Artesunate plus mefloquine versus mefloquine for treating uncomplicated malaria

Hasifa Bukirwa; Lois C Orton

doi:10.1002/14651858.CD004531.pub2

Artesunato más mefloquina versus mefloquina para el tratamiento del paludismo no complicado

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Referencias

Referencias de los estudios incluidos en esta revisión

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estudios excluidos
otras referencias

Karbwang J, Na Bangchang K, Thanavibul A, Back DJ, Bunnag D, Harinasuta T. Pharmacokinetics of mefloquine alone or in combination with artesunate. Bulletin of the World Health Organization 1994;72(1):83‐7.

Looareesuwan S, Viravan C, Vanijanonta S, Wilairatana P, Suntharasamai P, Charoenlarp P, et al. Randomised trial of artesunate and mefloquine alone and in sequence for acute uncomplicated falciparum malaria. Lancet 1992;339(8797):821‐4.

Marquino W, Huilca M, Calampa C, Falconi E, Cabezas C, Naupay R, et al. Efficacy of mefloquine and mefloquine‐artesunate combination therapy for the treatment of uncomplicated Plasmodium falciparum malaria in the Amazon Basin of Peru. American Journal of Tropical Medicine and Hygiene 2003;68(5):608‐12.

Pillai DR, Hijar G, Montoya Y, Marouino W, Ruebush TK, Wongsrichanalai C, et al. Lack of prediction of mefloquine and mefloquine‐artesunate treatment outcome by mutations in the Plasmodium falciparum multidrug resistance 1 (pfmdr1) gene for P. falciparum malaria in Peru. American Journal of Tropical Medicine and Hygiene 2003;68(1):107‐10.

Nosten F, Luxemburger C, ter Kuile FO, Woodrow C, Pah Eh J, Chongsuphajaisiddhi T, et al. Treatment of multidrug‐resistant Plasmodium falciparum malaria with 3‐day artesunate‐mefloquine combination. Journal of Infectious Diseases 1994;170(4):971‐7.

Price RN, Nosten F, Luxemburger C, Kham A, Brockman A, Chongsuphajaisiddhi T, et al. Artesunate versus artemether in combination with mefloquine for the treatment of multidrug‐resistant falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 1995;89(5):523‐7.

Smithuis F, Shahmanesh M, Kyaw MK, Savran O, Lwin S, White NJ. Comparison of chloroquine, sulfadoxine/pyrimethamine, mefloquine and mefloquine‐artesunate for the treatment of falciparum malaria in Kachin State, North Myanmar. Tropical Medicine and International Health 2004;9(11):1184‐90.

Thimasarn K, Sirichaisinthop J, Chanyakhun P, Palananth C, Rooney W. A comparative study of artesunate and artemether in combination with mefloquine on multidrug resistant falciparum malaria in Eastern Thailand. SouthEast Asian Journal of Tropical Medicine and Public Health 1997;28(3):465‐71.

Referencias de los estudios excluidos de esta revisión

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estudios incluidos
otras referencias

Adam I, A‐Elbasit IE, Elbashir MI. Efficacies of mefloquine alone and of artesunate followed by mefloquine, for the treatment of uncomplicated, Plasmodium falciparum malaria in eastern Sudan. Annals of Tropical Medicine and Parasitology 2005;99(2):111‐7.

Cardoso Bda S, Dourado HV, Pinheiro Mda C, Crescente JA, Amoras WW, Baena J, et al. An efficacy and tolerance study of oral artesunate alone and in combination with mefloquine in the treatment of umcomplicated falciparum malaria in an endemic area of Para, Brazil [Estudo da eficacia e tolerancia do artesunato oral isolado e em associacao com mefloquina, no tratamanto da malaria falciparum nao complicada em area endemica do Para, Brasil]. Revista da Sociedade Brasileira de Medicina Tropical 1996;29(3):251‐7.

Looareesuwan S, Vanijanonta S, Viravan C, Wilairatana P, Charoenlarp P, Andrial M. Randomized trial of mefloquine alone and artesunate followed by mefloquine for the treatment of acute uncomplicated falciparum malaria. Annals of Tropical Medicine and Parasitology 1994;88(2):131‐6.

