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Purpose: To evaluate a three-compartmental semi-physiological model for analysis of uptake clearance and efflux from brain tissue of the hydrophilic markers sucrose and mannitol, compared to non-compartmental techniques presuming unidirectional uptake., Methods: Stable isotope-labeled [ 13 C]sucrose and [ 13 C]mannitol (10 mg/kg each) were injected as IV bolus into the tail vein of awake young adult mice. Blood and brain samples were taken after different time intervals up to 8 h. Plasma and brain concentrations were quantified by UPLC-MS/MS. Brain uptake clearance (K in ) was analyzed using either the single-time point analysis, the multiple time point graphical method, or by fitting the parameters of a three-compartmental model that allows for symmetrical exchange across the blood-brain barrier and an additional brain efflux clearance., Results: The three-compartment model was able to describe the experimental data well, yielding estimates for K in of sucrose and mannitol of 0.068 ± 0.005 and 0.146 ± 0.020 μl.min -1 .g -1 , respectively, which were significantly different (p < 0.01). The separate brain efflux clearance had values of 0.693 ± 0.106 (sucrose) and 0.881 ± 0.20 (mannitol) μl.min -1 .g -1 , which were not statistically different. K in values obtained by single time point and multiple time point analyses were dependent on the terminal sampling time and showed declining values for later time points., Conclusions: Using the three-compartment model allows determination of K in for small molecule hydrophilic markers with low blood-brain barrier permeability. It also provides, for the first time, an estimate of brain efflux after systemic administration of a marker, which likely represents bulk flow clearance from brain tissue., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This study explored the cardiometabolic responses to sugar moieties acutely, and following a subsequent mixed meal tolerance test (MMTT). Twenty-one healthy adolescents ( N  = 10 female, 14.3 ± 0.4 years) completed 3 experimental and 1 control condition, in a counterbalanced order. These consisted of different drinks to compare the effect of 300 mL of water (control), or 300 mL of water mixed with 60 g of glucose, fructose or sucrose, on vascular function (flow-mediated dilation (FMD), microvascular reactivity (total hyperaemic response; TRH), and cerebrovascular reactivity (CVR)), and blood samples for uric acid, glucose, triglycerides and lactate concentrations. FMD increased 1 h after glucose and sucrose ( P  < 0.001, ES ≥ 0.92) but was unchanged following fructose and water ( P  ≥ 0.19, ES ≥ 0.09). CVR and TRH were unchanged 1 h following all conditions ( P  > 0.57, effect size (ES) > 0.02). Following the MMTT, FMD was impaired in all conditions ( P  < 0.001, ES > 0.40) with no differences between conditions ( P  > 0.13, ES < 0.39). Microvascular TRH was increased in all conditions ( P  = 0.001, ES = 0.88), and CVR was preserved in all conditions after MMTT ( P  = 0.87, ES = 0.02). Blood uric acid concentration was elevated following fructose consumption and the MMTT ( P  < 0.01, ES > 0.40). Consumption of a sugar sweetened beverage did not result in vascular dysfunction in healthy adolescents; however, the vascular and metabolic responses were dependent on sugar moiety. Novelty: Glucose consumption acutely increases peripheral vascular function in healthy adolescents. Acute sugar sweetened beverage consumption (sucrose) does not result in adverse vascular outcomes. Elevations in uric acid are observed with fructose consumption, which may have implications over repeated exposure.

Patients with haemophilia A who have similar FVIII levels show clinical heterogeneity, and 10-15% of patients with severe haemophilia do not have a severe bleeding phenotype. The aim of this study was to assess whether global haemostasis tests, such as thrombin generation assay (TGA) and thromboelastography (TEG), can predict the bleeding pattern of severe haemophilia better than trough levels and pharmacokinetic profiles, particularly in the prophylactic setting. The study group consisted of 39 patients with haemophilia A and 75 healthy controls. The annual bleeding rate (ABR) and Hemophilia Joint Health Score 2.1 (HJHS) of the patients were determined. Basal factor FVIII, inhibitor levels, TEG and TGA of participants with prophylaxis were performed after a washout period. Then, a recombinant FVIII product was administered to patients. After factor replacement, the above tests were repeated at 30 min, 6 and 48 h. There was a significant difference in the ABR and HJHS between the groups according to the basal factor VIII activity of patients after wash-out. TEG and TGA parameters of patients with factor activity above 1% were significantly better than those of patients with factor activity below 1%. After factor concentrate administration, factor activities, TEG and TGA parameters at 30 min, 6 and 48 h were similar in the two groups. We showed that the 1% trough level but not for the 3% trough level is critical for both clinical phenotypes and thrombin generation for haemophilia patients in the prophylactic setting., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Metabolic status can be impacted by general anesthesia and surgery. However, the exact effects of general anesthesia and surgery on systemic metabolome remain unclear, which might contribute to postoperative outcomes., Methods: Five hundred patients who underwent abdominal surgery were included. General anesthesia was mainly maintained with sevoflurane. The end-tidal sevoflurane concentration (ET sevo ) was adjusted to maintain BIS (Bispectral index) value between 40 and 60. The mean ET sevo from 20 min after endotracheal intubation to 2 h after the beginning of surgery was calculated for each patient. The patients were further divided into low ET sevo group (mean - SD) and high ET sevo group (mean + SD) to investigate the possible metabolic changes relevant to the amount of sevoflurane exposure., Results: The mean ET sevo of the 500 patients was 1.60% ± 0.34%. Patients with low ET sevo (n = 55) and high ET sevo (n = 59) were selected for metabolomic analysis (1.06% ± 0.13% vs. 2.17% ± 0.16%, P < 0.001). Sevoflurane and abdominal surgery disturbed the tricarboxylic acid cycle as identified by increased citrate and cis-aconitate levels and impacted glycometabolism as identified by increased sucrose and D-glucose levels in these 114 patients. Glutamate metabolism was also impacted by sevoflurane and abdominal surgery in all the patients. In the patients with high ET sevo , levels of L-glutamine, pyroglutamic acid, sphinganine and L-selenocysteine after sevoflurane anesthesia and abdominal surgery were significantly higher than those of the patients with low ET sevo , suggesting that these metabolic changes might be relevant to the amount of sevoflurane exposure., Conclusions: Sevoflurane anesthesia and abdominal surgery can impact principal metabolic pathways in clinical patients including tricarboxylic acid cycle, glycometabolism and glutamate metabolism. This study may provide a resource data for future studies about metabolism relevant to general anaesthesia and surgeries., Trial Registration: www.chictr.org.cn . identifier: ChiCTR1800014327 .

Scope : To identify a metabolomic profile related to postprandial satiety sensations involved in appetite control would help for a better understanding of the regulation of food intake. Methods and Results: A cross-sectional analysis of plasma metabolites was conducted over 151 overweight/obese adults from the "Satiety Innovation"-SATIN study, a randomized clinical trial of a 12-week weight-loss maintenance period. Postprandial satiety sensations (3 h-iAUC) were assessed by visual analogue scale (VAS) at the beginning and at the end of the study. Fasting plasma metabolites were profiled using a targeted multiplatform metabolomics approach before each appetite test meal. Associations between 124 metabolites and iAUC-satiety were assessed using elastic net linear regression analyses. The accuracy of the multimetabolite weighted models for iAUC-VAS was evaluated using a 10-fold cross-validation (CV) approach and the Pearson's correlation coefficients were estimated. Five and three metabolites were selected in the first and the second assessments, respectively. Circulating glycine and linoleic acid concentrations were consistently and positively associated with higher iAUC-satiety in both visits. Sucrose and sphingomyelins (C32:2, C38:1) were negatively associated with iAUC-satiety in the first visit. The Pearson correlations coefficients between the metabolomic profiles and iAUC-satiety in the first and the second appetite assessments were 0.37 and 0.27, respectively. Conclusion: Higher glycine and linoleic acid were moderately but consistently associated with higher postprandial satiety in two different appetite assessments in overweight and obese subjects.

