The effect of iron-fortified complementary food and intermittent preventive treatment of malaria on anaemia in 12- to 36-month-old children: a cluster-randomised controlled trial.

BACKGROUND: Iron deficiency (ID) and malaria co-exist in tropical regions and both contribute to high rates of anaemia in young children. It is unclear whether iron fortification combined with intermittent preventive treatment (IPT) of malaria would be an efficacious strategy for reducing anaemia in young children. METHODS: A 9-month cluster-randomised, single-blinded, placebo-controlled intervention trial was carried out in children aged 12-36 months in south-central Côte d'Ivoire, an area of intense and perennial malaria transmission. The study groups were: group 1: normal diet and IPT-placebo (n = 125); group 2: consumption of porridge, an iron-fortified complementary food (CF) with optimised composition providing 2 mg iron as NaFeEDTA and 3.8 mg iron as ferrous fumarate 6 days per week (CF-FeFum) and IPT-placebo (n = 126); group 3: IPT of malaria at 3-month intervals, using sulfadoxine-pyrimethamine and amodiaquine and no dietary intervention (n = 127); group 4: both CF-FeFum and IPT (n = 124); and group 5: consumption of porridge, an iron-fortified CF with the composition currently on the Ivorian market providing 2 mg iron as NaFeEDTA and 3.8 mg iron as ferric pyrophosphate 6 days per week (CF-FePP) and IPT-placebo (n = 127). The primary outcome was haemoglobin (Hb) concentration. Linear and logistic regression mixed-effect models were used for the comparison of the five study groups, and a 2 × 2 factorial analysis was used to assess treatment interactions of CF-FeFum and IPT (study groups 1-4). RESULTS: After 9 months, the Hb concentration increased in all groups to a similar extent with no statistically significant difference between groups. In the 2 × 2 factorial analysis after 9 months, no treatment interaction was found on Hb (P = 0.89). The adjusted differences in Hb were 0.24 g/dl (95 % CI -0.10 to 0.59; P = 0.16) in children receiving IPT and -0.08 g/dl (95 % CI -0.42 to 0.26; P = 0.65) in children receiving CF-FeFum. At baseline, anaemia (Hb <11.0 g/dl) was 82.1 %. After 9 months, IPT decreased the odds of anaemia (odds ratio [OR], 0.46 [95 % CI 0.23-0.91]; P = 0.023), whereas iron-fortified CF did not (OR, 0.85 [95 % CI 0.43-1.68]; P = 0.68), although ID (plasma ferritin <30 µg/l) was decreased markedly in children receiving iron fortified CF (OR, 0.19 [95 % CI 0.09-0.40]; P < 0.001). CONCLUSIONS: IPT alone only modestly decreased anaemia, but neither IPT nor iron fortified CF significantly improved Hb concentration after 9 months. Additionally, IPT did not augment the effect of the iron fortified CF. CF fortified with highly bioavailable iron improved iron status but not Hb concentration, despite three-monthly IPT of malaria. Thus, further research is necessary to develop effective combination strategies to prevent and treat anaemia in malaria endemic regions. TRIAL REGISTRATION: http://www.clinicaltrials.gov ; identifier NCT01634945; registered on July 3, 2012.

Amodiaquine-Ciprofloxacin: a potential combination therapy against drug resistant malaria.

Emergence of malaria parasites resistant to artemisinin necessitates the need for development of new antimalarial therapies. Ciprofloxacin (CFX) a second generation quinolone antibiotic possesses some antimalarial activities. We investigated the in vivo antimalarial activities of CFX in combination with amodiaquine in mice infected with chloroquine-resistant Plasmodium berghei ANKA. Animals were treated orally with 80 or 160 mg kg-1 body weight of CFX alone given twice daily or in combination with amodiaquine (AQ) 10 mg kg-1 body weight. Parasitological activity and survival of the animals were assessed over 21 days. Peak parasitaemia in the untreated control group was 72.51%. Treatment with AQ alone resulted in clearance of parasitaemia by day 4 while treatment with CFX 80 and 160 mg kg-1 alone suppressed parasitaemia by 13.94-54.64% and 35.6-92.7%, respectively. However, the combination of CFX with AQ significantly enhanced response of infection in the animals to treatment (P < 0.05) resulting in complete resolution of parasitaemia throughout follow up period with CFX 160 mg kg-1, delayed recrudescence time with CFX 80 mg kg-1 and significant increase in survival rate of the animals. The results demonstrate beneficial interaction between AQ and CFX which may provide a clinically relevant antimalarial/antibiotic therapeutic option in the management of malaria.

