Prospective assessment of the impact of intraoperative diuretics in kidney transplant recipient surgery.

BACKGROUND: The use of intraoperative diuretics, such as furosemide or mannitol, during kidney transplantation has been suggested to reduce the rate of delayed graft function (DGF). The evidence base for this is sparse, however, and there is substantial variation in practice. We sought to evaluate whether the use of intraoperative diuretics during kidney transplantation translated into a reduction in DGF. METHODS: We conducted a cohort study evaluating the use of furosemide or mannitol given intraoperatively before kidney reperfusion compared with control (no diuretic). Adult patients receiving a kidney transplant for end-stage renal disease were allocated to receive furosemide, mannitol, or no diuretic. The primary outcome was DGF; secondary outcomes were graft function at 30 days and perioperative changes in potassium levels. Descriptive and comparative statistics were used where appropriate. RESULTS: A total of 162 patients who received a kidney transplant from a deceased donor (either donation after neurologic determination of death or donation after circulatory death) were included over a 2-year period, with no significant between-group differences. There was no significant difference in DGF rates between the furosemide, mannitol, and control groups. When the furosemide and mannitol groups were pooled (any diuretic use) and compared with the control group, however, there was a significant improvement in the odds that patients would be free of DGF (odds ratio 2.10, 95% confidence interval 1.06-4.16, 26% v. 44%, p = 0.03). There were no significant differences noted in any secondary outcomes. CONCLUSION: This study suggests the use of an intraoperative diuretic (furosemide or mannitol) may result in a reduction in DGF in patients undergoing kidney transplantation. Further study in the form of a randomized controlled trial is warranted.

[Development and Assessment of a New Oral Selenium Fast-disintegrating Tablets].

Selenium is an essential trace element and its deficiency causes myositis, myocardial damage, and other symptoms. Patients receiving long-term intravenous nutrition or tube-feeding in particular are deficient in essential trace elements, including selenium, and require regular supplementation. In Japan, injectable selenium-containing products are listed on the National Health Insurance drug price list, and oral solutions are prepared and used in hospitals. However, these formulations have problems related to preservation and require complicated administration procedures. In this study, we developed a new fast-disintegrating tablet formulation of selenium, using SmartEx® (D-mannitol·low substituted hydroxypropylcellulose (L-HPC)·fully hydrolyzed polyvinyl alcohol (PVA) mixture) as a coprocessing additive, that can be administered orally or by feeding tube. The tablet formulation had excellent disintegrable capability, sufficient hardness, and did not cause tube blockage when administered in the simple suspension method. In addition, the tablet formulation showed no changes in properties in an accelerated test without packaging for 42 d, indicating that it could be stored for a long period. Fast-disintegrating tablets prepared with SmartEx® are expected to improve the adherence and quality of life of patients who require selenium supplementation.

Intestinal permeability assessment using lactulose and mannitol in celiac disease.

Alterations in intestinal permeability can lead to increased uptake of luminal antigens, which has been linked to several intestinal diseases, such as inflammatory bowel diseases, celiac disease, and irritable bowel syndrome, but also to extra-intestinal diseases. Promising therapies that target intestinal permeability could be developed, for instance tight junction modulators. Consequently, permeability assays are increasingly being used as treatment endpoints in clinical studies. Therefore, reliable, reproducible, and feasible methods for measuring intestinal permeability in the clinical setting are necessary. Currently, a variety of in vivo, ex vivo, and in vitro tests are available, some of which are only applicable to basic research. Despite the various options available to measure gut permeability, their use in clinical setting is still limited because of their heterogeneity. Here, we describe a clinical method to measure intestinal permeability using two non-metabolizable sugars.

Correlation of lactulose-to-mannitol ratios in plasma and urine for intestinal permeability assessment in pigs.

