Current Industrial Practices in Assessing CYP450 Enzyme Induction: Preclinical and Clinical

Induction of drug metabolizing enzymes, such as the cytochromes P450 (CYP) is known to cause drug-drug interactions due to increased elimination of co-administered drugs. This increased elimination may lead to significant reduction or complete loss of efficacy of the co-administered drug. Due to the significance of such drug interactions, many pharmaceutical companies employ screening and characterization models which predict CYP enzyme induction to avoid or attenuate the potential for drug interactions with new drug candidates. The most common mechanism of CYP induction is transcriptional gene activation. Activation is mediated by nuclear receptors, such as AhR, CAR, and PXR that function as transcription factors. Early high throughput screening models utilize these nuclear hormone receptors in ligand binding or cell-based transactivation/reporter assays. In addition, immortalized hepatocyte cell lines can be used to assess enzyme induction of specific drug metabolizing enzymes. Cultured primary human hepatocytes, the best established in vitro model for predicting enzyme induction and most accepted by regulatory agencies, is the predominant assay used to evaluate induction of a wide variety of drug metabolizing enzymes. These in vitro models are able to appropriately predict enzyme induction in patients when compared to clinical drug-drug interactions. Finally, transgenic animal models and the cynomolgus monkey have also been shown to recapitulate human enzyme induction and may be appropriate in vivo animal models for predicting human drug interactions

Strengthening insights into host responses to mastitis infection in ruminants by combining heterogeneous microarray data sources

<p>Abstract</p> <p>Background</p> <p>Gene expression profiling studies of mastitis in ruminants have provided key but fragmented knowledge for the understanding of the disease. A systematic combination of different expression profiling studies via meta-analysis techniques has the potential to test the extensibility of conclusions based on single studies. Using the program Pointillist, we performed meta-analysis of transcription-profiling data from six independent studies of infections with mammary gland pathogens, including samples from cattle challenged <it>in vivo </it>with <it>S. aureus</it>, <it>E. coli</it>, and <it>S. uberis</it>, samples from goats challenged <it>in vivo </it>with <it>S. aureus</it>, as well as cattle macrophages and ovine dendritic cells infected <it>in vitro </it>with <it>S. aureus</it>. We combined different time points from those studies, testing different responses to mastitis infection: overall (common signature), early stage, late stage, and cattle-specific.</p> <p>Results</p> <p>Ingenuity Pathway Analysis of affected genes showed that the four meta-analysis combinations share biological functions and pathways (e.g. protein ubiquitination and polyamine regulation) which are intrinsic to the general disease response. In the overall response, pathways related to immune response and inflammation, as well as biological functions related to lipid metabolism were altered. This latter observation is consistent with the milk fat content depression commonly observed during mastitis infection. Complementarities between early and late stage responses were found, with a prominence of metabolic and stress signals in the early stage and of the immune response related to the lipid metabolism in the late stage; both mechanisms apparently modulated by few genes, including <it>XBP1 </it>and <it>SREBF1</it>.</p> <p>The cattle-specific response was characterized by alteration of the immune response and by modification of lipid metabolism. Comparison of <it>E. coli </it>and <it>S. aureus </it>infections in cattle <it>in vivo </it>revealed that affected genes showing opposite regulation had the same altered biological functions and provided evidence that <it>E. coli </it>caused a stronger host response.</p> <p>Conclusions</p> <p>This meta-analysis approach reinforces previous findings but also reveals several novel themes, including the involvement of genes, biological functions, and pathways that were not identified in individual studies. As such, it provides an interesting proof of principle for future studies combining information from diverse heterogeneous sources.</p

Twenty-six years of HIV science: an overview of anti-HIV drugs metabolism

From the identification of HIV as the agent causing AIDS, to the development of effective antiretroviral drugs, the scientific achievements in HIV research over the past twenty-six years have been formidable. Currently, there are twenty-five anti-HIV compounds which have been formally approved for clinical use in the treatment of AIDS. These compounds fall into six categories: nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), cell entry inhibitors or fusion inhibitors (FIs), co-receptor inhibitors (CRIs), and integrase inhibitors (INIs). Metabolism by the host organism is one of the most important determinants of the pharmacokinetic profile of a drug. Formation of active or toxic metabolites will also have an impact on the pharmacological and toxicological outcomes. Therefore, it is widely recognized that metabolism studies of a new chemical entity need to be addressed early in the drug discovery process. This paper describes an overview of the metabolism of currently available anti-HIV drugs.Da identificação do HIV como o agente causador da AIDS, ao desenvolvimento de fármacos antirretrovirais eficazes, os avanços científicos na pesquisa sobre o HIV nos últimos vinte e seis anos foram marcantes. Atualmente, existem vinte e cinco fármacos anti-HIV formalmente aprovados pelo FDA para utilização clínica no tratamento da AIDS. Estes compostos são divididos em seis classes: inibidores nucleosídeos de transcriptase reversa (INTR), inibidores nucleotídeos de transcriptase reversa (INtTR), inibidores não-nucleosídeos de transcriptase reversa (INNTR), inibidores de protease (IP), inibidores da entrada celular ou inibidores de fusão (IF), inibidores de co-receptores (ICR) e inibidores de integrase (INI). O metabolismo consiste em um dos maiores determinantes do perfil farmacocinético de um fármaco. A formação de metabólitos ativos ou tóxicos terá impacto nas respostas farmacológicas ou toxicológicas do fármaco. Portanto, é amplamente reconhecido que estudos do metabolismo de uma nova entidade química devem ser realizados durante as fases iniciais do processo de desenvolvimento de fármacos. Este artigo descreve uma abordagem do metabolismo dos fármacos anti-HIV atualmente disponíveis na terapêutica

