Virtual Screening for Potential Inhibitors of NS3 Protein of Zika Virus

Zika virus (ZIKV) is a mosquito borne pathogen, belongs to Flaviviridae family having a positive-sense single-stranded RNA genome, currently known for causing large epidemics in Brazil. Its infection can cause microcephaly, a serious birth defect during pregnancy. The recent outbreak of ZIKV in February 2016 in Brazil realized it as a major health risk, demands an enhanced surveillance and a need to develop novel drugs against ZIKV. Amodiaquine, prochlorperazine, quinacrine, and berberine are few promising drugs approved by Food and Drug Administration against dengue virus which also belong to Flaviviridae family. In this study, we performed molecular docking analysis of these drugs against nonstructural 3 (NS3) protein of ZIKV. The protease activity of NS3 is necessary for viral replication and its prohibition could be considered as a strategy for treatment of ZIKV infection. Amongst these four drugs, berberine has shown highest binding affinity of –5.8 kcal/mol and it is binding around the active site region of the receptor. Based on the properties of berberine, more similar compounds were retrieved from ZINC database and a structure-based virtual screening was carried out by AutoDock Vina in PyRx 0.8. Best 10 novel drug-like compounds were identified and amongst them ZINC53047591 (2-(benzylsulfanyl)-3-cyclohexyl-3H-spiro[benzo[h]quinazoline-5,1'-cyclopentan]-4(6H)-one) was found to interact with NS3 protein with binding energy of –7.1 kcal/mol and formed H-bonds with Ser135 and Asn152 amino acid residues. Observations made in this study may extend an assuring platform for developing anti-viral competitive inhibitors against ZIKV infection.

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.

In vitro assessment of drug resistance in Plasmodium falciparum in five States of India.

Background & objectives: In vitro assays are an important tool to assess baseline sensitivity and monitor the drug response of Plasmodium falciparum over time and place and, therefore, can provide background information for the development and evaluation of drug policies. This study was aimed at determining the in vitro sensitivity of P. falciparum isolates to antimalarials. Methods: The in vitro activity of 108 P. falciparum isolates obtained from five States of India was evaluated using WHO microtest (Mark III) to chloroquine, monodesethylamodiaquine, dihydroartesunate and mefloquine. Samples were collected from the States of Orissa, Jharkhand, Karnataka, Goa and Chhattisgarh from September 2007 to August 2009. In addition, representative samples from different States of India cryopreserved and culture adapted in the Malaria Parasite Bank of National Institute of Malaria Research, New Delhi, were also evaluated. Results: The proportion of isolates resistant to chloroquine and monodesethylamodiaquine was 44.4 and 25 per cent, respectively. Of the 27 isolates resistant to monodesethylamodiaquine, 16 (59.3%) were cross-resistant to chloroquine. No isolate showed resistance to dihydroartesunate and mefloquine. Isolates from Orissa showed the highest degree of resistance to chloroquine and amodiaquine followed by Jharkhand. Forty two isolates were genotyped for pfcrt T76K chloroquine resistant mutation; mutations were seen in 38 (90.47%) isolates. Interpretation & conclusions: The Indian P. falciparum isolates showed a high degree of resistance to chloroquine followed by monodesethylamodiaquine. No resistance was recorded to mefloquine and dihydroartesunate.

Summary description of 24 cases of neonatal malaria seen at a tertiary health center in Nigeria

Neonatal malaria is a serious cause of morbidity and mortality in sub-Saharan Africa. Diagnosis of neonatal malaria is difficult because of the similarity in clinical presentation with other neonatal infections. This study aim to highlight the clinical presentations and high mortality still associated with neonatal malaria. Twenty four out of 41 neonates seen during a 6 months period were studied. Gestational age, age at presentation, birth weight and other clinical symptoms were documented. Questionnaires were used to collect pertinent pregnancy and perinatal history from the mothers. Data was analyzed using SPSS v18 and results expressed in tables using means, frequencies and percentages. All 24 neonates, 50% of whom were males, had a positive smear for malaria parasite. 29.2% were preterm, 17[70.8%] had congenital malaria, 18[75.0%] mothers used intermittent preventive treatment [IPT] of malaria prophylaxis in the index pregnancy and 1[4.2%] mother had HIV in pregnancy. Fever was the principal presenting symptom and 83.0% responded to treatment with amodiaquine. Neonatal malaria is still an important cause of mortality, a more effective malaria prophylaxis program and routine malaria parasite screening for neonates is recommended