OBJECTIVE: The lactulose-to-mannitol ratio test is a test to assess the disorders associated with gut permeability. The test requires an oral administration of the mixture of lactulose and mannitol and urine collection. The urinary ratio of lactulose to mannitol is an indicator of intestinal permeability. Due to the complexity of urine collection in animal studies, plasma exposure ratios of lactulose to mannitol compared to their urinary concentration ratios were evaluated following an oral administration of the sugar mixture in pigs. ANIMALS: 10 pigs were orally dosed with a solution of lactulose and mannitol mixture. PROCEDURES: Plasma samples were collected at predose, 10 and 30 minutes and 2, 4, and 6 hours postdosing, and cumulated urinary samples were collected at 6 hours for liquid chromatography-mass spectrometry analysis. The ratios of pharmacokinetic parameters of lactulose to mannitol and the plasma sugar ratios at a single time point or the mean values of several time points were compared to their urinary sugar ratios. RESULTS: The results revealed that the lactulose-to-mannitol ratios of AUC0-6h, AUCextrap, and Cmax were correlated to the urinary sugar ratios, and the plasma sugar ratios of a single time point at 2, 4, or 6 hours and the mean values of those time points were also appropriate to replace their urinary ratios in pigs. CLINICAL RELEVANCE: Following an oral administration of lactulose and mannitol mixture, blood collection, and assay can be an option for assessing intestinal permeability, especially in animal studies.

Assessment of Tribo-charging and Continuous Feeding Performance of Direct Compression Grades of Isomalt and Mannitol Powders.

Tribo-charging is often a root cause of mass flow deviations and powder adhesion during continuous feeding. Thus, it may critically impact product quality. In this study, we characterized the volumetric (split- and pre-blend) feeding behavior and process-induced charge of two direct compression grades of polyols, galenIQ™ 721 (G721) for isomalt and PEARLITOL® 200SD (P200SD) for mannitol, under different processing conditions. The feeding mass flow range and variability, hopper end fill level, and powder adhesion were profiled. The feeding-induced tribo-charging was measured using a Faraday cup. Both materials were comprehensively characterized for relevant powder properties, and their tribo-charging was investigated for its dependence on particle size and relative humidity. During split-feeding experiments, G721 showed a comparable feeding performance to P200SD with lower tribo-charging and adhesion to the screw outlet of the feeder. Depending on the processing condition, the charge density of G721 ranged from -0.01 up to -0.39 nC/g, and for P200SD from -3.19 up to -5.99 nC/g. Rather than differences in the particle size distribution of the two materials, their distinct surface and structural characteristics were found as the main factors affecting their tribo-charging. The good feeding performance of both polyol grades was also maintained during pre-blend feeding, where reduced tribo-charging and adhesion propensity was observed for P200SD (decreasing from -5.27 to -0.17 nC/g under the same feeding settings). Here, it is proposed that the mitigation of tribo-charging occurs due to a particle size-driven mechanism.

Microbial Degradation, Spectral analysis and Toxicological Assessment of Malachite Green Dye by Streptomyces exfoliatus.

Malachite green (MG) dye is a common environmental pollutant that threatens human health and the integrity of the Earth's ecosystem. The aim of this study was to investigate the potential biodegradation of MG dye by actinomycetes species isolated from planted soil near an industrial water effluent in Cairo, Egypt. The Streptomyces isolate St 45 was selected according to its high efficiency for laccase production. It was identified as S. exfoliatus based on phenotype and 16S rRNA molecular analysis and was deposited in the NCBI GenBank with the gene accession number OL720220. Its growth kinetics were studied during an incubation time of 144 h, during which the growth rate was 0.4232 (µ/h), the duplication time (td) was 1.64 d, and multiplication rate (MR) was 0.61 h, with an MG decolorization value of 96% after 120 h of incubation at 25 °C. Eleven physical and nutritional factors (mannitol, frying oil waste, MgSO4, NH4NO3, NH4Cl, dye concentration, pH, agitation, temperature, inoculum size, and incubation time) were screened for significance in the biodegradation of MG by S. exfoliatus using PBD. Out of the eleven factors screened in PBD, five (dye concentration, frying oil waste, MgSO4, inoculum size, and pH) were shown to be significant in the decolorization process. Central composite design (CCD) was applied to optimize the biodegradation of MG. Maximum decolorization was attained using the following optimal conditions: food oil waste, 7.5 mL/L; MgSO4, 0.35 g/L; dye concentration, 0.04 g/L; pH, 4.0; and inoculum size, 12.5%. The products from the degradation of MG by S. exfoliatus were characterized using high-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS). The results revealed the presence of several compounds, including leuco-malachite green, di(tert-butyl)(2-phenylethoxy) silane, 1,3-benzenedicarboxylic acid, bis(2-ethylhexyl) ester, 1,4-benzenedicarboxylic acid, bis(2-ethylhexyl) ester, 1,2-benzenedicarboxylic acid, di-n-octyl phthalate, and 1,2-benzenedicarboxylic acid, dioctyl ester. Moreover, the phytotoxicity, microbial toxicity, and cytotoxicity tests confirmed that the byproducts of MG degradation were not toxic to plants, microbes, or human cells. The results of this work implicate S. exfoliatus as a novel strain for MG biodegradation in different environments.

