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  1 / 433 MEDLINE  
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[PMID]:28536265
[Au] Autor:Taylor AB; Roberts KM; Cao X; Clark NE; Holloway SP; Donati E; Polcaro CM; Pica-Mattoccia L; Tarpley RS; McHardy SF; Cioli D; LoVerde PT; Fitzpatrick PF; Hart PJ
[Ad] Endereço:From the Departments of Biochemistry and Structural Biology and taylorab@uthscsa.edu.
[Ti] Título:Structural and enzymatic insights into species-specific resistance to schistosome parasite drug therapy.
[So] Source:J Biol Chem;292(27):11154-11164, 2017 Jul 07.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The antischistosomal prodrug oxamniquine is activated by a sulfotransferase (SULT) in the parasitic flatworm Of the three main human schistosome species, only is sensitive to oxamniquine therapy despite the presence of SULT orthologs in and The reason for this species-specific drug action has remained a mystery for decades. Here we present the crystal structures of and SULTs, including SULT in complex with oxamniquine. We also examined the activity of the three enzymes ; surprisingly, all three are active toward oxamniquine, yet we observed differences in catalytic efficiency that implicate kinetics as the determinant for species-specific toxicity. These results provide guidance for designing oxamniquine derivatives to treat infection caused by all species of schistosome to combat emerging resistance to current therapy.
[Mh] Termos MeSH primário: Resistência a Medicamentos
Proteínas de Helminto/química
Oxamniquine
Schistosoma haematobium/enzimologia
Schistosoma japonicum/enzimologia
Sulfotransferases/química
[Mh] Termos MeSH secundário: Animais
Cristalografia por Raios X
Proteínas de Helminto/genética
Proteínas de Helminto/metabolismo
Schistosoma haematobium/genética
Schistosoma japonicum/genética
Sulfotransferases/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Helminth Proteins); 0O977R722D (Oxamniquine); EC 2.8.2.- (Sulfotransferases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170714
[Lr] Data última revisão:
170714
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170525
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.766527


  2 / 433 MEDLINE  
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[PMID]:28495384
[Au] Autor:da Silva VBR; Campos BRKL; de Oliveira JF; Decout JL; do Carmo Alves de Lima M
[Ad] Endereço:Laboratório de Química e Inovação Terapêutica (LQIT), Departamento de Antibióticos, Centro de Ciências Biológicas, Universidade Federal de Pernambuco (UFPE), Av. Prof. Moraes Rego s/n, Cidade Universitária, 50670-901 Recife, PE, Brazil; Département de Pharmacochimie Moléculaire, UMR 5063 CNRS, Unive
[Ti] Título:Medicinal chemistry of antischistosomal drugs: Praziquantel and oxamniquine.
[So] Source:Bioorg Med Chem;25(13):3259-3277, 2017 Jul 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Neglected tropical diseases (NTDs) are a group of diseases that, besides prevailing in poverty conditions, contribute to the maintenance of social inequality, being a strong barrier to a country development. Schistosomiasis, a NTD, is a tropical and subtropical disease caused by the trematode Schistosoma mansoni (Africa, Middle East, Caribbean, Brazil, Venezuela, Suriname), japonicum (China, Indonesia, the Philippines), mekongi (several districts of Cambodia and the Lao People's Democratic Republic), intercalatum and guianensis (areas of tropical rainforests in Central Africa) and hematobium (Middle East Africa, Corsica, France) whose adult forms inhabit the mesenteric vessels of the host, while the intermediate forms are found in the aquatic gastropod snails of the genus Biomphalaria. Currently, praziquantel (PZQ) is the first line drug chosen for the treatment of schistosomiasis according to the World Health Organization (WHO) Model List of Essential Medicines, 2015. PZQ chemotherapy is considered to be the most important development for decades in the treatment of schistosomiasis. Beside the PZQ, oxamniquine (OXA) has been first described in 1969 and launched in Brazil by Pfizer under the name of Mansil® for oral administration. It has a lower cost when compared to PZQ, being active in the intestinal and hepatosplenic infections caused exclusively by S. mansoni, single species in Brazil. Both PZQ and OXA have limitations, as low efficacy in the treatment of acute schistosomiasis, low activity against S. mansoni in immature stages and resistance or tolerance, which is the reason why further research are still necessary for the development of a second generation of antischistosomal drugs. For the development of new PZQ analogs, three main strategies can be adopted: (a) synthesis and evaluation of PZQ analogues; (b) rational design of new pharmacophores; (c) discovery of new active compounds from screening programs on a large scale. Such (b) approach is difficult as the target of PZQ still unknown, the synthesis of new active analogues is possible from delineation of structure-activity relationships for PZQ. Thus, we proposed for a review article an accurate analysis of PZQ and OXA medicinal properties and uses, focusing on the pharmacochemical aspects of both drugs through 178 bibliographic references. The mechanisms of action will be discussed, with the latest information available in the literature (for the first time in the case of the oxamniquine). Cases of resistance are also discussed. As both drugs are available as a racemic mixture the biological impact of their stereochemistry to activity and side effects are reviewed. The results obtained for the combination of PZQ and artemisinin derivatives against immature worms are also introduced in the discussion. Using the information about more than 200 PZQ new derivatives synthetized during almost 35years since its discovery, a deep structure-activity relationship (SAR) is also proposed in this study.