Pharmaceutical Equivalence of Some Commercial Samples of Artesunate and Amodiaquine Tablets Sold in Southwestern Nigeria

Purpose: To study the physical properties and dissolution profiles of commercial samples of artesunate and amodiaquine tablets. Methods: Fifteen generic brands of artesunate and five generic brands of amodiaquine tablets were obtained from drug retail outlets in Oyo and Ogun States in southwestern Nigeria. The tablets were subjected to various compendial tests including identification; weight uniformity; uniformity of content; content of active ingredient and uniformity of diameter. Additional tests used as a basis for the assessment of the pharmaceutical equivalence of the products include hardness; disintegration time and dissolution rate. Data obtained were analysed by correlation analysis; Chi-square and ANOVA. Results: Thirteen generic brands of artesunate (87) and four amodiaquine brands (80) investigated were imported. Two brands of the imported artesunate brands were found to contain undetectable amount of artesunate while another 8 samples contained overages. All the amodiaquine brands passed the assay test as stipulated by United States Pharmacopoeia (USP) for amodiaquine tablets while tablet disintegration time of amodiaquine products ranged from 5.8 - 20.7 min. All but one artesunate sample passed the disintegration test too. A majority of the artesunate brands tested had significantly different dissolution profiles (p 0.05). Four (80) of the amodiaquine tablet brands tested had similar dissolution profiles and percent drug released within 30 min (p 0.05). One amodiaquine brand demonstrated poor dissolution profile as it did not meet minimum dissolution requirements within 30 min. Conclusion: The detection of substandard artesunate tablets and a poorly formulated amodiaquine tablet amongst the few sample brands studied highlights the need for increased drug surveillance and monitoring of the qualities of antimalarial medicines currently in use in order to prevent widespread treatment failure

[Synthesis and evaluation of 4-fleuroamodiaquine, a novel antimalarial drug against sensitive and resistant strains of plasmodium falciparum]

Resistance to chloroquine [CQ] in Plasmodium falciparum malaria has become a major health concern in the developing countries. This problem has prompted investigators for finding alternative antimalarials that may be effective against resistant strains. Amodiaquine [AQ] is an antimalarial which is effective against many choloroquine-resistant strains of P. falciparum. However, clinical use of AQ has severely been restricted because of its hepatotoxicity and agranulocytosis side effects. The aim of this study was to design and examine the effects of new analogues of amodiaquine. A successful four-step synthesis of a new series of 4-fluoro analogues was designed and applied to the synthesis of an array of 10 analogues. Antimalarial activity of these agents was assessed against chloroquine-resistant [TM6] and sensitive strains [3D7] of P. falciparum. Several analogues have shown potent antimalarial activity against sensitive 3D7 strain of the parasite. The 6h analogue was superior to the pyrollidino analogue 6b against all of the strains examined. The N-tert butyl analogue 6b was potent against choloroquine resistant strains, though it was not quite as active as amodiaquine [AQ] against both chloroquine sensitive and resistant parasites. From the different analogues made, it was shown that the analogue 6h was more potent than the others. However, this analogue has equal or slightly less potent than amodiaquine and chloroquine against P. falciparum. Further studies on the metabolism and pharmacokinetics of 6h are recommended

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.

Histomorphologic Alterations of the Cerebellum of Wistar Rats following Amodiaquine Plus Artesunate Administration

Amodiaquine and artesunate are two antimalarial drugs sold in combination as Larimalr'. This drug is a very effective artemisinin-base combination. This study was to access the effects of amodiaquine and artesunate combination on the histology of the cerebellum. Twenty adult Wistar rats weighing between 150-180g were divided into four groups (A; B; C and D) of five animals each. Group A served as the control and the animals received distilled water; while group B received 8.75+2.86mg/kg of amodiaquine and artesunate combination for three days; group C received 8.75+2.86mg/kg of amodiaquine and artesunate combination for six days and group D received 17.50+5.71mg/kg of amodiaquine and artesunate combination for three days. Histological sections showed destruction of the Purkinje cortical layers in group B; with increased destructions in groups C and D compared to the control. These results reveal that amodiaquine and artesunate combination causes histological alterations; which were dose and time dependent and these may result in cerebellar dysfunction

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.

