• 1

    Wongsrichanalai C, Pickard AL, Wernsdorfer WH, Meshnick SR, 2002. Epidemiology of drug-resistant malaria. Lancet Infect Dis 2 :209–218.

    • Search Google Scholar
    • Export Citation
  • 2

    Danis M, Bricaire F, 2003. The new drug combinations: their place in the treatment of uncomplicated Plasmodium falciparum malaria. Fundam Clin Pharmacol 17 :155–160.

    • Search Google Scholar
    • Export Citation
  • 3

    White NJ, Nosten F, Looareesuwan S, Watkins WM, Snow RW, Kokwaro G, Ouma J, Hien TT, Molyneux ME, Taylor TE, Newbold CI, Ruebush TK 2nd, Danis M, Greenwood BM, Anderson RM, Olliaro P, 1999. Averting a malaria disaster. Lancet 353 :1965–1967.

    • Search Google Scholar
    • Export Citation
  • 4

    Zongo I, Dorsey G, Rouamba N, Dokomajilar C, Lankoande M, Ouedraogo JB, Rosenthal PJ, 2005. Amodiaquine, sulfadoxine-pyrimethamine, and combination therapy for uncomplicated falciparum malaria: a randomized controlled trial from Burkino Faso. Am J Trop Med Hyg 73 :826–832.

    • Search Google Scholar
    • Export Citation
  • 5

    Chulay JD, Watkins WM, Sixsmith DG, 1984. Synergistic anti-malarial activity of pyrimethamine and sulfadoxine against Plasmodium falciparum in vitro. Am J Trop Med Hyg 33 :325–330.

    • Search Google Scholar
    • Export Citation
  • 6

    Srivastava IK, Vaidya AB, 1999. A mechanism for the synergistic antimalarial action of atovaquone and proguanil. Antimicrob Agents Chemother 43 :1334–1339.

    • Search Google Scholar
    • Export Citation
  • 7

    White NJ, 2004. Antimalarial drug resistance. J Clin Invest 113 :1084–1092.

  • 8

    Attaran A, Barnes KI, Curtis C, D’Alessandro U, Fanello CI, Galinski ME, Kokwaro G, Looareesuwan S, Makanga M, Mutabingwa TK, Talisuna A, Trape JF, Watkins WM, 2004. WHO, the Global Fund, and medical malpractice in malaria treatment. Lancet 363 :237–240.

    • Search Google Scholar
    • Export Citation
  • 9

    Rojanawatsirivej C, Vijaykadga S, Amklad I, Wilairatna P, Looareesuwan S, 2003. Monitoring the therapeutic efficacy of antimalarials against uncomplicated falciparum malaria in Thailand. Southeast Asian J Trop Med Public Health 34 :536–541.

    • Search Google Scholar
    • Export Citation
  • 10

    Clark RL, White TE, 2004. S AC, Gaunt I, Winstanley P and Ward SA. Developmental toxicity of artesunate and an artesunate combination in the rat and rabbit. Birth Defects Res B Dev Reprod Toxicol 71 :380–394.

    • Search Google Scholar
    • Export Citation
  • 11

    Anonymous, End decade databases—Fertility and Contraceptive Use. Vol. 2005: UNICEF Statistics

  • 12

    Steck EA, The Chemotherapy of Protozoan Diseases. Walter Reed Army Institute of Medicine, 1971

  • 13

    Thomas F, Erhart A, D’Alessandro U, 2004. Can amodiaquine be used safely during pregnancy? Lancet Infect Dis 4 :235–239.

  • 14

    Olliaro P, Mussano P, Amodiaquine for treating malaria. Cochrane Database Syst Rev 2003:CD000016

  • 15

    Taylor WR, White NJ, 2004. Antimalarial drug toxicity: a review. Drug Saf 27 :25–61.

  • 16

    Pussard E, Verdier F, Faurisson F, Scherrmann JM, Le Bras J, Blayo MC, 1987. Disposition of monodesethylamodiaquine after a single oral dose of amodiaquine and three regimens for prophylaxis against Plasmodium falciparum malaria. Eur J Clin Pharmacol 33 :409–414.

    • Search Google Scholar
    • Export Citation
  • 17

    Ringwald P, Bickii J, Basco LK, 1998. Amodiaquine as the first-line treatment of malaria in Yaounde, Cameroon: presumptive evidence from activity in vitro and cross-resistance patterns. Trans R Soc Trop Med Hyg 92 :212–213.

