696 resultados para plasmodium vivax
Chloroquine is grossly under dosed in young children with malaria : implications for drug resistance
Resumo:
Background: Plasmodium falciparum malaria is treated with 25 mg/kg of chloroquine (CQ) irrespective of age. Theoretically, CQ should be dosed according to body surface area (BSA). The effect of dosing CQ according to BSA has not been determined but doubling the dose per kg doubled the efficacy of CQ in children aged <15 years infected with P. falciparum carrying CQ resistance causing genes typical for Africa. The study aim was to determine the effect of age on CQ concentrations. Methods and Findings: Day 7 whole blood CQ concentrations were determined in 150 and 302 children treated with 25 and 50 mg/kg, respectively, in previously conducted clinical trials. CQ concentrations normalised for the dose taken in mg/kg of CQ decreased with decreasing age (p<0.001). CQ concentrations normalised for dose taken in mg/m(2) were unaffected by age. The median CQ concentration in children aged <2 years taking 50 mg/kg and in children aged 10-14 years taking 25 mg/kg were 825 (95% confidence interval [CI] 662-988) and 758 (95% CI 640-876) nmol/l, respectively (p = 0.67). The median CQ concentration in children aged 10-14 taking 50 mg/kg and children aged 0-2 taking 25 mg/kg were 1521 and 549 nmol/l. Adverse events were not age/concentration dependent. Conclusions: CQ is under-dosed in children and should ideally be dosed according to BSA. Children aged <2 years need approximately double the dose per kg to attain CQ concentrations found in children aged 10-14 years. Clinical trials assessing the efficacy of CQ in Africa are typically performed in children aged <5 years. Thus the efficacy of CQ is typically assessed in children in whom CQ is under dosed. Approximately 3 fold higher drug concentrations can probably be safely given to the youngest children. As CQ resistance is concentration dependent an alternative dosing of CQ may overcome resistance in Africa.
Resumo:
Objetivos: Desenvolver modelo de malária experiemtnal em ratos Wistar e avaliar a influência da infecção noperfil farmacocinético e na distirbuição tecidual da quinha (QN) Metodologia: No desenvolvimento da infecção exerimental de ratos Wistar por Plasmodium berghei foram testados diferente inóculos pela via i.v. e i.p. em diferentes idades. A adequabilidade do protocolo proposto foi avaliada utilizando cloroquina. Neste modelo, as doses efetivas da QN foram estabelecidas após administração oral, utilizando protocolo de tratamento padronizado. Os perfis famacocinéticos da QN após administração i.v. de 50 mg/kg a ratos sadios e oral de 250 mg/kg a ratos sadios e infectados por P. berghei, com baixa e alta parasitemia, foram avaliados após quantificação da QN através de metodologia por cromatografia em líquido de alta eficiência validada. A distribuição hepática e muscular do fármaco emr atos sadios e com alta parasitemia foi avaliada por microdiálise. Resultados e Discussão: O protocolo para desenvolver malária experimental em ratos Wistar utiliando inoculação i.v. de 10ª hemáceas parasitas por P. berghei em animais de 5 semanas mostrou-se adequado quando testado com cloroquina. As doses de QN de 50 e 250 mg/kg foram efetivas na cura da malária experimental. Após adminsitração i.v. de QN a ratos sadios, obteve-se volume dee distribuição (Vd) de 11.6 4.1 L.Kg , clearencece (CI) de 5,8 2,2 L.Kg .h e meia-vida de 2,1 1,2h. Após administração oral, uma tendência de redução do CI e aumento do Vd. proporcional ao nível parasitêmico, foi observada. As frações livres teciduais da QN em ratos infectados foram inferiores às obtidas em ratos sadios, observando-se maiores concentrações musculares do que hepáticas. Conclusões: As alterações famacocinéticas da QN causadas pelos diferentes níveis de parasitemia observadas na evolução da malária devem ser levadas em consideração quando da deeerminação do esquema posológico do fármaco, visando garantir o sucesso terapêutico e principalmente, a segurança para o indivíduo infectado.