Gametocitemia en malaria falciparum tratada con amodiaquina o artesunato / Gametocitaemia in falciparum malaria treated with amodiaquine or artesunate

Introducción. Las relaciones de la gametocitemia de Plasmodium falciparum con el tratamiento antipalúdico han sido poco estudiadas en América. Objetivo. Describir relaciones de la gametocitemia falciparum con el tratamiento con amodiaquina-sulfadoxina-pirimetamina, artesunato-sulfadoxina-pirimetamina o amodiaquina-artesunato. Materiales y métodos. Se usó diseño experimental, aleatorio, no balanceado, no ciego. El seguimiento fue de 21-28 días. La eficacia terapéutica se clasificó según el protocolo de la Organización Mundial de la Salud, 1998. Resultados. Se evaluaron 241 pacientes en Turbo, El Bagre y Zaragoza (Antioquia, Colombia). Amodiaquina-sulfadoxina-pirimetamina tuvo igual eficacia que artesunato-sulfadoxina-pirimetamina y amodiaquina-artesunato para controlar las fallas terapéuticas el día 21. Hubo cuatro fallas (1,66 por ciento). Amodiaquina-sulfadoxina-pirimetamina fue menos eficaz que los tratamientos con artesunato para reducir la tenencia de gametocitos. La mayoría (56 por ciento) de nuestros pacientes no tenía gametocitos pretratamiento y nunca los desarrolló. El tiempo para eliminar los gametocitos que se tienen al iniciar el tratamiento no fue mayor cuando la gametocitemia inicial fue más alta. Conclusión. Los tres tratamientos fueron iguales en cuanto a eficacia terapéutica e incapacidad de eliminar los gametocitos en siete días.

Eficacia de la combinación amodiaquina más sulfadoxina-pirimetamina y de la cloroquina para el tratamiento del paludismo en Córdoba, Colombia, 2006 / Efficacy of the amodiaquine+sulfadoxine-pyrimethamine combination and of chloroquine for the treatment of malaria in Córdoba, Colombia, 2006

Introducción. La disminución de la eficacia de los medicamentos antipalúdicos en el mundo y en Colombia, dificulta el control de la enfermedad. Objetivo. Evaluar la eficacia terapéutica in vivo de la combinación amodiaquina más sulfadoxina-pirimetamina para el tratamiento del paludismo no complicado por Plasmodium falciparum y de la cloroquina para el tratamiento del paludismo por P. vivax en Tierralta, Córdoba. Materiales y métodos. Durante el período de mayo a noviembre de 2006, se realizaron estudios de eficacia in vivo siguiendo los protocolos estandarizados por la Organización Mundial de la Salud y la Organización Panamericana de la Salud, con algunas modificaciones. Se estudiaron pacientes mayores de dos años, con parasitemia entre 500 y 50.000 formas asexuales/µl, seleccionados conforme a los criterios de inclusión y exclusión previamente definidos. Se administró tratamiento supervisado y se realizó seguimiento clínico y parasitológico en los días 0 (inclusión), 1, 2, 3, 7, 14, 21 y 28. El desenlace se definió como respuesta clínica y parasitológica adecuada, fracaso terapéutico precoz o fracaso tardío al tratamiento. Resultados. De los pacientes evaluados, 50/53 (94,3 por ciento) (IC95 por ciento: 70 por ciento-100 por ciento) presentaron respuesta clínica y parasitológica adecuada al tratamiento con amodiaquina más sulfadoxina-pirimetamina para paludismo no complicado por P. falciparum, un paciente presentó fracaso terapéutico precoz y dos presentaron fracaso terapéutico tardío. Los 50 pacientes evaluados (100 por ciento) (IC95 por ciento: 74 por ciento-100 por ciento) presentaron respuesta clínica y parasitológica adecuada al tratamiento con cloroquina para el paludismo por P. vivax. Conclusiones. En Córdoba, la combinación amodiaquina más sulfadoxina-pirimetamina y la cloroquina son eficaces para el tratamiento del paludismo no complicado por P. falciparum y por P. vivax, respectivamente.