Is parasite clearance clinically important after malaria treatment in a high transmission area? A 3-month follow-up of home-based management with herbal medicine or ACT.

Argemone mexicana (AM), a validated herbal medicine for uncomplicated malaria, seems to prevent severe malaria without completely clearing parasites in most patients. This study, in a high transmission area of South Mali, explores whether residual parasitaemia at day 28 was associated with subsequent malaria episodes and/or anaemia. Three hundred and one patients were randomly assigned to AM or artesunate/amodiaquine as first line treatment, of whom 294 were followed up beyond the standard 28 days, to 84 days. From day 29 to day 84, there were no significant differences between treatment groups in new clinical episodes of uncomplicated malaria (0.33 vs 0.31 episodes/patient), severe malaria (< 6% per month of patients aged ≤ 5 years) or moderate anaemia (hematocrit < 24%: 1.1% in both groups at day 84). Total parasite clearance at day 28 was not correlated with incidence of uncomplicated or severe malaria or of moderate anaemia over the subsequent two months. Total parasite clearance at day 28 was not clinically important in the context of high transmission. If this finding can be confirmed, some antimalarials which are clinically effective but do not completely clear parasites could nevertheless be appropriate in high transmission areas. Such a policy could be tested as a way to delay resistance to artemisinin combination therapies.

Argemone mexicana decoction versus artesunate-amodiaquine for the management of malaria in Mali: policy and public-health implications.

A classic way of delaying drug resistance is to use an alternative when possible. We tested the malaria treatment Argemone mexicana decoction (AM), a validated self-prepared traditional medicine made with one widely available plant and safe across wide dose variations. In an attempt to reflect the real situation in the home-based management of malaria in a remote Malian village, 301 patients with presumed uncomplicated malaria (median age 5 years) were randomly assigned to receive AM or artesunate-amodiaquine [artemisinin combination therapy (ACT)] as first-line treatment. Both treatments were well tolerated. Over 28 days, second-line treatment was not required for 89% (95% CI 84.1-93.2) of patients on AM, versus 95% (95% CI 88.8-98.3) on ACT. Deterioration to severe malaria was 1.9% in both groups in children aged 5 years) and 0% had coma/convulsions. AM, now government-approved in Mali, could be tested as a first-line complement to standard modern drugs in high-transmission areas, in order to reduce the drug pressure for development of resistance to ACT, in the management of malaria. In view of the low rate of severe malaria and good tolerability, AM may also constitute a first-aid treatment when access to other antimalarials is delayed.

Efficacy, safety, and selection of molecular markers of drug resistance by two ACTs in Mali.

We conducted a randomized single-blinded trial comparing the efficacy and safety of artesunate (AS) + amodiaquine (AQ, 3 days) versus AS (3 days) + sulfadoxine-pyrimethamine (SP, single dose) versus AS monotherapy (5 days) in Southern Mali. Uncomplicated malaria cases were followed for 28 days. Molecular markers of drug resistance were determined. After identification of recrudescences by genotyping, both artemisinin-based combination therapies (ACTs) reached nearly 100% efficacy at Day 14 and Day 28 versus 98.3% and 96.5% for AS, respectively (P > 0.05). AS + SP significantly selected DHFR and DHPS mutations associated with sulfadoxine and pyrimethamine resistance (P < 0.001), and AS + AQ equally selected PfCRT and PfMDR1 point mutations associated with chloroquine and AQ resistance (P < 0.001). No significant adverse event attributable to any of the study drugs was found. The ACTs were efficacious and safe, but the selection of markers for resistance to the partner drugs raises concerns over their lifespan in areas of intense malaria transmission.

Randomized, comparative study of the efficacy and safety of artesunate plus amodiaquine, administered as a single daily intake versus two daily intakes in the treatment of uncomplicated falciparum malaria.