We assessed the associations of genetically instrumented blood sucrose with risk of coronary heart disease (CHD) and its risk factors (i.e., type 2 diabetes, adiposity, blood pressure, lipids, and glycaemic traits), using two-sample Mendelian randomization. We used blood fructose as a validation exposure. Dental caries was a positive control outcome. We selected genetic variants strongly (P < 5 × 10 -6 ) associated with blood sucrose or fructose as instrumental variables and applied them to summary statistics from the largest available genome-wide association studies of the outcomes. Inverse-variance weighting was used as main analysis. Sensitivity analyses included weighted median, MR-Egger and MR-PRESSO. Genetically higher blood sucrose was positively associated with the control outcome, dental caries (odds ratio [OR] 1.04 per log 10 transformed effect size [median-normalized standard deviation] increase, 95% confidence interval [CI] 1.002-1.08, P = 0.04), but this association did not withstand allowing for multiple testing. The estimate for blood fructose was in the same direction. Genetically instrumented blood sucrose was not clearly associated with CHD (OR 1.01, 95% CI 0.997-1.02, P = 0.14), nor with its risk factors. Findings were similar for blood fructose. Our study found some evidence of the expected detrimental effect of sucrose on dental caries but no effect on CHD. Given a small effect on CHD cannot be excluded, further investigation with stronger genetic predictors is required.

Context: Sibiricose A5 (A5), sibiricose A6 (A6), 3,6'-disinapoyl sucrose (DSS), tenuifoliside A (TFSA) and 3,4,5-trimethoxycinnamic acid (TMCA) are the main active components of Polygala tenuifolia Willd. (Polygalaceae) (PT) that are active against Alzheimer's disease., Objective: To compare the pharmacokinetics and bioavailability of five active components in the roots of raw PT (RPT), liquorice-boiled PT (LPT) and honey-stir-baked PT (HPT)., Materials and Methods: The median lethal dose (LD 50 ) was evaluated through acute toxicity test. The pharmacokinetics of five components after oral administration of extracts of RPT, LPT, HPT (all equivalent to 1.9 g/kg of RPT extract for one dose) and 0.5% CMC-Na solution (control group) were investigated, respectively, in Sprague-Dawley rats (four groups, n  = 6) using UHPLC-MS/MS. In addition, the absolute bioavailability of A5, A6, DSS, TFSA and TMCA after oral administration (7.40, 11.60, 16.00, 50.00 and 3.11 mg/kg, respectively) and intravenous injection (1/10 of the corresponding oral dose) in rats ( n  = 6) was studied., Results: The LD 50 of RPT, LPT and HPT was 7.79, 14.55 and 15.99 g/kg, respectively. AUC 0- t of RPT, LPT and HPT were as follows: A5 (433.18 ± 65.48, 680.40 ± 89.21, 552.02 ± 31.10 ng h/mL), A6 (314.55 ± 62.73, 545.76 ± 123.16, 570.06 ± 178.93 ng h/mL) and DSS (100.30 ± 62.44, 232.00 ± 66.08, 197.58 ± 57.37 ng h/mL). The absolute bioavailability of A5, A6, DSS, TFSA and TMCA was 3.25, 2.95, 2.36, 1.17 and 42.91%, respectively., Discussion and Conclusions: The pharmacokinetic and bioavailability parameters of each compound can facilitate future clinical studies.

Background: Approximately 30% of patients on dialysis received combination therapy for their phosphate binder prescription; however, few studies for combined effects of phosphate binders are reported. For the purpose of evaluating the efficacy of combination therapy, we compared the efficacy of sucroferric oxyhydroxide (PA21) combined with calcium carbonate with that of lanthanum carbonate hydrate, sevelamer hydrochloride, and ferric citrate hydrate combined with calcium carbonate., Methods: For in vitro studies, calcium carbonate and the other phosphate binders alone or in combination were stirred in phosphate solution at pH 2-8 for 2 h. After centrifuging the suspension, the phosphorus level in the supernatant was determined. For in vivo studies, rats were orally administered calcium carbonate and the other phosphate binders (except for sevelamer hydrochloride) alone or in combination, followed by oral administration of phosphate solution adjusted to pH 2 or 7. Serum samples were collected from the rats at predetermined timepoints and the serum phosphorus levels were determined and analyzed using a two-way analysis of variance., Results: In the in vitro study, the measured phosphate-binding capacity of combining sevelamer hydrochloride, PA21, and lanthanum carbonate hydrate with calcium carbonate was approximately equal to or greater than the theoretical values under most conditions. Furthermore, these combined effects were insensitive to pH in that order. The measured phosphate-binding capacity of ferric citrate hydrate combined with calcium carbonate was smaller than the theoretical values, and the combination did not exhibit efficacy under any of the tested conditions. In the in vivo study, the combined effect of PA21 and calcium carbonate at both pH values and that of lanthanum carbonate hydrate and calcium carbonate at pH 2 were additive. In contrast, the combined effect of lanthanum carbonate hydrate and calcium carbonate at pH 7 and that of ferric citrate hydrate and calcium carbonate at pH 2 were antagonistic., Conclusions: These results suggest that coadministration of PA21 and calcium carbonate showed good and relatively stable efficacy throughout the range of the gastrointestinal pH and that combining lanthanum carbonate hydrate and ferric citrate hydrate with calcium carbonate may not produce the expected efficacy under certain conditions.

Abomasal ulcers are common in cattle, especially in calves, and to date, there is no reliable antemortem method for diagnosis, to our knowledge. We assessed if measuring sucrose in blood after oral administration in calves could be used to identify animals with abomasal ulcers. Terminally ill calves ( n = 12; part A) and calves designated for slaughter ( n = 123; part B) were given a sucrose solution per os, and blood samples were taken 15, 30, 60, 90, and 120 min (part A) or 30 and 60 min (part B) after administration. The calves were then euthanized or slaughtered, and their abomasa were examined. Serum samples were analyzed using highperformance liquid chromatography-mass spectrometry, and data were analyzed using general linear mixed models. Calves both with and without affected abomasa had increasing sucrose values over time without significant differences. Also, there was no relationship between the size of the mucosal lesion and sucrose values.

CSL112 (Apolipoprotein A-I [human]) is an intravenous preparation of apolipoprotein A-I (apoA-I), formulated with phosphatidylcholine (PC) and stabilized with sucrose, in development to prevent early recurrent cardiovascular events following acute myocardial infarction (AMI). This phase 1 study was designed to determine if moderate renal impairment (RI) influenced the pharmacokinetics (PK) and safety of CSL112. Thirty-two subjects, 16 with moderate RI (estimated glomerular filtration rate [eGFR] ≥ 30 and < 60 mL/min/1.73 m 2 ) and 16 age-, sex-, and weight-matched subjects with normal renal function (eGFR ≥ 90 mL/min/1.73 m 2 ) were randomized 3:1 to receive a single infusion of CSL112 2 g (n = 6) or placebo (n = 2), or CSL112 6 g (n = 6) or placebo (n = 2). PK sampling was at prespecified times from 48 hours prior to 144 hours following infusions, with final safety assessments at 90 days. Renal and hepatic safety, and adverse events (AEs) were monitored throughout the study. Plasma apoA-I and PC PK profiles were similar between renal function cohorts at both doses. For CSL112 6 g mean ± SD apoA-I AUC 0 - last was 7670 ± 1900 and 9170 ± 2910 mg·h/dL in normal renal function and moderate RI subjects, respectively. Renal apoA-I clearance was <1% of CSL112 dose. In moderate RI, sucrose clearance was slower; however, approximately 70% was excreted within 48 hours in both renal function cohorts. No CSL112-related serious AEs or clinically significant renal or hepatic safety changes were observed. Dose adjustment of CSL112 is not required in subjects with moderate RI, supporting its further investigation in AMI patients with moderate RI., (© 2018 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.)

Background: Cancer of oral cavity is a seriously growing problem in many parts of the world. In Indian subcontinent, most of these cases have been attributed to the use of tobacco-related products. This study is focused on the identification of distinguishing metabolites of oral cancer in comparison with tobacco snuff dippers and healthy controls., Methods: A total of 234 plasma samples including 62 healthy controls, 81 tobacco snuff dippers, and 91 oral cancer samples were analyzed using mass spectrometry., Results: Twenty-nine of 3326 metabolites were found to distinguish among oral cancer, tobacco snuff dippers, and healthy controls using P-value ≤.001 and fold change ≥3. Prediction model was generated with an overall accuracy of 89.3%. Two metabolites, that is, stearyl alcohol and sucrose, can be used as predictive biomarkers showing progression of tobacco snuff dippers toward oral cancer., Conclusion: The unique metabolite profile gives evidence of a strong correlation between tobacco snuff dipping and oral cancer., (© 2018 Wiley Periodicals, Inc.)

