RESUMO
In this work, two synthetic aurones revealed moderate schistosomicidal potential in inâ vitro and inâ vivo assays. Aurones (1) and (2) promoted changes in tegument integrity and motor activity, leading to death of adult Schistosoma mansoni worms in inâ vitro assays. When administered orally (two doses of 50â mg/kg) in experimentally infected animals, synthetic aurones (1) and (2) promoted reductions of 56.20 % and 57.61 % of the parasite load and stimulated the displacement towards the liver of the remaining adult worms. The oogram analysis revealed that the treatment with both aurones interferes with the egg development kinetics in the intestinal tissue. Seeking an action target for compounds (1) and (2), the connection with NTPDases enzymes, recognized as important therapeutic targets for S. mansoni, was evaluated. Molecular docking studies have shown promising results. The dataset reveals the anthelmintic character of these compounds, which can be used in the development of new therapies for schistosomiasis.
Assuntos
Anti-Helmínticos/farmacologia , Benzofuranos/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose/tratamento farmacológico , Administração Oral , Animais , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/química , Benzofuranos/administração & dosagem , Benzofuranos/química , Relação Dose-Resposta a Droga , Feminino , Camundongos , Estrutura MolecularRESUMO
Schistosomiasis is a neglected disease caused by helminth flatworms of the genus Schistosoma, affecting over 240 million people in more than 70 countries. The treatment relies on a single drug, praziquantel, making urgent the discovery of new compounds. Aurones are a natural type of flavonoids that display interesting pharmacological activities, particularly as chemotherapeutic agents against parasites. In pursuit of treatment alternatives, the present work conducted an in vitro and in vivo antischistosomal investigation with aurone derivatives against Schistosoma mansoni. After preparation of aurone derivatives and their in vitro evaluation on adult schistosomes, the three most active aurones were evaluated in cytotoxicity and haemolytic assays, as well as in confocal laser-scanning microscope studies, showing tegumental damage in parasites in a concentration-dependent manner with no haemolytic or cytotoxic potential toward mammalian cells. In a mouse model of schistosomiasis, at a single oral dose of 400 mg/kg, the selected aurones showed worm burden reductions of 35% to 65.0% and egg reductions of 25% to 70.0%. The most active thiophenyl aurone derivative 18, unlike PZQ, had efficacy in mice harboring juvenile S. mansoni, also showing significant inhibition of oviposition by parasites, giving support for the antiparasitic potential of aurones as lead compounds for novel antischistosomal drugs.
Assuntos
Benzofuranos/farmacologia , Flavonoides/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Esquistossomicidas/farmacologia , Animais , Modelos Animais de Doenças , Feminino , Flavonoides/uso terapêutico , Camundongos , Testes de Sensibilidade Parasitária , Praziquantel/uso terapêutico , Esquistossomose mansoni/parasitologia , Esquistossomicidas/uso terapêuticoRESUMO
NTPDases (EC 3.6.1.5) are enzymes belonging to a protein family which have as a common feature the ability to hydrolyze di- and triphosphate nucleotides (ADP and ATP) to monophosphate nucleosides (AMP) in the presence of Ca+2 and Mg+. The potato apyrase has been the first protein of the NTPDase family to be purified. In mammals, these enzymes are involved in physiologic and sick processes as thromboregulation, inflammatory and immunologic responses. In this study, we investigated the in vitro potential of synthetic chalcones on the inhibition of potato apyrase purified from Solanum tuberosum. The protein was purified with high grade purity and its identity was confirmed by electrophoresis, western blot, and LC-MS/MS. Five out of the eight chemically synthetized chalcones analyzed in this study showed significant inhibition of the apyrase activity. The compound with the best rate of inhibition of ATP hydrolytic activity was able to promote 54% inhibition with a concentration of 3.125 µM. Ticlopidine, used as an inhibition drug control, was able to promote inhibitions around 50% of the activity (IC50 = 2.167 µM). Our results with the potato apyrase inhibition with the synthetic chalcones suggest that these compounds may use as potential lead candidates for the treatment of some diseases associated with nucleotides.
Assuntos
Trifosfato de Adenosina/química , Apirase/antagonistas & inibidores , Chalconas/química , Trifosfato de Adenosina/genética , Sequência de Aminoácidos/genética , Antígenos CD/química , Antígenos CD/genética , Apirase/química , Apirase/genética , Biotecnologia , Chalconas/farmacologia , Cromatografia Líquida , Humanos , Hidrólise/efeitos dos fármacos , Engenharia de Proteínas , Solanum tuberosum/enzimologia , Espectrometria de Massas em TandemRESUMO
In this study, we evaluated the inâ vitro and inâ vivo schistosomicidal activities of chalcones against Schistosoma mansoni worms. In vitro assays revealed that chalcones 1 and 3 were the most active compounds, without affecting significantly mammalian cells. Confocal laser scanning microscopy and scanning electron microscopy studies revealed reduction on the numbers of tubercles and morphological alterations in the tegument of S. mansoni worms after inâ vitro incubation with chalcones 1 and 3. In a mouse model of schistosomiasis, the oral treatment (400â mg/kg) with chalcone 1 or 3 significantly caused a total worm burden reduction in mice. Chalcone 1 showed significant inhibition of the S. mansoni ATP diphosphohydrolase activity, which was corroborated by molecular docking studies. The results suggested that chalcones could be explored as lead compounds with antischistosomal properties.
