Untersuchungen zur Struktur/Aktivitätsbeziehung des humanen CC-Chemokins HCC-2

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OpenTox predictive toxicology framework: toxicological ontology and semantic media wiki-based OpenToxipedia

<p>Abstract</p> <p>Background</p> <p>The OpenTox Framework, developed by the partners in the OpenTox project (<url>http://www.opentox.org</url>), aims at providing a unified access to toxicity data, predictive models and validation procedures. Interoperability of resources is achieved using a common information model, based on the OpenTox ontologies, describing predictive algorithms, models and toxicity data. As toxicological data may come from different, heterogeneous sources, a deployed ontology, unifying the terminology and the resources, is critical for the rational and reliable organization of the data, and its automatic processing.</p> <p>Results</p> <p>The following related ontologies have been developed for OpenTox: a) Toxicological ontology – listing the toxicological endpoints; b) Organs system and Effects ontology – addressing organs, targets/examinations and effects observed in <it>in vivo</it> studies; c) ToxML ontology – representing semi-automatic conversion of the ToxML schema; d) OpenTox ontology– representation of OpenTox framework components: chemical compounds, datasets, types of algorithms, models and validation web services; e) ToxLink–ToxCast assays ontology and f) OpenToxipedia community knowledge resource on toxicology terminology.</p> <p>OpenTox components are made available through standardized REST web services, where every compound, data set, and predictive method has a unique resolvable address (URI), used to retrieve its Resource Description Framework (RDF) representation, or to initiate the associated calculations and generate new RDF-based resources.</p> <p>The services support the integration of toxicity and chemical data from various sources, the generation and validation of computer models for toxic effects, seamless integration of new algorithms and scientifically sound validation routines and provide a flexible framework, which allows building arbitrary number of applications, tailored to solving different problems by end users (e.g. toxicologists).</p> <p>Availability</p> <p>The OpenTox toxicological ontology projects may be accessed via the OpenTox ontology development page <url>http://www.opentox.org/dev/ontology</url>; the OpenTox ontology is available as OWL at <url>http://opentox.org/api/1 1/opentox.owl</url>, the ToxML - OWL conversion utility is an open source resource available at <url>http://ambit.svn.sourceforge.net/viewvc/ambit/branches/toxml-utils/</url></p

A k-NN Algorithm for Predicting Oral Sub-Chronic Toxicity in the Rat

Summary Repeated dose toxicity is of the utmost importance to characterize the toxicological profile o

Atenção Farmacêutica em Goiânia: inserção do farmacêutico na Estratégia Saúde da Família

In agreement with the Brazilian National Drug Policy, the School of Pharmacy of Universidade Federal de Goiás, in partnership with the Municipal Health Department of Goiânia, state of Goiás, created and implemented a university development project suggesting the inclusion of the pharmacist in the Family Health Strategy. Meetings were held in order to introduce the project to the respective primary care units and to train the teams of pharmacists in the exercise of pharmaceutical assistance. In the 12 months of the project, 50 patients with hypertension (70% female), with average age of 50, were assisted. Among those, 40 (80%) presented more than one associated illness and 46 (92%) used 2 or more drugs, simultaneously prescribed. In the study, 154 Medication-Related Problems (MRP) were detected, with an incidence of 3.1 MRP per patient. The most frequent MRP was lack of therapeutic efficacy (49%), and 26.3% of these were caused by lack of treatment adherence. It can be concluded that the health care problems caused by lack of pharmacotherapy efficiency assume important proportions. Pharmaceutical Care as a strategy of Pharmaceutical Assistance in Family Health can be an efficient alternative to obtain better clinical and economic results, and to improve the healthcare provided for users of Brazil's National Health System.Com vistas no estabelecido na Política Nacional de Medicamentos, a Faculdade de Farmácia da UFG implantou, em parceria com a Secretaria Municipal de Saúde de Goiânia/Goiás, projeto de extensão universitária que propõe a inserção do farmacêutico na Estratégia Saúde da Família. Encontros foram realizados para sensibilização e apresentação do projeto às respectivas unidades de saúde, e a equipe de farmacêuticos local foi treinada para o exercício da atenção farmacêutica. Em 12 meses de desenvolvimento do projeto, 50 pacientes (70% femininos), com idade média de 50 anos, foram assistidos. Entre estes, 40 (80%) apresentavam mais de uma enfermidade associada e 46 (92%) faziam o uso de dois ou mais fármacos, simultaneamente prescritos. Foram detectados 154 Problemas Relacionados com Medicamentos (PRM), com incidência de 3,1 PRM por paciente. O PRM mais frequente foi a falta de efetividade na terapêutica (49%), sendo 26,3% desses devido à falta de adesão ao tratamento. Conclui-se que a problemática envolvida na assistência à saúde devido à falta de eficiência da farmacoterapia assume dimensões importantes. Atenção Farmacêutica como estratégia de Assistência Farmacêutica mostrou-se, potencialmente, capaz de melhorar a assistência à saúde dos usuários do SUS