[Mh] Termos MeSH primário: Doenças Negligenciadas/tratamento farmacológico
Oxamniquine/farmacologia
Praziquantel/farmacologia
Schistosoma mansoni/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Química Farmacêutica
Relação Dose-Resposta a Droga
Seres Humanos
Estrutura Molecular
Oxamniquine/química
Praziquantel/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0O977R722D (Oxamniquine); 6490C9U457 (Praziquantel)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170803
[Lr] Data última revisão:
170803
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170513
[St] Status:MEDLINE


  3 / 433 MEDLINE  
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[PMID]:27073078
[Au] Autor:Chevalier FD; Le Clec'h W; Eng N; Rugel AR; Assis RR; Oliveira G; Holloway SP; Cao X; Hart PJ; LoVerde PT; Anderson TJ
[Ad] Endereço:Texas Biomedical Research Institute, Department of Genetics, P.O. Box 760549, San Antonio, TX 78245-0549, USA. Electronic address: fcheval@txbiomed.org.
[Ti] Título:Independent origins of loss-of-function mutations conferring oxamniquine resistance in a Brazilian schistosome population.
[So] Source:Int J Parasitol;46(7):417-24, 2016 06.
[Is] ISSN:1879-0135
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Molecular surveillance provides a powerful approach to monitoring the resistance status of parasite populations in the field and for understanding resistance evolution. Oxamniquine was used to treat Brazilian schistosomiasis patients (mid-1970s to mid-2000s) and several cases of parasite infections resistant to treatment were recorded. The gene underlying resistance (SmSULT-OR) encodes a sulfotransferase required for intracellular drug activation. Resistance has a recessive basis and occurs when both SmSULT-OR alleles encode for defective proteins. Here we examine SmSULT-OR sequence variation in a natural schistosome population in Brazil ∼40years after the first use of this drug. We sequenced SmSULT-OR from 189 individual miracidia (1-11 per patient) recovered from 49 patients, and tested proteins expressed from putative resistance alleles for their ability to activate oxamniquine. We found nine mutations (four non-synonymous single nucleotide polymorphisms, three non-coding single nucleotide polymorphisms and two indels). Both mutations (p.E142del and p.C35R) identified previously were recovered in this field population. We also found two additional mutations (a splice site variant and 1bp coding insertion) predicted to encode non-functional truncated proteins. Two additional substitutions (p.G206V, p.N215Y) tested had no impact on oxamniquine activation. Three results are of particular interest: (i) we recovered the p.E142del mutation from the field: this same deletion is responsible for resistance in an oxamniquine selected laboratory parasite population; (ii) frequencies of resistance alleles are extremely low (0.27-0.8%), perhaps due to fitness costs associated with carriage of these alleles; (iii) that four independent resistant alleles were found is consistent with the idea that multiple mutations can generate loss-of-function alleles.