Resumo:
Resistance of Plasmodium falciparum to the usual antimalarials, as well as their adverse effects and high cost, has led to the search of new drugs against malaria. Several of these have been developed from medicinal plants based on ethnopharmacology, including the most widely used antimalarials today: quinine and artemisinin. In the present study schizonticide activity of extracts and fractions of a number of medicinal plants from the Caatinga and Amazon biomes were assessed based on ethnopharmacological and chemosystematic information. These included Ximenia americana, Maytenus rigida, Sideroxylon obtusifolium, Stryphnodendro coriaceum, Bowdichia virgiliodes, Schinopis brasiliensis and Picrolemma sprucei, the last, an Amazon species. Antimalarial tests of blood schizonticides were conducted in Swiss mice infected with P. berghei and in vitro against P. falciparum. In vitro cytotoxicity studies were carried out using HeLa, CHO, 3T3, Raw and HEPG2 cell lines. Except for X. americana, all species exhibited in vivo or in vitro antimalarial activity, inhibiting parasitic growth by up to 79%. Extracts exhibited moderate toxicity with dosedependent kinetics. In this sense, ethnopharmacological and chemosystematic approaches were shown to be useful and promising tools in the search of new drugs. These findings represent a significant contribution to scientific knowledge of the antimalarial potential of Brazilian flora, thereby opening perspectives for the development of new antimalarials
Resumo:
Em agosto de 1983 foram observados 85 habitantes do Município de Humaitá, Estado do Amazonas, Brasil, com a finalidade de estudar a prevalência dos antígenos de HLA -A, -B, -C e DR, dentre os quais 38 eram doentes com malária causada pelo Plasmodium falciparum Todos eles foram examinados para avaliação de esplenomegalia, exame parasitológico de sangue e pesquisa de anticorpos de malária. Foram constituídos três grupos: (I) 25 indivíduos nascidos na região Amazônica que nunca tiveram malária; (II) 38 indivíduos naturais da Amazônia que tinham sido tratados de malária no passado, ou que estavam tendo malária atual, e (III) 22 doentes com malária que contraíram na Amazônia e eram procedentes de outras regiões do Brasil. Foram colhidas amostras de sangue de cada um deles, separados os linfôcitos e os antígenos de HLA foram tipados pelo teste de microlinfocitotoxidade. Houve elevada freqüência de antígenos não identificados, nos grupos estudados, o que sugere ou a existência de homozigoze, oufenôtipo não identificado nessa população. Houve alta freqüência fenotípica de antígeno deAg(W24) (44,7%) no Grupo II, quando comparado ao Grupo 1(32%) ou Grupo III (9%). Os indivíduos do Grupo II mostraram também elevada freqüência do antígeno DR4 (80%) quando comparado ao Grupo 1(36,3%) ou Grupo III(16,6%). Essas observações sugerem a possibilidade de suscetibilidadegenética ã malária entre os nativos da Amazônia e indicam a necessidade da realização de inquéritos mais extensos sobre a freqüência de antígenos de HLA em habitantes de zona endêmica de malária.
Resumo:
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Resumo:
Parasite virulence genes are usually associated with telomeres. The clustering of the telomeres, together with their particular spatial distribution in the nucleus of human parasites such as Plasmodium falciparum and Trypanosoma brucei, has been suggested to play a role in facilitating ectopic recombination and in the emergence of new antigenic variants. Leishmania parasites, as well as other trypanosomes, have unusual gene expression characteristics, such as polycistronic and constitutive transcription of protein-coding genes. Leishmania subtelomeric regions are even more unique because unlike these regions in other trypanosomes they are devoid of virulence genes. Given these peculiarities of Leishmania, we sought to investigate how telomeres are organized in the nucleus of Leishmania major parasites at both the human and insect stages of their life cycle. We developed a new automated and precise method for identifying telomere position in the three-dimensional space of the nucleus, and we found that the telomeres are organized in clusters present in similar numbers in both the human and insect stages. While the number of clusters remained the same, their distribution differed between the two stages. The telomeric clusters were found more concentrated near the center of the nucleus in the human stage than in the insect stage suggesting reorganization during the parasite's differentiation process between the two hosts. These data provide the first 3D analysis of Leishmania telomere organization. The possible biological implications of these findings are discussed.
Resumo:
Anopheles darlingi is the most important Brazilian malaria vector, with a widespread distribution in the Amazon forest. Effective strategies for vector control could be better developed through knowledge of its genetic structure and gene flow among populations, to assess the vector diversity and competence in transmitting Plasmodium. The aim of this study was to assess the genetic diversity of An. darlingi collected at four locations in Porto Velho, by sequencing a fragment of the ND4 mitochondrial gene. From 218 individual mosquitoes, we obtained 20 different haplotypes with a diversity index of 0.756, equivalent to that found in other neotropical anophelines. The analysis did not demonstrate significant population structure. However, haplotype diversity within some populations seems to be over-represented, suggesting the presence of sub-populations, but the presence of highly represented haplotypes complicates this analysis. There was no clear correlation among genetic and geographical distance and there were differences in relation to seasonality, which is important for malarial epidemiology.
Resumo:
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Resumo:
Anther development, micro sporogenesis and microgametogenesis in several species of Heliconia were investigated as part of a complementary embryological study of the Heliconiaceae. All studied Heliconia species present bithecate and tetrasporangiate anthers with fertile pollen grains; only H. rivularis, a natural hybrid, presented sterile pollen grains of variable size and no content. The anther wall has an uniseriate epidermis and endothecium, the latter with helicoidal thickenings, although some cells of the middle layers also showed thickenings; the biseriate tapetum is of amoeboid non-syncytial type, since the tapetum cells did not fuse together forming a true plasmodium. The microsporogenesis is successive leading to isobilateral tetrads. The inaperturate pollen grains had a very reduced exine consisting of a thin, more or less continuous layer with small spines upon; the pollen grain shape is variable among the species, all of them presenting heteropolar pollen, except H. angusta with isopolar ones. Most of these characteristics were shared with other studied Zingiberales, although more studies need to be done. (c) 2006 Elsevier GmbH. All rights reserved.
