Eficacia de la tafenoquina en la profilaxis y tratamiento de la malaria por Plasmodium vivax, revisión sistemática y metaanálisis / Efficacy of tafenoquine in the prophylaxis and treatment of malaria by Plasmodium vivax, systematic review and meta-analysis

Introducción. La tafenoquina fue aprobada en el 2018 por la Food and Drug Administration de Estados Unidos y, en el 2019, por la Therapeutic Goods Administration en Australia. Su administración en dosis única y su mecanismo de acción en las fases aguda y latente han sido objeto de estudio para cambiar el esquema de tratamiento de la malaria por Plasmodium vivax. Objetivo. Evaluar la evidencia científica disponible sobre la eficacia de la tafenoquina en la profilaxis y el tratamiento de la malaria por P. vivax, entre el 2009 y el 2019. Materiales y métodos. Se establecieron los descriptores MeSH y DeCS. Se utilizó la sintaxis ((Malaria Vivax) AND (tafenoquine) AND (prophylaxis)) OR [(Malaria Vivax) AND (tafenoquine) AND (relapse)] en las siguientes bases de datos: Pubmed, The Cochrane Central Register of Controlled Clinical Trials (CENTRAL), ISIS Web of Science, Lilacs y Scopus. Los resultados obtenidos se sometieron a análisis crítico (matriz CASPE). El análisis cuantitativo se realizó utilizando la diferencia de riesgos en análisis de supervivencia (Kaplan-Meier) en los tres artículos finales. Resultados. Se sometieron tres estudios a metaanálisis (Llanos-Cuentas, 2014; Llanos- Cuentas, 2019, y Lacerda, 2019) para evaluar la eficacia del tratamiento con tafenoquina en comparación con primaquina. Se obtuvo una diferencia de riesgo global de 0,04 (IC95% 0-0,08; p=0,07). La tafenoquina no mostró inferioridad en la eficacia del tratamiento frente al esquema de primaquina. Conclusión. La tafenoquina es una alternativa que mejora el cumplimiento del tratamiento, lo que podría acercar a Colombia a las metas de la Estrategia Técnica Mundial contra la Malaria, 2016-2030.

Introduction: Tafenoquine was approved in 2018 by the Food and Drug Administration in the United States and in 2019 by the Therapeutic Goods Administration in Australia. Its administration in a single dose and its mechanism of action in the acute and latent phases of the disease have been studied to change the treatment regimen for Plasmodium vivax malaria. Objective: To evaluate the available scientific evidence of the efficacy of tafenoquine in prophylaxis and treatment between 2009 and 2019. Materials and methods: We established the MeSH and DeCS descriptors and we used the syntax ((Malaria Vivax) AND (tafenoquine) AND (prophylaxis)) OR [(Malaria Vivax) AND (tafenoquine) AND (relapse)] in the following databases: Pubmed, The Cochrane Central Register of Controlled Clinical Trials (CENTRAL), ISIS Web of Science, Lilacs, and Scopus. The results obtained were subjected to critical analysis (CASPE matrix). The quantitative analysis was performed with risk differences in survival analysis (Kaplan Meier) in the final three articles. Results: Three studies underwent meta-analysis (Llanos-Cuentas, 2014; Llanos-Cuentas, 2019, and Lacerda, 2019) to evaluate the efficacy of the treatment with tafenoquine compared to primaquine. A global risk difference of 0.04 was obtained (95% CI: 0.00-0.08; p=0.07). Tafenoquine did not show inferiority in the efficacy of treatment compared to the primaquine scheme. Conclusion: Tafenoquine is a therapeutic alternative to primaquine that improves adherence, which could bring Colombia closer to the goals of the World Technical Strategy against Malaria 2016-2030.

Atovaquone, chloroquine, primaquine, quinine and tetracycline: antiproliferative effects of relevant antimalarials on Neospora caninum / Atovaquona, cloroquina, primaquina, quinino e tetraciclina: efeitos antiproliferativos de antimaláricos relevantes em Neospora caninum

Abstract Neospora caninum is an apicomplexan parasite that causes abortion in cattle, resulting in significant economic losses. There is no commercial treatment for neosporosis, and drug repositioning is a fast strategy to test possible candidates against N. caninum. In this article, we describe the effects of atovaquone, chloroquine, quinine, primaquine and tetracycline on N. caninum proliferation. The IC50 concentrations in N. caninum were compared to the current information based on previous studies for Plasmodium and Toxoplasma gondii, correlating to the described mechanisms of action of each tested drug. The inhibitory patterns indicate similarities and differences among N. caninum, Plasmodium and T. gondii. For example, atovaquone demonstrates high antiparasitic activity in all the analyzed models, while chloroquine does not inhibit N. caninum. On the other hand, tetracycline is effective against Plasmodium and N. caninum, despite its low activity in T. gondii models. The repurposing of antimalarial drugs in N. caninum is a fast and inexpensive way to develop novel formulations using well-established compounds.

