Antimalarial Agents Derived from Metal-Amodiaquine Complexes with Activity in Multiple Stages of the Plasmodium Life Cycle.

Malaria is the one of the deadliest infectious diseases worldwide. Chemically, quinolines are excellent ligands for metal coordination and are deployed as drugs for malaria treatment. There is a growing body of evidence indicating that metal complexes can be conjugated with antimalarial quinolines to be used as chemical tools to overcome the disadvantages of quinolines, improving their bioactive speciation, cellular distribution, and subsequently broadening the spectrum of activity to multiple stages of the complex Plasmodium life cycle. In this study, four novel complexes of ruthenium(II)- and gold(I)-containing amodiaquine (AQ) were synthesized, and a careful chemical characterization revealed the precise coordination site of AQ to the metals. Their speciation in solution was investigated, demonstrating the stability of the quinoline-metal bond. RuII - and AuI -AQ complexes were demonstrated to be potent and efficacious in inhibiting parasite growth in multiple stages of the Plasmodium life cycle as assayed in vitro and in vivo. These properties could be attributed to the ability of the metal-AQ complexes to reproduce the suppression of heme detoxification induced by AQ, while also inhibiting other processes in the parasite life cycle; this can be attributed to the action of the metallic species. Altogether, these findings indicate that metal coordination with antimalarial quinolines is a potential chemical tool for drug design and discovery in malaria and other infectious diseases susceptible to quinoline treatment.

Fixed-Dose Artesunate-Amodiaquine Combination vs Chloroquine for Treatment of Uncomplicated Blood Stage P. vivax Infection in the Brazilian Amazon: An Open-Label Randomized, Controlled Trial.

BACKGROUND: Despite increasing evidence of the development of Plasmodium vivax chloroquine (CQ) resistance, there have been no trials comparing its efficacy with that of artemisinin-based combination therapies (ACTs) in Latin America. METHODS: This randomized controlled trial compared the antischizontocidal efficacy and safety of a 3-day supervised treatment of the fixed-dose combination artesunate-amodiaquine Winthrop® (ASAQ) versus CQ for treatment of uncomplicated P. vivax infection in Manaus, Brazil. Patients were followed for 42 days. Primary endpoints were adequate clinical and parasitological responses (ACPR) rates at day 28. Genotype-adjustment was performed. RESULTS: From 2012 to 2013, 380 patients were enrolled. In the per-protocol (PP) analysis, adjusted-ACPR was achieved in 100% (165/165) and 93.6% (161/172) of patients in the ASAQ and CQ arm (difference 6.4%, 95% CI 2.7%; 10.1%) at day 28 and in 97.4% (151/155) and 77.7% (129/166), respectively (difference 19.7%, 95% CI 12.9%; 26.5%), at day 42. Apart from ITT D28 assessment, superiority of ASAQ on ACPR was demonstrated. ASAQ presented faster clearance of parasitaemia and fever. Based on CQ blood level measurements, CQ resistance prevalence was estimated at 11.5% (95% CI: 7.5-17.3) up to day 42. At least one emergent adverse event (AE) was recorded for 79/190 (41x6%) in the ASAQ group and for 85/190 (44x7%) in the CQ group. Both treatments had similar safety profiles. CONCLUSIONS: ASAQ exhibited high efficacy against CQ resistant P. vivax and is an adequate alternative in the study area. Studies with an efficacious comparator, longer follow-up and genotype-adjustment can improve CQR characterization. CLINICAL TRIALS REGISTRATION: NCT01378286.

Interactions of the antimalarial amodiaquine with lipid model membranes.