The effect of active acupoints versus inactive acupoints in treating hypertension is not well documented. Metabolic phenotypes, depicted by metabolomics analysis, reflect the influence of external exposures, nutrition, and lifestyle on the integrated system of the human body. Therefore, we utilized high-performance liquid chromatography tandem mass spectrometry to compare the targeted metabolic phenotype changes induced by two different acupoint treatments. The clinical outcomes show that active acupoint treatment significantly lowers 24-hour systolic blood pressure but not diastolic blood pressure, as compared with inactive acupoint treatment. Furthermore, distinctive changes are observed between the metabolomics data of the two groups. Multivariate analysis shows that only in the active acupoint treatment group can the follow-up plasma be clearly separated from the baseline plasma. Moreover, the follow-up plasma of these two groups can be clearly separated, indicating two different post-treatment metabolic phenotypes. Three metabolites, sucrose, cellobiose, and hypoxanthine, are shown to be the most important features of active acupoint treatment. This study demonstrates that metabolomic analysis is a potential tool that can be used to efficiently differentiate the effect of active acupoints from inactive acupoints in treating hypertension. Possible mechanisms are the alternation of hypothalamic microinflammation and the restoration of host-gut microbiota interactions induced by acupuncture.

Radix Polygala (Yuanzhi in Chinese) is well-known in traditional Chinese medicine (TCM) and has been used for treatment of depression, brain protection, and memory improvement for thousands of years. This plant medicine is rich in saponins, glycolipids, and organic acids. The purpose of the current study was to develop a rapid, accurate, and sensitive ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method for the simultaneous determination of the following seven active components of Radix Polygala extracts in rat plasma: sibiricose A5 (A5); sibiricose A6 (A6); 3,6'-disinapoyl sucrose (DSS); tenuifoliside A (TFSA); tenuifoliside B (TFSB); tenuifoliside C (TFSC); and 3,4,5-trimethoxycinnamic acid (TMCA). Then, the pharmacokinetics were studied following oral administration. Plasma samples were precipitated with methanol. Chromatographic separation was successfully performed on a thermo C 18 column (100 × 3.0 mm, 3 μm) with a mobile phase consisting of acetonitrile and 10 mmol/L of an ammonium acetate aqueous solution. Seven analytes were detected by multiple reaction monitoring (MRM) with an electrospray ionization source in the positive mode. The transitions of m/z were 517.1/174.9, 547.0/204.9, 753.2/205.2, 681.3/443.3, 667.2/205.1, 767.4/529.2, 236.8/103.2, and 136.9/92.9 for A5, A6, DSS, TFSA, TFSB, TFSC, TMCA, and salicylic acid (IS), respectively. The method validation showed good linearity in the range of 1-2000 ng/mL and LLOQs of 1 ng/mL for the 7 components in plasma. The accuracy, precision, and stability of QC samples were all within allowable ranges. In addition, no significant matrix effect was observed using this method. For the first time, the validated method has been successfully applied to the pharmacokinetic study of the seven components of Radix Polygala extracts in rat plasma. Moreover, this method may be applied for detecting prescriptions that contain Radix Polygala or other plant medicines that include one or more components above. The results of the pharmacokinetic study of the seven ingredients will provide important guidance to clinical medicine regarding Radix Polygala and prescriptions include Radix Polygala., (Copyright © 2018 Elsevier B.V. All rights reserved.)

We evaluated the influence of hesperidin and vitamin C (VitC) on glycemic parameters, lipid profile, and DNA damage in male Wistar rats treated with sucrose overload. Rats were divided into six experimental groups: I-water control; II-sucrose control; III-hesperidin control; IV-VitC control; V-co-treatment of sucrose plus hesperidin; VI-co-treatment of sucrose plus VitC. We measured the levels of triglycerides, total cholesterol, HDL-c, LDL-c, fasting glucose, and glycated hemoglobin (A1C). DNA damage was evaluated in blood and brain cells using the comet assay and the micronucleus test was used to evaluate chromosomal damages in the rat bone marrow. Co-treatment with VitC, but not with hesperidin, normalized the serum glucose. No effect of co-treatments was observed on A1C. The co-treatment with VitC or hesperidin did not influence the lipid profile (p>0.05). Rats co-treated with hesperidin had a significantly lower DNA damage level in blood (p<0.05) and brain (p<0.05). Rats treated with VitC only, but not those co-treated with VitC plus sucrose, had significantly higher DNA damage in brain (p<0.05). No significant differences were observed in the results of micronucleus test (p>0.05). Hesperidin and VitC showed different effects on sucrose and DNA damage levels. While VitC lowered the serum glucose, hesperidin reduced the DNA damage.

Background: Equine gastric ulcer syndrome is an important cause of morbidity in weanling foals. Many foals are asymptomatic, and the development of an inexpensive screening test to ensure an early diagnosis is desirable. The objective of this study was to determine the diagnostic accuracy of blood sucrose for diagnosis of EGUS in weanling foals., Results: 45 foals were studied 7 days before and 14 days after weaning. The diagnostic accuracy of blood sucrose for diagnosis of gastric lesions (GL); glandular lesions (GDL); squamous lesions (SQL) and clinically significant gastric lesions (CSL) at 45 and 90 min after administration of 1 g/kg of sucrose via nasogastric intubation was assessed using ROC curves and calculating the AUC. For each lesion type, sucrose concentration in blood was compared to gastroscopy; and sensitivities (Se) and specificities (Sp) were calculated across a range of sucrose concentrations. Cut-off values were selected manually to optimize Se. Because of concerns over the validity of the gold standard, additional Se, Sp, and lesion prevalence data were subsequently estimated and compared using Bayesian latent class analysis. Using the frequentist approach, the prevalence of GL; GDL; SQL and CSL before weaning was 21; 9; 7 and 8% respectively; and increased to 98; 59; 97 and 82% respectively after weaning. At the selected cut-off, Se ranged from 84 to 95% and Sp ranged from 47 to 71%, depending upon the lesion type and time of sampling. In comparison, estimates of Se and Sp were consistently higher when using a Bayesian approach, with Se ranging from 81 to 97%; and Sp ranging from 77 to 97%, depending upon the lesion type and time of sampling., Conclusions: Blood sucrose is a sensitive test for detecting EGUS in weanling foals. Due to its poor specificity, it is not expected that the sucrose blood test will replace gastroscopy, however it may represent a clinically useful screening test to identify foals that may benefit from gastroscopy. Bayesian latent class analysis represents an alternative method to evaluate the diagnostic accuracy of the blood sucrose test in an attempt to avoid bias associated with the assumption that gastroscopy is a perfect test.

Blood Brain Barrier (BBB) permeability is frequently compromised in the course of diseases affecting the central nervous system (CNS). Sucrose is a low molecular weight, hydrophilic marker with slow permeability at the naive BBB and therefore one of the widely used indicators of barrier integrity. Our laboratory recently developed a highly sensitive UPLC-MS/MS method for stable isotope labeled [ 13 C 12 ]sucrose in biological matrices. Correction of total brain concentration for contribution of intravascular space is required in such experiments in order to accurately measure BBB permeability, and it is often accomplished by vascular perfusion with buffer solutions prior to brain sampling. The purpose of the present study was to develop a UPLC-MS/MS method, which allows simultaneous analysis of two different stable isotope labeled sucrose variants, one of which can be utilized as a vascular marker. The first analyte, [ 13 C 12 ]sucrose, serves to quantify brain uptake clearance as a measure of BBB permeability, while the second analyte, [ 13 C 6 ]sucrose, is administered just before termination of the animal experiment and is considered as the vascular marker. [ 2 H 2 ]sucrose is used as the internal standard for both 13 C labeled compounds. Because the majority of recent studies on CNS diseases employ mice, another objective was to validate the new technique in this species. The UPLC-MS/MS method was linear (r 2  ≥ 0.99) in the tested concentration ranges, from 10 to 1000 ng/mL for both analytes in plasma, from 2 to 400 ng/g [ 13 C 12 ]sucrose in brain and from 10 to 400 ng/g [ 13 C 6 ]sucrose in brain. It was also validated in terms of acceptable intra and inter run accuracy and precision values (n = 5). The dual analyte technique was applied in a study in mice. One group received intravenous bolus injections of 10 mg/kg [ 13 C 12 ]sucrose at time 0, and 10 mg/kg [ 13 C 6 ]sucrose at 14.5 min, and subsequent terminal blood and brain sampling was performed at 15 min. For comparison, another group received an intravenous bolus dose of 10 mg/kg [ 13 C 12 ]sucrose and was submitted to transcardiac perfusion with buffer after 15 min. We demonstrate that the two alternative techniques to correct for intravascular content deliver equivalent values for brain concentration and brain uptake clearance., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The discovery of gut sweet taste receptors has led to speculations that non-nutritive sweeteners, including sucralose, may affect glucose control. A double-blind, parallel, randomized clinical trial, reported here and previously submitted to regulatory agencies, helps to clarify the role of sucralose in this regard. This was primarily an out-patient study, with 4-week screening, 12-week test, and 4-week follow-up phases. Normoglycemic male volunteers (47) consumed ∼333.3 mg encapsulated sucralose or placebo 3x/day at mealtimes. HbA1c, fasting glucose, insulin, and C-peptide were measured weekly. OGTTs were conducted in-clinic overnight, following overnight fasting twice during screening phase, twice during test phase, and once at follow-up. Throughout the study, glucose, insulin, C-peptide and HbA1c levels were within normal range. No statistically significant differences between sucralose and placebo groups in change from baseline for fasting glucose, insulin, C-peptide and HbA1c, no clinically meaningful differences in time to peak levels or return towards basal levels in OGTTs, and no treatment group differences in mean glucose, insulin, or C-peptide AUC change from baseline were observed. The results of other relevant clinical trials and studies of gastrointestinal sweet taste receptors are compared to these findings. The collective evidence supports that sucralose has no effect on glycemic control., (Copyright © 2017 Heartland Food Products Group. Published by Elsevier Inc. All rights reserved.)