[Mh] Termos MeSH primário: Mutação
Oxamniquine/farmacologia
Schistosoma mansoni/efeitos dos fármacos
Esquistossomose/parasitologia
Esquistossomicidas/farmacologia
[Mh] Termos MeSH secundário: Alelos
Animais
Brasil
Criança
Pré-Escolar
Resistência a Medicamentos/genética
Éxons/genética
Fezes/parasitologia
Frequência do Gene
Estudo de Associação Genômica Ampla
Seres Humanos
Lactente
Conformação Molecular
Reação em Cadeia da Polimerase
Polimorfismo de Nucleotídeo Único
Schistosoma mansoni/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Schistosomicides); 0O977R722D (Oxamniquine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171127
[Lr] Data última revisão:
171127
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160414
[St] Status:MEDLINE


  4 / 433 MEDLINE  
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[PMID]:26598562
[Au] Autor:Sabino KR; Nunes MB; Petroianu A
[Ad] Endereço:Department of Surgery, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil.
[Ti] Título:Ectopic Schistosoma mansoni Eggs Inside a Lipoma.
[So] Source:Am J Trop Med Hyg;94(1):156-7, 2016 Jan.
[Is] ISSN:1476-1645
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ectopic schistosomiasis is uncommon and tends to occur when the parasite's eggs or adult forms are located far from their normal site. This report presents the first described case of ectopic Schistosoma mansoni eggs inside a subcutaneous lipoma far from the tissues of this worm's life cycle and with no connection to either portal veins or any other vascular system. These eggs were found inside giant cells surrounded by inflammatory cells. In conclusion, in humans, ectopic S. mansoni eggs can be found far from the tissues of the described life cycle of this worm, with no connection to portal veins or other blood vessels used for their migration.
[Mh] Termos MeSH primário: Lipoma/patologia
Óvulo/classificação
Schistosoma mansoni/classificação
Esquistossomose mansoni/patologia
[Mh] Termos MeSH secundário: Adulto
Animais
Seres Humanos
Lipoma/parasitologia
Lipoma/cirurgia
Masculino
Oxamniquine/uso terapêutico
Esquistossomose mansoni/tratamento farmacológico
Esquistossomose mansoni/parasitologia
Esquistossomicidas/uso terapêutico
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Schistosomicides); 0O977R722D (Oxamniquine)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:151125
[St] Status:MEDLINE
[do] DOI:10.4269/ajtmh.15-0287


  5 / 433 MEDLINE  
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[PMID]:26485649
[Au] Autor:Taylor AB; Pica-Mattoccia L; Polcaro CM; Donati E; Cao X; Basso A; Guidi A; Rugel AR; Holloway SP; Anderson TJ; Hart PJ; Cioli D; LoVerde PT
[Ad] Endereço:Departments of Biochemistry, the University of Texas Health Science Center, San Antonio, Texas, United States of America; X-ray Crystallography Core Laboratory, the University of Texas Health Science Center, San Antonio, Texas, United States of America.
[Ti] Título:Structural and Functional Characterization of the Enantiomers of the Antischistosomal Drug Oxamniquine.
[So] Source:PLoS Negl Trop Dis;9(10):e0004132, 2015.
[Is] ISSN:1935-2735
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: For over two decades, a racemic mixture of oxamniquine (OXA) was administered to patients infected by Schistosoma mansoni, but whether one or both enantiomers exert antischistosomal activity was unknown. Recently, a ~30 kDa S. mansoni sulfotransferase (SmSULT) was identified as the target of OXA action. METHODOLOGY/PRINCIPAL FINDINGS: Here, we separate the OXA enantiomers using chromatographic methods and assign their optical activities as dextrorotary [(+)-OXA] or levorotary [(-)-OXA]. Crystal structures of the parasite enzyme in complex with optically pure (+)-OXA and (-)-OXA) reveal their absolute configurations as S- and R-, respectively. When tested in vitro, S-OXA demonstrated the bulk of schistosomicidal activity, while R-OXA had antischistosomal effects when present at relatively high concentrations. Crystal structures R-OXA•SmSULT and S-OXA•SmSULT complexes reveal similarities in the modes of OXA binding, but only the S-OXA enantiomer is observed in the structure of the enzyme exposed to racemic OXA. CONCLUSIONS/SIGNIFICANCE: Together the data suggest the higher schistosomicidal activity of S-OXA is correlated with its ability to outcompete R-OXA binding the sulfotransferase active site. These findings have important implications for the design, syntheses, and dosing of new OXA-based antischistosomal compounds.