A detailed molecular description of the mechanism of action of the antimalarial drug amodiaquine (AQ) is still an open issue. To gain further insights on that, we studied the interactions of AQ with lipid model membranes composed of dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylserine (DPPS) by spin labeling electron spin resonance (ESR) and differential scanning calorimetry (DSC). Both techniques indicate a coexistence of an ordered DPPS-rich domain with a disordered DPPC-rich domain in the binary DPPC/DPPS system. We found that AQ slightly lowered the melting transition temperatures associated to both domains and significantly increased the enthalpy change of the whole DPPC/DPPS phase transition. DSC and ESR data also suggest that AQ increases the number of DPPC molecules in the DPPC-rich domains. AQ also causes opposing ordering effects on different regions of the bilayer: while the drug increases the ordering of the lipid acyl chains from carbon 7 to 16, it decreases the order parameter of the lipid head group and of carbon 5. The gel phase was mostly affected by the presence of AQ, suggesting that AQ is able to influence more organized lipid domains. Moreover, the effects of AQ and cholesterol on lipid acyl chain ordering and mobility were compared at physiological temperature and, in a general way, they are similar. Our results suggest that the quinoline ring of AQ is located completely inside the lipid bilayers with its phenol ring and the tertiary amine directed towards the head group region. The nonspecific interaction between AQ and DPPC/DPPS bilayers is a combination of electrostatic and hydrophobic interactions.

In vitro effects of amodiaquine on paired Schistosoma mansoni adult worms at concentrations of less than 5 µg/mL

In this study, the in vitro effects of amodiaquine (AQ) monotherapy on the egg output of paired adult Schistosoma mansoni worms and their survival during in vitro culture were assessed. In addition, the gross morphological alterations of male and female worms caused by AQ were visually observed under a dissecting microscope. AQ significantly reduced the daily egg output of paired adult S. mansoni worms following incubation for 14 days at 1-5 µg/mL, but not at 0.5 µg/mL, compared with the control group. AQ also reduced the survival of male and female worms at concentrations of 2 and 5 µg/mL, respectively. Moreover, exposure to 5 µg/mL AQ caused severe swelling and/or localisation of black content in the body of all male and female worms within one or two days of incubation; subsequently, shrinkage in the male worms and elongation in the female worms were observed. The initial morphological alterations caused by AQ occurred along the intestinal tract of the male and female worms. To our knowledge, this is the first study to report not only the efficacy of AQ at concentrations lower than 5 µg/mL on paired adult S. mansoni worms, but also the effects of AQ on the intestinal tracts of worms in in vitro culture.

Eficacia terapéutica y eventos adversos de tratamientos para malaria vivax y malaria falciparum en gestantes en las regiones de Urabá y Alto San Jorge, Colombia, 2008-2011 / Therapeutic efficacy and adverse events of treatments for vivax and falciparum malaria in pregnant women in the regions of Uraba and Alto San Jorge, Colombia, 2008-2011

Objetivo: evaluar, con el protocolo de la Organización Mundial de la Salud (OMS) de 1998, la respuesta terapéutica antimalárica (RTA) y los eventos adversos (EA) en cuatro esquemas de tratamiento antiplasmodial en gestantes colombianas, con diagnóstico de malaria no complicada por P. vivax o por P. falciparum, según gota gruesa.Materiales y métodos: experimento controlado aleatorizado en paralelo. Se calculó un tamaño muestral de 60 pacientes con P. vivax y 30 con P. falciparum. Se evaluaron cuatro tratamientos: malaria vivax en cualquier trimestre de gestación tratada con cloroquina o con amodiaquina; malaria falciparum en trimestres 2 y 3, terapia tratada con artesunato-mefloquina o arteméter-lumefantrina. Se hizo seguimiento por 28 días. Se midió la proporción de falla terapéutica y de eventos adversos. Los grupos se comparan mediante análisis univariado. El protocolo del estudio fue registrado en el sitio: ClinicalTrials. gov bajo el registro: MGP-02. Resultados: se trataron 90 pacientes. La RTA fue adecuada en 97-100% de los casos de malaria vivax (variación del método de análisis) y en 100% de los casos con malaria falciparum. Los EA más comunes fueron dolor epigástrico, mareo, tinitus y visión borrosa. No hubo eventos adversos graves.Conclusiones: la cloroquina y la amodiaquina tienen igual respuesta terapéutica adecuada. Las combinaciones artesunato-mefloquina y arteméterlumefantrina no mostraron fallas terapéuticas. Se requieren estudios en otros lugares del país con los esquemas evaluados y con otros.

