• 1

    Bjorkman A, Phillips-Howard PA, 1990. The epidemiology of drug-resistant malaria. Trans R Soc Trop Med Hyg 84 :177–180.

  • 2

    Gatton ML, Martin LB, Cheng Q, 2004. Evolution of resistance to sulfadoxine-pyrimethamine in Plasmodium falciparum. Antimicrob Agents Chemother 48 :2116–2123.

    • Search Google Scholar
    • Export Citation
  • 3

    Roper C, Pearce R, Bredenkamp B, Gumede J, Drakeley C, Mosha F, Chandramohan D, Sharp B, 2003. Antifolate antimalarial resistance in southeast Africa: a population-based analysis. Lancet 361 :1174–1181.

    • Search Google Scholar
    • Export Citation
  • 4

    Winkler S, Brandts C, Wernsdorfer WH, Graninger W, Bienzle U, Kremsner PG, 1994. Drug sensitivity of Plasmodium falciparum in Gabon. Activity correlations between various antimalarials. Trop Med Parasitol 45 :214–218.

    • Search Google Scholar
    • Export Citation
  • 5

    Roper C, Pearce R, Nair S, Sharp B, Nosten F, Anderson T, 2004. Intercontinental spread of pyrimethamine-resistant malaria. Science 305 :1124.

    • Search Google Scholar
    • Export Citation
  • 6

    Pukrittayakamee S, Supanaranond W, Looareesuwan S, Vanijanonta S, White NJ, 1994. Quinine in severe falciparum malaria: evidence of declining efficacy in Thailand. Trans R Soc Trop Med Hyg 88 :324–327.

    • Search Google Scholar
    • Export Citation
  • 7

    Kremsner PG, Krishna S, 2004. Antimalarial combinations. Lancet 364 :285–294.

  • 8

    Hien TT, White NJ, 1993. Qinghaosu. Lancet 341 :603–608.

  • 9

    Adjuik M, Babiker A, Garner P, Olliaro P, Taylor W, White N, 2004. Artesunate combinations for treatment of malaria: meta-analysis. Lancet 363 :9–17.

    • Search Google Scholar
    • Export Citation
  • 10

    Yeung S, Pongtavornpinyo W, Hastings IM, Mills AJ, White NJ, 2004. Antimalarial drug resistance, artemisinin-based combination therapy, and the contribution of modeling to elucidating policy choices. Am J Trop Med Hyg 71 :179–186.

    • Search Google Scholar
    • Export Citation
  • 11

    Borrmann S, Adegnika AA, Missinou MA, Binder RK, Issifou S, Schindler A, Matsiegui PB, Kun JF, Krishna S, Lell B, Kremsner PG, 2003. Short-course artesunate treatment of uncomplicated Plasmodium falciparum malaria in Gabon. Antimicrob Agents Chemother 47 :901–904.

    • Search Google Scholar
    • Export Citation
  • 12

    Ittarat W, Pickard AL, Rattanasinganchan P, Wilairatana P, Looareesuwan S, Emery K, Low J, Udomsangpetch R, Meshnick SR, 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.

    • Search Google Scholar
    • Export Citation
  • 13

    Bunnag D, Viravan C, Looareesuwan S, Karbwang J, Harinasuta T, 1991. Double blind randomised clinical trial of two different regimens of oral artesunate in falciparum malaria. Southeast Asian J Trop Med Public Health 22 :534–538.

    • Search Google Scholar
    • Export Citation
  • 14

    Bunnag D, Viravan C, Looareesuwan S, Karbwang J, Harinasuta T, 1991. Clinical trial of artesunate and artemether on multidrug resistant falciparum malaria in Thailand. A preliminary report. Southeast Asian J Trop Med Public Health 22 :380–385.

    • Search Google Scholar
    • Export Citation
  • 15

    Bunnag D, Viravan C, Looareesuwan S, Karbwang J, Harinasuta T, 1991. Double blind randomised clinical trial of oral artesunate at once or twice daily dose in falciparum malaria. Southeast Asian J Trop Med Public Health 22 :539–543.