[Mh] Termos MeSH primário: Anti-Helmínticos/química
Anti-Helmínticos/farmacologia
Oxamniquine/química
Oxamniquine/farmacologia
Sulfotransferases/antagonistas & inibidores
Sulfotransferases/química
[Mh] Termos MeSH secundário: Animais
Cromatografia
Cristalografia por Raios X
Feminino
Camundongos
Modelos Moleculares
Testes de Sensibilidade Parasitária
Ligação Proteica
Conformação Proteica
Schistosoma mansoni/efeitos dos fármacos
Schistosoma mansoni/enzimologia
Estereoisomerismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Anthelmintics); 0O977R722D (Oxamniquine); EC 2.8.2.- (Sulfotransferases)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151021
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pntd.0004132


  6 / 433 MEDLINE  
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[PMID]:25048426
[Au] Autor:Chevalier FD; Valentim CL; LoVerde PT; Anderson TJ
[Ti] Título:Efficient linkage mapping using exome capture and extreme QTL in schistosome parasites.
[So] Source:BMC Genomics;15:617, 2014 Jul 21.
[Is] ISSN:1471-2164
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Identification of parasite genes that underlie traits such as drug resistance and host specificity is challenging using classical linkage mapping approaches. Extreme QTL (X-QTL) methods, originally developed by rodent malaria and yeast researchers, promise to increase the power and simplify logistics of linkage mapping in experimental crosses of schistosomes (or other helminth parasites), because many 1000s of progeny can be analysed, phenotyping is not required, and progeny pools rather than individuals are genotyped. We explored the utility of this method for mapping a drug resistance gene in the human parasitic fluke Schistosoma mansoni. RESULTS: We staged a genetic cross between oxamniquine sensitive and resistant parasites, then between two F1 progeny, to generate multiple F2 progeny. One group of F2s infecting hamsters was treated with oxamniquine, while a second group was left untreated. We used exome capture to reduce the size of the genome (from 363 Mb to 15 Mb) and exomes from pooled F2 progeny (treated males, untreated males, treated females, untreated females) and the two parent parasites were sequenced to high read depth (mean = 95-366×) and allele frequencies at 14,489 variants compared. We observed dramatic enrichment of alleles from the resistant parent in a small region of chromosome 6 in drug-treated male and female pools (combined analysis: Z = 11.07, p = 8.74 × 10(-29)). This region contains Smp_089320 a gene encoding a sulfotransferase recently implicated in oxamniquine resistance using classical linkage mapping methods. CONCLUSIONS: These results (a) demonstrate the utility of exome capture for generating reduced representation libraries in Schistosoma mansoni, and (b) provide proof-of-principle that X-QTL methods can be successfully applied to an important human helminth. The combination of these methods will simplify linkage analysis of biomedically or biologically important traits in this parasite.
[Mh] Termos MeSH primário: Exoma/genética
Locos de Características Quantitativas
Schistosoma mansoni/genética
[Mh] Termos MeSH secundário: Animais
Mapeamento Cromossômico
Cricetinae
Cruzamentos Genéticos
Feminino
Frequência do Gene
Ligação Genética
Genótipo
Masculino
Oxamniquine/uso terapêutico
Fenótipo
Esquistossomose mansoni/tratamento farmacológico
Esquistossomicidas/uso terapêutico
Sulfotransferases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Schistosomicides); 0O977R722D (Oxamniquine); EC 2.8.2.- (Sulfotransferases)
[Em] Mês de entrada:1503
[Cu] Atualização por classe:161228
[Lr] Data última revisão:
161228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140723
[St] Status:MEDLINE
[do] DOI:10.1186/1471-2164-15-617


  7 / 433 MEDLINE  
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Araújo, Neusa
Coelho, Paulo Marcos Zech
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[PMID]:24271044
[Au] Autor:Vimieiro AC; Araújo N; Katz N; Kusel JR; Coelho PM
[Ad] Endereço:Fundação Hospitalar do Estado de Minas Gerais, Hospital Alberto Cavalcanti, Belo HorizonteMG, Brasil.
[Ti] Título:Schistogram changes after administration of antischistosomal drugs in mice at the early phase of Schistosoma mansoni infection.
[So] Source:Mem Inst Oswaldo Cruz;108(7):881-6, 2013 Nov.
