Entity

Time filter

Source Type


Abdel-Hafez S.M.,Ain Shams University | Hathout R.M.,Ain Shams University | Hathout R.M.,Leiden Amsterdam Center for Drug Research | Sammour O.A.,Ain Shams University
International Journal of Biological Macromolecules | Year: 2014

The aim of this study is to utilize statistical designs and mathematical modeling to end the continuous debate about the different variables that influence the production of nanoparticles using the ionic gelation method between the biopolymer chitosan (CS) and tripolyphosphate (TPP) ion. Preliminary experiments were adopted to extract the optimum conditions for the nanoparticles preparation and model construction. Critical process parameters were screened using the one-factor-at-a-time (OFAT) approach to select optimum experimental regions. Finally, these factors were optimized using two different methods of response surface modeling; the Box-Behnken and the D-optimal. The significant models showed excellent fitting of the data. The two methods were validated using a set of check points and were subsequently compared. Good agreement between actual and predicted values was obtained though the D-optimal model was more successful in predicting the particle size of the prepared nanoparticles with percentage bias as small as 1.49%. Nanoparticles were produced with diameters ranging from 52.21. nm to 400.30. nm, particle polydispersity from 0.06 to 0.40 and suitable morphology. This work provides an overview on the production of chitosan nanoparticles with desirable size enabling their successful use in drugs delivery and targeting or in any nanotechnology or interfacial application. © 2013 Elsevier B.V. Source


Sahota T.,Glaxosmithkline | Pasqua O.D.,Glaxosmithkline | Pasqua O.D.,Leiden Amsterdam Center for Drug Research
Antimicrobial Agents and Chemotherapy | Year: 2012

Historically, dosing regimens for the treatment of tuberculosis (TB) have been proposed in an empirical manner. Dose selection has often been the result of efficacy trials in which drugs were administered regardless of the magnitude of the effect of demographic factors on drug disposition. This has created challenges for the prescription of fixed-dose combinations with novel therapeutic agents. The objectives of this investigation were to evaluate the impact of body weight on the overall systemic exposure to pyrazinamide (PZA) and to assess whether the use of one fixed dose, without adjustment according to weight, would ensure target exposure and safety requirements across the overall patient population. Using a population pharmacokinetic model, simulation scenarios were explored based on population demographics from clinical trials in TB patients and on historical hepato-toxicity data. The systemic drug exposure (area under the concentration-time curve [AUC]), peak concentrations (the maximum concentration of drug in serum [Cmax]), the time above the MIC (t > MIC), and the risk of hepatotoxicity were evaluated for the current weight-banded regimen and compared to fixed doses under the assumption that pharmacokinetic differences are the primary drivers of toxicity. Evaluation of the standard weight banding reveals that more than 50% of subjects in the weight range of 45 to 55 kg remain below the proposed target exposure to PZA. In contrast, the use of a fixed 1,500-mg dose resulted in a lower proportion of subjects under the target value, with a 0.2% average overall increase in the risk of hepatotoxicity. Our results strongly support the use of a fixed-dose regimen for PZA in coformulation or combination with novel therapeutic agents. Copyright © 2012, American Society for Microbiology. All Rights Reserved. Source


Ali S.,Leiden University | Champagne D.L.,Leiden University | Champagne D.L.,Leiden Amsterdam Center for Drug Research | Spaink H.P.,Leiden University | Richardson M.K.,Leiden University
Birth Defects Research Part C - Embryo Today: Reviews | Year: 2011

