Background
Amodiaquine (AQ) is a 4-aminoquinoline, similar to chloroquine (CQ), that has been used widely to treat and prevent malaria. AQ is a cheap alternative to CQ, and is available in several countries, some with local production facilities. It is more palatable than CQ and therefore easier to administer to children. It has also been suggested that it may be a less toxic alternative to sulphadoxine-pyrimethamine (SP) in people infected with HIV in Sub Saharan Africa (Coopman 1993). It is also used in combination with the antimalarial drugs artesunate and SP. These combinations are the subject of other Cochrane Reviews (IASG 2002; MacIntosh 2002).
Amodiaquine was first added to the World Health Organization (WHO) Essential Drugs List (EDL) in 1977. In 1979, the committee decided to delete it from the List due to its similarity with CQ. However, it was quickly reinstated in the same year (WHO 2002). In the mid 1980s, fatal adverse drug reactions were described in travellers using AQ for prophylaxis (Hatton 1986; Neftel 1986). As a result, the manufacturer (Parke-Davis) modified the labelling and withdrew prophylaxis as an indication, while, in 1988, the WHO deleted it from the EDL and prevented its use in malaria control programmes (WHO 1990).
The WHO'srecommendations confused policy and practice. Several countries banned its use altogether, whilst others have continued to use the drug as first line treatment for uncomplicated malaria - either giving it alone or in combination with other drugs. In the light of this, the 19th Expert Committee on Malaria, held in 1993, modified their statement to say that "amodiaquine could be used for treatment if the risk of infection outweighs the potential for ADRs [adverse drug reactions]", but still did not recommend AQ as first line treatment (WHO 1993).
This Cochrane Review, first published in 1996, compares the effectiveness of AQ, CQ and SP for treating uncomplicated falciparum malaria. The 1996 version concluded that AQ was a valuable drug and supported its continued use for the treatment of uncomplicated malaria with the proviso that, due to the partial cross-resistance with CQ, research must continue into both its effectiveness and safety. These findings led the WHO to modify its recommendations and reinstate AQ as an option for treating falciparum malaria (WHO 1997).
Objectives
To compare amodiaquine with chloroquine and sulphadoxine-pyrimethamine for treating uncomplicated malaria in adults and children.
Methods
Criteria for considering studies for this review
Types of studies
Randomized and quasi-randomized controlled trials conducted during and after 1980.
The year restriction takes account of the changing patterns of resistance development to antimalarial drugs, which can affect the treatment outcome.
Types of participants
Individuals with uncomplicated falciparum malaria infection. Defined as either:
(1) fever or a history of fever, accompanied by P. falciparum parasitaemia ("symptomatic") or;
(2) P. falciparum parasitaemia detected through blood survey and no fever ("asymptomatic").
Types of interventions
Intervention
Amodiaquine (AQ).
Control
Chloroquine (CQ) or sulphadoxine-pyrimethamine (SP).
Types of outcome measures
Primary
Parasitological conversion, defined as conversion from a positive blood smear at baseline to a negative smear for P. falciparum at day 7, 14, or 28.
Secondary
Time to sustained parasite clearance (restricted to days 0 through 7).
Adverse events
Adverse events that are:
1. Fatal, life threatening, or require hospitalization;
2. Result in the discontinuation of treatment.
Search methods for identification of studies
We attempted to identify all relevant studies regardless of language or publication status (published, unpublished, in press, and in progress).
We used the following search terms for all trial registers and databases: malaria; amod*.
We searched the Cochrane Infectious Diseases Group specialized trials register for relevant trials up to February 2003. Full details of the Cochrane Infectious Diseases Group methods and the journals hand searched are published in The Cochrane Library in the section on Collaborative Review Groups.
We searched the Cochrane Central Register of Controlled Trials, published in The Cochrane Library (Issue 1, 2003). This contains mainly reference information to randomized controlled trials and controlled clinical trials in health care.