    • Search Google Scholar
    • Export Citation
  • 16

    Alin MH, Kihamia CM, Bjorkman A, Bwijo BA, Premji Z, Mtey GJ, Ashton M, 1995. Efficacy of oral and intravenous artesunate in male Tanzanian adults with Plasmodium falciparum malaria and in vitro susceptibility to artemisinin, chloroquine, and mefloquine. Am J Trop Med Hyg 53 :639–645.

    • Search Google Scholar
    • Export Citation
  • 17

    Hassan AM, Ashton M, Kihamia CM, Mtey GJ, Bjorkman A, 1996. Multiple dose pharmacokinetics of oral artemisinin and comparison of its efficacy with that of oral artesunate in falciparum malaria patients. Trans R Soc Trop Med Hyg 90 :61–65.

    • Search Google Scholar
    • Export Citation
  • 18

    Looareesuwan S, Wilairatana P, Vanijanonta S, Pitisuttithum P, Ratanapong Y, Andrial M, 1997. Monotherapy with sodium artesunate for uncomplicated falciparum malaria in Thailand: a comparison of 5- and 7-day regimens. Acta Trop 67 :197–205.

    • Search Google Scholar
    • Export Citation
  • 19

    Price R, van Vugt M, Nosten F, Luxemburger C, Brockman A, Phaipun L, Chongsuphajaisiddhi T, White N, 1998. Artesunate versus artemether for the treatment of recrudescent multidrug-resistant falciparum malaria. Am J Trop Med Hyg 59 :883–888.

    • Search Google Scholar
    • Export Citation
  • 20

    Gomez EA, Jurado MH, Cambon N, 2003. Randomised efficacy and safety study of two 3-day artesunate rectal capsule/mefloquine regimens versus artesunate alone for uncomplicated malaria in Ecuadorian children. Acta Trop 89 :47–53.

    • Search Google Scholar
    • Export Citation
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5-DAY NONOBSERVED ARTESUNATE MONOTHERAPY FOR TREATING UNCOMPLICATED FALCIPARUM MALARIA IN YOUNG GABONESE CHILDREN

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  • 1 Medical Research Unit, Albert Schweitzer Hospital Lambaréné, Gabon; Institute of Tropical Medicine, Department of Parasitology, University of Tübingen, Tübingen, Germany

Despite different recommendations from WHO and national authorities, artesunate monotherapy is increasingly used for treating African children with malaria. A 5-day course of oral artesunate (first day: 4 mg/kg body weight, observed intake; and 2 mg/kg body weight on the following days with nonobserved drug intake) yielded a PCR-corrected Day 28 cure rate of 90% (45 of 50 patients; CI 78–97%) in Gabonese children aged between 2 and 18 months. Artesunate was well tolerated, and no severe adverse events were reported.

INTRODUCTION

Plasmodium falciparum resistance to previously effective drugs is one of the greatest obstacles for efforts to lower the morbidity and mortality caused by malaria worldwide, particularly in sub-Saharan Africa. Chloroquine resistance reached East Africa in 1978 and had crossed the continent by 1985,1 thus making blunt one of the most important weapons against malaria. Two other cheap and readily available antimalarial drugs, sulfadoxine-pyrimethamine (SP) and amodiaquine, are now used as first-line treatment in many countries. A single-dose treatment with SP can cure malaria and therefore avoids treatment failures due to incomplete adherence to a multidose drug regimen. Unfortunately, resistance against SP is spreading2 and has already been described in various areas of Africa.3,4 Parasite strains from Southeast Asia are often resistant to sulfadoxine-pyrimethamine and even to quinine, and their spread might contribute to increase the malaria burden in sub-Saharan Africa.5,6

Amodiaquine has been associated with agranulocytosis and liver damage and, like chloroquine, frequently causes an unignorable pruritus, particularly in Africans.7

The artemisinin derivates are the most potent antimalarial compounds available for human use.8 They show a very fast parasite clearance and kill malaria parasites that are resistant to other drugs. Most malaria treatment protocols recommend the use of artemisinin derivates in combination with other antimalarial drugs,9,10 as they have a relatively high treatment failure rate when used as monotherapy in short treatment regimens.11,12 Artesunate combination treatment regimens are theoretically favorable, but an optimal combination partner is lacking so far, with considerable degrees of pharmacokinetic mismatch being one main problem.7

Despite the WHO-recommended strategy of using artemisinins in artemisinin combination therapies (ACT), artemisinin monotherapies are informally used in many African countries. We therefore understand that it is important to evaluate these in settings that allow for control and observation of such an intervention. Characteristics of clinical studies of artesunate montotherapy with different drug regimens are listed in Table 1.