Resumo Neospora caninum é um parasita Apicomplexa relacionado a abortos no gado bovino, que resultam em impactos econômicos. Não há tratamento comercial para neosporosis e o reposicionamento de drogas indica uma estratégia rápida para testar candidatos anti-N. caninum. Neste artigo, são descritos os efeitos da atovaquona, cloroquina, quinino, primaquine e tetraciclina na proliferação de N. caninum. As concentrações IC50 em N. caninum foram comparadas com a informação disponível, baseada em estudos publicados previamente para Plasmodium e Toxoplasma gondii, incluindo a correlação com os mecanismos de ação descritos para cada droga testada. Os padrões de inibição indicam pontos de similaridades e diferenças entre N. caninum, Plasmodium e T. gondii. Por exemplo, a atovaquona demonstra uma alta atividade antiparasitária em todos os modelos testados, enquanto a cloroquina não inibe N. caninum. Por outro lado, a tetraciclina é efetiva contra Plasmodium e N. caninum, em contraste com a baixa atividade em modelos de T. gondii. O reposicionamento de drogas antimaláricas em N. caninum é uma forma rápida e de baixo custo para o desenvolvimento de novas formulações que usam compostos bem estabelecidos.

Informe diário de evidências COVID-19: busca realizada em 14 de maio de 2020 / COVID-19 daily evidence report: search conducted on May 14, 2020

Essa é uma produção do Departamento de Ciência e Tecnologia (Decit) da Secretaria de Ciência, Tecnologia, Inovação e Insumos Estratégicos em Saúde (SCTIE) do Ministério da Saúde (Decit/SCTIE/MS), que tem como missão promover a ciência e tecnologia e o uso de evidências científicas para a tomada de decisão do SUS, tendo como principal atribuição o incentivo ao desenvolvimento de pesquisas em saúde no Brasil, de modo a direcionar os investimentos realizados em pesquisa pelo Governo Federal às necessidades de saúde pública. Informar sobre as principais evidências científicas descritas na literatura internacional sobre tratamento farmacológico para a COVID-19. Além de resumir cada estudo identificado, o informe apresenta também uma avaliação da qualidade metodológica e a quantidade de artigos publicados, de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, entre outros). Foram encontrados 15 artigos.

A newly validated high-performance liquid chromatography method with diode array ultraviolet detection for analysis of the antimalarial drug primaquine in the blood plasma

Abstract INTRODUCTION: Primaquine (PQ) diphosphate is an 8-aminoquinoline antimalarial drug with unique therapeutic properties. It is the only drug that prevents relapses of Plasmodium vivax or Plasmodium ovale infections. In this study, a fast, sensitive, cost-effective, and robust method for the extraction and high-performance liquid chromatography with diode array ultraviolet detection (HPLC-DAD-UV ) analysis of PQ in the blood plasma was developed and validated. METHODS: After plasma protein precipitation, PQ was obtained by liquid-liquid extraction and analyzed by HPLC-DAD-UV with a modified-silica cyanopropyl column (250mm × 4.6mm i.d. × 5μm) as the stationary phase and a mixture of acetonitrile and 10mM ammonium acetate buffer (pH = 3.80) (45:55) as the mobile phase. The flow rate was 1.0mL·min-1, the oven temperature was 50OC, and absorbance was measured at 264nm. The method was validated for linearity, intra-day and inter-day precision, accuracy, recovery, and robustness. The detection (LOD) and quantification (LOQ) limits were 1.0 and 3.5ng·mL-1, respectively. The method was used to analyze the plasma of female DBA-2 mice treated with 20mg.kg-1 (oral) PQ diphosphate. RESULTS: By combining a simple, low-cost extraction procedure with a sensitive, precise, accurate, and robust method, it was possible to analyze PQ in small volumes of plasma. The new method presents lower LOD and LOQ limits and requires a shorter analysis time and smaller plasma volumes than those of previously reported HPLC methods with DAD-UV detection. CONCLUSIONS: The new validated method is suitable for kinetic studies of PQ in small rodents, including mouse models for the study of malaria.

Desenvolvimento somático e neurocomportamental da prole de ratas tratadas com o antimalárico primaquina durante a gravidez

A primaquina é o único fármaco que promove a cura radical da doença causada por P.vivax e possivelmente também por P. ovale, porém possui diversos problemas em se utilizar aprimaquina durante a gravidez, pois é um fármaco capaz de penetrar a placenta, e por não seconhecer o estado de enzima glicose-6-fosfato desidrogenase (G6DP) do feto, ametabolização do fármaco no feto pode ser deficitária. No entanto não tem se pesquisado queproblemas essa terapia pode causar a uma gravidez e a prole, o ineditismo do trabalhocontribui para o campo de estudo por elucidar os desafios que tal terapia enfrentaria. Nesseestudo foi visto que a primaquina não é capaz de ser transmitida para a prole através daamamentação, e que não afetou os parâmetros de desenvolvimento e crescimento dos jovensexpostos intra-utero ao fármaco, mas teve efeito na sobrevida dos filhotes e nocomportamento no teste de campo aberto (open-field).

Primaquine is the only drug that promotes the radical cure of the disease caused by p. Vivax and possibly also by p. Ovale, but has several problems in using primaquine during pregnancy, since it is a drug capable of penetrating the placenta, and by not knowing the state of the enzyme glucose 6-phosphate dehydrogenase (g6dp) of the fetus, the fetus in drug metabolism may be deficient. However, it has not been investigated what problems this therapy can cause to a pregnancy and the offspring, the novelty of the work contributes to the field of study to elucidate the challenges that such therapy would face. In this study, primaquine was not able to be transmitted to the offspring through breastfeeding, and did not affect the developmental and growth parameters of the intra-uterus exposed to the drug, but had an effect on the survival of the pups and behavior in the open-field test.

