Intestinal GLP-1 and satiation: from man to rodents and back.

In response to luminal food stimuli during meals, enteroendocrine cells release gastrointestinal (GI) peptides that have long been known to control secretory and motor functions of the gut, pancreas and liver. Glucagon-like peptide-1 (GLP-1) has emerged as one of the most important GI peptides because of a combination of functions not previously ascribed to any other molecule. GLP-1 potentiates glucose-induced insulin secretion, suppresses glucagon release, slows gastric emptying and may serve as a satiation signal, although the physiological status of the latter function has not been fully established yet. Here we review the available evidence for intestinal GLP-1 to fulfill a number of established empirical criteria for assessing whether a hormone inhibits eating by eliciting physiological satiation in man and rodents.

English language version of the S3-consensus guidelines on chronic pancreatitis: Definition, aetiology, diagnostic examinations, medical, endoscopic and surgical management of chronic pancreatitis.

Chronic pancreatitis is a disease of the pancreas in which recurrent inflammatory episodes result in replacement of pancreatic parenchyma by fibrous connective tissue. This fibrotic reorganization of the pancreas leads to a progressive exocrine and endocrine pancreatic insufficiency. In addition, characteristic complications arise, such as pseudocysts, pancreatic duct obstructions, duodenal obstruction, vascular complications, obstruction of the bile ducts, malnutrition and pain syndrome. Pain presents as the main symptom of patients with chronic pancreatitis. Chronic pancreatitis is a risk factor for pancreatic carcinoma. Chronic pancreatitis significantly reduces the quality of life and the life expectancy of affected patients. These guidelines were researched and compiled by 74 representatives from 11 learned societies and their intention is to serve evidence-based professional training as well as continuing education. On this basis they shall improve the medical care of affected patients in both the inpatient and outpatient sector. Chronic pancreatitis requires an adequate diagnostic workup and systematic management, given its severity, frequency, chronicity, and negative impact on the quality of life and life expectancy.

Nonanesthesiologist-administered propofol sedation: from the exception to standard practice. Sedation and monitoring trends over 20 years.

The practice of sedation, including monitoring practice for digestive endoscopy, continues to evolve throughout the world. In many countries, including Switzerland, there is a trend towards increased utilization of sedation during both routine and advanced endoscopic procedures. Sedation improves patient satisfaction with endoscopy and also improves the quality of the examination. In addition, a trend can be observed towards an increasing use of propofol as the preferred sedative drug. Here we review the latest published data from surveys describing sedation and monitoring practice in different countries and compare them with our own data from successive nationwide surveys among Swiss gastroenterologists over a period of 20 years. This development between these socioeconomically very similar Western industrialized countries, however, shows some unique and surprising differences. In Germany and Switzerland, propofol use has become increasingly widespread, in Switzerland even to the extent that during the last few years propofol has overtaken benzodiazepine sedation, with an absolute majority of Swiss gastroenterologists using it without the assistance of an anesthesiologist. In addition, the change in Switzerland reflects a successful generalization of nonanesthesiologist-administered propofol (NAAP) sedation from the hospital setting to private practice.

The role of the gut sweet taste receptor in regulating GLP-1, PYY, and CCK release in humans.