Background: Equine gastric ulcer syndrome (EGUS) is common in adult horses, particularly those involved in performance disciplines. Currently, detection of EGUS by gastroscopy is the only reliable ante mortem method for definitive diagnosis; however it is unsuitable as a screening test because it is expensive, time consuming, and is not readily available to most veterinarians. Sucrose permeability testing represents a simple, economical alternative to gastroscopy for screening purposes, and the feasibility of this approach in the horse has been previously reported. The aim of this study was to determine the diagnostic accuracy of blood sucrose as a screening test for EGUS in a large group of adult horses with and without naturally occurring gastric disease., Results: One hundred and one adult horses with or without naturally occurring gastric ulceration were studied. The diagnostic accuracy of blood sucrose for diagnosis of gastric lesions (GL), glandular lesions (GDL), squamous lesions (SQL), and clinically significant lesions (CSL) at 45 and 90 min after administration of 1 g/kg of sucrose via nasogastric intubation was assessed using receiver operator characteristics (ROC) curves and calculating the area under the curve (AUC). For each lesion type, sucrose concentration in blood was compared to gastroscopy, as the gold standard, and sensitivities (Se) and specificities (Sp) were calculated across a range of sucrose concentrations. Ulcer grading was performed blindly by one observer; and the results were validated by comparing them with that of two other observers, and calculating the level of agreement. Cut-off values were selected manually to optimize Se. The prevalence of GL, GDL, SQL, and CSL was 83, 70, 53 and 58% respectively. At the selected cut-offs, Se ranged from 51 to 79% and Sp ranged from 43 to 72%, depending upon the lesion type and time of sampling., Conclusions: Blood sucrose is neither a sensitive or specific test for detecting EGUS in this population of adult horses with naturally occurring gastric ulceration. Further studies aimed at evaluating the performance characteristics of the test in different study populations are warranted. Given the limitations of endoscopy, due consideration should also be given to alternative methods for comparison of blood sucrose with a gold standard.

Background: Topical drug application is used to avoid systemic side effects. The aim of this study was to analyze whether locally applied iloprost or nitroglycerin influence gastric mucosal perfusion, oxygenation, and barrier function during physiological and hemorrhagic conditions., Methods: In repeated experiments, 5 anesthetized dogs received iloprost, nitroglycerin, or normal saline during physiological and hemorrhagic (-20% blood volume) conditions. Macro- and microcirculatory variables were recorded continuously. Gastric barrier function was assessed via translocation of sucrose into the blood., Results: During hemorrhage, gastric mucosal oxygenation decreased from 77 ± 4 to 37 ± 7%. This effect was attenuated by nitroglycerin (78 ± 6 to 47 ± 13%) and iloprost (82 ± 4 to 54 ± 9%). Sucrose plasma levels increased during hemorrhage from 7 ± 4 to 55 ± 15 relative amounts. This was alleviated by nitroglycerin (5 ± 8 to 29 ± 38 relative amounts). These effects were independent of systemic hemodynamic variables., Conclusions: During hemorrhage, topical nitroglycerin and iloprost improve regional gastric oxygenation without affecting perfusion. Nitroglycerin attenuated the shock-induced impairment of the mucosal barrier integrity. Thus, local drug application improves gastric microcirculation without compromising systemic hemodynamic variables, and it may also protect mucosal barrier function., (© 2017 S. Karger AG, Basel.)

Accurate and reproducible measurement of blood-brain barrier (BBB) integrity is critical in the assessment of the pathophysiology of the central nervous system disorders and in monitoring therapeutic effects. The widely-used low molecular weight marker [(14)C]sucrose is non-specific in the absence of chromatographic separation. The purpose of this study was to develop and validate a sensitive and reproducible LC-MS/MS method for the analysis of stable isotope-modified [(13)C12]sucrose in brain, plasma, and blood to determine BBB permeability to sucrose. After addition of internal standard (IS, [(13)C6]sucrose), the marker and IS were recovered from diluted rat blood, plasma, and brain homogenate by protein precipitation using acetonitrile. The recovery of the marker and IS was almost quantitative (90-106%) for all three matrices. The recovered samples were directly injected into an isocratic UPLC system with a run time of 6 min. Mass spectrometry was conducted using multiple reaction monitoring in negative mode. The method was linear (r(2)≥0.99) in the concentration ranges tested for the diluted blood and plasma (10-1000 ng/mL) and brain homogenate (1-200 ng/mL). The lower limit of quantitation of the assay was 0.5 pg injected on column. The assay was validated (n=5) based on acceptable intra- and inter-run accuracy and precision values. The method was successfully used for the measurement of serial blood and plasma and terminal brain concentrations of [(13)C12]sucrose after a single intravenous dose (10 mg/kg) of the marker to rats. As expected, the apparent brain uptake clearance values of [(13)C12]sucrose were low in healthy rats. The method may be useful for determination of the BBB integrity in animal models., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Scope: The intake of sucrose is of public health concern but limited information is available on the metabolic effects of short-term exposure. Our aim was to use metabolomics to investigate the metabolic impact of acute sucrose exposure., Methods and Results: We performed a randomized, parallel, single-dose feeding study on healthy females (n = 90, aged 29.9 ± 4.7 years, BMI 23.3 ± 2.5 kg/m(2) ) consuming either 0, 50, or 100 g sucrose in 500 mL water. Blood and urine samples were taken before and 24 h post sucrose intake. Urine and plasma samples underwent detailed metabolite profiling analysis using established protocols. Flow-injection electrospray MS fingerprinting analysis showed that 3 h after intake was the most informative time point in urine and plasma and out of 120 explanatory signals, highlighted 16 major metabolite signals in urine and 25 metabolite signals in plasma that were discriminatory and correlated with sucrose intake over time. The main confirmed metabolites positively correlated with intake were sucrose, fructose, and erythronic acid, while those negatively correlating with intake included fatty acids and derivatives, acyl-carnitines, and ketone bodies. GC-TOF-MS profiling analysis confirmed the fingerprinting data., Conclusion: Acute exposure to sucrose identified a number of metabolites correlated with sucrose intake and several compounds attributed to metabolic fasting., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

New thiazolylmethoxyphenyl pyrimidines (7a-g) have been conveniently synthesized with better yields by cyclocondensing 3-(4-((2-phenylthiazol-4-yl)methoxy)phenyl)-1-(4-substituted phenyl)prop-2-en-1-ones (4a-g) with thiourea in aqueous emulsion of tetradecyltrimethylammonium bromide (TTAB) at 80 °C. Antihyperglycemic activity of the new thiazolylmethoxyphenyl pyrimidines (7a-d), thiazolylmethoxyphenyl pyrazolines (5a-d) and thiazolylmethoxyphenyl isoxazolines (6a-d) has been evaluated in sucrose loaded rat model. Among these compounds; 5a, 5c, 6b, 7c and 7d have displayed noticeable antihyperglycemic activity. Pyrimidines and pyrazolines have displayed better antihyperglycemic activity than the analogues isoxazolines., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Non-alcoholic steatohepatitis (NASH) has a relation to obesity. It may lead to hepatocellular carcinoma. To date, the therapeutic options are limited due to complex pathogenesis. This study aimed to investigate the effect of atorvastatin and omega 3 fatty acids on experimentally-induced NASH. Sixty male albino rats were divided into 6 equal groups; control group, high fat emulsion/sucrose (HFE/S) diet, HFE/S+carboxymethyl cellulose, HFE/S +Atorvastatin, HFE/S+Fish oil and HFE/S+Atorvastatin+Fish oil. Serum alanine aminotransferase, total cholesterol (TC), triglycerides (TG), high density lipoproteins, insulin, glucose, C-reactive protein and quantitative insulin sensitivity check index were measured. Also, hepatic TC, TG, malondialdehyde, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and transforming growth factor beta 1 (TGF-β1) were determined. Liver sections were examined histopathologically. Atorvastatin improved lipid profile, inflammation and oxidative stress but did not improve insulin resistance, hepatic TGF-β1 or body weight while fish oil improved lipid profile, decreased inflammation and oxidative stress, improved insulin resistance, hepatic TGF-β1 and body weight compared to HFE/S group. Atorvastatin/fish oil combination produced significant improvement in the lipid profile, inflammation, oxidative stress, insulin resistance, hepatic TGF-β1 and body weight compared to the use of each of these drugs alone. This might be attributed to the effect of fish oil on the lipid profile, inflammatory cytokines, insulin resistance and TGF-β1 which potentiates the effect of atorvastatin on NASH., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A novel, specific and sensitive bioanalytical method has been developed for the determination of sucrose octasulfate (SOS) in dog plasma and urine using ion-pair reversed-phase ultraperformance liquid chromatography coupled with electrospray triple quadruple mass spectrometry (IPRP-UPLC ESI MS/MS). (13)C-labeled sucrose octasulfate-(13)C12 sodium salt is used as the internal standard. 200 μL of plasma or serum sample is extracted using weak anion exchange solid phase cartridge. In this method, a polar amide column is employed for the liquid chromatograph (LC) separation while the diethylamine and formic acid buffer is used as the ion-pairing reagent. The low limitation of quantitation of sucrose octasulfate is 0.20 ng on the column with a signal to noise ratio larger than 50. Parameters such as linearity, accuracy and precision have been validated in full compliance with the FDA guidelines for the bioanalytical method development and validation. A linear regression model fit the calibration curve very well with R>0.99. The bias and coefficient of variation of all levels of QCs are within the range of 15%. The selectivity, matrix effect and stabilities of analytes in solution and matrix have also been evaluated and the results met the acceptance criteria according to the guidelines. Based on these results, the method has qualified to analyze sucrose octasulfate in dog plasma for clinic research. This method has been applied to 1000 preclinical samples., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Methadone plays an increasing role in drug-related deaths in Hamburg. To find out whether intravenous application of methadone plays a relevant role in methadone-related deaths, body fluids of all methadone-positive cases (n=130) and three buprenorphine-positive cases where a urine sample was available (n=58+3) were investigated for disaccharides (sucrose and lactose as markers for intravenous methadone abuse). Sixty-four percent of the urine samples of the methadone cases showed positive results for disaccharides (22 times sucrose alone, range 2 to >1,000 mg/L; 6 times lactose and sucrose; and 9 times lactose alone, range 22 to 382 mg/L). The three buprenorphine cases showed positive results for lactose in urine. In blood, it was not possible to detect any disaccharides. Of the 116 fatal methadone intoxications, 49 % were under opiate maintenance treatment (OMT) at the point of death (A-OMT), 30 % were never in OMT (N-OMT) and 21 % were formerly in an OMT, but not at the point of death (F-OMT). Of the deceased in the OMT group, 12 % (n=7) died within the first 2 weeks of treatment, six of them within the first week. Overall, intravenous abuse of methadone plays a relevant role in methadone-related fatal cases of substituted patients and of drug consumers not in therapy. Thus, it is necessary that therapists keep to the statutory regulations and give take-home doses only after at least 6 months of successful therapy and when there is no suspicion of intravenous abuse.

A simple and accurate method for quantifying sucrose in equine serum that can be applied to sucrose permeability testing in the horse was developed and validated using gas chromatography with flame ionization detection. The assay provided an acceptable degree of linearity, accuracy, and precision at concentrations of sucrose as low as 2.34 μmol/l and as high as 20.45 μmol/l. Percentage recovery of sucrose from serum ranged from 89% to 102%; repeatability and intermediate precision (relative standard deviation) ranged from 3.6% to 6.7% and 4.1% to 9.3%, respectively. The limit of detection was 0.73 μmol/l. No interfering peaks were observed except lactose, which gave 2 peaks, one of which overlapped partially with sucrose. To evaluate the suitability of the method for quantifying sucrose in serum samples from horses with naturally occurring gastric ulceration, 10 horses with and without naturally occurring gastric ulceration were subjected to sucrose permeability testing. All horses demonstrated an increase in serum sucrose concentration over time following oral administration of sucrose; however, the increase from baseline was significant for horses with gastric ulceration at 45 min (P = 0.0082) and 90 min (P = 0.0082) when compared with healthy horses. It was concluded that gas chromatography with flame ionization detection is a valid method for quantifying sucrose in equine serum and can be applied directly to the analysis of sucrose in equine serum as part of a larger validation study aimed at developing a blood test for the diagnosis of gastric ulcers in horses.

Unlabelled: Intravenous (IV) ferric iron (Fe)-carbohydrate complexes are used for treating Fe deficiency in children with iron-refractory iron-deficiency anemia (IRIDA). An optimal treatment has yet to be determined. There are relatively little publications on the responsiveness to IV iron therapy in children with IRIDA., Patients and Method: This study analyzed responses to IV iron sucrose therapy given to 11 children, ranging in age from 2 to 13 years (mean 4.8 years), with iron-deficiency anemia who were unresponsive to oral iron therapy., Results: The hemoglobin and ferritin values (mean) of the 11 children with IRIDA were 7.7 g/dL and 4.8 ng/mL at diagnosis. Both hemoglobin and ferritin levels increased to 9.5 g/dL, and 24 ng/mL, respectively, at 6 weeks after the first therapy. Although the level of hemoglobin was steady at 6 months after the first, and 6 weeks after the second therapy, the ferritin levels continued to increase up to 30 ng/mL and 47 ng/mL at 6 months after the first and 6 weeks after the second therapy, respectively., Conclusion: We recommend that IRIDA should be considered in patients presenting with iron-deficiency anemia of unknown cause that is unresponsive to oral iron therapy. Our results suggest that IV iron therapy should be administered only once in cases of IRIDA. Continued administration of IV iron would be of no benefit to increase hemoglobin levels. On the contrary, ferritin levels may continue to increase resulting in untoward effects of hyperferritinemia.

Objective: In Sprague-Dawley rats (SD), we compared two categories of natural dietary supplements that influence carbohydrate (CHO) metabolism via different basic mechanisms to ameliorate insulin resistance (IR) and elevated blood pressure (BP) associated with heavy sugar/starch consumption. Two dietary supplements (bean extract and l-arabinose) are often referred to as carb blockers (CBs), because they slow the gastrointestinal absorption of CHO. Trivalent chromium (CR) falls into a group of so-called insulin sensitizers, because its major effect is to enhance peripheral insulin sensitivity., Method: We divided 48 mature male SD into 4 groups of 12. The first group received powdered baseline diet alone (Con). The remaining 3 SD groups (groups 2-4) ingested regular rat chow containing 20% w/w sucrose and 20% w/w rice starch. The second group received only this CHO-enriched chow. To the high-CHO diets of the remaining two groups, either CB to slow CHO absorption (CHO + CB) (group 3) or an insulin sensitizer, trivalent CR (CHO + CR; group 4), was added., Results: Compared to Con group 1, adding high CHO content to the diet of group 2 significantly increased circulating glucose levels and systolic BP (SBP). Addition of CB or CR to the feed of groups 3 and 4 overcame the perturbations that occurred with high CHO challenge in group 2; that is, they lowered circulating glucose concentrations to Con levels, enhanced response to exogenous insulin, and overcame the gradual elevation of SBP. Compared to group 2, the two treatment groups (3 and 4) also showed decreased renin-angiotensin system activity, decreased serum angiotensin-converting enzyme activity, and enhanced nitric oxide activity., Conclusions: Our data indicate that high doses of CB and CR, despite their different mechanisms of action, can completely overcome CHO-induced IR and BP elevations. The data further suggest that CB and CR affect only the changes brought on by heavy CHO ingestion, because IR and SBP in groups 3 and 4 mirrored Con values (group 1), never producing values lower than baseline. Earlier use of CB and CR in the life cycle appears more effective in overcoming CHO-induced perturbations than later use.

