Use Of Amodiaquine Research Articles

Spectroscopic properties (FT-IR, NMR and UV) and DFT studies of amodiaquine

Amodiaquine (AQ) was synthesized by a condensation reaction and characterized by experimental FT-IR, 1H and 13C nuclear magnetic resonance (NMR) and UV spectroscopies. In the present work, Density Functional Theory (DFT) calculations using B3LYP method with 6–311++G(d,p) and 6–311++G(2d, p) basis sets were performed, first, to confirm its structure, then to explain its reactive nature through its molecular properties such as natural charges, local and global reactivity descriptors or natural bond orbital (NBO). The 1H and 13C NMR chemical shifts were calculated by using the gauge-independent atomic orbital (GIAO) method, while the electronic UV–Vis spectrum is predicted using the time-dependent density functional theory (TD-DFT). Globally, the computerized results showed close similarity with the experimental values.The calculated energy band gap (ELUMO-EHOMO) value of AQ was found to be 4.09 eV suggesting that it could be considered as a hard molecule with high stability, supported by global reactivity descriptors. Molecular electrostatic potential (MEP) analysis revealed heteroatoms (oxygen and nitrogen) as the most putative nucleophilic sites when hydrogen atoms to which they are linked appear as electrophilic sites. The potential use of amodiaquine as non-linear optical (NLO) material and its thermodynamic indicators have also been assessed.

The cardiovascular effects of amodiaquine and structurally related antimalarials: An individual patient data meta-analysis.

BackgroundAmodiaquine is a 4-aminoquinoline antimalarial similar to chloroquine that is used extensively for the treatment and prevention of malaria. Data on the cardiovascular effects of amodiaquine are scarce, although transient effects on cardiac electrophysiology (electrocardiographic QT interval prolongation and sinus bradycardia) have been observed. We conducted an individual patient data meta-analysis to characterise the cardiovascular effects of amodiaquine and thereby support development of risk minimisation measures to improve the safety of this important antimalarial.Methods and findingsStudies of amodiaquine for the treatment or prevention of malaria were identified from a systematic review. Heart rates and QT intervals with study-specific heart rate correction (QTcS) were compared within studies and individual patient data pooled for multivariable linear mixed effects regression.The meta-analysis included 2,681 patients from 4 randomised controlled trials evaluating artemisinin-based combination therapies (ACTs) containing amodiaquine (n = 725), lumefantrine (n = 499), piperaquine (n = 716), and pyronaridine (n = 566), as well as monotherapy with chloroquine (n = 175) for uncomplicated malaria. Amodiaquine prolonged QTcS (mean = 16.9 ms, 95% CI: 15.0 to 18.8) less than chloroquine (21.9 ms, 18.3 to 25.6, p = 0.0069) and piperaquine (19.2 ms, 15.8 to 20.5, p = 0.0495), but more than lumefantrine (5.6 ms, 2.9 to 8.2, p < 0.001) and pyronaridine (−1.2 ms, −3.6 to +1.3, p < 0.001). In individuals aged ≥12 years, amodiaquine reduced heart rate (mean reduction = 15.2 beats per minute [bpm], 95% CI: 13.4 to 17.0) more than piperaquine (10.5 bpm, 7.7 to 13.3, p = 0.0013), lumefantrine (9.3 bpm, 6.4 to 12.2, p < 0.001), pyronaridine (6.6 bpm, 4.0 to 9.3, p < 0.001), and chloroquine (5.9 bpm, 3.2 to 8.5, p < 0.001) and was associated with a higher risk of potentially symptomatic sinus bradycardia (≤50 bpm) than lumefantrine (risk difference: 14.8%, 95% CI: 5.4 to 24.3, p = 0.0021) and chloroquine (risk difference: 8.0%, 95% CI: 4.0 to 12.0, p < 0.001). The effect of amodiaquine on the heart rate of children aged <12 years compared with other antimalarials was not clinically significant. Study limitations include the unavailability of individual patient-level adverse event data for most included participants, but no serious complications were documented.ConclusionsWhile caution is advised in the use of amodiaquine in patients aged ≥12 years with concomitant use of heart rate–reducing medications, serious cardiac conduction disorders, or risk factors for torsade de pointes, there have been no serious cardiovascular events reported after amodiaquine in widespread use over 7 decades. Amodiaquine and structurally related antimalarials in the World Health Organization (WHO)-recommended dose regimens alone or in ACTs are safe for the treatment and prevention of malaria.