Luxemburger C, ter Kuile FO, Nosten F, Dolan G, Bradol JH, Phaipun L, et al. Single day mefloquine‐artesunate combination in the treatment of multi‐drug resistant falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 1994;88(2):213‐7.

Price R, Luxemburger C, van Vugt M, Nosten F, Kham A, Simpson J, et al. Artesunate and mefloquine in the treatment of uncomplicated multidrug‐resistant hyperparasitaemic falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 1998;92(2):207‐11.

Referencias adicionales

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estudios excluidos

Angus BJ, Thaiaporn I, Chanthapadith K Suputtamongkol Y, White NJ. Oral artesunate dose‐response relationship in acute falciparum malaria. Journal of the Medical Association of Thailand 2001;84(9):1289‐99.

Bethell DB, Teja‐Isavadharm P, Cao XT, Pham TT, Ta TT, Tran TN, et al. Pharmacokinetics of oral artesunate in children with moderately severe Plasmodium falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 1997;91(2):195‐8.

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ir a:

estudios excluidos

Karbwang 1994

Methods	Randomized controlled trial Length of follow up: 42 d Generation of allocation sequence: no details available Allocation concealment: not mentioned Blinding: not mentioned Inclusion of all randomized participants: 9.1% (2/22) excluded after randomization due to vomiting of trial drugs
Participants	Number enrolled: 22 participants aged 17 to 48 years Inclusion criteria: adult male patients; aged 17 to 48 years; 45 to 70 kg bodyweight; uncomplicated malaria; asexual parasites < 5% Exclusion criteria: history of liver or kidney disease
Interventions	1. Artesunate plus mefloquine 2. Mefloquine Artesunate: 200 mg Mefloquine: 750 mg followed by 500 mg 6 h later
Outcomes	1. Mean fever clearance time 2. Mean parasite clearance time 3. Adverse events 4. Parasite counts at various time points reportedly measured but not reported
Notes	Location: Bangkok, Thailand Date: not given Source of funding: UNDP/World Bank/WHO Special Programme for Training in Tropical Diseases, Atlantic Co. Ltd (Thailand), and Hoffmann‐La Roche (Thailand)

Looareesuwan 1992a

Methods	Randomized controlled trial Length of follow up: 28 d Generation of allocation sequence: no details available Allocation concealment: not mentioned Blinding: not mentioned Inclusion of all randomized participants: 9.4% (8/85) excluded at day 28 from analysis due to severe vomiting of study drugs and concomitant illness but other losses to follow up were not accounted for
Participants	Number enrolled: 127 participants between 16 and 56 years old Inclusion criteria: acute uncomplicated falciparum malaria; 100 to 200,000 parasites/µL blood; 16 to 60 years old; 45 to 60 kg bodyweight who agreed to stay in hospital for 28 days Exclusion criteria: pregnancy; severe malaria; and history of antimalarial drug treatment in preceding 1 week
Interventions	1. Artesunate plus mefloquine 2. Mefloquine Artesunate: 100 mg followed by 50 mg/12 h for 5 d Mefloquine: 750 mg followed by 500 mg after 6 h Not included in this review: 3. Artesunate
Outcomes	1. Number cured at 28 d 2. Mean parasite clearance time 3. Mean fever clearance time 4. Adverse events
Notes	Location: Bangkok, Thailand Date: January to May 1991 Source of funding: Mahidol University research grant and Roche Research Foundation of Hong Kong; Atlantic Pharmaceutical Co. Ltd supplied artesunate tablets

Marquino 2003

Methods	Randomized controlled trial Length of follow up: 28 d Generation of allocation sequence: table of random numbers Allocation concealment: not mentioned Blinding: not mentioned Inclusion of all randomized participants: 14.8% (17/115) were excluded from analysis at day 28 because of loss to follow up and taking antimalarial medication outside of the trial
Participants	Number enrolled: 115 children and adults aged 5 to 50 years Inclusion criteria: falciparum mono infection with 500 to 30,000 parasites/µl of blood; axillary temperature at least 37.5 °C and/or history of fever in previous 48 h Exclusion criteria: severe malaria; presence of other causes of fever; pregnancy; and history of allergy to trial medication
Interventions	1. Artesunate plus mefloquine 2. Mefloquine Artesunate: 4 mg/kg/d for 3 d, single dose Mefloquine: 15 mg/kg, single dose
Outcomes	1. Fever on day 3 2. Parasite carriage at days 3, 7, 14, 21, and 28 3. Adverse events
Notes	Location: Peruvian Amazon Date: June to September 2000 Source of funding: US Agency for International Development, the US Naval Medical Research Command, and the Government of Peru

