On the processes limiting oral drug absorption when amorphous solid dispersions are administered after a high-calorie, high-fat meal: Sporanox® pellets.

OBJECTIVES: 1) Identify processes limiting the arrival of itraconazole at the intestinal epithelium when Sporanox® amorphous solid dispersion (ASD) pellets are transferred from the stomach through the upper small intestine, after a high-calorie, high-fat meal. 2) Evaluate whether itraconazole concentrations in the colloidal phase of aqueous contents of the upper small intestine are useful for the assessment of dose effects in the fed state and food effects on plasma levels. METHODS: Itraconazole concentrations, apparent viscosity, and solubilization capacity were measured in aspirates from the upper gastrointestinal lumen collected during a recently performed clinical study in healthy adults. Published itraconazole concentrations in plasma, after a high-calorie high-fat meal and Sporanox® ASD pellets, and in contents of the upper small intestine of healthy adults, after administration of Sporanox® ASD pellets in the fasted state, were used to achieve the second objective. RESULTS: When Sporanox® ASD pellets (up to 200 mg) are transferred from the stomach through the upper small intestine, after a high-calorie, high-fat meal, itraconazole concentrations in the colloidal phase or the micellar phase of aqueous contents of the upper small intestine are unsaturated, in most cases. During the first 3 h post-dosing after a high-calorie, high-fat meal, the impact of dose (200 mg vs. 100 mg) on itraconazole concentrations in the colloidal phase of aqueous contents of the upper small intestine seems to underestimate the impact of dose on plasma levels. When Sporanox® ASD pellets are administered after a high-calorie, high-fat meal at the 200 mg dose level, itraconazole concentrations in the colloidal phase of aqueous contents of the upper small intestine are, on average, lower than those achieved in fasted state. CONCLUSIONS: When Sporanox® ASD pellets are transferred from the stomach to the upper small intestine after a high-calorie, high-fat meal, itraconazole's arrival at the intestinal epithelium seems to be limited by its arrival at the colloidal phase of aqueous contents of the upper small intestine. The impact of dose (100 mg vs. 200 mg) on plasma levels after a high-calorie, high-fat meal and during the gastrointestinal transfer of Sporanox® pellets requires consideration of pre-systemic itraconazole metabolism. At the 200 mg dose level, after taking into consideration differences in the volume of the contents of the upper small intestine between the fasted and the fed state during the gastrointestinal transfer of Sporanox® ASD pellets, itraconazole concentrations in the colloidal phase of aqueous contents of the upper small intestine suggest a mild negative food effect on average plasma levels; published clinical data are inconclusive.

Understanding the Conditions Under Which Drugs are Transferred from the Stomach Through the Upper Small Intestine After a High-Calorie, High-Fat Meal.

Information on the conditions under which drugs are transferred from the stomach through the upper small intestine after a high-calorie, high-fat meal is very limited. To simulate the drug presence after disintegration and arrival in the antral region, paracetamol solution and Sporanox® amorphous solid dispersion pellets at two dose levels were administered to the antrum of 8 healthy adults 30 min after administration of a high-calorie, high-fat meal on a crossover basis. The overall median buffer capacity of antral contents was estimated to be 18.0 and 24.0 mmol/ml/ΔpH when titrating with NaOH and HCl, respectively. The corresponding values for the contents of upper the small intestine were 14.0 and 16.8 mmol/ml/ΔpH, respectively. The drug transfer process from the antrum through the upper small intestine occurred with apparent first-order kinetics. The best estimate for the antral emptying half-life was 39min and 45min for paracetamol and itraconazole, respectively, the apparent volume of contents of the upper small intestine was more than double compared with previously reported values in the fasted state, the half-life of drug elimination from the upper small intestine was similar to recent estimates for highly permeable drugs in the fasted state, and the apparent volume of antral contents during the first couple of hours post drug administration was 303mL. Information collected in this study could increase the reliability of in silico and/or in vitro modelling approaches applied in clinical drug development.

Treatment of superficial vein thrombosis with intermediate dose of tinzaparin: A real word cohort study - The SeVEN EXTension study.

