simulation

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Development of a Training Model for Small Animal Thoracocentesis and Chest Tube Thoracostomy

Julie A. Williamson and Robin M. Fio Rito

Training veterinary students to perform emergency procedures, such as thoracocentesis and chest tube thoracostomy, poses challenges in terms of providing adequate hands-on experience without compromising animal welfare. A small animal thoracocentesis and chest tube thoracostomy model has been developed, that allows repetitive practice in a safe, standardised environment. The model has been incorporated into a clinical skills laboratory, where students work through computerised case studies in small groups, performing thoracocentesis or chest tube thoracostomy where indicated during the case. Student feedback indicated a high degree of satisfaction with the model and the laboratory experience, high perceived value of the case studies in improving learning, and increased confidence to perform the procedures under supervision. This model can replace the use of live animals while students are practising these procedures, improving their technique, and learning the appropriate safeguards used to prevent
injuries such as pulmonary trauma.

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Designing Validation Studies More Efficiently According to the Modular Approach: Retrospective Analysis of the EPISKIN Test for Skin Corrosion

Sebastian Hoffmann and Thomas Hartung

It is claimed that the modular approach to validation, which involves seven independent modules, will make the assessment of test validity more flexible and more efficient. In particular, the aspects of between-laboratory variability and predictive capacity are formally separated. Here, the main advantage of the approach is to offer the opportunity for reduced labour, and thus to allow study designs to be more time efficient and cost effective. The impact of this separation was analysed by taking the ECVAM validation study on in vitro methods for skin corrosivity as an example of a successful validation study — two of its methods triggered new OECD test guidelines. Lean study designs, which reduced the number of tests required by up to 60%, were simulated with the original validation data for the EPISKIN™ model. By using resampling techniques, we were able to demonstrate the effects of the lean designs on three between-laboratory variability measures and on the predictive capacity in terms of sensitivity and specificity, in comparison with the original study. Overall, the study results, especially the levels of confidence, were only slightly affected by the lean designs that were modelled. It is concluded that the separation of the two modules is a promising way to speed-up prospective validation studies and to substantially reduce costs, without compromising study quality.
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The Automated, Accurate and Reproducible Determination of Steady-state Permeation Parameters from Percutaneous Permeation Data

Frank Niedorf, Elisabeth Schmidt and Manfred Kietzmann

Procedures for the in vitro determination of percutaneous permeation with Franz diffusion cells are widely accepted. However, the calculation of relevant endpoints, such as the steady-state flux (J) and the permeation coefficient (Papp), still depends on visual data inspection or an approximation of the steady-state flux as the maximum observed absorption rate. As both these approaches must be considered inappropriate, an automated and reproducible algorithm to analyse permeation data is presented. The method detects both lag-times and non-linear data resulting from substance accumulation in the acceptor compartment of static diffusion cells. It was evaluated by using simulated data, and data from experiments with caffeine and testosterone on bovine udder skin and human reconstituted epidermis (SkinEthic®), which represent model barriers with high and low barrier strengths, respectively. It was shown that the algorithm is a suitable method for the identification of steady-state ranges in permeation data. If used on data generated with appropriate experimental approaches, it is a reproducible and time-saving alternative to the visual analysis of diffusion data.
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Physiologically-based Simulation Modelling for the Reduction of Animal Use in the Discovery of Novel Pharmaceuticals

Simon Thomas

The global pharmaceutical industry is estimated to use close to 20 million animals annually, in in vivo studies which apply the results of fundamental biomedical research to the discovery and development of novel pharmaceuticals, or to the application of existing pharmaceuticals to novel therapeutic indications. These applications of in vivo experimentation include: a) the use of animals as disease models against which the efficacy of therapeutics can be tested; b) the study of the toxicity of those therapeutics, before they are administered to humans for the first time; and c) the study of their pharmacokinetics — i.e. their distribution throughout, and elimination from, the body. In vivo pharmacokinetic (PK) studies are estimated to use several hundred thousand animals annually. The success of pharmaceutical research currently relies heavily on the ability to extrapolate from data obtained in such in vivo studies to predict therapeutic behaviour in humans. Physiologically-based modelling has the potential to reduce the number of in vivo animal studies that are performed by the pharmaceutical industry. In particular, the technique of physiologically-based pharmacokinetic (PBPK) modelling is sufficiently developed to serve as a replacement for many in vivo PK studies in animals during drug discovery. Extension of the technique to incorporate the prediction of in vivo therapeutic effects and/or toxicity is less well-developed, but has potential in the longer-term to effect a significant reduction in animal use, and also to lead to improvements in drug discovery via the increased rationalisation of lead optimisation.
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