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Antimicrobial Agents and Chemotherapy, May 2007, p. 1694-1699, Vol. 51, No. 5
0066-4804/07/$08.00+0     doi:10.1128/AAC.00077-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Activities of Amodiaquine, Artesunate, and Artesunate-Amodiaquine against Asexual- and Sexual-Stage Parasites in Falciparum Malaria in Children{triangledown}

Akintunde Sowunmi,* Tunde Balogun, Grace O. Gbotosho, Christian T. Happi, Ahmed A. Adedeji, and Fatai A. Fehintola

Department of Pharmacology and Therapeutics and Institute for Medical Research and Training, University of Ibadan, Ibadan, Nigeria

Received 18 January 2007/ Returned for modification 11 February 2007/ Accepted 18 February 2007


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The activities of amodiaquine, artesunate, and artesunate-amodiaquine against asexual- and sexual-stage parasites were evaluated in 360 Nigerian children with uncomplicated Plasmodium falciparum malaria randomized to the standard dose regimens of the three drugs/combination. Clinical recovery from illness occurred in all children. There were no significant differences in fever clearance times. Patients treated with artesunate or artesunate-amodiaquine had significantly shorter parasite clearance times (1.4 ± 0.5 days or 1.4 ± 0.6 days versus 3.2 ± 2.3 days, P = 0.0001) and lower gametocyte carriage rates (3.3 or 1.7% versus 11.7%, P = 0.001) than those treated with amodiaquine alone. Gametocytemia was detected in 62 patients (11.7% before treatment and 5.6% after treatment). The pretreatment gametocyte sex ratio, which was female biased, increased significantly during the course of treatment with amodiaquine but not with artesunate and artesunate-amodiaquine. These results suggest that artesunate and artesunate-amodiaquine reduce gametocyte carriage and may reduce transmissibility in P. falciparum malaria by accelerating asexual clearance and influencing gametocyte sex ratio.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Multidrug resistance in Plasmodium falciparum is an increasing public health problem in much of sub-Saharan Africa where malaria is endemic. As part of efforts to combat drug resistance, the World Health Organization recommended the use of artemisinin-based combination antimalarial therapy in this and other areas of endemicity (20). Combination regimens which include artesunate clear parasitemia rapidly and may reduce gametocyte transmissibility in areas of low transmission (11, 12).

In areas of endemicity of West Africa, up to 14 to 17% of the children with acute, uncomplicated falciparum malaria may carry gametocytes in their peripheral blood at presentation (16-18). These carriage rates may be increased after treatment with antimalarial monotherapy (17). In these areas, one of the most frequently used artemisinin-based combination antimalarial therapies is artesunate-amodiaquine, the individual components of which are readily available and readily used uncombined. However, the effects of these combination treatments on gametocyte carriage in areas of intense transmission in Africa have been less frequently evaluated. In addition, the effects of these combinations and those of their individual components on P. falciparum gametocyte sex ratio are unknown.

The aim of the present study was to evaluate the effects of adding artesunate to amodiaquine compared to the use of amodiaquine or artesunate alone on asexual parasites, gametocyte carriage, and sex ratio in children suffering from acute uncomplicated falciparum malaria.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients. The study was conducted in children aged <11 years with acute uncomplicated P. falciparum malaria in Ibadan, an area where malaria is endemic (14), in southwestern Nigeria. Fully informed consent was obtained from the parents or guardians of each child. The inclusion criteria were as follows: the presence of fever or history of fever in the 24 to 48 h preceding presentation, a pure P falciparum parasitemia level of >2,000 asexual forms/µl, the absence of other concomitant illness, no history of antimalarial use in the 2 weeks preceding presentation, and negative urine tests for antimalarial drugs (Dill-Glazko and lignin). Patients with severe malaria (19), severe malnutrition, serious underlying diseases (renal, cardiac, or hepatic), and known allergies to study drugs were excluded from the study. The study protocol was approved by the Ethics Committee of the Ministry of Health, Ibadan, Nigeria.

Drug management. After clinical assessment, blood was obtained for hematocrit determination and for quantification of asexual and sexual parasitemia. Patients were randomized to (i) a 3-day regimen of amodiaquine base at 10 m/kg daily (day 0 to 2), (ii) artesunate at 4 mg/kg daily for 7 days (day 0 to 6), and (iii) and a 3-day combination of artesunate and amodiaquine at the doses given for patient groups i and ii above. All drugs were given orally, and all patients waited for at least 3 h after to ensure the drug was not vomited. If it was, the patient was excluded form the study.

Oral paracetamol (acetaminophen) at 10 to 15 mg/kg every 6 h was given for 12 to 24 h if the body temperature was >38°C. Patients were seen daily, at approximately the same time of the day, for the first 5 days (days 0 to 4) and then daily on days 7, 14, 21, and 28 and when necessary on day 35 after treatment had begun. At each visit, patients were assessed clinically, and thick and thin blood smears were obtained for quantification of the parasitemia.

The fever clearance time was defined as the time taken for the body temperature to fall to below 37.5°C and remain below this value for >48 h.

Laboratory investigations. Asexual parasite and gametocyte counts were measured daily for the first 5 days (days 0 to 4) and thereafter on days 7, 14, 21, and 28. Quantification in Giemsa-stained thick blood films was done against 500 leukocytes in the case of asexual parasitemia and against 1,000 leukocytes in the case of gametocytes, and from this figure the parasite density was calculated assuming a leukocyte count of 6,000/µl of blood. Parasite clearance time (PCT) was the time interval from the start of antimalarial treatment until the asexual parasite count fell below the detectable levels in a peripheral blood smear. Capillary blood, collected before and during follow-up, was used to measure packed cell volume (PCV). PCVs were measured by using a microhematocrit tube and microcentrifuge (Hawksley, Lancing, United Kingdom). Routine hematocrit was done on days 0, 3, 7, 14, 21 and 28.

Determination of gametocyte sex ratio. Gametocyte sex determination was based on the following criteria (4, 13): males (microgametocytes) are smaller than females (macrogametocytes), the nucleus is larger in males than females, the ends of the cells are rounder in males and angular in females, with Giemsa the cytoplasm stains purple in males and deep blue in females, and the granules of malaria pigment are centrally located females and more widely scattered in males. The sex ratio was defined as the proportion of gametocytes in peripheral blood that were male (10). Gametocytes were sexed if the gametocyte density was ≥15/µl of blood.

For each patient, gametocyte densities were plotted against time. The areas under the curve of gametocytemia versus time (AUCgm) were determined by a noncompartmental method using a computer program Turbo Ken (Clinical Pharmacology Group, University of Southampton, Southampton, United Kingdom, through the courtesy of A. G. Renwick) as previously described (16). Briefly AUCgms were obtained, using the linear trapezoidal rule, from time zero (0 h, day 0) to the time of gametocyte clearance or if, there was no clearance, till 672 h (day 28). The final gametocytemia level at the time of clearance was assumed to be 0.001 sexual forms (sf)/µl of blood (a level assumed to be below microscopic detection).

Data analysis. Data were analyzed by using version 6 of the Epi-Info software (2) and the statistical program SPSS for Windows version 10.01 (3). Variables considered in the analysis were related to the densities of P. falciparum gametocytes and trophozoites. Proportions were compared by calculating {chi}2 with Yates' correction or by the Fisher exact or by Mantel Haenszel tests. Normally distributed, continuous data were compared by using the Student t tests and analysis of variance. The data not conforming to a normal distribution were compared by the Mann-Whitney U tests and Kruskal-Wallis tests (or by the Wilcoxon ranked-sum test). Kaplan-Meier plots are also presented to compare gametocyte carriage rates after treatment in subjects who were gametocytemic at presentation. Differences in survival time were assessed by inspection of Kaplan-Meier curves and log-rank tests. All tests of significance were two tailed. P values of ≤0.05 were taken to indicate significant differences. The data were double entered serially using the patients' codes and were only analyzed at the end of the study.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patients. Between November 2005 and October 2006, 360 children (178 males, 182 females) with P. falciparum malaria, aged between 0.5 and <11 years (mean ± the standard deviation [SD] = 6.3 ± 2.6 years) were enrolled. A total of 120 patients were randomized to each of the three treatment arms (Table 1). There were no significant differences in the enrollment characteristics between all of the three treatment groups, but children enrolled in the artesunate-amodiaquine group weighed significantly more than those enrolled in the amodiaquine- and artesunate-only groups.