BACKGROUND: To assess the treatment of superficial vein thrombosis (SVT) with intermediate dose of tinzaparin in a setting of real world practice. METHODS: Prospective observational study of consecutive patients treated by vascular physicians in the private sector with tinzaparin (131 IU/Kg) once daily. Treatment duration was at the treating physician's discretion. The outcomes of the study were symptomatic venous thromboembolism, extension of thrombus and bleeding complications. RESULTS: 660 patients were included and followed up for at least 3 months. Median duration of treatment was 30 days (14-120). History of prior deep vein thrombosis (HR 2.77; 95% CI= 1.18-6.49; p = 0.018) and current SVT above the knee (HR1.84; 95% CI = 1.33-3.53; p = 0.0002) were associated with prolonged treatment duration. Primary efficacy outcomes occurred in 20 (3%) patients. The median time to the event was 24 (6-92) days and was not related to treatment duration. CONCLUSIONS: Tinzaparin at intermediate dose is an effective and safe treatment for SVT.

Characteristics of Contents of Lower intestine in the 65-74 Years of Age Range Could Impact the Performance of Safe and Efficacious Modified Release Products.

We characterized the contents of distal ileum and proximal colon of older people from a pharmaceutical product performance perspective, under two extreme situations, i.e. 5 h after a glass of water to fasted volunteers (fasted state) and 5 h after a high-calorie, high-fat meal to fasted volunteers (fed state). Five males and three females (65-70 y) participated in a two-phase crossover study. Contents were collected via colonoscopy. In distal ileum, luminal pH was lower and buffer capacity was higher than in young adults; differences reached significance for pH in the fed state. In proximal colon, differences reached significance for pH/fasted state and for buffer capacity/both fasted and fed states. Aqueous fraction of contents contained more short chain fatty acids than previously observed in young adults. In distal ileum, osmolality was significantly higher than in young adults. In proximal colon, aqueous fraction in the fasted state was significantly lower and long chain fatty acids 5 h after meal was significantly higher than in young adults. Characteristics of contents of lower intestine that are relevant to the performance of certain modified release products differ between individuals 65-74 years old and young adults, the typical age group employed in safety and efficacy studies of oral drug products.

Characteristics of contents in the upper gastrointestinal lumen after a standard high-calorie high-fat meal and implications for the in vitro drug product performance testing conditions.

OBJECTIVES: To measure the pH, buffer capacity, lipid content, bile acid content, and viscosity in the upper gastrointestinal (GI) lumen after a standard high-calorie, high-fat meal as well as the osmolality, lipid content and bile acid content in the aqueous phase of the gastric contents and the micellar phase of contents of the upper small intestine. To evaluate the implications of these findings for the composition of biorelevant media employed in vitro oral drug product performance testing representing the upper GI conditions after ingestion of the standard meal. METHODS: Eight healthy male adult volunteers participated in a two-phase, crossover study in which a homogenized standard meal was administered to the antrum via the gastric port of a naso-gastro-intestinal tube. A glass of tap water and single paracetamol and danazol doses were administered to the antrum of the stomach 30 min after the initiation of meal administration (Pentafragka et al., 2020). Samples were aspirated from the antrum and the upper small intestine over the next four hours. The pH and the buffer capacity of the samples were measured immediately upon aspiration, while viscosity, osmolality, and presence of solubilizing agents were measured after storage at -70 °C. RESULTS: The composition of gastric contents over time fluctuated less after the homogenized standard meal than after liquid meals with similar composition. Intra-subject variability of pH and buffer capacity in the stomach and in the upper small intestine was low. Mean viscosity values in the stomach at 100 s-1 were 80-800 times higher than in the fasted state for more than 3 h after the standard meal. In the upper small intestine, mean viscosity values at 100 s-1 were at least 100 times higher than in the fasted state for 4 h after the standard meal. CONCLUSIONS: Based on data collected in this study, Level I and Level II biorelevant media simulating the intragastric conditions after ingestion of a standard meal could be simplified whereas FeSSIF-V2 composition was confirmed to be representative of the composition of contents in the upper small intestine. Representative values of viscosity in the stomach and the upper small intestine and Level II composition of the aqueous phase of gastric contents, after the standard meal, are proposed for first time.