Glucose-6-phosphate dehydrogenase deficiency and the use of primaquine: top-down and bottom-up estimation of professional costs / Deficiência de glicose-6-fosfato desidrogenase e uso de primaquina: estimativa de custos de profissionais por macrocusteio e microcusteio

ABSTRACT The aim of this study has been to study whether the top-down method, based on the average value identified in the Brazilian Hospitalization System (SIH/SUS), is a good estimator of the cost of health professionals per patient, using the bottom-up method for comparison. The study has been developed from the context of hospital care offered to the patient carrier of glucose-6-phosphate dehydrogenase (G6PD) deficiency with severe adverse effect because of the use of primaquine, in the Brazilian Amazon. The top-down method based on the spending with SIH/SUS professional services, as a proxy for this cost, corresponded to R$60.71, and the bottom-up, based on the salaries of the physician (R$30.43), nurse (R$16.33), and nursing technician (R$5.93), estimated a total cost of R$52.68. The difference was only R$8.03, which shows that the amounts paid by the Hospital Inpatient Authorization (AIH) are estimates close to those obtained by the bottom-up technique for the professionals directly involved in the care.

RESUMO A pesquisa teve por objetivo estudar se o macrocusteio, baseado no valor médio identificado no Sistema de Internação Hospitalar (SIH/SUS), constitui um bom estimador do custo de profissionais de saúde por paciente, tendo como comparação o método de microcusteio. O estudo foi desenvolvido no contexto da assistência hospitalar oferecida ao portador da deficiência de glicose-6-fosfato desidrogenase (dG6PD) do sexo masculino com evento adverso grave devido ao uso da primaquina, na Amazônia Brasileira. O macrocusteio baseado no gasto em serviços profissionais do SIH/SUS, como proxy desse custo, correspondeu a R$60,71, e o microcusteio, baseado nos salários do médico (R$30,43), do enfermeiro (R$16,33) e do técnico de enfermagem (R$5,93), estimou um custo total de R$52,68. A diferença foi de apenas R$8,03, mostrando que os valores pagos pela Autorização de Internação Hospitalar (AIH) são estimadores próximos daqueles obtidos por técnica de microcusteio para os profissionais envolvidos diretamente no cuidado.

Therapeutic efficacy of alternative primaquine regimens to standard treatment in preventing relapses by Plasmodium vivax: A systematic review and meta-analysis / Eficacia terapéutica de esquemas de Primaquina usados como alternativa al tratamiento estándar en la prevención de recaídas por Plasmodium vivax: Una revisión sistemática y meta-análisis

Objective: To compare efficacy and safety of primaquine regimens currently used to prevent relapses by P. vivax. Methods: A systematic review was carried out to identify clinical trials evaluating efficacy and safety to prevent malaria recurrences by P. vivax of primaquine regimen 0.5 mg/kg/day for 7 or 14 days compared to standard regimen of 0.25 mg/kg/day for 14 days. Efficacy of primaquine according to cumulative incidence of recurrences after 28 days was determined. The overall relative risk with fixed-effects meta-analysis was estimated. Results: For the regimen 0.5 mg/kg/day/7 days were identified 7 studies, which showed an incidence of recurrence between 0% and 20% with follow-up 60-210 days; only 4 studies comparing with the standard regimen 0.25 mg/kg/day/14 days and no difference in recurrences between both regimens (RR= 0.977, 95% CI= 0.670 to 1.423) were found. 3 clinical trials using regimen 0.5 mg/kg/day/14 days with an incidence of recurrences between 1.8% and 18.0% during 330-365 days were identified; only one study comparing with the standard regimen (RR= 0.846, 95% CI= 0.484 to 1.477). High risk of bias and differences in handling of included studies were found. Conclusion: Available evidence is insufficient to determine whether currently PQ regimens used as alternative rather than standard treatment have better efficacy and safety in preventing relapse of P. vivax. Clinical trials are required to guide changes in treatment regimen of malaria vivax.

Objetivo: Comparar la eficacia y seguridad de los esquemas de primaquina actualmente usados para prevenir las recaídas de malaria por P. vivax. Métodos: A través de una revisión sistemática se identificaron ensayos clínicos que evaluaran la eficacia y seguridad para prevenir recurrencias por P. vivax del régimen de primaquina 0.5 mg/Kg/día por 7 o 14 días comparado al régimen estándar de 0.25 mg/Kg/día por 14 días. Se determinó la eficacia de primaquina con la incidencia acumulada de recurrencias posterior a 28 días. Se estimó el riesgo relativo global con un meta-análisis de efectos fijos. Resultados: Se identificaron 7 ensayos clínicos para el régimen 0.5 mg/Kg/día/7 días que mostraron una incidencia de recurrencias entre 0% y 20% con un seguimiento de 60 a 210 días; solo 4 estudios compararon con el régimen estándar y no se encontraron diferencias en las recurrencias entre ambos esquemas (RR= 0.977; IC 95%= 0.670-1.423). Se identificaron tres ensayos clínicos que usaron el esquema 0.5 mg/Kg/día/14 días con una incidencia de recurrencias entre 1.8% y 18.0% para 330 a 365 días; solo un estudio comparó con el régimen estándar (RR= 0.846; IC 95%= 0.484-1.477). Se encontró alto riesgo de sesgo y diferencias en la conducción de los estudios incluidos. Conclusión: No hay suficiente evidencia para determinar si los regímenes de primaquina usados como alternativas al tratamiento estándar tienen mejor eficacia para prevenir las recaídas de P. vivax. Se requieren ensayos clínicos para orientar los cambios en el esquema de tratamiento de este tipo de malaria.