If malaria is treated on an outpatient basis, the first dose of the drug can be given in the hospital, but remaining doses usually have to be taken or given by a guardian at home. Therefore, the success of a 5-day treatment protocol strongly depends on the compliance of the patients’ caregivers. A 5-day artesunate monotherapy regimen in Gabonese children has not yet been evaluated in a clinical trial. As artesunate is usually well tolerated and therefore better accepted by the patients than other antimalarial drugs, we expect an acceptable treatment outcome of a relatively long treatment regimen of 5 days, even under nonobserved drug intake conditions. We report the results of a study that assessed the outcome of a nonobserved treatment with a 5-day artesunate regimen for uncomplicated malaria in 50 African children between 2 and 18 months of age.

MATERIALS AND METHODS

Study site.

This trial was conducted from December 2002 to August 2004 in the Medical Research Unit of the Albert Schweitzer Hospital in Lambaréné, Gabon. The study site is located near the Equator within the African rain-forest belt. There is little seasonal variability in transmission rates or parasite prevalence. Ninety-five percent of all malaria infections are caused by Plasmodium falciparum and the entomological inoculation rate is about 50 infective bites per person per year.21,22

Patients.

Study subjects were recruited from participants in another longitudinal study. They were treated with 5 days of artesunate monotherapy in the case of uncomplicated malaria between December 2002 and August 2004. Informed consent of the parents or the guardians of the children were obtained at enrolment into the main study, usually after birth in the maternity ward of the Albert Schweitzer Hospital or the Public Regional Hospital in Lambaréné. Ethical clearance was obtained from the Ethics Committee of the International Foundation of the Albert Schweitzer Hospital in Lambaréné.

Uncomplicated malaria was defined as the presence of asexual parasitemia with Plasmodium falciparum and a rectal temperature of at least 38.2°C or a history of fever in the last 48 hours reported by the mother or the guardian and the absence of signs of severe malaria as defined by the WHO.23 The first dose of the study drug (4 mg/kg body weight) was given in the study center by an investigator on the day of presentation. The tablets (Arsumax 50, provided by Sanofi-Synthélabo, Gentilly, France) that had to be given by the mother or the guardian were cut into dosage-appropriate pieces (2 mg/kg body weight) and put into little sealed plastic bags. The following 4 days, the drug had to be given once a day by the mother or a guardian at home without observation by an investigator. A routine full blood count was performed prior to treatment and repeated on the Day 5 and Day 28 follow-up examinations alongside with a clinical assessment and a thick blood smear control. Inclusion criteria were informed consent of the parents to and participation in the study and uncomplicated malaria as defined above. All children who had a Day 28 follow-up visit (± 1 week) with a thick smear control were included in the analysis. Most of the children also had a Day 4 follow-up visit. Exclusion criteria were severe malaria with hospitalization and intravenous quinine treatment and administration of another antimalarial drug before presentation in our study center or during the 28-day postmalaria follow-up period by the parents or another health institution. Figure 1 shows the study flow.

MSA-1 genotyping.

Preparation of deoxyribonucleic acid and the polymerase chain reaction.

Deoxyribonucleic acid (DNA) from dried blood spots was purified using DNA purification kits (Qiagen, Hilden, Germany). DNA was enriched using GenomiPhi according to the supplier’s instructions (Amersham, Freiburg, Germany). MSA1 genotyping was done on a thermocycler (Biometra, Göttingen, Germany) according to standard procedures24 with primers amplifying all variants. The primers were Lisa-1 5′-ACATGAAAGTTATCAAGAACTTGTC-3′ and Lisa 5′-TACGTCTAATTCATTTGCACGAA-3′. PCR was initiated by 94°C for 5 minutes, followed by 35 cycles with a melting temperature of 10 seconds, with an annealing temperature of 55°C for 45 seconds and an extension for 60 seconds at 70°C. A nested PCR was performed to distinguish the three allelic families. Fifteen cycles were carried out on a RapidCyclerTM (Idaho Technologies, Salt Lake City, UT). The temperatures were 94°C, 53°C, and 72°C, the time was set to 0. Primer T22 (5′-GTTGTTGCAAAGCCTGCAGGTGCT-3′ or T23 5′-ACAAGTGGAACAGCTGTTACAA-3′ was combined with Lisa-2 for RO33 or MAD20 identification, respectively. K1 was identified by PCR with the primers Lisa-1 and T24 5′-GCATCAGCTGGAGGGCTTGCACCAGAT-3′. PCR products were separated on an agarose gel. DNA fragments were visualized on a Dark Reader (Clare Chemical Research Inc., Dolores, CO) after SYBR green staining (Biozym, Hessisch Oldendorf, Germany). Size was the main criterion to distinguish different genotypes. Single infections with the same sized bands were analyzed by DNA sequencing. No multiple infection with an identical band pattern was observed.