Resumo:
In malaria endemic regions of Africa, resistance to infection by Plasmodium has been observed in under 6-month-old children, when there are higher fetal hemoglobin (Hb F) levels. Research performed in the São José do Rio Preto region, central-east Brazil, reported increased levels of Hb F in blood donors. The purpose of this work was to evaluate the A2 hemoglobin (Hb A2) and Hb F concentrations in blood donors deriving from the Brazilian malaria endemic region. Forty-five blood donor samples from Macapá, from patients with varying genders, ages and ethnic origins, were collected by venous puncture after informed consent was obtained. The samples were analyzed by High Performance Liquid Chromatography (HPLC) - System Variant (Bio-Rad). The HPLC demonstrated sensitivity and rapidity in the identification and measurement of the hemoglobins and gave precise results. Moreover, it provided measurement of hemoglobin variants, even when they were present in small amounts, providing a diagnosis of hemoglobinopathies. Hb F levels above the normal were observed in 33.3% of the analyzed samples. The presence of increased Hb F can suggest resistance to infection by Plasmodium falciparum, as there have been reports that infected red blood cells interfere in the development of the parasite.
Resumo:
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Resumo:
O desenvolvimento de linhagens resistentes de Plasmodium falciparum tem encorajado a busca por novas drogas antimalariais. A febrifugina é uma substância natural com alta atividade contra o P. falciparum que apresenta propriedade emética e toxicidade para o fígado tal que não permitem o seu uso clínico. A busca por análogos que possam ter uma performance clínica melhor é um tema de pesquisa atual. Nosso objetivo é investigar a estrutura eletrônica teórica de uma família de derivados da febrifugina empregando cálculos semi-empíricos de orbitais moleculares, procurando por índices eletrônicos que possam ajudar a modelar novos derivados mais eficientes. Os resultados teóricos mostram que para as moléculas mais seletivas existe um agrupamento dos valores de determinados índices em intervalos bem definidos. O modelo proposto para se obter alta seletividade foi testado com sucesso.
Resumo:
The Amazon Indians Waiapi living in the West of Amapa State of Brazil, treat malaria with an inhalation of vapor obtained from leaves of Viola surinamensis. The essential oil obtained from adult and plantlet leaves was analyzed by GC/MS and 11 monoterpenes, 11 sesquiterpenes and three phenylpropanoids were identified. Plantlet essential oil caused 100% of growth inhibition after 48 h in the development of the young trophozoite to schizont stage and the sesquiterpene nerolidol (100 mu g/ml) was identified as one of the active constituents (100% of growth inhibition was obtained). In addition, examination of [(UC)-C-14]-glucose incorporation showed that activity of nerolidol is related to the inhibition of glycoprotein biosynthesis. (C) 1999 Elsevier B.V. Ireland Ltd. All rights reserved.
Resumo:
Tuberculosis (TB) remains the leading cause of mortality due to a bacterial pathogen, Mycobacterium tuberculosis. However, no new classes of drugs for TB have been developed in the past 30 years. Therefore there is an urgent need to develop faster acting and effective new antitubercular agents, preferably belonging to new structural classes, to better combat TB, including MDR-TB, to shorten the duration of current treatment to improve patient compliance, and to provide effective treatment of latent tuberculosis infection. The enzymes in the shikimate pathway are potential targets for development of a new generation of antitubercular drugs. The shikimate pathway has been shown by disruption of aroK gene to be essential for the Mycobacterium tuberculosis. The shikimate kinase (SK) catalyses the phosphorylation of the 3-hydroxyl group of shikimic acid (shikimate) using ATP as a co-substrate. SK belongs to family of nucleoside monophosphate (NMP) kinases. The enzyme is an alpha/beta protein consisting of a central sheet of five parallel beta-strands flanked by alpha-helices. The shikimate kinases are composed of three domains: Core domain, Lid domain and Shikimate-binding domain. The Lid and Shikimate-binding domains are responsible for large conformational changes during catalysis. More recently, the precise interactions between SK and substrate have been elucidated, showing the binding of shikimate with three charged residues conserved among the SK sequences. The elucidation of interactions between MtSK and their substrates is crucial for the development of a new generation of drugs against tuberculosis through rational drug design.
Resumo:
This report demonstrates that due to the presence of residual reactive sites in their matrices, classical diethylaminoethyl-attaching commercial anion-exchanger resins such as DEAE-MacroPrep and DEAE-Sephadex A50 supports can be used for peptide synthesis. Moreover, due to the high stability of the peptide-resin bond in the final cleavage treatments, desired peptidyl-resins free of side-chain protecting groups, which enables them to be further used as solid support for affinity chromatography, can be obtained. To demonstrate this potentiality, a fragment corresponding to the antigenic and immunodominant epitope of sporozoites of the Plasmodium falciparum malaria parasite was synthesized in these traditional resins and antibody molecules generated against the peptide sequence were successfully retained in these peptidyl supports. Due to the maintenance of their original anion-exchange capacities, the present findings open the unique possibility of applying, simultaneously, dual anion-exchange and affinity procedures for purification of a variety of macromolecules. (C) 2003 Elsevier B.V. (USA). All rights reserved.