Objective: To assess, using the 1998 WHO protocol, adequate clinical and parasitological response (ACPR) and adverse events (AEs) to 4 antiplasmodial treatment regimens in pregnant Colombian women diagnosed with uncomplicated P. vivax or P. falciparum malaria on the basis of thick blood smear.Materials and methods: Parallel randomized controlled trial. The estimated sample size was 60 patients with P. vivax and 30 with P. falciparum. Four treatments were assessed: vivax malaria in any trimester treated with chloroquine or amodiaquine; falciparum malaria in second and third trimesters treated with artesunate-mefloquine or artemether-lumefantrine. Patients were followed for 28 days. Measurements included the proportion of therapeutic failures and of adverse events. Groups were compared using univariate analysis. The study protocol was registered in ClinicalTrials.gov under the Protocol Record MGP-02. Results: Overall, 90 patients were treated. ACPR was adequate in 97-100% of vivax cases (analytical method variation) and in 100% of falciparum cases. The most common AEs were epigastric pain, dizziness, tinnitus and blurred vision. There were no serious adverse events. Conclusions: Both chloroquine as well as amodiquine have similar adequate responses. No therapeutic failures were found for the combinations of artesunate-mefloquine and artemether-lumefantrine. Studies need to be done in other places of the country using the regimens assessed as well as others.

Artesunate + amodiaquine versus artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in the Colombian Pacific region: a noninferiority trial / Artesunato + amodiaquina versus artemether-limefantrina para o tratamento da malaria não complicada por Plamodium falciparum no Pacifico Colombiano: um estudo de não inferioridade

INTRODUCTION: In Colombia, there are no published studies for the treatment of uncomplicated Plasmodium falciparum malaria comparing artemisinin combination therapies. Hence, it is intended to demonstrate the non-inferior efficacy/safety profiles of artesunate + amodiaquine versus artemether-lumefantrine treatments. METHODS: A randomized, controlled, open-label, noninferiority (Δ≤5%) clinical trial was performed in adults with uncomplicated P. falciparum malaria using the 28‑day World Health Organization validated design/definitions. Patients were randomized 1:1 to either oral artesunate + amodiaquine or artemether-lumefantrine. The primary efficacy endpoint: adequate clinical and parasitological response; secondary endpoints: - treatment failures defined per the World Health Organization. Safety: assessed through adverse events. RESULTS: A total of 105 patients was included in each group: zero censored observations. Mean (95%CI - Confidence interval) adequate clinical and parasitological response rates: 100% for artesunate + amodiaquine and 99% for artemether-lumefantrine; the noninferiority criteria was met (Δ=1.7%). There was one late parasitological therapeutic failure (1%; artemether-lumefantrine group), typified by polymerase chain reaction as the MAD20 MSP1 allele. The fever clearance time (artesunate + amodiaquine group) was significantly shorter (p=0.002). Respectively, abdominal pain for artesunate + amodiaquine and artemether-lumefantrine was 1.9% and 3.8% at baseline (p=0.68) and 1% and 13.3% after treatment (p<0.001). CONCLUSIONS: Uncomplicated P. falciparum malaria treatment with artesunate + amodiaquine is noninferior to the artemether-lumefantrine standard treatment. The efficacy/safety profiles grant further studies in this and similar populations.