We searched the following electronic databases using the topic search terms in combination with the search strategy developed by the Cochrane Collaboration and detailed in the Cochrane Reviewers' Handbook (Clarke 2003); MEDLINE (1966 to February 2003); EMBASE (1980 to December 2002); and LILACS (La Literatura Latinoamericana y del Caribe de Informacion en Ciencias de Salud) www.bireme.br; accessed February 2003.
We contacted organizations, individual researchers working in the field, and pharmaceutical companies for unpublished and ongoing trials.
We sought unpublished and raw data by extensive liaison with experienced researchers in the field, and by requests to the pharmaceutical companies manufacturing the product. In view of the large amount of unpublished studies known to exist on amodiaquine, we contacted key researchers known to the World Health Organization and set up meetings, during which we explained the objectives of the systematic review, sought and collected data, reviewed and discussed the results.
We also checked the reference lists of all trials identified by the above methods.
Data collection and analysis
Selection of studies
The main author scanned the results of the literature search for potentially relevant trials. We retrieved the full articles for all trials thought to be potentially relevant. Three people independently assessed the potentially relevant trials for inclusion in the review.
Data extraction and management
The data were extracted by two reviewers independently, using a data extraction form. Where there were disagreements, these were resolved by discussion. The data were entered into Review Manager 5 by the main reviewer, and checked by Ms Mussano for all editions of the review. We contacted the authors to obtain additional data, unpublished components of studies, and to clarify details of the methods used.
Assessment of risk of bias in included studies
We assessed the methodological quality of each included trial with respect to the generation of allocation sequence, allocation concealment, blinding, and loss to follow up.
Data synthesis
We analysed data using Review Manager 5.
Whenever possible, we contacted authors and asked them to help in the production of this review by reanalysing their data and/or to provide individual patient data to reanalyse the data using pre-specified outcome measures. In cases where the authors provided crude data, we entered these into a statistical package for analysis.
To minimize selection bias and the effect of participant attrition, we calculated the proportion of parasitological conversion from the total number of participants reportedly "evaluable" on day 7, 14, and 28. "Success" was a participant who was assessed and had a negative smear, while "failures" were participants who were either assessed and had a positive smear, or were lost to follow up. We calculated the Peto odds ratio and 95% confidence intervals (log odds, Peto) for individual studies and in meta-analysis.
We calculated the time to sustained parasitological clearance, for individual studies and the pooled data, using the Kaplan-Meier method. We created two pools of data, dependent on the time points available for analysis, for trials using chloroquine as the comparator drug.Pool A had 6 time points (days 0, 1, 2, 3, 5, and 7); and pool B had assessments only on days 0, 1, 2, and 7. For trials of comparisons of amodiaquine (AQ) and sulphadoxine-pyrimethamine, we used 5 time points (day 0, 1, 2, 3, and 7). We used the log-rank test to compare the results in the AQ and comparator arms. Parasite clearance times, reported in the individual papers, measure the time to clearance of only those participants who were eventually cured, and exclude people that are treatment failures. However, in the various analyses described above, we considered all participants with a baseline positive smear regardless of whether they achieved parasite clearance or not.
Results
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies.
[See Appendices]
Eligibility
Of the 101 studies identified, 56 met the inclusion criteria. Where articles or communications reported more than one study; each study has been individually referenced (Appendix 1).
Publication status and language
The eligible studies included both published (47) and unpublished (9) reports. We also analyzed the single patient data where this was made available by the trialists or Parke-Davis (18 studies, published and unpublished). Single patient data accounted for approximately one fourth of total amodiaquine (AQ) participants in the studies compared with chloroquine (CQ) and approximately half of those comparing AQ with sulphadoxine-pyrimethamine (SP).
The studies were written in English (34); French (20); Portuguese (1); and Spanish (1).
