Using Computer-aided Drug Design and Medicinal Chemistry Strategies in the Fight Against Diabetes

The aim of this work is to present a simple, practical and efficient protocol for drug design, in particular Diabetes, which includes selection of the illness, good choice of a target as well as a bioactive ligand and then usage of various computer aided drug design and medicinal chemistry tools to design novel potential drug candidates in different diseases. We have selected the validated target dipeptidyl peptidase IV (DPP-IV), whose inhibition contributes to reduce glucose levels in type 2 diabetes patients. The most active inhibitor with complex X-ray structure reported was initially extracted from the BindingDB database. By using molecular modification strategies widely used in medicinal chemistry, besides current state-of-the-art tools in drug design (including flexible docking, virtual screening, molecular interaction fields, molecular dynamics. ADME and toxicity predictions), we have proposed 4 novel potential DPP-IV inhibitors with drug properties for Diabetes control, which have been supported and validated by all the computational tools used herewith.

O conceito de vivência em Freud e Husserl

Este artigo visa explicitar as concepções freudiana e husserliana de “vivência” (Erlebnis). Por “vivência” entende-se genericamente um tipo fundamental de experiência do mundo. Esse tema, ainda que não diretamente explorado por Freud, tornou-se necessário em sua teoria desde a descoberta da etiologia da histeria no início dos anos 1890 à luz do método catártico: a da vivência traumática. Por outro lado, Husserl, a partir do problema filosófico de garantir a possibilidade do conhecimento universal e necessário, se viu obrigado a combater o naturalismo das ideias, em 1900, e o naturalismo da consciência, em 1913, em ambos os casos partindo de uma análise das vivências (intencionais). Mostrarei que a abordagem freudiana (natural-científica) visa explicar metapsicologicamente a vivência, ao passo que a abordagem husserliana pretende descrever a estrutura da vivência (intencional). Por fim, apontarei para algumas das grandes diferenças entre ambas as abordagens desse tema.

A situação epidemiológica da tuberculose na República da Guiné-Bissau, 2000 - 2005

INTRODUÇÃO: A tuberculose na República da Guiné-Bissau não apresenta bons indicadores de saúde, assim como na maioria dos países em vias de desenvolvimento. OBJETIVO: Estudar na República da Guiné-Bissau e nas suas Províncias, a situação epidemiológica da doença no período de 2000 a 2005. MÉTODO: Realizou-se levantamento de dados secundários junto ao Programa Nacional de Luta Contra Lepra e Tuberculose, no período de 2000 a 2005, e análise de relatórios anuais da Capital e das Províncias da Guiné-Bissau, para o cálculo de coeficientes e taxas dos indicadores. RESULTADOS: O número de casos de tuberculose manteve-se estável no período de 2000 (1.959 casos) a 2005 (1.888 casos). O percentual de casos pulmonares variou de 96,0 a 98,8%, dos quais 55% eram bacilíferos. Em 2005 o coeficiente de prevalência foi de 142,4/100.000, o de incidência 131,3/100.000 e o de mortalidade, 16,8/100.000 habitantes. A maior concentração de casos ocorreu na região da Capital. A taxa de cura variou entre 46,5% em 2000 e 69,6% em 2005, e a de abandono de tratamento de 29,8% em 2000 para 12,1% em 2005. CONCLUSÃO: Os indicadores do Plano Estratégico Nacional devem ser melhorados, sobretudo no que diz respeito à busca ativa de casos, à descentralização do atendimento aos doentes, à implantação da estratégia DOTS e à necessidade de um sistema de informação e notificação eficientes.