Disposition of two highly permeable drugs in the upper gastrointestinal lumen of healthy adults after a standard high-calorie, high-fat meal.

OBJECTIVES: To quantify the presence of two model highly permeable drugs, paracetamol and danazol, in the upper gastrointestinal lumen under conditions simulating the situation after disintegration of immediate release dosage forms administered in bioavailability/bioequivalence studies in the fed state. To understand the drug transfer process from the antral contents through the upper small intestine based on luminal drug data. METHODS: 8 healthy male adult volunteers participated in a randomized, single dose, two-phase, crossover study. After evaluating the impact of homogenization on meal's viscosity and particle size, the meal, containing phenol red as non-absorbable marker, was administered to the antrum via the gastric lumen of a naso-gastro-intestinal tube. The drugs were administered in solution form (Phase I) and in suspension form (Phase II) with a glass of tap water to the antrum of the stomach, 30 min after the initiation of meal administration. Samples were aspirated from the antrum and the upper small intestine up to 4 hours post drug administration. RESULTS: Apparent concentrations in the aqueous contents of the antrum were higher than apparent concentrations in the micellar contents of the upper small intestine for paracetamol; the opposite was observed for danazol. Based on total drug amount per volume data in contents of the upper gastrointestinal lumen, the transfer of paracetamol (aqueous solution or suspension) and danazol (aqueous suspension) through the upper small intestine could be described as an apparent first-order process. Transfer of a long-chain triglyceride solution of danazol was highly variable. CONCLUSIONS: Concentrations in the aqueous/micellar phase of luminal contents and values of parameters controlling the transfer from bulk gastric contents through the upper small intestine after a high-calorie, high-fat meal, were reported for the first time for highly permeable drugs. Data are expected to enhance the development of biorelevant in vitro and physiologically based biopharmaceutics modelling methodologies.

Exploring the impact of Crohn's disease on the intragastric environment of fasted adults.

We explored the potential impact of Crohn's disease on the intragastric environment of fasted adults with a view to potential effects on intragastric performance of orally administered drugs in the fasted state. Data were collected from 15 healthy individuals and 15 patients with Crohn's disease. All subjects remained fasted for at least 12h prior to gastroscopy. Intragastric resting volume and pH were measured upon aspiration. Osmolality, surface tension, pepsin activity, and content of six bile acids were measured within 4 months upon sample collection. Unlike intragastric volumes, intragastric osmolality was significantly increased by Crohn's disease. However, mean osmolality value in patients was only slightly higher than in healthy individuals (293 vs. 257 mOsmol/kg, respectively), therefore, unlikely to affect intragastric drug product performance. Primarily due to the high variability of data in healthy individuals, the potential effects on intragastric pH and surface activity could not be evaluated on a statistical basis. However, based on average (mean and median) values, even if they are statistically significant, it seems unlikely to be of clinical significance. Inter-subject variability of pepsin activity, and total bile acids content was high in both the healthy and the patients' groups. Statistical investigation of the potential impact of Crohn's disease on these parameters requires prior designation of the minimum differences to be detected; such differences will determine the minimum sample size required of relevant investigations.

On the Design of Food Effect Studies in Adults for Extrapolating Oral Drug Absorption Data to Infants: an Exploratory Study Highlighting the Importance of Infant Food.