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  		TABLE 1. Demographic data and immediate therapeutic response for children with P. falciparum malaria

 
Clinical responses. All children responded promptly to treatment, and none developed severe malaria. The overall median (range) fever clearance time was 1.0 day (range, 1 to 3 days) and was not significantly different between the three treatment groups. None of the studied children had significant adverse effects as monitored by clinical symptoms (data not shown), but three and four children treated with amodiaquine, and artesunate-amodiaquine, respectively, reported pruritus that interfered with sleep.

Parasitological responses. The overall mean PCT ± the SD was 1.9 ± 1.6 days and was significantly shorter in the artesunate (1.4 ± 0.5 days) and artesunate-amodiaquine (1.4 ± 0.6 days) groups than in the amodiaquine alone (3.0 ± 2.3 days) group (P = 0.0001) (Table 1). There was no significant difference in mean PCT between the artesunate and artesunate-amodiaquine groups (P = 0.16). The parasite reduction ratios (PRRs) (parasite count at enrollment/parasite count at day 2) were significantly higher in the artesunate alone (median, 99.4 x 103; range, 500 to 666,000) and artesunate-amodiaquine (median, 74; range, 3 to 827,200) groups than in the amodiaquine alone (median, 52.6; range, 1 to 1,668,000) group (P = 0.03) (Table 1). There was no significant difference in PRR between the artesunate and artesunate-amodiaquine groups (P = 0.119).

Clinical course. Overall, 351 (97.5%) of the enrolled children completed at least 21 days of follow-up (Table 2). Of these 351, 25 had subsequent reappearance of P. falciparum. Children treated with artesunate had a significantly higher rate of reappearance (20 of 111) than children treated with amodiaquine alone (4 of 120) and artesunate-amodiaquine (1 of 120) ({chi}2 = 29.7, df = 2, P = 0.0000003). There was no significant difference in the rate of reappearance between the amodiaquine alone and the artesunate-amodiaquine groups (P = 0.36). Overall, the PCR-uncorrected cure rate was 92.8%, and it ranged from 81.9% in the artesunate group to 96.7% in the amodiaquine group to 99.2% in the artesunate-amodiaquine group. Overall, after clearance of parasitemia, the interval to reappearance was 17.6 ± 4.8 days (mean ± the SD) and was similar in the amodiaquine alone (14.0 ± 0.0 days) and artesunate alone (18.6 ± 4.3 days) alone groups. In artesunate-treated children, the parasitemia at enrollment in those in whom parasitemia reappeared within 2 weeks of treatment (geometric mean, 42,482; range, 42,111 to 42,857; n = 2) was similar to parasitemia in those in whom parasitemia appeared between 16 and 21 days (geometric mean, 48,791; range, 1,300 to 597,600; n = 10) (P = 0.55). Gametocytes were detected at the time of reappearance of parasitemia in one child each from the artesunate and amodiaquine alone groups but not from any child in the artesunate-amodiaquine group.


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  		TABLE 2. Clinical outcome and time to reappearance of parasitemia for children monitored for 21 days or more after starting treatment

 
Gametocytemia. Gametocytes were detected in peripheral blood in 62 children (17.2%) from all three groups (in 42 children before treatment and in 20 children after initiation of treatment) (Table 3). The overall detection rate at enrollment was 11.7% (n = 42), and it was not significantly different between the three treatment groups (P = 0.72). After treatment, the emergence of gametocytes was significantly less frequent in the artesunate and artesunate-amodiaquine groups than in the amodiaquine alone group (4 and 2 children, respectively, versus 14 children) (P = 0.001). The gametocyte detection rates after treatment with artesunate and artesunate-amodiaquine were not significantly different (P = 0.6).