Causas múltiplas de morte relacionadas às doenças cerebrovasculares no Estado do Paraná

OBJETIVO: Identificar as causas associadas de morte e o número de causas informadas nas declarações de óbito por doenças cerebrovasculares entre residentes no Estado do Paraná. MATERIAL E MÉTODOS: O banco de dados de mortalidade do ano de 2004 foi obtido do Sistema de Informação de Mortalidade disponível no endereço eletrônico do Datasus. A população escolhida foi separada pelo programa TabWin e as causas múltiplas foram processadas pelo programa Tabulador de Causas Múltiplas de Morte. RESULTADOS: O número médio de causas informadas foi de 2,92 para as mulheres e 2,97 para os homens. A maioria dos óbitos (74,8%) foi de pessoas com 65 anos ou mais de idade. Entre as causas associadas aos óbitos por doenças cerebrovasculares se destacaram as doenças do aparelho respiratório (37,9%), as doenças hipertensivas (37,5%) e os sintomas, sinais e achados anormais de exames clínicos e de laboratório (32,3%). CONSIDERAÇÕES FINAIS: Foi observada relativa melhora na qualidade dos dados de mortalidade em relação ao número de causas citadas. A hipertensão arterial como uma das principais causas associadas sugere a necessidade do seu controle no combate à mortalidade por doenças cerebrovasculares. Incentivos devem ser promovidos para estudos com causas múltiplas, para que se utilizem melhor informações tão importantes, que são desprezadas em estudos de mortalidade feitos somente com a causa básica de morte.

Resgate histórico do controle do tabagismo na Faculdade de Saúde Pública da Universidade de São Paulo: relato de uma experiência

A ação da Faculdade de Saúde Pública da Universidade de São Paulo na luta contra o tabagismo teve início em 1975, quando a instituição participou da III Conferência Mundial de Fumo e Saúde, realizada em New York (EUA). Depois de três décadas de trabalho ininterrupto, ela recebeu, em 2008, da Secretaria de Estado da Saúde de São Paulo, o selo prata de certificação de ambiente livre do tabaco. Nesse espaço de tempo, ao lado de um trabalho educativo, realizado corpo a corpo com docentes, funcionários e alunos, foram realizadas pesquisas, treinamentos e desenvolvido toda uma programação orientada pelo Ministério da Saúde / Instituto Nacional do Câncer. Foram também produzidas inúmeras monografias de mestrado, teses de doutorado e de livre docência, tendo como tema o tabagismo do ponto de vista educativo, social, médico e sanitário. Este artigo pretendeu fazer o relato dessa trajetória

A questão social na França contemporânea: uma experiência de pesquisa

A França passou por conflitos urbanos em seus bairros populares. Incidentes com a polícia marcados pela morte de um morador, geralmente jovem ou adolescente, são seguidos por manifestações violentas: quebra-quebras, incêndios de carros e/ou estabelecimentos públicos e privados, enfrentamentos com a polícia. Nos conflitos da "banlieue" francesa podem ser percebidos elementos comuns a eventos ingleses e/ou americanos de outras décadas.OBJETIVO: consiste em identificar a percepção e as representações de moradores sobre suas condições de vida e saúde na França.MÉTODO: pesquisa qualitativa realizada em Les Aubiers, bairro popular de Bordeaux, nos anos de 2002 e 2005. A população de moradores desse bairro e é composta principalmente por imigrantes ou fanceses de origem estrangeira, provenientes de diferentes locais: África do Norte, África Sub-Sahariana, Turquia, Portugal , Ilha de Reunião. Os indicadores sociais e econômicos apresentam níveis significativamente mais baixos do que os de outros bairros de Bordeaux, acompanhando as tendências encontradas nas outras "banlieues". Entre esses indicadores, a taxa de desemprego, principalmente entre jovens, é alarmante (40 por cento).RESULTADOS E DISCUSSÃO: as políticas sociais deveriam ser mais voltadas para os indivíduos do que para o território, pois este só poderá ser transformado pelos primeiros e não o contrário. Um bairro e uma população estigmatizados, estão contemplados por uma ampla política social. Ainda que passível de crítica, não se pode ignorar a existência de esforços sistematicos de integração, nem a existência de políticas sociais. Se elas são inadequadas, trata-se de ampliar o espaço de discusão para sua reforma. Trata-se de saber qual a disposição das sociedades contemporâneas, como um todo, para lutar contra as inequidades e segregações