In the present investigation, it was explored whether food effect on drug absorption in adults is similar with the food effect after administration of an infant meal with the drug product to adults. After confirming lack of pharmaceutical and pharmacokinetic interaction, a paracetamol suspension and an ibuprofen suspension were co-administered to eight healthy adults on a crossover basis in three different occasions, i.e. in the fasted state (as defined by regulatory agencies, fasted conditions), in the fed state (as defined by regulatory agencies, fed conditions) and under conditions simulating the fed state in infants (infant fed conditions). Unlike under fed conditions, under infant fed conditions early exposure was significantly lower than under fasted conditions for both paracetamol and ibuprofen. Also, for ibuprofen, Cmax values under infant fed conditions were significantly higher than under fed conditions. These data suggest that, even for drugs with non-problematic absorption administered in simple dosage forms, food effects in infants may not be adequately evaluated if the protocol suggested by regulatory agencies is applied. The usefulness of the methodology employed in the present investigation for simulating the fed state in infants deserves further evaluation. Until then, food effects in infants should be considered cautiously or be evaluated in infants.

The effect of anti-TNF therapy on thyroid function in patients with inflammatory bowel disease.

The aim of this study was to investigate for first time the thyroid function in patients with inflammatory bowel disease (IBD) and the potential effect of anti-TNF (tumor necrosis factor) therapy. We evaluated 41 patients with IBD (25M/16F, 36.5 ± 11.3 y, 27 with Crohn's disease and 14 with ulcerative colitis), without any known thyroid disorder. Eighteen patients (9M/9F, 33.6 ± 8.8 y) were on anti-TNF therapy, while 23 patients (16M/7F, 38.7 ± 12.5 y) were treated with Azathioprine and Mesalazine (Aza/Mes) for more than 1 year. Twelve patients from the second group were then treated with anti-TNF and studied 6 months later. We assessed thyroid function by measuring thyroid stimulating hormone (TSH), free thyroxine (FT4), triiodothyronine (T3), thyroid peroxidase autoantibodies (TPOAb) and thyroglobulin autoantibodies (TgAb) levels. One patient presented with overt and one with subclinical hyperthyroidism. Thyroid auto-antibodies were positive in 12.2%. Patients from the anti-TNF group had lower levels of FT4 (1.09 ± 0.15 vs. 1.38 ± 0.9 ng/dL, p = 0.042), while TSH and T3 were comparable. The percentage of patients with positive thyroid auto-antibodies was lower in the anti-TNF group (5.6% vs. 17.4%). In the subgroup of patients who changed to anti-TNF, we found statistically significant reduction in FT4 after 6 months (1.26 ± 0.24 vs. 1.08 ± 0.15 ng/dL, p = 0.044), without changes in TSH and T3 levels. There was no change regarding thyroid auto-antibodies. In conclusion, patients with IBD showed a quite high percentage of thyroid autoimmunity. After treatment with anti-TNF, FT4 levels were found to be reduced, while no changes in TSH, T3 levels and thyroid auto-antibodies were noted.

Favorable Effect of Anti-TNF Therapy on Insulin Sensitivity in Nonobese, Nondiabetic Patients with Inflammatory Bowel Disease.

BACKGROUND: The aim of this study was to investigate the effect of anti-TNF therapy on glucose and lipid metabolism in nondiabetic, nonobese patients with inflammatory bowel disease (IBD). PATIENTS AND METHODS: We studied 44 patients with IBD, without a known history of diabetes. Three of the patients were diagnosed with overt diabetes and were excluded. Eighteen of the remaining patients (9 M/9 F, 33.6 ± 8.8 years) were on anti-TNF therapy for longer than 1 year, while 23 patients (16 M/7 F, 38.7 ± 12.5 years) were treated with aminosalicylates (AMSs). Twelve of the patients from the second group were then treated with anti-TNF and reassessed 6 months later. Fasting glucose, insulin, c-peptide, HbA1c, lipid, CRP, and fibrinogen levels were determined, and HOMA-IR index was calculated in all patients. RESULTS: Patients from the two therapy groups were matched for age and BMI and were not obese. We did not find any differences between patients from the two therapy groups regarding fasting glucose, c-peptide, HbA1c, total cholesterol, HDL, LDL, triglycerides, CRP, and HOMA-IR index. In patients who were treated for 6 months with anti-TNF, a statistically significant decrease in insulin (before 15.5 ± 5.9 versus after 9.9 ± 2.9 µIU/ml, p = 0.042) and c-peptide (before 2.4 ± 1 versus after 1.3 ± 0.4 ng/ml, p = 0.030) levels as well as the HOMA-IR index (before 4.2 ± 1.9 versus after 2.2 ± 0.9, p = 0.045) was observed, without any changes in weight, BMI, glucose, HbA1c, lipid, CRP, and fibrinogen levels. CONCLUSION: Anti-TNF therapy exerts a favorable effect on insulin sensitivity, while it has no effect on lipid levels in nondiabetic, nonobese patients with inflammatory bowel disease.