    • Search Google Scholar
    • Export Citation
  • 18

    Ringwald P, Bickii J, Basco LK, 1999. In vitro activity of dihydroartemisinin against clinical isolates of Plasmodium falciparum in Yaounde, Cameroon. Am J Trop Med Hyg 61 :187–192.

    • Search Google Scholar
    • Export Citation
  • 19

    Caramello P, Canta F, Cavecchia I, Sergi G, Balbiano R, Ariaudo S, Audagnotto S, DiPerri G, 2005. Chemosusceptibility analysis of Plasmodium falciparum imported malaria in Italy. Diagn Microbiol Infect Dis 52 :107–112.

    • Search Google Scholar
    • Export Citation
  • 20

    Graupner J, Gobels K, Grobusch MP, Lund A, Richter J, Haussinger D, 2005. Efficacy of amodiaquine in uncomplicated falciparum malaria in Nigeria in an area with high-level resistance to chloroquine and sulphadoxine/pyrimethamine. Parasitol Res 96 :162–165.

    • Search Google Scholar
    • Export Citation
  • 21

    Molta NB, Oguche S, Pam SD, Omalu IC, Afolabi BM, Odujoko JB, Amajoh CN, Adeniji B, Wuyep VP, Ekanem OJ, 2003. Amodiaquine treatment of uncomplicated malaria in children, in an area of chloroquine-resistant Plasmodium falciparum in north-central Nigeria. Ann Trop Med Parasitol 97 :663–669.

    • Search Google Scholar
    • Export Citation
  • 22

    Sendagire H, Kaddumukasa M, Ndagire D, Agutta C, Nassejje M, Pettersson M, Swedberg G, Kironde F, 2005. Rapid increase in resistance of Plasmodium falciparum to chloroquine-Fansidar in Uganda and the potential of amodiaquine-Fansidar as a better alternative. Acta Trop 95 :172–182.

    • Search Google Scholar
    • Export Citation
  • 23

    Rwagacondo CE, Karema C, Mugisha V, Erhart A, Dujardin JC, Van Overmeir C, Ringwald P, D’Alessandro U, 2004. Is amodiaquine failing in Rwanda? Efficacy of amodiaquine alone and combined with artesunate in children with uncomplicated malaria. Trop Med Int Health 9 :1091–1098.

    • Search Google Scholar
    • Export Citation
  • 24

    Basco LK, Same-Ekobo A, Ngane VF, Ndounga M, Metoh T, Ringwald P, Soula G, 2002. Therapeutic efficacy of sulfadoxine-pyrimethamine, amodiaquine and the sulfadoxine-pyrimethamine-amodiaquine combination against uncomplicated Plasmodium falciparum malaria in young children in Cameroon. Bull World Health Organ 80 :538–545.

    • Search Google Scholar
    • Export Citation
  • 25

    Dinis DV, Schapira A, 1990. Comparative study of sulfadoxine-pyrimethamine and amodiaquine + sulfadoxine-pyrimethamine for the treatment of malaria caused by chloroquine-resistant Plasmodium falciparum in Maputo, Mozambique. Bull Soc Pathol Exot 83 :521–527; discussion 528

    • Search Google Scholar
    • Export Citation
  • 26

    Dorsey G, Njama D, Kamya MR, Cattamanchi A, Kyabayinze D, Staedke SG, Gasasira A, Rosenthal PJ, 2002. Sulfadoxine/pyrimethamine alone or with amodiaquine or artesunate for treatment of uncomplicated malaria: a longitudinal randomised trial. Lancet 360 :2031–2038.

    • Search Google Scholar
    • Export Citation
  • 27

    Gasasira AF, Dorsey G, Nzarubara B, Staedke SG, Nassali A, Rosenthal PJ, Kamy MR, 2003. Comparative efficacy of aminoquinoline-antifolate combinations for the treatment of uncomplicated falciparum malaria in Kampala, Uganda. Am J Trop Med Hyg 68 :127–132.

    • Search Google Scholar
    • Export Citation
  • 28

    Huang OL, Ouyang WC, Zhou JX, Wu Z, Zhang KY, Huang JK, Cai XZ, Pang XJ, Fu SG, Wang XF, et al., 1988. Effectiveness of amodiaquine, sulfadoxine-pyrimethamine, and combinations of these drugs for treating chloroquine-resistant falciparum malaria in Hainan Island, China. Bull World Health Organ 66 :353–358.