A Novel Organotellurium Compound (RT-01) as a New Antileishmanial Agent

Leishmaniasis is a neglected disease and endemic in developing countries. A lack of adequate and definitive chemotherapeutic agents to fight against this infection has led to the investigation of numerous compounds. The aim of this study was to investigate the effect of RT-01, an organotellurane compound presenting biological activities, in 2 experimental systems against Leishmania amazonensis. The in vitro system consisted of promastigotes and amastigotes forms of the parasite, and the in vivo system consisted of L. amazonensis infected BALB/c mice, an extremely susceptible mouse strain. The compound proved to be toxic against promastigotes and amastigotes. The study also showed that treatment with RT-01 produces an effect similar to that treatment with the reference antimonial drug, Glucantime, in L. amazonensis infected mice. The best results were obtained following RT-01 intralesional administration (720 mu g/kg/day); mice showed significant delay in the development of cutaneous lesions and decreased numbers of parasites obtained from the lesions. Significant differences in tissue pathology consisted mainly of no expressive accumulation of inflammatory cells and well-preserved structures in the skin tissue of RT-01-treated mice compared with expressive infiltration of infected cells replacing the skin tissue in lesions of untreated mice. These findings highlight the fact that the apparent potency of organotellurane compounds, together with their relatively simple structure, may represent a new avenue for the development of novel drugs to combat parasitic diseases.

Ultra-Deep Sequencing Reveals the microRNA Expression Pattern of the Human Stomach

Background: While microRNAs (miRNAs) play important roles in tissue differentiation and in maintaining basal physiology, little is known about the miRNA expression levels in stomach tissue. Alterations in the miRNA profile can lead to cell deregulation, which can induce neoplasia. Methodology/Principal Findings: A small RNA library of stomach tissue was sequenced using high-throughput SOLiD sequencing technology. We obtained 261,274 quality reads with perfect matches to the human miRnome, and 42% of known miRNAs were identified. Digital Gene Expression profiling (DGE) was performed based on read abundance and showed that fifteen miRNAs were highly expressed in gastric tissue. Subsequently, the expression of these miRNAs was validated in 10 healthy individuals by RT-PCR showed a significant correlation of 83.97% (P<0.05). Six miRNAs showed a low variable pattern of expression (miR-29b, miR-29c, miR-19b, miR-31, miR-148a, miR-451) and could be considered part of the expression pattern of the healthy gastric tissue. Conclusions/Significance: This study aimed to validate normal miRNA profiles of human gastric tissue to establish a reference profile for healthy individuals. Determining the regulatory processes acting in the stomach will be important in the fight against gastric cancer, which is the second-leading cause of cancer mortality worldwide.

Cost-effectiveness analysis of PCR for the rapid diagnosis of pulmonary tuberculosis