[Is] ISSN:1678-8060
[Cp] País de publicação:Brazil
[La] Idioma:eng
[Ab] Resumo:Mice infected with Schistosoma mansoni were treated with oxamniquine, praziquantel, artesunate at the pre-patent phase, aiming at observing schistogram alterations. Half of the animals were perfused five days post-treatment for counting and classification of immature worms, based on pre-established morphological criteria (schistogram); the remaining animals were evaluated 42 or 100 days after infection and perfusion of the portal-system was performed for collection and counting of adult worms and oogram. It was observed that oxamniquine and artesunate treatment administered at the pre-postural phase causes significant reduction in the number of immature and adult worms. However, there was little reduction with praziquantel when used at the dose of 400 mg/kg for treatments administered 14, 15, 21 or 23 days post-infection. Artesunate was responsible for significant alterations in development of young worms, as well as for a higher number of worms presenting intestinal damages. Immature adult worms were detected in mice treated with artesunate or oxamniquine at the pre-patent phase of infection and recovered by perfusion 100 days after infection. Schistogram proved to be a very useful tool for experimental evaluation of the activity of antischistosomal drugs and a good model to identify the most sensitive stages to drugs.
[Mh] Termos MeSH primário: Artemisininas/uso terapêutico
Schistosoma mansoni/efeitos dos fármacos
Esquistossomose mansoni/tratamento farmacológico
Esquistossomicidas/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Quimioterapia Combinada/métodos
Feminino
Camundongos
Oxamniquine/uso terapêutico
Contagem de Ovos de Parasitas
Parasitemia/tratamento farmacológico
Praziquantel/uso terapêutico
Schistosoma mansoni/crescimento & desenvolvimento
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Artemisinins); 0 (Schistosomicides); 0O977R722D (Oxamniquine); 60W3249T9M (artesunate); 6490C9U457 (Praziquantel)
[Em] Mês de entrada:1502
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:131126
[St] Status:MEDLINE


  8 / 433 MEDLINE  
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[PMID]:24263136
[Au] Autor:Valentim CL; Cioli D; Chevalier FD; Cao X; Taylor AB; Holloway SP; Pica-Mattoccia L; Guidi A; Basso A; Tsai IJ; Berriman M; Carvalho-Queiroz C; Almeida M; Aguilar H; Frantz DE; Hart PJ; LoVerde PT; Anderson TJ
[Ad] Endereço:Departments of Biochemistry and Pathology, University of Texas Health Science Center, San Antonio, TX 78229, USA.
[Ti] Título:Genetic and molecular basis of drug resistance and species-specific drug action in schistosome parasites.
[So] Source:Science;342(6164):1385-9, 2013 Dec 13.
[Is] ISSN:1095-9203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Oxamniquine resistance evolved in the human blood fluke (Schistosoma mansoni) in Brazil in the 1970s. We crossed parental parasites differing ~500-fold in drug response, determined drug sensitivity and marker segregation in clonally derived second-generation progeny, and identified a single quantitative trait locus (logarithm of odds = 31) on chromosome 6. A sulfotransferase was identified as the causative gene by using RNA interference knockdown and biochemical complementation assays, and we subsequently demonstrated independent origins of loss-of-function mutations in field-derived and laboratory-selected resistant parasites. These results demonstrate the utility of linkage mapping in a human helminth parasite, while crystallographic analyses of protein-drug interactions illuminate the mode of drug action and provide a framework for rational design of oxamniquine derivatives that kill both S. mansoni and S. haematobium, the two species responsible for >99% of schistosomiasis cases worldwide.
[Mh] Termos MeSH primário: Resistência a Medicamentos/genética
Proteínas de Helminto/genética
Oxamniquine/farmacologia
Schistosoma mansoni/efeitos dos fármacos
Schistosoma mansoni/genética
Esquistossomicidas/farmacologia
Sulfotransferases/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Técnicas de Silenciamento de Genes
Ligação Genética
Seres Humanos
Dados de Sequência Molecular
Mutação
Filogenia
Conformação Proteica
Locos de Características Quantitativas
Interferência de RNA
Sulfotransferases/química
Sulfotransferases/classificação
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Helminth Proteins); 0 (Schistosomicides); 0O977R722D (Oxamniquine); EC 2.8.2.- (Sulfotransferases)
[Em] Mês de entrada:1312
[Cu] Atualização por classe:161203
[Lr] Data última revisão:
161203
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:131123
[St] Status:MEDLINE
[do] DOI:10.1126/science.1243106


  9 / 433 MEDLINE  
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[PMID]:23450530
[Au] Autor:Danso-Appiah A; Olliaro PL; Donegan S; Sinclair D; Utzinger J
[Ad] Endereço:International Health Group, Liverpool School of Tropical Medicine, Liverpool, UK. tdappiah@yahoo.co.uk
[Ti] Título:Drugs for treating Schistosoma mansoni infection.