BACKGROUND: Artesunate plus amodiaquine is a coblistered ACT, given as a single daily intake. It has been suggested that, in view of the number of tablets to be taken (particularly in adults), it may be possible to improve compliance by allowing patients to divide the daily dose. The objectives of this randomized, comparative, open-label, multicentre study, conducted in Senegal and in Cameroon in 2005, was to demonstrate the non-inferiority and to compare the safety of artesunate plus amodiaquine, as a single daily intake versus two daily intakes. METHODS: A three-day treatment period and 14-day follow-up period was performed in any subject weighting more than 10 kg, presenting with a malaria paroxysm confirmed by parasitaemia > or = 1,000/microl, after informed consent. Patients were randomly allocated into one of the two regimens, with dosage according to bodyweight range. All products were administered by an authorized person, blinded to both the investigating physician and the biologist. The primary endpoint was an adequate response to treatment on D14 (WHO definition). The two-sided 90% confidence interval of the difference was calculated on intent to treat (ITT) population; the acceptance limit for non-inferiority was 3%. The safety was evaluated by incidence of adverse events. RESULTS: Three-hundred and sixteen patients were included in the study. The two patient groups were strictly comparable on D0. The adequate responses to treatment were similar for the two treatment regimens on D14, PCR-corrected (99,4% in the one-daily intake group versus 99,3% in the comparative group). The statistical analyses demonstrated the non-inferiority of administering artesunate/amodiaquine as two intakes. The drug was well tolerated. The main adverse events were gastrointestinal disorders (2.5%) and pruritus (2.5%); safety profiles were similar in the two groups. CONCLUSION: This pilot study confirms the efficacy and good tolerability of artesunate plus amodiaquine, administrated either in one or in two daily intakes.

Efficacy and safety of artesunate plus amodiaquine in routine use for the treatment of uncomplicated malaria in Casamance, southern Sénégal.

BACKGROUND: There are no data on the long term use of an artemisinin combination treatment in moderate or high transmission areas of Africa. METHODS AND FINDINGS: Artesunate plus amodiaquine (AS+AQ) was used to treat slide-proven Plasmodium falciparum-infected patients of all ages in the Oussouye district, Casamance, Senegal, over a period of six years (2000 to 2005). Efficacy, by Kaplan Meier survival analysis (n = 966), and safety (adverse event rates, n = 752) were determined over 28 days. A weight-based dosing regimen was used for the loose tablets during 2000-2003 (n = 731) and a commercially available co-blister was used during 2004-2005 (n = 235). Annual crude (non PCR corrected) rates remained stable over the study period [range 88.5-96.7%; overall 94.6 (95% CI 92.9-95.9)]. Nine co-blister treated patients (0.9%) withdrew because of drug-related adverse events; seven had gastrointestinal complaints of whom two were hospitalized for vomiting. By Day 28, the mean total bilirubin (n = 72), AST (n = 94) and ALT (n = 95) values decreased. Three patients had Day 28 AST/ALT values > 40 < 200 IU/L. Changes in white cell counts were unremarkable (n = 87). CONCLUSION: AS+AQ in combination was highly efficacious and well-tolerated in this area and justifies the decision to use it as first line treatment. Long-term monitoring of safety and efficacy should continue.

Amodiaquine in future combination treatment of malaria in Ghana.

A total of 198 patients were treated with amodiaquine for uncomplicated malaria. Parasite clearance at day 14 was 85.4 and 48% at day 28.

Artesunate-amodiaquine for the treatment of uncomplicated malaria.

Without an effective vaccine for the prevention of malaria, a fundamental component of the strategy for the control of this disease is based on prompt and effective treatment. Due to the high resistance level of Plasmodium falciparum to the most affordable drugs such as chloroquine and sulfadoxine-pyrimethamine, artemisinin-based combination therapies are presently used in many countries or are being developed for registration. One artemisinin combination therapy that is drawing a certain degree of interest is the combination of artesunate (a short half-life drug) plus amodiaquine (a long half-life drug that is presently used in loose combination in many countries). The short half-life drug achieves substantial and rapid parasite killing, while a high concentration of the long half-life drug kills off the remaining malaria parasites. In addition to the effectiveness of 3 days of treatment (rapid clearance of fever and malaria parasites) in western and central Africa, where resistance to amodiaquine is low, the combination of artesunate plus amodiaquine may delay or prevent the emergence of resistance to both drugs. An important step is the recent registration in Morocco (the country where the drug is manufactured) of a fixed combination of artesunate plus amodiaquine by the Drugs for Neglected Diseases initiative with sanofi-aventis as the industrial partner. A prequalification dossier of this fixed combination has been submitted to the WHO. This new co-formulation will almost certainly increase its effectiveness by improving drug compliance.

Efficacy of artesunate plus amodiaquine, artesunate plus sulfadoxine-pyrimethamine, and chloroquine plus sulfadoxine-pyrimethamine in patients with uncomplicated Plasmodium falciparum in the Comoros Union.