G6PD deficiency in Latin America: systematic review on prevalence and variants

Plasmodium vivax radical cure requires the use of primaquine (PQ), a drug that induces haemolysis in glucose-6-phosphate dehydrogenase deficient (G6PDd) individuals, which further hampers malaria control efforts. The aim of this work was to study the G6PDd prevalence and variants in Latin America (LA) and the Caribbean region. A systematic search of the published literature was undertaken in August 2013. Bibliographies of manuscripts were also searched and additional references were identified. Low prevalence rates of G6PDd were documented in Argentina, Bolivia, Mexico, Peru and Uruguay, but studies from Curaçao, Ecuador, Jamaica, Saint Lucia, Suriname and Trinidad, as well as some surveys carried out in areas of Brazil, Colombia and Cuba, have shown a high prevalence (> 10%) of G6PDd. The G6PD A-202A mutation was the variant most broadly distributed across LA and was identified in 81.1% of the deficient individuals surveyed. G6PDd is a frequent phenomenon in LA, although certain Amerindian populations may not be affected, suggesting that PQ could be safely used in these specific populations. Population-wide use of PQ as part of malaria elimination strategies in LA cannot be supported unless a rapid, accurate and field-deployable G6PDd diagnostic test is made available.

Plasmodium vivax malaria elimination: should innovative ideas from the past be revisited?

In the 1950s, the strategy of adding chloroquine to food salt as a prophylaxis against malaria was considered to be a successful tool. However, with the development of Plasmodium resistance in the Brazilian Amazon, this control strategy was abandoned. More than 50 years later, asexual stage resistance can be avoided by screening for antimalarial drugs that have a selective action against gametocytes, thus old prophylactic measures can be revisited. The efficacy of the old methods should be tested as complementary tools for the elimination of malaria.

Triagem neonatal de deficiência de glicose-6-fosfato desidrogenase e prevalência das mutações G202A (G6PD A-) e C563T (G6PD Mediterrâneo) em Mato Grosso/Brasil / Neonatal Screening for glucose-6-phosphate dehydrogenase deficiency and prevalence of G202A (G6PD A-) and C563T (G6PD mediterranean) mutations in Mato Grosso / Brazil

Objetivos: A deficiência de glicose-6-fosfato desidrogenase (G6PD) está associada a um maior risco de encefalopatia bilirrubínica e de crise hemolítica aguda grave desencadeada por drogas como a primaquina e a dapsona. Conhecer a prevalência dessa deficiência enzimática em área onde a malária e a hanseníase ainda estão presentes e conhecer a prevalência das principais mutações traz subsídios para planejamento de estratégias com vistas à redução de riscos associados a esta deficiência enzimática. Métodos: Estudo descritivo transversal conduzido em uma região do centro-oeste do Brasil. Exame de triagem para deficiência de G6PD foi realizado em 3573 recémnascidos. Exame confirmatório foi necessário em 188 crianças triadas como possíveis portadores de deficiência. Nas crianças em que foi confirmada a deficiência de G6PD foi feita pesquisa das mutações G202A (G6PD A-) e C563T (G6PD Mediterrâneo) por PCR. Resultados: A deficiência de G6PD foi confirmada em 63 crianças, sendo 60 meninos (95,2%) e três meninas (4,8%). O percentual de exames falso-positivos na fase de triagem foi de 66,5%, estando o percentual de falso-positivos associado à temperatura e tempo de transporte das amostras. Entre as crianças que confirmaram deficiência de G6PD, foi mais frequente a história de anemia em familiares e de icterícia neonatal. Houve associação entre hematócrito baixo e deficiência enzimática, mas não com hemoglobina, contagem de reticulócitos ou neutrófilos. A prevalência da deficiência de G6PD (IC95%) foi de 1,76% (1,37; 2,24) entre os recém-nascidos triados e de 3,34% entre os meninos (2,58; 4,25). A mutação C563T não foi identificada em nenhuma criança, mas a mutação G202A estava presente em 58 crianças - 92,06% (IC95%: 83,29 - 97,03): 56/60 meninos e em 2/3 meninas homozigotas. Foi identificado um menino com Kernicterus portador da mutação G202A em hemizigose. Conclusão: O elevado percentual de falso-positivos na etapa de triagem, o tempo necessário entre coleta...

Objective: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with an increased risk of bilirubin encephalopathy in neonates and acute hemolytic crisis triggered by drugs such as primaquine and dapsone. In an area where malaria and Hansen's disease are still present, knowing the prevalence of this enzyme defect and determining the prevalence of major mutations is important for planning strategies for reducing the risks associated with this enzyme deficiency. Methods: Sectional study was conducted in a Midwestern region of Brazil. Screening for G6PD deficiency was performed in 3,573 neonates. Confirmatory tests were necessary for 188 positively screened children. After confirmation, PCR investigation was utilized to identify the mutations. Results: G6PD deficiency was confirmed in 63 children: 60 boys (95.2%) and 3 girls (4.8%). The percentage of false-positive cases in the screening phase, 66.5% and was associated with the temperature and transportation time of the samples. Family history of anemia and jaundice was more frequent among the children with confirmed G6PD deficiency. An association between a low hematocrit and enzyme deficiency was observed. However, there was no association with hemoglobin reticulocyte or neutrophils counts. The prevalence of G6PD deficiency (CI95%) was 1.76% (1.37; 2.24) among all screened neonates and 3.34% (2.58; 4.25) among male children. The C563T mutation was not identified in any child. The G202A mutation was present in 58 children - 92.06% (CI95%: 83.29 - 97.03), 56/60 boys and 2/3 homozygous girls. One boy with a hemizygous G202A mutation was identified as having Kernicterus. Conclusion: The high percentage of false-positive results when first screening for G6PD deficiency; the long delay time between the test and result; along with the high cost of the this screening test, are all factors that do not support adding this test to the already established Brazilian neonatal screening programs. The prevalence...