    • Search Google Scholar
    • Export Citation
  • 29

    Menard D, Madji N, Manirakiza A, Djalle D, Koula MR, Talarmin A, 2005. Efficacy of chloroquine, amodiaquine, sulfadoxine-pyrimethamine, chloroquine-sulfadoxine-pyrimethamine combination, and amodiaquine-sulfadoxine-pyrimethamine combination in Central African children with non-complicated malaria. Am J Trop Med Hyg 72 :581–585.

    • Search Google Scholar
    • Export Citation
  • 30

    Mockenhaupt FP, Ehrhardt S, Dzisi SY, Teun Bousema J, Wassilew N, Schreiber J, Anemana SD, Cramer JP, Otchwemah RN, Sauerweim RW, Eggelte TA, Bienzle U, 2005. A randomized, placebo-controlled, double-blind trial on sulfadoxine-pyrimethamine alone or combined with artesunate or amodiaquine in uncomplicated malaria. Trop Med Int Health 10 :512–520.

    • Search Google Scholar
    • Export Citation
  • 31

    Mutabingwa TK, Anthony D, Heller A, HallettR, Ahmed J, Drakeley C, Greenwood BM, Whitty CJ, 2005. Amodiaquine alone, amodiaquine+sulfadoxine-pyrimethamine, amodiaquine+artesunate, and artemether-lumefantrine for outpatient treatment of malaria in Tanzanian children: a four-arm randomised effectiveness trial. Lancet 365 :1474–1480.

    • Search Google Scholar
    • Export Citation
  • 32

    Schapira A, Schwalbach JF, 1988. Evaluation of four therapeutic regimens for falciparum malaria in Mozambique, 1986. Bull World Health Organ 66 :219–226.

    • Search Google Scholar
    • Export Citation
  • 33

    Schellenberg D, Kahigwa E, Drakeley C, Malende A, Wigayi J, Msokame C, Aponte JJ, Tanner M, Mshinda H, Menendez C, Alonso PL, 2002. The safety and efficacy of sulfadoxine-pyrimethamine, amodiaquine, and their combination in the treatment of uncomplicated Plasmodium falciparum malaria. Am J Trop Med Hyg 67 :17–23.

    • Search Google Scholar
    • Export Citation
  • 34

    Staedke SG, Kamya MR, Dorsey G, Gasasira A, Ndeezi G, Charlebois ED, Rosenthal PJ, 2001. Amodiaquine, sulfadoxine/pyrimethamine, and combination therapy for treatment of uncomplicated falciparum malaria in Kampala, Uganda: a randomised trial. Lancet 358 :368–374.

    • Search Google Scholar
    • Export Citation
  • 35

    Melander H, Ahlqvist-Rastad J, Meijer G, Beermann B, 2003. Evidence b(i)ased medicine–selective reporting from studies sponsored by pharmaceutical industry: review of studies in new drug applications. BMJ 326 :1171–1173.

    • Search Google Scholar
    • Export Citation
  • 36

    Tierney JF, Stewart LA, 2005. Investigating patient exclusion bias in meta-analysis. Int J Epidemiol 34 :79–87.

  • 37

    Schulz KF, Grimes DA, 2002. Sample size slippages in randomised trials: exclusions and the lost and wayward. Lancet 359 :781–785.

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AMODIAQUINE AND COMBINATION CHEMOTHERAPY FOR MALARIA

STEVEN R. MESHNICKDepartment of Epidemiology, University of North Carolina School of Public Health

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ALISA P. ALKERDepartment of Epidemiology, University of North Carolina School of Public Health

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Antimalarial drug resistance is becoming an increasingly important public health problem.1 There is a consensus among malariologists that combination chemotherapy is the best way to treat malaria, which is resistant to current drugs, and to mitigate the emergence of resistance to new drugs.2,3 But there is no consensus about which antimalarial drugs to combine. The paper by Zongo and others,4 in this issue, should elicit a serious discussion of the issues involved.