Health policy makers in Comoros Union have considered a policy change recommending combination treatment to control malaria. We evaluated the efficacy of three antimalarial drug combinations, taken orally, to enable the authorities to make an evidence-based choice. The study was carried out in patients of 2-70 years old in Moroni, Moheli and Anjouan in 2003. We enrolled 168 patients with uncomplicated malaria from 1097 outpatients screened at the health centres. One hundred and fifty-eight patients, of whom half were under five years old, (mean age=11.1+/-13.9 years), were followed up for 14 days. According to PCR adjusted outcome, the therapeutic efficacy of artesunate+amodiaquine (AS+AQ) (n=54) and artesunate+sulfadoxine-pyrimethamine (AS+SP) (n=53) was 100%, whereas that of chloroquine+sulfadoxine-pyrimethamine (CQ+SP) was 98% (50/51). The key difference between these treatments was the higher parasite clearance rate on Day 2 obtained with artesunate-containing combinations (P<0.001). These results provide a baseline for monitoring changes in the susceptibility of Plasmodium falciparum to artesunate+amodiaquine and artesunate+sulfadoxine-pyrimethamine (ACTs) in the Comoros Union. Health policy changes involving the replacement of chloroquine in the Indian Ocean subregion are discussed.

Efficacy and tolerability of four antimalarial combinations in the treatment of uncomplicated Plasmodium falciparum malaria in Senegal.

BACKGROUND: In view of the high level of chloroquine resistance in many countries, WHO has recommended the use of combination therapy with artemisinin derivatives in the treatment of uncomplicated malaria due to Plasmodium falciparum. Four antimalarial drug combinations, artesunate plus amodiaquine (Arsucam), artesunate plus mefloquine (Artequin), artemether plus lumefantrine (Coartem; four doses and six doses), and amodiaquine plus sulphadoxine-pyrimethamine, were studied in five health districts in Senegal. METHODS: This is a descriptive, analytical, open, randomized study to evaluate the efficacy and tolerability of these four antimalarial combinations in the treatment of uncomplicated falciparum malaria using the 2002 WHO protocol. RESULTS: All drug combinations demonstrated good efficacy. On day 28, all combinations resulted in an excellent clinical and parasitological response rate of 100% after correction for PCR results, except for the four-dose artemether-lumefantrine regimen (96.4%). Follow-up of approximately 10% of each treatment group on day 42 demonstrated an efficacy of 100%.The combinations were well tolerated clinically and biologically. No unexpected side-effect was observed and all side-effects disappeared at the end of treatment. No serious side-effect requiring premature termination of treatment was observed. CONCLUSION: The four combinations are effective and well-tolerated.

Artesunate--amodiaquine combination therapy for falciparum malaria in young Gabonese children.

BACKGROUND: Artesunate-amodiaquine combination for the treatment of childhood malaria is one of the artemisinin combination therapies (ACTs) recommended by National authorities in many African countries today. Effectiveness data on this combination in young children is scarce. METHODS: The effectiveness of three daily doses of artesunate plus amodiaquine combination given unsupervised (n = 32), compared with the efficacy when given under full supervision (n = 29) to children with falciparum malaria were assessed in an unrandomized study. RESULTS: 61 patients analysed revealed a PCR-corrected day-28 cure rate of 86 % (25 of 29 patients; CI 69-95 %) in the supervised group and 63 % (20 of 32 patients; CI 45-77 %) in the unsupervised group. The difference in outcome between both groups was statistically significant (p = 0.04). No severe adverse events were reported. CONCLUSION: The effectiveness of this short course regimen in young children with falciparum malaria could be augmented by increased adherence and improved formulation.

Artemisinin-based combination therapy for uncomplicated Plasmodium falciparum malaria in Colombia.