Study location
The majority of studies were conducted between 1983 and 2001 in the following Africa countries (Appendix 2): Burkina Faso (1); Cameroon (12); Congo (4); Equatorial Guinea (1); Gabon (2); Gambia (1); Ivory Coast (1); Kenya (17); Madagascar (2); Malawi (1); Mozambique (1); Nigeria (3); Senegal (3); Tanzania (2); and Uganda (1). Studies were also conducted in China (1); Brazil (1); Colombia (1); and the Philippines (1).
Participants
A total number of 2429 participants were followed up in the 56 studies (Appendix 3). Comparisons of AQ with CQ were made in 41 studies (34 involving symptomatic participants and 7 involving asymptomatic participants); and comparisons of AQ with SP were made in 19 studies (all with symptomatic malaria). Appendix 1 shows the studies included.
The number of patients followed up decreases with the length of follow up, which ranges from 7 to 28 days (Appendix 2). This is due to the combined effect of fewer studies following up participants for longer periods and increasing dropout rates. Some studies only reported results at the end of the follow-up period, that is, with no results available at intermediate times. Appendix 5 summarises the evaluable patients.
Interventions
AQ was administered, at doses ranging from 15.6 to 35 mg/kg, over three days. It was compared to CQ administered at doses ranging from 25 to 35 mg/kg over three days and SP (fixed ratio sulfadoxine:pyrimethamine of 1:20) administered as standard single dose of 25 mg of sulfadoxine (Appendix 2).
Outcomes
All studies reported on the outcome of parasitological conversion (Appendix 4). Eighteen of these studies sought adverse outcomes, either clinical or laboratory.
As some studies conducted multiple comparisons and varied in their reporting of results at day 7, 14 and/or 28, the breakdown for individual comparisons do not add up to these totals. Considering all parasitological outcomes, 1538 and 1166 AQ symptomatic patients were reported for the comparisons with CQ and SP, respectively. In the comparator arms, 101 asymptomatic infections and 1538 uncomplicated malaria cases were treated with CQ, while 1158 cases were treated with SP (Appendix 4).
Risk of bias in included studies
Generation of allocation sequence
Six trials specified the method of generating the allocation sequence; 22 mentioned randomization but were not specific about the method used; and 28 used other methods that appeared to be unbiased.
Allocation concealment
Allocation was adequately concealed in three trials, and was either not clearly described or unconcealed in the remaining 53.
Blinding
With the exception of one trial in the Philippines and one in China, no study was blinded.
Loss to follow up
Nine studies used an intention-to-treat analysis with few losses to follow up. Eight trials reported exclusion levels of less than 10%, while in the remaining 23 trials, there was either no reporting of exclusions, or exclusions were greater than 10%.
Quality of number generation and analysis was better in the three trials with adequate concealment of allocation. There were 8 trials that scored low on all three quality parameters.
Diagnostic procedures varied between centres.In most, patients were admitted on the basis of thick and thin blood film results. No quality control of slide reading was mentioned in any of the studies. In Kenya, an observer checked 10% of slides without knowledge of the first reading.
Effects of interventions
Parasitological outcomes
1. Amodiaquine versus chloroquine
In 34 studies, a total of 1538 participants receiving amodiaquine (AQ) were compared with 1166 participants receiving chloroquine (CQ). These studies were conducted at 33 different sites, 30 of them in Africa (accounting for 96% of the AQ participants), predominantly Kenya and Cameroon.
a. Parasitological conversion
i. Symptomatic participants
Twenty seven studies reported parasitological conversion. On day 7, a total of 1230 participants received AQ while 1234 received CQ. The parasitological conversion success rate ranged from 33% to 100% for AQ and from 9 to 100% for CQ. The meta-analysis shows that, on day 7, those receiving AQ had a statistically significantly higher level of parasitological conversion than those receiving CQ (Peto odds ratio (Peto OR) 4.42; 95% confidence interval (CI) 3.65 to 5.35). In this analysis, participants with a positive smear, or no data, on day 7 were deemed 'failures'.
