Characterizing interregional differences in the rheological properties and composition of rat small intestinal mucus.

The mucus layer in the small intestine is generally regarded as a barrier to drug absorption. However, the mucus layer is a complex system, and presently, only a few studies have been conducted to elucidate its physicochemical properties. The current study hypothesizes that the mucus layer contains solubility-enhancing surfactants and thus might aid the oral absorption of poorly water-soluble drugs. Mucus was sampled from sections of the small intestine of fasted rats to analyze the rheological properties and determine the mucus pH and concentrations of proteins and endogenous surfactants, i.e., bile salts, polar lipids, and neutral lipids. The mucus layer in the two proximal sections of the small intestine exhibited different rheological properties such as higher zero-shear viscosity and lower loss tangent and higher protein concentrations compared to all subsequent sections of the small intestine. The pH of the mucus layer was stable at ~ 6.5 throughout most of the small intestine, but increased to 7.5 in the ileum. The bile salt concentrations increased from the duodenum (16.0 ± 2.2 mM) until the mid jejunum (55.1 ± 9.5 mM), whereas the concentrations of polar lipids and neutral lipids decreased from the duodenum (17.4 ± 2.2 mM and 37.8 ± 1.6 mM, respectively) until the ileum (4.8 ± 0.4 mM and 10.7 ± 1.1 mM, respectively). In conclusion, the mucus layer of the rat small intestine contains endogenous surfactants at levels that might benefit solubilization and absorption of orally administered poorly water-soluble drugs.

Assessing acute colitis induced by dextran sulfate sodium in rats and its impact on gastrointestinal fluids.

Dextran sulfate sodium (DSS) is commonly used to induce colitis in rats. While the DSS-induced colitis rat model can be used to test new oral drug formulations for the treatment of inflammatory bowel disease, the effect of the DSS treatment on the gastrointestinal tract has not been thoroughly characterized. Additionally, the use of different markers to assess and confirm successful induction of colitis is somewhat inconsistent. This study aimed to investigate the DSS model to improve the preclinical evaluation of new oral drug formulations. The induction of colitis was evaluated based on the disease activity index (DAI) score, colon length, histological tissue evaluation, spleen weight, plasma C-reactive protein, and plasma lipocalin-2. Furthermore, the study investigated how the DSS-induced colitis affected the luminal pH, lipase activity, and concentrations of bile salts, polar lipids, and neutral lipids. For all evaluated parameters, healthy rats were used as a reference. The DAI score, colon length, and histological evaluation of the colon were effective disease indicators in DSS-induced colitis rats, while spleen weight, plasma C-reactive protein, and plasma lipocalin-2 were not. The luminal pH of the colon and bile salt- and neutral lipid concentrations in regions of the small intestine were lower in DSS-induced rats compared to healthy rats. Overall, the colitis model was deemed relevant for investigating ulcerative colitis-specific formulations.

Impact of oral gavage technique of drug-containing microcontainers on the gastrointestinal transit and absorption in rats.

Oral gavage is the most common way to administer drug formulations orally to rats. Yet, the technique applied and its influence on gastrointestinal (GI) transit receive little attention. This study aims to investigate the impact of three oral gavage techniques on GI transit and drug absorption utilizing microcontainers (MCs). The MCs were filled with paracetamol and BaSO4 (1:1 w/w ratio), coated with Eudragit S100, and filled into size-9 gelatin capsules. An in vitro study confirmed the intactness of the coating, and the capsules were administered to rats with air, water, or a piston. X-ray imaging determined the locations of the MCs, and the corresponding plasma concentration of paracetamol established a correlation with the location. The fastest GI transit occurred with air-dosing, while water-dosing caused delayed gastric emptying for 3 h with non-quantifiable paracetamol absorption. Piston-dosed MCs were retained in the stomach for up to 1 h, though for 3 h in one rat. Air-dosing caused discomfort and stress in rats, thus limiting its ethical and physiological relevance. Water-dosing confined its use due to delayed gastric emptying. In conclusion, the oral gavage technique affected the GI transit of MCs and, consequently, drug absorption. Piston-dosing appeared to be the superior dosing technique.

MR arthrography of the shoulder; correlation with arthroscopy.

BACKGROUND: Shoulder dislocation is a common injury, particularly in the younger population. Common long-term sequelae include pain, recurrence, and shoulder arthritis. Immediate and correct diagnosis following shoulder dislocation is key to achieving optimum outcomes. Although magnetic resonance arthrography (MRA) is frequently used for diagnosing shoulder instabilities, arthroscopy is still considered the gold standard. PURPOSE: This study aims to compare the diagnostic value of arthroscopy and MRA of the shoulder joint. MATERIALS AND METHODS: This retrospective study estimates the sensitivity and specificity of MRA of the shoulder. Data from patients who had undergone shoulder MRA and subsequent arthroscopy during a 5-year period were retrospectively collected. Sensitivity and specificity were calculated using the arthroscopic findings as the gold standard. Moreover, diagnostic accuracy was estimated using McNemar's test. RESULTS: In total, 205 cases were included from which 372 pathological findings were uncovered during the arthroscopic procedures as opposed to 360 findings diagnosed from the MRA images. The glenoid labral tear was the most common finding reported by MRA and arthroscopy. For the detection of glenoid labral tears on MRA, the sensitivity was 0.955 but with eight missed lesions; the specificity was 0.679. Capsular tears, rotator cuff tears, and cartilage lesions proved the most difficult to correctly diagnose using MRA with sensitivities of 0.2, 0.346, and 0.366, respectively. CONCLUSIONS: With a sensitivity of 95%, MRA is a valuable diagnostic tool for assessing shoulder instabilities, particularly when diagnosing labral lesions, including bony and soft-tissue Bankart lesions. Sensitivities and specificities for other glenohumeral lesions are less convincing, however.