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  		TABLE 3. Gametocyte carriage in children with P. falciparum malaria before and after treatment with amodiaquine, artesunate, or artesunate-amodiaquine

 
Duration of gametocyte carriage in children with gametocytemia at enrollment. The probability of a mosquito infectivity after a blood meal is related to gametocyte density and the duration of carriage by the host. Figure 1 is a Kaplan-Meier plot (survival curve) of the cumulative probability of remaining gametocyte-free after treatment with amodiaquine, artesunate, and artesunate-amodiaquine in children who were gametocytemic at presentation. This probability was highest with artesunate alone and lowest with amodiaquine alone. Thus, compared to amodiaquine alone, children treated with artesunate alone had a significantly higher propensity to remain gametocyte free (log-rank statistic = 4.97, P = 0.02). Compared to artesunate-amodiaquine-treated children, the probability of remaining gametocyte-free in children treated with artesunate alone was not significantly different (log-rank statistic = 3.16, P = 0.07). Comparison of this probability between children treated with amodiaquine alone and those treated with artesunate-amodiaquine was also not significantly different (log-rank statistic = 0.02, P = 0.88).


Figure 1
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  		FIG. 1. Kaplan-Meier plot (survival curve) of cumulative probability of remaining gametocyte-free after treatment with amodiaquine (solid line), artesunate (thick broken line), or amodiaquine-artesunate (thin broken line) for children who were gametocytemic at enrollment.

 
Temporal changes in gametocyte sex ratio. In the 42 children who were gametocytemic at presentation, totals of 1,440, 1,068, 1152, 1,554, 264, 1,254, 276, 30, and 582 gametocytes were counted on days 0, 1, 2, 3, 4, 7, 14, 21, and 28, respectively. Of these, 1,158, 858, 954, 1494, 240, 1,152, 270, 30, and 420 gametocytes could be sexed on days 0, 1, 2, 3, 4, 7, 14, 21, and 28, respectively. The corresponding numbers of patients in whom the gametocytes were counted were 42, 24, 23, 32, 8, 25, 11, 2, and 2, respectively.

A male-biased sex ratio may increase the chance of transmission. After treatment, in amodiaquine-treated children, the gametocyte sex ratio was significantly more male biased on days 3 and 7 than for those treated with artesunate or artesunate-amodiaquine (Table 4). After treatment with amodiaquine, the gametocyte sex ratio increased significantly over the course of the infection and up to 14 days after start of treatment in children who were gametocytemic at enrollment (Fig. 2 and Table 4): 24% of the gametocytes were male at day 0, 60% were male at day 3, and 63% were male at day 7 ({chi}2 = 4.5, P = 0.03). In contrast, there was no significant increase in gametocyte sex ratio in children treated with artesunate alone (11% of the gametocytes were male at day 0, 16% were male at day 3, and 0% were male at day 7 [{chi}2 = 1.1, P = 0.27]) and artesunate-amodiaquine (6% of the gametocytes were male at day 0, 9% were male at day 3, and 7% were male at day 7 [{chi}2 = 0.29, P = 0.58]) (Table 4). The increase in sex ratio in amodiaquine-treated children was associated with an increase in mean gametocyte density and an initial reduction followed by a rise in packed cell volume. In contrast, a minimal increase in sex ratio in children treated with artesunate and artesunate-amodiaquine was accompanied by a decrease in gametocyte density and an initial reduction followed by a rise in packed cell volume (Fig. 2).