One thousand six hundred and ten participants (802 receiving AQ; and 808 receiving CQ) were followed up to day 14 . The parasitological conversion success rate ranged from 15% to 100% for AQ and from 10 to 93% for CQ. Participants receiving AQ experienced statistically significantly higher levels of parasitological conversion (Peto OR 6.44; 95% CI 5.09 to 8.15).
Only three studies reported results on day 28.Two hundred and fifty four participants received AQ while 248 received CQ. The parasitological conversion success rate ranged from 25% to 95% for AQ and from 24% to 58% for CQ. As for day 7 and day 14, participants receiving AQ experienced statistically significantly higher levels of parasitological conversion than those receiving CQ (Peto OR 3.62; 95% CI 2.49 to 5.29).
There was significant heterogeneity in all comparisons, as may be anticipated with varying age groups and malaria endemicities.
The Peto ORs for days 7, 14, and 28 should not be compared directly for two reasons: (1) participants who were not available for follow up at day 14 were simply excluded in most cases and; (2) some studies reported results on only one of the three visits.
No variation was observed when the analysis was restricted to the African studies. The Peto OR was 4.94 (95% CI 4.06 to 6.02) at day 7; 6.86 (95% CI 5.38 to 8.75) at day 14; and 3.62 (95% CI 2.49 to 5.29) at day 28.
ii. Asymptomatic participants
An additional nine studies tested AQ against CQ in people who were asymptomatic but found to be parasitaemic at cross sectional blood survey. In these studies, 543 participants received AQ and were compared to 586 participants who received CQ. AQ recipients experienced statistically significantly higher levels of parasitological conversion at day 7 than CQ recipients (Peto OR 3.64; 95% CI 2.65 to 5.00).
b. Time to sustained parasite clearance
i. Symptomatic participants
Time to sustained parasite clearance (day 0 through 7) was calculated for participants with 6 data points (pool A: day 0, 1, 2, 3, 5, and 7) or 4 data points (pool B: day 0, 1, 2, and 7). Pool A comprised 3 studies with 108 AQand 109 CQrecipients, of whom 99 and 78, respectively, achieved a sustained parasitological conversion. Pool B (11 studies) included 519 AQand 509 CQrecipients, with 478 and 307 successes, respectively. The time to parasite clearance was significantly shorter for AQ in both analyses (log to rank p = 0.0025 and 0.0001, respectively).
ii. Asymptomatic participants
No data.
c. Adverse events
No difference in event rate was seen between the two groups (Peto OR 0.85, 95%CI 0.50 to 1.42).
2. Amodiaquine versus sulphadoxine-pyrimethamine
Sulphadoxine-pyrimethamine (SP) was used as comparator in 19 studies (16 from Africa), enrolling 1166 amodiaquine (AQ) and 1158 SP recipients ("evaluable patient population").
a. Parasitological conversion
i. Symptomatic participants
Parasitological outcome was reported by 14 studies on day 7 and 14; five of these studies only reported results for day 14. Seven studies reported results on day 28.
On day seven, 824 participants received AQ while 818 received SP. The parasitological conversion success rate ranged from 42% to 100% for AQ and from 67% to 100% for SP. The graphical display shows no obvious trend, and meta-analysis did not demonstrate a statistically significant difference between AQ and SP for parasitological conversion (Peto OR 0.73; 95% CI 0.53 to1.01).
On day 14, 786 participants received AQand 821 received SP. The parasitological conversion success rate ranged from 58% to 100% for AQ and from 65% to 100% for SP. As for day 7, the graphical display showed no trend and there was no statistically significant difference between AQ and SP for parasitological conversion (Peto OR 0.86; 95% CI 0.64 to 1.14).
By day 28, 667 participants remained in the analysis was (345 receiving AQ;and 322 receiving SP). The parasitological conversion success rate ranged from 48% to 92% for AQ and from 54% to 100% forCQ. SP recipients had a statistically significantly higher level of parasitological conversion than AQ recipients (Peto OR 0.41; 95% CI 0.28 to 0.61).