Hot punching for loading of biodegradable microcontainers with budesonide-Soluplus film.

Micro-reservoir based drug delivery systems have the potential to provide targeted drug release locally in the intestine, i.e. at the inflamed areas of the intestine of patients with inflammatory bowel disease (IBD). In this study, microcontainers with a diameter of 300 µm and a height of 100 µm, asymmetrical geometry and the possibility to provide unidirectional release, are fabricated in the biodegradable polymer poly-ɛ-caprolactone (PCL) using hot punching. As a first step towards local treatment of IBD, a novel method for loading of microcontainers with the corticosteroid budesonide is developed. For this purpose, a budesonide-Soluplus drug-polymer film is prepared by spin coating and loaded into the microcontainer reservoirs using hot punching. The processing parameters are optimized to achieve a complete loading of a large number of containers in a single step. A poly(lactic-co-glycolic acid) (PLGA) 50:50 lid is subsequently applied by spray coating. Solid-state characterization indicates that the drug is in an amorphous state in the drug-polymer films and the in vitro drug release profile showed a 68% release over 10 h. The results demonstrate that hot punching can be employed both as a production and loading method for PCL microcontainers with the perspective of local treatment of IBD.

X-ray Imaging for Gastrointestinal Tracking of Microscale Oral Drug Delivery Devices.

Microscale devices are promising tools to overcome specific challenges within oral drug delivery. Despite the availability of advanced high-quality imaging techniques, visualization and tracking of microscale devices in the gastrointestinal (GI) tract is still a challenge. This work explores the possibilities of applying planar X-ray imaging and computed tomography (CT) scanning for visualization and tracking of microscale devices in the GI tract of rats. Microcontainers (MCs) are an example of microscale devices that have shown great potential as an oral drug delivery system. Barium sulfate (BaSO4) loaded into the cavity of the MCs increases their overall X-ray contrast, which allows them to be easily tracked. The BaSO4-loaded MCs are quantitatively tracked throughout the entire GI tract of rats by planar X-ray imaging and visualized in 3D by CT scanning. The majority of the BaSO4-loaded MCs are observed to retain in the stomach for 0.5-2 h, enter the cecum after 3-4 h, and leave the cecum and colon 8-10 h post-administration. The imaging approaches can be adopted and used with other types of microscale devices when investigating GI behavior in, for example, preclinical trials and potential clinical studies.

Assessment of the analgesic dipyrone as a possible (anti)androgenic endocrine disruptor.

Mild analgesics have been associated with antiandrogenic effects, but there are no such studies on dipyrone, despite its high prevalence of use in many countries. We examined the production of steroid hormones in human H295R cells after exposure to dipyrone and two metabolites, 4-Methylaminoantipyrine (MAA) and 4-Aminoantipyrine (AA), as well as fetal testicular testosterone production in rats following maternal dipyrone exposure. Androgen agonistic/antagonistic effects were examined in vitro for dipyrone and its metabolites in the Yeast Androgen Screen (YAS) assay and in vivo for dipyrone through the Hershberger assay. In vitro we tested dipyrone, MAA, and AA (0.1-1000 µM) while in vivo we used dipyrone (50, 100, 200 mg/kg/day). In the H295R assay, dipyrone, MAA and AA reduced the production of androgens and corticosteroids. Testosterone was reduced at concentrations 4-13 times higher than the maximum plasma concentrations reported in humans for MAA and AA. No effects were observed in the fetal testosterone production assay. In the YAS and Hershberger assays, no androgen agonistic/antagonistic activities were observed. These results indicate that dipyrone and its metabolites do not interact with the androgen receptor, but have the potential to inhibit steroidogenesis, however only at concentrations that are not relevant under normal medical use.

Cross-sectional survey on the use and impact of the Danish national antibiotic use guidelines for companion animal practice.

BACKGROUND: The Danish antibiotic use guidelines for companion animal practice were published by the Danish Veterinary Association in 2012. Since then, national surveillance data indicate a 10% reduction in the total use of antibiotics for companion animals, particularly a marked reduction in the use of third generation cephalosporins. The aim of the study was to assess if and how the guidelines have impacted diagnostic and antibiotic prescription habits of the users, and to identify user perceived barriers to implementation. RESULTS: An online questionnaire was sent to all 882 members of the Danish Small Animal Veterinary Association in October 2015. The survey was completed by 151 veterinarians. Respondents most frequently consulted the recommendations on skin and urinary tract infections (UTI), and users generally reported a high degree of adherence to the recommendations. Sixty-five per cent indicated that the guidelines had influenced their habits in one or more of the areas being investigated, i.e. perioperative use of antibiotics, use of first line antibiotics for the treatment of pyoderma or UTI, and/or use of microbiological diagnostics. Perioperative use of antibiotics for clean surgeries was uncommon, irrespective of whether respondents had consulted the relevant recommendations or not. On the contrary, significant differences in the prescribing habits between guideline users and non-users were observed for pyoderma and UTI, suggesting an impact of the guidelines towards more prudent antimicrobial use. The diagnostic habits were examined in a subgroup of 63 guideline users. Of those, 19 and 39% reported frequent use of culture and susceptibility (C&S) testing prior to treating pyoderma and UTI respectively, whereas 68-84% reported C&S testing in the event of poor response to treatment or recurrence of infections. The main barriers for implementation of therapeutic recommendations were confidence in old prescribing practices and unavailability of recommended drugs. The main barriers for C&S testing were good experience with empiric treatment, and the owners' financial situation. CONCLUSIONS: The findings suggest a positive influence of the national antibiotic guidelines on prescription patterns among companion animal practitioners in Denmark. Sustained campaign activity is encouraged and should include promotion of bacteriological testing.