RESULTS

Of 50 children treated with a 5-day artesunate monotherapy regimen, 38 (76%) were parasite-free on Day 28. For 7 of 12 children with reappearing parasites, PCR analysis revealed different MSA-1 genotypes. These children were assumed to have been reinfected and were therefore classified as initially cured. For 4 of 12 children with reappearing parasites, PCR analysis revealed the same MSA-1 genotypes, thus indicating treatment failure. In one case, no filter paper was available, and it was also classified as a treatment failure. The PCR-corrected parasitological cure rate on day 28 (± 1 week) was therefore 90% (45 of 50 patients; CI 78–97%). Forty of the 50 children had a thick blood smear control taken during a visit on Day 4. All 40 thick smears taken on Day 4 were negative. Only one child had fever on Day 4, which was most probably caused by a respiratory tract infection. The treatment was well tolerated and no drug-associated adverse event was observed. The baseline characteristics of the children are summarized in Table 2.

DISCUSSION

Five-day artesunate monotherapy is often used in Africa, and this study shows that it is an acceptable regimen for the treatment of malaria in Gabonese children in terms of effectiveness and tolerability; thus meaning that it may constitute an adequate therapy if correctly applied by the caregiver and with good adherence and/or compliance of the patient. However, as current ACT recommendations of WHO are valid, it should not be advocated. The PCR-corrected effectiveness of this regimen in our study was 90% (45 of 50 patients; CI 78–97%). For public health initiatives in endemic regions, effectiveness of a regimen should not fall under 75%.7 With controlled drug treatment, the percentage of sustainably cured patients is expected to be even higher, as we understand that some of the treatment failures occurred due to lack of compliance. In a similar study with 50 children from Lambaréné between 4 and 15 years of age, the efficacy of a 3-day artesunate regimen was only 72%.11 The efficacy of a 5-day artesunate monotherapy in children from Lambaréné still remains to be evaluated, as up to now no clinical trial on a 5-day artesunate therapy with investigator-observed drug intake has been carried out.

Usually, efforts are undertaken to shorten treatment duration, as patients’ compliance is presumed to decline at the end of a therapeutic regimen. This is especially the case when a drug has uncomfortable side effects, such as a 7-day quinine monotherapy regimen. However, it might be the reverse case and compliance might be reduced with short combination regimens in which the second, treatment duration-abridging partner introduces discomfort to the patient, as the amodiaquine component in the 3-day artesunate-amodiaquine regimen does, an effect that is particularly prominent in children. Artesunate monotherapy is usually well tolerated. As the participants of our study were babies, compliance was not only directly dependent on the patient but on the mother or the guardian.

Most drug trials focus on the efficacy of a drug, where investigators observe drug intake. However, the success of a malaria therapy for most African children depends not only on the efficacy of a drug but also on the effectiveness. Often there are significant differences between treatment policies and the actual usage patterns of antimalarial drugs potentially leading to a low effectiveness.25 Therefore, it is good to know about the effectiveness of commonly used regimens, even though they may not be officially recommended. To collect more information on the effectiveness of a drug regimen, efforts should be undertaken to keep track of the treatment outcome of malaria patients, whose drug intake is not being observed.

