Guia de tratamento da malária no Brasil / Malaria treatment guide in Brazil

Este documento constitui-se em um guia de orientação geral para o tratamento da malária, e fundamenta-se em uma revisão das melhores evidências da eficácia e da segurança dos antimaláricos. Entretanto, é indispensável lembrar-se de que casos que não estejam contemplados neste Guia devem ser discutidos diretamente com profissionais e unidades de referência.

Antimalarial effect of two photo-excitable compounds in a murine model with Plasmodium berghei (Haemosporida: Plasmodiidae) / Efecto antimalárico de dos compuestos foto-excitables en un modelo murino con Plasmodium berghei (Haemosporida: Plasmodiidae)

Abstract Malaria represents a major health problem worldwide, affecting around 198 million people in 2016 according to WHO database. For decades, anti-malarial drug therapy has been used in the battle against this disease and its uncontrolled usage in endemic areas has developed the appearance of the drug resistance. Thus, it has emerged the necessity of finding new treatments that could be used as an alternative cure to malaria infection. The aim of this work was the evaluation of two photo-excitable compounds: Compound 1, which is (2E)-3-(4-dimethylamino-phenyl)-1-(4-imidazol-1-yl-phenyl)prop-2-en-1-one) and Compound 2, (1E,4E)1-[4-(dimethylamino)phenyl]-5-(4-methoxyphenyl)-1,4-pentadiene-3-one) as possible anti-malaria drugs with Plasmodium berghei ANKA strain in BALB/c mice as murine model. Cytotoxicity effect was evaluated by a cell proliferation by colorimetry assay (MTS); and the drug incorporation into the parasite was assessed in vitro with Indirect Immunofluorescence Assay (IFA) to determine the localization of the drugs into the parasitized red blood cells (RBCs). Finally, the curative effect of compounds no-radiation (fundamental state) and ration drugs were evaluated by oral drug administration of this drugs in BALB/c mice and chloroquine was used as positive control. This curative effect was determined daily by the parasitemia percentage. The results showed that both compounds were cytotoxic in fundamental state. Furthermore, cytotoxic effect was increased after radiation into the Solar Simulator, and compound 2 was more cytotoxic than compound 1. Curative assays showed that both compounds in fundamental state were non effective as anti-malarial drug. However, in the curative assays in the mice treated with compound 2, when this was ration showed a survival rate of 33 % and a parasitemia percentage decrease in compare to compound 1. Although the compounds did not show a similar or better anti-malarial effect than Chloroquine, Compound 2 presented certain anti-malarial effect after solar radiation. Rev. Biol. Trop. 66(2): 880-891. Epub 2018 June 01.

Resumen La malaria representa un importante problema de salud en todo el mundo, afectando a alrededor de 198 millones de personas en 2016 según la base de datos de la OMS. Durante décadas, se ha utilizado la terapia con fármacos anti-malpricos en la lucha contra esta enfermedad y su uso incontrolado en las zonas endémicas ha desarrollado la aparición de resistencia a los fármacos. Por lo tanto, se ha surgido la necesidad de encontrar nuevos tratamientos que podrían ser utilizados como una cura alternativa para la infección por el paludismo. El objetivo de este trabajo fue evaluar dos compuestos foto-excitables: El compuesto 1, que es (2E) -3- (4-dimetilamino-fenil) -1- (4-imidazol-1-ilfenil) prop-2 1-ona) y el Compuesto 2, (1E, 4E) -1- [4- (dimetilamino) fenil] -5- (4-metoxifenil) -1,4-pentadieno-3-ona) como posibles drogas antimaláricas con la cepa ANKA de Plasmodium berghei en ratones BALB / c como modelo murino. El efecto de la citotoxicidad se evaluó mediante una proliferación celular con el ensayo de colorimetría (MTS); y la incorporación del fármaco en el parásito se evaluó in vitro con Ensayo de Inmunofluorescencia Indirecta (IFA) para determinar la localización de los fármacos en los glóbulos rojos parasitados (RBCs). Finalmente, se evaluó el efecto curativo de los compuestos sin radiación (estado fundamental) y los fármacos irradiados mediante la administración oral de los fármacos en los ratones BALB / c, y se usó cloroquina como control positivo de cura. Este efecto curativo se determinó diariamente por el porcentaje de parasitemia. Los resultados mostraron que ambos compuestos eran citotóxicos en estado fundamental. Además, el efecto citotóxico se incrementó después de la radiación en el Simulador Solar, y el compuesto 2 fue más citotóxico que el compuesto 1. Los ensayos curativos mostraron que ambos compuestos en estado fundamental no eran eficaces como fármacos antimaláricos. Sin embargo, en los ensayos curativos en los ratones tratados con el compuesto 2, cuando fue irradiado, se observó una tasa de supervivencia del 33 % y una disminución del porcentaje de parasitemia en comparación con el compuesto 1. Aunque los compuestos no mostraron un efecto similar o mejor antimalárico que la cloroquina, el compuesto 2 presentó cierto efecto antimalárico después de la radiación solar.

