The pharmacokinetics of the interstitial space in humans

BACKGROUND: The pharmacokinetics of extracellular solutes is determined by the blood-tissue exchange kinetics and the volume of distribution in the interstitial space in the different organs. This information can be used to develop a general physiologically based pharmacokinetic (PBPK) model applicable to most extracellular solutes. METHODS: The human pharmacokinetic literature was surveyed to tabulate the steady state and equilibrium volume of distribution of the solutes mannitol, EDTA, morphine-6-glucuronide, morphine-3-glucuronide, inulin and β-lactam antibiotics with a range of protein binding (amoxicillin, piperacillin, cefatrizine, ceforanide, flucloxacillin, dicloxacillin). A PBPK data set was developed for extracellular solutes based on the literature for interstitial organ volumes. The program PKQuest was used to generate the PBPK model predictions. The pharmacokinetics of the protein (albumin) bound β-lactam antibiotics were characterized by two parameters: 1) the free fraction of the solute in plasma; 2) the interstitial albumin concentration. A new approach to estimating the capillary permeability is described, based on the pharmacokinetics of the highly protein bound antibiotics. RESULTS: About 42% of the total body water is extracellular. There is a large variation in the organ distribution of this water – varying from about 13% of total tissue water for skeletal muscle, up to 70% for skin and connective tissue. The weakly bound antibiotics have flow limited capillary-tissue exchange kinetics. The highly protein bound antibiotics have a significant capillary permeability limitation. The experimental pharmacokinetics of the 11 solutes is well described using the new PBPK data set and PKQuest. CONCLUSIONS: Only one adjustable parameter (systemic clearance) is required to completely characterize the PBPK for these extracellular solutes. Knowledge of just this systemic clearance allows one to predict the complete time course of the absolute drug concentrations in the major organs. PKQuest is freely available

Estas son algunas de las habilidades blandas demandadas en Colombia

Este producto forma parte de una serie de infografías de divulgación científica que buscan reseñar algunas de las investigaciones más importantes en las que ha tenido participación la Universidad EAFIT, publicadas en las revistas especializadas más prestigiosas del mund

Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management. Scientific Steering Committee on behalf of the Simon Broome Register Group.

Clinical management of heterozygous familial hypercholesterolaemia is largely based on evidence from a small number of observational studies and extrapolation from the results of clinical trials of lipid-lowering in patients with polygenic hypercholesterolaemia The objectives of this study were (i) to determine the absolute and relative mortality of patients with treated heterozygous familial hypercholesterolaemia, (ii) to estimate the effect of changes in treatment efficacy on mortality trends over time, and (iii) to examine the implications of these findings for patient management. A cohort of 605 men and 580 women aged 20-79 years with heterozyous familial hypercholesterolaemia were recruited from 21 out-patient lipid clinics in the UK. Patients were followed prospectively from 1980 to 1995 for 8770 person-years. Absolute mortality was calculated, and relative risk was expressed as the ratio of the number of observed deaths to the number expected in the general population of England and Wales. Forty six of the 73 deaths were due to coronary heart disease. In women aged 20-39, despite treatment, the relative risk of a fatal coronary event was increased 125-fold (95% confidence intervals 15-451) and the annual coronary mortality was 0.17%. In men aged 20-39 the relative risk was increased 48-fold (17-105) and the annual coronary mortality was 0.46%. The relative risk decreased with age but the absolute risk increased. For men and women aged 60-79, the annual coronary mortality was 1.1% representing a significant excess mortality for women (relative risk 2.6, 1.3-4.5) but not for men (RR 1.1, 0.5-2.3). Non-coronary mortality was not increased at any age (RR for all ages 0.68, 0.45-0.99). There was a decline in the relative risk for coronary mortality in patients aged 20-59 from an eight-fold (4.8-7.2) increased risk before 1992 to 3.7 (1.6-7.2.) thereafter (P=0.08). The results suggest that the prognosis for patients with heterozygous familial hypercholesterolaemia has improved with the introduction of more effective treatment, and that lipid-lowering therapy is not associated with increased non-coronary mortality. These findings and the excess coronary mortality observed suggest that all affected adult men and post-menopausal women should be treated with HMG-CoA reductase inhibitors

A project for assessing public management competencies

From 2017 onwards, the Italian National School of Administration (SNA) launched innovative activities to measure and assess the competencies of senior executives, managers, and officials of central administrations. In particular, it designed an experimental path to identify a “protocol” to read and evaluate the individual and collective competencies of Public Administration (PA) managers. This pilot study involved 51 first- and second-level senior managers of the Presidency of the Council of Ministers (PCM), where the positions, the competencies necessary to cover them, and the competencies actually possessed by the individual managers were assessed. The comparison between necessary and available competencies rendered it possible to identify individual development spaces and organizational development paths. This chapter presents and critically interprets the action-research project, jointly launched by the Italian Prime Minister’s Office and the Italian SNA, entitled “Analysis, Evaluation and Strengthening of Managerial Competencies in the Italian Presidency of the Council of Ministers”. The main aim of the project was to assess the competencies of a sample of public managers working at the Italian PCM in order to redesign the ideal profiles their roles require. A team of experts were involved, including human resources scholars and psychologists, and a multi-method approach based on individual interviews and assessment was adopted. This project was conceived as a pilot for a possible subsequent broader intervention; it may also be considered an essential prerequisite for designing appropriate development and training paths in a differentiated and targeted manner, as well as fostering a process of constant development of strategic managerial competencies