The recent identification of sweet taste receptors in the gastrointestinal tract has important implications in the control of food intake and glucose homeostasis. Lactisole can inhibit the sweet taste receptor T1R2/T1R3. The objective was to use lactisole as a probe to investigate the physiological role of T1R2/T1R3 by assessing the effect of T1R2/T1R3 blockade on GLP-1, PYY, and CCK release in response to 1) intragastric administration of nutrients or 2) intraduodenal perfusion of nutrients. The study was performed as a randomized, double-blind, placebo-controlled crossover study that included 35 healthy subjects. In part I, subjects received intragastrically 75 g of glucose in 300 ml of water or 500 ml of a mixed liquid meal with or without lactisole. In part II, subjects received an intraduodenal perfusion of glucose (29.3 g glucose/100 ml; rate: 2.5 ml/min for 180 min) or a mixed liquid meal (same rate) with or without lactisole. The results were that 1) lactisole induced a significant reduction in GLP-1 and PYY but not CCK secretion in both the intragastric and the intraduodenal glucose-stimulated parts (P ≤ 0.05), 2) comparison of the inhibitory effect of lactisole showed a significantly greater suppression of the hormone response in the intragastric part (P = 0.023), and 3) lactisole had no effect on liquid meal-stimulated parameters. We conclude that T1R2/T1R3 is involved in glucose-dependent secretion of satiation peptides. However, the results of the liquid meal-stimulated parts show that the receptor alone is not responsible for peptide secretion.

Metabolic surgery-principles and current concepts.

INTRODUCTION: In the almost six decades of bariatric surgery, a variety of surgical approaches to treating morbid obesity have been developed. HISTORY AND EVOLUTION: Rather than prior techniques being continually superseded by new ones, a broad choice of surgical solutions based on restrictive, malabsorptive, humoral effects, or combinations thereof, is now available. In fact, in recent years, the advent of surgically modifying human metabolism promises new approaches to ameliorate traditionally medically treated metabolic entities, i.e., diabetes, even in the non-obese. The understanding of the various metabolic effects have led to a paradigm shift from bariatric surgery as a solely weight-reducing procedure to metabolic surgery affecting whole body metabolism. CONCLUSION: The bariatric surgeon now faces the challenge and opportunity of selecting the most suitable technique for each individual case. To assist in such decision-making, this review, Metabolic surgery-principles and current concepts, is presented, tracing the historical development; describing the various surgical techniques; elucidating the mechanisms by which glycemic control can be achieved that involve favorable changes in insulin secretion and insulin sensitivity, gut hormones, adipokines, energy expenditure, appetite, and preference for low glycemic index foods; as well as exploring the fascinating future potential of this new interdisciplinary field.

Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial.

OBJECTIVE: Eosinophilic oesophagitis (EoO) is a clinicopathological condition defined by proton pump inhibitor-refractory oesophageal symptoms combined with oesophageal eosinophilia. The pharmacodynamic effect of mepolizumab (a humanised anti-interleukin-5 monoclonal antibody) in EoO was evaluated. METHODS: Eleven adults with active EoO (>20 peak eosinophil number/high power field (hpf) and dysphagia) were randomised to 750 mg of mepolizumab (n = 5) or placebo (n = 6) and received two intravenous infusions, 1 week apart. Those not in complete remission (<5 peak eosinophil number/hpf) after 8 weeks received two further doses 4 weeks apart, 1500 mg of mepolizumab or placebo. The effect of mepolizumab was assessed clinically, endoscopically, histologically, and via blood and tissue biomarkers. RESULTS: As assessed by immunofluorescence, a marked reduction of mean oesophageal eosinophilia (p = 0.03) was seen in the mepolizumab group (-54%) compared with the placebo group (-5%) 4 weeks after initiation of treatment. No further reduction of eosinophil numbers was observed in response to the two additional infusions in either group. Mepolizumab reduced tenascin C (p = 0.033) and transforming growth factor beta1 (p = 0.05) expression in the oesophageal epithelial layer 13 weeks after initiation of treatment. Clinically, limited improvement of symptoms was seen, although a trend was seen between 4 and 13 weeks after initiation of mepolizumab treatment. Mepolizumab was well tolerated. CONCLUSIONS: Mepolizumab significantly reduced eosinophil numbers in oesophageal tissues in adult patients with active EoO, and changes in the expression of molecules associated with oesophageal remodelling were reversed. Minimal clinical improvement was achieved in a subgroup of patients with EoO. Mepolizumab had an acceptable safety profile, even at the high 1500 mg dose level. TRIAL REGISTRATION NUMBER: NCT00274703.