Caracterización de la transmisión de la malaria por Plasmodium vivax en la región fronteriza de Panamá con Costa Rica en el municipio de Barú, Panamá / Characterization of Plasmodium vivax malaria transmission at the border of Panamá and Costa Rica

Introducción. Pocos estudios describen los factores asociados con la dinámica de transmisión de la malaria, o paludismo, por Plasmodium vivax en las regiones endémicas de Panamá. Objetivo. Caracterizar la dinámica de transmisión de la malaria producida por P. vivax en la región fronteriza de Panamá con Costa Rica. Materiales y métodos. Se llevó a cabo un estudio observacional, descriptivo y transversal. Se evaluaron la incidencia parasitaria anual, el índice de láminas positivas y el índice anual de exámenes de sangre. Se identificaron los anofelinos vectores, y se caracterizaron sus criaderos preferenciales, densidad larvaria e índice de picada/hombre/noche. Se hizo búsqueda pasiva y activa de casos sospechosos mediante examen de gota gruesa. Resultados. De 10.401 muestras de gota gruesa, 83 resultaron positivas para P. vivax. El 84 % de los casos provenía de zonas rurales, el 79 % constituía una población económicamente activa, la mediana de edad fue de 36 años y, la media, de 30 años. El 58,5 % de los casos fueron de sexo masculino. La incidencia parasitaria anual fue de 4,1 por 1.000 habitantes; el índice de láminas positivas fue de 0,8 % y el índice anual de exámenes de sangre fue de 51,9 %. El 65,0 % de los casos diagnosticados registró entre 100 y 2.000 parásitos/μl de sangre. Se identificaron los mosquitos vectores Anopheles albimanus y An. punctimacula. Conclusión. Es necesario el seguimiento de estudios entomológicos, el fortalecimiento de la vigilancia epidemiológica, la consideración de los factores de riesgo y la realización de un trabajo en coordinación con las autoridades de salud de Costa Rica, para controlar la malaria en esta región.

Introduction. Few studies have described the factors associated with Plasmodium vivax transmission dynamics in endemic regions from Panamá. Objective. Malaria transmission dynamics produced by P. vivax were characterized at the border between Panamá and Costa Rica. Materials and methods. In the municipality of Barú, an observational, descriptive and cross-sectional study was undertaken to measure the annual parasite index (API), slide positivity index (SPR), and the annual blood examination rate (ABER). The most frequent symptoms and signs in malaria patients were recorded. The anopheline species were identified in the area and the preferred larval habitats, the density of larval populations in the larval habitats and the bites/human/night were characterized. Results. Of a total of 10,401 thick smear blood samples, 83 were positive for P. vivax. Of these, 84% came from rural areas and 79% were from economically active individuals. The median and average ages were 36 and 30 years, respectively, and 58.5% of the malaria cases were male. API was 4.1/1,000 inhabitants; SPR was 0.8% and ABER was 51.9%. Of the diagnosed cases, 54% showed blood parasitemias ranging between 100-2,000 parasites/μl. The majority of the cases were observed in May and June. Two mosquito vector species were identified-- Anopheles albimanus and An. punctimacula. Conclusion. These observations indicate the advisibility of continued entomological studies, strengthening of epidemiological surveillance, consideration of additional risk factors and evaluation of work performance in the border region. This will require coordination with health authorities of both countries to control malaria in this region.

Recurrencias de malaria por Plasmodium vivax según el uso de primaquina: análisis de estudios descriptivos longitudinales / Plasmodium vivax malaria recurrence according to the use of primaquine: analysis of longitudinal descriptive studies

ANTECEDENTES: la primaquina (PQ) es el único medicamento disponible en el mercado para prevenir recurrencias del paludismo por Plasmodium vivax pero varios aspectos suyos se desconocen. OBJETIVO: comparar regímenes de PQ para prevenir recurrencias de malaria vivax. METODOLOGÍA: revisión sistemática de datos. RESULTADOS: 1. ¿Según los estudios descriptivos, la PQ es eficaz para prevenir las recurrencias del paludismo vivax? Sí. La comparación de estudios que no usaron PQ con otros que sí la aplicaron, en cualquier esquema, mostró que si no se usa PQ la recurrencia es altamente probable. 2. ¿Tienen la misma eficacia dosis diarias (mg/kg) iguales pero dosis totales diferentes? La dosis total de 75 mg es tanto o más eficaz que la de 210 mg. 3. ¿La eficacia anti-recurrencias depende del lugar donde sucede la infección? Si. Hay variación según país y región. 4. ¿La frecuencia de recurrencias depende del tiempo de seguimiento post tratamiento? La respuesta no es uniforme para todos los lugares. CONCLUSIONES: la PQ resultó eficaz para prevenir las recurrencias, pero no fue 100%. Las dosis totales de 210 y de 75 mg tuvieron igual eficacia, pero 75 mg sólo han sido evaluados en India, donde P. vivax parece ser más sensible a la PQ que en otros lugares. Parece indudable la influencia del lugar en la proporción de recurrencias, incluso con una misma dosis total. El papel del tiempo de seguimiento no resultó claro. Deben evaluarse esquemas alternativos al estándar, que tiene eficacia promedio de 90% o más.