BACKGROUND: Artemisinin-based combination therapy (ACT) is being widely promoted as a strategy to counteract the increase in Plasmodium falciparum antimalarial drug resistance. METHODS: A randomized, double-blind, placebo-controlled, clinical trial of the efficacy, effect on gametocytes and safety of the addition of artesunate/placebo (4 mg/kg/day x 3 d) to amodiaquine (10 mg/kg/day x 3 d) was conducted in Choco department, a low intensity transmission area in northwest Colombia. RESULTS: From 2,137 screened subjects, 85 entered the study: 43 in the amodiaquine plus placebo and 42 in the amodiaquine plus artesunate groups. Potentially eligible cases failed to qualify mostly because they were not available for follow-up visits (73%). Based on a per protocol analysis, the therapeutic response to both treatments was high: amodiaquine/placebo 35/36, 97.2% (95% CI 85.5-99.9), and amodiaquine/artesunate 32/32, 100% (89.1-100) after PCR genotyping. The Kaplan-Meier survival estimates based on all eligible patients enrolled (amodiaquine/placebo: n = 42; amodiaquine/artesunate: n = 41) were similar in the two study groups (P = 0.3). The addition of artesunate significantly decreased gametocyte carriage on Day 4 (OR = 0.1 95% CI 0.02-0.6), Day 7 (OR = 0.2 95%CI 0.04-0.9), Day 14 (OR = 0.09 95% CI 0-0.8), and Day 21 (OR95%CI 0-0.9). Most subjects in both groups (81% in amodiaquine/placebo and 75.6% in amodiaquine/artesunate) reported at least one drug related adverse event. Symptoms were generally mild and self-limiting and there was no serious adverse event. Two patients on amodiaquine/artesunate voluntarily withdrew from study because they could not tolerate the medication. CONCLUSION: Both drug regimens were effective in this area of Colombia. The addition of artesunate reduced gametocyte carriage and did not adversely affect tolerability. In this set of patients, the rate of adverse events was higher than in other studies. Patients' follow-up is problematic in areas with dispersed population and affects the conduct of clinical studies and monitoring of treatment effects. The results are discussed in the light of concurrent increase resistance to amodiaquine in other endemic areas in Colombia and the factors that may influence a change in the national antimalarial drug policy.

Activities of amodiaquine, artesunate, and artesunate-amodiaquine against asexual- and sexual-stage parasites in falciparum malaria in children.

The activities of amodiaquine, artesunate, and artesunate-amodiaquine against asexual- and sexual-stage parasites were evaluated in 360 Nigerian children with uncomplicated Plasmodium falciparum malaria randomized to the standard dose regimens of the three drugs/combination. Clinical recovery from illness occurred in all children. There were no significant differences in fever clearance times. Patients treated with artesunate or artesunate-amodiaquine had significantly shorter parasite clearance times (1.4 +/- 0.5 days or 1.4 +/- 0.6 days versus 3.2 +/- 2.3 days, P = 0.0001) and lower gametocyte carriage rates (3.3 or 1.7% versus 11.7%, P = 0.001) than those treated with amodiaquine alone. Gametocytemia was detected in 62 patients (11.7% before treatment and 5.6% after treatment). The pretreatment gametocyte sex ratio, which was female biased, increased significantly during the course of treatment with amodiaquine but not with artesunate and artesunate-amodiaquine. These results suggest that artesunate and artesunate-amodiaquine reduce gametocyte carriage and may reduce transmissibility in P. falciparum malaria by accelerating asexual clearance and influencing gametocyte sex ratio.

Efficacy of three artemisinin combination therapies for the treatment of uncomplicated Plasmodium falciparum malaria in the Republic of Congo.

BACKGROUND: Presented here are the results of a comparative trial on the efficacy of three artemisinin-based combinations conducted from May to October 2004, in Pool Province, Republic of Congo. METHODS: The main outcome was the proportion of cases of true treatment success at day 28. Recrudescences were distinguished from re-infections by PCR analysis. A total of 298 children of 6-59 months were randomized to receive either artesunate + SP (AS+SP), artesunate + amodiaquine (AS+AQ) or artemether + lumefantrine (AL), of which 15 (5%) were lost to follow-up. RESULTS: After 28 days, there were 21/85 (25%) recurrent parasitaemias in the AS+SP group, 31/97 (32%) in the AS+AQ group and 13/100 (13%) in the AL group. The 28-day PCR-corrected cure rate was 90.1% [95% CI 80.7-95.9] for AS+SP, 98.5% [95% CI 92.0-100] for AS+AQ and 100% [95.8-100] for AL, thereby revealing a weaker response to AS+SP than to AL (p = 0.003) and to AS+AQ (p = 0.06). A potential bias was the fact that children treated with AL were slightly older and in better clinical condition, but logistic regression did not identify these as relevant factors. There was no significant difference between groups in fever and parasite clearance time, improvement of anaemia and gametocyte carriage at day 28. No serious adverse events were reported. CONCLUSION: Considering the higher efficacy of AL as compared to AS+SP and the relatively high proportion of cases with re-infections in the AS+AQ group, we conclude that AL is clinically more effective than AS+SP and AS+AQ in this area of the Republic of Congo. Implementation of the recently chosen new national first-line AS+AQ should be monitored closely.