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  		TABLE 4. Variations in mean gametocyte sex ratio with time after treatment with amodiaquine, artesunate, or artesunate-amodiaquine

 

Figure 2
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  		FIG. 2. Variations in the packed cell volume, density of gametocytes, and gametocyte sex ratio over the course of treatment of malaria infections with amodiaquine (solid line), artesunate (thick broken line), or amodiaquine-artesunate (thin broken line) for children with acute P. falciparum infection.

 
AUCgms were determined only in patients who carried gametocytes at presentation, that is, the 16, 12, and 14 patients who were treated with amodiaquine, artesunate, and artesunate-amodiaquine, respectively. The AUCgms were 492 ± 362 (mean ± standard error of the mean; range, 4.4 to 1,449.6 sexual forms/µl.d), 126.7 ± 32.3 (range, 4.4 to 111.8 sexual forms/µl.d), and 167.5 ± 78.8 (range, 4.4 to 295.1 sexual forms/µl.d) in the amodiaquine, artesunate, and artesunate-amodiaquine treatment groups, respectively. The mean AUCgm for amodiaquine was four- and threefold higher than those for artesunate and artesunate-amodiaquine, respectively.


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
For control programs, the ideal antimalarial or combination antimalarial should rapidly clear asexual parasitemia and its associated clinical symptoms and signs within the shortest possible time, in addition to preventing transmissibility and reducing the chances of development of drug resistance. We have documented the effects of using amodiaquine, artesunate, or both on asexual- and sexual-stage parasites in a cohort of children with uncomplicated falciparum malaria in an area of endemicity. The study was based on a follow-up period of 28 days. The results showed that amodiaquine, artesunate, or a combination of both rapidly cleared asexual parasitemia without producing undue deleterious effects. Artesunate alone or in combination with amodiaquine was more rapidly acting than amodiaquine alone, as assessed by the parasite clearance times and parasite reduction ratios. These findings support previous reports from the same region of Africa (1). Although the cure rates from the three treatment groups were similar on day 28, a longer period of follow-up, in addition to molecular genotyping to distinguish recrudescence from reinfection, would have made it possible to determine the true cure rates.

In the present study, parasites reappeared in peripheral blood in 7% of the children by day 21 of the observation period. The rate of reappearance was significantly higher when artesunate was used alone than with its combination with amodiaquine or the use of amodiaquine alone. A striking feature of the patients with a reappearance of parasitemia in the artesunate-treated children was that reappearance within 2 weeks was not associated with higher parasite burden at enrollment compared to the parasite burden at enrollment in children in whom there was a reappearance after 2 weeks. Since recrudescence after artesunate monotherapy is often associated with heavy parasite burden at enrollment (7), we have no clear explanation for our observation. Although parasite genotyping was not done before and after reappearance, it is likely that the early reappearance was due to recrudescence and the late reappearance was due to reinfection. In this regard, molecular genotyping would have been of great value in distinguishing recrudescence from reinfection.

Overall, children treated with artesunate or its combination with amodiaquine had significantly lower gametocyte carriage rates than those treated with amodiaquine alone. In addition, the cumulative probability of remaining gametocyte-free in those who were gametocytemic at enrollment was highest in children treated with artesunate alone. The latter would suggest that the artemisinin derivatives have significant effects on gametocyte clearance, as previously suggested by others (12). However, we have no explanation for the finding that the use of artesunate-amodiaquine was not better than the use of amodiaquine alone, although the AUCgm for amodiaquine was threefold higher than the AUCgm for artesunate-amodiaquine. The mechanisms by which the artemisinin derivatives clear gametocytemia have not been fully elucidated. Our results suggest that artesunate may not rapidly clear mature gametocytes from the peripheral circulation; rather, the drug, by rapidly clearing asexual parasites, prevents the progression of committed asexual parasites to gametocytes.