Effectiveness of supersaturation promoting excipients on albendazole concentrations in upper gastrointestinal lumen of fasted healthy adults.

PURPOSE: To evaluate the impact of dosage form relevant levels of a polymeric precipitation inhibitor and of lipid excipients on supersaturation of upper gastrointestinal contents with albendazole, a lipophilic weak base. MATERIALS AND METHODS: Albendazole concentrations in stomach and in duodenum were evaluated after administration of 1) a suspension in water (Susp-Control), 2) a suspension in water in which hydroxyprolylmethylcellulose E5 (HPMC E5) had been pre-dissolved (Susp-HPMC), and 3) and 4) two contrasting designs of lipid based suspensions dispersed in water (Susp-IIIA and Susp-IV), on a cross-over basis to fasted healthy adults. RESULTS: Limited, but statistically significant supersaturation of duodenal contents was observed after Susp-HPMC, Susp-IIIA, and Susp-IV; supersaturation was more consistent after Susp-HPMC administration. Based on total albendazole amount per volume, gastric secretions did not significantly alter volumes of bulk gastric contents during the first 40min post administration of a glass of non-caloric water-based fluid. Αlbendazole gastric concentrations were higher than in the administered suspensions, but similar for all four formulations. Gastric emptying of albendazole after administration of Susp-Control or Susp-HPMC was slower than after administration of Susp-IIIA or Susp-IV. CONCLUSIONS: Small amounts of HPMC E5 were as effective as lipid excipients in achieving supersaturation of duodenal contents with albendazole, a fast precipitating weak base, in fasted adults. However, compared with the effect of HPMC E5 the effect of lipid excipients was delayed and variable.

Identification of key factors affecting the oral absorption of salts of lipophilic weak acids: a case example.

OBJECTIVES: Evaluate the ability of biorelevant media to adequately predict solubility in human gastrointestinal aspirates collected in the fasted state for the sodium salt of a highly dosed, Biopharmaceutics Classification System II (BCS II) compound with weakly acidic properties (L-870,810, pKa 7.3, HA (5-(1,1-dioxothiazinan-2-yl)-N-((4-fluorophenyl)methyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide)). Identify key luminal processes that dictate the behaviour of sodium salt of HA (NaA), after single-dose administrations of high (relatively to solubility limit) doses corresponding to 400 and 800 mg of HA in the fasted state. METHODS: Aspirates from stomach and upper small intestine were collected from eight healthy fasted adults, after administration of 240 ml of water. Solubilities of NaA and HA were measured in aspirated samples and biorelevant media. Dissolution experiments of NaA granules were performed in biorelevant media. Prediction of oral pharmacokinetics was evaluated in silico using Stella software. KEY FINDINGS: Equilibrium solubility of NaA in fluids aspirated from the upper gastrointestinal tract is more transient than of HA. Solubility in upper gastrointestinal lumen was adequately estimated by data in biorelevant media. Supersaturation, followed by precipitation, which did not fully revert to the equilibrium solubility of HA, was observed during the dissolution of NaA granules in biorelevant media. Physiologically based pharmacokinetic modelling indicated that while intragastric processes had no significant impact on absorption kinetics, dissolution kinetics, kinetic solubility, radial transport rates and, for the 800-mg dose, precipitation kinetics in the small intestine had the greatest impact on absorption profiles. CONCLUSIONS: Adequate prediction of the average plasma profile, after administration of NaA, required consideration of region-dependent dissolution rates and/or solubilisation.

Correlation between depression, anxiety, and polymorphonuclear cells' resilience in ulcerative colitis: the mediating role of heat shock protein 70.