Amodiaquine-Associated Asthenia: A Case Based Review and Gaps in Literature

Introduction: Amodiaquine is a partner drug in the artemisinin-based combination therapy artesunate-amodiaquine. Reports of the adverse drug reaction known as amodiaquine-associated asthenia are scarce, and this adverse reaction needs to be investigated in detail. This article presents and reviews a case of amodiaquine-associated asthenia. A literature search for the characteristics of this adverse reaction highlighted gaps in the literature. Methods: A case of probable amodiaquine asthenia was described and discussed under the sub-headings of epidemiology, clinical features, laboratory features, aetiopathogenesis, and management. A literature search limited to Medline Health Databases (Medline and PubMed Central, PMC) using the search terms and was conducted on 10 March 2015. Retrieved literature on the subject was closely scrutinized for relevant details of adverse drug reactions to amodiaquine when used in the management or prophylaxis of malaria. Cited literature within retrieved manuscripts was examined manually for other relevant literature. Papers retrieved from the search were used to describe the existing knowledge and gaps in it of the adverse drug reaction under sub-categories of incidence, clinical features, laboratory features, aetiopathogenesis, and management. Results: Thirty-nine manuscripts were retrieved; 20 had content relevant to the objectives of this review. The frequency of amodiaquine-associated asthenia in different populations ranged from 12–36%. There is a paucity of reports, and no detailed study of this adverse reaction has been published in popular English medical literature. Conclusion: With the use of amodiaquine as a partner drug in antimalarial combination therapies being scaled up, well-structured studies are needed on adverse reactions to amodiaquine and to investigate amodiaquine-associated asthenia. In addition, approaches to elucidating this adverse reaction more effectively in children need to be developed.

Design, Synthesis and Evaluation of New Fluoroamodiaquine Analogues

Malaria is one of the most important tropical diseases; the use of amodiaquine as a current chemotherapy in the treatment of malaria has shown some problems such as hepatotoxicity and agranulocytosis. In this work we present the rational design, synthesis, and biological evaluation (antimalarial activity, cytotoxicity and genotoxicity) of four new fluoroamodiaquine analogues. The results showed significant correlation between MolDock score and IC50 values. The molecules 7b and c were the most active of the planned compounds, with lower IC50 against Plasmodium falciparum W2 strain (0.9 and 0.8 µM, respectively) and an excellent cytotoxicity profile. The present study revealed no mutagenicity or genotoxicity for the analogues. Confirming our docking results, the molecular dynamics showed that compound 7b remains stably bound to the heme group by means of π-stacking interactions between quinoline and the porphyrin ring. Based on these findings, this study may prove to be an efficient approach for the rational design of hemozoin inhibiting compounds to treat malaria.

Selection of drug resistance-mediating Plasmodium falciparum genetic polymorphisms by seasonal malaria chemoprevention in Burkina Faso.