The sub-basin springs of Poxim river, state of Sergipe: the degradation to restoration

Estudos ambientais em bacias hidrográficas são fundamentais para o entendimento do uso dos recursos naturais e dos problemas relacionados à ocupação do espaço. Em Sergipe, há necessidade de se obter informações para fins de planejamento e gestão futura de suas bacias hidrográficas, uma vez que gradualmente observa-se uma redução do volume produzido nos cursos d'água e da qualidade de suas águas, que são imprescindíveis para o abastecimento humano, a utilização na agricultura e na indústria. Devido ao acelerado processo de supressão da vegetação na sub-bacia hidrográfica do rio Poxim, formada pelos rios Poxim-mirim, Poxim-açu, e Pitanga e seus pequenos tributários, foi realizado um diagnóstico para se verificar o estado de conservação das suas principais nascentes, a situação quanto ao fluxo de água, as formas de uso e ocupação do solo no entorno destas e os tipos fisionômicos de vegetação remanescentes. As informações obtidas serão úteis para a realização de projetos de restauração ambiental, a promoção de melhorias no ambiente e nas comunidades rurais e resgate da diversidade da flora e fauna nestas áreas. Observou-se que as 20 principais nascentes dos rios e tributários que compõem a sub-bacia hidrográfica do rio Poxim, apresentam alterações decorrentes da acelerada antropização (90%), a maioria delas (65%) com elevada degradação (sem raio mínimo de 50m de vegetação) e ocupadas por agricultura (50%) e pastagens (35%). Somente duas nascentes encontram-se preservadas. Quanto à composição florística, as espécies identificadas (43) podem ser utilizadas em projetos futuros para restauração das nascentes e dos cursos d'água nesta sub-bacia hidrográfica. _________________________________________________________________________________________ ABSTRACT: Environmental studies on river basins are fundamental to understanding the natural resources use and the problems related to the space occupation. In Sergipe, it is necessary to obtain information for planning purposes and future management of their watersheds, once the watercourses volume and its quality are reducing gradually, which are essential for human supply and use in agriculture and industry. Due to the accelerated removal of vegetation in the river Poxim sub-basin, formed by the Poxim-Mirim, Poxim-Açu, Pitanga rivers, and its small tributaries, a diagnosis was carried out to verify the conservation status of their main sources, the situation on the water flow, the different uses, and land use around these sources and the remaining vegetation physiognomic types. The information is useful for carrying out environmental restoration projects, promoting improvements in the environment and in the rural communities and for the flora and fauna diversity rescue in these areas. It was observed that the 20 rivers sources top and tributaries that compose the river Poxim sub-basin showed changes from accelerated human anthropization (90%), most (65%) with high degradation (no vegetation in the minimum radius of 50 m), being occupied by agriculture (50%) and pastures (35%). Only two sources were preserved. The floristic composition, the identified species (43) can be used in future projects for sources and watercourses restoration in this sub-basin

Hepatocyte growth factor/scatter factor (HGF/SF) signals via the STAT3/APRF transcription factor in human hepatoma cells and hepatocytes

AbstractAcute phase protein expression is regulated by a variety of cytokines such as IL-1, IL-6, IL-11, tumour necrosis factor α, interferon-γ, oncostatin-M, leukemia inhibitory factor, ciliary neurotrophic factor and cardiotrophin-1. Presently, IL-6 is regarded as the most potent mediator of acute phase protein (APP) synthesis. It was shown that IL-6 and IL-6-type cytokines activate the so-called JAK/STAT pathway and finally regulate APP expression in liver cells. Since HGF/SF is also capable of regulating APP expression, we asked whether it might also signal via the JAK/STAT pathway. Here we show that incubation of human hepatocytes as well as hepatoma cells (HepG2) with HGF/SF results in activation of the transcription factor STAT3. This STAT3 activation after HGF/SF did not occur before 5–7 h and was maintained up to 28 h. These observations are in contrast to the rapid and transient activation of STAT1 and STAT3 mediated by IL-6.© 1997 Federation of European Biochemical Societies