The Peto ORs remained almost unchanged when the analyses were restricted to studies conducted in Africa, or to Africa after 1990 (when the use of SP started, particularly in the East and the South of the continent). In this latter case, the Peto ORs on day 7, 14, and 28 were 0.81 (95% CI 0.57 to 1.15); 0.92 (95% CI 0.68 to 1.23); and 0.58 (95% CI 0.37 to 0.91), respectively.
ii. Asymptomatic participants
Two of the AQ versus CQ studies (above), on asymptomatic P.falciparum infected participants, also had an SP arm. They enrolled 143 participants to receive AQ and 122 to receive SP, with a success rate on day 7 of 93% and 99%, respectively.
b. Time to sustained parasite clearance
i. Symptomatic participants
The time to sustained parasitological clearance (days 0 to 7) was similar in the two groups. Participants had parasitological assessments on day 0, 1, 2, 3, and 7. Overall, 385 of the 424 participants receiving AQ, and 401 of the 451 participants receiving SP, reached the endpoint and remained negative until day 7 (log to rank p value = 0.27).
ii. Asymptomatic participants
No data available.
c. Adverse effects
Three studies reported on this, with no obvious difference between the two groups (Peto OR 1.68, 95%CI 0.84 to 3.38).
Results are summarised in Appendix 6.
Adverse events were reported for 52 AQ recipients (8.8%), 36 CQ recipients (8.8%), and 15 SP recipients (14.3%). The most commonly reported adverse events were gastrointestinal adverse events (nausea and vomiting) and pruritus. The adverse events were reportedly minor and moderate; no serious or life-threatening adverse events were reported among AQ recipients.
No statistically significant difference was observed in the incidence of adverse events between AQ and CQ recipients (Peto OR 0.85; 95% CI 0.50 to 1.42) or AQ and SP recipients (Peto OR 1.68; 95% CI 0.84 to 3.38).
A complete biochemical and haematological evaluation was performed for the 62 AQ and 59 CQrecipients recruited to a study in Ivory Coast. No difference was observed between the two groups. Neutrophil counts on thick smear were available for 191 AQ, 22 CQ, and 116 SP recipients from Kenya. Paired observations of neutrophil counts on day 14 (compared to baseline values of Ivory Coast and Kenya patients) showed no significant change.
A systematic review of prospective observational and experimental studies of adverse events is currently under way (MacLehose H, Klaes D, Garner P. Amodiaquine: a systematic review of adverse events [2003] (unpublished document)). This review will include additional studies to those reported in this Cochrane Review. The results of this review are available on http://archives.who.int/eml/expcom/expcom13/Amodiaquine-adv-events.pdf. We will update the Cochrane Review with a summary derived from the systematic review of adverse events in subsequent issues of the Cochrane Library.
Discussion
Some of the methodological deficiencies of articles and trials have inevitably led to a bias in the analyses. Most articles report data only on the patients deemed "evaluable" as per the protocol, usually those who completed the scheduled study period (7, 14, or 28 days). As no details were given on the "eligible" patients, and those prematurely discontinued, withdrawn, or lost to follow to up, no true intent-to-treat analysis could be performed here. Obtaining raw data has partially rectified the problem, although a selection bias still remains in favour of sensitivity. In contrast, the criteria adopted in the analysis of efficacy (that is, missing data counted as failures) will introduce a bias toward resistance. In fact, non-attendees were shown to do well in an ad-hoc study in Kenya (C.Nevill, unpublished). The availability of data to reanalyze has led us to identify two populations, the "evaluable" patients, and those actually assessed at each target visit. The denominator did not vary substantially, though, and nor did the level of significance of the comparisons in the sets of patients.