Table 1

Overview on clinical studies of artesunate monotherapy for P. falciparum malaria

PaperDuration of courseApplication schemePatientsCure rate at Day 28CountryPCR corrected
Bunnag and others135 daysOral: 200 mg on the first day then 100 mg for 4 days (total dose 600 mg)Older than 14 years85% (39/46)ThailandNo
Bunnag and others141 dayOral: 200 mg initially and 12 and 24 hours later (total dose 600 mg)Males older than 14 years0% (0/5)ThailandNo
Bunnag and others142 daysOral: 100 mg 8 hourly for 2 days (total dose 600 mg)Males older than 14 years0% (0/5)ThailandNo
Bunnag and others143 daysIV: initially 120 mg, 4 hours later 60 mg, then 60 mg daily for 2 days (total dose 300 mg)Males older than 14 years20% (1/5)ThailandNo
Bunnag and others145 daysOral: 12 hourly first two doses 100 mg, then 50 mg (total dose 600 mg)Males older than 14 years90% (9/10)ThailandNo
Bunnag and others145 daysOral: 12 hourly 200 mg initially, then 50 mg (total dose 650 mg)Males older than 14 years95% (20/21)ThailandNo
Bunnag and others145 daysOral: 12 hourly first two doses 200 mg, then 100 mg (total dose 1200 mg)Males older than 14 years100% (6/6)ThailandNo
Bunnag and others155 daysOral: 200 mg on the first day, then 100 mg daily for 4 days (total dose 600 mg)15–52 years72% (18/25)ThailandNo
Bunnag and others155 daysOral: twice daily 100 mg 12 hourly on first day, then 50 mg 12 hourly for 4 days (total 600 mg)15–52 years76% (19/25)ThailandNo
Alin and others164 daysOral: 100 mg initially, then 50 mg 12 hourly for 4 days (total dose 550 mg)Males between 15 and 55 years80% (20/25)TanzaniaNo
Alin and others164 daysIV: 2 × 0.8 mg/kg initially followed by 0.8 mg/kg 12 hourly/4 days (total dose 8.8 mg/kg)Males between 15 and 55 years84% (21/25)TanzaniaNo
Hassan and others175 daysOral: 100 mg initially, then 50 mg twice daily for 5 days (total dose 600 mg)15–45 years80% (16/20)TanzaniaNo
Looareesuwan and others185 daysOral: 400 mg on the first day, then 200 mg daily for 4 days (total of 1,200 mg)16–60 years100% (42/42)ThailandNo
Looareesuwan and others187 daysOral: 400 mg on the first day, then 200 mg daily for 6 days (total of 1,600 mg)16–60 years98% (39/40)ThailandNo
Price and others197 daysOral: 2 mg/kg/day for 5 days, then 1 mg/kg/day for 2 daysAdults and children above 5 kg92% (164/172)BurmaNo
Borrmann and others113 daysOral: 4 mg/kg daily for 3 daysChildren 4–15 years72% (36/50)GabonYes
Gomez and others206 daysRectal: over 6 days total dose 40 mg/kgChildren 1–12 years above 10 kg76% (38/50)EcuadorNo
Ittarat and others123 daysOral: 600 mg total doseOlder than 18 years71% (72/104)ThailandYes
Table 2

Demographic, laboratory, and clinical characteristics at baseline

Malaria cases (N = 50)Cured on Day 28 (N = 45)With reappearing parasitemia (N = 5)
HGB = hemoglobin; HCT = hematocrit; μ = micron.
Male/female24/2621/243/2
Mean age in months (SE, N)7.7 (3.3, 50)7.5 (3.3, 45)9.1 (3.0, 5)
Median parasitemia (range, N)11,600 (24–180,000, 50)10,000 (24–180,000 45)31,000 (6,000–90,000 5)
Mean body temp (SD, N)38.8 (1.1, 50)38.7 (1.1, 45)39.5 (1.5, 5)
Mean WBC/103 μL (SD, N)9.8 (3.5, 47)9.9 (3.5, 42)8.0 (4.0, 5)
RBC/103 μL (SD, N)4.0 (0.7, 47)4.0 (0.7, 42)4.1 (0.7, 5)
HGB g/dL (SD, N)8.6 (1.3, 47)8.5 (1.2, 42)9.4 (1.3, 5)
HCT% (SD, N)25.8 (4.0, 47)25.5 (3.9, 42)27.4 (4.7, 5)
MCV fL (SD, N)65.1 (6.6, 47)64.5 (6.3, 42)66.2 (2.1, 5)
Platelets M/μL (SD, N)219.8 (122.4 47)225.6 (118.6, 42)188.2 (138.5, 5)
Creatinine μmol/L (SD, N)38.4 (6.9, 41)38.1 (6.5, 36)40.6 (10.5, 5)
ALT IU/μL39.8 (19.7, 27)39.9 (20.1, 23)39.3 (20.2, 4)
No. (%) of children with the following symptoms and signs on presentation
    Diarrhea (%, N)15 (30, 50)14 (31, 45)1 (20, 5)
    Vomiting (%, N)12 (24, 50)11 (24, 45)1 (20, 5)
    Splenomegaly (%, N)13 (38, 34)12 (37, 32)1 (33, 3)
    History of fever (%, N)49 (90, 50)44 (97, 45)5 (100, 5)
    History of fever in the last 48 hours (SD, N)45 (90, 50)40 (88, 45)5 (100, 5)
    Temp. of at least 38.2°C at presentation (SD, N)31 (62, 50)28 (62, 45)4 (80, 5)
Figure 1.
Figure 1.

