Metformin and cimetidine: Physiologically based pharmacokinetic modelling to investigate transporter mediated drug–drug interactions

Metformin is used as a probe for OCT2 mediated transport when investigating possible DDIs with new chemical entities. The aim of the current study was to investigate the ability of physiologically-based pharmacokinetic (PBPK) models to simulate the effects of OCT and MATE inhibition by cimetidine on metformin kinetics. PBPK models were developed, incorporating mechanistic kidney and liver sub-models for metformin (OCT and MATE substrate) and a mechanistic kidney sub-model for cimetidine. The models were used to simulate inhibition of the MATE1, MATE2-K, OCT1 and OCT2 mediated transport of metformin by cimetidine. Assuming competitive inhibition and using cimetidine Ki values determined in vitro, the predicted metformin AUC ratio was 1.0 compared to an observed value of 1.46. The observed AUC ratio could only be recovered with this model when the cimetidine Ki for OCT2 was decreased 1000-fold or the Ki's for both OCT1 and OCT2 were decreased 500- fold. An alternative description of metformin renal transport by OCT1 and OCT2, incorporating electrochemical modulation of the rate of metformin uptake together with 8–18-fold decreases in cimetidine Ki's for OCTs and MATEs, allowed recovery of the extent of the observed effect of cimetidine on metformin AUC. While the final PBPK model has limitations, it demonstrates the benefit of allowing for the complexities of passive permeability combined with active cellular uptake modulated by an electrochemical gradient and active efflu

Reverse Monte Carlo modeling of amorphous silicon

An implementation of the Reverse Monte Carlo algorithm is presented for the study of amorphous tetrahedral semiconductors. By taking into account a number of constraints that describe the tetrahedral bonding geometry along with the radial distribution function, we construct a model of amorphous silicon using the reverse monte carlo technique. Starting from a completely random configuration, we generate a model of amorphous silicon containing 500 atoms closely reproducing the experimental static structure factor and bond angle distribution and in improved agreement with electronic properties. Comparison is made to existing Reverse Monte Carlo models, and the importance of suitable constraints beside experimental data is stressed.Comment: 6 pages, 4 PostScript figure

Mineral nutrition of vegetable crops: XXV - Mineral nutrition of new zealand spinach plant (Tetragonia expansa Murr.)

The present work was carried out in order to study: a - the effect of omission and presence of the macronutrients and boron on the growth of the plants; b - deficiency symptoms of macronutrients, as well of boron; c - the effect of the deficiency of each nutrient on the chemical composition of the plants. Young spinach plants were grown in pots containing pure quartz sand. Several times a day the plants were irrigated by percolation with nutrient solutions. The treatments were: complete solution and deficient solution, in which each one of the macronutrients was omitted as well boron. Soon as the malnutrition symptoms appered, the plants were harvested and analysed chemically. - symptoms of malnutrition are easily observed for N, K, Ca and B. - symptoms of malnutrition for P, S and Mg are not easily identified. - the nutrient content, in dry matter, in deficient leaves and healthy leaves is:O trabalho teve como objetivo estudar alguns aspectos da nutrição mineral do espinafre (Tetragonia expansa Murr.) no que concerne: 1 - Efeitos da omissão dos macronutrientes e do boro, na obtenção de um quadro sintomatológico; 2 - Efeitos das carências na produção de matéria seca e composição química da planta. Mudas com trinta dias de idade foram transplantadas para soluções nutritivas carentes nos macronutrientes e/ou em boro. A coleta das plantas foi realizada quando os sintomas de deficiência se tornaram evidentes. No material seco procedeu-se a análise química. Os dados mostram que: 1 - os sintomas visuais de deficiência de N, K, Ca e B apresentam-se bem definidos; sendo que os de P, Mg e S são de difícil caracterização ; 2 - os teores dos nutrientes em plantas sadias e deficientes são

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries