Influence of Plasma Protein Binding on Pharmacodynamics: Estimation of In Vivo Receptor Affinities of beta Blockers Using a New Mechanism-Based PK-PD Modelling Approach

The objective of this investigation was to examine in a systematic manner the influence of plasma protein binding on in vivo pharmacodynamics. Comparative pharmacokinetic-pharmacodynamic studies with four beta blockers were performed in conscious rats, using heart rate under isoprenaline-induced tachycardia as a pharmacodynamic endpoint. A recently proposed mechanism-based agonist-antagonist interaction model was used to obtain in vivo estimates of receptor affinities (K(B),(vivo)). These values were compared with in vitro affinities (K(B),(vitro)) on the basis of both total and free drug concentrations. For the total drug concentrations, the K(B),(vivo) estimates were 26, 13, 6.5 and 0.89 nM for S(-)-atenolol, S(-)-propranolol, S(-)-metoprolol and timolol. The K(B),(vivo) estimates on the basis of the free concentrations were 25, 2.0, 5.2 and 0.56 nM, respectively. The K(B),(vivo)-K(B),(vitro) correlation for total drug concentrations clearly deviated from the line of identity, especially for the most highly bound drug S(-)-propranolol (ratio K(B),(vivo)/K(B),(vitro) similar to 6.8). For the free drug, the correlation approximated the line of identity. Using this model, for beta-blockers the free plasma concentration appears to be the best predictor of in vivo pharmacodynamics. (C) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3816-3828, 2009

Using multidimensional projection techniques for reaching a high distinguishing ability in biosensing

Recent advances in the control of molecular engineering architectures have allowed unprecedented ability of molecular recognition in biosensing, with a promising impact for clinical diagnosis and environment control. The availability of large amounts of data from electrical, optical, or electrochemical measurements requires, however, sophisticated data treatment in order to optimize sensing performance. In this study, we show how an information visualization system based on projections, referred to as Projection Explorer (PEx), can be used to achieve high performance for biosensors made with nanostructured films containing immobilized antigens. As a proof of concept, various visualizations were obtained with impedance spectroscopy data from an array of sensors whose electrical response could be specific toward a given antibody (analyte) owing to molecular recognition processes. In addition to discussing the distinct methods for projection and normalization of the data, we demonstrate that an excellent distinction can be made between real samples tested positive for Chagas disease and Leishmaniasis, which could not be achieved with conventional statistical methods. Such high performance probably arose from the possibility of treating the data in the whole frequency range. Through a systematic analysis, it was inferred that Sammon`s mapping with standardization to normalize the data gives the best results, where distinction could be made of blood serum samples containing 10(-7) mg/mL of the antibody. The method inherent in PEx and the procedures for analyzing the impedance data are entirely generic and can be extended to optimize any type of sensor or biosensor.

MULTIDIMENSIONAL SCALING OF MUSICAL TIME ESTIMATIONS

The aim of this study was to identify the psycho-musical factors that govern time evaluation in Western music from baroque, classic, romantic, and modern repertoires. The excerpts were previously found to represent variability in musical properties and to induce four main categories of emotions. 48 participants (musicians and nonmusicians) freely listened to 16 musical excerpts (lasting 20 sec. each) and grouped those that seemed to have the same duration. Then, participants associated each group of excerpts to one of a set of sine wave tones varying in duration from 16 to 24 sec. Multidimensional scaling analysis generated a two-dimensional solution for these time judgments. Musical excerpts with high arousal produced an overestimation of time, and affective valence had little influence on time perception. The duration was also overestimated when tempo and loudness were higher, and to a lesser extent, timbre density. In contrast, musical tension had little influence.

Modelling congenital transmission of Chagas` disease

The successful elimination of vectorial and transfusional transmission of Chagas` disease from some countries is a result of the reduction of domestic density of the primary vector Triatoma infestans, of almost 100% of coverage in blood serological selection and to the fact that the basic reproductive number of Chagas` disease is very close to one (1.25). Therefore, congenital transmission is currently the only way of acquiring Chagas` Disease in such regions. In this paper we propose a model of congenital transmission of Chagas` disease. Its aim is to provide an estimation of the time period it will take to eliminate this form of transmission in regions where vetorial transmission was reduced to close to zero, like in Brazil. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Modelling the control strategies against dengue in Singapore

Notified cases of dengue infections in Singapore reached historical highs in 2004 (9459 cases) and 2005 (13 817 cases) and the reason for such all increase is still to be established. We apply a mathematical model for dengue infection that takes into account the seasonal variation in incidence, characteristic of dengue fever, and which mimics the 2004-2005 epidemics in Singapore. We simulated a set of possible control strategies and confirmed the intuitive belief that killing adult mosquitoes is the most effective strategy to control an ongoing epidemic. On the other hand, the control of immature forms was very efficient ill preventing the resurgence of dengue epidemics. Since the control of immature forms allows the reduction of adulticide, it seems that the best strategy is to combine both adulticide and larvicide control measures during an outbreak, followed by the maintenance of larvicide methods after the epidemic has subsided. In addition, the model showed that the mixed strategy of adulticide and larvicide methods introduced by the government seems to be very effective in reducing the number of cases in the first weeks after the start of control.