Seasonal malaria chemoprevention (SMC), with regular use of amodiaquine plus sulfadoxine-pyrimethamine (AQ/SP) during the transmission season, is now a standard malaria control measure in the Sahel subregion of Africa. Another strategy under study is SMC with dihydroartemisinin plus piperaquine (DP). Plasmodium falciparum single nucleotide polymorphisms (SNPs) in P. falciparum crt (pfcrt), pfmdr1, pfdhfr, and pfdhps are associated with decreased response to aminoquinoline and antifolate antimalarials and are selected by use of these drugs. To characterize selection by SMC of key polymorphisms, we assessed 13 SNPs in P. falciparum isolated from children aged 3 to 59 months living in southwestern Burkina Faso and randomized to receive monthly DP or AQ/SP for 3 months in 2009. We compared SNP prevalence before the onset of SMC and 1 month after the third treatment in P. falciparum PCR-positive samples from 120 randomly selected children from each treatment arm and an additional 120 randomly selected children from a control group that did not receive SMC. The prevalence of relevant mutations was increased after SMC with AQ/SP. Significant selection was seen for pfcrt 76T (68.5% to 83.0%, P = 0.04), pfdhfr 59R (54.8% to 83.3%, P = 0.0002), and pfdhfr 108N (55.0% to 87.2%, P = 0.0001), with trends toward selection of pfmdr1 86Y, pfdhfr 51I, and pfdhps 437G. After SMC with DP, only borderline selection of wild-type pfmdr1 D1246 (mutant; 7.7% to 0%, P = 0.05) was seen. In contrast to AQ/SP, SMC with DP did not clearly select for known resistance-mediating polymorphisms. SMC with AQ/SP, but not DP, may hasten the development of resistance to components of this regimen. (This study has been registered at ClinicalTrials.gov under registration no. NCT00941785.).

Changes in drug sensitivity and anti-malarial drug resistance mutations over time among Plasmodium falciparum parasites in Senegal

BackgroundMalaria treatment efforts are hindered by the rapid emergence and spread of drug resistant parasites. Simple assays to monitor parasite drug response in direct patient samples (ex vivo) can detect drug resistance before it becomes clinically apparent, and can inform changes in treatment policy to prevent the spread of resistance.MethodsParasite drug responses to amodiaquine, artemisinin, chloroquine and mefloquine were tested in approximately 400 Plasmodium falciparum malaria infections in Thiès, Senegal between 2008 and 2011 using a DAPI-based ex vivo drug resistance assay. Drug resistance-associated mutations were also genotyped in pfcrt and pfmdr1.ResultsParasite drug responses changed between 2008 and 2011, as parasites became less sensitive to amodiaquine, artemisinin and chloroquine over time. The prevalence of known resistance-associated mutations also changed over time. Decreased amodiaquine sensitivity was associated with sustained, highly prevalent mutations in pfcrt, and one mutation in pfmdr1 – Y184F – was associated with decreased parasite sensitivity to artemisinin.ConclusionsDirectly measuring ex vivo parasite drug response and resistance mutation genotyping over time are useful tools for monitoring parasite drug responses in field samples. Furthermore, these data suggest that the use of amodiaquine and artemisinin derivatives in combination therapies is selecting for increased drug tolerance within this population.

Antimalarial activity of isoquine against Kenyan Plasmodium falciparum clinical isolates and association with polymorphisms in pfcrt and pfmdr1 genes

The use of amodiaquine in prophylaxis is associated with serious toxicity, resulting from its metabolic conversion into a reactive quinone-imine metabolite by the hepatic cytochrome P450. To circumvent this toxicity, several amodiaquine analogues that lack the potential to form a quinone-imine derivative, while retaining antimalarial activity, have been designed. Isoquine is one of these promising molecules that has already reached Phase I clinical trials in humans. We analysed the in vitro activity of isoquine against 62 Plasmodium falciparum isolates collected in Kenya and the association of this activity with polymorphisms in pfcrt and pfmdr1 genes. The median concentration of isoquine that inhibited 50% of parasite growth (IC50) was 9 nM, compared with 56 nM chloroquine, 8 nM amodiaquine, 10 nM desethylamodiaquine, 69 nM lumefantrine and 1 nM dihydroartemisinin. Isoquine activity was correlated with polymorphisms in pfcrt at codon 76, but not in pfmdr1 at codon 86. The high activity of isoquine against field isolates, including chloroquine-resistant isolates, with IC50 <10 nM, warrants its further development as an antimalarial.

Hematoxicity of amodiaquine in sprague-dawley rats

Objective:The use of amodiaquine (AQ) and its associated toxic effect has been a major public health concern since cases of life-threatening agranulocytosis and hepatic toxicity were reported during its prophylactic use. The objective of this study was to evaluate the hematological safety profile of AQ therapy.Materials and Methods:Sprague-Dawley rats were randomly distributed into four groups (n=5). Group 1 was the control, while groups 2, 3, and 4 received AQ treatment for 14 days at varying doses of 5 mg/kgBW, 10 mg/kgBW, and 15 mg/kgBW daily, respectively.Results:Following treatment, hematological variables were comparable in all groups (P>0.05).Conclusion:This study provides evidence to support the use of AQ in the treatment of uncomplicated malaria. However, to prevent emergence of local drug resistance, it should be used as part of a combination therapy. Monitoring for adverse effects is suggested.