The data are mainly from Africa (Eastern, Central, and Western countries) and ,although a wide range of malaria epidemiological patterns and levels of drug resistance are represented, care should be taken in transposing these results elsewhere. In this review, amodiaquine (AQ) was found to be significantly more effective than chloroquine (CQ) in clearing parasites. With respect to sulphadoxine-pyrimethamine (SP), no difference in parasitological outcomes was observed within 7 days of study.However, SP showed superiority during longer-term follow to up. This finding is not unexpected owing to the long half life of SP. Whether the difference observed is due to recrudescent parasites, or to re-infections, cannot be verified. As reported previously, an improvement in symptomatic amelioration was apparent with AQ. This could be ascribed to the anti-inflammatory/antipyretic effect of the aminoquinolines.
Based on the results of this review, AQ (when administered at a dose of up to 35 mg/kg, over 3 days) appears to be no more toxic than CQ or SP when used for treating adults and children with uncomplicated falciparum malaria. Under these conditions of use, and within the limitations of the sample size, no severe, life-threatening or fatal adverse reaction occurred.
Location and year of study are potential confounders particularly for the comparison with SP. The efficacy of this drug is known to decline with use, due to the selection of parasites with increasing numbers of mutations in their genome associated with resistance.
After oral intake, AQ is rapidly and extensively metabolised to a pharmacologically active metabolite, desethylamodiaquine. Both AQ and desethylamodiaquine are chemically unstable in aqueous solutions, and undergo transformation yielding a protein-arylating quinone imine (Maggs 1988). The mechanism of toxicity of AQ seems not to be related to direct toxicity of the parent compound or metabolites in bone marrow cell precursors (Winstanley 1990), but rather to the immunogenic properties of the quinone imine (Clarke 1990). It is still unclear why, while most people exposed would have antidrug antibody, only very few people suffer from organ specific toxicity.
So far, serious and life-threatening adverse drug reactions have been described only during prophylaxis. Based on reported rates, the risk of serious adverse drug reactions associated with the prophylactic use of AQ can be estimated to be approximately 1:2,100 treatments for agranulocytosis; 1:15,500 for hepatotoxicity; and 1:30,000 for aplastic anaemia, with a total case fatality rate of 1:15,650 (Phillips-Howard, personal communication). The risk of fatal adverse drug reactions to AQ is in the same order of magnitude to that to SP.
Thus, AQ treatment appears to be safer than AQ prophylaxis.
Authors' conclusions
Implications for practice This review has collected convincing evidence of amodiaquine (AQ) superiority over chloroquine (CQ), even in areas with considerable CQ resistance. Clearly, therefore, there is a role for AQ in areas with CQ resistance although the lifespan of that role may be curtailed by partial AQ cross resistance with CQ. The comparison with sulphadoxine-pyrimethamine (SP) is potentially more important in view of the value of low cost antimalarial drugs and the concerns around the lifespan of long half-life sulfadrugs after introduction for wide use in sub-Saharan Africa. While the faster symptomatic recovery with AQ would not necessitate concurrent antipyretics, the longer protection induced by SP may prove a hazard long-term as it could encourage the selection of resistant parasites. This review makes the most comprehensive attempt to date to identify all published and unpublished trials relevant to the inclusion criteria. Another review (A. Rietveld and P. Trigg, unpublished data), using a different methodology, also assessed the World Health Organisations (WHO) recommendation to no longer use AQ for treatment in malaria control programmes. This review was more prudent than practical, particularly in light of the limited availability of alternative affordable antimalarial drugs. When CQ, AQ, and SP are no longer effective, the next antimalarial drugs in line cost at least 7 to 60 times as much (A.Rietveld, personal communication). This places a full treatment course financially out of reach of many patients. In terms of adverse events, this review of Randomised Controlled Trials (RCTs) has not identified a problem. It is apparent that serious and life threatening adverse drug reactions have been described only during prophylaxis in case reports. |
Implications for research The review supports the continued use of AQ in the treatment of uncomplicated malaria, with the proviso that there is partial cross resistance between CQ and AQ, and that monitoring of effectiveness, as well as surveillance for evidence of toxicity, must continue. |
Acknowledgements
This review was made possible by researchers who kindly provided data and made comments, and include Dr B.Greenwood and Dr O.Müller (The Gambia); L.Salako (Nigeria); A.Shapira (World Health Organisation (WHO), Vietnam); B.Dubois (Parke-Davis, France). Data on amodiaquine adverse events was kindly provided by M Petersson, WHO Collaborating Centre, Sweden. Other people who have helped with specialist advice include Dr A.Rietveld and Mrs V.Mattei (WHO, Switzerland); Mr J.Portal (Parke-Davis, France); Dr P.Winstanley (UK); Dr A.Oxman (Denmark); Dr A.Herxheimer (UK). Elements of an unpublished WHO study by A.Rietveld and P.Trigg were also used. This review was conducted as an activity of the Cochrane Infectious Diseases Group, who are supported by a grant from the Department for International Development (UK), and of the United Nations Development Programme (UNDP)/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR). However, the data presented and the views expressed are the responsibility of the authors of this paper, and not the agencies employing them or providing them with funds.