Combination antimalarial therapy works for two reasons. First, some antimalarial combinations contain component drugs that potentiate each other, like sulfadoxine-pyrimethamine5 and atovaquone-proguanil.6 The second reason has to do with resistance. Mutations that confer resistance occur spontaneously at a small but finite rate (~10−6 per generation). When exposed to two drugs, parasites would need to develop mutations at two resistance loci simultaneously, and the likelihood of this occurring (i.e., 10−6 × 10−6 = 10−12) becomes extremely small.7

Partnering of artemisinins with other drugs, dubbed artemisinin combination therapy (ACT), has been heralded as the next great weapon in our fight against malaria.8 While ACTs, such as artesunate-mefloquine and artemethether-lumefantrine (Coartem®), have been extremely effective in Southeast Asia,9 they might not be appropriate for sub-Saharan Africa for two reasons. First, artemisinin derivatives have very short half-lives; when used as a partner to a long-half-life drug, patients may have subtherapeutic concentrations of the latter drug alone in their plasma for days or weeks. In Southeast Asia, where the risk of new infection is rare, this may not be a problem. However, in sub-Saharan Africa, people may be subjected to infectious mosquito bites on a daily basis. Thus, parasites could easily be exposed to subtherapeutic concentrations of single antimalarial agents, an ideal scenario for the development of resistance.

A second strike against ACTs is the possible reproductive toxicity of artemisinin derivatives.10 Artesunate, at normal therapeutic doses, was found to cause fetal death and malformations in pregnant rodents in the equivalent of the first trimester of pregnancy. In light of the fact that the average woman in sub-Saharan Africa gives birth 5.7 times,11 women between ages 15 and 45 might simply be ineligible for this treatment.

What other combinations can be used? As suggested in Zongo and others4 one possibility is the combination of amodiaquine with other antimalarials. Amodiaquine was developed during World War II by the US Army-sponsored program to develop alternatives to quinine.12 It became widely used both prophylactically and therapeutically. In the 1980s, amodiaquine prophylaxis was found to be associated with agranulocytosis, neutropenia, and hepatitis, and its use was halted.13 Later, it was reintroduced for therapeutic use only. To date, there is no evidence for serious toxicity associated with amodiaquine therapy.14 This is reminiscent of the situation with sulfadoxine-pyrimethamine (SP).15

Another advantage of amodiaquine over the artemisinin derivatives is the long half-life of its principal active metabolite (9–18 days).16 Thus, if it were partnered with another drug with a long half-life (such as SP), there would be little chance of exposing parasites to subcurative concentrations of a single antimalarial.

What about amodiaquine resistance? Very little is known about the mechanism or epidemiology of amodiaquine resistance. In vitro studies have found that resistance to chloroquine and amodiaquine are correlated; however, chloroquine-resistant strains appear to have lower levels of resistance to amodiaquine.1719 There is also evidence that amodiaquine is effective against chloroquine-resistant malaria in vivo.2022 However, amodiaquine resistance does occur in areas where it has been used regularly.23 More work on this topic is clearly needed.

The paper by Zongo and others4 evaluates the combination of amodiaquine with SP in Burkino Faso in a randomized placebo-controlled clinical trial (RCT). This study was performed using the best available methodology—28-day follow-up using polymerase chain reaction (PCR) to correct for reinfection. No matter how failure is defined (parasitologically, clinically, or both), amodiaquine-SP performed better than SP alone. A large number of studies by this group and others have also shown the increased efficacy of this combination.8,2434 Both amodiaquine and SP are inexpensive and readily available, so a policy switch from SP, for example, to amodiaquine-SP can be made quickly and easily. Even though SP and amodiaquine resistance may preexist, SP-amodiaquine could be of great benefit for the short term.

How compelling are the arguments for switching to SP-amodiaquine? In the current study, amodiaquine-SP appeared to be more than twice as efficacious as SP alone—only 4.2% of patients failed amodiaquine-SP (by any definition) compared with 9.1% of SP patients.4 Are these improvements significant enough to warrant policy change from SP to amodiaquine-SP? This study, like many of the others, was analyzed on a per-protocol basis as opposed to intention-to-treat. This means that patients who were lost to follow-up or excluded during the course of the study were dropped from the final analysis. Most randomized trials rely on intention-to-treat analyses, meaning that these patients who drop out are defined as failures. This is done for two reasons. First, the randomization of patients, made on admission into the trial, minimizes selection bias and confounding. Since patients might not drop out randomly, per-protocol analyses permit these to creep back in. Second, intention-to-treat analyses make a clinical trial more like an effectiveness study and more relevant to policy makers.3537 If a certain percentage of patients drop out of an RCT, then it is safe to say that the same percentage or higher will drop out when the treatment enters clinical practice. When we recalculated the data from Zongo and others4 on an intention-to-treat basis, then the failure rates for amodiaquine-SP and SP would be 15.5% and 21.0%, respectively. Would this difference merit a policy change? Probably not. But, given the cost and availability of both drugs, the combination might still be useful in the short-term.