Nosten 1994a

Methods	Randomized controlled trial Length of follow up: 28 d Generation of allocation sequence: randomization in pairs, no further details available Allocation concealment: not mentioned Blinding: not mentioned Inclusion of all randomized participants: 21.4% (65/304) excluded at day 28 due to vomiting trial medication and loss to follow up
Participants	Number enrolled: 304 adults and children Inclusion criteria: slide‐confirmed malaria; weight > 5 kg; no use of other antimalarial in previous month; no signs of severe disease; and not pregnant
Interventions	1. Artesunate plus mefloquine 2. Mefloquine Artesunate: 4 mg/kg, single dose Mefloquine: 25 mg/kg, single dose
Outcomes	1. Fever clearance time 2. Parasite clearance time 3. Parasite carriage at days 1, 2, 3, 4, 5, 7, 14, and 28 4. Adverse events
Notes	Location: Thai‐Burmese boarder near Mae Sot Date: January to July 1992 Source of funding: not reported Nosten 1994a and Nosten 1994b are published in the same article

Nosten 1994b

Methods	Randomized controlled trial Length of follow up: 63 d Generation of allocation sequence: no details Allocation concealment: not mentioned Blinding: not mentioned Inclusion of all randomized participants: 11.8% excluded at day 28 and 31.9% excluded at day 63 due to vomiting trial medication and attrition
Participants	Number enrolled: 348 adults and children Inclusion criteria: slide‐confirmed malaria; weight > 5 kg; no use of other antimalarial in previous month; no signs of severe disease; and not pregnant
Interventions	1. Artesunate plus mefloquine 2. Mefloquine Artesunate: 4 mg/kg followed by 2 mg daily for 3 d Mefloquine: 25 mg/kg, single dose
Outcomes	1. Fever clearance time 2. Parasite clearance time 3. Parasite carriage at days 1, 2, 3, 4, 5, 7, 14, and 28 4. Adverse events
Notes	Location: Thai‐Burmese boarder near Mae Sot Date: October 1992 to June 1993 Source of funding: not reported Nosten 1994a and Nosten 1994b are published in the same article

Price 1995

Methods	Randomized controlled trial Length of follow up: 63 d Generation of allocation sequence: randomized in blocks of three, no further details available Allocation concealment: not mentioned Blinding: not mentioned Inclusion of all randomized participants: 14.1% (46/362) lost to follow up at day 28, and 28.3% (98/362) lost to follow up at day 63; participants excluded because of vomiting and for reasons reportedly unrelated to the trial
Participants	Number enrolled: 550 Inclusion criteria: weight at least 5 kg; slide‐confirmed falciparum malaria; and no antimalarial treatment in preceding 63 d Exclusion criteria: pregnancy; signs of severe malaria or concomitant illness requiring hospitalization; and history of neuropsychiatric illness
Interventions	1. Artesunate plus mefloquine 2. Mefloquine Artesunate: 4 mg/kg/d for 3 d Mefloquine: 25 mg/kg, single dose on day 2 Not included in this review: 3. Artemether plus mefloquine
Outcomes	1. Parasite clearance time 2. Fever clearance time 3. Symptom clearance time 4. Adjusted cumulative failure rates at days 7, 28, 42, and 63 5. Adverse events
Notes	Location: Thai‐Myanmar border Date: June 1993 to May 1994 Source of funding: Wellcome Trust of Great Britain

Smithius 2004

Methods	Randomized controlled trial Length of follow up: 42 d Generation of allocation sequence: not mentioned Allocation concealment: not mentioned Blinding: not mentioned Inclusion of all randomized participants: not possible to calculate losses to follow up because numbers were not clear
Participants	Number enrolled: 317, but only 156 given interventions relevant to this review Inclusion criteria: axillary temperature at least 37.5 °C or history of fever in previous 2 d; Plasmodium falciparum parasites of at least 1000/mm³ blood Exclusion criteria: body weight < 5 kg; pregnant women; signs and symptoms of complicated malaria or suggestive of another cause of fever; patients with a recent history of mefloquine use; patients with a parasite count > 250,000/mm³ and mixed infections
Interventions	1. Artesunate plus mefloquine 2. Mefloquine Artesunate: 4 mg/kg, single dose Mefloquine: 15 mg/kg, single dose Not included in this review: 3. Chloroquine 4. Sulfadoxine‐pyrimethamine
Outcomes	1. Treatment failure at days 14, 28, and 42 2. Parasitaemia at day 3 3. Fever at day 3
Notes	Location: Kachin State, north Myanmar Date: July to August 2004 Source of funding: Médecins Sans Frontières (Holland)

