysis and compared by using the log
rank test. The gametocytemia rates were compared by stratified analysis with the
Mantel-Haenszel test. Gametocyte carriage was assessed by two-way analysis of
variance after square root transformation. All statistical analyses were performed
with the statistical computing package SPSS version 10.1 for Windows (SSPS
Inc.). Quinine ⫹ primaquineb

10,306 (168–229,094)

139 (1.3–4,270)
RESULTS

48 (8–152)
78 ⫾ 23
25 ⫾ 9
29

Patients. The study included 176 male patients with P. fal-

ciparum malaria, aged between 14 and 62 (mean ⫾ standard
deviation [SD] ⫽ 24 ⫾ 9) years. Patients were randomized to
one of six oral treatment regimens with quinine or artesunate
or combined therapy with primaquine or quinine-tetracycline
as detailed in Table 1. The majority of patients (n ⫽ 143; 81%)
came from the western border of Thailand, where the most
14,066 (630–231,104)
Quinine ⫹ tetracycline

176 (⬍1–8,895)

multidrug-resistant P. falciparum is prevalent. More than half

of the patients had a history of previous malaria infection (n ⫽
33 (8–117)
81 ⫾ 19
27 ⫾ 9

91; 52%). There were no significant differences in admission

30

parasite counts between the quinine groups (P ⫽ 0.33), but

patients who received artesunate alone had significantly higher
baseline parasitemias than those treated with artesunate-pri-
maquine (P ⫽ 0.021) (Table 1). Between the six treatment
groups, there were no significant differences in rates of previ-
ous malaria infection or other baseline laboratory data. Ele-
9,004 (234–116,054)

PRR48, parasite reduction ratio at 48 h.

vated serum bilirubin (total bilirubin of ⱖ3 mg/dl) was noted in

35 (⬍1–3,038)

30 patients from all groups. None of the studied patients had

80 ⫾ 26
Quinine

63 (7–152)
24 ⫾ 8

Primaquine was at 0.25 mg/day.

Primaquine was at 0.50 mg/day.

other complications, and all patients with hyperbilirubinemia

30

had normal bilirubin levels by day 14.

Clinical responses. Clinical recovery following treatment oc-
curred in all patients, and none developed severe malaria (Ta-
ble 1). The overall median (range) FCT was 46 (7 to 180) h and
was not significantly different between patients treated with the
artesunate regimens (33 [7 to 180] h) and those treated with
Parameter

the quinine regimens (50 [7 to 154 h]) (P ⫽ 0.10). Between the

Age (yr)

FCT (h)
PCT (h)
PRR48d
Parasite
count
(/␮l)

four quinine groups, the combined therapies yielded shorter

d
a
b
c

FCTs than quinine alone, but this was statistically significant

n
VOL. 48, 2004 SEXUAL- AND ASEXUAL-STAGE P. FALCIPARUM 1331

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FIG. 1. PCTs and GCTs in the six treatment groups of patients with P. falciparum malaria. The average values are shown as means (circles)
and medians (squares). Primaquine was given at 0.25 or 0.50 (*) mg/day.