Artemether-lumefantrine versus artesunate plus amodiaquine for treating uncomplicated childhood malaria in Nigeria: randomized controlled trial.

BACKGROUND: The therapeutic efficacy of artesunate plus amodiaquine and artemether/lumefantrine were assessed in an area of Nigeria with high levels of Plasmodium falciparum resistance to chloroquine and sulphadoxine-pyrimethamine. PARTICIPANTS: Children aged 6 to 59 months with uncomplicated P. falciparum infection and parasite density 1,000 to 200,000 parasites/microL enrolled following informed consent by parents. METHODS: Eligible children were randomly assigned to receive either a 3-day course of artesunate (4 mg/kg) plus amodiaquine (10 mg/kg) or 6-dose course of artemether/lumefantrine (20/120 mg tablets) over three days. Patients were followed up with clinical and laboratory assessments until day 14 using standard WHO in-vivo antimalarial drug test protocol. RESULTS: A total 119 eligible children were enrolled but 111 completed the study. Adequate clinical and parasitological response (ACPR) was 47 (87.0%) and 47 (82.5%) for artemether-lumefantrine (AL) and artesunate+amodiaquine (AAMQ) respectively (OR 0.7, 95% confidence interval 0.22 to 2.22). Early treatment failure (ETF) occurred in one participant (1.8%) treated with AAQ but in none of those with AL. Two (3.7%) patients in the AL group and none in the AAQ group had late clinical failure. Late parasitological failure was observed in 9 (15.8) and 5 (9.3%) of patients treated with AAQ and AL respectively. None of participants had a serious adverse event. CONCLUSION: Artemether-lumenfantrine and artesunate plus amodiaquine have high and comparable cure rates and tolerability among under-five children in Calabar, Nigeria.

El citocromo P-450 y la respuesta terapéutica a los antimaláricos / Cytochrome P-450 and the response to antimalarial drugs

OBJETIVOS: Evaluar la relación entre los factores genéticos y fenotípicos del sistema enzimático del citocromo P-450 y la respuesta terapéutica antimalárica a la cloroquina, la amodiaquina, la mefloquina y el proguanil, así como determinar la influencia de algunos factores biológicos y sociales del hospedero en el comportamiento de este complejo enzimático. MÉTODOS: Revisión sistemática de las bases de literatura biomédica PubMed, Excerpta Medica, LILACS y SciELO mediante descriptores en español e inglés. Se usaron los siguientes descriptores: "CYP-450" y "citocromo P-450" y sus combinaciones con "proguanil" (y lo mismo con "mefloquina", "cloroquina" y "amodiaquina"), "farmacocinética de proguanil" (y lo mismo con "mefloquina", "cloroquina" y "amodiaquina"), "resistencia a proguanil" (y lo mismo con "mefloquina", "cloroquina" y "amodiaquina"), "metabolismo", "farmacogenética", "enfermedad", "inflamación", "infección", "enfermedad hepática", "malaria", "nutrición" y "desnutrición". Estos mismos términos se usaron en inglés. La búsqueda se limitó a los artículos publicados en español, inglés y portugués hasta el 30 de junio de 2005 y a cuatro medicamentos antimaláricos: amodiaquina, cloroquina, mefloquina y proguanil. RESULTADOS: Algunos factores genéticos del citocromo P-450 humano (principalmente su polimorfismo), así como otros de tipo biológico y social (la propia presencia de enfermedad, inflamación o infección, la administración de medicamentos antimaláricos y su combinación, y el estado nutricional del paciente), influyen en la actividad de ese complejo enzimático. Solo en la última década se ha abordado el estudio de las bases genéticas de los citocromos y se han podido dilucidar los mecanismos de algunas interacciones entre fármacos y del metabolismo de estos, lo que ha permitido caracterizar el proceso de biotransformación de la amodiaquina y de la cloroquina. Se espera que nuevas investigaciones permitan responder a las interrogantes que aún subsisten, entre ellas cuál es la ruta metabólica de otros medicamentos antimaláricos, la distribución en la población de los alelos de las enzimas que participan en su metabolismo, y la contribución de tales mutaciones al fracaso terapéutico, y predecir la respuesta a los tratamientos antimaláricos. CONCLUSIONES. La respuesta terapéutica a los medicamentos antimaláricos es un proceso multifactorial y poco comprendido, por lo que no es posible asignar a un fenotipo o a un genotipo una determinada responsabilidad en la respuesta terapéutica antimalárica. Se debe contemplar la influencia de factores biológicos y sociales, tales como la alimentación, el estado nutricional y cualquier proceso inflamatorio e infeccioso concomitante, que puedan ser frecuentes en las zonas con malaria endémica.

