BackgroundModelling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs. These approaches require reliable in vitro data for physicochemical properties, permeability, binding, intrinsic clearance and cytochrome P450 inhibition. This work was conducted to generate an in vitro data toolbox using standardized methods for a set of 45 anti-malarial drugs and to assess changes in physicochemical properties in relation to changing target product and candidate profiles.MethodsIonization constants were determined by potentiometric titration and partition coefficients were measured using a shake-flask method. Solubility was assessed in biorelevant media and permeability coefficients and efflux ratios were determined using Caco-2 cell monolayers. Binding to plasma and media proteins was measured using either ultracentrifugation or rapid equilibrium dialysis. Metabolic stability and cytochrome P450 inhibition were assessed using human liver microsomes. Sample analysis was conducted by LC–MS/MS.ResultsBoth solubility and fraction unbound decreased, and permeability and unbound intrinsic clearance increased, with increasing Log D7.4. In general, development compounds were somewhat more lipophilic than legacy drugs. For many compounds, permeability and protein binding were challenging to assess and both required the use of experimental conditions that minimized the impact of non-specific binding. Intrinsic clearance in human liver microsomes was varied across the data set and several compounds exhibited no measurable substrate loss under the conditions used. Inhibition of cytochrome P450 enzymes was minimal for most compounds.ConclusionsThis is the first data set to describe in vitro properties for 45 legacy and development anti-malarial drugs. The studies identified several practical methodological issues common to many of the more lipophilic compounds and highlighted areas which require more work to customize experimental conditions for compounds being designed to meet the new target product profiles. The dataset will be a valuable tool for malaria researchers aiming to develop PBPK models for the prediction of human PK properties and/or drug–drug interactions. Furthermore, generation of this comprehensive data set within a single laboratory allows direct comparison of properties across a large dataset and evaluation of changing property trends that have occurred over time with changing target product and candidate profiles.

Background: Fatty acid-binding proteins (FABPs) chaperone intracellular transport of lipophilic ligands. Results: FABP1 and FABP2 differentially promote drug activation of peroxisome proliferator-activated receptor ␣ (PPAR␣) via ligand-dependent protein-protein interactions. Conclusion: Drug activation of PPAR␣ is regulated by the presence of different FABPs. Significance: FABPs may act in a tissue-specific manner to enhance the selectivity of PPAR␣ agonists.

Soft tissue reconstructs require materials that form three-dimensional (3-D) structures supportive to cell proliferation and regenerative processes. Polysaccharides, due to their hydrophilicity, biocompatibility, biodegradability, abundance, and presence of derivatizable functional groups, are distinctive scaffold materials. Superior mechanical properties, physiological signaling, and tunable tissue response have been achieved through chemical modification of polysaccharides. Moreover, an appropriate formulation strategy enables spatial placement of the scaffold to a targeted site. With the advent of newer technologies, these preparations can be tailor-made for responding to alterations in temperature, pH, or other physiological stimuli. In this review, we discuss the developmental and biological aspects of scaffolds prepared from four polysaccharides, viz. alginic acid (ALG), chitosan (CHI), hyaluronic acid (HA), and dextran (DEX). Clinical studies on these scaffolds are also discussed.

This study showed shift to higher age of presentation, more number of dengue hemorrhagic fever and associated co-infections in children. The complications and mortality was low and platelet recovery time was not influenced by disease category.

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