only for the quinine-tetracycline group (P ⬍ 0.001). Patients layed appearance of vivax malaria. Among the six treatment
treated with artesunate either alone or in combination with groups, there were no significant differences in recrudescence
primaquine had similar FCTs (P ⫽ 0.92). None of the studied rates (P ⫽ 0.16) or rates of recurrent P. vivax infection (P ⫽
patients developed allergic rashes or other serious adverse 0.33). The overall cure rate (no subsequent appearance of P.
effects as monitored by clinical symptoms and laboratory data falciparum malaria) was 84%, and it ranged from 100% in the
(data not shown). quinine-tetracycline group to 72% in the quinine-primaquine
Parasitological responses. The overall mean PCT ⫾ SD was group. The cure rate in the quinine-tetracycline group was
75.4 ⫾ 21.5 h and was significantly shorter in the artesunate
groups (65 ⫾ 18 h) than in the quinine groups (79 ⫾ 21 h) (P
⬍ 0.001) (Fig. 1). There was no significant difference in PCT TABLE 2. Clinical outcomes for patients monitored up to 28 days
between the quinine subgroups (P ⫽ 0.93) or between the after starting treatment
artesunate subgroups (P ⫽ 0.26). The parasite reduction ratios No. (%) of patients with:
at 48 h (parasite count on admission/parasite count at 48 h)
Treatment group Completed Subsequent appearance of:
were significantly higher in the artesunate groups (median
follow-up P. falciparum P. vivax
[range] ⫽ 798 [59 to 12,521]) than in the quinine groups (136
[0.2 to 8,895]) (P ⬍ 0.001). There was no significant difference Quinine 25 4 (16) 2 (8)
in the 48-h parasite reduction ratio between the quinine sub- Quinine ⫹ tetracycline 22 0 4 (18)
groups (P ⫽ 0.19) or between the artesunate subgroups (P ⫽ Quinine ⫹ primaquine 18 5 (28) 3 (17)
(0.25 mg/day)
0.55). Quinine ⫹ primaquine 31 8 (7) 5 (16)
Clinical course. Overall, 142 (84%) of the recruited patients (0.50 mg/day)
completed at least 28 days of follow-up or remained in the Artesunate 21 2 (9.5) 5 (23.8)
hospital until appearance of vivax or falciparum malaria (Table Artesunate ⫹ primaquine 25 4 (16.0) 3 (12.0)
2). Of these 142 patients, 23 (16%) had subsequent reappear-
Total 142 23 (16.2) 22 (15.5)
ance of P. falciparum malaria and another 22 (16%) had de-
1332 PUKRITTAYAKAMEE ET AL. ANTIMICROB. AGENTS CHEMOTHER.

TABLE 3. Gametocytemia rates and GCTs in patients with P. falciparum malaria

No. (%) of patients with gametocyte appearances: Median GCT
Treatment group n
On admission After treatment Total (h) (range)

Quinine 30 7 (23.3) 10 (33.3) 17 (56.7) 216 (6–624)

Quinine ⫹ tetracycline 30 7 (23.3) 16 (53.3) 23 (76.7) 288 (6–662)
Quinine ⫹ primaquine (0.25 mg/day) 29 4 (13.8) 17 (58.6) 21 (72) 48 (6–324)
Quinine ⫹ primaquine (0.50 mg/day) 37 8 (21.6) 9 (24.3) 17 (45.9) 87 (5–207)
Artesunate 23 6 (26.1) 4 (17.4) 10 (43.5) 138 (12–264)
Artesunate ⫹ primaquine (0.50 mg/day) 27 7 (25.9) 3 (11.1) 10 (37.0) 73 (6–145)

Total 176 39 (22.2) 59 (33.5) 98 (55.7) 112 (5–662)

significantly higher than that in the other three quinine groups quinine-primaquine groups as one) in a two-way analysis of

