Concepts for increasing gentamicin release from handmade bone cement beads

Background and purpose Commercial gentamicin-loaded bone cement beads (Septopal) constitute an effective delivery system for local antibiotic therapy. These beads are not available in all parts of the world, and are too expensive for frequent use in others. Thus, orthopedic surgeons worldwide make antibiotic-loaded beads themselves. However, these beads are usually not as effective as the commercial beads because of inadequate release kinetics. Our purpose was to develop a simple, cheap, and effective formulation to prepare gentamicin-loaded beads with release properties and antibacterial efficacy similar to the commercially ones. Methods Acrylic beads were prepared with variable monomer content: 100% (500 μL/g polymer), 75%, and 50% to increase gentamicin release through creation of a less dense polymer matrix. Using the optimal monomer content, different gel-forming polymeric fillers were added to enhance the permeation of fluids into the beads. Polyvinylpyrrolidone (PVP) 17 was selected as a suitable filler; its concentration was varied and the antibiotic release and antibacterial efficacy of these beads were compared with the corresponding properties of the commercial ones. Results Gentamicin release rate and the extent of release from beads prepared with 50% monomer increased when the PVP17 content was increased. Beads with 15 w/w% PVP17 released 87% of their antibiotic content. This is substantially more than the gentamicin release from Septopal beads (59%). Acrylic beads with 15 w/w% PVP17 reduced bacterial growth by up to 93%, which is similar to the antibacterial properties of the commercial ones. Interpretation A simple, cheap, and effective formulation and preparation process has been described for hand-made gentamicin-releasing acrylic beads, with better release kinetics and with antibacterial efficacy similar to that of the commercial ones

Accepting higher morbidity in exchange for sacrificing fewer animals in studies developing novel infection-control strategies.

Preventing bacterial infections from becoming the leading cause of death by the year 2050 requires the development of novel, infection-control strategies, building heavily on biomaterials science, including nanotechnology. Pre-clinical (animal) studies are indispensable for this development. Often, animal infection outcomes bear little relation to human clinical outcome. Here, we review conclusions from pathogen-inoculum dose-finding pilot studies for evaluation of novel infection-control strategies in murine models. Pathogen-inoculum doses are generally preferred that produce the largest differences in quantitative infection outcome parameters between a control and an experimental group, without death or termination of animals due to having reached an inhumane end-point during the study. However, animal death may represent a better end-point for evaluation than large differences in outcome parameters or number of days over which infection persists. The clinical relevance of lower pre-clinical outcomes, such as bioluminescence, colony forming units (CFUs) retrieved or more rapid clearance of infection is unknown, as most animals cure infection without intervention, depending on pathogen-species and pathogen-inoculum dose administered. In human clinical practice, patients suffering from infection present to hospital emergency wards, frequently in life-threatening conditions. Animal infection-models should therefore use prevention of death and recurrence of infection as primary efficacy targets to be addressed by novel strategies. To compensate for increased animal morbidity and mortality, animal experiments should solely be conducted for pre-clinical proof of principle and safety. With the advent of sophisticated in vitro models, we advocate limiting use of animal models when exploring pathogenesis or infection mechanisms

Development of a zero-order sustained-release tablet containing mesalazine and budesonide intended to treat the distal gastrointestinal tract in inflammatory bowel disease

Ulcerative colitis (UC) and Crohn's disease (CD) are diseases affecting the gastrointestinal tract. Treatment depends on the severity of the disease, site of inflammation, and patient's response. The aim of this study was to develop a zero-order sustained-release tablet containing both the anti-inflammatory drugs mesalazine and budesonide as a new treatment option for ileo-colonic CD and UC. Tablets were attained by wet granulation with hydroxypropyl methylcellulose and direct compression. Our newly developed tablet core was coated with different ColoPulse (R) coating thicknesses and the mesalazine and budesonide release profiles were investigated in a 600-min gastrointestinal simulation system (GISS) experiment, together with commercially available MMX (R)-mesalazine and MMX (R)-budesonide. Lag-time, release rate (k(0)), completeness of release, and zero-order correlation coefficient (R-0(2)) could be manipulated by varying ColoPulse (R) coating thickness. Our newly developed combination preparation (C[4.92]) complied with all conducted European Pharmacopoeia tests as well as an accelerated 6-month stability test and had a lag-time of 250 min (simulated ileum targeted), a linear release profile (mesalazine R-0(2) = 0.9002; budesonide R-0(2) = 0.9481), and drug release of 100% mesalazine and 77% budesonide. Like C[4.92], MMX (R)-mesalazine had a linear (R-0(2) = 0.9883) and complete release profile (96%). However, C[4.92] lag-time was longer (250 vs. 210 min), assuring simulated ileum specificity. Remarkably, MMX (R)-budesonide lag-time was 480 min and release was only 7% with a linear character (R-0(2) = 0.9906). The in vitro results suggest that MMX (R)-budesonide effectiveness may be improved if budesonide release in the aqueous phase would be increased and that C[4.92] is a potential, new treatment option for ileo-colonic CD and UC. (C) 2016 Elsevier B.V. All rights reserved

Marked Endotheliotropism of Highly Pathogenic Avian Influenza Virus H5N1 following Intestinal Inoculation in Cats

Highly pathogenic avian influenza virus (HPAIV) H5N1 can infect mammals via the intestine; this is unusual since influenza viruses typically infect mammals via the respiratory tract. The dissemination of HPAIV H5N1 following intestinal entry and associated pathogenesis are largely unknown. To assess the route of spread of HPAIV H5N1 to other organs and to determine its associated pathogenesis, we inoculated infected chicken liver homogenate directly into the intestine of cats by use of enteric-coated capsules. Intestinal inoculation of HPAIV H5N1 resulted in fatal systemic disease. The spread of HPAIV H5N1 from the lumen of the intestine to other organs took place via the blood and lymphatic vascular systems but not via neuronal transmission. Remarkably, the systemic spread of the virus via the vascular system was associated with massive infection of endothelial and lymphendothelial cells, resulting in widespread hemorrhages. This is unique for influenza in mammals and resembles the pathogenesis of HPAIV infection in terrestrial poultry. It contrasts with the pathogenesis of systemic disease from the same virus following entry via the respiratory tract, where lesions are characterized mainly by necrosis and inflammation and are associated with the presence of influenza virus antigen in parenchymal, not endothelial cells. The marked endotheliotropism of the virus following intestinal inoculation indicates that the pathogenesis of systemic influenza virus infection in mammals may differ according to the portal of entry