Population pharmacokinetic model of canrenone after intravenous administration of potassium canrenoate to paediatric patients

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Little is known about the pharmacokinetics of potassium canrenoate/canrenone in paediatric patients WHAT THIS STUDY ADDS • A population pharmacokinetic model has been developed to evaluate the pharmacokinetics of canrenone in paediatric patients who received potassium canrenoate as part of their therapy in the intensive care unit. AIMS To characterize the population pharmacokinetics of canrenone following administration of potassium canrenoate to paediatric patients. METHODS Data were collected prospectively from 23 paediatric patients (2 days to 10 years of age; median weight 4 kg, range 2.16–28.0 kg) who received intravenous potassium canrenoate (K-canrenoate) as part of their intensive care therapy for removal of retained fluids, e.g. in pulmonary oedema due to chronic lung disease and for the management of congestive heart failure. Plasma samples were analyzed by HPLC for determination of canrenone (the major metabolite and pharmacologically active moiety) and the data subjected to pharmacokinetic analysis using NONMEM. RESULTS A one compartment model best described the data. The only significant covariate was weight (WT). The final population models for canrenone clearance (CL/F) and volume of distribution (V/F) were CL/F (l h−1) = 11.4 × (WT/70.0)0.75 and V/F (l) = 374.2 × (WT/70) where WT is in kg. The values of CL/F and V/F in a 4 kg child would be 1.33 l h−1 and 21.4 l, respectively, resulting in an elimination half-life of 11.2 h. CONCLUSIONS The range of estimated CL/F in the study population was 0.67–7.38 l h−1. The data suggest that adjustment of K-canrenoate dosage according to body weight is appropriate in paediatric patients.

A novel concentration dependent amino acid ion pair strategy to mediate drug permeation using indomethacin as a model insoluble drug

Assessment of oral drug bioavailability is an important parameter for new chemical entities (NCEs) in drug development cycle. After evaluating the pharmacological response of these new molecules, the following critical stage is to investigate their in vitro permeability. Despite the great success achieved by prodrugs, covalent linking the drug molecule with a hydrophobic moiety might result in a new entity that might be toxic or ineffective. Therefore, an alternative that would improve the drug uptake without affecting the efficacy of the drug molecule would be advantageous. The aim of the current study is to investigate the effect of ion-pairing on the permeability profile of a model drug: indomethacin (IND) to understand the mechanism behind the permeability improvement across Caco-2 monolayers. Arginine and lysine formed ion-pairs with IND at various molar ratios 1:1, 1:2, 1:4 and 1:8 as reflected by the double reciprocal graphs. The partitioning capacities of the IND were evaluated using octanol/water partitioning studies and the apparent permeabilities (P app) were measured across Caco-2 monolayers for the different formulations. Partitioning studies reflected the high hydrophobicity of IND (Log P = 3) which dropped upon increasing the concentrations of arginine/lysine in the ion pairs. Nevertheless, the prepared ion pairs improved IND permeability especially after 60 min of the start of the experiment. Coupling partitioning and permeability results suggest a decrease in the passive transcellular uptake due to the drop in IND portioning capacities and a possible involvement of active carriers. Future work will investigate which transport gene might be involved in the absorption of the ion paired formulations using molecular biology technologies. © 2014 Elsevier B.V. All rights reserved.

Is the French model giving way to a new 'Logic of Appropriateness'? Lessons from urban waste management

Processes of European integration and growing consumer scrutiny of public services have served to place the spotlight on the traditional French model of public/private interaction in the urban services domain. This article discusses recent debates within France of the institutionalised approach to local public/private partnership, and presents case study evidence from three urban agglomerations of a possible divergence from this approach. Drawing on the work of French academic, Dominique Lorrain, whose historical institutionalist accounts of the French model are perhaps the most comprehensive and best known, the article develops two hypotheses of institutional change, one from the historical institutionalist perspective of institutional stability and persistence, and the other from an explicitly sociological perspective, which emphasises the legitimating benefits of following appropriate rules of conduct. It argues that further studying the French model as an institution offers valuable empirical insight into processes of institutional change and persistence. © 2004 Taylor & Francis Ltd.