A case for improved assessment of gut permeability: a meta-analysis quantifying the lactulose:mannitol ratio in coeliac and Crohn's disease.

BACKGROUND: A widely used method in assessing small bowel permeability is the lactulose:mannitol test, where the lactulose:mannitol ratio (LMR) is measured. However, there is discrepancy in how the test is conducted and in the values of LMR obtained across studies. This meta-analysis aims to determine LMR in healthy subjects, coeliac and Crohn's disease. METHODS: A literature search was performed using PRISMA guidance to identify studies assessing LMR in coeliac or Crohn's disease. 19 studies included in the meta-analysis measured gut permeability in coeliac disease, 17 studies in Crohn's disease. Outcomes of interest were LMR values and comparisons of standard mean difference (SMD) and weighted mean difference (WMD) in healthy controls, inactive Crohn's, active Crohn's, treated coeliac and untreated coeliac. Pooled estimates of differences in LMR were calculated using the random effects model. RESULTS: Pooled LMR in healthy controls was 0.014 (95% CI: 0.006-0.022) while pooled LMRs in untreated and treated coeliac were 0.133 (95% CI: 0.089-0.178) and 0.037 (95% CI: 0.019-0.055). In active and inactive Crohn's disease, pooled LMRs were 0.093 (95% CI: 0.031-0.156) and 0.028 (95% CI: 0.015-0.041). Significant differences were observed in LMR between: (1) healthy controls and treated coeliacs (SMD = 0.409 95% CI 0.034 to 0.783, p = 0.032), (2) healthy controls and untreated coeliacs (SMD = 1.362 95% CI: 0.740 to 1.984, p < 0.001), (3) treated coeliacs and untreated coeliacs (SMD = 0.722 95% CI: 0.286 to 1.157, p = 0.001), (4) healthy controls and inactive Crohn's (SMD = 1.265 95% CI: 0.845 to 1.686, p < 0.001), (5) healthy controls and active Crohn's (SMD = 2.868 95% CI: 2.112 to 3.623, p < 0.001), and (6) active Crohn's and inactive Crohn's (SMD = 1.429 (95% CI: 0.580 to 2.278, p = 0.001). High heterogeneity was observed, which was attributed to variability in protocols used across different studies. CONCLUSION: The use of gut permeability measurements in screening and monitoring of coeliac and Crohn's disease is promising. LMR is useful in performing this function with significant limitations. More robust alternative tests with higher degrees of clinical evidence are needed if measurements of gut permeability are to find widespread clinical use.

Assessment of small-intestine permeability in healthy Nigerian children is altered by urinary volume and voiding status.