[So] Source:Cochrane Database Syst Rev;(2):CD000528, 2013 Feb 28.
[Is] ISSN:1469-493X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Schistosoma mansoni is a parasitic infection common in the tropics and sub-tropics. Chronic and advanced disease includes abdominal pain, diarrhoea, blood in the stool, liver cirrhosis, portal hypertension, and premature death. OBJECTIVES: To evaluate the effects of antischistosomal drugs, used alone or in combination, for treating S. mansoni infection. SEARCH METHODS: We searched MEDLINE, EMBASE and LILACS from inception to October 2012, with no language restrictions. We also searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2012) and mRCT. The reference lists of articles were reviewed and experts were contacted for unpublished studies. SELECTION CRITERIA: Randomized controlled trials of antischistosomal drugs, used alone or in combination, versus placebo, different antischistosomal drugs, or different doses of the same antischistosomal drug for treating S. mansoni infection. DATA COLLECTION AND ANALYSIS: One author extracted data and assessed eligibility and risk of bias in the included studies, which were independently checked by a second author. We combined dichotomous outcomes using risk ratio (RR) and continuous data weighted mean difference (WMD); we presented both with 95% confidence intervals (CI). We assessed the quality of evidence using the GRADE approach. MAIN RESULTS: Fifty-two trials enrolling 10,269 participants were included. The evidence was of moderate or low quality due to the trial methods and small numbers of included participants.Praziquantel: Compared to placebo, praziquantel 40 mg/kg probably reduces parasitological treatment failure at one month post-treatment (RR 3.13, 95% CI 1.03 to 9.53, two trials, 414 participants, moderate quality evidence). Compared to this standard dose, lower doses may be inferior (30 mg/kg: RR 1.52, 95% CI 1.15 to 2.01, three trials, 521 participants, low quality evidence; 20 mg/kg: RR 2.23, 95% CI 1.64 to 3.02, two trials, 341 participants, low quality evidence); and higher doses, up to 60 mg/kg, do not appear to show any advantage (four trials, 783 participants, moderate quality evidence).The absolute parasitological cure rate at one month with praziquantel 40 mg/kg varied substantially across studies, ranging from 52% in Senegal in 1993 to 92% in Brazil in 2006/2007. Oxamniquine: Compared to placebo, oxamniquine 40 mg/kg probably reduces parasitological treatment failure at three months (RR 8.74, 95% CI 3.74 to 20.43, two trials, 82 participants, moderate quality evidence). Lower doses than 40 mg/kg may be inferior at one month (30 mg/kg: RR 1.78, 95% CI 1.15 to 2.75, four trials, 268 participants, low quality evidence; 20 mg/kg: RR 3.78, 95% CI 2.05 to 6.99, two trials, 190 participants, low quality evidence), and higher doses, such as 60 mg/kg, do not show a consistent benefit (four trials, 317 participants, low quality evidence).These trials are now over 20 years old and only limited information was provided on the study designs and methods. Praziquantel versus oxamniquine: Only one small study directly compared praziquantel 40 mg/kg with oxamniquine 40 mg/kg and we are uncertain which treatment is more effective in reducing parasitological failure (one trial, 33 participants, very low quality evidence). A further 10 trials compared oxamniquine at 20, 30 and 60 mg/kg with praziquantel 40 mg/kg and did not show any marked differences in failure rate or percent egg reduction.Combination treatments: We are uncertain whether combining praziquantel with artesunate reduces failures compared to praziquantel alone at one month (one trial, 75 participants, very low quality evidence).Two trials also compared combinations of praziquantel and oxamniquine in different doses, but did not find statistically significant differences in failure (two trials, 87 participants). Other outcomes and analyses: In trials reporting clinical improvement evaluating lower doses (20 mg/kg and 30 mg/kg) against the standard 40 mg/kg for both praziquantel or oxamniquine, no dose effect was demonstrable in resolving abdominal pain, diarrhoea, blood in stool, hepatomegaly, and splenomegaly (follow up at one, three, six, 12, and 24 months; three trials, 655 participants).Adverse events were not well-reported but were mostly described as minor and transient.In an additional analysis of treatment failure in the treatment arm of individual studies stratified by age, failure rates with 40 mg/kg of both praziquantel and oxamniquine were higher in children. AUTHORS' CONCLUSIONS: Praziquantel 40 mg/kg as the standard treatment for S. mansoni infection is consistent with the evidence. Oxamniquine, a largely discarded alternative, also appears effective.Further research will help find the optimal dosing regimen of both these drugs in children.Combination therapy, ideally with drugs with unrelated mechanisms of action and targeting the different developmental stages of the schistosomes in the human host should be pursued as an area for future research.
