Efficacy of sequential administration of artesunate and artesunate-amodiaquine for the treatment of falciparum malaria in South Sudan / 新乡医学院学报

Objective To investigate the efficacy of sequential administration of artesunate injection and artesunateamodiaquine tablets for the treatment of falciparum malaria in South Sudan.Methods The clinical data of thirty-one patients with falciparum malaria in Level One Hospital of the Chinese Peacekeeping Infantry Battalion from April 2016 to July 2017 were analyzed retrospectively.All patients were administered artesunate injection (120 mg for the first time,60 mg 4 h later,then 60 mg once daily) by intramscular injection for 1-3 d.The patients took orally artesunate-amodiaquine tablets (2 tablets) at 24,48,72 h after the body temperature restored to normal (totally 6 tablets).The efficacy of this sequential treatment for falciparum malaria was observed.Results The total cure rate of the 31 falciparum malaria patients was 100.0％ (31/31);the cure rate of patients after 3 days treatment was 90.3％ (28/31) and the cure rate of patients after 3-6 days treatment was 9.7％ (3/31).Mild side effects,such as nausea,vomiting,anorexia,abdominal distension,diarrhea or dizziness were observed in 4 patients (12.9％) and all these symptoms disappeared after the end of treatment.Conclusion The sequential administration of artesunate injection and artesunate-amodiaquine tablets has optimal curative efficacy on falciparum malaria in South Sudan,and the tolerance is well.

Rapid HPLC Testing Method for Anti-Malarial Drugs / 中国药师

Objective:To establish a rapid HPLC testing method for chloroquine phosphate,hydroxychloroquine sulfate and amodiaquine hydrochloride.Methods:The chromatographic separation was performed on a GRACE prevail C18(53 mm×7 mm,3 μm)column,and the column temperature was maintained at 30℃.Acetonitrile-0.3% triethylamine acetonitrile solution (adjusting pH to 3.0 with phosphoric acid) (12∶88) was used as the mobile phase,the flow rate was 1.0 ml· min-1 and the UV detection wavelength was 254 nm.The qualitative research was performed using relative retention time and spectral similarity as the double indicators.The relative correction factor in the quantification analysis was used for the content determination.Results:Three anti-malarial drugs showed good behavior in one chromatographic system.The rapid HPLC testing analysis could be achieved.The qualitative research was more accurate by using the double indicators (UV spectral similarity and relative capacity factor).The HPLC qualitative accuracy was increased.The relative correction factor method for the quantification could effectively reduce the use of reference substances and speed up the analysis of HPLC.Conclusion:The method is rapid and simple,and suitable for the rapid determination of drugs.

Determination of artesunate in artesunate and amodiaquine hydrochloride tablets by HPLC / 中国生化药物杂志

Objective To establish an HPLC method for the determination of artesunate in artesunate and amodiaquine hydrochloride tablets. Methods WondaSil C18-WR column was used with mobile phase consisted of acetonitrile:phosphoric acid aqueous solution(adjust pH to 3,gradient elution);wavelength was 210 nm; flow rate was 1 mL/min and the column temperature was 30℃.Results The standard curve was linear in the range of 0.2~3.2 mg/mL(r=0.9997), average recoveries were 99.0%(RSD=1.35%, n=6).Conclusion The method is accurate and sensitive, and it can be used to control the quality of artesunate and amodiaquine hydrochloride tablets.

<i>Comparison of the in vitro</i> effects of one-day exposure to amodiaquine and praziquantel on <i>Schistosoma mansoni</i> adult worm pairs

It has been demonstrated that continuous exposure to amodiaquine (AQ) alone elicits <i>in vitro</i> antischistosomal activities at concentrations of 1 - 10 µg/ml. However, orally administered drugs reach a peak blood concentration within one or two hours and then gradually decrease. The blood concentration does not remain at a constant level over several days as <i>in vitro</i> concentration of continuous drug exposure. <i>In vitro</i> activities by one day exposure to AQ better reflect the actual antischistosomal activities after oral administration than those elicited by continuous exposure.The objective of the present study is to compare the antischistosomal potential of one-day exposure to AQ with that to praziquantel (PZQ), a current antischistosomal drug. <i>Schistosoma mansoni</i> adult worm pairs were incubated with 0 (control), 1, 2, 5 and 10 µg/ml AQ as well as 0.01, 0.02, 0.05 and 0.1 µg/ml PZQ for the first day, and were subsequently incubated in drug-free media for a period of 14 days. The one-day exposure to AQ significantly reduced the daily egg output of the worm pairs at 1 - 10 µg/ml. The inhibitory effect on egg production continued at 5 and 10 µg/ml but proved temporary at 1 and 2 µg/ml. Furthermore, AQ-induced specific morphological alterations (severe swelling and/or localization of hemozoin) were observed in the worms at 5 and 10 µg/ml. The AQ-specific appearance of the male worms gradually faded during subsequent incubation in drug-free media, although the female worms showed elongation. Meanwhile, PZQ inhibited the egg output of adult worm pairs at concentrations of 0.01 - 0.1 µg/ml during exposure. The inhibitory effect on egg production continued at 0.05 and 0.1 µg/ml but proved temporary at 0.01 and 0.02 µg/ml. Furthermore, PZQ induced a visible contraction and shortening of the male and female worms at 0.05 and 0.1 µg/ml during exposure, but the PZQ-specific alterations quickly disappeared during subsequent incubation in drug-free media. To our knowledge, this is the first report showing that one-day exposure to AQ inhibits the egg production of adult worm pairs at 1 - 10 µg/ml and induces specific morphological alterations in the worms at 5 and 10 µg/ml. The present findings have important implications for the evaluation of the therapeutic effects of both AQ monotherapy and combination therapy with artesunate on schistosomiasis in clinical field trials.