OBJECTIVE: This study aimed to uncover the effect of voided urinary volume on small intestine permeability ratios in healthy children. METHODS: We assessed small intestine permeability in 155 apparently healthy children, aged 3-5 years old, without any visible symptoms of disease, in a rural, malaria-endemic setting in Nigeria, using a multi-sugar test solution, comprising lactulose, sucrose, mannitol, and rhamnose. Children were categorized into low urinary volume (LV) and high urinary volume (HV), based on the volume of urine voided per kg body weight per hour. LV children voided less than 25th percentile of the total population, while HV children voided greater than 75th percentile of the total population. Urinary volume excreted over a 90-minute period after administration of the test solution was measured, and differences in sugar ratios were compared between children with high (HV) and low urinary volumes (LV), as well as between children who voided (VC) or who were not able to void (NVC) before administration of the test solution. RESULTS: Urinary mannitol and rhamnose recovery were 44% (p = 0.002) and 77% (p<0.001) higher in HV children compared to LV children respectively, while urinary lactulose recovery was 34% lower (p = 0.071). There was no difference in urinary sucrose recovery between groups (p = 0.74). Lactulose-mannitol ratio, lactulose-rhamnose ratio and sucrose-rhamnose ratio were all significantly higher in children in the LV group compared to children in the HV group (p<0.001). In a multiple regression analysis, urinary volume and voiding status combined, explained 13%, 23% and 7% of the variation observed in lactulose-mannitol, lactulose-rhamnose and sucrose-rhamnose ratios, respectively. CONCLUSION: Sugar permeability ratios vary significantly with total urinary volume in multi-sugar small-intestine permeability tests. Voiding status before sugar administration appears to influence lactulose recovery, lactulose-rhamnose and sucrose-rhamnose ratios independently of total urinary volume. Evidence from this study suggests the need to take urinary volume into account when conducting multi-sugar small-intestine permeability tests.

Morphologic assessment of hypertonic citrate adenine, histidine-tryptophan-ketoglutarate, and university of Wisconsin solutions for hypothermic uterus preservation in rats.

AIM: Optimizing perfusate for static cold storage is one of the key ways of reducing organ dysfunction and rejection in organ transplantation. Here, we tested the effectiveness of the three different solutions for hypothermic uterus preservation. METHODS: Twenty rats were divided into four groups, five in each group. Uterine grafts were retrieved and perfused in situ. The uteri were preserved at 4°C in normal saline as control group (group NS), hypertonic citrate adenine (group HCA), histidine-tryptophan-ketoglutarate (group HTK), or university of Wisconsin solutions (group UW) for 0, 12, 24, and 48 h, respectively. HE, electron microscopy, TUNEL staining, and Cleaved Caspase3 immunohistochemical staining were assessed at each time point. RESULTS: There was no significant difference in the uterine retrieval time, perfusion time, and the amount of perfusion solution in NS, HCA, HTK, and UW groups (p > 0.05). HCA and HTK can well preserve the pathological morphology of rat uterine tissues for up to 24 h, and the apoptosis rates of the two groups are 7.2% and 7.1%, respectively, with no statistical difference (p > 0.05). Still, the protective effect of HTK on the ultrastructure of cells was much better than HCA. There was a significant difference in the apoptosis rate of UW (6.5%), HTK (8.8%), and HCA (9.4%) at 48 h, with mitochondrial and endoplasmic reticulum structure well preserved only in UW. CONCLUSION: At 4°C, normal saline is not suitable to preserve rat uterus for more than 12 h. The morphologic results would favor the use of HTK rather than HCA for short-term hypothermic uterus preservation (≤24 h). UW is better than HTK and HCA for 48 h hypothermic uterus preservation.

Simultaneous assessment of intestinal permeability and lactase activity in human-milk-fed preterm infants by sugar absorption test: Clinical implementation and analytical method.

BACKGROUND & AIMS: Experimental (nutritional) interventions in preterm infants frequently focus on intestinal maturation, as improving tolerance to enteral nutrition is a major goal. Intestinal permeability and lactase activity serve as markers for intestinal maturation. We aimed to develop a protocol for the simultaneous assessment of both markers in human-milk-fed preterm infants by a sugar absorption test. In addition, we developed a new gas chromatography-mass spectrometry (GC-MS) method for the analysis of lactulose, lactose, and mannitol in urine and milk collected during the sugar absorption test. METHODS: The sugar absorption test was performed on days 4, 7, and 14 postpartum in 12 preterm infants (gestational age of 26-32 weeks). Human milk was collected, pooled, and divided into equal portions to provide a stable lactose intake for 24 h. Urine was collected in the last 6 h of this 24 h period, after administration of a bolus test sugar solution. Samples were analyzed by GC-MS after derivatization by oxime formation combined with acetylation. RESULTS: The GC-MS method was validated and used for the accurate measurement of lactulose, lactose, and mannitol concentrations. The urinary lactulose/mannitol ratio declined with time, suggesting a decreased intestinal permeability. The urine-to-milk-lactulose/lactose ratio increased as a result of increased lactase activity with time. CONCLUSIONS: The developed protocol for simultaneous assessment of intestinal permeability and lactase activity can be used to monitor the effect of experimental (nutritional) interventions in human-milk-fed preterm infants. Urine and milk samples obtained during the sugar absorption test can be accurately analyzed by GC-MS.