INTRODUÇÃO: Na Colômbia não existem estudos publicados sobre o tratamento da malária não complicada por Plasmodium falciparum comparando as terapias combinadas com artemisinina. Destarte, quer se demonstrar a não inferioridade dos perfis de eficácia/segurança dos tratamentos com artesunato+amodiaquina versus artemeter-lumefantrina. MÉTODOS: Foi realizado um estudo clínico de não inferioridade (∆≤5%), aleatório, controlado, aberto, em adultos com malária não complicada por P. falciparum usando o desenho validado de 28 dias e os desenhos validados/definidos pela Organização Mundial da Saúde. Os pacientes foram aleatorizados (1:1) para ambos artesunato+amodiaquina ou artemeter-lumefantrina orais. Critérios primários de eficácia: resposta clínica e parasitológica adequada; Criterios de eficácia secundários: as falhas de tratamento definidos pela Organização Mundial da Saúde. A segurança: avaliada através de eventos adversos. RESULTADOS: Foram incursos 105 pacientes em cada grupo: zero observações censuradas. As taxas médias da resposta clínica e parasitológica adequada (95% IC - intervalo de confiança): 100% para artesunato+amodiaquina e 99% para artemeter-lumefantrina; atingiu-se o critério de não inferioridade (∆=1.7%). Houve uma falha terapêutica parasitológica tardia (1%; grupo artemeter-lumefantrina), caracterizada mediante reação em cadeia da polimerase como o alelo MAD20 MSP1. Tempo de remissão da febre (grupo artesunato+amodiaquina), foi significativamente mais curto (p=0.002). Dor abdominal, para artesunato+amodiaquina e artemeter-lumefantrina, respectivamente, 1.9% e 3.8% (p=0.68) na linha de base, 1% e 13.3% pós-tratamento (p<0.001). CONCLUSÕES: O tratamento com artesunato+amodiaquina da malária não complicada por P. falciparum é não inferior ao tratamento normal com artemeter-lumefantrina. Os perfis de eficácia/segurança justificam estudos adicionais nesta e outras populações semelhantes.

Malaria: eficacia de amodiaquina-sulfadoxina-pirimetamina, estado nutricional y variantes alélicas del gen CYP2C8 / Malaria: efficacy of amodiaquine-sulfadoxine-pyrimethamine, nutritional status and alellic variaton of CYP2C8 gen

Problema: La respuesta terapéutica antimalárica depende de múltiples determinantes asociados con el plasmodio (especie, mutaciones, cantidad, etc.) y al hospedero (nutrición, genes, metabolismo, etc.), pero los últimos son poco conocidos. Objetivos: Evaluar en pacientes con malaria falciparum no complicada, tratados con amodiaquina-sulfadoxina-pirimetamina (AQ-SP), algunas relaciones entre la respuesta terapéutica (RTA), el estado nutricional y las variaciones alélicas del gen CYP2C8. Metodología: Estudio clínico controlado, con asignación aleatoria, balanceado, no ciego. La RTA se evaluó según la Organización Mundial de la Salud. Se hizo análisis antropométrico, se midieron las concentraciones plasmáticas de retinol, ferritina y selenio; se analizaron las variantes 2C8*1 (silvestre), 2C8*2 (Il29F) y 2C8*3 (R139K y K399R) del gen CYP2C8. Resultados: Se evaluaron 33 pacientes, todos con respuesta terapéutica adecuada con AQ-SP; 10% presentó deficiencia de retinol, 25% de selenio y 40% de ferritina. Sólo un paciente presentó la variante CYP2C8*2 en forma heterozigótica y el resto fueron homocigóticos para el alelo silvestre de este gen. Ninguno presentó la mutación R139K en CYP2C8*3. Del alelo K339R de CYP2C8*3 no se pudieron obtener fragmentos aptos de digerir, aún haciendo adaptaciones del método y no fue posible conocer la razón de este hecho. Estos datos concuerdan con los resultados de otro análisis similar en 23 pacientes, tratados solo con amodiaquina: 22% presentaron alguna variante (5 con CYP2C8*2 y 2 con CYP2C8*3). En el gen CYP2C8*3 se identificó sólo la mutación R139K, presente en 2 individuos.Conclusión: Sólo uno de los 33 pacientes (3%) presentó la variante CYP2C8*2, en forma heterozigótica; el resto fueron homocigóticos para el alelo silvestre de esta variante. Ninguno presentó la mutación R139K de la variante CYP2C8*3. Es el primer informe para Latinoamérica.