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combined (P ⫽ 0.01). Between the six treatment groups, there variance, primaquine was associated with a significant short-
were no significant differences in the cumulative cure rates, ening of GCTs (P ⬍ 0.001) but artesunate was not (P ⫽ 0.25).
intervals to onset of recrudescent infection (mean ⫾ SD ⫽ 21 There were no significant correlations between GCT and PCT
⫾ 3 days), or intervals to onset of P. vivax infection (23 ⫾ 4 either within the quinine or artesunate groups or within the
days) (P ⱖ 0.12). three combined primaquine regimens (r ⱕ 0.20; P ⱖ 0.27).
Gametocytemia. Circulating gametocytes were detected in
98 patients (56%) from all groups (in 39 patients before treat- DISCUSSION
ment and in 59 after initiation of treatment) (Table 3). The
overall gametocyte detection rate on admission was 22% (n ⫽ The primary objective of antimalarial treatment is to cure the
39), and it was not significantly different between the six treat- infection, but an important secondary objective is to prevent
ment groups (P ⫽ 0.88). Following treatment, the emergence transmission. Primaquine has unique multiple-stage activity
of gametocytes was significantly less frequent in the artesunate against malaria parasites. In 1951, primaquine was selected as the
group than the quinine groups (14 versus 47%) (relative risk most active and least toxic hypnozoitocidal drug among the
[95% confidence interval] ⫽ 0.34 [0.17 to 0.70]; P ⬍ 0.001). 8-aminoquinoline series (5). The causal prophylactic and game-
The gametocyte detection rates after the different treatments tocytocidal effects of primaquine in P. falciparum were character-
were not significantly different between the two artesunate ized later (6). Since then primaquine has been recommended and
groups (P ⫽ 0.80). Among quinine-treated patients, the overall used as a transmission-blocking agent in falciparum malaria, al-
rate of gametocytemia was lower in the high-dose quinine- beit with little evidence that this policy has a significant effect on
primaquine group than in the normal-dose quinine-prima- the incidence of malaria at the community level. Primaquine is
quine group or the quinine-tetracycline group (P ⱕ 0.045). By considered to have insignificant activity against asexual stages of
stratified analysis, the addition of primaquine to the two other P. falciparum (20), although there have been uncertainties as to
drugs resulted in a significant reduction in gametocyte carriage whether or not this results from resistance. Primaquine does have
rates (odds ratio [95% confidence interval] ⫽ 0.42 [0.20 to significant activity against asexual blood stages in P. vivax malaria,
0.83]; P ⫽ 0.009). but the activity is weaker than those of other major antimalarial
Duration of gametocyte carriage. Transmission potential is drugs (15). A new long-acting 8-aminoquinoline, tafenoquine
related to the duration of gametocyte carriage. The average (19), has been shown in vitro to be more effective than prima-
gametocyte carriage of all studied patients was 92 person-
hours. The combined primaquine regimens were associated
with shorter overall gametocyte carriage times than the corre-
sponding regimens without primaquine (Fig. 2) (50 versus 229
person-hours for the quinine regimens [P ⫽ 0.004] and 27
versus 65 person-hours for the artesunate regimens [P ⫽
0.12]). The overall median (range) of GCTs of the 98 patients
with gametocytemia was 112 h (5 to 662 h). Combinations
containing primaquine resulted in significantly shorter GCTs
(median [range] ⫽ 66 [5 to 324] h versus 271 [6 to 662] h for
quinine groups and 73 [6 to 145] h versus 137 [12 to 264] h for
artesunate groups; P ⱕ 0.038). There were no significant dif-
ferences in GCTs between the two quinine-primaquine regi-
mens (normal- and high-dose primaquine) (median [range] ⫽
48 [6 to 324] h versus 87 [5 to 207] h; P ⫽ 0.45) or between the
nonprimaquine artesunate and quinine regimens (median
[range] ⫽ 138 [12 to 264] h versus 271 [6 to 662] h; P ⫽ 0.14). FIG. 2. Mean gametocyte carriage (in person-hours) in patients
When all of the groups were pooled (and considering the with P. falciparum malaria treated with artesunate or quinine in the
quinine and quinine-tetracycline groups as one and the two presence and absence of primaquine.
VOL. 48, 2004 SEXUAL- AND ASEXUAL-STAGE P. FALCIPARUM 1333

quine against asexual stages of malaria parasites and is still under quine is a potent gametocytocidal drug. In the present study,
investigation for the treatment and prophylaxis of falciparum ma- the overall GCTs did not correlate with PCTs, supporting the
laria infection. unrelated activities of primaquine against asexual and mature
In the present study, primaquine in combination with qui- gametocyte stages of P. falciparum. In summary, the results of
nine or artesunate had no additional significant effects on the the present study indicate that artesunate is a potent inhibitor
activity of either drug against asexual blood stages as assessed of gametocytogenesis but is inferior to primaquine in terms of
by FCT and PCT. This confirms earlier in vivo studies indicat- gametocyte clearance. In reducing transmission potential, pri-
ing a lack of activity against blood stages in falciparum malaria maquine had a greater effect when added to quinine than to
(1). Only the quinine-tetracycline regimen gave a 100% cure artesunate. Of all the studied regimens, the artesunate-prima-
rate, which is significantly better than those of the other qui- quine combination gave the lowest rate of gametocyte detec-
nine-containing regimens. In areas where malaria is endemic, tion and the shortest duration of gametocytemia.
mixed infection with P. falciparum and P. vivax is common, and
mixed infection is found in over 30% of patients coming from ACKNOWLEDGMENT
the border areas of Thailand where malaria transmission is This study was part of the Wellcome Trust-Mahidol University Ox-
high (8, 15, 18). However, 7-day regimens of primaquine as ford Tropical Medicine Research Programme funded by the Wellcome