Assessment of tolerance and acceptability between mannitol solution and polyethylene glycol as bowel preparation for colonoscopy: a three-center study.

INTRODUCTION: Adequate bowel preparation is one of the most important factors related to the yield of colonoscopy. Lowquality bowel preparation has been associated with lower adenoma detection rates and increased healthcare expenses. Bowel preparation is a major impediment to undergo colonoscopy since it is perceived as an unpleasant experience by patients. OBJECTIVE: This study was aimed to assess tolerance and acceptability of the bowel preparation using either polyethylene glycol (PEG) or mannitol solution. MATERIALS AND METHODS: We enrolled 140 patients with indications of screening for colorectal cancer or with suspected large bowel diseases. They received either mannitol solution or PEG as bowel preparation. Patients were asked to fill a questionnaire about the bowel preparation experience. RESULTS: Patients perceived more burdensome the preparation with PEG than mannitol for the variables nausea overall experience, post-procedure discomfort, disagreeable flavor, volume ingested and cost (p<0.05). A similar tolerance was reported for abdominal pain, bloating and anal irritation (p>0.05). The acceptability was 82.9% and 71.4% in the Mannitol group and in the PEG group, respectively (p=0.10). CONCLUSION: Acceptance of the bowel preparation between mannitol solution and PEG was comparable. However, mannitol was better tolerated by the patients in regard to most of the evaluated items.

Recent advances in the biotechnological production of erythritol and mannitol.

Dietary habits that include an excess of added sugars have been strongly associated with an increased risk of obesity, heart disease, diabetes, and tooth decay. With this association in view, modern food systems aim to replace added sugars with low calorie sweeteners, such as polyols. Polyols are generally not carcinogenic and do not trigger a glycemic response. Furthermore, owing to the absence of the carbonyl group, they are more stable compared to monosaccharides and do not participate in Maillard reactions. As such, since polyols are stable at high temperatures, and they do not brown or caramelize when heated. Therefore, polyols are widely used in the diets of hypocaloric and diabetic patients, as well as other specific cases where controlled caloric intake is required. In recent years, erythritol and mannitol have gained increased importance, especially in the food and pharmaceutical industries. In these areas, research efforts have been made to improve the productivity and yield of the two polyols, relying on biotechnological manufacturing methods. The present review highlights the recent advances in the biotechnological production of erythritol and mannitol and summarizes the benefits of using the two polyols in the food and pharmaceutical industries.

Update on compatibility assessment of empagliflozin with the selected pharmaceutical excipients employed in solid dosage forms by thermal, spectroscopic and chromatographic techniques.

Empagliflozin (EGF) received USFDA approval in 2014 for oral use to control the glucose levels in adults with type 2 diabetes mellitus. Albeit, a systematic drug-excipient compatibility study of EGF has not been reported in the open literature. As physical and chemical interactions affect the performance of the formulation, this study intended to unveil the drug and excipients interactions which would later help in development of a robust solid dosage form. Differential scanning calorimetry (DSC) was applied as a screening tool for the assessment of compatibility between EGF and the list of excipients mentioned in the EMEA summary of product characteristics (SmPC)-section 6.1, along with mannitol and polyvinylpyrrolidone. Thermogravimetric analysis (TGA), Fourier Transform Infrared Spectroscopy (FTIR), X-ray Powder Diffraction (PXRD) and Hot Stage Microscopy (HSM) methods were utilized to appraise the interpretation of DSC results adequately. Isothermal stress testing (IST) studies of EGF were performed using the selected excipients to check the presence of interaction products (IPs) and the drug content by HPLC. Additional peaks were observed in the EGF-macrogol mixture than the drug peak in the HPLC analysis after two and half months, and those were separated and identified by the Ultra-High Performance Liquid Chromatography-Quadrupole Time of Flight Mass Spectrometry (UHPLC-QTOF-MS). Overall, EGF had shown compatibility with 13 selected excipients; however, initial observation of DSC and IST studies indicated plausible interaction of the EGF with macrogol.