Problem: Therapeutic response to antimalarials depends on multiple determinants associated with the parasite (species, mutations, parasitaemia, etc.) and the host (nutrition, genes, metabolism, etc.), but little is known about the host factors. Objectives: To evaluate in non-complicated falciparum malaria patients undergoing treatment with amodiaquine-sulfadoxine-pyrimethamine (AQ-SP), some relationships between treatment response, nutritional status and characteristics of the gen CYP2C8. Methodology: A randomly assigned, balanced, non blind, controlled clinical design. Treatment response was assessed according to WHO 1998 criteria. Analysis included anthropometry, plasma levels of retinol, ferritin and selenium, and assessment of 2C8*1 (wild), 2C8*2 (Il29F) and 2C8*3 variants of CYP2C8 (R139K y K399R). Results: 33 patients were studied, all of them evidenced adequate treatment response, 10% had retinol deficiency, 25% selenium deficiency and 40% low ferritine levels. One patient exhibited the variant Il29F of CYP2C8*2 in a heterozygous fashion, the remaining individuals were homozygous for the wild form of this gene. The mutant R139K of CYP2C8*3 was absent in all individuals. Amplification fragments obtained of K339R (CYP2C8*3 gen) were not suitable for digestion, regardless of the modifications performed. These results confirm previous findings made in 22% of 23 patients in whom some variation was observed (5 in CYP2C8*2 and 2 in CYP2C8*3). For CYP2C8*3 the mutant R139K, was observed in 2 individuals. Conclusion: only one of the 33 patients (3%) had CYP2C8*2 in a heterozygous fashion, the remaining were homozygous for the wild allele of this variant. None of the patients had the mutation R139K of the CYP2C8*3 variant. This is a novel report for Latin America.

Some features of primary and recrudescent amodiaquine-resistant Plasmodium falciparum infections in Nigerian children

Characteristics of primary and recrudescent Plasmodium falciparum infections were evaluated in 25 children who did not recover after amodiaquine (AQ) treatment. Recrudescence was detected by a thick blood smear and confirmed by polymerase chain reaction. Over half of recrudescent events occurred after 14 days of initiation of treatment and were associated with relatively low asexual parasitaemia. We examined the gametocyte sex ratio (GSR) in these children and in age and gender-matched controls that had AQ-sensitive (AQ-S) infections (n = 50). In both AQ-S and AQ-resistant (AQ-R) infections, the GSR was female-biased pre-treatment and became male-biased by the third day after treatment initiation. However, gametocyte males persisted after this period in children with AQ-R infections. AQ-recrudescent infections are relatively low (25 of 612.4 percent) in children from this endemic area.

Seguridad hepatica y hematica de la sulfadoxina-pirimetamina en el tratamiento de malaria por Plasmodium falciparum no complicada / Liver and haematological safety of sulfadoxine-pyrimethamine treatment in non-complicated falciparum malaria

Introducción: Entre los farmacos ampliamente usados en la actualidad para el tratamiento de la malaria por Plasmodium falciparum se encuentra la sulfadoxina-pirimetamina, que es comúnmente administrada en combinación con otros medicamentos. Los eventos adversos informados se han asociado con altas dosis, uso como profilactico o en personas con hipersensibilidad a las sulfas. Objetivo: Evaluar la toxicidad hepßtica y hematica de la sulfadoxina-pirimetamina (SP) administrada en dosis y tiempos terapéuticos para la malaria por P. falciparum no complicada.Metodología: Como parte de un estudio con dise±o experimental, con determinación abierta del efecto, se hizo evaluación hematica y hepatica a 17 personas tratadas con SP. En Turbo (Antioquia, Colombia), los pacientes se captaron consecutivamente y se siguieron por 10 días. Resultados: Las variables hepßticas y hematicas estuvieron alteradas durante el cuadro malarico antes del tratamiento y se normalizaron al poco tiempo del inicio del mismo (1-5 días), que fue eficaz en 100% de los pacientes (medido el día 10). La normalidad de todas las variables en los días 5 y 10 (fase postratamiento) sugiere la ausencia de efectos tóxicos imputables al medicamento. Los efectos adversos fueron pocos y leves y desaparecieron en el control del día 10. Conclusiones: La SP no mostró eventos adversos, toxicidad hepatica ni hemßtica usada en la dosis y el tiempo definidos para el tratamiento de la malaria por P. falciparum sin complicaciones.