Assuntos
Anti-Helmínticos/química , Chalconas/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Administração Oral , Animais , Anti-Helmínticos/síntese química , Anti-Helmínticos/farmacologia , Anti-Helmínticos/uso terapêutico , Apirase/antagonistas & inibidores , Apirase/metabolismo , Sítios de Ligação , Chalconas/síntese química , Chalconas/química , Chalconas/uso terapêutico , Modelos Animais de Doenças , Proteínas de Helminto/antagonistas & inibidores , Proteínas de Helminto/metabolismo , Camundongos , Microscopia Confocal , Microscopia Eletrônica de Varredura , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Schistosoma mansoni/enzimologia , Esquistossomose mansoni/tratamento farmacológico , Esquistossomose mansoni/patologia , Relação Estrutura-AtividadeRESUMO
Background. False negative fistula testing in patients with chronic suppurative otitis media is a dilemma when proceeding to surgery. It is imperative to rule out a dead labyrinth or a mass effect secondary to the cholesteatoma in an otherwise normally functioning inner ear. We present a case series of three patients in whom a bedside vestibuloocular reflex (VOR) evaluation using a head impulse test was used successfully for further evaluation prior to surgery. Results. In all three cases with a false negative fistula test we were able to further evaluate at the bedside and were not only able to register the abnormal VOR but also localize its deterioration to a particular semicircular canal eroded by the fistula. Conclusion. Vestibuloocular reflex evaluation is mandatory in patients with suspected labyrinthine fistula due to cholesteatoma of the middle ear before proceeding to surgery. We demonstrate successful use of a bedside head impulse test for further evaluation prior to surgery in patients with false negative fistula test.
RESUMO
Three series of d-galactose derivatives linked to a lipophilic aminoalcohol moiety were synthesized and their antibacterial activity was evaluated against Mycobacterium tuberculosis and representative species of Gram positive and Gram negative bacteria. Five out of the thirteen tested compounds displayed activity against M. tuberculosis, with a minimal inhibitory concentration (MIC) of 12.5 µg/mL and seven compounds were active against the four bacterial strains tested. The best results were obtained for amino alcohols 10 and 11 against Staphylococcus epidermidis (MIC = 2 µg/mL). The antitumor activity was evaluated against three tumor cell lines (MCF-7, HeLa and MO59J) and compared to the normal cell line GM07492A. The results showed that the lowest IC50 values were observed for the amino alcohol 16 against MCF-7 (11.9 µM) and MO59J (10.0 µM).
Assuntos
Amino Álcoois/farmacologia , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Amino Álcoois/síntese química , Amino Álcoois/química , Antibacterianos/síntese química , Antibacterianos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Polyamines are substances involved in many aspects of cell growth, division, and differentiation. Because of the metabolic differences between host cells and parasite cells, polyamine metabolism has been considered as a potential target for the chemotherapy of parasitic diseases. The aim of this work was to evaluate the schistosomicidal activity of different N-alkylated diamines (3a-3h), amino alcohols (4a-4d), and glycosylated amino alcohols (10a-10d). Compounds were prepared by synthetic methods and submitted to in vitro evaluation against adult worms of Schistosoma mansoni. At 100 µM, 3b, 3e, and 3h as well as 4a, 4b, 4d, 10a, 10b, and 10d resulted in 100% mortality of adult schistosomes. Compound 3d (12.5 to 100 µM) caused the death of 100% of both male and female adult schistosomes, while 3f (12.5 to 100 µM) resulted in 100% mortality of only male adult worms, whereas no mortality in female worms was observed. Compounds 3d and 3f were also able to reduce viability and decrease production of developed eggs in comparison with the negative control group. Diamines 3d and 3f may represent useful lead compounds for further optimization in order to develop new schistosomicidal agents.
