Mechanism-based inhibition of CYP2C8 by gemfibrozil in humans : characterisation of time and dose relationships

Drug-drug interactions may cause serious, even fatal clinical consequences. Therefore, it is important to examine the interaction potential of new chemical entities early in drug development. Mechanism-based inhibition is a pharmacokinetic interaction type, which causes irreversible loss of enzyme activity and can therefore lead to unusually profound and long-lasting consequences. The in vitro in vivo extrapolation (IVIVE) of drug-drug interactions caused by mechanism-based inhibition is challenging. Consequently, many of these interactions have remained unrecognised for many years. The concomitant use of the fibrate-class lipid-lowering agent gemfibrozil increases the concentrations of some drugs and their effects markedly. Even fatal cases of rhabdomyolysis occurred in patients administering gemfibrozil and cerivastatin concomitantly. One of the main mechanisms behind this effect is the mechanism-based inhibition of the cytochrome P450 (CYP) 2C8 enzyme by a glucuronide metabolite of gemfibrozil leading to increased cerivastatin concentrations. Although the clinical use of gemfibrozil has clearly decreased during recent years, gemfibrozil is still needed in some special cases. To enable safe use of gemfibrozil concomitantly with other drugs, information concerning the time and dose relationships of CYP2C8 inhibition by gemfibrozil should be known. This work was carried out as four in vivo clinical drug-drug interaction studies to examine the time and dose relationships of the mechanism-based inhibitory effect of gemfibrozil on CYP2C8. The oral antidiabetic drug repaglinide was used as a probe drug for measuring CYP2C8 activity in healthy volunteers. In this work, mechanism-based inhibition of the CYP2C8 enzyme by gemfibrozil was found to occur rapidly in humans. The inhibitory effect developed to its maximum already when repaglinide was given 1-3 h after gemfibrozil intake. In addition, the inhibition was shown to abate slowly. A full recovery of CYP2C8 activity, as measured by repaglinide metabolism, was achieved 96 h after cessation of gemfibrozil treatment. The dose-dependency of the mechanism-based inhibition of CYP2C8 by gemfibrozil was shown for the first time in this work. CYP2C8 activity was halved by a single 30 mg dose of gemfibrozil or by twice daily administration of less than 30 mg of gemfibrozil. Furthermore, CYP2C8 activity was decreased over 90% by a single dose of 900 mg gemfibrozil or twice daily dosing of approximately 100 mg gemfibrozil. In addition, with the application of physiological models to the data obtained in the dose-dependency studies, the major role of mechanism-based inhibition of CYP2C8 in the interaction between gemfibrozil and repaglinide was confirmed. The results of this work enhance the proper use of gemfibrozil and the safety of patients. The information related to time-dependency of CYP2C8 inhibition by gemfibrozil may also give new insights in order to improve the IVIVE of the drug-drug interactions of new chemical entities. The information obtained by this work may be utilised also in the design of clinical drug-drug interaction studies in the future.

New Concepts for Three-Dimensional Shape Analysis

A new approach to machine representation and analysis of three-dimensional objects is presented. The representation, based on the notion of "skeleton" of an object leads to a scheme for comparing two given object views for shape relations. The objects are composed of long, thin, rectangular prisms joined at their ends. The input picture to the program is the digitized line drawing portraying the three-dimensional object. To compare two object views, two characteristic vertices called "cardinal point" and "end-cardinal point," occurring consistently at the bends and open ends of the object are detected. The skeletons are then obtained as a connected path passing through these points. The shape relationships between the objects are then obtained from the matching characteristics of their skeletons. The method explores the possibility of a more detailed and finer analysis leading to detection of features like symmetry, asymmetry and other shape properties of an object.

Crowd Sourcing a New Paradigm for Interactome Driven Drug Target Identification in Mycobacterium tuberculosis

A decade since the availability of Mycobacterium tuberculosis (Mtb) genome sequence, no promising drug has seen the light of the day. This not only indicates the challenges in discovering new drugs but also suggests a gap in our current understanding of Mtb biology. We attempt to bridge this gap by carrying out extensive re-annotation and constructing a systems level protein interaction map of Mtb with an objective of finding novel drug target candidates. Towards this, we synergized crowd sourcing and social networking methods through an initiative `Connect to Decode' (C2D) to generate the first and largest manually curated interactome of Mtb termed `3interactome pathway' (IPW), encompassing a total of 1434 proteins connected through 2575 functional relationships. Interactions leading to gene regulation, signal transduction, metabolism, structural complex formation have been catalogued. In the process, we have functionally annotated 87% of the Mtb genome in context of gene products. We further combine IPW with STRING based network to report central proteins, which may be assessed as potential drug targets for development of drugs with least possible side effects. The fact that five of the 17 predicted drug targets are already experimentally validated either genetically or biochemically lends credence to our unique approach.