Antimycobacterial and antimalarial activities of endophytic fungi associated with the ancient and narrowly endemic neotropical plant Vellozia gigantea from Brazil

BACKGROUND Endophytic fungi, present mainly in the Ascomycota and Basidiomycota phyla, are associated with different plants and represent important producers of bioactive natural products. Brazil has a rich biodiversity of plant species, including those reported as being endemic. Among the endemic Brazilian plant species, Vellozia gigantea (Velloziaceae) is threatened by extinction and is a promising target to recover endophytic fungi. OBJECTIVE The present study focused on bioprospecting of bioactive compounds of the endophytic fungi associated with V. gigantea, an endemic, ancient, and endangered plant species that occurs only in the rupestrian grasslands of Brazil. METHODS The capability of 285 fungal isolates to produce antimicrobial and antimalarial activities was examined. Fungi were grown at solid-state fermentation to recover their crude extracts in dichloromethane. Bioactive extracts were analysed by chromatographic fractionation and NMR and displayed compounds with antimicrobial, antimycobacterial, and antimalarial activities. FINDINGS Five fungi produced antimicrobial and antimalarial compounds. Extracts of Diaporthe miriciae showed antifungal, antibacterial, and antimalarial activities; Trichoderma effusum displayed selective antibacterial activity against methicillin-resistant Staphylococcus aureus and Mycobacterium intracellulare; and three Penicillium species showed antibacterial activity. D. miriciae extract contained highly functionalised secondary metabolites, yielding the compound epoxycytochalasin H with high antimalarial activity against the chloroquine-resistant strain of Plasmodium falciparum, with an IC50 approximately 3.5-fold lower than that with chloroquine. MAIN CONCLUSION Our results indicate that V. gigantea may represent a microhabitat repository hotspot of potential fungi producers of bioactive compounds and suggest that endophytic fungal communities might be an important biological component contributing to the fitness of the plants living in the rupestrian grassland.

In vitro antimicrobial assessment of Cuban propolis extracts

Propolis is a resinous mixture of different plant exudates collected by honeybees. Currently, propolis is widely used as a food supplement and in folk medicine. We have evaluated 20 Cuban propolis extracts of different chemical types, brown (BCP), red and yellow (YCP), with respect to their in vitro antibacterial, antifungal and antiprotozoal properties. The extracts inhibited the growth of Staphylococcus aureus and Trichophyton rubrum at low µg/mL concentrations, whereas they were not active against Escherichia coli and Candida albicans. The major activity of the extracts was found against the protozoa Leishmania, Trypanosoma and Plasmodium, although cytotoxicity against MRC-5 cells was also observed. The BCP-3, YCP-39 and YCP-60 extracts showed the highest activity against P. falciparum, with 50% of microbial growth (IC50) values of 0.2 µg/mL. A positive correlation between the biological activity and the chemical composition was observed for YCP extracts. The most promising antimicrobial activity corresponds to YCP subtype B, which contains acetyl triterpenes as the main constituents. The present in vitro study highlights the potential of propolis against protozoa, but further research is needed to increase selectivity towards the parasite. The observed chemical composition-activity relationship of propolis can contribute to the identification of the active principles and standardisation of this bee product.