Assessment of tolerance and acceptability between mannitol solution and polyethylene glycol as bowel preparation for colonoscopy: a three-center study / Evaluación de tolerancia y aceptabilidad entre la solución de manitol y el polietilenglicol como preparación intestinal para la colonoscopía: un estudio de tres centros

ABSTRACT Introduction: Adequate bowel preparation is one of the most important factors related to the yield of colonoscopy. Low quality bowel preparation has been associated with lower adenoma detection rates and increased healthcare expenses. Bowel preparation is a major impediment to undergo colonoscopy since it is perceived as an unpleasant experience by patients. Objective: This study was aimed to assess tolerance and acceptability of the bowel preparation using either polyethylene glycol (PEG) or mannitol solution. Materials and methods: We enrolled 140 patients with indications of screening for colorectal cancer or with suspected large bowel diseases. They received either mannitol solution or PEG as bowel preparation. Patients were asked to fill a questionnaire about the bowel preparation experience. Results: Patients perceived more burdensome the preparation with PEG than mannitol for the variables nausea overall experience, post-procedure discomfort, disagreeable flavor, volume ingested and cost (p<0.05). A similar tolerance was reported for abdominal pain, bloating and anal irritation (p>0.05). The acceptability was 82.9% and 71.4% in the Mannitol group and in the PEG group, respectively (p=0.10). Conclusion: Acceptance of the bowel preparation between mannitol solution and PEG was comparable. However, mannitol was better tolerated by the patients in regard to most of the evaluated items.

RESUMEN Introducción: La preparación intestinal adecuada es uno de los factores más importantes relacionados con el rendimiento de la colonoscopía. La preparación intestinal de baja calidad se ha asociado con tasas de detección de adenoma más bajas y mayores gastos de atención sanitaria. La preparación intestinal es un impedimento importante para someterse a una colonoscopía, ya que los pacientes la perciben como una experiencia desagradable. Objetivo: Este estudio tuvo como objetivo evaluar la tolerancia y la aceptabilidad de la preparación intestinal utilizando polietilenglicol (PEG) o solución de manitol. Materiales y métodos: Fueron incluidos 140 pacientes con indicación de pesquisa de cáncer colorrectal o con sospecha de enfermedades del intestino grueso. Los pacientes recibieron solución de manitol o PEG como preparación intestinal. Se pidió a los pacientes que completaran un cuestionario sobre la experiencia de preparación intestinal. Resultados: Los pacientes percibieron más agobiante la preparación con PEG que el manitol para las variables náuseas, experiencia general, molestias posteriores al procedimiento, sabor desagradable, volumen ingerido y costo (p<0,05). Se informó una tolerancia similar para el dolor abdominal, distensión abdominal e irritación anal (p>0,05). La aceptabilidad fue de 82,9% y 71,4% en el grupo de manitol y en el grupo de PEG, respectivamente (p=0,10). Conclusión: La aceptación de la preparación intestinal entre la solución de manitol y el PEG fue comparable. Sin embargo, el manitol fue mejor tolerado por los pacientes con respecto a la mayoría de las variables evaluadas.

Assessment of intracranial pressure monitoring in patients with moderate traumatic brain injury: A retrospective cohort study.