Discovery of novel glitazones incorporated with phenylalanine and tyrosine: Synthesis, antidiabetic activity and structure-activity relationships

We report a series of new glitazones incorporated with phenylalanine and tyrosine. All the compounds were tested for their in vitro glucose uptake activity using rat-hemidiaphragm, both in presence and absence of insulin. Six of the most active compounds from the in vitro screening were taken forward for their in vivo triglyceride and glucose lowering activity against dexamethazone induced hyperlipidemia and insulin resistance in Wistar rats. The liver samples of rats that received the most active compounds, 23 and 24, in the in vivo studies, were subjected to histopathological examination to assess their short term hepatotoxicity. The investigations on the in vitro glucose uptake, in vivo triglyceride and glucose lowering activity are described here along with the quantitative structure-activity relationships. (C) 2012 Elsevier Inc. All rights reserved.

Assessment of the Relationships Among Design Methods, Design Activities, and Creativity

This paper presents an experimental study that was conducted to compare the results obtained from using different design methods (brainstorming (BR), functional analysis (FA), and SCAMPER) in design processes. The objectives of this work are twofold. The first was to determine whether there are any differences in the length of time devoted to the different types of activities that are carried out in the design process, depending on the method that is employed; in other words, whether the design methods that are used make a difference in the profile of time spent across the design activities. The second objective was to analyze whether there is any kind of relationship between the time spent on design process activities and the degree of creativity in the solutions that are obtained. Creativity evaluation has been done by means of the degree of novelty and the level of resolution of the designed solutions using creative product semantic scale (CPSS) questionnaire. The results show that there are significant differences between the amounts of time devoted to activities related to understanding the problem and the typology of the design method, intuitive or logical, that are used. While the amount of time spent on analyzing the problem is very small in intuitive methods, such as brainstorming and SCAMPER (around 8-9% of the time), with logical methods like functional analysis practically half the time is devoted to analyzing the problem. Also, it has been found that the amount of time spent in each design phase has an influence on the results in terms of creativity, but results are not enough strong to define in which measure are they affected. This paper offers new data and results on the distinct benefits to be obtained from applying design methods. DOI: 10.1115/1.4007362]

Tectonic inheritance of the Indian Shield: New insights from its elastic thickness structure

A new evaluation of the elastic thickness (Te) structure of the Indian Shield, derived from isotropic fan wavelet methodology, documents spatial variations of lithospheric deformation in different tectonic provinces correlated with episodic tectono-thermal events. The Te variations corroborated by shear velocity, crustal thickness, and seismogenic thickness reveal the heterogeneous rheology of the Indian lithosphere. The thinned, attenuated lithosphere beneath Peninsular India is considered to be the reason for its mechanically weak strength (<30 km), where a decoupled crust-mantle rheology under different surface/subsurface loading structures may explain the prominent low Te patterns. The arcuate Te structure of the Western Dharwar province and a NNE-trending band of low Te anomaly in the Southern Granulite Terrane are intriguing patterns. The average Te values (40-50 km) of the Central Indian Tectonic Zone, the Bastar Craton, and the northern Eastern Ghats Mobile Belt are suggestive of old, stable, Indian lithosphere, which was not affected by any major tectono-thermal events after cratonic stabilization. We propose that the anomalously high Te (60-85 km) and high S-wave velocity zone to the north of the Narmada-Son Lineament, mainly in NW Himalaya, and the northern Aravalli and Bundelkhand Cratons, suggest that Archean lithosphere characterized by a high velocity mantle keel supports the orogenic topographic loads in/near the Himalaya. The Te map clearly segments the volcanic provinces of the Indian Shield, where the signatures of the Reunion, Marion, and Kerguelen hotspots are indicated by significantly low Te patterns that correlate with plume- and rift-related thermal and mechanical rejuvenation, magmatic underplating, and crustal necking. The correlations between Te variations and the occurrence of seismicity over seismically active zones reveal different causal relationships, which led to the current seismogenic zonation of the Indian Shield. (C) 2013 Elsevier B.V. All rights reserved.

Scaling relationships in conical indentation of elastic perfectly plastic solids

Using dimensional analysis and finite element calculations we derive several scaling relationships for conical indentation into elastic-perfectly plastic solids. These scaling relationships provide new insights into the shape of indentation curves and form the basis for understanding indentation measurements, including nano- and micro-indentation techniques. They are also helpful as a guide to numerical and finite element calculations of conical indentation problems. Finally, the scaling relationships are used to reveal the general relationships between hardness, contact area, initial unloading slope, and mechanical properties of solids.