[Spatial accessibility to animal health care - a GIS based analysis]. / Räumliche Zugänglichkeit zu tiermedizinischer Versorgung ­ eine GIS-basierte Analyse.

INTRODUCTION: Various studies from the past years examine the changing conditions and challenges in the veterinary sector. Secured access to public and private care services is a prerequisite for a holistically oriented health care system ("One Health"). In the present study, a multidimensional concept of accessibility to care services was used for the first time to determine and visualize the density of the animal health care system in Switzerland. Traditional indicators used to describe care structures focus either on availability or accessibility. In order to overcome the limitations of traditional indicators, the family of methods known as Floating-Catchment-Area-Methods (FCA) has been developed in care geographical research. The strength of FCA methods lies in the fact that they output accessibility independent of administrative boundaries and at the same time consider the spatial distance and available capacities. The study provides insight into the density of animal health care services using FCA methods and geographical information systems (GIS). Data on providers of veterinary services in the companion animal sector and, on the demand side, data on dogs and cats kept in Switzerland served as illustrative example. The result was interactive maps of the density of health care and the structure of spatial accessibility to veterinary providers and consumers. As expected, high spatial accessibility is found in the urban centers and the agglomerations of the Central Plateau. In contrast, spatial accessibility to medical services for dogs and cats is often lower in peripheral areas. Due to hitherto unavailable data, various analyses had to be postponed for the time being. For example, the model could of course be extended to all animal species and all types of medical services. In addition, it would also be possible to forecast the future density of health care, or to optimize the care system. Together with the relevant industry stakeholders, these gaps could be closed, and the model and the resulting findings could be further differentiated. The results should serve private actors in the concerned value chains, but also decision-makers in the public veterinary service, governmental authorities, agricultural bodies, universities, etc. as a basis for strategic decisions regarding the issue of medical supply density and care services in the animal sector.

INTRODUCTION: Ces dernières années, divers travaux ont examiné l'évolution des conditions cadres et des défis dans le secteur vétérinaire. L'assurance d'un accès aux soins publics et privés est une condition préalable à un système de santé holistique (« One Health ¼). Dans le travail présent, on a tenté pour la première fois d'enregistrer et de visualiser la densité d'approvisionnement du système de soins vétérinaires en Suisse en utilisant un concept multidimensionnel d'accessibilité aux offres de soins. Les indicateurs traditionnels pour décrire les structures de soins se concentrent soit sur la disponibilité soit sur l'accessibilité. Afin de contrer les limites des indicateurs traditionnels, la famille de méthodes du Floating-Catchment-Area (FCA) s'est développée dans la recherche en géographie sanitaire. La force des méthodes FCA est qu'elles fournissent un accès indépendamment des limites administratives, tout en tenant compte de la distance spatiale et de la capacité disponible. Ce travail permet d'avoir un aperçu de la densité de l'offre vétérinaire en utilisant la méthodologie FCA en tenant compte de systèmes d'information géographique (SIG). Les données sur les prestataires de services vétérinaires dans le secteur des animaux de compagnie et sur la demande concernant les chiens et les chats vivant en Suisse ont servi d'exemple. Le résultat a été des cartes interactives de la densité de l'offre et de la structure de l'accessibilité spatiale aux prestataires vétérinaires et de celle des consommateurs. Comme prévu, il existe un degré élevé d'accessibilité spatiale dans les centres urbains et les agglomérations du plateau suisse. En revanche, l'accessibilité spatiale aux services vétérinaires pour chiens et chats est souvent plus basse dans les zones périphériques. En raison de données indisponibles précédemment, diverses analyses ont dû être abandonnées dans un premier temps. Ce modèle pourrait être étendu à toutes les espèces animales et aux diverses offres vétérinaires. En outre, il serait également possible de faire des prévisions sur la future densité de l'offre ou sur son optimisation. Conjointement avec les acteurs de la branche concernés, ces lacunes pourraient être comblées avec certitude et le modèle et les résultats qui en résulteraient seraient encore plus différenciés. Les résultats sont destinés à aider les acteurs privés dans les chaînes de valeur ajoutée, mais ils pourraient aussi servir de base aux décideurs des services vétérinaires publics, aux autorités d'exécution, aux organes de l'agriculture, aux universités, etc., pour prendre des décisions stratégiques autour du thème de la densité de l'offre médicale dans le secteur animal.