OBJECTIVES. To assess the relationship between the genetic and phenotypic factors linked to the cytochrome P-450 enzyme system and the response to the antimalarial drugs chloroquine, amodiaquine, mefloquine, and proguanil, as well as to determine how certain biological and social factors of the host influence the behavior of this enzymatic complex. METHODS. We performed a systematic review of the medical bibliographic databases PubMed, Excerpta Medica, LILACS, and SciELO by using the following Spanish and English descriptors: "CYP-450" and "citocromo P-450" in combination with "proguanil" (and with "mefloquina," "cloroquina," and "amodiaquina"), "farmacocinética de proguanil" (and the same using "mefloquina," "cloroquina," and "amodiaquina"), "resistencia a proguanil" (and the same using "mefloquina," "cloroquina," and "amodiaquina"), "metabolismo," "farmacogenética," "enfermedad," "inflamación," "infección," "enfermedad hepática," "malaria," "nutrición," and "desnutrición." The same terms were used in English. The search included only articles published in Spanish, English, and Portuguese on or before 30 June 2005 that dealt with only four antimalarial drugs: amodiaquine, chloroquine, mefloquine, and proguanil. RESULTS. Some genetic factors linked to human cytochrome P-450 (mainly its polymorphism), as well as other biological and social factors (the presence of disease itself, or of inflammation and infection, the use of antimalarials in their various combinations, and the patient's nutritional status) influence the behavior of this complex enzymatic system. It has only been in the last decade that the genetics of the cytochromes has been explored and that the mechanisms underlying some therapeutic interactions and aspects of drug metabolism have been uncovered, making it possible to characterize the biotransformation pathway of amodiaquine and chloroquine. Hopefully new research will help answer the questions that still remain, some of which pertain to the metabolism of other antimalarial drugs, the distribution in the population of the genetic alleles linked to the enzymes involved in their metabolism, the contribution of these genetic mutations to therapeutic failure, and the possibility of predicting the response to antimalarial therapy. CONCLUSIONS. The therapeutic response to antimalarial drugs is a multifactorial process that is poorly understood, so that it is not possible to ascribe to a specific phenotype or genotype a role in the response to antimalarial therapy. Attention should be given to biological and social factors, such as diet, nutritional status, and inflammatory and infectious processes that are often present in areas where malaria is endemic.

Efficacy of artesunate plus amodiaquine versus that of artemether-lumefantrine for the treatment of uncomplicated childhood Plasmodium falciparum malaria in Zanzibar, Tanzania.

BACKGROUND: This is the first clinical trial comparing the efficacy of artesunate plus amodiaquine (ASAQ) and artemether-lumefantrine (AL)--the major artemisinin-based combination therapy (ACT) candidates for treatment of malaria in Africa--that involved an extended, 42-day follow-up period, polymerase chain reaction-adjusted parasitological cure rates (PCR APCRs), and systematic analyses of genetic markers related to quinoline resistance. METHODS. A total of 408 children with uncomplicated Plasmodium falciparum malaria in Zanzibar, Tanzania, were enrolled. Children who were 6-8 months of age and/or who weighed 6-8 kg were assigned to receive ASAQ for 3 days. Children who were 9-59 months of age and who weighted > or =9 kg were randomly assigned to receive either ASAQ or AL for 3 days in standard doses. Intention-to-treat analyses were performed. RESULTS: Age- and weight-adjusted PCR-APCRs by follow-up day 42 were 91% (188 of 206 patients) in the ASAQ group and 94% (185 of 197 patients) in the AL group (odds ratio [OR] for the likelihood of cure, 2.07; 95% confidence interval [CI], 0.84-5.10; P=.115). A total of 5 and 7 recrudescences occurred after day 28 in the ASAQ and AL groups, respectively. On the assumption that 10 malaria episodes with uncertain PCR results were recrudescences, PCR-APCRs decreased to 88% in the ASAQ group and to 92% in the AL group. Unadjusted cure rates by day 42 were 56% (116 of 206 patients) in the ASAQ group versus 77% (151 of 197 patients) in the AL group (OR, 2.55; 95% CI, 1.66-3.91; P<.001). Rates of reinfection by day 42 were 36% (65 of 181 patients) in the ASAQ arm versus 17% (31 of 182 patients) in the AL arm (OR, 0.37; 95% CI, 0.22-0.60; P<.001). A significant selection of P. falciparum multidrug resistance gene 1 allele 86N was found in isolates associated with reinfection after AL treatment, compared with isolates at baseline (2.2-fold increase; P<.001). CONCLUSIONS: Both treatments were highly efficacious, but AL provided stronger prevention against reinfection. The high proportion of recrudescences found after day 28 and the genetic selection by the long-acting partner drug underlines the importance of long follow-up periods in clinical trials. A long follow-up duration and performance of PCR genotyping should be implemented in programmatic surveillance of antimalarial drugs.