BACKGROUND: To investigate whether anxiety and depression levels are associated with Heat Shock Protein 70 (HSP70) induction in the colon of patients with ulcerative colitis (UC). METHODS: The design was cross-sectional. Clinical activity was assessed by the Rachmilewitz Index (CAI). Three psychometric questionnaires were used: Zung Depression Rating Scale (ZDRS), Spielberg State-Trait Anxiety Inventory (STAI), Hospital Anxiety and Depression Scale (HADS). Colon biopsies were obtained from each affected anatomical site. Severity of inflammation was assessed by eosin/hematoxylin. Constitutive (HSP70c) and inducible (HSP70i) HSP70 expression were immunohistochemically studied. RESULTS: 29 UC patients were enrolled (69% men). Mean age was 46.5 years (SD: 19.5). Inflammation severity was moderate in 17 patients, severe in 6, and mild in 6. The mean number of years since diagnosis was 7.9 (SD: 6.5). The mean CAI was 6.4 (SD: 3.1). In active UC, there was downregulation of HSP70c in inflamed epithelium, without significant HSP70 induction. In 22/29 cases of active cryptitis, polymorphonuclear cells (PMN) clearly expressed HSP70i, with weak, focal positivity in the other 7 cases. Except for the hospital anxiety scale, scores in all psychometric tools were higher in patients with strong HSP70i immunoreactivity in the PMN. Logistic regression showed a strong positive relationship between HSP70i immunoreactivity in the PMN cells and scores in the trait anxiety, ZDRS, and hospital depression scales, (Odds ratios 1.3, 1.3, and 1.5; P = 0.018, 0.023, and 0.038; Wald test, 5.6, 5.2, and 4.3 respectively) and a weaker but significant positive correlation with the CAI (Odds ratio 1.654; P = 0.049; Wald test 3.858). CONCLUSION: HSP70 is induced in PMN cells of UC patients and its induction correlates with depression and anxiety levels.

Do self-perceptions of emotional intelligence predict health-related quality of life? A case study in hospital managers in Greece.

The aim of this study was to examine HRQoL outcome and EI of managers of Health Organizations. We collected data from 120 general managers of Greek public hospitals who completed the Assessing Emotions Scale (AES) and the SF-36 Health Survey. The results showed that male managers generally exhibited better HRQoL and slightly worse EI than females, although differences were not significant throughout. The three EI factors of the AES addressing appraisal, optimism/regulation and utilization of emotions correlated from 0.18 to 0.39 with sub-dimensions of HRQoL mostly related to mental -rather than physical- aspects of health, and were also significant predictors of HRQoL. There was a noteworthy gender difference in the manner in which EI predicted HRQoL and this suggests more testing. Overall, this study might enrich the potential for EI studies in Greece as well as to contribute to the international literature.

Precipitation in and supersaturation of contents of the upper small intestine after administration of two weak bases to fasted adults.

PURPOSE: To evaluate precipitation in and supersaturation of intestinal contents after administration of pharmacologically relevant doses of dipyridamole and ketoconazole to 12 healthy adults. METHODS: On two separate days each subject was administered in stomach 240 ml aqueous solutions of two dipyridamole doses (30/90 mg) and two ketoconazole doses (100/300 mg). Physicochemical characteristics, total drug content, and drug concentration were measured in individual intestinal contents (≤7 ml) aspirated at specific times post-dosing. Drug concentration after incubation (37°C/48 h) and equilibrium solubility were measured. Precipitate crystallinity was evaluated by x-ray powder diffraction. RESULTS: Precipitated fraction was minimal (dipyridamole, ≤7%) or limited (ketoconazole, ≤16%). Ketoconazole precipitates were mostly amorphous. Depending on dose, intestinal contents with pH > 3.6 were supersaturated with dipyridamole up to 10 and 30 min and with ketoconazole up to 30 and 50 min post-administration. Intestinal contents with pH > 5 and concentration of micellar components <5 mM were supersaturated with ketoconazole or dipyridamole, but precipitated fraction was significant only for ketoconazole. After incubation, crystalline precipitates were found in almost all samples. Slow precipitation of base and/or precipitation of other phases account for this observation. CONCLUSIONS: Intralumenal precipitation of weakly alkaline, lipophilic, high permeability drugs may not be substantial. Estimating intestinal supersaturation in regard to free base is inadequate as other phases may precipitate.