BACKGROUND: primaquine (PQ) is the only drug available in the market to prevent Plasmodium vivax malaria recurrence, but several aspects are still unknown. OBJECTIVE: To compare PQ regimens to prevent recurrence of vivax malaria. METHODS: systematic review and meta-analysis of data. RESULTS: 1. According to descriptive studies, is PQ effective in preventing recurrence of vivax malaria? Yes. The comparison of studies that did not use PQ to others that did, using any regimen, showed that if PQ is not used, recurrence is highly likely. 2. Are equal daily doses effective (mg/kg) but total doses different? The total dose of 75 mg is equally or more effective than 210 mg. 3. Does the efficacy depend on where the infection happens? Yes. There is variation by country and region. 4. Does the recurrence rate depend on the post-treatment time follow-up? The answer is not uniform everywhere. CONCLUSIONS: Although not 100%, PQ is effective in preventing recurrence. Total doses of 210 and 75 mg are equally effective, but 75 mg alone has been evaluated in India, where P. vivax seems to respond better to PQ than elsewhere. The effect of place in the proportion of recurrences seems evident, even using the same total dose. The role of follow-up time is not clear. Although the standard regimen has an average effectiveness of 90% or more, alternative regimens should be assessed.

Primaquina, gametocitemia de Plasmodium falciparum y bloqueo de transmisión: ineficacia del actual régimen de dosificación / Primaquine, Plasmodium falciparum gameto cytemia and blocking transmission: inefficiency of the current dosing scheme

Antecedentes: Los esquizonticidas anti-Plasmodium falciparum reducen la gametocitemia, sin erradicarla; por ello, se adiciona primaquina (PQ). Esta se administra al terminar el esquizonticida: día 4; 0,75 mg/kg; dosis única (régimen estándar). Las artemisininas actúan sobre gametocitos inmaduros I-IV de P. falciparum; la PQ actúa (stages I-IV) of P. falciparum; PQ acts on mature sobre gametocitos maduros (estadio V). ¿Cuál es la eficacia antigametocitos de la combinación esquizonticida-PQ? Objetivo: Analizar la eficacia de PQ-régimen estándar contra gametocitos de P. falciparum, asociada al esquizonticida. Metodología:Revisión sistemática de los artículos hallados en Pubmed y Lilacs. Resultados y conclusiones: Ningún esquizonticida elimina totalmente los gametocitos en 6-7 días iniciales de tratamiento. La adición de PQ-régimen estándar tiene potente acción antigametocitos. Ninguna combinación esquizonticida-PQ tiene eficacia total en ese plazo. No conocemos cómo varía la eficacia antigametocitos de PQ dada los días 1 a 3, ni en dosis diferentes a la estándar, ni en múltiples dosis. [Carmona-Fonseca J, Arango EM. Primaquina, gametocitemia de Plasmodium falciparum y bloqueo de transmisión: ineficacia del actual régimen de dosificación. the current dosing scheme. MedUNAB 2012; 15:14-21].

Background: Anti-Plasmodium falciparum schizontocides decrease gametocytemia, not eliminate it; by this, he added primaquine (PQ). The PQ is administered after the treatment schizonticide: day 4; 0.75 mg/kg single dose (standard regimen). The artemisinins act on immature gametocytes (stages I-IV) of P. falciparum; PQ acts on mature gametocytes (stage V). What is the efficacy of the combination schizontocide-PQ against gametocytes? Objective: Analyze the effectiveness of PQ-standard regimen against gametocytes of P. falciparum, associated with schizonticide. Methodology: Systematic review of articles found in PubMed and Lilacs. Results and conclusions: No schizonticide completely eliminates the gametocytes in initial treatment 6-7 days. The addition of PQ-standard regimen has potent anti-gametocytes. No combination has efficacy schizonticide-PQ total in that period. We do not know how the efficiency varies anti-gametocytes of PQ given on days 1 to 3, or different from the standard dose or multiple doses. [Carmona-Fonseca J, Arango EM. Primaquine, Plasmodium falciparum gametocytemia and blocking transmission: inefficiency of the current dosing scheme. MedUNAB 2012; 15:14-21].

Quality of essential drugs in tropical countries: evaluation of antimalarial drugs in the Brazilian Health System / Qualidade de medicamentos essenciais em países tropicais: avaliação de medicamentos antimaláricos no Sistema de Saúde do Brasil

INTRODUCTION: The emergence of drug resistance is one of the main problems concerning malaria treatment. The use of counterfeit and/or substandard antimalarial drugs can contribute to the development of parasite resistance. Thus, the aim of this study was to evaluate the quality of antimalarial drugs distributed in Brazil. METHODS: Samples containing chloroquine phosphate, mefloquine hydrochloride, primaquine phosphate, and quinine sulfate tablets were delivered to the Rio de Janeiro central storeroom (CENADI), state storerooms (SS), and Basic Health Units (BHUs) in the north region of Brazil - a total of 10 sample sets. After 5 months of storage, the samples were collected, and in vitro quality control analyses according to official and published methods were performed. RESULTS: Inadequate drug storage conditions were found in two SS and in all BHUs evaluated. There were no quality deviations found in the chloroquine samples. The quinine samples exhibited weight variation above the allowed limits. The primaquine samples were found to have packaging deficiency. The release of mefloquine in samples from some regions showed a statistically significant difference when compared with the CENADI samples. CONCLUSIONS: It is important to periodically evaluate the quality and storage conditions of essential drugs. The quality deviations found with the primaquine and quinine samples are not related to storage conditions and must be addressed urgently. The decreased mefloquine release from tablets is related to formulation problems or influenced by inadequate storage conditions, prompting further investigation. Even with the mentioned problems, the samples would probably not contribute to resistant parasite selection.