Objective: To test the hypothesis that replacement of sucrose with isomaltulose in sweet foods and beverages improves metabolic control in patients with type 2 diabetes., Research Design and Methods: One hundred ten patients with type 2 diabetes were randomized to receive sweet foods containing either 50 g/day isomaltulose or sucrose for 12 weeks as part of their habitual diet under free-living conditions. HbA(1c) at 12 weeks was the primary outcome parameter., Results: In the final analysis comprising 101 patients, isomaltulose did not significantly affect HbA(1c) at 12 weeks (sucrose: 7.39 ± 0.78%; isomaltulose: 7.24 ± 0.76%; regression coefficient [b]: 0.02 [95% CI: -0.21 to 0.25], P = 0.844). Triglycerides at 12 weeks were significantly lower in the isomaltulose versus the sucrose group (b: 34.01 [6.59-61.44], P = 0.016). Other secondary parameters did not significantly differ between groups., Conclusions: Isomaltulose did not influence glycemic control assessed as HbA(1c) in type 2 diabetes under free-living conditions but was associated with lower triglyceride levels.

Mucosal integrity may be objectively assessed by determination of the absorption of exogenous substances such as sucrose. Gas chromatography-mass spectrometry (GC/MS) and liquid chromatography-mass spectrometry (LC/MS) have been reported for the accurate quantification of low concentrations of sucrose in serum. LC/MS offered the advantage of high sensitivity and mass selectivity without the need for extensive sample derivatization required for GC/MS methods. However, the high polarity and non-volatile nature of the sucrose molecule renders LC/MS techniques challenging. Previously published reports lacked sufficient detail to permit replication of methodology. Problems encountered with existing protocols included poor peak resolution and weak fragmentation of the parent molecule. This communication describes a LC/MS protocol developed to provide improved resolution and product detection., (Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.)

Effects of sucralose sweetener on blood constituents labelled with technetium-99m ((99m)Tc) on red blood cell (RBC) morphology, sodium pertechnetate (Na(99m)TcO(4)) and diethylenetriaminepentaacetic acid labeled with (99m)Tc ((99m)Tc-DTPA) biodistribution in rats were evaluated. Radiolabeling on blood constituents from Wistar rats was undertaken for determining the activity percentage (%ATI) on blood constituents. RBC morphology was also evaluated. Na(99m)TcO(4) and (99m)Tc-DTPA biodistribution was used to determine %ATI/g in organs. There was no alteration on RBC blood constituents and morphology %ATI. Sucralose sweetener was capable of altering %ATI/g of the radiopharmaceuticals in different organs. These findings are associated to the sucralose sweetener in specific organs., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

3,6'-Disinapoylsucrose (DSS), a major active component of traditional Chinese medicine Yuan-Zhi (the roots of Polygala tenuifolia), has significant effects for neuroprotection and improving learning memory. In order to explore the pharmacokinetic properties of DSS so as to further understand its in vivo activities, a sensitive LC-MS/MS method was developed for determination of DSS in rat plasma and applied to a pharmacokinetic study in the present study. After treatment by protein precipitation, the plasma sample was separated on a C(18) HPLC column and analyzed by a mass spectrometry under positive electrospray ionization. Multiple-reaction monitoring was employed to measure the ion transition at m/z 777.4 --> 409.2 for DSS and m/z 557.2 --> 309.1 for forsythin as internal standard. The method was linear over the studied concentration range of 0.5-1000.0 ng/mL. The precision and accuracy ranged from 1.4 to 18.4%, and from -3.7 to -9.5%, respectively, for within-day and between-day assay. Extraction recovery was higher than 86.6%. The limits of detection and quantification were 0.3 and 0.5 ng/mL, respectively. The present method was successfully applied to a pharmacokinetic study. DSS was found to have poor oral absorption with only about 0.5% bioavailability.

A novel 13-membered ring thiocyclitol, isolated from an aqueous extract of Kothala-himbutu (Salacia reticulata), inhibited alpha-glucosidase in vitro. The inhibitory activity was investigated by maltose- and sucrose-loading on Wistar rats. This study found significant lowering of postprandial glucose levels, and the potency of 13-membered ring thiocyclitol was confirmed in vivo.

Damage to white matter in some premature infants exposed to intrauterine infections is thought to involve disruption of the blood-brain barrier. We have examined the effect of minocycline, an agent reported to reduce brain damage resulting from inflammation, on inflammation-induced disruption of the blood-brain barrier and damage to white matter. Post-natal marsupial opossums (Monodelphis domestica) were studied as most brain development in this species occurs after birth. Single intraperitoneal lipopolysaccharide (LPS) injection (0.2 mg/kg) with or without minocycline (45 mg/kg) at post-natal day (P)35 caused short-lasting barrier breakdown to plasma proteins but not to (14)C-sucrose. By P44, blood-brain barrier integrity was intact but a reduced volume of white matter was present. At P44 after prolonged inflammation (5 x 0.2 mg/kg LPS at 48 h intervals), proteins from blood were observed within brain white matter and permeability to (14)C-sucrose in the hindbrain increased by 31%. The volume of the external capsule and the proportion of myelin were 70 and 57%, respectively, of those in control animals. Minocycline administered during prolonged inflammation restored blood-brain barrier integrity but not LPS-induced damage to white matter. These data suggest that long-term changes in blood-brain barrier permeability occur only after a prolonged period of inflammation during development; however, damage to white matter can result from even a short-lasting breakdown of the barrier. Manipulation of the inflammatory response may have implications for prevention of some developmentally induced neurological conditions.

Objective: To measure concentrations of sucrose in the serum of captive dolphins after oral administration of a sucrose solution and determine the suitability of this method for use as a test to detect gastric ulcers., Animals: 8 adult captive bottlenose dolphins (Tursiops truncatus)., Procedures: Blood samples were collected from the ventral fluke vein of dolphins before and 45 minutes after oral administration of 500 mL of solution containing 25 or 50 g of sucrose; oral administration was achieved by use of gastric intubation. Serum was separated, diluted in a solution of 90% acetonitrile-to 10% water that contained 10 ng of an internal standard (trichlormethiazide)/microL, mixed, and centrifuged. Supernatant was analyzed by use of liquid chromatography-mass spectrometry-mass spectrometry (LC-MS-MS)., Results: Serum sucrose concentrations of dolphins were at or less than the limits of detection before oral administration. Values after administration of sucrose solution varied among dolphins and were higher and more variable after administration of 50 g, compared with concentrations after administration of 25 g., Conclusions and Clinical Relevance: Serum sucrose concentrations in samples collected during routine health evaluations of captive dolphins can be reliably measured by use of LC-MS-MS. Correlating serum sucrose concentrations with endoscopic observations of the gastric mucosa of dolphins will validate this approach for use in screening for the prevalence and severity of gastric ulcers and determining the efficacy of treatment regimens.

A urine sucrose test has recently been reported to be a reliable method of detecting gastric ulcers in horses; however, technical difficulties associated with urine collection have limited the practical value of the test. The objective of this pilot study was to determine whether gastric sucrose permeability, as evaluated by serum sucrose concentration, could be used to detect gastric mucosal injury in horses. Twelve adult horses with naturally acquired gastric ulceration were studied. After a 20-hour nonfeeding period, each horse was dosed with 250 g of sucrose via nasogastric intubation. Blood samples were collected at 0, 15, 30, 45, 60, and 90 minutes, and horses underwent gastroscopy 4 hours later. The severity of gastric ulceration in each horse was defined by means of a 4-point ulcer-scoring system, and the relationship with serum sucrose concentration was analyzed by means of a linear mixed-effects model. Serum sucrose concentration was measured by liquid chromatography operating in tandem with electrospray mass spectrometry. After nasogastric administration of table sugar, horses with moderate to severe gastric ulceration had significant increase in serum sucrose concentration at 30, 45, 60, and 90 minutes, relative to earlier times (P < .05). Peak sucrose concentration was observed at 45 minutes, and was correlated with ulcer severity (Spearman's rank correlation coefficient = 0.898, P < .05). These data indicate that determination of sucrose concentration in equine serum may be a useful test for identifying horses with endoscopically visible gastric ulceration and has potential use as a noninvasive method for screening and monitoring horses engaged in racing training and other performance-related disciplines.