Our study evaluated the effects of treatment with amodiaquine, artesunate, or artesunate plus amodiaquine on the gametocyte sex ratio in children who were gametocytemic at presentation. To our knowledge, this is the first study of the effects of these drugs on the gametocyte sex ratio in African children. Overall, the gametocyte sex ratio was female-biased at enrollment in keeping with that of the natural population (15). In children treated with amodiaquine the gametocyte sex ratio increased over the course of treatment in the presence of increased gametocyte density and despite clearance of asexual parasitemia by day 3 of treatment, suggesting that the drug may have some effect on the gametocyte sex ratio. However, the presence of anemia, a factor that enhances gametocyte maleness (8, 9) in these children, suggests that there may be other contributory factors to the maleness observed. This interaction requires further elucidation. In contrast, despite the presence of anemia, and the decreased gametocyte density, factors that promote gametocyte maleness, the gametocyte sex ratio was still female-biased in the children treated with artesunate or artesunate-amodiaquine. The reasons for our observations are unclear. The artemisinin derivatives, compared to the other antimalarial drugs such as, for example, quinine, are less likely to provoke anemia when asexual parasites are eliminated from the infected red blood cells (5). In addition, rapid clearance of asexual parasites by artesunate may have blunted the cues for gametocyte maleness that normally follow the course of infection (8). An unexplored possibility for the artesunate-related female-biased gametocyte sex ratio is that the artemisinin derivatives may selectively kill male gametocytes. Whatever their modes of influence on the gametocyte sex ratio, carefully designed studies, are urgently required to delineate the influence of the artemisinin derivatives on the sex ratio of Plasmodium spp.; for example, laboratory mosquito feeding studies are necessary to assess transmissibility. Thus, in addition to reducing gametocyte carriage and infectiousness to mosquitoes (6), artesunate may reduce transmissibility, possibly by influencing the gametocyte sex ratio after treatment.


   ACKNOWLEDGMENTS
 
We are grateful to our clinic staff and especially to Moji Amao and Adeola Alabi for assistance with running the study.


   FOOTNOTES
 
* Corresponding author. Mailing address: Department of Clinical Pharmacology, University College Hospital, Ibadan, Nigeria. Phone: 234-2-2412101. Fax: 234-2-2411843. E-mail: akinsowunmi{at}hotmail.com Back