OBJECTIVES: intracranial pressure (ICP) monitoring has now been a standard technique for the treatment of severe traumatic brain injury (sTBI), while the effect of ICP monitoring for moderate traumatic brain injury (mTBI) is not clear. Moreover, evidence comparing the two types of ICP monitoring: ventricular drainage (VD) catheter and intraparenchymal (IP) catheter is scarce. PATIENTS AND METHODS: 91 patients with mTBI were reviewed retrospectively. They were divided into VD, IP and Non-ICP group. Baseline parameters were recorded. The clinical outcome was reflected by Glasgow Outcome Scale (GOS) and mortality at discharge and six months after injury. The rate of surgical decompression, refractory intracranial hypertension, neuroworsening, dose of mannitol and cranial CT were recorded. Meningitis and intracranial hematoma, two major complications of ICP monitoring, were also collected. RESULTS: the three groups showed no significant difference in GOS at discharge and six months after injury. The mortality was similar among the three groups at six months after injury, while the Non-ICP group had the highest mortality at discharge. The Non-ICP group was administered the most mannitol while the VD group was administered the least. The Non-ICP group also received the most cranial CT scans among the three groups. Incidence of meningitis and intracranial hematoma were not significantly different among the VD and IP group. CONCLUSION: use of ICP monitoring could hardly improve the functional outcome of mTBI, but may possibly reduce the in-hospital mortality. By using ICP monitoring, the dose of mannitol and cranial CT scan for mTBI patients may be decreased.

A unified in vitro test system for the assessment of tight junction modulators.

Tight junction (TJ) modulation is a promising approach for improving drug bioavailability by enhancing the absorption of active pharmaceutical ingredients. However, the application of many different test methods to determine the efficacy of new TJ modulators (TJMs) or to assess different compounds is accompanied by a lack of comparable results, reducing the rational evaluation and commercial marketing of these pharmaceutical excipients. The establishment of unified testing methods can fill this gap and offers the opportunity to compare results from different laboratories. Furthermore, the calculation of a TJ modulation score allows the objective comparison of TJ modulators and facilitates the selection of appropriate candidates. In this study, eight well-known TJ modulators were tested with a focus on four different in vitro bioassays carried out with MDCK cells. The extent of TJ modulation was determined by transepithelial electric resistance (TEER) measurements and permeability studies with mannitol. To evaluate tolerability, cell viability (MTT) and cytotoxicity (CellTox™ Green) assays were performed, and TEER regeneration was monitored for 24 h after exposure. With the exception of labradimil, seven TJ modulators caused significant TEER reduction of up to 100 %. For five compounds, an enhancement of mannitol permeation was observed. As expected, first-generation enhancers exhibited lower cell compatibility than mechanism-based modulators. Based on the experimental results of this study, for the first time, an evaluation system (tight junction modulator scoring system, TJMSS) is presented that provides a ranking of the tested modulators depending on weighted parameters. Such a system offers the possibility of rational formulation development for drugs requiring improved absorption.

Cost Effectiveness of Inhaled Mannitol (Bronchitol®) in Patients with Cystic Fibrosis.

BACKGROUND: Inhaled mannitol (Bronchitol®) is licensed in Australia as a safe and efficacious addition to best supportive care in patients with cystic fibrosis. OBJECTIVE: The objective of this study was to assess the cost effectiveness of inhaled mannitol (in addition to best supportive care) in the Australian setting from the perspective of a government-funded national healthcare system. METHODS: A probabilistic patient-level simulation Markov model estimated life-time costs and outcomes of mannitol when added to best supportive care, compared with best supportive care alone in patients aged 6 years and older. We estimated treatment-related inputs (initial change in percentage of predicted forced expiratory volume, relative reduction in severe pulmonary exacerbations, and treatment discontinuations) from two phase III trials. Longer term natural history rates of predicted forced expiratory volume decline over time and severe pulmonary exacerbation rates for best supportive care were taken from Australian CF registries. The utility value for the cystic fibrosis health state was as measured in the trials using the Health Utility Index, whereas the impact of pulmonary exacerbations and lung transplantation on utility was ascertained from the published literature. The underlying cost of managing cystic fibrosis, and the cost associated with pulmonary exacerbations and transplantations was taken from published Australian sources. RESULTS: The addition of inhaled mannitol to best supportive care resulted in a discounted cost per quality-adjusted life-year of AU$39,165. The result was robust with 77% of probabilistic sensitivity analysis samples below a willingness-to-pay threshold of AU$45,000/quality-adjusted life-year. CONCLUSION: Benchmarked against an implicit Australian willingness-to-pay threshold for life-threatening diseases, our model suggests inhaled mannitol provides a cost-effective addition to best supportive care in patients with cystic fibrosis, irrespective of concomitant dornase alfa use.