In summary, the paper by Zongo and others strongly suggest that amodiaquine combination therapies for malaria should be evaluated. Further analyses (both intention-to-treat and cost-benefit) need to be performed to make the results more relevant for policy makers.

*

Address correspondence to Steven R. Meshnick, University of North Carolina School of Public Health, Department of Epidemiology, Chapel Hill, NC 27599. E-mail: meshnick@unc.edu

REFERENCES

  • 1

    Wongsrichanalai C, Pickard AL, Wernsdorfer WH, Meshnick SR, 2002. Epidemiology of drug-resistant malaria. Lancet Infect Dis 2 :209–218.

    • Search Google Scholar
    • Export Citation
  • 2

    Danis M, Bricaire F, 2003. The new drug combinations: their place in the treatment of uncomplicated Plasmodium falciparum malaria. Fundam Clin Pharmacol 17 :155–160.

    • Search Google Scholar
    • Export Citation
  • 3

    White NJ, Nosten F, Looareesuwan S, Watkins WM, Snow RW, Kokwaro G, Ouma J, Hien TT, Molyneux ME, Taylor TE, Newbold CI, Ruebush TK 2nd, Danis M, Greenwood BM, Anderson RM, Olliaro P, 1999. Averting a malaria disaster. Lancet 353 :1965–1967.

    • Search Google Scholar
    • Export Citation
  • 4

    Zongo I, Dorsey G, Rouamba N, Dokomajilar C, Lankoande M, Ouedraogo JB, Rosenthal PJ, 2005. Amodiaquine, sulfadoxine-pyrimethamine, and combination therapy for uncomplicated falciparum malaria: a randomized controlled trial from Burkino Faso. Am J Trop Med Hyg 73 :826–832.

    • Search Google Scholar
    • Export Citation
  • 5

    Chulay JD, Watkins WM, Sixsmith DG, 1984. Synergistic anti-malarial activity of pyrimethamine and sulfadoxine against Plasmodium falciparum in vitro. Am J Trop Med Hyg 33 :325–330.

    • Search Google Scholar
    • Export Citation
  • 6

    Srivastava IK, Vaidya AB, 1999. A mechanism for the synergistic antimalarial action of atovaquone and proguanil. Antimicrob Agents Chemother 43 :1334–1339.

    • Search Google Scholar
    • Export Citation
  • 7

    White NJ, 2004. Antimalarial drug resistance. J Clin Invest 113 :1084–1092.

  • 8

    Attaran A, Barnes KI, Curtis C, D’Alessandro U, Fanello CI, Galinski ME, Kokwaro G, Looareesuwan S, Makanga M, Mutabingwa TK, Talisuna A, Trape JF, Watkins WM, 2004. WHO, the Global Fund, and medical malpractice in malaria treatment. Lancet 363 :237–240.

    • Search Google Scholar
    • Export Citation
  • 9

    Rojanawatsirivej C, Vijaykadga S, Amklad I, Wilairatna P, Looareesuwan S, 2003. Monitoring the therapeutic efficacy of antimalarials against uncomplicated falciparum malaria in Thailand. Southeast Asian J Trop Med Public Health 34 :536–541.

    • Search Google Scholar
    • Export Citation
  • 10

    Clark RL, White TE, 2004. S AC, Gaunt I, Winstanley P and Ward SA. Developmental toxicity of artesunate and an artesunate combination in the rat and rabbit. Birth Defects Res B Dev Reprod Toxicol 71 :380–394.

    • Search Google Scholar
    • Export Citation
  • 11

    Anonymous, End decade databases—Fertility and Contraceptive Use. Vol. 2005: UNICEF Statistics

  • 12

    Steck EA, The Chemotherapy of Protozoan Diseases. Walter Reed Army Institute of Medicine, 1971

  • 13

    Thomas F, Erhart A, D’Alessandro U, 2004. Can amodiaquine be used safely during pregnancy? Lancet Infect Dis 4 :235–239.