Appropriateness of colonoscopy in Europe (EPAGE II). Chronic diarrhea and known inflammatory bowel disease.

BACKGROUND AND STUDY AIMS: To summarize the published literature on assessment of appropriateness of colonoscopy for investigation of chronic diarrhea, management of patients with known inflammatory bowel disease (IBD), and for colorectal cancer (CRC) surveillance in such patients, and to report report appropriateness criteria developed by an expert panel, the 2008 European Panel on the Appropriateness of Gastrointestinal Endoscopy, EPAGE II. METHODS: A systematic search of guidelines, systematic reviews, and primary studies regarding the evaluation of chronic diarrhea, the management of IBD, and colorectal cancer surveillance in IBD was performed. The RAND/UCLA Appropriateness Method was applied to develop appropriateness criteria for colonoscopy for these conditions. RESULTS: According to the literature, colonoscopic evaluation may be justified for patients aged > 50 years with recent-onset chronic diarrhea or with alarm symptoms. Surveillance colonoscopy for CRC should be offered to all patients with extensive ulcerative colitis or colonic Crohn's disease of 8 years' duration, and to all patients with less extensive disease of 15 years' duration. Intervals for surveillance colonoscopy depend on duration of evolution, initial diagnosis, and histological findings. The EPAGE II criteria also confirmed the appropriateness of diagnostic colonoscopy for diarrhea of > 4 weeks' duration. They also suggest that, in addition to assessing extent of IBD by colonoscopy, further colonoscopic examination is appropriate in the face of persistent or worsening symptoms. Surveillance colonoscopy in IBD patients was generally appropriate after a lapse of 2 years. In the presence of dysplasia at previous colonoscopy, it was not only appropriate but necessary. CONCLUSIONS: Despite or perhaps because of the limitations of the available published studies, the panel-based EPAGE II (http://www.epage.ch) criteria can help guide appropriate colonoscopy use in the absence of strong evidence from the literature.

Pharmacokinetics and pharmacodynamic effects of oral GLP-1 and PYY3-36: a proof-of-concept study in healthy subjects.

This proof-of-concept study was performed in order to establish the pharmacokinetics and pharmacodynamics of increasing oral doses of the satiety peptides glucagon-like peptide-1 (GLP-1) and peptide YY3-36 (PYY3-36). Six healthy male subjects were given oral doses of either a placebo or GLP-1 in a dose-escalating schedule (doses of 0.5, 1.0, 2.0, and 4.0 mg). Next, another group of six healthy male subjects were given oral doses of either a placebo or PYY3-36 in the same pattern of escalating doses (doses of 0.25, 0.5, 1.0, 2.0, and 4.0 mg). In healthy male volunteers, (i) oral administration of either of the peptides induced a rapid and dose-dependent increase in plasma drug concentrations; (ii) oral administration of GLP-1 induced a potent effect on insulin release; and (iii) both peptides suppressed ghrelin secretion. In conclusion, this study showed, for the first time, that satiety peptides such as GLP-1 and PYY3-36 can be orally delivered safely and effectively in humans.

Two-marker protein profile predicts poor prognosis in patients with early rectal cancer.