Chloroquine resistant Plasmodium falciparum malaria in Osogbo Nigeria: efficacy of amodiaquine + sulfadoxine-pyrimethamine and chloroquine + chlorpheniramine for treatment

Chloroquine (CQ) resistance in Plasmodium falciparum contributes to increasing malaria-attributable morbidity and mortality in Sub-Saharan Africa. Despite a change in drug policy, continued prescription of CQ did not abate. Therefore the therapeutic efficacy of CQ in uncomplicated falciparum malaria patients was assessed in a standard 28-day protocol in 116 children aged between six and 120 months in Osogbo, Southwest Nigeria. Parasitological and clinical assessments of response to treatment showed that 72 (62.1 percent) of the patients were cured and 44 (37.9 percent) failed the CQ treatment. High initial parasite density and young age were independent predictors for early treatment failure. Out of the 44 patients that failed CQ, 24 received amodiaquine + sulphadoxine/pyrimethamine (AQ+SP) and 20 received chlorpheniramine + chloroquine (CH+CQ) combinations. Mean fever clearance time in those treated with AQ+SP was not significantly different from those treated with CH+CQ (p = 0.05). There was no significant difference in the mean parasite density of the two groups. The cure rate for AQ+SP group was 92 percent while those of CH+CQ was 85 percent. There was a significant difference in parasite clearance time (p = 0.01) between the two groups. The 38 percent treatment failure for CQ reported in this study is higher than the 10 percent recommended by World Health Organization in other to effect change in antimalarial treatment policy. Hence we conclude that CQ can no more be solely relied upon for the treatment of falciparum malaria in Osogbo, Nigeria. AQ+SP and CH+CQ are effective in the treatment of acute uncomplicated malaria and may be considered as useful alternative drugs in the absence of artemisinin-based combination therapies.

Biological and Haematological Safety Profile of Oral Amodiaquine and Chloroquine in Healthy Volunteers with or without Plasmodium falciparum Infection in Northeast Tanzania

Amodiaquine (AQ); an effective antimalarial drug for uncomplicated malaria; has been greatly restricted after cases of life-threatening agranulocytosis and hepatic toxicity during prophylactic use. We conducted a hospital based open-label randomised clinical trial in 40 indigenous semi-immune healthy adult male volunteers with and without malaria parasites. The objective was to collect data on biological and haematological safety; tolerability; and parasitological efficacy to serve as baseline in the evaluation of the effectiveness of AQ preventive intermittent treatment against malaria morbidity in infants. Volunteers were stratified according to parasitaemia status and randomly assigned 20 participants each arm to three days treatment with either AQ or chloroquine (CQ). The level of difference of selected haematological and hepatological values pre-and post-trial were marginal and within the normal limits. Clinical adverse effects mostly mild and transient were noticed in 33.3CQ treated-aparasitaemic; 23.8of CQ treated-parasitaemic; 28.6of AQ-treated parasitaemic and 14.3of aparasitaemic receiving AQ. Amodiaquine attained 100parasitological clearance rate versus 70in CQ-treated volunteers. The findings indicate that there was no agranulocytosis or hepatic toxicity suggesting that AQ may pose no public health risk in its wide therapeutic dosage uses. Larger studies are needed to exclude rare adverse effects

Enhanced efficacy of amodiaquine and chlorpheniramine combination over amodiaquine alone in the treatment of acute uncomplicated plasmodium falciparum malaria in children