Amodiaquine-associated adverse effects after inadvertent overdose and after a standard therapeutic dose

A case of an acute dystonic reaction in a child presumptively treated for malaria with amodiaquine, and a case of persistent asymptomatic bradycardia in another child with mild pulmonary stenosis treated with a standard dose of amodiaquine for parasitologically confirmed uncomplicated malaria, is reported. Both subjects were homozygous for the wild type allele of cytochrome P450 2C8, the main enzyme responsible for amodiaquine metabolism. In both subjects, plasma concentrations of N-desethylamodiaquine and N-bis-desethylamodiaquine, the main metabolites of amodiaquine, were normal. No other drugs were detectable in the plasma of these two subjects after further toxicological screening. These observations, which suggest altered metabolism in the subject with an acute dystonic reaction, support the assertion that amodiaquine-associated dystonia is an idiosyncratic reaction. However, the occurrence of bradycardia after a standard dose of amodiaquine, which coincided with the time of expected peak concentrations of the active metabolite of amodiaquine, suggests a direct drug effect. These less reported adverse effects are likely to increase in parallel with the increased use of amodiaquine as a partner drug for combination therapy of malaria in Ghana. Further studies aimed at elucidating the mechanisms underlying these effects are, therefore, required.

Treatment of malaria from monotherapy to artemisinin-based combination therapy by health professionals in rural health facilities in southern Cameroon

BackgroundOne year after the adoption of artesunate-amodiaquine (AS/AQ) as first-line therapy for the treatment of uncomplicated malaria, this study was designed to assess the treatment practices regarding anti-malarial drugs at health facilities in four rural areas in southern Cameroon.MethodsBetween April and August 2005, information was collected by interviewing fifty-two health professionals from twelve rural health facilities, using a structured questionnaire.ResultsIn 2005, only three anti-malarial drugs were used in rural health facilities, including: amodiaquine, quinine and sulphadoxine-pyrimethamine. Only 2.0% of the health professionals prescribed the recommended AS/AQ combination. After reading the treatment guidelines, 75.0% were in favour of the treatment protocol with the following limitations: lack of paediatric formulations, high cost and large number of tablets per day. Up to 21.0% of professionals did not prescribe AS/AQ because of the level of adverse events attributed to the use of amodiaquine as monotherapy.ConclusionThe present study indicates that AS/AQ was not available in the public health facilities at the time of the study, and health practitioners were not informed about the new treatment guidelines. Results of qualitative analysis suggest that prescribers should be involved as soon as possible in projects related to the optimization of treatment guidelines and comply with new drugs. Adapted formulations should be made available at the international level and implemented locally before new drugs and treatments are proposed through a national control programme. This baseline information will be useful to monitor progresses in the implementation of artemisinin-based combination therapy in Cameroon.

In Vivo and In Vitro Efficacy of Amodiaquine againstPlasmodium falciparumin an Area of Continued Use of 4‐Aminoquinolines in East Africa