Actividad antiplasmodial in vivo de las esponjas Mycale laxissima y Clathria echinata / In vivo antiplasmodial activity of Mycale laxissima and Clathria echinata sponges

Introducción: la búsqueda de nuevas sustancias antimaláricas incluye entre sus retos el desarrollo de alternativas para el tratamiento de la malaria cerebral, debido a la alta mortalidad y las deficiencias neurológicas persistentes después del tratamiento con los medicamentos recomendados actualmente. Objetivos: evaluar la actividad de fracciones orgánicas de Mycale laxissima y Clathria echinata en el modelo de malaria cerebral producida por la infección de ratones C57BL/6 con Plasmodium berghei ANKA. Métodos: se evaluaron fracciones orgánicas obtenidas mediante cromatografía flash en fase inversa a partir de los extractos crudos de las dos especies. Se realizó un análisis químico cualitativo para detectar la presencia de saponinas, triterpenos/esteroides y alcaloides en estas fracciones. El efecto esquizonticida de las fracciones se determinó mediante la prueba de supresión de la parasitemia al inicio de la infección. Se evaluaron la supervivencia, los síntomas neurológicos y la reducción del peso corporal en los días subsiguientes. Resultados: las fracciones orgánicas de Mycale laxissima a dosis de 200 mg/kg y Clathria echinata a100 mg/kg no mostraron una disminución sustancial del peso de los animales o muertes hasta el día 4; para las cuales se obtuvieron reducciones significativas de las medianas de la parasitemia de 45 % y 53 %, respectivamente. La fracción de Mycale laxissima a 200 mg/kg produjo un incremento significativo en el tiempo de supervivencia hasta 20 d, mientras los animales tratados con Clathria echinata a 100 mg/kg presentaron una mediana de tiempo de supervivencia de 16 d. Ambos incrementos fueron superiores a 7 d. En este período, los animales tratados con las fracciones orgánicas de Clathria echinata y Mycale laxissima no presentaron los síntomas neurológicos observados en los controles. Esta prolongación de la supervivencia fue similar a la observada en presencia de dosis de 7,5 mg/kg de cloroquina. Conclusiones: las fracciones orgánicas de Mycale laxissima y Clathria echinata mostraron actividades antimaláricas, promisorias en el modelo de infección de ratones C57BL/6 con Plasmodium berghei ANKA, que sugieren el estudio de sus constituyentes químicos activos.

Introduction: the search of new antimalarial compounds comprises, among its challenges, the development of therapeutic alternatives for cerebral malaria; due to the high mortality and neurological deficiencies that persist after treatment with recommended drugs. Objectives: to evaluate the activity of organic fractions of Mycale laxissima and Clathria echinata in the cerebral malaria model of infection of C57BL/6 mice with Plasmodium berghei ANKA. Methods: preparative fractions of both species were obtained by reverse-phase flash chromatography. In order to detect the presence of saponins, triterpenods/steroids and alkaloids, a qualitative chemical analysis was performed. The schyzontocidal effect of the extracts was determined by the suppression test at the beginning of the infection. Survival, neurological symptoms and body weight changes were evaluated in subsequent days. Results: the organic fractions of Mycale laxissima at 200 mg/kg and Clathria echinata at 100 mg/kg showed neither substantial reductions of body weights, nor deaths of animals until day 4; but caused significant reductions of median parasitemia of 45 % and 53 % respectively. The fraction of Mycale laxissima at 200 mg/kg caused a significant increase in the median survival time up to day 20, whereas animals treated with Clathria echinata at 100 mg/kg presented a survival of 16 days. Both increases the survival time 7 days. Neurological alterations were not observed in the groups treated with organic fractions when compared to the control group. This survival extension was similar to the effect of administration of 7.5 mg/kg of chloroquine. Conclusions: the organic fractions of Mycale laxissima and Clathria echinata exhibited promising antimalarial activities in the infection model of C57BL/6 mice with Plasmodium berghei ANKA. This indicates that their active chemical constituents should be studied.