The aim of this study was to establish an immunohistochemical protein profile to complement preoperative staging and identify rectal cancer patients at high-risk of adverse outcome. Immunohistochemistry was performed on a tissue microarray including 482 rectal cancers for APAF-1, EphB2, MST1, Ki67, p53, RHAMM, RKIP and CD8(+) tumour infiltrating lymphocytes (TILs). After resampling of the data and multivariable analysis, the most reproducible markers were combined and prognosis evaluated as stratified by pT and pN status. In multivariable analysis, only positive RHAMM (P<0.001; HR=1.94 (1.44-2.61)) and loss of CD8(+) TILs (P=0.006; HR=0.63 (0.45-0.88)) were independent prognostic factors. The 5-year cancer-specific survival rate for RHAMM+/TIL- patients was 30% (95% CI 21-40%) compared to 76% (95% CI: 66-84%) for RHAMM-/TIL+ patients (P<0.001). The 5-year cancer-specific survival of T1/T2/RHAMM+/TIL- patients was 48% (20-72%) and significantly worse compared to T3/T4/RHAMM-/TIL+ patients (71% 95% CI 56-82%); P=0.039). Stratifying by nodal status, only N+/RHAMM+/TIL- patients demonstrated a significantly worse prognosis than N0/RHAMM+/TIL- patients (P=0.005). Loss of CD8(+) TILs was predictive of local recurrence in RHAMM+ tumours (P=0.009) only. RHAMM and CD8(+) TILs may assist in identifying early stage rectal cancer patients facing a particularly poor prognosis and who may derive a benefit from preoperative therapy.

Effect of yacon (Smallanthus sonchifolius) on colonic transit time in healthy volunteers.

BACKGROUND: Yacon is a root crop which contains high amounts of fructooligosaccharides (FOS). The aim of this study was to investigate the effects of yacon syrup on colon transit time in healthy volunteers. METHODS: In a placebo-controlled, double-blind study yacon was administered to 16 healthy individuals (8 males, 8 females) in a dose of 20 g daily (equal to 6.4 g FOS) in a 2-week crossover design. Each period was interrupted by a 2-week wash-out phase. Transit time was assessed by a radio-opaque marker technique. RESULTS: Transit time (mean +/- SEM) through the gastrointestinal tract was significantly decreased from 59.7 +/- 4.3 to 38.4 +/- 4.2 h (p < 0.001). Yacon was well tolerated with an excellent side effect profile. Bloating is not an uncommon side effect observed with FOS, but bloating-related disturbances were not significantly more often reported with yacon compared to placebo. Stool frequency increased from 1.1 +/- 0.1 to 1.3 +/- 0.2 times per day and the consistency showed a tendency for softer stools as assessed by a numerical depicted stool protocol. Neither parameter did, however, reach statistical significance. CONCLUSION: Yacon markedly accelerates colonic transit in healthy individuals. Further studies are needed in constipated patients to confirm these preliminary data. Due to the low caloric content of yacon, the root could be a useful treatment in constipated diabetics or obese patients.

Circulating somatostatin. Physiological regulator of pancreatic function?

The present study was designed to determine whether somatostatin is released into the circulation in sufficient amounts to regulate exocrine and endocrine pancreatic function and to evaluate the possible role of somatostatin as a hormonal regulator of the pancreas. Mean plasma somatostatin levels (SLI) increased from 11 +/- 2 pmol liter-1 to peak concentrations of 18 +/- 2 in six healthy male volunteers after a steak meal (P less than 0.05). Infusion of somatostatin inhibited hormone-induced exocrine pancreatic secretion and suppressed cerulein-stimulated pancreatic polypeptide (PP) secretion, but did not significantly change arginine-stimulated insulin and glucagon release at mean plasma somatostatin concentrations within the range seen after a meal. The amount of somatostatin released after a meal thus was of sufficient magnitude to inhibit exocrine pancreatic function and PP release. On the other hand, basal and arginine-stimulated glucagon and insulin secretions were not significantly affected by these plasma concentrations of intravenous somatostatin suggesting that the exocrine pancreas might be more sensitive to somatostatin than the islet cells. We conclude that somatostatin in concentrations within the range seen after a meal is a potent inhibitor of stimulated acinar cell function in man. The findings support the hypothesis that somatostatin acts as a true hormonal regulator.