Background: Tuberculosis is one of the most prominent health problems in the world, causing 1.75 million deaths each year. Rapid clinical diagnosis is important in patients who have comorbidities such as Human Immunodeficiency Virus (HIV) infection. Direct microscopy has low sensitivity and culture takes 3 to 6 weeks [1-3]. Therefore, new tools for TB diagnosis are necessary, especially in health settings with a high prevalence of HIV/TB co-infection. Methods: In a public reference TB/HIV hospital in Brazil, we compared the cost-effectiveness of diagnostic strategies for diagnosis of pulmonary TB: Acid fast bacilli smear microscopy by Ziehl-Neelsen staining (AFB smear) plus culture and AFB smear plus colorimetric test (PCR dot-blot). From May 2003 to May 2004, sputum was collected consecutively from PTB suspects attending the Parthenon Reference Hospital. Sputum samples were examined by AFB smear, culture, and PCR dot-blot. The gold standard was a positive culture combined with the definition of clinical PTB. Cost analysis included health services and patient costs. Results: The AFB smear plus PCR dot-blot require the lowest laboratory investment for equipment (US$ 20,000). The total screening costs are 3.8 times for AFB smear plus culture versus for AFB smear plus PCR dot blot costs (US$ 5,635,760 versus US$ 1,498, 660). Costs per correctly diagnosed case were US$ 50,773 and US$ 13,749 for AFB smear plus culture and AFB smear plus PCR dot-blot, respectively. AFB smear plus PCR dot-blot was more cost-effective than AFB smear plus culture, when the cost of treating all correctly diagnosed cases was considered. The cost of returning patients, which are not treated due to a negative result, to the health service, was higher in AFB smear plus culture than for AFB smear plus PCR dot-blot, US$ 374,778,045 and US$ 110,849,055, respectively. Conclusion: AFB smear associated with PCR dot-blot associated has the potential to be a cost-effective tool in the fight against PTB for patients attended in the TB/HIV reference hospital.

Computer-aided drug design and ADMET predictions for identification and evaluation of novel potential farnesyltransferase inhibitors in cancer therapy

We have used various computational methodologies including molecular dynamics, density functional theory, virtual screening, ADMET predictions and molecular interaction field studies to design and analyze four novel potential inhibitors of farnesyltransferase (FTase). Evaluation of two proposals regarding their drug potential as well as lead compounds have indicated them as novel promising FTase inhibitors, with theoretically interesting pharmacotherapeutic profiles, when Compared to the very active and most cited FTase inhibitors that have activity data reported, which are launched drugs or compounds in clinical tests. One of our two proposals appears to be a more promising drug candidate and FTase inhibitor, but both derivative molecules indicate potentially very good pharmacotherapeutic profiles in comparison with Tipifarnib and Lonafarnib, two reference pharmaceuticals. Two other proposals have been selected with virtual screening approaches and investigated by LIS, which suggest novel and alternatives scaffolds to design future potential FTase inhibitors. Such compounds can be explored as promising molecules to initiate a research protocol in order to discover novel anticancer drug candidates targeting farnesyltransferase, in the fight against cancer. (C) 2009 Elsevier Inc. All rights reserved.

Maximum inhibitory dilution of mouthwashes containing chlorhexidine and polyhexamethylene biguanide against salivary staphylococcus aureus

OBJECTIVE: The aim of the present study was to determine the in vitro maximum inhibitory dilution (MID) of two chlorhexidinebased oral mouthwashes (CHX): Noplak®, Periogard®, and one polyhexamethylene biguanide-based mouthwash (PHMB): Sanifill Premium® against 28 field Staphylococcus aureus strains using the agar dilution method. MATERIALS AND METHODS: For each product, decimal dilutions ranging from 1/10 to 1/655,360 were prepared in distilled water and added to Mueller Hinton Agar culture medium. After homogenization, the culture medium was poured onto Petri dishes. Strains were inoculated using a Steers multipoint inoculator and dishes were incubated at 37ºC for 24hours. For reading, MID was considered as the maximum dilution of the mouthwash still capable of inhibiting microbial growth. RESULTS: Sanifill Premium® inhibited the growth of all strains at 1/40 dilution and of 1 strain at 1/80 dilution. Noplak® inhibited the growth of 23 strains at 1/640 dilution and of all 28 strains at 1/320 dilution. Periogard® showed inhibited growth of 7 strains at 1/640 dilution and of all 28 strains at 1/320 dilution. Data were submitted to Kruskal-Wallis statistical test, showing significant differences between the mouthwashes evaluated (p<0.05). No significant difference was found between Noplak® and Periogard® (p>0.05). Sanifill Premium® was the least effective (p<0.05). CONCLUSION: It was concluded that CHX-based mouthwashes present better antimicrobial activity against S. Aureus than the PHMB-based mouthwash.