INTRODUÇÃO: O aparecimento de resistência aos medicamentos é um dos maiores problemas do tratamento da malária. O uso de medicamentos falsos e/ou de má qualidade pode contribuir para o desenvolvimento de resistência no parasita. Este estudo tem por objetivo avaliar a qualidade dos medicamentos antimaláricos distribuídos no Brasil. MÉTODOS: Amostras contendo comprimidos de difosfato de cloroquina, cloridrato de mefloquina, difosfato de primaquina e sulfato de quinina foram enviadas ao almoxarifado central na Cidade do Rio de Janeiro (CENADI), almoxarifados estaduais (SS) e Unidades Básicas de Saúde (UBS) nos estados da região norte do Brasil, totalizando dez amostras. Após cinco meses de armazenamento, as amostras foram coletadas e analisadas segundo métodos oficiais e da literatura. RESULTADOS: Foram encontradas condições inadequadas de armazenamento de medicamentos em duas SS e em todas as UBS avaliadas. Não foram encontrados problemas de qualidade com as amostras de cloroquina. As amostras de quinina apresentaram variação de peso acima dos limites permitidos. Amostras de primaquina foram encontradas com problemas na embalagem. A cedência de mefloquina de comprimidos, em algumas regiões, apresentou diferença estatisticamente significativa quando comparada com a amostra do CENADI. CONCLUSÕES: É importante avaliar, periodicamente, a qualidade e as condições de armazenamento de medicamentos essenciais. Desvios de qualidade encontrados com as amostras de primaquina e quinina não estão relacionados às condições de armazenamento e devem ser corrigidos urgentemente. O decréscimo na cedência de mefloquina dos comprimidos está relacionado com a formulação ou foi influenciada por condições de armazenamento inadequadas, necessitando de uma investigação posterior. Apesar dos problemas mencionados, as amostras provavelmente não contribuiriam para a seleção de parasitas resistentes.

Metemoglobinemia em pacientes com malária por Plasmodium vivax em uso oral de primaquina / Methemoglobinemia in patients with Plasmodium vivax receiving oral therapy with primaquine

INTRODUÇÃO: A primaquina pode acarretar sérios eventos adversos, com destaque para a toxicidade ao sangue. O objetivo deste trabalho é determinar a metemoglobinemia de 20 pacientes com malária por Plasmodium vivax tratados com primaquina, comparando-os segundo o sexo e a expressão da glicose-6-fosfato desidrogenase. MÉTODOS: Quantificação da metemoglobina por espectrofotometria visível e avaliação qualitativa da glicose-6-fosfato desidrogenase. RESULTADOS: A metemoglobinemia variou de 2,85 a 5,45 por cento nos pacientes do sexo masculino e de 3,77 a 7,34 por cento no feminino. CONCLUSÕES: A instituição da terapia aumentou de maneira significativa os teores de metemoglobina, sem manifestação clínica evidente e independente do sexo e da atividade enzimática.

INTRODUCTION: Primaquine can produce adverse reactions as toxicity to blood when used in the treatment of vivax malaria. This work aimed to determine methemoglobinemia in patients with vivax malaria receiving oral therapy with primaquine. METHODS: Spectrophotometric quantification of methemoglobinemia and qualitative assay for glucose-6-phosphate dehydrogenase. RESULTS: Methemoglobinemia ranged from 2.85 to 5.45 percent in male patients and 3.77 to 7.34 percent in female patients. CONCLUSIONS: A statistically significant increase in methemoglobinemia was observed following oral therapy with primaquine, with no clinical manifestations, and independent of sex and the qualitative expression of glucose-6-phosphate dehydrogenase.

Plan de mejoramiento del control de la malaria hacia su eliminación en Mesoamérica / Plan to improve malaria control towards its elimination in Mesoamerica

Desarrollar un plan de fortalecimiento del control de la mala-ria hacia su eliminación. En 2009, bajo la coordinación del Instituto Nacional de Salud Pública, se integró un equipo técnico transdisciplinario para hacer un diagnóstico situacional de la malaria y de los programa de control y para la selección de prácticas efectivas de intervención que serían incorporadas al plan, en el marco de un ejercicio de teoría de cambio. Se establecieron criterios de estratificación de las localidades con base en sus condiciones de transmisión. Se identificaron limitaciones estructurales y operativas de los programas de control. Se elaboró un plan de intervenciones para mejorar la cobertura de vigilancia epidemiológica, intervenciones antimaláricas y diagnóstico y tratamiento oportunos de casos. El plan delinea con fases progresivas de implementación: reorganización, intensificación de intervenciones y evaluación de la factibilidad de eliminación. La adopción de un plan estratégico único brindará lineamientos y elementos administrativos para conformar un sistema que coordine las actividades de los programas nacionales de control y facilite la eliminación de la malaria en la región.