Relationships between hardness, elastic modulus, and the work of indentation

The work done during indentation is examined using dimensional analysis and finite element calculations for conical indentation in elastic-plastic solids with work hardening. An approximate relationship between the ratio of hardness to elastic modulus and the ratio of irreversible work to total work in indentation is found. Consequently, the ratio of hardness to elastic modulus may be obtained directly from measuring the work of indentation. Together with a well-known relationship between elastic modulus, initial unloading slope, and contact area, a new method is then suggested for estimating the hardness and modulus of solids using instrumented indentation with conical or pyramidal indenters.

Physical Constraints to Aquatic Plant Growth in New Zealand Lakes

The nature of aquatic plant communities often defines benthic habitat within oligotrophic and mesotrophic lakes and lake management increasingly recognizes the importance of maintaining plant diversity in order to sustain biological diversity and capacity within lakes. We have developed simple statistical relationships between key physical and vegetation variables that define the habitat requirements, or “habitat-templates”, of key vegetation types to facilitate management of plant communities in New Zealand lakes. Statistical relationships were derived from two datasets. The first was a multi-lake dataset to determine the effects of water level fluctuation and water clarity. The second dataset was from a comprehensive shoreline survey of Lake Wanaka, which allowed us to examine within-lake variables such as beach slope and wave action. Sufficient statistical relationships were established to develop a habitat template for each of the major species or assemblages. The relationships suggested that the extent and diversity of shallow-growing species was related to a combination of the extent of water level fluctuation and wave exposure. (PDF contains 9 pages.)

Investigations of certain eco-physiological characteristics of the broad and long-pincered crayfish in connection with their interspecific relationships. [Translation from: Lietuvas TSR Mokslu Akademijos Darbai, C Serija 2(40), 279-286, 1966.]

The results are described of eco-physiological investigations of the broad-pincered (Astacus astacus L.J.) crayfish and the long-pincered (Astacus astacus Esch.) crayfish, conducted in 1963—64 in the Institute of Zoology and Parasitology of the Academy of Science of the Lithuanian SSR, for the purpose of studying the interspecific relationship of these two species. In the course of the investigation were determined: the influence of the temperature of the environment on the consumption of oxygen by full grown individuals of both species and on the respiratory movements of the scaphognathites, the threshold temperatures and the saturation of the water by oxygen, the diel activity in the winter period.

Expondo-se conscientemente: vivendo e caracterizando relacionamento nos tempos de aids

Trata-se de pesquisa descritiva com abordagem qualitativa cujo objeto é o processo de interação da mulher com as características do relacionamento estável, a partir dos significados por ela atribuídos no contexto da aids. Os objetivos são: identificar os significados das características de relacionamento estável para as mulheres; Descrever o processo de interação social da mulher em relacionamento estável no contexto da aids, a partir dos significados por ela atribuídos; Analisar e interpretar o processo de interação social feminina com base nos princípios do interacionismo Simbólico e elaborar um modelo teórico explicativo do processo de interação social da mulher em relacionamento estável no contexto da epidemia da aids. O estudo foi realizado no Município do Rio de Janeiro, em lugares de grande circulação de pessoas. A escolha deste cenário se deu em função do local ser rico na diversidade de mulheres, de diferentes raças, condições socioeconômicas, idades, religiões e comportamentos, que frequentaram e transitaram por estes espaços durante os meses de novembro de 2011 a março de 2012. Para responder os objetivos foram formados quatro grupos amostrais com mulheres que se auto-declaram em um relacionamento estável, com idade acima de 18 anos, sem predeterminação de ocupação e raça. Foram atendidas todas as exigências preconizadas na Resolução 196/1996 do Conselho Nacional de Saúde. As entrevistas foram gravadas em aparelho de mp4, seu conteúdo foi transcrito o mais rápido possível para análise concomitante dos dados. O processo de coleta e análise dos dados foi guiado pela amostragem teórica, que consiste em definir quais dados coletar e onde localizá-los. Este é um dos elementos essenciais do processo de construção da teoria. O processo de análise foi baseado nos pressupostos teórico-metodológicos do Interacionismo Simbólico e da Grounded Theory. Os dados foram organizados em 3 categorias e mostraram que as mulheres valorizam e idealizam as características do relacionamento estável pautadas pelo amor romântico. A aids incluiu novas concepções de insegurança/ desconfiança/ dúvida, porém demonstra ser um objeto social de pouca influência para tomada de decisão para autoproteção contra a aids. Para as mulheres, a lógica de prevenção ainda se dá na crença nos valores inerentes ao relacionamento estável e com cuidados de saúde. Assim, a mulher decide não se proteger contra aids devido às construções culturais de gênero e aos aspectos afetivos do relacionamento.