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used here are probably not sufficient to eradicate the hypno- Trust of Great Britain.
zoites of P. vivax (2).
REFERENCES
Artemisinin derivatives are the most active of the antima-
1. Arnold, J., A. S. Alving, R. S. Hockwald, C. B. Clayman, R. J. Dern, E.
larial drugs against the asexual blood stages of malaria par- Beutler, C. L. Flanagan, and G. M. Jeffery. 1955. The antimalarial action of
asites. They also reduce gametocyte carriage in P. falcipa- primaquine against the blood and tissue stages of falciparum malaria (Pan-
rum infections (4, 13, 14, 22). In recent field studies in ama, P-F-6 strain). J. Lab. Clin. Med. 46:391–397.
2. Baird, J. K., and K. H. Rieckmann. 2003. Can primaquine therapy for vivax
Thailand, this effect has been greater than that with prima- malaria be improved? Trends Parasitol. 19:115–120.
quine (21). In the present study, artesunate with or without 3. Bunnag, D., T. Harinasuta, S. Pinichpongse, and P. Suntharasamai. 1980.
Effect of primaquine on gametocytes of Plasmodium falciparum in Thailand.
primaquine was more rapidly acting than the quinine regi- Lancet ii:91.12.
mens as assessed by PCTs, although recrudescence rates and 4. Chen, P. Q., G. Q. Li, X. B. Guo, K. R. He, Y. X. Fu, L. C. Fu, and Y. Z. Song.
rates of cryptic vivax infections in the artesunate groups 1994. The infectivity of gametocytes of Plasmodium falciparum from patients
treated with artemisinin. Chin. Med. J. 107:709–711.
were not significantly different from those in the quinine 5. Cooper, W. C., A. V. Myatt, Z. T. Hernande, G. M. Jeffery, and G. R.
groups. Patients treated with artesunate alone had signifi- Coatney. 1953. Studies in human malaria. XXXI. Comparison of prima-
cantly lower gametocyte carrier rates (44%) than those quine, isopentaquine, SN-3883, and pamaquine as curative agent against
Chesson strain vivax malaria. Am. J. Trop. Med. Hyg. 2:949–957.
treated with the other nonprimaquine regimens (57% for 6. Grewal, R. S. 1981. Pharmacology of 8-aminoquinolines. Bull. W. H. O.
quinine and 77% for quinine-tetracycline). Artesunate ef- 59:397–406.
7. Kumar, N., and H. Zheng. 1990. Stage-specific gametocytocidal effect in vitro
fectively prevented the appearance of gametocytemia. The of the antimalaria drug qinghaosu on Plasmodium falciparum. Parasitol. Res.
average GCT with artesunate alone (median ⫽ 138 h) was 76:214–218.
also shorter than that with quinine or quinine-tetracycline 8. Looareesuwan, S., N. J. White, S. Chittamas, D. Bunnag, and T. Harinasuta.
1987. High rate of Plasmodium vivax relapse following treatment of falcipa-
(216 and 288 h, respectively), but there was considerable rum malaria in Thailand. Lancet ii:1052–1055.
variation and these differences were not statistically signif- 9. Looareesuwan, S., P. Wilairatana, S. Vanijanonta, D. Kyle, and K. Webster.
icant. The mechanism whereby artemisinins reduce P. falci- 1992. Efficacy of quinine-tetracycline for acute uncomplicated falciparum
malaria in Thailand. Lancet i:367–370.
parum gametocytemia in vivo (4, 13, 14, 21, 22) and in vitro 10. McGready, R., T. Cho, Samuel, L. Villegas, A. Brockman, M. van Vugt, S.
(7, 11) has not been fully elucidated. The artemisinin deriv- Looareesuwan, N. J. White, and F. Nosten. 2001. Randomized comparison of
quinine-clindamycin versus artesunate in the treatment of falciparum ma-
atives could act in three linked ways: they may possess laria in pregnancy. Trans. R. Soc. Trop. Med. Hyg. 95:651–656.
gametocytocidal effects against more mature sexual stages, 11. Mehra, N., and V. K. Bhasin. 1993. In vitro gametocytocidal activity of
as in the case of primaquine; they may directly inhibit ga- artemisinin and its derivatives on Plasmodium falciparum. Jpn. J. Med. Sci.
Biol. 46:37–43.
metocyte development by preventing development of the 12. Nosten, F., M. van Vugt, R. Price, C. Luxemburger, K. L. Thway, A. Brock-
younger sequestered stages (stages I to III); or they may man, R. McGready, F. ter Kuile, S. Looareesuwan, and N. J. White. 2000.
simply prevent gametocytogenesis through rapid elimination Effects of artesunate-mefloquine combination on incidence of Plasmodium
falciparum malaria and mefloquine resistance in western Thailand: a pro-
of the asexual stages. These results confirm that artesunate spective study. Lancet 356:297–302.
is more effective than quinine in the prevention of gameto- 13. Nosten, F., T. T. Hien, and N. J. White. 1998. Use of artemisinin derivatives
for the control of malaria. Med. Trop. 58(Suppl. 3):45–49.
cyte development. 14. Price, R. N., F. Nosten, C. Luxemburger, F. O. ter Kuile, L. Paiphun, T.
Primaquine at all studied doses showed significant gameto- Chongsuphajaisiddhi, and N. J. White. 1996. Effects of artemisinin deriva-
cytocidal effects, in that gametocyte clearance was accelerated, tives on malaria transmissibility. Lancet 347:1654–1658.
15. Pukrittayakamee, S., A. Chantra, J. A. Simpson, S. Vanijanonta, R. Clem-
but primaquine did not prevent gametocyte development, and ens, S. Looareesuwan, and N. J. White. 2000. Therapeutic responses to
there was no evidence of synergy with quinine or artesunate different antimalarial drugs in vivax malaria. Antimicrob. Agents Che-
against asexual stages of P. falciparum. The incidences of ga- mother. 44:1680–1685.
16. Pukrittayakamee, S., A. Chantra, S. Vanijanonta, R. Clemens, S. Looareesu-
metocytemia in patients treated with combined primaquine wan, and N. J. White. 2000. Therapeutic responses to quinine and clinda-
regimens were not significantly different from those for the mycin in multidrug-resistant falciparum malaria. Antimicrob. Agents Che-
mother. 44:2395–2398.
nonprimaquine regimens in either the quinine or artesunate 17. Pukrittayakamee, S., and N. J. White. 2001. Combination therapy: making
groups, but combinations including primaquine shortened the the best use of existing drugs. Pharm. News 8:21–25.
duration of gametocyte carriage two- to sixfold compared to 18. Pukrittayakamee, S., S. Vanijanonta, A. Chantra, R. Clemens, and N. J.
White. 1994. Blood stage antimalarial efficacy of primaquine in Plasmodium
the corresponding regimens without primaquine (P ⱕ 0.038). vivax malaria. J. Infect. Dis. 169:932–935.
This corresponds with earlier studies and indicates that prima- 19. Ramharter, M., H. Noedl, K. Thimasarn, G. Wiedermann, G. Wernsdorfer,
1334 PUKRITTAYAKAMEE ET AL. ANTIMICROB. AGENTS CHEMOTHER.