A physiologic role for somatostatin 28 as a regulator of insulin secretion.

Somatostatin 28 (S-28) is a peptide produced in the intestinal tract which rises in the circulation during nutrient absorption. We tested the hypothesis that S-28 regulates B-cell function by (a) studying the effects on insulin secretion of "physiologic" infusions of S-28 and (b) measuring insulin responses during elevated nutrient-stimulated endogenous S-28 levels. (a) Synthetic S-28 was infused on separate days into six healthy men at rates of 25 and 50 ng/kg per h which mimicked postprandial levels. Subjects were given a bolus of glucose (0.1 g/kg) after 120 min. Insulin responses during S-28 infusions were compared to a control study using a saline infusion in the same individuals. Glucose-stimulated insulin secretion was inhibited during the infusion of 50 ng/kg per h S-28 when compared to control (P less than 0.05). (b) Insulin secretion during elevations of endogenous S-28 was studied in healthy men who received a bolus of 2.5 g arginine (n = 14) or 25 U of secretin (n = 8) 120 min after swallowing 50 g fat, or, on a separate day, an equivalent volume of water. S-28 levels rose significantly after fat ingestion but did not change after water. Arginine and secretin-stimulated insulin secretion was inhibited following ingestion of fat compared with intake of water (P less than 0.05). Arginine-enhanced glucagon secretion was not changed by fat ingestion. We conclude that elevations in plasma S-28 levels, occurring during the postprandial state, attenuate B-cell secretion and this peptide may be a physiologic modulator of nutrient-stimulated insulin release.

Pancreatic enzyme response to a liquid meal and to hormonal stimulation. Correlation with plasma secretin and cholecystokinin levels.

Pancreatic trypsin output and plasma secretin and cholecystokinin (CCK) levels were measured in five healthy volunteers to investigate the mechanisms involved in regulating postprandial pancreatic secretion. The pancreas was stimulated by a liquid test meal or by either intravenous secretin (1-82 pmol/kg-1 per h-1) or caerulein, a CCK analogue (2.3-37 pmol/kg-1 per h-1), or by a combination of secretin and caerulein. Pancreatic secretion was assessed by a marker perfusion technique (polyethylene glycol [PEG 4000]), plasma secretin, and CCK by specific radioimmunoassays. Increasing doses of secretin produced increasing bicarbonate output (P less than 0.01), whereas trypsin was not stimulated over basal. Graded caerulein produced a stepwise increase in trypsin and bicarbonate output (P less than 0.01). Potentiation occurred for bicarbonate secretion between secretin and caerulein, but not for trypsin output. Postprandial trypsin secretion averaged 29.1 IU/min-1 over 150 min (equal to 55% of maximal response to caerulein). The peak trypsin response amounted to 90% of maximal caerulein. Significant increases of plasma secretion (P less than 0.05) and CCK (P less than 0.01) were observed after the meal. Comparison of enzyme and CCK responses to the testmeal or to exogenous caerulein suggested that the amount of CCK released after the meal could account for the postprandial trypsin secretion. We conclude that (a) the postprandial enzyme response in man is submaximal in comparison to maximal exogenous hormone stimulation; (b) CCK is a major stimulatory mechanism of postprandial trypsin secretion, whereas secretin is not involved; and (c) Potentiation of enzyme secretion is not a regulatory mechanism of the postprandial secretory response.

Effects of a cholecystokinin receptor antagonist on intestinal phase of pancreatic and biliary responses in man.