  • 14

    Olliaro P, Mussano P, Amodiaquine for treating malaria. Cochrane Database Syst Rev 2003:CD000016

  • 15

    Taylor WR, White NJ, 2004. Antimalarial drug toxicity: a review. Drug Saf 27 :25–61.

  • 16

    Pussard E, Verdier F, Faurisson F, Scherrmann JM, Le Bras J, Blayo MC, 1987. Disposition of monodesethylamodiaquine after a single oral dose of amodiaquine and three regimens for prophylaxis against Plasmodium falciparum malaria. Eur J Clin Pharmacol 33 :409–414.

    • Search Google Scholar
    • Export Citation
  • 17

    Ringwald P, Bickii J, Basco LK, 1998. Amodiaquine as the first-line treatment of malaria in Yaounde, Cameroon: presumptive evidence from activity in vitro and cross-resistance patterns. Trans R Soc Trop Med Hyg 92 :212–213.

    • Search Google Scholar
    • Export Citation
  • 18

    Ringwald P, Bickii J, Basco LK, 1999. In vitro activity of dihydroartemisinin against clinical isolates of Plasmodium falciparum in Yaounde, Cameroon. Am J Trop Med Hyg 61 :187–192.

    • Search Google Scholar
    • Export Citation
  • 19

    Caramello P, Canta F, Cavecchia I, Sergi G, Balbiano R, Ariaudo S, Audagnotto S, DiPerri G, 2005. Chemosusceptibility analysis of Plasmodium falciparum imported malaria in Italy. Diagn Microbiol Infect Dis 52 :107–112.

    • Search Google Scholar
    • Export Citation
  • 20

    Graupner J, Gobels K, Grobusch MP, Lund A, Richter J, Haussinger D, 2005. Efficacy of amodiaquine in uncomplicated falciparum malaria in Nigeria in an area with high-level resistance to chloroquine and sulphadoxine/pyrimethamine. Parasitol Res 96 :162–165.

    • Search Google Scholar
    • Export Citation
  • 21

    Molta NB, Oguche S, Pam SD, Omalu IC, Afolabi BM, Odujoko JB, Amajoh CN, Adeniji B, Wuyep VP, Ekanem OJ, 2003. Amodiaquine treatment of uncomplicated malaria in children, in an area of chloroquine-resistant Plasmodium falciparum in north-central Nigeria. Ann Trop Med Parasitol 97 :663–669.

    • Search Google Scholar
    • Export Citation
  • 22

    Sendagire H, Kaddumukasa M, Ndagire D, Agutta C, Nassejje M, Pettersson M, Swedberg G, Kironde F, 2005. Rapid increase in resistance of Plasmodium falciparum to chloroquine-Fansidar in Uganda and the potential of amodiaquine-Fansidar as a better alternative. Acta Trop 95 :172–182.

    • Search Google Scholar
    • Export Citation
  • 23

    Rwagacondo CE, Karema C, Mugisha V, Erhart A, Dujardin JC, Van Overmeir C, Ringwald P, D’Alessandro U, 2004. Is amodiaquine failing in Rwanda? Efficacy of amodiaquine alone and combined with artesunate in children with uncomplicated malaria. Trop Med Int Health 9 :1091–1098.

    • Search Google Scholar
    • Export Citation
  • 24

    Basco LK, Same-Ekobo A, Ngane VF, Ndounga M, Metoh T, Ringwald P, Soula G, 2002. Therapeutic efficacy of sulfadoxine-pyrimethamine, amodiaquine and the sulfadoxine-pyrimethamine-amodiaquine combination against uncomplicated Plasmodium falciparum malaria in young children in Cameroon. Bull World Health Organ 80 :538–545.

    • Search Google Scholar
    • Export Citation
  • 25

    Dinis DV, Schapira A, 1990. Comparative study of sulfadoxine-pyrimethamine and amodiaquine + sulfadoxine-pyrimethamine for the treatment of malaria caused by chloroquine-resistant Plasmodium falciparum in Maputo, Mozambique. Bull Soc Pathol Exot 83 :521–527; discussion 528

    • Search Google Scholar
    • Export Citation
  • 26

    Dorsey G, Njama D, Kamya MR, Cattamanchi A, Kyabayinze D, Staedke SG, Gasasira A, Rosenthal PJ, 2002. Sulfadoxine/pyrimethamine alone or with amodiaquine or artesunate for treatment of uncomplicated malaria: a longitudinal randomised trial. Lancet 360 :2031–2038.