Análisis proteómico de Plasmodium, el agente causal de la malaria / Proteomic analysis of Plasmodium, the causal agent of Malaria

Los plasmodios son protozoarios cuyo complejo ciclo de vida se lleva a cabo en dos hospederos, el vertebrado y el mosquito. La infección de los seres humanos produce la enfermedad conocida como malaria. La secuenciación del genoma de Plasmodium falciparum y el desarrollo de la proteómica han permitido un gran avance en el conocimiento de la biología de este letal parásito. La presente revisión se centra en describir los logros recientes en el estudio del proteoma de Plasmodium falciparum y algunas de las implicaciones en la búsqueda de nuevos fármacos antimaláricos, así como en la generación de vacunas para el control de la enfermedad.

Plasmodia are protozoa whose complex life cycle takes place in two different hosts, the vertebrate and the mosquito. The human infection produces the malaria disease. The genome sequence of Plasmodium falciparum and the proteomic tools have enabled a huge advance in knowledge of the biology of this parasite. This review will focus on the recent advances in proteomic studies of Plasmodium falciparum and some implications for the search of new antimalarial drugs as well as vaccines for the control of the disease.

Challenges associated with scaling up artemisinin combination therapy in Sub-Saharan Africa a review article

Malaria is the leading cause of morbidity and mortality in Sub-Saharan Africa. One key strategic intervention is provision of early diagnosis and prompt effective treatment. A major setback has been the development of drug resistance to commonly used antimalarials. To overcome this, most countries in Sub-Saharan Africa have adopted Artemisinin Combination Therapy [ACT] as a first line treatment for uncomplicated malaria. Artemether Lumefantrine [AL] and Artesunate Amodiaquine [ASAQ] are the main drugs of choice. There are key implementation issues, which may have a bearing on the scaling up of this new treatment. This article reviewed the published papers on ACT with focus on sustainability, compliance, and diagnosis. ACTs are costly, but highly effective. Their scaling up is the most cost effective malaria intervention currently available. Most countries rely heavily on the Global Fund for their scaling up. AL has a short shelf life, a complicated six-dose regimen that requires intake with fat to ensure sufficient bioavailability. High rates of adherence have been reported. Use of parasitic diagnosis is advocated to ensure rational use. Parasitic diagnostics like rapid test and microscopy are currently inadequate. The majority of malaria cases may continue to be diagnosed clinically leading to over prescription of drugs. ACTs are currently not available at the community level for home based management of malaria. Issues related to safety and rational use need to be addressed before their use in the informal health sector like community drug sellers and community health workers. The majority of malaria cases at the community level could go untreated or continue to be treated using less effective drugs. We conclude that ACTs are highly effective. A major challenge is ensuring rational use and access at the household level. It is hoped that addressing these issues will increase the likelihood that ACT achieves its intended goals of reducing morbidity and mortality due to malaria, and delaying the onset of drug resistance