To evaluate the comparative efficacy of amodiaquine [AMQ] alone and the combination of AMQ and chlorpheniramine [CP] in the treatment of acute uncomplicated malaria in children. Of the 110 children enrolled in the study, 103 with acute uncomplicated malaria, aged 6 months to 12 years, were evaluated using the 14-day modification of the WHO field test. The patients were randomized to 2 groups. Group 1 received supervised treatment with AMQ alone [10 mg AMQ base/kg daily for 3 days], while group 2 received supervised treatment with AMQ [same dose as group 1] plus CP [AMQCP] for 7 days. Both treatment regimens were well tolerated and no patient was withdrawn as a result of recurrent vomiting or drug-related adverse events. There was no significant difference in mean fever and parasite clearance times. The cure rates at day 7 were 90.2 versus 100% [= 0.027] for AMQ versus AMQCP, while the day 14 cure rates were 85.9 versus 98.1% for AMQ versus AMQCP, respectively [= 0.016]. The combination of AMQ plus CP proved significantly more effective than AMQ alone in the treatment of acute uncomplicated falciparum malaria, most probably due to the enhancement of the antimalarial effect of AMQ by CP. The combination of AMQCP could be a better alternative to AMQ alone as a companion drug in artemisinin-based combination therapies

Polimorfismos del gen pfmdr1 en muestras clínicas de Plasmodium falciparum y su relación con la respuesta terapéutica a antipalúdicos y paludismo grave en Colombia / Polymorphisms of the pfmdr1 gene in field samples of Plasmodium falciparum and their association with therapeutic response to antimalarial drugs and severe malaria in Colombia

Introducción. El gen pfmdr1 de Plasmodium falciparum se describió como un gen de resistencia a diversos antipalúdicos. Sin embargo, no se han estudiado el papel de su polimorfismo en la respuesta terapéutica al tratamiento con antipalúdicos en Colombia, ni su relación con paludismo grave. Objetivos. Este trabajo determinó la asociación entre los polimorfismos Asn86Tir y Asp1246Tir del gen pfmdr1 con la respuesta terapéutica a cloroquina, amodiaquina y mefloquina, en tres municipios antioqueños, y la asociación de estos polimorfismos con paludismo grave en muestras de pacientes del municipio de Tumaco. Materiales y métodos. Los polimorfismos del gen pfmdr1 se determinaron mediante amplificación de ácidos nucleicos y análisis con enzimas de restricción. Resultados. El alelo silvestre Asn86 se encontró en 97 por ciento (137/141) de las muestras en el estudio de respuesta terapéutica a cloroquina, amodiaquina y mefloquina; no se observó ninguna asociación entre su presencia y la falla terapéutica como sí lo reportan otros autores. El alelo 1246Tir se encontró en una alta proporción en el estudio de respuesta terapéutica, tanto en las muestras del día cero como en los del día de la falla después del tratamiento con los antipalúdicos. Conclusiones. Los polimorfismos 86Tir y 1246Tir en el gen pfmdr1 no son útiles como factores de predicción de falla terapéutica o paludismo grave en los municipios estudiados. Este estudio describe por primera vez la presencia del alelo 86Tir en cuatro muestras clínicas de Suramérica.

Introduction. The pfmdr1 gene of Plasmodium falciparum has been described as a gene conferring resistance to several antimalarial drugs. In particular, polymorphisms on specific codons have been associated with resistance and treatment failure with cloroquine, amodiaquine and mefloquine. However, the role of these polymorphisms in treatment response to antimalarials remains unexplored in Colombia. Furthermore, the relationship of these polymorphisms to severe malaria is unknown. Objective. This work studied the association of the Asn86Tyr and Asp1246Tyr pfmdr1 polymorphisms with response to cloroquine, amodiaquine and mefloquine treatment in three municipalities of Antioquia, and severe malaria cases from the municipality Tumaco. Materials and methods.The polymorphisms were assessed by nucleic acid amplification followed by restriction length polymorphism analysis. Results. The wild-type codon Asn86 was detected in 97% of the clinical samples from the treatment response study. No association was detected between this polymorphism and treatment failure to the three antimalarials administered. The 1246Tyr polymorphism was detected with a higher frequency in the samples from Antioquia 92% (130/141) than in those from Tumaco 22% (20/89). However, again, no association was found between the presence of a specific polymorphism and the presence of severe malaria in the municipality of Tumaco. Conclusions. The 86Tyr and 1246Tyr polymorphisms of the pfmdr1 gene are not useful as predictors of treatment failure or severe malaria in the municipalities studied. In addition, we report for the first time, the presence of the mutant codon 86Tyr in field samples in South America.

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.