In light of reports of increasing resistance of parasites to amodiaquine in African countries in which Plasmodium falciparum is endemic as well as the paucity of recent in vitro sensitivity data, we assessed the in vivo and in vitro sensitivity to amodiaquine of P. falciparum isolates from 128 pediatric outpatients (0.5-10 years old) in Pingilikani, Kilifi District, Kenya, who were treated with amodiaquine (10 mg/kg/day for 3 days). The polymerase chain reaction-corrected parasitological cure rate on day 28 (by Kaplan-Meier analysis) was 82% (95% confidence interval [CI], 74%-88%). Twenty-six percent (17/66) of tested pretreatment P. falciparum field isolates had 50% in vitro growth inhibition at concentrations of N-desethyl-amodiaquine (DEAQ)-the major biologically active metabolite of amodiaquine-above the proposed resistance threshold of 60 nmol/L, but baseline median DEAQ 50% inhibitory concentration values were not associated with subsequent risk of asexual parasite recrudescence (29 nmol/L [95% CI, 23-170 nmol/L] and 34 nmol/L [95% CI, 30-46 nmol/L] for patients with and those without recrudescences, respectively). The median absolute neutrophil count dropped by 1.3 X 10(3) cells/microL (95% CI, -1.7 X 10(3) to -0.7 X 10(3) cells/microL) between days 0 and 28. The high prevalence of in vitro and in vivo resistance precludes the use of amodiaquine on its own as second-line treatment. These findings also suggest that the value of amodiaquine combinations as first- or second-line treatment in areas with similar patterns of 4-aminoquinoline resistance should be reassessed.

Deux hépatites fulminantes survenues au cours d’un traitement curatif par l’association artésunate–amodiaquine

Two previously healthy young women presented with a lethal hepatitis a few days after the onset of an artesunate–amodiaquine combination at the recommended doses for a bout of fever. Nothing proved the fever was due to malaria, the toxic cause of hepatitis, or to the drugs used. Imputability was based on chronology (fever, drug combination, sudden onset of severe fatigue, hepatitis lethal in a few days) and on the absence of any other evident cause for hepatitis. Severe hepatitis under prolonged amodiaquine treatment has been reported since 1985, the risk is estimated at 1/15 500 treatments and the symptoms usually appear within 10 to 160 days. The current international recommendations are to promptly treat uncomplicated malaria access, with an artemisinin-based combination therapy, especially with artesunate–amodiaquine. The risk of iterative amodiaquine use could be the same as prolonged treatments, given that the suspected toxicity mechanisms are metabolite accumulation or an immunoallergic phenomenon. All adverse effects must be reported.

The use of artemether‐lumefantrine by febrile children following national implementation of a revised drug policy in Kenya

To examine access to, timing and use of artemisinin-based combination therapy among rural Kenyan febrile children before and following the introduction of artemether-lumefantrine (AL) as first-line antimalarial drug policy. In August 2006, a cohort was established within 72 rural clusters in four sentinel districts to monitor the period prevalence of fever and treatment in children aged 0-4 years through four repeat cross-sectional surveys (one prior to introduction of AL and three post-AL introduction: January-June 2007). Mothers/guardians of children were asked about fever in the last 14 days and related treatment actions including the timing, drugs used, dosing and adherence supported by visual aids of commonly available drug products. A total of 2526 child-observations were recorded during the four survey rounds. The period prevalence of fever was between 20% and 26% with little variation between survey rounds. The overall proportion of children with fever receiving antimalarial drugs for their fever was 31 % (95% CI, 26-36%) and the proportion of febrile children receiving antimalarial drugs within 48 h was 23.3% (95% CI, 18.6-28.0%). The proportion of febrile children who received first-line recommended AL within 48 h was 10.2% (95% CI, 7.0-13.4%), compared to only 4.6% (95% CI, 3.8-5.4%) of children receiving sulphadoxine-pyrimethamine first-line therapy in 2001. Although Kenya was less than a year into the new policy implementation and AL is restricted to the public formal sector, access to antimalarial drugs among children within 48 h and to the first-line therapy has improved. But it remains well below national and international targets. The continued use of amodiaquine and artemisinin monotherapies constrains effective implementation of artemisinin-based combination therapy policy in Kenya.

The safety of amodiaquine use in pregnant women

Few antimalarial drugs have been evaluated extensively in pregnancy because of fears over toxicity. However, increasing Plasmodium falciparum resistance to chloroquine and sulfadoxine–pyrimethamine makes finding alternative antimalarials that are safe and effective in pregnancy a priority. There is a renewed interest in amodiaquine as a potential candidate, particularly as a partner drug in artemisinin-based combination therapy. The available data suggest that, at standard dosages, amodiaquine is not teratogenic and that the adverse events associated with taking amodiaquine in pregnancy are not greater than those associated with falciparum malaria in pregnancy. Thus, amodiaquine in combination with other antimalarial drugs may be useful for malaria treatment in pregnancy, but inadequate data on its safety and pharmacokinetics in pregnancy limits its deployment for intermittent preventive treatment in pregnancy.