Coadaptation and malaria control

Malaria emerges from a disequilibrium of the system 'human-plasmodium-mosquito' (HPM). If the equilibrium is maintained, malaria does not ensue and the result is asymptomatic plasmodium infection. The relationships among the components of the system involve coadaptive linkages that lead to equilibrium. A vast body of evidence supports this assumption, including the strategies involved in the relationships between plasmodium and human and mosquito immune systems, and the emergence of resistance of plasmodia to antimalarial drugs and of mosquitoes to insecticides. Coadaptive strategies for malaria control are based on the following principles: (1) the system HPM is composed of three highly complex and dynamic components, whose interplay involves coadaptive linkages that tend to maintain the equilibrium of the system; (2) human and mosquito immune systems play a central role in the coadaptive interplay with plasmodium, and hence, in the mainten-ance of the system's equilibrium; the under- or overfunction of human immune system may result in malaria and influence its severity; (3) coadaptation depends on genetic and epigenetic phenomena occurring at the interfaces of the components of the system, and may involve exchange of infectrons (genes or gene fragments) between the partners; (4) plasmodia and mosquitoes have been submitted to selective pressures, leading to adaptation, for an extremely long while and are, therefore, endowed with the capacity to circumvent both natural (immunity) and artificial (drugs, insecticides, vaccines) measures aiming at destroying them; (5) since malaria represents disequilibrium of the system HPM, its control should aim at maintaining or restoring this equilibrium; (6) the disequilibrium of integrated systems involves the disequilibrium of their components, therefore the maintenance or restoration of the system's equilibrium depend on the adoption of integrated and coordinated measures acting on all components,...

Artemether, an effective new agent for chemoprophylaxis against shistosomiasis in China: its in vivo effect on the biochemical metabolism of the Asian schistosome.

Conventional drug chemotherapy against human schistosomiasis currently relies on treatment with praziquantel to eliminate adult schistosome worm pairs. The use of praziquantel for control purposes is limited, however, by high rates of post-treatment re-infection with subsequent parasite egg deposition and host end-organ damage. Artemether, a methyl ether derivative of the anti-malarial drug quinghaosu, was discovered recently to also have anti-schistosomal properties. Because artemether selectively targets the larval migratory stages of the parasite, known as schistosomulae, it blocks the development of ovipositing adult schistosome worm pairs in the vasculature. On this basis, we have since shown in clinical trials conducted in China that artemether has proven benefit as an agent for chemoprophylaxis. In vivo studies using laboratory animals suggest that artemether causes damage to the tegument and musculature of schistosomulae. Artemether may exert its helminthotoxic effect through synergy with hemin or related heme-containing compounds. Schistosomes recovered from artemether treated laboratory animals have increased glycogen phosphorylase activity, but decreased glucose uptake. These findings may account for their decreased glycogen content, relative to schistosomes recovered from untreated laboratory animals. The artemether-damaged schistosomes also have decreased activities of a number of enzymes and enzyme systems, including glycolysis. This might suggest common pathways by which artemether may target human parasites that live in the bloodstream.

Status of malaria in Thailand.

Despite decades of control success and a competent network of country-wide health infrastructure, malaria remains an important health threat in rural Thailand. All 4 known human malaria parasites have been reported present, with Plasmodium falciparum and Plasmodium vivax predominant. The expansion and intensity of multi-drug resistant Plasmodium falciparum is the most serious development to occur the last several decades. Members of 3 anopheline species complexes, Anopheles dirus, Anopheles minimus, and Anopheles manculatus, are considered to be primary malaria vectors in the country. Representatives within all 3 taxa are difficult or impossible to separate morphologically from one another, and insufficient information exists about population genetics between sibling species and vector status. Vector control in Thailand has been the primary means of malaria control, mainly by the use of routine residual insecticide spray inside houses. The use of DDT in vector control has resulted in measurable successes to interrupt malaria transmission in many parts of the country. Since 1949, DDT has been the predominant compound used: however, its public health use has continued to decline as a result of perceived operational difficulties, political issues and environmental concerns. The increased use of pyrethroids to impregnate bednets and for intradomiciliary spraying are generally more accepted by rural populations and are rapidly replacing the use of DDT. Organized malaria control activities have reduced malaria morbidity from 286/1,000 population in 1947 to 1.5/1,000 population by 1996. Despite encouraging trends in dramatically reducing malaria, the rates of disease may be re-emerging in the country as evidence from an increased annual parasite index from 1.78/1,000 in 1997 to 2.21 in 1998. The possible reasons for the apparent increase in incidence are discussed in terms of the technical, operational and social obstacles in malaria control in Thailand.