Determination of the maximum inhibitory dilution of cetylpyridinium chloride-based mouthwashes against staphylococcus aureus: an in vitro study

The aim of this in vitro study was to determine the maximum inhibitory dilution (MID) of four cetylpyridinium chloride (CPC)-based mouthwashes: CPC+Propolis, CPC+Malva, CPC+Eucaliptol+Juá+Romã+Propolis (Natural Honey®) and CPC (Cepacol®), against 28 Staphylococcus aureus field strains, using the agar dilution method. Decimal dilutions ranging from 1/10 to 1/655,360 were prepared and added to Mueller Hinton Agar. Strains were inoculated using Steers multipoint inoculator. The inocula were seeded onto the surface of the culture medium in Petri dishes containing different dilutions of the mouthwashes. The dishes were incubated at 37ºC for 24 h. For readings, the MID was considered as the maximum dilution of mouthwash still capable of inhibiting microbial growth. The obtained data showed that CPC+Propolis had antimicrobial activity against 27 strains at 1/320 dilution and against all 28 strains at 1/160 dilution, CPC+Malva inhibited the growth of all 28 strains at 1/320 dilution, CPC+Eucaliptol+Juá+Romã+Propolis inhibited the growth of 2 strains at 1/640 dilution and all 28 strains at 1/320 dilution, and Cepacol® showed antimicrobial activity against 3 strains at 1/320 dilution and against all 28 strains at 1/160 dilution. Data were submitted to Kruskal-Wallis test, showing that the MID of Cepacol® was lower than that determined for the other products (p<0.05). In conclusion, CPC-mouthwashes showed antimicrobial activity against S. aureus and the addition of other substances to CPC improved its antimicrobial effect.

Antibacterial activity of four mouthrinses containing triclosan against salivary Staphylococcus aureus

The maximum inhibitory dilution (MID) of triclosan-based mouthwashes against 28 Staphylococcus aureus strains was evaluated. Dilutions ranging from 1/10 to 1/655,360 were prepared. Strains were inoculated using a Steers multipoint inoculator. The MID was considered as the maximum dilution capable of inhibiting microorganism growth. The mouthwashes presented different MIDs.

The anticancer drug tamoxifen is active against Trypanosoma cruzi in vitro but ineffective in the treatment of the acute phase of Chagas disease in mice

The activity of the antineoplastic drug tamoxifen was evaluated against Trypanosoma cruzi. In vitro activity was determined against epimastigote, trypomastigote and amastigote forms of CL14, Y and Y benznidazole resistant T. cruzi strains. Regardless of the strain used, the drug was active against all life-cycle stages of the parasite with a half maximal effective concentration ranging from 0.7-17.9 µM. Two experimental models of acute Chagas disease were used to evaluate the in vivo efficacy of treatment with tamoxifen. No differences in parasitemia and mortality were observed between control mock-treated and tamoxifen-treated mice.

Matrizes clínicas e ética em Freud

O presente estudo hipotetiza que as diferentes matrizes clínicas que Freud encontrava em sua prática, e que lhe possibilitavam acréscimos teóricos, direcionaram seus distintos olhares sobre a cultura, fazendo-o privilegiar alguns elementos éticos em detrimento de outros. Desse modo, indicaremos: (1) como a histeria gerou a questão do conflito entre sexualidade e moral na civilização; (2) como a neurose obsessiva possibilitou a entrada dos temas da agressividade e do ódio como entraves contra os quais a cultura se esforça por lutar, assim como a presença marcante no psiquismo da consciência moral e do sentimento de culpa; (3) por fim, como as ditas afecções narcísicas trouxeram a Freud o papel do egoísmo e da destrutividade como inimigos da cultura. Nesse percurso nos aproximaremos das questões ligadas à problematização ética na "psicologia" freudiana e, a partir daí, do destaque que terá a dimensão moral na concepção freudiana do sujeito.