Comparison of the <i>in vitro</i> Effects of One-day Exposure to Amodiaquine and Praziquantel on <i>Schistosoma mansoni</i> Adult Worm Pairs

It has been demonstrated that continuous exposure to amodiaquine (AQ) alone elicits <i>in vitro</i> antischistosomal activities at concentrations of 1–10 μg/ml. However, orally administered drugs reach a peak blood concentration within one or two hours and then gradually decrease. The blood concentration does not remain at a constant level over several days as <i>in vitro</i> concentration of continuous drug exposure. <i>In vitro</i> activities by one day exposure to AQ better reflect the actual antischistosomal activities after oral administration than those elicited by continuous exposure.The objective of the present study is to compare the antischistosomal potential of one-day exposure to AQ with that to praziquantel (PZQ), a current antischistosomal drug. <i>Schistosoma mansoni</i> adult worm pairs were incubated with 0 (control), 1, 2, 5 and 10 μg/ml AQ as well as 0.01, 0.02, 0.05 and 0.1 μg/ml PZQ for the first day, and were subsequently incubated in drug-free media for a period of 14 days. The one-day exposure to AQ significantly reduced the daily egg output of the worm pairs at 1–10 μg/ml. The inhibitory effect on egg production continued at 5 and 10 μg/ml but proved temporary at 1 and 2 μg/ml. Furthermore, AQ-induced specific morphological alterations (severe swelling and/or localization of hemozoin) were observed in the worms at 5 and 10 μg/ml. The AQ-specific appearance of the male worms gradually faded during subsequent incubation in drug-free media, although the female worms showed elongation. Meanwhile, PZQ inhibited the egg output of adult worm pairs at concentrations of 0.01–0.1 μg/ml during exposure. The inhibitory effect on egg production continued at 0.05 and 0.1 μg/ml but proved temporary at 0.01 and 0.02 μg/ml. Furthermore, PZQ induced a visible contraction and shortening of the male and female worms at 0.05 and 0.1 μg/ml during exposure, but the PZQ-specific alterations quickly disappeared during subsequent incubation in drug-free media. To our knowledge, this is the first report showing that one-day exposure to AQ inhibits the egg production of adult worm pairs at 1–10 μg/ml and induces specific morphological alterations in the worms at 5 and 10 μg/ml. The present findings have important implications for the evaluation of the therapeutic effects of both AQ monotherapy and combination therapy with artesunate on schistosomiasis in clinical field trials.

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.

Selective High Performance Liquid Chromatographic Determination of Amodiaquine and Artesunate in bulk and pharmaceutical formulation.

Aim of the study was to develop a new selective high-performance liquid chromatography (HPLC) method for the quantification of amodiaquine and artesunate in bulk and pharmaceutical dosage form. The HPLC analysis was performed on the LCGC Qualisil C 8 (5 m, 250 mm  4.6 mm i.d.) column in isocratic mode, at 300C temperature using a mobile phase consisting of Acetonitrile: phosphate buffer (70:30, v/v) at a flow rate of 0.8 ml/min. The detection was carried out at 254nm for amodiaquine and 221nm for artesunate. The retention time for AMQ and ART were found to be 2.8 min. and 5.6 min. respectively. The method was validated for precision, recovery, robustness, specificity, and detection and quantification limits, in accordance with International Conference on Harmonization guidelines. Linearity was observed in the concentration range from 2-12 μg/ml (r2=0.998) for AMQ and for ART 0.2-1.2 mg/ml (r2=0.998). The limit of detection and quantification of AMQ were 0.07 μg/ml and 0.21 μg/ml respectively. While for ART it was 0.044 mg/ml and 0.133 mg/ml, respectively. The method has been successively applied for the determination of AMQ and ART in tablets. There was no interference from the excipients commonly present in the tablets. The drug content was found to be 100.83 % for AMQ and 98.63 for ART. Accuracy of the method was studied by the recovery studies at three different levels 80 %, 100 % and 120 %. The % recovery was found to be within the limits of the acceptance criteria with average recovery of 98.55–101.46% for AMQ and 99.48–101.60% for ART. The % RSD below 2.0 shows the high precision of proposed method. The above method was a rapid and cost-effective quality-control tool for routine analysis of amodiaquine and artesunate in bulk and in pharmaceutical dosage form.