and W. H. Wernsdorfer. 2002. In vitro activity of tafenoquine alone and in M. Pinder, T. Doherty, C. Sutherland, G. Walraven, and P. Milligan. 2001.
combination with artemisinin against Plasmodium falciparum. Am. J. Trop. Artesunate reduces but does not prevent posttreatment transmission of
Med. Hyg. 67:39–43. Plasmodium falciparum to Anopheles gambiae. J. Infect. Dis. 183:1254–1259.
20. Schmidt, L. H. 1969. Chemotherapy of the drug-resistant malarias. Annu. 23. White, N. J., F. Nosten, S. Looareesuwan, W. M. Watkins, K. Marsh, R. W.
Rev. Microbiol. 23:427–454. Snow, G. Kokwaro, J. Ouima, T. T. Hien, M. E. Molyneux, T. E. Taylor, C. I.
21. Suputtamongkol, Y., S. Chindarat, S. Silpasakorn, S. Chaikachonpatd, K. Newbold, T. K. Ruebush, M. Danis, B. M. Greenwood, R. M. Anderson, and
Lim, K. Chanthapakajee, N. Kaewkaukul, and V. Thamlikitkul. 2003. The P. Olliaro. 1999. Averting a malaria disaster. Lancet 353:1965–1967.
efficacy of combined mefloquine-artesunate versus mefloquine-primaquine 24. World Health Organization. 1990. Severe and complicated malaria. Trans.
on subsequent development of Plasmodium falciparum gametocytemia. R. Soc. Trop. Med. Hyg. 84(Suppl. 2):1–65.
Am. J. Trop. Med. Hyg. 68:620–623. 25. World Health Organization. 1994. W. H. O./MAL/94.1070. World Health
22. Targett, G., C. Drakeley, M. Jawara, L. von Seidlein, R. Coleman, J. Deen, Organization, Geneva, Switzerland.

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