The present study was designed (a) to characterize the activity of loxiglumide as a peripheral cholecystokinin (CCK) antagonist in healthy human subjects, and (b) to determine whether CCK is a physiologic regulator of the intestinal phase of meal-stimulated exocrine pancreatic and biliary secretions in man. Intravenous loxiglumide (22 mumol/kg per h) was highly potent in antagonizing CCK8-induced pancreatic enzyme and bile acid secretion as well as pancreatic polypeptide release. The potency and selectivity of loxiglumide as an antagonist of CCK provides the tool for evaluating the role of CCK as a physiological mediator of meal-induced pancreatic and biliary responses in humans. Infusion of a liquid test meal into the duodenum evoked an immediate response of pancreatic enzyme and bilirubin outputs, respectively. Intravenous loxiglumide significantly inhibited the meal-induced pancreatic amylase output by 63% (P less than 0.05), lipase output by 43% (P less than 0.05), and bilirubin output by 59% (P less than 0.05). These data suggest that CCK is a physiological mediator of the intestinal phase of meal-stimulated pancreatic and biliary responses.

Effects of budesonide on P-glycoprotein expression in intestinal cell lines.

BACKGROUND AND PURPOSE: P-glycoprotein (P-gp) is an important efflux transporter that supports the barrier function of the gut against invading antigens and against administered drugs. Since glucocorticoids, such as budesonide, are frequently used during inflammatory bowel disease we investigated how budesonide influences P-gp expression in different intestinal cell lines. EXPERIMENTAL APPROACH: LS180 and Caco-2 cells were incubated with budesonide and changes in P-gp expression were determined on mRNA, protein and functional level. The mRNA expression levels of glucocorticoid receptor (GR) and pregnane X receptor (PXR) were determined in these cell lines. PXR receptor was transiently transfected into Caco-2 cells. KEY RESULTS: Budesonide showed an induction of P-gp in LS180 cells and a down-regulation in Caco-2 cells. Expression levels of nuclear receptors revealed high expression of PXR only in LS180 cells and exclusive expression of GR in Caco-2 cells. Mifepristone, an anti-glucocorticoid, could not reverse the down-regulation of P-gp by budesonide in Caco-2 cells. In PXR-transfected Caco-2 cells the budesonide-mediated down-regulation of P-gp was abolished. Furthermore the expression of cytochrome P450 3A4 (CYP3A4), another PXR target gene, was induced in PXR-transfected Caco-2 cells after budesonide treatment. CONCLUSIONS AND IMPLICATIONS: Budesonide has the potential to influence MDR1 expression in vitro. In LS180 cells, the induction of MDR1 by budesonide probably is mediated via PXR. The mechanism of the down-regulation in Caco-2 cells still remains unclear, but GR does not seem to be involved. Further studies are required to evaluate how budesonide alters P-gp expression in vivo.

Glucagon-like peptide 1 receptor expression in primary porcine proximal tubular cells.

BACKGROUND: GLP-1 is secreted into the circulation after food intake. The main biological effects of GLP-1 include stimulation of glucose dependent insulin secretion and induction of satiety feelings. Recently, it was demonstrated in rats and humans that GLP-1 can stimulate renal excretion of sodium. Based on these data, the existence of a renal GLP-1 receptor (GLP-1R) was postulated. However, the exact localization of the GLP-1R and the mechanism of this GLP-1 action have not yet been investigated. METHODS: Primary porcine proximal tubular cells were isolated from porcine kidneys. Expression of GLP-1R was measured at the mRNA level by quantitative RT-PCR. Protein expression of GLP-1R was verified with immunocytochemistry, immunohistochemistry and Western blot analysis. Functional studies included transport assessments of sodium and glucose using three different GLP-1 concentrations (200 pM, 2 nM and 20 nM), 200 pM exendin-4 (GLP-1 analogue) and an inhibitor of the dipeptidylpeptidase IV (DPPIV) enzyme (P32/98 at 10 microM). Finally, the expression of NHE3, the predominant Na(+)/H(+) exchanger in proximal tubular cells, was also investigated. RESULTS: GLP-1R, NHE3 and DPPIV were expressed at the mRNA level in porcine proximal tubular kidney cells. GLP-1R expression was confirmed at the protein level. Staining of human and pig kidney cortex revealed that GLP-1R was predominantly expressed in proximal tubular cells. Functional assays demonstrated an inhibition of sodium re-absorption with GLP-1 after 3 h of incubation. Exendin-4 and GLP-1 in combination with P32/98 co-administration had no clear influence on glucose and sodium uptake and transport. CONCLUSION: GLP-1R is functionally expressed in porcine proximal tubular kidney cells. Addition of GLP-1 to these cells resulted in a reduced sodium re-absorption. GLP-1 had no effect on glucose re-absorption. We conclude that GLP-1 modulates sodium homeostasis in the kidney most likely through a direct action via its GLP-1R in proximal tubular cells.