Technological innovation has helped the zebrafish embryo gain ground as a disease model and an assay system for drug screening. Here, we review the use of zebrafish embryos and early larvae in applied biomedical research, using selected cases. We look at the use of zebrafish embryos as disease models, taking fetal alcohol syndrome and tuberculosis as examples. We discuss advances in imaging, in culture techniques (including microfluidics), and in drug delivery (including new techniques for the robotic injection of compounds into the egg). The use of zebrafish embryos in early stages of drug safety-screening is discussed. So too are the new behavioral assays that are being adapted from rodent research for use in zebrafish embryos, and which may become relevant in validating the effects of neuroactive compounds such as anxiolytics and antidepressants. Readouts, such as morphological screening and cardiac function, are examined. There are several drawbacks in the zebrafish model. One is its very rapid development, which means that screening with zebrafish is analogous to "screening on a run-away train." Therefore, we argue that zebrafish embryos need to be precisely staged when used in acute assays, so as to ensure a consistent window of developmental exposure. We believe that zebrafish embryo screens can be used in the pre-regulatory phases of drug development, although more validation studies are needed to overcome industry scepticism. Finally, the zebrafish poses no challenge to the position of rodent models: it is complementary to them, especially in early stages of drug research. © 2011 Wiley-Liss, Inc. Source


Jaakola V.-P.,University of Oulu | IJzerman A.P.,Leiden Amsterdam Center for Drug Research
Current Opinion in Structural Biology | Year: 2010

G-protein-coupled receptors, GPCRs, are key elements in the vertebrate signal transduction system, and constitute the majority of drug targets. Solved 10 years ago, the crystal structure of inactive state rhodopsin with covalently linked cis-retinal as an inverse agonist provided the first near-atomic view of the GPCR architecture. The inherent instability and low abundance from both natural and recombinant sources are only two factors that long hampered a similar structure elucidation of other GPCRs that have diffusible ligands such as neurotransmitters and hormones. However, in the last three years this situation has changed with the advent of structures of the human adenosine A2A receptor, avian β1-adrenoceptor, human β2-adrenoceptor, squid rhodopsin and activated form of bovine (rhod)opsin. In this review the structural features of the human adenosine A2A receptor and the main differences with β-adrenoceptor and rhodopsin structures are highlighted. Furthermore, the implications of this structural information for drug screening and structure-based drug design will be discussed. © 2010 Elsevier Ltd. Source


Ali S.,Leiden University | Champagne D.L.,Leiden University | Champagne D.L.,Leiden Amsterdam Center for Drug Research | Alia A.,Leiden University | Richardson M.K.,Leiden University
PLoS ONE | Year: 2011

Background: In humans, ethanol exposure during pregnancy causes a spectrum of developmental defects (fetal alcohol syndrome or FAS). Individuals vary in phenotypic expression. Zebrafish embryos develop FAS-like features after ethanol exposure. In this study, we ask whether stage-specific effects of ethanol can be identified in the zebrafish, and if so, whether they allow the pinpointing of sensitive developmental mechanisms. We have therefore conducted the first large-scale (>1500 embryos) analysis of acute, stage-specific drug effects on zebrafish development, with a large panel of readouts. Methodology/Principal Findings: Zebrafish embryos were raised in 96-well plates. Range-finding indicated that 10% ethanol for 1 h was suitable for an acute exposure regime. High-resolution magic-angle spinning proton magnetic resonance spectroscopy showed that this produced a transient pulse of 0.86% concentration of ethanol in the embryo within the chorion. Survivors at 5 days postfertilisation were analysed. Phenotypes ranged from normal (resilient) to severely malformed. Ethanol exposure at early stages caused high mortality (≥88%). At later stages of exposure, mortality declined and malformations developed. Pharyngeal arch hypoplasia and behavioral impairment were most common after prim-6 and prim-16 exposure. By contrast, microphthalmia and growth retardation were stage-independent. Conclusions: Our findings show that some ethanol effects are strongly stage-dependent. The phenotypes mimic key aspects of FAS including craniofacial abnormality, microphthalmia, growth retardation and behavioral impairment. We also identify a critical time window (prim-6 and prim-16) for ethanol sensitivity. Finally, our identification of a wide phenotypic spectrum is reminiscent of human FAS, and may provide a useful model for studying disease resilience. © 2011 Ali et al. Source

Discover hidden collaborations