Thimasarn 1997

Methods	Randomized controlled trial Length of follow up: 28 d Generation of allocation sequence: no details available Allocation concealment: not mentioned Blinding: not mentioned Inclusion of all randomized participants: 3% (12/394) excluded post‐randomization for taking wrong regimen and vomiting of trial drugs but distribution across groups not given
Participants	Number enrolled: 394 participants Inclusion criteria: symptomatic adults > 15 years old with malaria contracted within 50 km radius of the trial clinics; asexual parasitaemia 500 to 400,000 parasites/µL blood; no signs of complications; no history of antimalarial drug intake in previous 2 weeks; and consent to stay in malaria free area for the period of follow up Exclusion criteria: pregnancy
Interventions	1. Artesunate plus mefloquine 2. Mefloquine Artesunate: 300 mg/d for 2 d Mefloquine: 750 mg on day 1 and 500 mg on day 2 Not included in this review: 3. Artesunate 4. Artemether 5. Quinine 6. Artemether‐mefloquine 7. Artesunate plus mefloquine with a different mefloquine dose
Outcomes	1. Cure rate at day 28 2. Adverse events Not included in this review: 3. Parasite malaria drug sensitivity 4. Parasite malaria drug resistance
Notes	Location: Thai‐Cambodia border Date: July 1993 to December 1994 Source of funding: World Health Organization country budget for Thailand (THA/DPC/001)

Allocation concealment: B = unclear, see 'Methods of the review' for details and a summary of the quality assessment in Table 04

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos

Study	Reason for exclusion
Adam 2005	Used different mefloquine doses for combination and mefloquine alone study arms
Cardoso 1996	Used different mefloquine doses for combination and mefloquine alone study arms
Looareesuwan 1993	Used different mefloquine doses for combination and mefloquine alone study arms
Luxemburger 1991	Used different mefloquine doses for combination and mefloquine alone study arms
Price 1998	Compared artesunate plus mefloquine with artesunate rather than mefloquine

Data and analyses

Open in table viewer

Comparison 1. Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.1 Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 1 Treatment failure.
1.1 Day 28	4	824	Risk Ratio (M‐H, Random, 95% CI)	0.17 [0.06, 0.47]
1.2 Day 42	1	298	Risk Ratio (M‐H, Random, 95% CI)	0.23 [0.14, 0.39]
1.3 Day 63	2	501	Risk Ratio (M‐H, Random, 95% CI)	0.26 [0.09, 0.77]
2 Parasitaemia Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.2 Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 2 Parasitaemia.
2.1 Day 3	2	716	Risk Ratio (M‐H, Fixed, 95% CI)	0.04 [0.02, 0.11]
2.2 Day 7	2	700	Risk Ratio (M‐H, Fixed, 95% CI)	0.02 [0.00, 0.11]
2.3 Day 14	1	339	Risk Ratio (M‐H, Fixed, 95% CI)	0.09 [0.03, 0.28]
3 Fever Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.3 Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 3 Fever.
3.1 Day 2	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Mean fever clearance time (h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.4 Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 4 Mean fever clearance time (h).
5 Mean parasite clearance time (h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.5 Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 5 Mean parasite clearance time (h).
6 Adverse events Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.6 Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 6 Adverse events.
6.1 Serious adverse events	1	368	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 8.04]
6.2 Adverse events requiring discontinuation of treatment	2	444	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.04, 3.23]
6.3 Abdominal pain	2	196	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.31, 1.20]
6.4 Cardiovascular abnormalities	1	120	Risk Ratio (M‐H, Random, 95% CI)	1.95 [0.08, 46.79]
6.5 Central nervous system abnormalities	1	120	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.53, 1.36]
6.6 Diarrhoea	2	196	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.48, 2.77]
6.7 Dizziness	1	76	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.10, 1.24]
6.8 Headache	2	196	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.38, 0.69]
6.9 Itching and rash	1	76	Risk Ratio (M‐H, Random, 95% CI)	2.85 [0.12, 67.83]
6.10 Nausea	2	196	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.33, 1.16]
6.11 Palpitations/anxiety	1	368	Risk Ratio (M‐H, Random, 95% CI)	2.97 [0.12, 72.38]
6.12 Psychosis	1	654	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.01, 7.91]
6.13 Vomiting	4	1218	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.39, 1.62]
6.14 Other adverse events	1	120	Risk Ratio (M‐H, Random, 95% CI)	8.43 [0.49, 146.28]