Malaria en el Uruguay: vigilancia de los casos posteriores al regreso de misiones a zonas endémicas / Malaria in Uruguay: surveillance of cases after missions' return from endemic areas

Desde 1992 Uruguay participa en misiones de Paz de la ONU, enviando contingentes militares a zonas del sudeste asiático y de Africa Sudsahariana, con alta endemia malárica. Esto determinó el regreso masivo de una población expuesta a riesgo; Uruguay no tiene y nunca tuvo malaria autóctona. Se aplicaron medidas de control antes de la partida, durante la misión y al regreso: quimioprofilaxis, educación del personal para la protección individual y del ambiente, y tratamiento precoz de los casos. En el período 14/01/93 a 30/03/95 regresaron al Uruguay 4143 efectivos militares, produciéndose 150 casos de malaria (3,62 por ciento): 114 procedieron de Camboya (76 por ciento) y 36 de Mozambique (24 por ciento). El diagnóstico etiológico se efectuó por examen microscópico de sangre periférica (estudio seriado de frotis y gota espesa con técnica de Giemsa); se monitoreo la parasitemia durante el tratamiento. Los plasmodios detectados fueron: P. vivax 138 casos (92 por ciento), P. Falciparum 9 (6 por ciento), P. malariae 1 (0,7 por ciento) y 2 (1,3 por ciento) sin identificar la especie. El período transcurrido entre el regreso y el comienzo del cuadro clínico varió entre 3 y 719 días. Se realizó tratamiento con cloroquina y primaquina para P. vivax y con quinina y doxiciclina para P. falciparum; la evolución clínica fue satisfactoria (letalidad 0). Se produjeron recaídas en 25 pacientes (16,6 por ciento), entre 30 y 367 días del alta. Los datos aportados señalan una nueva situación epidemiológica para el Uruguay. No obstante el regreso de un número importante de personas infectadas, no constituye riesgo de creación de focos autóctonos, ya que no existe transmisión vectorial natural en el país. Se establece una estrecha vigilancia de los donantes de sangre

Towards a malaria vaccine: riding the rollercoaster between unrealistic optimism and lethal pessimism.

Activity in many laboratories over the past decade has resulted in many vaccine candidates nearing clinical trials. These include several antigens from the sporozoite stage; merozoite surface antigens MSA1 and MSA2, RESA, the rhoptry proteins RAP-1 and RAP-2 from the asexual blood stage; the pfs25, pfg45 and pfg230 from the ookinete and gamete stages. This progress in the identification of potential vaccine candidates now highlights a series of scientific, developmental, economic and operational problems the solutions to which will be as critical to the development of a vaccine as the cloning and expression of parasite genes.

La chimioresistance du paludisme en Afrique de l'Ouest : situation actuelle dans les Etats de l'OCCGE

Dans le cadre du reseau de surveillance de la chimioresistance du paludisme dans les Etats de l'OCCGE; des enquetes de chimioresistance ont ete menees par les equipes nationales. les tests d'etude in vivo ont principalement ete utilises en enquete de surveillance passive. Les sujets autochtones; generalement les enfants d'age scolaire; ont ete etudies. La chloroquinoresistance decelee chez ces sujets en 1987 au Benin a ete observee la meme annee au Togo et en Cote d'Ivoire. Durant l'annee 1988 elle est apparue au Senegal et au Burkina Faso. Elle a ete notee en 1989 au Niger et en 1990 au Mali. Seule la Mauritanie est encore epargnee. Les caracteristiques de cette resistance chez les sujets autochtones sont decrites. La resistance est surtout parasitologique et en moyenne; son taux se situe au dessous de 50 pour cent