An enactive and dynamical systems theory account of dyadic relationships

Many social relationships are a locus of struggle and suffering, either at the individual or interactional level. In this paper we explore why this is the case and suggest a modeling approach for dyadic interactions and the well-being of the participants. To this end we bring together an enactive approach to self with dynamical systems theory. Our basic assumption is that the quality of any social interaction or relationship fundamentally depends on the nature and constitution of the individuals engaged in these interactions. From an enactive perspective the self is conceived as an embodied and socially enacted autonomous system striving to maintain an identity. This striving involves a basic two-fold goal: the ability to exist as an individual in one's own right, while also being open to and affected by others. In terms of dynamical systems theory one can thus consider the individual self as a self-other organized system represented by a phase space spanned by the dimensions of distinction and participation, where attractors can be defined. Based on two everyday examples of dyadic relationship we propose a simple model of relationship dynamics, in which struggle or well-being in the dyad is analyzed in terms of movements of dyadic states that are in tension or in harmony with individually developed attractors. Our model predicts that relationships can be sustained when the dyad develops a new joint attractor toward which dyadic states tend to move, and well-being when this attractor is in balance with the individuals' attractors. We outline how this can inspire research on psychotherapy. The psychotherapy process itself provides a setting that supports clients to become aware how they fare with regards to the two-fold norm of distinction and participation and develop, through active engagement between client (or couple) and therapist, strategies to co-negotiate their self-organization.

Electrical phase angle as a new method to measure fish condition

In this study, phase angle (the ratio of resistance and reactance of tissue to applied electrical current) is presented as a possible new method to measure fish condition. Condition indices for fish have historically been based on simple weight-at-length relationships, or on costly and timeconsuming laboratory procedures that measure specific physiological parameters. Phase angle is introduced to combine the simplicity of a quick field-based measurement with the specificity of laboratory analysis by directly measuring extra- and intracellular water distribution within an organism, which is indicative of its condition. Phase angle, which can be measured in the field or laboratory in the time it takes to measure length and weight, was measured in six species of fish at different states (e.g., fed vs. fasted, and postmortem) and under different environmental treatments (wild vs. hatchery, winter vs. spring). Phase angle reflected different states of condition. Phase angles <15° indicated fish in poor condition, and phase angles >15° indicated fish that were in better condition. Phase angle was slightly affected by temperatures (slope = – 0.19) in the 0–8°C range and did not change in fish placed on ice for <12 hours. Phase angle also decreased over time in postmortem fish because of cell membrane degradation and subsequent water movement from intra- to extracellular (interstitial) spaces. Phase angle also reflected condition of specific anatomical locations within the fish.

Multiple stable reference points in oyster populations: biological relationships for the eastern oyster (Crassostrea virginica) in Delaware Bay

Abstract—In the first of two companion papers, a 54-yr time series for the oyster population in the New Jersey waters of Delaware Bay was analyzed to develop biological relationships necessary to evaluate maximum sustainable yield (MSY) reference points and to consider how multiple stable points affect reference point-based management. The time series encompassed two regime shifts, one circa 1970 that ushered in a 15-yr period of high abundance, and a second in 1985 that ushered in a 20-yr period of low abundance. The intervening and succeeding periods have the attributes of alternate stable states. The biological relationships between abundance, recruitment, and mortality were unusual in four ways. First, the broodstock–recruitment relationship at low abundance may have been driven more by the provision of settlement sites for larvae by the adults than by fecundity. Second, the natural mortality rate was temporally unstable and bore a nonlinear relationship to abundance. Third, combined high abundance and low mortality, though likely requiring favorable environmental conditions, seemed also to be a self-reinforcing phenomenon. As a consequence, the abundance –mortality relationship exhibited both compensatory and depensatory components. Fourth, the geographic distribution of the stock was intertwined with abundance and mortality, such that interrelationships were functions both of spatial organization and inherent populatio

Prosomal-width-to-weight relationships in American horseshoe crabs (Limulus polyphemus): examining conversion factors used to estimate landings

Horseshoe crabs (Limulus polyphemus) are valued by many stakeholders, including the commercial fishing industry, biomedical companies, and environmental interest groups. We designed a study to test the accuracy of the conversion factors that were used by NOAA Fisheries and state agencies to estimate horseshoe crab landings before mandatory reporting that began in 1998. Our results indicate that the NOAA Fisheries conversion factor consistently overestimates the weight of male horseshoe crabs, particularly those from New England populations. Because of the inaccuracy of this and other conversion factors, states are now mandated to report the number (not biomass) and sex of landed horseshoe crabs. However, accurate estimates of biomass are still necessary for use in prediction models that are being developed to better manage the horseshoe crab fishery. We recommend that managers use the conversion factors presented in this study to convert current landing data from numbers to biomass of harvested horseshoe crabs for future assessments.