Threshold of Toxicological Concern - an update for non-genotoxic carcinogens

The Threshold of Toxicological Concern (TTC) concept can be applied to organic compounds with known chemical structure to derive a threshold for exposure below which a toxic effect on human health by the compound is not expected. The TTC concept distinguishes between carcinogens that may act as genotoxic and non-genotoxic compounds. A positive prediction of a genotoxic mode of action, either by structural alerts or experimental data, leads to the application of the threshold value for genotoxic compounds. Non-genotoxic substances are assigned to the TTC value of their respective Cramer class even though it is recognized that they could test positive in a rodent cancer bioassay. This study investigated the applicability of the Cramer classes specifically to provide adequate protection for non-genotoxic carcinogens. For this purpose, benchmark dose levels based on tumour incidence were compared with no observed effect levels (NOEL) derived from non-, pre- or neoplastic lesions. One key aspect was the categorization of compounds as non-genotoxic carcinogens. The recently finished CEFIC LRI project B18 classified the carcinogens of the CPDB as either non- or genotoxic compounds based on experimental or in silico data. A detailed consistency check resulted in a data set of 137 non-genotoxic organic compounds. For these 137 compounds, NOEL values were derived from high quality animal studies with oral exposure and chronic duration using well known repositories including RepDose, ToxRef and COSMOS DB. Further, an effective tumour dose (ETD10) was calculated and compared to the lower confidence limit on benchmark dose levels (BMDL10) derived by model averaging. Comparative analysis of NOEL/EDT10/BMDL10 values showed that potentially bioaccumulative compounds in humans, as well as steroids, which both belong to the exclusion categories, occur predominantly in region of the 5th percentiles of the distributions. Excluding these 25 compounds resulted in significantly higher, but comparable 5th percentile chronic NOEL and BMDL10 values, while the 5th percentile EDT10 value was slightly higher, but not statistically significant. The comparison of the obtained distributions of NOELs with the existing Cramer classes and their derived TTC values supports the application of Cramer class thresholds to all non genotoxic compounds, including non_genotoxic carcinogens

Substantiate a read-across hypothesis by using transcriptome data—A case study on volatile diketones

This case study explores the applicability of transcriptome data to characterize a common mechanism of action within groups of short-chain aliphatic α-, β-, and γ-diketones. Human reference in vivo data indicate that the α-diketone diacetyl induces bronchiolitis obliterans in workers involved in the preparation of microwave popcorn. The other three α-diketones induced inflammatory responses in preclinical in vivo animal studies, whereas beta and gamma diketones in addition caused neuronal effects. We investigated early transcriptional responses in primary human bronchiolar (PBEC) cell cultures after 24 h and 72 h of air-liquid exposure. Differentially expressed genes (DEGs) were assessed based on transcriptome data generated with the EUToxRisk gene panel of Temp-O-Seq®. For each individual substance, genes were identified displaying a consistent differential expression across dose and exposure duration. The log fold change values of the DEG profiles indicate that α- and β-diketones are more active compared to γ-diketones. α-diketones in particular showed a highly concordant expression pattern, which may serve as a first indication of the shared mode of action. In order to gain a better mechanistic understanding, the resultant DEGs were submitted to a pathway analysis using ConsensusPathDB. The four α-diketones showed very similar results with regard to the number of activated and shared pathways. Overall, the number of signaling pathways decreased from α-to β-to γ-diketones. Additionally, we reconstructed networks of genes that interact with one another and are associated with different adverse outcomes such as fibrosis, inflammation or apoptosis using the TRANSPATH-database. Transcription factor enrichment and upstream analyses with the geneXplain platform revealed highly interacting gene products (called master regulators, MRs) per case study compound. The mapping of the resultant MRs on the reconstructed networks, visualized similar gene regulation with regard to fibrosis, inflammation and apoptosis. This analysis showed that transcriptome data can strengthen the similarity assessment of compounds, which is of particular importance, e.g., in read-across approaches. It is one important step towards grouping of compounds based on biological profiles