Data and analyses
- Top of page
- Background
- Objectives
- Methods
- Results
- Discussion
- Authors' conclusions
- Acknowledgements
- Data and analyses
- Appendices
- What's new
- History
- Contributions of authors
- Declarations of interest
- Sources of support
- Notes
- Index terms
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Appendices
Appendix 1. References to studies conducted at several sites with different identifiers in the review
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Appendix 2. Characteristics of included studies
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AQ, amodiaquine; CQ, chloroquine; SP, sulfadoxine-pyrimethamine
Appendix 3. Participant characteristics
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Appendix 4. Outcomes
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Appendix 5. Evaluable participants for parasitological outcomes at day 7, 14, and 28
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AQ, amodiaquine; CQ, chloroquine; SP, sulfadoxine-pyrimethamine
Appendix 6. Summary of results
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What's new
Last assessed as up-to-date: 3 February 2003.
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History
Protocol first published: Issue 1, 1995
Review first published: Issue 2, 1996
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Contributions of authors
Piero Olliaro extracted the data in the first and second edition of the review; the second person extracting data independently was Ms Mussano and Philippe Brasseur (1st edition), and Pierre Ringwald (2nd edition). Dr Olliaro entered the data and this was checked by Ms Mussano.
Declarations of interest
We certify that we have no affiliations with or involvement in any organization or entity with a direct financial interest in the subject matter of the review (eg, employment, consultancy, stock ownership, honoraria, expert testimony).
Sources of support
Internal sources
- UNDP/World Bank/WHO Tropical Diseases Programme, World Health Organization, Switzerland.
- Liverpool School of Tropical Medicine, UK.
External sources
- Department for International Development, UK.
Notes
2011, Issue 9: The Cochrane Infectious Diseases Group are piloting a system to indicate whether the question is currently relevant, and the status of the review with regards to being up to date.
For relevance, we classify reviews into:
- historical question, where an intervention or policy has been superseded by new medical developments (such as a new drug),
- current question, which are still relevant to current policy or practice.
For status, we have three categories, with an explanation after each: “up to date”; “update pending”; “no update intended”.
For this review, we have categorised the review as: Historical question - no update intended.
For the most up-to-date information regarding malria treatments, please see: Sinclair D, Zani B, Donegan S, Olliaro P, Garner P. Artemisinin-based combination therapy for treating uncomplicated malaria. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD007483. DOI: 10.1002/14651858.CD007483.pub2.)
February 2003: review updated and text amended; tables describing studies revised.
Index terms
Medical Subject Headings (MeSH)
Amodiaquine [*therapeutic use]; Antimalarials [*therapeutic use]; Chloroquine [therapeutic use]; Drug Combinations; Malaria, Falciparum [*drug therapy]; Pyrimethamine [therapeutic use]; Randomized Controlled Trials as Topic; Sulfadoxine [therapeutic use]
MeSH check words
Humans
* Indicates the major publication for the study