Open in table viewer

Comparison 2. Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.1 Comparison 2 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 1 Treatment failure.
1.1 Day 28	2	259	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.50, 1.38]
1.2 Day 42	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	2.67 [0.36, 19.71]
2 Parasitaemia Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 2.2 Comparison 2 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 2 Parasitaemia.
2.1 Day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Day 7	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.3 Day 14	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Fever Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 2.3 Comparison 2 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 3 Fever.
3.1 Day 2	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Mean fever clearance time (h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 2.4 Comparison 2 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 4 Mean fever clearance time (h).
5 Mean parasite clearance time (h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 2.5 Comparison 2 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 5 Mean parasite clearance time (h).

Open in table viewer

Comparison 3. Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (15 mg)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Parasitaemia Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 3.1 Comparison 3 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 1 Parasitaemia.
1.1 Day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Fever Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 3.2 Comparison 3 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 2 Fever.
2.1 Day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Adverse event Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
Open in figure viewer Analysis 3.3 Comparison 3 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 3 Adverse event.
3.1 Insomnia	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Open in table viewer

Comparison 4. Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (15 mg)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
Open in figure viewer Analysis 4.1 Comparison 4 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 1 Treatment failure.
1.1 Day 14	1	149	Risk Ratio (M‐H, Random, 95% CI)	1.27 [0.35, 4.53]
1.2 Day 28	1	142	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.16, 1.21]
1.3 Day 42	1	147	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.48, 1.65]
2 Parasitaemia Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 4.2 Comparison 4 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 2 Parasitaemia.
2.1 Day 3	1	156	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.14, 1.29]
3 Fever Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 4.3 Comparison 4 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 3 Fever.
3.1 Day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Analysis 1.1

Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 1 Treatment failure.

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Analysis 1.2

Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 2 Parasitaemia.

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Analysis 1.3

Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 3 Fever.

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Analysis 1.4

Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 4 Mean fever clearance time (h).

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Analysis 1.5

Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 5 Mean parasite clearance time (h).

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Analysis 1.6

Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 6 Adverse events.

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Analysis 2.1

Comparison 2 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 1 Treatment failure.

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Analysis 2.2

Comparison 2 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 2 Parasitaemia.

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Analysis 2.3

Comparison 2 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 3 Fever.

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Analysis 2.4

Comparison 2 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 4 Mean fever clearance time (h).

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Analysis 2.5

Comparison 2 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 5 Mean parasite clearance time (h).

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Analysis 3.1

Comparison 3 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 1 Parasitaemia.

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Analysis 3.2

Comparison 3 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 2 Fever.

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Analysis 3.3

Comparison 3 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 3 Adverse event.

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Analysis 4.1

Comparison 4 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 1 Treatment failure.

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Analysis 4.2

Comparison 4 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 2 Parasitaemia.

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Analysis 4.3

Comparison 4 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 3 Fever.

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Table 1. Detailed search strategies