Comercialização, dispensação e prescrição de Nutracêuticos antioxidantes por farmacêuticos: Marketing, dispensing and prescription of antioxidant Nutraceutics by pharmacists

OBJETIVO: O presente estudo busca elencar nutracêuticos comercializados em Drogarias na cidade de Goiânia, Brasil e avaliar o grau de conhecimento do profissional farmacêutico sobre o uso destes produtos, boas práticas de armazenamento, orientações para a dispensação e prescrição farmacêutica. MÉTODOS: Pesquisa quantitativa, observacional do tipo transversal, realizado por meio de um questionário eletrônico distribuído aos farmacêuticos nas farmácias comunitárias, localizadas na região sul em Goiânia- Goiás. No período de 15 de julho a 15 de agosto de 2021. Na ocasião foi realizado a visita e entrevista a 30 farmácias ¬¬nas quais foram entrevistados 30 farmacêuticos. RESULTADOS: Verificamos que os nutracêuticos mais vendidos foram, destacadamente: Propolis (Apis melífera), Maca Peruana (Lepidium meyeni) Alho (Allium sativum), e os indicados/ SEM PRESCRIÇÃO pelo farmacêutico; Propolis, Cranberry (Vaccnium macrocarpom) e Maca Peruana e prescritos Alho, Cha verde (Camellia sinensis) e Açafrão (Curcuma longa). CONCLUSÕES: A resolução nº 586 objetivou permitir aos farmacêuticos habilitados prescrever terapias farmacológicas. Identificamos que 46,7% nunca prescreveu um MIP, e 43,3% nunca prescreveu nutracêuticos, o que ultrapassa 60% dos entrevistados que nunca realizou uma prescrição farmacêutica., observa-se grande número de usuários de nutracêuticos sem o acompanhamento de um profissional habilitado, seja o farmacêutico ou nutricionista.&nbsp; É importante ressaltar que nenhum dos profissionais avaliados fizeram a prescrição de nutracêuticos. Essa atividade necessita ser implementada, pois embora haja a garantia legal para a realização da prescrição pelo farmacêutico, ainda não se observa na rotina de trabalho do farmacêutico a realização dessa atribuição clínica.&nbsp

Collaborative development of predictive toxicology applications

OpenTox provides an interoperable, standards-based Framework for the support of predictive toxicology data management, algorithms, modelling, validation and reporting. It is relevant to satisfying the chemical safety assessment requirements of the REACH legislation as it supports access to experimental data, (Quantitative) Structure-Activity Relationship models, and toxicological information through an integrating platform that adheres to regulatory requirements and OECD validation principles. Initial research defined the essential components of the Framework including the approach to data access, schema and management, use of controlled vocabularies and ontologies, architecture, web service and communications protocols, and selection and integration of algorithms for predictive modelling. OpenTox provides end-user oriented tools to non-computational specialists, risk assessors, and toxicological experts in addition to Application Programming Interfaces (APIs) for developers of new applications. OpenTox actively supports public standards for data representation, interfaces, vocabularies and ontologies, Open Source approaches to core platform components, and community-based collaboration approaches, so as to progress system interoperability goals

Adverse outcome pathways:opportunities, limitations and open questions

Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory purposes. AOP links a molecular initiating event (MIE) to the adverse outcome (AO) via key events (KE), in a way specified by key event relationships (KER). Although this approach to formalize mechanistic toxicological information only started in 2010, over 200 AOPs have already been established. At this stage, new requirements arise, such as the need for harmonization and re-assessment, for continuous updating, as well as for alerting about pitfalls, misuses and limits of applicability. In this review, the history of the AOP concept and its most prominent strengths are discussed, including the advantages of a formalized approach, the systematic collection of weight of evidence, the linkage of mechanisms to apical end points, the examination of the plausibility of epidemiological data, the identification of critical knowledge gaps and the design of mechanistic test methods. To prepare the ground for a broadened and appropriate use of AOPs, some widespread misconceptions are explained. Moreover, potential weaknesses and shortcomings of the current AOP rule set are addressed (1) to facilitate the discussion on its further evolution and (2) to better define appropriate vs. less suitable application areas. Exemplary toxicological studies are presented to discuss the linearity assumptions of AOP, the management of event modifiers and compensatory mechanisms, and whether a separation of toxicodynamics from toxicokinetics including metabolism is possible in the framework of pathway plasticity. Suggestions on how to compromise between different needs of AOP stakeholders have been added. A clear definition of open questions and limitations is provided to encourage further progress in the field