Introduction: Sulfadoxine-pyrimethamine is an antimalarial used currently in worldwide for non-complicated falciparum malaria. This drug is administrated in combination with other ones. Previously adverse events had been reported with high doses, used in malaria prophylaxis and patients with hypersensibility to sulfas. Objetive: To evaluate hepatic and haematic toxicity of treatment with sulfadoxine-pyrimethamine (SP) in non-complicated falciparum malaria. Methodology: This was a non-blinded experimental design. In Turbo (Antioquia, Colombia), 17 subjects treated with SP were evaluated for liver and hematic function. All individual were followed for 10 days. Results: Before treatment, liver and hematic function tests were slight altedered. Hematic and liver variables returned to physiological levels after treatment. Treatment had 100% efficacy. All tests were within normal levels throughout the following period (postreatment); this suggests absence of toxic effects associates with treatment. Adverse effects were few and slight, and disappeared on day-10.Conclusions: When is used in time and dose for treatment of non-complicated falciparum malaria, SP neither increased adverse events nor hepatic or hematic toxicity.

Enhancement of the antimalarial efficacy of amodiaquine by chlorpheniramine in vivo

Resistance in Plasmodium falciparum to amodiaquine (AQ) can be reversed in vitro with with antihistaminic and tricyclic antidepressant compounds, but its significance in vivo is unclear. The present report presents the enhancement of the antimalarial efficacy of AQ by chlorpheniramine, an H1 receptor antagonist that reverses chloroquine (CQ) resistance in vitro and enhances its efficacy in vivo, in five children who failed CQ and/or AQ treatment, and who were subsequently retreated and cured with a combination of AQ plus CP, despite the fact that parasites infecting the children harboured mutant pfcrtT76 and pfmdr1Y86 alleles associated with AQ resistance. This suggests a potential clinical appliation of the reversal phenomenon.

Seguridad hepática y hemática de la amodiaquina en el tratamiento de la malaria no complicada por plasmodium falciparum / Liver and haematological safety of amodiaquine treatment in non-complicated falciparum malaria

Introducción: Actualmente existe un número limitado de antimaláricos eficaces, entre ellos amodiaquina; sin embargo, su uso se ha restringido por informes previos de toxicidad hepática y hemática a dosis superiores a 1,500 mg administradas como profiláctico para malaria. No obstante, en dosis terapéuticas antimaláricas los efectos adversos son de intensidad leve o moderada, e incluyen náuseas, vómito y prurito. Objetivo: Evaluar la toxicidad hepática y hemática de la amodiaquina en dosis y tiempo establecidos para tratar la malaria por Plasmodium falciparum no complicada. Metodología: Diseño longitudinal con determinación no ciega del efecto. Se captaron 57 pacientes, seguidos por 10 días (evaluación clínico-parasitológica). Resultados: Antes del tratamiento, las variables hemáticas y hepáticas mostraron alteración leve y se normalizaron postratamiento, que fue 100% eficaz. Los días 5 y 10 del tratamiento todas las variables estaban normales, lo que sugiere ausencia de efectos tóxicos imputables al medicamento. Los efectos adversos fueron pocos, leves y desaparecieron completamente el día 10. Conclusiones: Usada en la dosis (25 mg/kg peso) y el tiempo (3 días) definidos para el tratamiento de la malaria por P. falciparum sin complicaciones, la amodiaquina no mostró efectos adversos ni toxicidad hepática ni hemática.