Flow chart of patients followed up and analyzed.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 73, 4; 10.4269/ajtmh.2005.73.705

*

Address correspondence to Martin P. Grobusch, University of the Witwatersrand, Infectious Diseases Unit, Johannesburg, South Africa. E-mail: grobuschmp@pathology.wits.ac.za.

Authors’ addresses: Norbert G. Schwarz, Sunny Oyakhirome, Marc Pötschke, Benjamin Gläser, Handan Altun, and Saadou Issifou, Medical Research Unit, Albert Schweitzer Hospital, B.P. 118, Lambaréné, Gabon, Telephone: +241581099. Peter Klein Klouwenberg, Ayola A. Adegnika, Jürgen F. J. Kun, Peter G. Kremsner, and Martin P. Grobusch, Institute of Tropical Medicine, Department of Parasitology, Eberhard Karls University, Wilhelmstr. 27, D-72074 Tübingen, Germany, Telephone: +49 7071 298 0234; Fax +49 7071 29 4684.

Acknowledgments: We are grateful to the children and their parents for participation in our longitudinal study. The authors thank Silvelia Grummes for performing the PCR genotyping and all the staff of the Medical Research Unit, the Pediatric Ward and the Maternity Ward of the Albert Schweitzer Hospital for their excellent cooperation.

REFERENCES

  • 1

    Bjorkman A, Phillips-Howard PA, 1990. The epidemiology of drug-resistant malaria. Trans R Soc Trop Med Hyg 84 :177–180.

  • 2

    Gatton ML, Martin LB, Cheng Q, 2004. Evolution of resistance to sulfadoxine-pyrimethamine in Plasmodium falciparum. Antimicrob Agents Chemother 48 :2116–2123.

    • Search Google Scholar
    • Export Citation
  • 3

    Roper C, Pearce R, Bredenkamp B, Gumede J, Drakeley C, Mosha F, Chandramohan D, Sharp B, 2003. Antifolate antimalarial resistance in southeast Africa: a population-based analysis. Lancet 361 :1174–1181.

    • Search Google Scholar
    • Export Citation
  • 4

    Winkler S, Brandts C, Wernsdorfer WH, Graninger W, Bienzle U, Kremsner PG, 1994. Drug sensitivity of Plasmodium falciparum in Gabon. Activity correlations between various antimalarials. Trop Med Parasitol 45 :214–218.

    • Search Google Scholar
    • Export Citation
  • 5

    Roper C, Pearce R, Nair S, Sharp B, Nosten F, Anderson T, 2004. Intercontinental spread of pyrimethamine-resistant malaria. Science 305 :1124.

    • Search Google Scholar
    • Export Citation
  • 6

    Pukrittayakamee S, Supanaranond W, Looareesuwan S, Vanijanonta S, White NJ, 1994. Quinine in severe falciparum malaria: evidence of declining efficacy in Thailand. Trans R Soc Trop Med Hyg 88 :324–327.

    • Search Google Scholar
    • Export Citation
  • 7

    Kremsner PG, Krishna S, 2004. Antimalarial combinations. Lancet 364 :285–294.

  • 8

    Hien TT, White NJ, 1993. Qinghaosu. Lancet 341 :603–608.