[Mh] Termos MeSH primário: Oxamniquine/uso terapêutico
Praziquantel/uso terapêutico
Esquistossomose mansoni/tratamento farmacológico
Esquistossomicidas/uso terapêutico
[Mh] Termos MeSH secundário: Adolescente
Adulto
Criança
Seres Humanos
Extratos Vegetais/uso terapêutico
Ensaios Clínicos Controlados Aleatórios como Assunto
Resinas Vegetais
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Plant Extracts); 0 (Resins, Plant); 0 (Schistosomicides); 0O977R722D (Oxamniquine); 6490C9U457 (Praziquantel); 9000-45-7 (myrrh resin)
[Em] Mês de entrada:1303
[Cu] Atualização por classe:160602
[Lr] Data última revisão:
160602
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130302
[St] Status:MEDLINE
[do] DOI:10.1002/14651858.CD000528.pub2


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[PMID]:22588172
[Au] Autor:Yuen T; Iqbal J; Zhu LL; Sun L; Lin A; Zhao H; Liu J; Mistry PK; Zaidi M
[Ad] Endereço:The Mount Sinai Bone Program, Mount Sinai School of Medicine, NY, USA.
[Ti] Título:Disease-drug pairs revealed by computational genomic connectivity mapping on GBA1 deficient, Gaucher disease mice.
[So] Source:Biochem Biophys Res Commun;422(4):573-7, 2012 Jun 15.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We have reported that, in addition to recapitulating the classical human Gaucher disease (GD1) phenotype, deletion of the glucocerebrosidase (GBA1) gene in mice results in the dysfunction of a diverse population of immune cells. Most of immune-related, non-classical features of GD1, including gammopathies and autoimmune diathesis, are resistant to macrophage-directed therapies. This has prompted a search for newer agents for human GD1. Here, we used high-density microarray on splenic and liver cells from affected GBA1(-/-) mice to establish a gene "signature", which was then utilized to interrogate the Broad Institute database, CMAP. Computational connectivity mapping of disease and drug pairs through CMAP revealed several highly enriched, non-null, mimic and anti-mimic hits. Most notably, two compounds with anti-helminthic properties, namely albendazole and oxamniquine, were identified; these are particularly relevant for future testing as the expression of chitinases is enhanced in GD1.
[Mh] Termos MeSH primário: Biologia Computacional/métodos
Descoberta de Drogas/métodos
Doença de Gaucher/tratamento farmacológico
Doença de Gaucher/genética
Genômica/métodos
Glucosilceramidase/deficiência
Mimetismo Molecular
[Mh] Termos MeSH secundário: Albendazol/farmacologia
Animais
Anti-Helmínticos/farmacologia
Modelos Animais de Doenças
Deleção de Genes
Glucosilceramidase/genética
Fígado/efeitos dos fármacos
Fígado/metabolismo
Camundongos
Análise de Sequência com Séries de Oligonucleotídeos/métodos
Oxamniquine/farmacologia
Baço/efeitos dos fármacos
Baço/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anthelmintics); 0O977R722D (Oxamniquine); EC 3.2.1.45 (Glucosylceramidase); F4216019LN (Albendazole)
[Em] Mês de entrada:1209
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120517
[St] Status:MEDLINE
[do] DOI:10.1016/j.bbrc.2012.05.027



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