Sex-specific foraging behaviour might be influenced by digestive constraints. However, evidence for sex differences in digestive performance is limited. Various physiological traits are known to be body size dependent. Therefore, we hypothesized that body size differences between male and female birds may lead to differences in their digestive characteristics. We predicted that if food intake and digestive functions are only governed by body mass, then males that are heavier than females would have higher food intake, food assimilation efficiency and gut transit time, but not after controlling for the effect of body mass. We fed a diet of equicaloric solutions of sucrose and a 1:1 mixture of glucose and fructose (hexose mixture) solutions to Palestine sunbirds (Nectarinia osea). When fed sucrose solutions, males had longer transit times but similar absorption efficiencies as females. Transit times, corrected for differences in body mass and food intake, were still longer in males than in females when fed on sucrose solutions. The sex-specific differences in transit time disappeared when the birds were fed the hexose mixture. Our results suggest that males take longer to digest than females when fed on sucrose-rich nectars as opposed to hexose-rich nectars, and therefore can allow themselves a relatively lower digestive capacity. This may suggest sex-specific co-evolution of sunbirds within mixed plant communities, which have both sucrose- and hexose-rich nectar-producing plants. Furthermore, future studies on digestion in birds may pay attention to sex-specific differences.

Aim: To investigate the usefulness of sucrose permeability test using serum in the diagnosis of gastric diseases, with special reference to early gastric cancer (EGC)., Methods: A total of 63 subjects, including 11 patients with gastric ulcer, 20 patients with gastric cancer (13, early; 7, advanced) and 32 healthy controls, were studied. Blood and urine samples were collected repeatedly for 5 h before and after the sucrose loading. Sucrose levels were measured by a newly developed enzymatic method., Results: Serum sucrose levels started to increase 15 min after loading, and peaked at 60 min in the gastric disease groups. The levels for gastric ulcer, EGC and advanced gastric cancer (AGC) at 60 min were significantly higher than that in the healthy controls (26.9+/-2.4, 34.4+/-5.0, and 71.8+/-15.6 vs 7.9+/-0.7 mol/L, respectively, P<0.01). The cut-off level set at 15.4 mol/L (60 min) offered the best distinction between EGC patients and healthy controls; and the sensitivity and specificity were 92.3% and 93.8%, respectively, while those of the urine method were 76.9% and 93.8%, respectively., Conclusions: The gastric permeability test using serum is reliable for the detection of EGC, and this test can provide results much earlier than the conventional urine method. This test may offer a useful alternative to more invasive tests for EGC.

Background: Sucrose permeability has been suggested as a simple and non-invasive marker of gastric mucosal damage. We here report on a sensitive enzymatic assay using four sequential enzyme reactions coupled with reduced thio-NADPH., Methods: Sucrose is phosphorylated by sucrose phosphorylase (EC2.4.1.7). The subsequent reaction in the presence of phosphoglucomutase (EC5.4.2.2) and glucose-1,6-diphosphate forms glucose-6-phosphate. Sucrose of the monad forms the dyad thio-NADPH. The reaction is monitored by changes in absorbance at 405 nm., Results: The lower limit of detection (3SD method) was 2.8 micromol/l for serum and 7.0 micromol/l for urine. The precision of the method was <4.0%, and has sufficient analytical range., Conclusions: The assay was sensitive enough to monitor serum sucrose concentrations during the sucrose permeability test and an automated assay may be useful in a large number of subjects.

Background: Oxidative stress and inflammation contribute to the high prevalence and severity of atherosclerosis, infections, and beta2-microglobulin amyloidosis; and thus, to reduced survival rate and quality of life in hemodialysis (HD) patients. Inflammation induces oxidative stress by production of the oxidants: superoxide anion, hydrogen peroxide, and hypochlorite. Intravenous iron (IVIR), administered in HD patients to correct anemia, can release free iron, that may react with hydrogen peroxide to produce the strong oxidant hydroxyl radical. Inflammation-induced lipid and protein oxidation and IVIR-induced lipid oxidation were shown in HD patients. However, IVIR-induced protein oxidation and a relationship between inflammation and IVIR-induced oxidative stress have not been reported to date., Methods: We examined the effect of IVIR administration on markers of protein oxidation in HD patients (advanced oxidation protein products [AOPPs], thiol, and dityrosine) in relation to such inflammatory markers as C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-alpha). Iron saccharate, 100 mg, was administered to 19 HD patients for 1 hour after 3.5 hours of high-flux dialysis. Blood samples were drawn pre-HD, pre-IVIR, and post-IVIR for iron, transferrin, TNF-alpha, AOPP, thiol, total antioxidant capacity (TEAC), and dityrosine levels and pre-HD for ferritin and CRP levels., Results: IVIR administration induced a 37% increase in AOPP level (P < 0.001), which correlated positively with pre-HD CRP level (r = 0.72; P < 0.05) and was greater in patients with a greater pre-HD TNF-alpha level (P < 0.05). IVIR administration did not affect TEAC, thiol, dityrosine, or TNF-alpha levels., Conclusion: IVIR administration induced an increase in protein oxidation (AOPP levels) that was related to the degree of inflammation., (Copyright 2002 by the National Kidney Foundation, Inc.)

The aim of this study was to determine whether respiratory acidosis favors the cerebral distribution of cyanide, and conversely, if respiratory alkalosis limits its distribution. The pharmacokinetics of a nontoxic dose of cyanide were first studied in a group of 7 rats in order to determine the distribution phase. The pharmacokinetics were found to best fit a 3-compartment model with very rapid distribution (whole blood T(1/2)alpha = 21.6 +/- 3.3 s). Then the effects of the modulation of arterial pH on the distribution of a nontoxic dose of intravenously administered cyanide into the brains of rats were studied by means of the determination of the permeability-area product (PA). The modulation of arterial blood pH was performed by variation of arterial carbon dioxide tension (PaCO2) in 3 groups of 8 anesthetized mechanically ventilated rats. The mean arterial pH measured 20 min after the start of mechanical ventilation in the acidotic, physiologic, and alkalotic groups were 7.07 +/- 0.03, 7.41 +/- 0.01, and 7.58 +/- 0.01, respectively. The mean PAs in the acidotic, physiologic, and alkalotic groups, determined 30 s after the intravenous administration of cyanide, were 0.015 +/- 0.002, 0.011 +/- 0.001, and 0.008 +/- 0.001 s(-1), respectively (one-way ANOVA; p < 0.0087). At alkalotic pH the mean permeability-area product was 43% of that measured at acidotic pH. This effect of pH on the rapidity of cyanide distribution does not appear to be limited to specific areas of the brain. We conclude that modulation of arterial pH by altering PaCO2 may induce significant effects on the brain uptake of cyanide.

The recombinant full-length FVIII product Kogenate has been reformulated using sucrose (rFVIII-FS) instead of human serum albumin as a stabiliser in purification and formulation. The in vivo recovery, haemostatic efficacy, and safety of rFVIII-FS were investigated in 20 previously treated patients with severe or moderate haemophilia A for > or = 24 weeks. In vivo recoveries of 73.5 +/- 16.3%, 78.4 +/- 16.1%, and 82.8 +/- 23.9% after the initial infusion of 50 IU kg(-1) rFVIII-FS and at weeks 12 and 24, respectively, showed no significant changes over time. A total of 1115 infusions (mean dose 24.1 +/- 8.4 IU kg(-1)) were included in the analysis of haemostatic efficacy. One (80.5%) or two (8.2%) infusions achieved adequate haemostasis in 88.7% of all bleeding episodes, and haemostatic efficacy was judged 'excellent' or 'good' in 749 of 764 episodes (98.0%). The haemostatic efficacy was judged as 'excellent' or 'good' in 924 of 1115 (82.9%) infusions. Twenty-one adverse events were observed in 12 patients in the total 1541 infusions included in the safety analysis. Causality with respect to rFVIII-FS could not be ruled out in three events in one HIV-negative patient: elevated CD4(%), decreased CD8(%), and elevated CD4/CD8 ratio. No FVIII inhibitor development was observed in any patient. ELISA assay testing for antibodies to rFVIII, baby hamster kidney cell (BHK) protein, and murine IgG were all negative. These results show that rFVIII-FS is a safe and effective for long-term treatment of patients with haemophilia A.