Search set	CIDG SR^a	CENTRAL	MEDLINE^b	EMBASE^b	LILACS^b	BIOSIS
1	artesunate	artesunate	ARTESUNATE	ARTESUNATE	artesunate	artesunate
2	mefloquine	mefloquine	artesunate	artesunate	mefloquine	mefloquine
3	Lariam	Lariam	arsumax	arsumax	malaria	Lariam
4	—	2 or 3	1 or 2 or 3	1 or 2 or 3	1 and 2 and 3	—
5	—	1 and 4	MEFLOQUINE	mefloquine	—	—
6	—	—	mefloquine	MEFLOQUINE	—	—
7	—	—	Lariam	mephaquim	—	—
8	—	—	5 or 6 or 7	Lariam	—	—
9	—	—	4 and 8	5 or 6 or 7 or 8	—	—
10	—	—	exp MALARIA	4 and 9	—	—
11	—	—	malaria	malaria	—	—
12	—	—	exp PLASMODIUM	MALARIA	—	—
13	—	—	plasmodium	PLASMODIUM‐FALCIPARUM	—	—
14	—	—	10 or 11 or 12 or 13	11 or 12 or 13	—	—
15	—	—	9 and 14	10 and 14	—	—
^aCochrane Infectious Diseases Group Specialized Register. ^bSearch terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration Higgins 2005; upper case: MeSH or EMTREE heading; lower case: free text term.

Table 1. Detailed search strategies

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Table 2. Methods for future updates

Method	Details
Recrudesced and new infections	In areas of intense malaria transmission, blood smears positive for malaria parasites after day 14 may be a result of new infections or a recrudescence of the original infection. Polymerase chain reaction (PCR) is a method that can be used to differentiate between new and old infections. We will use the results of PCR analyses, if they become available, to differentiate between recrudesced and new infections
Continuous data reported with geometric means	We will extract the standard deviations on the log scale, and extract minimum and maximum values for medians. We will combine the findings on a log scale and report on the original scale; we will report medians and ranges in tables
Exploring potential sources of heterogeneity using subgroup analyses	1. Intervention: simultaneous versus sequential regimens; mefloquine dose; and artesunate dose 2. Trial setting: level of background mefloquine resistance; high malaria transmission (an area of hyperendemicity or holoendemicity) versus low transmission (an area of hypoendemicity or mesoendemicity) 3. Pre‐treatment malaria parasite density: < 250,000/µL or 5% of total red blood cells and at least 250,000/µL or 5% of total red blood cells 4. Age: ≤ 5 years and > 5 years
Sensitivity analyses	We will conduct sensitivity analyses for each of the components of methodological quality
Funnel plots	We will examine funnel plots for asymmetry, keeping in mind that the asymmetry could be caused by publication bias, differences in methodological quality, or heterogeneity

Table 2. Methods for future updates

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Table 3. Total dose and regimens: artesunate and mefloquine

Trial	Artesunate		Mefloquine
Trial	Total dose (mg/kg)	Regimen	Total dose (mg/kg)	Regimen
Karbwang 1994	3.33^a	1 dose	21^b	2 doses over 1 day
Looareesuwan 1992a	10	11 doses over 5 days	21^b	2 doses over 1 day
Marquino 2003	12	3 doses over 3 days	15	1 dose
Nosten 1994a	4	1 dose	25	1 dose
Nosten 1994b	10	4 doses over 3 days	25	1 dose
Price 1995	12	3 doses over 3 days	25	1 dose
Smithius 2004	4	1 dose	15	1 dose
Thimasarn 1997	10^a	2 doses over 2 days	21^b	2 doses over 3 days
^aAssuming 60 kg person (actual dose 200 mg). ^bAssuming 60 kg person (actual dose 1250 mg).

Table 3. Total dose and regimens: artesunate and mefloquine

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Table 4. Risk of bias assessment

Trial	Generation of allocation sequence^c	Allocation concealment^d	Blinding^e	Inclusion of all randomized participants in final analysis^b
Karbwang 1994	Unclear	Unclear	Unclear	Adequate
Looareesuwan 1992a	Unclear	Unclear	Unclear	Inadequate
Marquino 2003	Adequate	Unclear	Unclear	Inadequate
Nosten 1994a	Unclear	Unclear	Unclear	Inadequate
Nosten 1994b	Unclear	Unclear	Unclear	Inadequate
Smithius 2004	Unclear	Unclear	Unclear	Inadequate
Thimasarn 1997	Unclear	Unclear	Unclear	Adequate
Price 1998	Unclear	Unclear	Unclear	Inadequate
^aSee the 'Assessment of risk of bias in included studies' for the assessment methods, and the Characteristics of included studies' for the methods used in each trial. ^bFor primary outcomes. ^cUnclear: reported as random but method not revealed. ^dUnclear: not mentioned. ^eUnclear: unlikely to be blinded.