Comparative efficacy of antimalarial drugs including ACTs in the treatment of uncomplicated malaria among children under 5 years in Ghana.

The emergence and spread of Plasmodium falciparum resistance to commonly used antimalarials such as chloroquine and sulphadoxine/pyrimethamine poses major challenges to malaria control in sub-Saharan Africa. We undertook a study on the efficacy of some antimalarial drugs in 2003 with the view of supporting the National Malaria Control Programme in the review of the antimalarial drug treatment policy in Ghana. Children aged 6-59 months with signs/symptoms of uncomplicated malaria including axillary temperature > or =37.5 degrees C; mono infection with P. falciparum; and parent's willingness to give consent, were randomized into four treatment groups and followed up for a maximum of 28 days. The treatment groups were chloroquine (CHQ), sulphadoxine/pyrimethamine (SP), amodiaquine+artesunate (ADQ+ART) combination, and artemether+lumefantrine (Coartem) combination. Clinical evaluation of 168 children studied showed that cumulative pcr-corrected cure rates on day 28 were 100% for ADQ+ART; 97.5% for coartem, 60% for SP and 25% for CHQ. The artemisinin-based combinations effected rapid fever and parasite clearance. Prevalence of gametocytaemia was highest in the SP group whilst the CHQ group did not show any significant changes in haemoglobin levels during the follow-up period. The findings are in agreement with current recommendations for using artemisinin-based combinations for treating uncomplicated malaria in areas of high CHQ failure such as Ghana.

Artemisinin versus nonartemisinin combination therapy for uncomplicated malaria: randomized clinical trials from four sites in Uganda.

BACKGROUND: Drug resistance in Plasmodium falciparum poses a major threat to malaria control. Combination antimalarial therapy including artemisinins has been advocated recently to improve efficacy and limit the spread of resistance, but artemisinins are expensive and relatively untested in highly endemic areas. We compared artemisinin-based and other combination therapies in four districts in Uganda with varying transmission intensity. METHODS AND FINDINGS: We enrolled 2,160 patients aged 6 mo or greater with uncomplicated falciparum malaria. Patients were randomized to receive chloroquine (CQ) + sulfadoxine-pyrimethamine (SP); amodiaquine (AQ) + SP; or AQ + artesunate (AS). Primary endpoints were the 28-d risks of parasitological failure either unadjusted or adjusted by genotyping to distinguish recrudescence from new infections. A total of 2,081 patients completed follow-up, of which 1,749 (84%) were under the age of 5 y. The risk of recrudescence after treatment with CQ + SP was high, ranging from 22% to 46% at the four sites. This risk was significantly lower (p < 0.01) after AQ + SP or AQ + AS (7%-18% and 4%-12%, respectively). Compared to AQ + SP, AQ + AS was associated with a lower risk of recrudescence but a higher risk of new infection. The overall risk of repeat therapy due to any recurrent infection (recrudescence or new infection) was similar at two sites and significantly higher for AQ + AS at the two highest transmission sites (risk differences = 15% and 16%, p < 0.003). CONCLUSION: AQ + AS was the most efficacious regimen for preventing recrudescence, but this benefit was outweighed by an increased risk of new infection. Considering all recurrent infections, the efficacy of AQ + SP was at least as efficacious at all sites and superior to AQ + AS at the highest transmission sites. The high endemicity of malaria in Africa may impact on the efficacy of artemisinin-based combination therapy. The registration number for this trial is ISRCTN67520427 (http://www.controlled-trials.com/isrctn/trial/|/0/67520427.html).