Emergency Liver Transplantation in Amodiaquine-Induced Fulminant Hepatitis

Amodiaquine is an amino-4-quinoline with the basic spectrum of activity of chloroquine. It has been used widely to treat and prevent malaria. From the mid-1980s, there were reports of fatal adverse drug reactions described in travelers using amodiaquine as antimalarial prophylaxis. In 1990, the World Health Organization (WHO) stopped using this drug in malaria control programs. The WHO Expert Committee on Malaria modified this in 1993 and reported that amodiaquine could be used for treatment if the risk of infection outweighs the potential for adverse drug reactions. Currently, amodiaquine is a potential useful drug, especially if used with artemisinin-based combination therapy and with sulfadoxine-pyrimethamine to improve treatment efficacy for chloroquine-resistant strains of Plasmodium falciparum and P. vivax. We report a case of fulminant hepatitis induced by antimalarial prophylactic use of amodiaquine that necessitated emergency orthotopic liver transplantation.

Occurrence of the Southeast Asian/South American SVMNT Haplotype of the Chloroquine‐Resistance Transporter Gene inPlasmodium falciparumin Tanzania

Two main haplotypes, CVIET and SVMNT, of the Plasmodium falciparum chloroquine-resistance transporter gene (Pfcrt) are linked to 4-aminoquinoline resistance. The CVIET haplotype has been reported in most malaria-endemic regions, whereas the SVMNT haplotype has only been found outside Africa. We investigated Pfcrt haplotype frequencies in Korogwe District, Tanzania, in 2003 and 2004. The SVMNT haplotype was not detected in 2003 but was found in 19% of infected individuals in 2004. Amodiaquine use has increased in the region. The introduction and high prevalence of the SVMNT haplotype may reflect this and may raise concern regarding the use of amodiaquine in artemisinin-based combination therapies in Africa.

Amodiaquine treatment of uncomplicated malaria in children, in an area of chloroquine-resistant Plasmodium falciparum in north-central Nigeria.

The efficacy of amodiaquine against Plasmodium falciparum malaria was assessed in an area of confirmed chloroquine resistance in the cool, north-central plateau of Nigeria, using a 14-day protocol. The patients were all children aged <5 years of age. The drug proved highly efficacious, giving a cure 'rate' of 100% on day 14 and mean fever- and parasite-clearance times of 1.11 and 3.11 days, respectively. It was also well tolerated. Following treatment, packed-cell volumes (PCV) generally increased (65% of patients) but remained constant (12%) or even decreased (23%) in some patients; the overall improvement in PCV was not statistically significant (P >0.05). The results justify the use of amodiaquine to treat P. falciparum malaria in those who have failed treatment with chloroquine and the second-line drugs (e.g. sulfadoxine-pyrimethamine) currently used in Nigeria. As the amodiaquine would be better employed as one part of a combination than on its own, there is a need to identify suitable partner compounds.

Amodiaquine for treating malaria.

Amodiaquine has been widely used to treat malaria. Due to reports of fatal adverse drug reactions, discontinuation or modification of its use has been suggested. The objective of this review was to assess the effects of amodiaquine for treating malaria. We searched the Cochrane Infectious Diseases Group trials register and Medline. We also contacted researchers in the field and drug companies. Randomised and quasi-randomised trials comparing amodiaquine with other treatment for uncomplicated malarial infections in adults and children. Both reviewers independently extracted data and assessed trial quality. Forty trials were included. Allocation was adequately concealed in three trials. Amodiaquine was more effective than chloroquine for parasite clearance. The combined results of parasite clearance at seven days from 24 trials was 83% for amodiaquine and 56% for chloroquine (odds ratio 4.29, 95% confidence interval 3.51 to 5.24). The odds ratio for parasite clearance at 14 days was 6.00, 95% confidence interval 4.38 to 8.21. Amodiaquine and sulfadoxine/pyrimethamine showed similar results for parasite clearance on day seven, but sulfadoxine/pyrimethamine appeared to be more effective on day 14 and 28. No significant difference for adverse events was observed between amodiaquine and chloroquine and sulfadoxine/pyrimethamine. Reported adverse effects were minor or moderate, not life threatening. There is some evidence to support the continued use of amodiaquine in the treatment of uncomplicated malaria, although drug resistance should be considered. Monitoring for toxicity should also continue.