Comparison of two antacid preparations on intragastric acidity--a two-centre open randomised cross-over placebo-controlled trial.

BACKGROUND: Rennie and Riopan Gel are 2 of the most well-known and popular over-the-counter antacids; for heartburn symptoms, pain relief is fast with both preparations. A direct comparison with respect to intragastric acidity has not been done yet. The aim of our study was therefore to compare the effects of both preparations on intragastric acidity of fasting volunteers. METHODS: The study was conducted as an open, randomised, placebo-controlled, 2-centre cross-over study. On different days, 24 healthy adult volunteers (11 males and 13 females) received equimolar acid-neutralising amounts of either Riopan Gel (800 mg magaldrate) or 2 tablets of Rennie (680 mg calcium carbonate and 80 mg magnesium carbonate) or no drug (control) with a wash-out period of at least 4 days between applications. The intragastric pH was measured for 3 h by intragastric pH-metry. The primary endpoint was the median time lag before intragastric pH >3.0 was reached for 10 consecutive min after drug administration. RESULTS: For both antacids, the median pH during the first 30 min after drug administration was statistically significantly different from placebo (p < 0.05), but there was a statistically significant increase in pH during the first 5 min for Riopan Gel only. CONCLUSION: Compared to placebo, both antacids (Rennie and Riopan Gel) have short-lasting effects on intragastric acidity. There is no statistically significant difference between the 2 preparations, except in the first 5 min, indicating a faster onset of action for Riopan Gel. We conclude that the antacid formulation (tablet or liquid) has little influence on intragastric acidity.

Differential regulation of somatostatin receptor type 2 (sst 2) expression in AR4-2J tumor cells implanted into mice during octreotide treatment.

Octreotide is a somatostatin analogue that is widely used for cancer therapy and tumor imaging. Its efficacy in tumors depends mainly on the expression of the somatostatin receptor type 2 (sst 2). Desensitization and down-regulation of sst 2 after agonist exposure can have important consequences for patients under ongoing octreotide therapy because it may induce temporary tumor unresponsiveness and impair sst 2-based tumor scintigraphy. Therefore, we have investigated the effect of octreotide on sst 2 expression in vitro, as well as in a tumor mouse model. In vitro, short exposure to octreotide induced rapid dose-dependent down-regulation of sst 2 in the rat pancreatic AR4-2J cell line. Within 0.5 h, 80% of sst 2 had disappeared from the cell surface. A total recovery required 24 h and was shown to depend on protein synthesis, but not on new sst 2 mRNA transcription, indicating that sst 2 was probably degraded during the down-regulation process. Similar results were obtained in vivo. On the other hand, long-term continuous release of octreotide for 7 days, as achieved with octreotide-containing osmotic minipumps, caused sst 2 up-regulation in vivo, but not in vitro. Furthermore, this up-regulation of sst 2 in tumor-bearing scid mice was shown to depend on constant exposure of the animals to octreotide, as it was not observed when octreotide was given discontinuously in two s.c. daily injections. These results demonstrate that the continuous release of a small amount of octreotide, which in cancer therapy may be achieved with long-acting release formulations of the peptide, can induce sst 2 up-regulation on cancer cells. This may improve the efficacy of both tumor imaging and long-term octreotide therapy.