Degradation kinetics of metronidazole and olsalazine by bacteria in ascending colon and in feces of healthy adults.

PURPOSE: To compare the degradation kinetics of metronidazole and olsalazine by the bacteria of ascending colon and the bacteria of feces of healthy adults. METHODS: Contents of the ascending colon of seven healthy adults were collected under conditions simulating the bioavailability/bioequivalence studies in the fasted and in the fed states on a crossover basis. Material from the contents of the ascending colon was prepared by ultracentrifuging and diluting the precipitate with a volume of normal saline equivalent to that of the supernatant. Fecal material was prepared from feces of three healthy adults collected at two occasions that were separated by at least 6 months. Ex vivo drug degradation kinetics were evaluated under anaerobic conditions. RESULTS: Mean half-lives of metronidazole degradation in material from the contents of the ascending colon collected in the fasted state and in fecal material were 16.1 and 2.4 min, respectively (p<0.001). The corresponding numbers for olsalazine were 57.8 and 9.2 min, respectively (p<0.001). Both compounds were stable in material from the contents of ascending colon collected in the fed state. CONCLUSIONS: Compared with data in fecal material, degradation of metronidazole and olsalazine in material from the contents of the ascending colon is significantly slower and it becomes non-significant during the arrival of fresh food remnants in the region.

The use of self-expanding stents in esophageal and gastroesophageal junction cancer palliation: a meta-analysis and meta-regression analysis of outcomes.

BACKGROUND: The objective of this study was to examine the impact of self-expanding stents versus locoregional treatment modalities in the setting of esophageal cancer palliation. METHODS: The present meta-analysis pooled the effects of outcomes of 1,027 patients enrolled in 16 randomized controlled trials. RESULTS: The meta-analysis revealed an advantage to the use of stents compared to locoregional modality treatments with respect to the number of patients requiring reinterventions, although the latter treatment arm had a higher 1-year survival. No difference was observed between the use of the antireflux stents and conventional stents in relieving reflux. Previous chemoradiotherapy had no impact on complications, procedural deaths, and overall patient survival. Differences in outcomes among stents were minimal. CONCLUSIONS: Conventional self-expanding stents and anti-reflux stents are equally effective. Although the risk difference for 1-year survival favoured locoregional palliative treatment modalities, the latter were associated with a higher number of patients requiring reintervention.

Characterization of the ascending colon fluids in ulcerative colitis.

PURPOSE: To characterize the fluid composition in ascending colon of fasted adults with ulcerative colitis in relapse and in remission with a view to predicting variations on dosage form performance in the lower inflamed gut. METHODS: Twelve patients participated in a two-phase, crossover study. Enrollment to the relapse phase (Phase A) and designation of the remission state for the second colonoscopy (Phase B) were based on Clinical Rachmilewicz Index values. Samples were analyzed for pH and buffer capacity immediately upon collection. After ultracentrifugation, osmolality, surface tension, soluble protein, soluble carbohydrates, and the levels of ten bile acids, seven short-chain fatty acids (SCFAs), three long-chain fatty acids, triglycerides, diglycerides, monoglycerides, phosphatidylcholine, and cholesterol were measured. RESULTS: Total SCFAs are significantly decreased in relapse, but pH remains unaffected. Regardless of remission/relapse status, pH and isobutyric acid levels are lower than in healthy adults. Buffer capacity, osmolality, and soluble protein are higher than in healthy adults. Treatment with prednisolone increases the volume of intracolonic contents. CONCLUSION: Variations in fluid composition of the ascending colon with activity and severity of ulcerative colitis may have an impact on the performance of orally administered products that are targeted to release the therapeutic agent in the colon.