Assuntos
Amino Álcoois/administração & dosagem , Diaminas/administração & dosagem , Schistosoma mansoni/efeitos dos fármacos , Esquistossomicidas/administração & dosagem , Amino Álcoois/química , Animais , Diaminas/química , Humanos , Poliaminas/química , Esquistossomose/tratamento farmacológico , Esquistossomose/patologia , Esquistossomicidas/químicaRESUMO
CONTEXTO: O beber pesado episódico (BPE) tem sido fortemente associado a danos e a uma carga social consideráveis. OBJETIVOS: Este estudo tem como finalidade avaliar o panorama brasileiro a partir de aspectos sociodemográficos, fatores individuais e sociais relacionados ao beber pesado. MÉTODOS: A busca de artigos científicos foi realizada com base em um programa de computador nos principais bancos de dados científicos. RESULTADOS: Os homens beberam pesado mais freqüentemente que as mulheres. O beber pesado episódico foi mais prevalente em adolescentes e adultos jovens, e a prevalência tende a diminuir com o aumento da idade. As condições socioeconômicas parecem ter um efeito sobre o beber pesado. O início precoce do beber pesado esteve associado com história de dependência do álcool na vida adulta. O beber pesado episódico esteve associado ao uso concomitante de outras substâncias psicoativas. Os fatores de risco para BPE incluíram atividades sociais e disponibilidade de dinheiro. A pressão dos pares mostrou influenciar mais do que o suporte parental especialmente no final de adolescência. O BP também variou de acordo com a cultura, com mais episódios de BP no Sul em comparação com o Norte do País. CONCLUSÕES: Uma variedade de aspectos sociodemográficos e individuais associados ao beber pesado foi identificada. Porém, o conhecimento nessa área ainda é muito limitado. Mais pesquisas no Brasil são urgentemente necessárias visto que os resultados provenientes de outras culturas não podem ser generalizados.
BACKGROUND: Heavy episodic drinking has been shown to be closely associated with considerable damage to and burden on society. OBJECTIVES: This review aims to give an overview of the Brazilian reality based on socio-demographic aspects, considering individual and social factors related to heavy drinking. METHODS: A computer-assisted search of relevant articles was conducted in the foremost scientific databases. RESULTS: Males tended to heavy drinking more frequently than females. Heavy episodic drinking was most prevalent among adolescents and young adults, though this prevalence tended to level off as they age. Socioeconomic conditions appear to have an effect on heavy drinking. The early onset of heavy drinking has been associated with a history of alcohol dependency in the adult phase. Heavy episodic drinking coincided with other psychoactive substance usage. Motives for heavy drinking included both social activities as well as the availability of money. Peer pressure was one of the strongest influencing factors in binge drinking and seemed to outweigh parental influence, particularly from late adolescence onward. Heavy drinking also varied according to both the predominant adult and adolescent drinking culture, with more binge drinking in the southern areas of Brazil as compared with the northern and central regions. CONCLUSIONS: A myriad of socio-demographical, individual, and social characteristics associated with heavy drinking have been identified. However, knowledge in these areas remain limited, as most research has been conducted on specific groups and situations, in particular, that of North American college students. More research in Brazil is urgently needed, as results from other cultural contexts should not be generalized.
Assuntos
Alcoolismo/epidemiologia , População , BrasilRESUMO
O objetivo do presente estudo consistiu em efetuar uma análise crítica da produção científica discente de programas de pós-graduação em Educação e Psicologia, baseada em 18 estudos sobre o tema "profissionalização de indivíduos com deficiências, encontrados em um rol de 479 dissertações e teses. Os estudos foram analisados segundo a distribuição dos locais onde foram produzidos, população alvo, metodologia adotada, tipo de revisão da literatura, referencial bibliográfico e concepção de deficiência. Em resumo, os resultados apontam a precariedade dos programas vocacionais realizados nas instituições especializadas e a desvinculação destes à realidade do trabalho competitivo, e sugerem maior cautela na seleção dos participantes a fim de evitar alguns problemas metodológicos. No geral, aparece uma tendência para estudos descritivos e sobre indivíduos com graus leves de deficiência intelectual, o que permite sugerir a necessidade aumento de estudos direcionados para outros tipos de deficiências, com maior diversidade metodológica, e o voltados para avaliar programas educacionais em ambientes normais como apoio para a inclusão social.(AU)
The present work was a critical study on students of graduate programs on Education and Psychologys production under the issue "professionalization of people with disabilities", until 1999. Of 479 theses and doctoral dissertation revealed, 18 of these studies focused on the subject matter. These studies were analysed according to the place where they were conducted, the target population, the methodology adopted, the kind of literature review, theoretical foundations, and the conceptions of authors about deficiency. Evidence suggests that a critical point in the area is the poor quality of vocational training programs, and its detachment from the competitive labour market. Due to methodological problems found in the studies the present authors recommend more caution on the choice of subjects. In the whole, there is a tendency to descriptive studies and to studies that focus on given levels of mental disabilities revealing the need to implement research on all type of disabilities and to do research with new methodological approaches focusing on the evaluation of educational programs on regular environments and with the support the social inclusion.(AU)