Aminoglutethimide-induced leucopenia in a mouse model:effects of metabolic and structural determinates

A model of human leucopenia has been developed further in the female mouse. Following daily administration to female mice of 50 mg/kg of the aromatase inhibitor aminoglutethimide, significant falls in platelet and white cell counts occurred after 2 and 3 weeks. At week 4, drug dosage was stopped and the cell counts recovered at the end of that week, although on rechallenge at the beginning of week 5, both platelet and white cell counts fell rapidly. Administration to the mice of structural analogues of aminoglutethimide, such as WSP-3, glutethimide and 4-nitroglutethimide, showed no reductions in platelet and white cell counts. The haemotoxicity of aminoglutethimide over 21 days was unaffected by the presence of either the P-450 inhibitor SKF-525A or the hepatic P-450 inducer phenobarbitone. However, the co-administration of cimetidine abolished the haemotoxicity of aminoglutethimide in terms of platelet and white cell levels. In in vitro studies, both aminoglutethimide and WSP-3 were oxidised to cytotoxic species, although aminoglutethimide was significantly more cytotoxic than WSP-3. The NADPH-dependent covalent binding of 14C aminoglutethimide to mouse microsomes in vitro was significantly reduced by the presence of cimetidine. The activation of the compound to reactive species in vitro, the inhibitory effects of cimetidine in vivo and in vitro, as well as the rapid fall in the in vivo white cell count on rechallenge with aminoglutethimide suggest that this model illustrates a form of leucopenia which may be related to hapten formation and subsequent immune-mediated platelet and white cell lysis. © 2003 Elsevier B.V. All rights reserved.

The MIMIC model and formative variables:problems and solutions

The use of the multiple indicators, multiple causes model to operationalize formative variables (the formative MIMIC model) is advocated in the methodological literature. Yet, contrary to popular belief, the formative MIMIC model does not provide a valid method of integrating formative variables into empirical studies and we recommend discarding it from formative models. Our arguments rest on the following observations. First, much formative variable literature appears to conceptualize a causal structure between the formative variable and its indicators which can be tested or estimated. We demonstrate that this assumption is illogical, that a formative variable is simply a researcher-defined composite of sub-dimensions, and that such tests and estimates are unnecessary. Second, despite this, researchers often use the formative MIMIC model as a means to include formative variables in their models and to estimate the magnitude of linkages between formative variables and their indicators. However, the formative MIMIC model cannot provide this information since it is simply a model in which a common factor is predicted by some exogenous variables—the model does not integrate within it a formative variable. Empirical results from such studies need reassessing, since their interpretation may lead to inaccurate theoretical insights and the development of untested recommendations to managers. Finally, the use of the formative MIMIC model can foster fuzzy conceptualizations of variables, particularly since it can erroneously encourage the view that a single focal variable is measured with formative and reflective indicators. We explain these interlinked arguments in more detail and provide a set of recommendations for researchers to consider when dealing with formative variables.

Energy-efficient multihop cooperative MISO transmission with optimal hop distance in wireless ad hoc networks

In this paper, we investigate the hop distance optimization problem in ad hoc networks where cooperative multiinput- single-output (MISO) is adopted to improve the energy efficiency of the network. We first establish the energy model of multihop cooperative MISO transmission. Based on the model, the energy consumption per bit of the network with high node density is minimized numerically by finding an optimal hop distance, and, to get the global minimum energy consumption, both hop distance and the number of cooperating nodes around each relay node for multihop transmission are jointly optimized. We also compare the performance between multihop cooperative MISO transmission and single-input-single-output (SISO) transmission, under the same network condition (high node density). We show that cooperative MISO transmission could be energyinefficient compared with SISO transmission when the path-loss exponent becomes high. We then extend our investigation to the networks with varied node densities and show the effectiveness of the joint optimization method in this scenario using simulation results. It is shown that the optimal results depend on network conditions such as node density and path-loss exponent, and the simulation results are closely matched to those obtained using the numerical models for high node density cases.