Systematic review of amodiaquine treatment in uncomplicated malaria

Opinion and policy over the use of amodiaquine for treating malaria vary. Amodiaquine is more palatable than chloroquine and may be more effective but serious adverse events have been reported in travellers taking it as prophylaxis. It is not recommended as first-line treatment. In the light of the global debate over the use of this drug, we conducted a systematic review of the effectiveness and tolerability of amodiaquine in the treatment of uncomplicated falciparum malaria. This is a systematic review of published and unpublished randomised or pseudorandomised trials of amodiaquine. Observational reports were also systematically identified and reviewed to access evidence of serious adverse events. 40 trials met the inclusion criteria. Symptomatic patients were enrolled in 24 studies in comparisons of amodiaquine (n = 1071) with chloroquine (n = 1097). Amodiaquine was significantly more effective than chloroquine, with odds ratios and 99% confidence intervals (OR [99% CI]) of 4.29 (3.30-5.58) on day 7 and 6.00 (3.97-9.06) on day 14. Time to parasite clearance was significantly shorter with amodiaquine and fever clearance times were marginally faster. Eight studies compared amodiaquine with chloroquine in asymptomatic parasitaemia, with effects on parasitological outcomes similar to those for symptomatic malaria. At twelve sites, 692 amodiaquine and 679 sulfadoxine/pyrimethamine (S/P) recipients were enrolled. The two drugs did not differ significantly on day 7 (OR 0.74 [0.48-1.15]) but the odds ratios favoured S/P on day 14 (OR 0.51 [0.28-0.93]) and on day 28 (OR 0.30 [0.16-0.55]). The time to parasitological clearance was similar in the two groups; fever clearance times were significantly shorter with amodiaquine. Tolerability was assessed for both comparative and non-comparative trials. The rates of adverse events in controlled trials were 10.7%, 8.8%, and 14.3% with amodiaquine, chloroquine, and S/P, respectively. No life-threatening adverse events and no significant shifts in laboratory indices were reported. This systematic review of published and unpublished trials supports the use of amodiaquine in the treatment of uncomplicated malaria. However, there is partial cross-resistance between chloroquine and amodiaquine, and monitoring of the effectiveness of this drug and surveillance for evidence of toxicity must continue.

In vivo and in vitro sensitivity of Plasmodium falciparum to chloroquine at Lubwe and Kalene in Zambia: use of amodiaquine as an alternative antimalarial drug

The response of Plasmodium falciparum to chloroquine in Zambia was determined by the in vivo and in vitro microtechniques. A total dose of 25mg chloroquine base/kg body weight (over 3 d) was administered to 60 children at Lubwe and 42 at Kalene. The in vivo test was successfully completed on 55 cases at Lubwe and 39 at Kalene, chloroquine resistance being detected in 43·6% and 10·3% of the cases respectively. Out of the 32 successful in vitro microtests conducted at Lubwe and 28 at Kalene, schizont maturation at chloroquine concentrations ⩾5·7 pmol/ well was observed in 81·3% of the isolates at Lubwe and 60·7% of those at Kalene. Most of the resistant isolates at both localities exhibited high minimum inhibitory concentrations (MICs): 44% of those at Lubwe had MICs ⩾32 pmol/well (6·4 μmol/litre), while 42·8% of those at Kalene had MICs of 16 pmol/well (3·2 μmol/litre). Amodiaquine administered in the recommended dose of 25mg/kg body weight over 3 d failed to clear asexual parasitaemia in 15·4% and 15·8% of the cases at Lubwe and Kalene respectively; mean parasite clearance times were 1·9 and 2·2 d. The usefulness of amodiaquine as a second-line drug for the treatment of malaria in Zambia is discussed.