Oral exposure to dietary fat augments the postprandial triacylglycerol (TAG) concentration. We investigated the TAG response after oral exposure to butter and selected fat replacers. At 2200 h, 17 healthy adults consumed 80 g of almonds and fasted until 0700 h. Safflower oil (50 g in 1-g capsules) was then consumed. Oral stimulation was provided periodically for 2 h as potatoes, potatoes containing butter or one of three fat replacers or no oral stimulation in random order at weekly intervals. Blood was collected at stipulated intervals for 8 h. Oral exposure to butter led to a significantly longer postprandial TAG elevation than the other treatments. The results could not be explained by differential stimulus ingestion, palatability or perceived fat content. There was no significant treatment effect on concentrations of serum oleic acid, apolipoprotein (apo)B-48 or apoB-100, suggesting any oral exposure influence on release of dietary lipid stored in the lacteals or chylomicron and VLDL particle number contributed little to the postprandial TAG rise. In summary, oral exposure to butter elicited a greater postprandial TAG elevation than the tested fat replacers, possibly due to reduced TAG clearance.

Impotence commonly occurs after events such as acute myocardial infarction, coronary bypass, head trauma, and cerebral bleeding, including subarachnoid hemorrhage. We hypothesize that the hypoxia accompanying these events could damage the blood-testis barrier (BTB) and so cause testicular dysfunction, a possible cause of impotence. We examined the effect of cardiac arrest in mice on testis weight and various aspects of BTB function. Testis weight was decreased by about 24% 12 hours after cardiac arrest but had recovered fully by day 7. The testis/serum ratio for albumin was increased 12 hours after arrest, showing a disruption in the vascular BTB with recovery by 24 hours. The testis/serum ratio for sucrose was not consistently elevated, showing that the Sertoli cell BTB remained intact. The testis/serum ratio for verapamil was increased on day 3 of cardiac arrest, suggesting impaired function of the BTB's p-glycoprotein efflux transporter. Transporters for pituitary adenylate cyclase activating polypeptide and tumor necrosis factor-alpha were not affected by cardiac arrest. These results show that cardiac arrest affects testis weight and some aspects of BTB function. Such changes might have long-term effects on testicular function.

We report an investigation on the influence of high frequency electromagnetic fields (EMF) on the permeability of an in vitro model of the blood-brain barrier (BBB). Our model was a co-culture consisting of rat astrocytes and porcine brain capillary endothelial cells (BCEC). Samples were characterized morphologically by scanning electron microscopy and immunocytochemistry. The BBB phenotype of the BCEC was shown by the presence of zona occludens protein (ZO-1) as a marker for tight junctions and the close contact of the cells together with the absence of intercellular clefts. Permeability measurements using (14)C-sucrose indicated a physiological tightness which correlated with the morphological findings and verified the usefulness of our in vitro model. Samples were exposed to EMF conforming to the GSM1800-standard used in mobile telephones (1.8 GHz). The permeability of the samples was monitored over four days and compared with results of samples that were cultured identically but not exposed to EMF. Exposure to EMF increased permeability for (14)C-sucrose significantly compared to unexposed samples. The underlying pathophysiological mechanism remains to be investigated., (Copyright 2000 Wiley-Liss, Inc.)

Multiple-indicator dilution experiments with labeled lactate were performed in the livers of anesthetized dogs. A mixture of (51)Cr-labeled erythrocytes, [(3)H]sucrose, and L-[1-(14)C]lactate or a mixture of (51)Cr-labeled erythrocytes, [(14)C]sucrose, and L-[2-(3)H]lactate was injected into the portal vein, and samples were obtained from the hepatic vein. Data were evaluated using a model comprising flow along sinusoids, exchange of lactate between plasma and erythrocytes and between plasma and hepatocytes, and, in the case of L-[1-(14)C]lactate, metabolism to H[(14)C]O(-)(3) within hepatocytes. The coefficient for lactate efflux from erythrocytes was 0.62 +/- 0.24 s(-1), and those for influx into and efflux from hepatocytes were 0.44 +/- 0.13 and 0.14 +/- 0.07 s(-1), respectively. The influx permeability-surface area product of the hepatocyte membrane for lactate (P(in)S, in ml x s(-1) x g(-1)) varied with total flow rate (F, in ml s(-1) x g(-1)) according to P(in)S = (3.1 +/- 0.5)F + (0.021 +/- 0.014). Lactate in plasma, erythrocytes, and hepatocytes was close to equilibrium, whereas lactate metabolism was rate limiting.

The pharmacokinetics and metabolism of sucralose were investigated in dogs following intravenous or oral administration. Oral doses of (14)C-sucralose were rapidly absorbed, although there was some variation in the extent of absorption (range 18-48% of the dose). After intravenous or oral administration, radioactivity excreted in the urine was associated mainly with unchanged sucralose. One urinary metabolite was detected after both intravenous and oral doses and was identified by mass spectrometry as a glucuronic acid conjugate of sucralose. This metabolite accounted for about 15-20% of the intravenous dose but for only about 2-8% of the oral dose.

Two tolerance studies were conducted in healthy human adult volunteers. The first study was an ascending dose study conducted in eight subjects, in which sucralose was administered at doses of 1, 2. 5, 5 and 10mg/kg at 48-hour intervals and followed by daily dosing at 2mg/kg for 3 days and 5mg/kg for 4 days. In the second study, subjects consumed either sucralose (n=77) or fructose (50g/day) (n=31) twice daily in single blind fashion. Sucralose dosage levels were 125mg/day for weeks 1-3, 250mg/day during weeks 4-7, and 500mg/day during weeks 8-12. No adverse experiences or clinically detectable effects were attributable to sucralose in either study. Similarly, haematology, serum biochemistry, urinalysis and EKG tracings were unaffected by sucralose administration. In the 13-week study, serial slit lamp ophthalmologic examination performed in a random subset of the study groups revealed no changes. Fasting and 2-hour post-dosing blood sucralose concentrations obtained daily during week 12 of the study revealed no rising trend for blood sucralose. Sucralose was well tolerated by human volunteers in single doses up to 10mg/kg/day and repeated doses increasing to 5mg/kg/day for 13 weeks. Based on these studies and the extensive animal safety database, there is no indication that adverse effects on human health would occur from frequent or long-term exposure to sucralose at the maximum anticipated levels of intake.

The metabolic and pharmacokinetic profile of sucralose was studied in human volunteers. Following a single oral dose of (14)C-sucralose (1mg/kg, 100 microCi) to eight male subjects, a mean of 14.5% (range 8.9 to 21.8%) of the radioactivity was excreted in urine and 78.3% (range 69.4 to 89.6%) in the faeces, within 5 days. The total recovery of radioactivity averaged 92.8%. Plasma concentrations of radioactivity were maximal at about 2 hours after dosing. The mean residence time (MRT) for sucralose was 18.8hr, while the effective half-life for the decline of plasma radioactivity was 13hr. Two volunteers given a higher oral dose (10mg/kg, 22.7 microCi) excreted a mean of 11.2% (9.6 and 12.7%) of the radioactivity in urine, and 85.5% (84.1 and 86.8%) in faeces over 5 days. The total recovery of radioactivity was 96.7%. The radiolabelled material present in faeces was essentially unchanged sucralose. Sucralose was the principal component in the urine together with two more polar components which accounted for only 2.6% of the administered dose (range 1.5 to 5.1% of dose); both metabolites possessed characteristics of glucuronide conjugates of sucralose.

The teratogenic potential of sucralose was examined following gavage administration to pregnant rats and rabbits during organogenesis. Groups of 20 mated rats were dosed on days 6-15 of gestation inclusive at 500, 1000 or 2000mg/kg/day; groups of 16 to 18 inseminated rabbits were dosed on days 6 to 19 of gestation inclusive at 175, 350 or 700mg/kg/day following preliminary studies at higher doses. Concurrent control groups received vehicle alone. Rats were killed on day 21 and rabbits on day 29 of gestation. Foetuses were evaluated at necropsy and after processing for possible soft tissue and skeletal alterations. There was no evidence of teratogenicity for either species. The only observed response to treatment in rats was a slight increase in water intake. Some adult rabbits receiving 700mg/kg/day exhibited marked gastrointestinal disturbance, also seen at higher doses in preliminary studies. Gastrointestinal effects such as these occur non-specifically in response to high doses of poorly absorbed compounds, and in the present study were considered to be responsible for two maternal deaths and four abortions. Full evaluation of rabbit foetuses in the main study (up to 700mg/kg/day) and necropsy of foetuses in a preliminary study with pregnant animals (up to 1000mg/kg/day) showed no evidence of adverse foetal response to sucralose. These teratology studies in both pregnant rodent and non-rodent animal models demonstrate that maternal consumption of high levels of sucralose during the period of organogenesis has no effect on normal foetal development in the rat or rabbit.