Methods for the Simple and Reliable Assessment of Barley Sensitivity to Abiotic Stresses During Early Development.

Physiological assays that facilitate screening for various types of responses to abiotic stresses are well established for model plants such as Arabidopsis; however, there is a need to optimize similar tests for cereal crops, including barley. We have developed a set of stress assays to characterize the response of different barley lines during two stages of development-seed germination and seedling growth. The assays presented, including the response to osmotic, salt, oxidative stresses, and exogenously applied abscisic acid, can be used for forward screening of populations after mutagenesis as well as for phenotyping of already isolated mutants, cultivars, or breeding lines. As well as protocols for stress treatments, we also provide methods for plant stress response evaluation, such as chlorophyll a fluorescence (ChlF) and image analysis.

The Effect of Histidine-tryptophan-ketoglutarate Solution and University of Wisconsin Solution: An Analysis of the Eurotransplant Registry.

BACKGROUND: Both University of Wisconsin (UW) and histidine-tryptophan-ketoglutarate (HTK) solutions are currently used in the Eurotransplant region for preservation of liver allografts. Previous studies on their effect have led to a lot of discussion. This study aims to compare the effect of HTK and UW on graft survival. METHODS: First liver transplantations in recipients 18 years or older from January 1, 2007, until December 31, 2016, were included. Graft survival was compared for livers preserved with HTK and UW at 30 days, 1, 3, and 5 years. Multivariable analysis of risk factors was performed and outcome was adjusted for important confounders. RESULTS: Of all 10 628 first liver transplantations, 8176 (77%) and 2452 (23%) were performed with livers preserved with HTK and UW, respectively. Kaplan-Meier curves showed significant differences in graft survival between HTK and UW at 30 days (89% vs 93%, P=<0.001), 1 year (75% vs 82%, P=<0.001), 3 years (67% vs 72%, P<0.001), and at 5 years (60% vs 67%, P<0.001). No significant differences in outcome were observed in separate analyses of Germany or non-German countries. In multivariable analysis, UW was associated with a decreased risk of graft loss at 30 days (HR 0.772, P=0.002) and at 1 year (0.847 (0.757-0.947). When adjusted for risk factors, no differences in long term outcome could be detected. CONCLUSIONS: Because the use of preservation fluids is clustered geographically, differences in outcome by preservation fluids are strongly affected by regional differences in donor and recipient characteristics. When adjusted for risk factors, no differences in graft survival exist between transplantations performed with livers preserved with either HTK or UW.

Interference Assessment of Various Endogenous and Exogenous Substances on the Performance of the Eversense Long-Term Implantable Continuous Glucose Monitoring System.

BACKGROUND: A variety of prescriptions and over-the-counter medications interfere with transcutaneous continuous glucose monitoring (CGM) sensors. This study characterized the interference profile of the Eversense® CGM System (Senseonics, Inc., Germantown, MD), which has a different mechanism of glucose detection than other CGM systems. MATERIALS AND METHODS: Sensor bias (sensor glucose concentration measurement - plasma glucose concentration measured by a reference test) was measured in vitro against 41 different substances at supratherapeutic/supraphysiologic plasma concentrations. Testing was performed using a paired-sample method adapted from the Clinical and Laboratory Standards Institute guidance document EP7-A2. Any substance producing sensor bias that exceeded the International Organization for Standardization (ISO) document 15197:2013 limits was then tested using an in vitro dose-response method to determine whether the concentration producing a significant sensor bias was within physiologic/therapeutic concentration ranges. RESULTS: Eight of 41 substances produced a sensor bias that exceeded ISO 15197:2013 limits when tested in vitro at supratherapeutic/supraphysiologic plasma concentrations. Only two of these substances (tetracycline and mannitol) exceeded bias limits within therapeutic concentration ranges. Notably, neither acetaminophen nor ascorbic acid, which are substances reported to interfere with other CGM systems, produced sensor bias that exceeded ISO limits when used at physiologic concentrations. CONCLUSIONS: Although tetracycline and mannitol interfered with the Eversense sensor, substances frequently reported to interfere with enzymatic, electrochemical-based transcutaneous CGM systems, such as acetaminophen and ascorbic acid, did not affect Eversense readings.