Background: At present there are few effective antimalarial drugs, amodiaquine is one of them; however, its use has been restricted by previous information about hematic and hepatic toxicity when it is administered as prophylactic at doses greater than 1,500 mg. But at therapeutic doses, the side effects are either slight or of moderate intensity and include nausea, vomit and pruritus. Objective: To evaluate the hepatic and hematic toxicity of amodiaquine administered at doses and time recommended for treatment of uncomplicated Plasmodium falciparum malaria. Methods: Longitudinal design with no blind determination of the effect. A total of 57 patients were included and followed up for 10 days (clinical-parasitological evaluation). Results: Hematic and hepatic variables showed slight alteration previous treatment and were normal postreatment. Therapeutic efficacy of amodiaquine was 100%. All variables were normal at days 5 and 10, suggesting absence of toxic effects imputable to amodiaquine. The side effects were few, slight and disappeared completely at day 10. Conclusions: Amodiaquine administered at doses (25 mg/kg weight) and time (3 days) established for treatment of uncomplicated Plasmodium falciparum malaria is safe, it did not show neither hematic nor hepatic toxicity.

El tratamiento amodiaquina-sulfadoxinapirimetamina tiene eficacia del 98 por ciento para la malaria falciparum no complicada (Antioquia, Colombia; 2003) / Treatment with amodiaquine-sulfadoxine-pyrimethamine is 98 per cent effective against uncomplicated falciparum malaria

Antecedentes: la combinación amodiaquina (AQ) con sulfadoxinapirimetamina (SP) es el tratamiento de primera elección para la malaria falciparum no complicada (MFNC) en el departamento de Antioquia desde 1985 y en Colombia desde 2000. Objetivo: medir la frecuencia de falla terapéutica de AQ-SP en pacientes con MFNC, residentes en Turbo (zona de Urabá) y en El Bagre (zona del Bajo Cauca), Antioquia. Metodología: este estudio hace parte de uno mayor, que tiene diseño experimental balanceado, con ocho grupos; muestra de tamaño 50 en cada municipio, diseñada con criterios estadísticos y epidemiológicos; tratamiento aplicado en orden de llegada de los pacientes y según los esquemas usuales; seguimiento por 21 días; evaluación no ciega del efecto con el protocolo 1998 de la Organización Mundial de la Salud OMS. Resultados: se evaluaron 90 pacientes con MFNC; la falla terapéutica fue 2.2 por ciento: un caso precoz y otro tardío. El tratamiento fue bien tolerado. La parasitemia asexual se eliminó totalmente en 90 por ciento en los tres días de tratamiento (otro 10 por ciento tenía 40-80 parásitos/?L, que no es falla) y en 100 por ciento antes de 7 días de haber iniciado el tratamiento. AQ-SP mostró total capacidad de eliminar la fiebre: 100 por ciento afebriles el día 3. En los pacientes con gametocitos la cantidad de estos creció entre los días 0 y 7 y decreció luego hasta el día 21, cuando 52 por ciento los presentaban (promedio: 63 gametocitos/?L), pero no se evaluaron la viabilidad ni la fertilidad de tales gametocitos.Conclusión: el tratamiento de la MFNC con AQ-SP es altamente eficaz y debe mantenerse como la primera opción terapéutica, reforzada su eficacia antimalárica por el bajo costo, la buena tolerancia y la escasez y levedad de los efectos adversos imputables al tratamiento. AUT

Abstract Background: The combination of amodiaquine (AQ) and sulfadoxine-pyrimethamine (SP) is the firstchoice treatment for uncomplicated falciparum malaria (UCFM) in Antioquia (northwestern Colombia) since 1985 and in the country at large, since 2000. Objective: To measure the frequency of therapeutic failure of AQ-SP in patients with UCFM, residents of Turbo (Urabá zone) and El Bagre (Bajo Cauca zone) of Antioquia in northwestern Colombia. Methodology: This study is part of a larger one which has balanced design, with eight groups; the sample size in each municipality was 50 patients and it was obtained with statistical and epidemiological criteria; treatment was administered in the order of admission of patients according to the usual schedule; follow-up was done during 21 days; not-blind evaluation of the effect with the 1998 WHO protocol. Results: Ninety patients with UCFM were evaluated; therapeutic failure frequency was 2%; that is 2 cases, one early and one late. Conclusion: Treatment of UCFM with AQ-SP is highly effective and should be maintained as the first therapeutic choice; its effectiveness is reinforced by its low cost and good tolerance; also by the fact that undesirable effects attributable to the treatment are few and mild