Table 4. Risk of bias assessment

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Comparison 1. Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Day 28	4	824	Risk Ratio (M‐H, Random, 95% CI)	0.17 [0.06, 0.47]
1.2 Day 42	1	298	Risk Ratio (M‐H, Random, 95% CI)	0.23 [0.14, 0.39]
1.3 Day 63	2	501	Risk Ratio (M‐H, Random, 95% CI)	0.26 [0.09, 0.77]
2 Parasitaemia Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Day 3	2	716	Risk Ratio (M‐H, Fixed, 95% CI)	0.04 [0.02, 0.11]
2.2 Day 7	2	700	Risk Ratio (M‐H, Fixed, 95% CI)	0.02 [0.00, 0.11]
2.3 Day 14	1	339	Risk Ratio (M‐H, Fixed, 95% CI)	0.09 [0.03, 0.28]
3 Fever Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3.1 Day 2	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Mean fever clearance time (h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

5 Mean parasite clearance time (h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

6 Adverse events Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

6.1 Serious adverse events	1	368	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 8.04]
6.2 Adverse events requiring discontinuation of treatment	2	444	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.04, 3.23]
6.3 Abdominal pain	2	196	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.31, 1.20]
6.4 Cardiovascular abnormalities	1	120	Risk Ratio (M‐H, Random, 95% CI)	1.95 [0.08, 46.79]
6.5 Central nervous system abnormalities	1	120	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.53, 1.36]
6.6 Diarrhoea	2	196	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.48, 2.77]
6.7 Dizziness	1	76	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.10, 1.24]
6.8 Headache	2	196	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.38, 0.69]
6.9 Itching and rash	1	76	Risk Ratio (M‐H, Random, 95% CI)	2.85 [0.12, 67.83]
6.10 Nausea	2	196	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.33, 1.16]
6.11 Palpitations/anxiety	1	368	Risk Ratio (M‐H, Random, 95% CI)	2.97 [0.12, 72.38]
6.12 Psychosis	1	654	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.01, 7.91]
6.13 Vomiting	4	1218	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.39, 1.62]
6.14 Other adverse events	1	120	Risk Ratio (M‐H, Random, 95% CI)	8.43 [0.49, 146.28]

Comparison 1. Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg)

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Comparison 2. Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Day 28	2	259	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.50, 1.38]
1.2 Day 42	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	2.67 [0.36, 19.71]
2 Parasitaemia Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2.1 Day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Day 7	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.3 Day 14	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Fever Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3.1 Day 2	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Mean fever clearance time (h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

5 Mean parasite clearance time (h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 2. Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg)

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Comparison 3. Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (15 mg)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Parasitaemia Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.1 Day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Fever Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2.1 Day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Adverse event Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3.1 Insomnia	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 3. Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (15 mg)

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Comparison 4. Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (15 mg)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Day 14	1	149	Risk Ratio (M‐H, Random, 95% CI)	1.27 [0.35, 4.53]
1.2 Day 28	1	142	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.16, 1.21]
1.3 Day 42	1	147	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.48, 1.65]
2 Parasitaemia Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Day 3	1	156	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.14, 1.29]
3 Fever Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3.1 Day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 4. Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (15 mg)

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Referencias

Referencias de los estudios incluidos en esta revisión

Karbwang 1994 {published data only}

Looareesuwan 1992a {published data only}

Marquino 2003 {published data only}

Nosten 1994a {published data only}

Nosten 1994b {published data only}

Price 1995 {published data only}

Smithius 2004 {published data only}

Thimasarn 1997 {published data only}

Referencias de los estudios excluidos de esta revisión

Adam 2005 {published data only}

Cardoso 1996 {published data only}

Looareesuwan 1993 {published data only}

Luxemburger 1991 {published data only}

Price 1998 {published data only}

Referencias adicionales

Angus 2001

Bethell 1997

Brewer 1994

Gilles 2000

Higgins 2005

Hoshen 2000

Jüni 2001

Kain 1995

Looareesuwan 1992b

Looareesuwan 1998

McIntosh 1999

McIntosh 2000

Olliaro 1996

Price 1996

RBM 2001a

RBM 2001b

RBM 2001c

Review Manager 5 [Computer program]

Trung 2001

Weinke 1991

White 1996

White 1997

White 1999

WHO 2001

WHO 2002

WHO 2006

WHO/UNICEF 2003

Wongsrichanalai 2002

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Data and analyses

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