    • Search Google Scholar
    • Export Citation
  • 27

    Gasasira AF, Dorsey G, Nzarubara B, Staedke SG, Nassali A, Rosenthal PJ, Kamy MR, 2003. Comparative efficacy of aminoquinoline-antifolate combinations for the treatment of uncomplicated falciparum malaria in Kampala, Uganda. Am J Trop Med Hyg 68 :127–132.

    • Search Google Scholar
    • Export Citation
  • 28

    Huang OL, Ouyang WC, Zhou JX, Wu Z, Zhang KY, Huang JK, Cai XZ, Pang XJ, Fu SG, Wang XF, et al., 1988. Effectiveness of amodiaquine, sulfadoxine-pyrimethamine, and combinations of these drugs for treating chloroquine-resistant falciparum malaria in Hainan Island, China. Bull World Health Organ 66 :353–358.

    • Search Google Scholar
    • Export Citation
  • 29

    Menard D, Madji N, Manirakiza A, Djalle D, Koula MR, Talarmin A, 2005. Efficacy of chloroquine, amodiaquine, sulfadoxine-pyrimethamine, chloroquine-sulfadoxine-pyrimethamine combination, and amodiaquine-sulfadoxine-pyrimethamine combination in Central African children with non-complicated malaria. Am J Trop Med Hyg 72 :581–585.

    • Search Google Scholar
    • Export Citation
  • 30

    Mockenhaupt FP, Ehrhardt S, Dzisi SY, Teun Bousema J, Wassilew N, Schreiber J, Anemana SD, Cramer JP, Otchwemah RN, Sauerweim RW, Eggelte TA, Bienzle U, 2005. A randomized, placebo-controlled, double-blind trial on sulfadoxine-pyrimethamine alone or combined with artesunate or amodiaquine in uncomplicated malaria. Trop Med Int Health 10 :512–520.

    • Search Google Scholar
    • Export Citation
  • 31

    Mutabingwa TK, Anthony D, Heller A, HallettR, Ahmed J, Drakeley C, Greenwood BM, Whitty CJ, 2005. Amodiaquine alone, amodiaquine+sulfadoxine-pyrimethamine, amodiaquine+artesunate, and artemether-lumefantrine for outpatient treatment of malaria in Tanzanian children: a four-arm randomised effectiveness trial. Lancet 365 :1474–1480.

    • Search Google Scholar
    • Export Citation
  • 32

    Schapira A, Schwalbach JF, 1988. Evaluation of four therapeutic regimens for falciparum malaria in Mozambique, 1986. Bull World Health Organ 66 :219–226.

    • Search Google Scholar
    • Export Citation
  • 33

    Schellenberg D, Kahigwa E, Drakeley C, Malende A, Wigayi J, Msokame C, Aponte JJ, Tanner M, Mshinda H, Menendez C, Alonso PL, 2002. The safety and efficacy of sulfadoxine-pyrimethamine, amodiaquine, and their combination in the treatment of uncomplicated Plasmodium falciparum malaria. Am J Trop Med Hyg 67 :17–23.

    • Search Google Scholar
    • Export Citation
  • 34

    Staedke SG, Kamya MR, Dorsey G, Gasasira A, Ndeezi G, Charlebois ED, Rosenthal PJ, 2001. Amodiaquine, sulfadoxine/pyrimethamine, and combination therapy for treatment of uncomplicated falciparum malaria in Kampala, Uganda: a randomised trial. Lancet 358 :368–374.

    • Search Google Scholar
    • Export Citation
  • 35

    Melander H, Ahlqvist-Rastad J, Meijer G, Beermann B, 2003. Evidence b(i)ased medicine–selective reporting from studies sponsored by pharmaceutical industry: review of studies in new drug applications. BMJ 326 :1171–1173.

    • Search Google Scholar
    • Export Citation
  • 36

    Tierney JF, Stewart LA, 2005. Investigating patient exclusion bias in meta-analysis. Int J Epidemiol 34 :79–87.

  • 37

    Schulz KF, Grimes DA, 2002. Sample size slippages in randomised trials: exclusions and the lost and wayward. Lancet 359 :781–785.

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