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 effect of current antimalarial drugs on the survival of paired Schistosoma mansoni adult worms and their egg production

Some field trials have already demonstrated the high antischistosomal potential of combination therapies using Artesunate (ART) and current antimalarial drugs (Boulanger <I>et al.,</I> 2007; Mohamed <I>et al.,</I> 2009; Sissoko <I>et al.,</I> 2009). The antischistosomal effects of these drugs are noteworthy, especially when they are used for the treatment of malaria in schistosomiasis endemic areas. However, the antischistosomal effects of Amodiaquine (AQ), Primaquine (PQ), Chloroquine (CQ) and Pyrimethamine (Py) have never been assessed by <I>in vitro</I> incubation. The objective of the present study is to assess the <I>in vitro</I> effects of current antimalarial drugs on the egg productivity of adult worm pairs of <I>S. mansoni</I> and their survival times. The effect of the current antimalarial drugs Mefloquine (MQ), quinine (QN), AQ, PQ, CQ, Sulfadiazine (Sf) and Py on the egg output of adult worm pairs of <I>Schistosoma mansoni</I> and their survival times during <I>in vitro</I> culture were assessed at a concentration of 10 Μg⁄ml. AQ, PQ, CQ and Py significantly inhibited the daily egg output of paired female worms at a concentration of 10 Μg⁄ml during the 1 or 2-day <I>in vitro</I> cultivation. However, QN and Sf did not significantly affect the daily egg output during the 8-day incubation. One-day exposure to MQ killed all paired male and female adult worms. AQ and PQ significantly decreased the survival of both paired male and female worms during the 14-day incubation, but QN, CQ, Py and Sf did not exert any similar effect. The present result is consistent with an assessment of the antischistosomal effects of artemisinin-based combination therapy in malaria and schistosomiasis co-endemic areas.

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.

Efficacy of chloroquine, chloroquine plus sulphadoxine-pyrimethamine, and amodiaquine for treatment of vivax malaria in Bangka island, Indonesia: a randomized trial.

Plasmodium vivax malaria resistant to chloroquine is alarming in Indonesia and has been also reported in other countries. An alternative drug is needed. The study was a prospective evaluation and a comparative study of the therapeutic efficacy of chloroquine 25 mg base/kg bw for 3 days (CQ3, n=75), CQ3 plus sulfadoxine-pyrimethamine based on pyrimethamine dosage of 1.25 mg/kg bw single dose (SP1) [CQ3+SP1, n=84] and amodiaquine 25 mg base/kg bw for 3 days (AQ3, n=83) in symptomatic vivax malaria patients in children and adults. The new version of 2001 WHO test system was used in this study. PCR for genotyping was also done to validate and confirm the treatment outcomes. The therapeutic efficacy of CQ3, CQ3+SP1 and AQ3 on day 14 were very high (94.4%, 97.4% and 98.8%), and dropped on day 28 (81.7%, 87.2% and 96.2% by evaluable analysis; 78.9%. 82.0% and 92.5% after confirmation with PCR; and 74.7%, 78.0% and 90.2% by intention to treat analysis). Most of the ACPR cases (>96%) showed hematological recovery. Gametocyte carriages were documented on day 7 (2.9%, 1.3% and 1.2%), day 14 (4.3%, 1.3% and 1.2%) and day 28 (6.6%, 4.2% and none) in CQ3, CQ3+SP1 and AQ3 groups. Of these 3 regimens, AQ3 showed a better therapeutic efficacy than CQ3 and combined CQ3+SP1 by day 28. Introducing primaquine at the beginning of treatment day or giving a radical treatment in vivax malaria may improve the cure rate.

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

Determination of amodiaquine in human plasma by high performance liquid chromatography / 中国新药与临床杂志

AIM:To establish HPLC method for the determination of amodiaquine in human plasma.METHODS: Amodiaquine and internal standard(hydroxychloroquine) were analyzed on C18 column(150 mm ×4.6 mm, 5 μm) with methanol: water:triethylamine: orthophosphoric acid (21:77.5:1:0.5 )as mobile phase at the flow rate of 1.0 mL · min-1The UV detector was set at 294 nm. RESULTS: The retention times of amodiaquine and internal standard were 5.82, 8.56 min, respectively. The calibration curve was linear in the range from 10 to 1 000 μg ·L- 1 ( r = 0.999 8, n = 9 ). The limit of quantitation was5 μg· L-1. The extraction recovery was between 75.5 % and 82.7 %, and the methodological recovery was between 97.0 % and 104.8 %. The intra-day and inter-day RSD were less than 6.0 % and 7.5 %, respectively. CONCLUSION: This HPLC method is simple, sensitive and suitable for pharmacokinetic study of amodiaquine.