  • 9

    Adjuik M, Babiker A, Garner P, Olliaro P, Taylor W, White N, 2004. Artesunate combinations for treatment of malaria: meta-analysis. Lancet 363 :9–17.

    • Search Google Scholar
    • Export Citation
  • 10

    Yeung S, Pongtavornpinyo W, Hastings IM, Mills AJ, White NJ, 2004. Antimalarial drug resistance, artemisinin-based combination therapy, and the contribution of modeling to elucidating policy choices. Am J Trop Med Hyg 71 :179–186.

    • Search Google Scholar
    • Export Citation
  • 11

    Borrmann S, Adegnika AA, Missinou MA, Binder RK, Issifou S, Schindler A, Matsiegui PB, Kun JF, Krishna S, Lell B, Kremsner PG, 2003. Short-course artesunate treatment of uncomplicated Plasmodium falciparum malaria in Gabon. Antimicrob Agents Chemother 47 :901–904.

    • Search Google Scholar
    • Export Citation
  • 12

    Ittarat W, Pickard AL, Rattanasinganchan P, Wilairatana P, Looareesuwan S, Emery K, Low J, Udomsangpetch R, Meshnick SR, 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.

    • Search Google Scholar
    • Export Citation
  • 13

    Bunnag D, Viravan C, Looareesuwan S, Karbwang J, Harinasuta T, 1991. Double blind randomised clinical trial of two different regimens of oral artesunate in falciparum malaria. Southeast Asian J Trop Med Public Health 22 :534–538.

    • Search Google Scholar
    • Export Citation
  • 14

    Bunnag D, Viravan C, Looareesuwan S, Karbwang J, Harinasuta T, 1991. Clinical trial of artesunate and artemether on multidrug resistant falciparum malaria in Thailand. A preliminary report. Southeast Asian J Trop Med Public Health 22 :380–385.

    • Search Google Scholar
    • Export Citation
  • 15

    Bunnag D, Viravan C, Looareesuwan S, Karbwang J, Harinasuta T, 1991. Double blind randomised clinical trial of oral artesunate at once or twice daily dose in falciparum malaria. Southeast Asian J Trop Med Public Health 22 :539–543.

    • Search Google Scholar
    • Export Citation
  • 16

    Alin MH, Kihamia CM, Bjorkman A, Bwijo BA, Premji Z, Mtey GJ, Ashton M, 1995. Efficacy of oral and intravenous artesunate in male Tanzanian adults with Plasmodium falciparum malaria and in vitro susceptibility to artemisinin, chloroquine, and mefloquine. Am J Trop Med Hyg 53 :639–645.

    • Search Google Scholar
    • Export Citation
  • 17

    Hassan AM, Ashton M, Kihamia CM, Mtey GJ, Bjorkman A, 1996. Multiple dose pharmacokinetics of oral artemisinin and comparison of its efficacy with that of oral artesunate in falciparum malaria patients. Trans R Soc Trop Med Hyg 90 :61–65.

    • Search Google Scholar
    • Export Citation
  • 18

    Looareesuwan S, Wilairatana P, Vanijanonta S, Pitisuttithum P, Ratanapong Y, Andrial M, 1997. Monotherapy with sodium artesunate for uncomplicated falciparum malaria in Thailand: a comparison of 5- and 7-day regimens. Acta Trop 67 :197–205.

    • Search Google Scholar
    • Export Citation
  • 19

    Price R, van Vugt M, Nosten F, Luxemburger C, Brockman A, Phaipun L, Chongsuphajaisiddhi T, White N, 1998. Artesunate versus artemether for the treatment of recrudescent multidrug-resistant falciparum malaria. Am J Trop Med Hyg 59 :883–888.

    • Search Google Scholar
    • Export Citation
  • 20

    Gomez EA, Jurado MH, Cambon N, 2003. Randomised efficacy and safety study of two 3-day artesunate rectal capsule/mefloquine regimens versus artesunate alone for uncomplicated malaria in Ecuadorian children. Acta Trop 89 :47–53.

    • Search Google Scholar
    • Export Citation
  • 21

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Author Notes

Reprint requests: Martin P. Grobusch, University of the Witwatersrand, Infectious Diseases Unit, Johannesburg, South Africa, Telephone: +2711 489 8537; Fax: +2711 489 8530, E-mail: grobuschmp@pathology.wits.ac.za.
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