{triangledown} Published ahead of print on 26 February 2007. Back


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Adjuik, M., P. Agnamey, A. Babiker, S. Borrmann, P. Brasseur, M. Cisse, F. Cobelens, S. Diallo, J. F. Faucher, P. Garner, S. Gikunda, P. G. Kremsner, S. Krishna, B. Lell, M. Loolpapit, P.-B. Matsiegui, M. A. Missinou, J. Mwanza, F. Ntoumi, P. Olliaro, P. Osimbo, P. Rezbach, E. Some, and W. R. J. Taylor. 2002. Amodiaquine-artesunate versus amodiaquine for uncomplicated Plasmodium falciparum malaria in African children: a randomized, multicentre trial. Lancet 359:1365-1372.[CrossRef][Medline]
  2. Anonymous. 1994. Epi-Info version 6: a word processing data base and statistics program for public health on IBM-compatible microcomputers. Centers for Disease Control and Prevention, Atlanta, GA.
  3. Anonymous. 1999. SPSS for Windows, release 10.01 (standard version). SPSS, Inc., Chicago, IL.
  4. Carter, R., and P. M. Graves. 1988. Gametocytes, p. 253-303. In W. H. Wernsdorfer and I. McGregor (ed.), Malaria: principles and practice of malariology, vol. I. Churchill Livingstone, Edinburgh, United Kingdom.
  5. Chotivanich, K., R. Udomsangpetch, A. Dondrop, T. Williams, B. Angus, J. A. Simpson, S. Pukrittayakamee, S. Looarensuwan, C. I. Newbold, and N. J. White. 2000. The mechanism of parasite clearance after antimalarial treatment of Plasmodium falciparum malaria. J. Infect. Dis. 182:629-633.[CrossRef][Medline]
  6. Drakeley, C. J., M. Jawara, G. A. T. Targett, G. Walraven, U. Obisike, R. Coleman, M. Pinder, and C. J. Sutherland. 2003. Addition of artesunate to chloroquine for the treatment of Plasmodium falciparum malaria in Gambian children causes a significant but short-lived reduction in infectiousness for mosquitoes. Trop. Med. Int. Health 9:53-61.[CrossRef]
  7. Ittarat, W., A. L. Pickard, P. Rattanasinganchan, P. Wilairatana, S. Looareesuwan, K. Emery, J. Low, R. Udomsangpetch, and S. R. Meshnick. 2003. Recrudescence in artesunate-treated patients with falciparum malaria is dependent on parasite burden not on parasite factors. Am. J. Trop. Med. Hyg. 68:147-152.[Abstract/Free Full Text]
  8. Paul, R. E. L., T. N. Coulson, A. Raiband, and P. T. Brey. 2000. Sex determination in malaria parasites. Science 287:128-131.[Abstract/Free Full Text]
  9. Paul, R. E. L., P. T. Brey, and A. F. Read. 2002. Plasmodium sex determination and transmission to mosquitoes. Trends Parasitol. 18:32-38.[CrossRef][Medline]
  10. Pickering, J., A. F. Read, S. Guerrero, and S. A. West. 2000. Sex ratio and virulence in two species of lizard malaria parasites. Evol. Ecol. Res. 2:171-184.
  11. Price, R. N., F. Nosten, C. Luxemburger, F. O. ter Kuile, L. Paiphun, T. Chongsuphajasiddhi, and N. J. White. 1996. Effects of artemisinin derivatives on malaria transmissibility. Lancet 347:1654-1658.[CrossRef][Medline]
  12. Pukrittayakamee, S., K. Chotivanich, A. Chantra, R. Clemens, S. Looareesuwan, and N. J. White. 2004. Activities of artesunate and primaquine against asexual- and sexual-stage parasites in falciparum malaria. Antimicrob. Agents Chemother. 48:1329-1334.[Abstract/Free Full Text]
  13. Robert, V., A. F. Read, J. Essong, T. Chuinkam, B. Mulder, J. P. Verhave, and P. Carnevale. 1996. Effects of gametocyte sex ratio on infectivity of Plasmodium falciparum to Anopheles gambiae. Trans. R. Soc. Trop. Med. Hyg. 90:621-662.[CrossRef][Medline]
  14. Salako, L. A., F. O. Ajayi, A. Sowunmi, and O. Walker. 1990. Malaria in Nigeria: a revisit. Ann. Trop. Med. Parasitol. 84:435-445.[Medline]
  15. Schall, J. J. 1989. The sex ratio of Plasmodium falciparum gametocytes. Parasitology 98:343-350.
  16. Sowunmi, A., and B. A. Fateye. 2003. Plasmodium falciparum gametocytaemia in Nigerian children: before during and after treatment with antimalarial drugs. Trop. Med. Int. Health 8:783-792.[CrossRef][Medline]
  17. Sowunmi, A., B. A. Fateye, A. A. Adedeji, F. A. Fehintola, and T. C. Happi. 2004. Risk factors for gametocyte carriage in uncomplicated falciparum malaria in children. Parasitology 129:255-262.[Medline]
  18. von Seidlein, L., C. Drakeley, B. Greenwood, G. Walraven, and G. Targett. 2001. Risk factors for gametocyte carriage in Gambian children. Am. J. Trop. Med. Hyg. 65:523-526.[Abstract]
  19. World Health Organization. 2000. Severe falciparum malaria. Trans. R. Soc. Trop. Med. Hyg. 94(Suppl. 1):1-90.[Medline]
  20. World Health Organization. 2001. Antimalarial drug combination therapy: report of a WHO technical consultation. Document WHO/CDS/RBM/2001.35. World Health Organization, Geneva, Switzerland.

Antimicrobial Agents and Chemotherapy, May 2007, p. 1694-1699, Vol. 51, No. 5
0066-4804/07/$08.00+0     doi:10.1128/AAC.00077-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.




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Clin. Vaccine Immunol. Clin. Microbiol. Rev.
J. Clin. Microbiol. ALL ASM JOURNALS