To develop a plan to strengthen the control of malaria towards its elimination. In 2009, under the coordination of the National Public HealthInstitute ofMexico, atransdisciplinary equipment of technical and operative experts was conformed to carry out a situational analysis of malaria and control programs and for the selection of effective practices of intervention that would be incorporated to the plan, within the framework of an exercise in Theory of Change. Criteria for thestratificationof thelocalities, based ontheirtransmission characteristics were established. The structural and operative limitations of the control programs were identified. A plan of interventions was elaborated to improve the coverage of epidemiological surveillance, anti-malaria interventions and opportune diagnosis and treatment of cases. The plan delineates progressive phases of implementation: reorganization, intensification of interventions and evaluation of elimination feasibility. The adoption of a regional strategic plan will provide guidance and administrative elements to conform a system that coordinates the activities of the national control programs and facilitate the elimination of malaria in the region.

Subdoses of primaquine in overweight patients and malaria vivax relapses: report of two cases in the Federal District, Brazil / Subdoses de primaquina associadas a recaídas de malária vivax em pacientes com peso elevado: relato de dois casos no Distrito Federal

Two cases of malaria by Plasmodium vivax relapsed after treatment with drugs in doses recommended by the Ministry of Health are presented. Both patients were overweight and were followed in the Federal District, an area considered free from vector transmission of the disease. Radical cure was obtained after medication with the same drugs in weight proportional doses.

São apresentados dois casos de pacientes com malária por Plasmodium vivax que apresentaram recaídas após tratamento com medicamentos em doses indicadas pelo Ministério da Saúde. Ambos os pacientes tinham pesos elevados e foram acompanhados no Distrito Federal, área considerada sem transmissão vetorial da doença. A cura radical foi obtida após medicação em dose proporcional ao peso corpóreo dos pacientes.

The monitoring of hematopoietic stem cell transplant donors and recipients from endemic areas for malaria / Monitoramento de doadores e receptores provenientes de áreas endêmicas para malária em transplante de células-tronco hematopoiéticas

Malaria is an unusual complication after hematopoietic stem cell transplantation in non-endemic countries. However, transplant candidates, recipients and donors living in endemic regions frequently report previous episodes of malaria. This fact could represent an important risk for immunosuppressed recipients that could develop severe malaria cases. We report a case of hematopoietic stem cell transplant (HSCT) in which the donor had a history of previous malaria, and close monitoring was performed before and after procedure by parasitological and molecular tests. The donor presented Plasmodium vivax in thick blood smears one month after transplant and was treated according to Brazilian Health Ministry guidelines. The polymerase chain reaction (PCR) was able to detect malaria infection in the donor one week earlier than thick blood film. Even without positive results, the recipient was pre-emptively treated with chloroquine in order to prevent the disease. We highlight the importance of monitoring recipients and donors in transplant procedures with the aim of reducing the risk of malaria transmission.

A malária é complicação incomum após o transplante de células-tronco hematopoiéticas em países endêmicos. No entanto, candidatos a transplantes, receptores e doadores que vivem em regiões endêmicas frequentemente relatam episódios anteriores de malária. Este fato pode representar um risco importante para receptores imunossuprimidos, que podem desenvolver casos de malária grave. Relatamos um caso de transplante de células-tronco hematopoiéticas (TCTH) em que o doador teve história de malária anterior e um monitoramento por meio de exames parasitológicos e moleculares foi realizado antes e após o procedimento. O doador apresentou Plasmodium vivax na gota espessa um mês após o transplante e foi tratado de acordo com as orientações do Ministério da Saúde brasileiro. A reação em cadeia da polimerase (PCR) foi capaz de detectar a infecção por malária no doador uma semana mais cedo do que a gota espessa. Mesmo sem resultados positivos, o receptor foi preventivamente tratado com cloroquina, a fim de prevenir as formas sanguíneas assexuadas. Destacamos a importância do monitoramento de receptores e doadores em procedimentos de transplante, com o objetivo de reduzir o risco de transmissão da malária.

Clinical aspects of hemolysis in patients with P. vivax malaria treated with primaquine, in the Brazilian Amazon

This report describes the development of hemolysis in eighteen glucose-6-phosphate dehydrogenase deficient patients treated for Plasmodium vivax malaria with chloroquine and primaquine. The most frequent findings accompanying hemolysis were fever and leukocytosis, in addition to anemia requiring red blood cell transfusion, and development of acute renal failure. Hemolysis in patients using primaquine is not infrequent and contributes to the morbidity of infection caused by Plasmodium vivax.

Malária vivax com tempo de incubação prolongado, detectada no Distrito Federal: relato de três casos / Vivax malaria with long incubation period, detected in the Federal District: three case reports

Foram detectados três casos de malária vivax em Brasília, Distrito Federal, área considerada indene, procedentes da Amazônia, seis meses após estarem residindo em Brasília. Período de incubação prolongado tem sido descrito apenas para infecções por cepas de Plasmodium vivax de clima temperado. Não foi possível genotipar os parasitos.

Three cases of vivax malaria originating from the Amazon region were detected after living in Brasilia, Federal District (considered to be a non-endemic area), for six months. Long incubation periods have been described only for infections due to strains of Plasmodium vivax in temperate climates. It was not possible to genotype the parasites.