A low mortality, high morbidity Reduced Intensity Status Epilepticus (RISE) model of epilepsy and epileptogenesis in the rat

Animal models of acquired epilepsies aim to provide researchers with tools for use in understanding the processes underlying the acquisition, development and establishment of the disorder. Typically, following a systemic or local insult, vulnerable brain regions undergo a process leading to the development, over time, of spontaneous recurrent seizures. Many such models make use of a period of intense seizure activity or status epilepticus, and this may be associated with high mortality and/or global damage to large areas of the brain. These undesirable elements have driven improvements in the design of chronic epilepsy models, for example the lithium-pilocarpine epileptogenesis model. Here, we present an optimised model of chronic epilepsy that reduces mortality to 1% whilst retaining features of high epileptogenicity and development of spontaneous seizures. Using local field potential recordings from hippocampus in vitro as a probe, we show that the model does not result in significant loss of neuronal network function in area CA3 and, instead, subtle alterations in network dynamics appear during a process of epileptogenesis, which eventually leads to a chronic seizure state. The model’s features of very low mortality and high morbidity in the absence of global neuronal damage offer the chance to explore the processes underlying epileptogenesis in detail, in a population of animals not defined by their resistance to seizures, whilst acknowledging and being driven by the 3Rs (Replacement, Refinement and Reduction of animal use in scientific procedures) principles.

Perception of global image contrast is predicted by the same spatial integration model of gain control as detection and discrimination

How are the image statistics of global image contrast computed? We answered this by using a contrast-matching task for checkerboard configurations of ‘battenberg’ micro-patterns where the contrasts and spatial spreads of interdigitated pairs of micro-patterns were adjusted independently. Test stimuli were 20 × 20 arrays with various sized cluster widths, matched to standard patterns of uniform contrast. When one of the test patterns contained a pattern with much higher contrast than the other, that determined global pattern contrast, as in a max() operation. Crucially, however, the full matching functions had a curious intermediate region where low contrast additions for one pattern to intermediate contrasts of the other caused a paradoxical reduction in perceived global contrast. None of the following models predicted this: RMS, energy, linear sum, max, Legge and Foley. However, a gain control model incorporating wide-field integration and suppression of nonlinear contrast responses predicted the results with no free parameters. This model was derived from experiments on summation of contrast at threshold, and masking and summation effects in dipper functions. Those experiments were also inconsistent with the failed models above. Thus, we conclude that our contrast gain control model (Meese & Summers, 2007) describes a fundamental operation in human contrast vision.

Improving energy efficiency in a wireless sensor network by combining cooperative MIMO with data aggregation

In wireless sensor networks where nodes are powered by batteries, it is critical to prolong the network lifetime by minimizing the energy consumption of each node. In this paper, the cooperative multiple-input-multiple-output (MIMO) and data-aggregation techniques are jointly adopted to reduce the energy consumption per bit in wireless sensor networks by reducing the amount of data for transmission and better using network resources through cooperative communication. For this purpose, we derive a new energy model that considers the correlation between data generated by nodes and the distance between them for a cluster-based sensor network by employing the combined techniques. Using this model, the effect of the cluster size on the average energy consumption per node can be analyzed. It is shown that the energy efficiency of the network can significantly be enhanced in cooperative MIMO systems with data aggregation, compared with either cooperative MIMO systems without data aggregation or data-aggregation systems without cooperative MIMO, if sensor nodes are properly clusterized. Both centralized and distributed data-aggregation schemes for the cooperating nodes to exchange and compress their data are also proposed and appraised, which lead to diverse impacts of data correlation on the energy performance of the integrated cooperative MIMO and data-aggregation systems.

The MG Rover closure and policy response: an evaluation of the Task Force model in the UK

In recent years there have been a number of high-profile plant closures in the UK. In several cases, the policy response has included setting up a task force to deal with the impacts of the closure. It can be hypothesised that task force involving multi-level working across territorial boundaries and tiers of government is crucial to devising a policy response tailored to people's needs and to ensuring success in dealing with the immediate impacts of a closure. This suggests that leadership, and vision, partnership working and community engagement, and delivery of high quality services are important. This paper looks at the case of the MG Rover closure in 2005, to examine the extent to which the policy response to the closure at the national, regional and local levels dealt effectively with the immediate impacts of the closure, and the lessons that can be learned from the experience. Such lessons are of particular relevance given the closure of the LDV van plant in Birmingham in 2009 and more broadly – such as in the case of the downsizing of the Opel operation in Europe following its takeover by Magna.