Propagation of Population Pharmacokinetic Information Using a Bayesian Approach: Comparison with Meta-Analysis

We investigated the propagation of population pharmacokinetic information across clinical studies by applying Bayesian techniques. The aim was to summarize the population pharmacokinetic estimates of a study in appropriate statistical distributions in order to use them as Bayesian priors in consequent population pharmacokinetic analyses. Various data sets of simulated and real clinical data were fitted with WinBUGS, with and without informative priors. The posterior estimates of fittings with non-informative priors were used to build parametric informative priors and the whole procedure was carried on in a consecutive manner. The posterior distributions of the fittings with informative priors where compared to those of the meta-analysis fittings of the respective combinations of data sets. Good agreement was found, for the simulated and experimental datasets when the populations were exchangeable, with the posterior distribution from the fittings with the prior to be nearly identical to the ones estimated with meta-analysis. However, when populations were not exchangeble an alternative parametric form for the prior, the natural conjugate prior, had to be used in order to have consistent results. In conclusion, the results of a population pharmacokinetic analysis may be summarized in Bayesian prior distributions that can be used consecutively with other analyses. The procedure is an alternative to meta-analysis and gives comparable results. It has the advantage that it is faster than the meta-analysis, due to the large datasets used with the latter and can be performed when the data included in the prior are not actually available.     

Modeling and Monte Carlo simulations in oral drug absorption

Drug dissolution, release and uptake are the principal components of oral drug absorption. All these processes take place in the complex milieu of the gastrointestinal tract and they are influenced by physiological (e.g. intestinal pH, transit time) and physicochemical factors (e.g. dose, particle size, solubility, permeability). Due to the enormous complexity issues involved, the models developed for drug dissolution and release attempt to capture their heterogeneous features. Hence, Monte Carlo simulations and population methods have been utilized since both dissolution and release processes are considered as time evolution of a population of drug molecules moving irreversibly from the solid state to the solution. Additionally, mathematical models have been proposed to determine the effect of the physicochemical properties, solubility/dose ratio and permeability on the extent of absorption for regulatory purposes, e.g. biopharmaceutics classification. The regulatory oriented approaches are based on the tube model of the intestinal lumen and apart from the drug's physicochemical properties, take into account the formulation parameters the dose and the particle size.     

Phytoplankton community in a recreational fishing lake, Brazil

OBJECTIVE: The assessment of water quality and phytoplankton community in recreational environments allows to setting management programs aiming at preventing potential harm to human health. The purpose of the present study was to describe phytoplankton seasonal changes in a freshwater system and their relation to water quality. METHODS: The recreational fishing lake is located in the southern area of the city of S?o Paulo, Brazil. Water samples were collected in three previously selected sites in the lake throughout a year and analyzed regarding floristic composition and physical and chemical parameters. RESULTS: The phytoplankton qualitative analysis revealed 91 taxa distributed among eight classes: Chlorophyceae, Cyanophyceae, Euglenophyceae, Zygnemaphyceae, Bacillariophyceae, Xantophyceae, Dinophyceae, and Chrysophyceae. Some physical and chemical parameters seemed to influence phytoplankton community behavior. Chlorophyceae development was favored by local conditions. Among the species of cyanobacteria identified, Microcystis paniformis, Cylindrospermopsis raciborskii, and Anabaena species were the most important due to their ability to produce toxins, posing a high risk to public health. CONCLUSIONS: Some physical and chemical parameters had an impact on the structure of phytoplankton community. The presence of Microcystis paniformis, Cylindrospermopsis raciborskii and Anabaena species indicates toxic potential and likelihood of public health problems unless there is constant monitoring. Further studies are recommended to prevent hazardous effects to the environment and public health.     

The Mean Dissolution Time Depends on the Dose/Solubility Ratio

Purpose. To investigate the relationship between mean dissolution time (MDT) and dose/solubility ratio (q) using the diffusion layer model. Methods. Using the classic Noyes-Whitney equation and considering a finite dose, we derived an expression for MDT as a function of q under various conditions. q was expressed as a dimensionless quantity by taking into account the volume of the dissolution medium. Our results were applied to in vitro and in vivo data taken from literature. Results. We found that MDT depends on q when q > 1 and is infinite when q > 1 and that the classic expression of MDT = 1/k, where k is the dissolution rate constant, holds only in the special case of q = 1. For the case of perfect sink conditions, MDT was found to be proportional to dose. Using dissolution data from literature with q < 1, we found better estimates of MDT when dependency on dose/solubility ratio was considered than with the classic approach. Prediction of dissolution limited absorption was achieved for some of the in vivo drug examples examined. Conclusion. The mean dissolution time of a drug depends on dose/solubility ratio, even when the model considered is the simplest possible. This fact plays an important role in drug absorption when absorption is dissolution limited.     

Population depletion activates autonomous CD154-dependent survival in biopsylike Burkitt lymphoma cells

Population size is governed through cells reacting to a variety of intrinsic and extrinsic cues. Tumors, while liberated from many of the homeostatic constraints placed on physiologic counterparts, can nonetheless remain subject to both social and environmental control. Burkitt lymphoma cells faithful to the biopsy phenotype were used to model the reliance of the colony, if any, on an inbuilt population sensor. Below a normally suicidal threshold number of cells, low picomolar quantities of exogenous CD40 ligand (CD40L/CD154) were found to sustain the clone without the discernible shift in phenotype that accompanies high CD40L encounter. Although CD154 was undetectable in populous cultures, message was induced as numbers became limiting. Correspondingly, attempts to neutralize endogenous CD40L activity failed to perturb cells at optimal densities but resulted in their marked decline as the critical threshold was approached. These data reveal an auto-inducible survival mechanism seemingly regulated through the monitoring of population size, a process somewhat akin to that of "quorum sensing" among gram-negative bacteria in which diffusible molecules provide a means of communication to coordinate gene expression with population density. This process could be activated as cells discern depletions in their community or when deprived of signals otherwise furnished within an appropriate environmental niche.