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ABSTRACTBackgroundThere is a growing consensus that sugar consumption should be reduced and the naturally occurring, low-calorie sweeteners xylitol and erythritol are gaining popularity as substitutes, but their effect on brain circuitry regulating appetite is unknown.AimThe study’s objective was to examine the effects of the two sweeteners on cerebral blood flow (rCBF) and resting functional connectivity in brain networks involved in appetite regulation, and test whether these effects are related to gut hormone release.MethodsThe study was performed as a randomized, double-blind, placebo-controlled, cross-over trial. Twenty volunteers received intragastric (ig) loads of 50g xylitol, 75g erythritol, 75g glucose dissolved in 300mL tap water or 300mL tap water. Resting perfusion and blood oxygenation level-dependent data were acquired to assess rCBF and functional connectivity. Blood samples were collected for determination of CCK, PYY, insulin and glucose.ResultsWe found: (i) xylitol, but not erythritol, increased rCBF in the hypothalamus, whereas glucose had the opposite effect; (ii) graph analysis of resting functional connectivity revealed a complex pattern of similarities and differences in brain network properties following xylitol, erythritol, and glucose; (iii) erythritol and xylitol induced a rise in CCK and PYY, (iv) erythritol had no and xylitol only minimal effects on glucose and insulin.ConclusionXylitol and erythritol have a unique combination of properties: no calories, virtually no effect on glucose and insulin while promoting the release of gut hormones, and impacting appetite-regulating neurocircuitry consisting of both similarities and differences with glucose.

ObjectiveThe best approach for Helicobacter pylorimanagement remains unclear. An audit process is essential to ensure clinical practice is aligned with best standards of care.DesignInternational multicentre prospective non-interventional registry starting in 2013 aimed to evaluate the decisions and outcomes in H. pylorimanagement by European gastroenterologists. Patients were registered in an e-CRF by AEG-REDCap. Variables included demographics, previous eradication attempts, prescribed treatment, adverse events and outcomes. Data monitoring was performed to ensure data quality. Time-trend and geographical analyses were performed.Results30 394 patients from 27 European countries were evaluated and 21 533 (78%) first-line empirical H. pyloritreatments were included for analysis. Pretreatment resistance rates were 23% to clarithromycin, 32% to metronidazole and 13% to both. Triple therapy with amoxicillin and clarithromycin was most commonly prescribed (39%), achieving 81.5% modified intention-to-treat eradication rate. Over 90% eradication was obtained only with 10-day bismuth quadruple or 14-day concomitant treatments. Longer treatment duration, higher acid inhibition and compliance were associated with higher eradication rates. Time-trend analysis showed a region-dependent shift in prescriptions including abandoning triple therapies, using higher acid-inhibition and longer treatments, which was associated with an overall effectiveness increase (84%–90%).ConclusionManagement of H. pyloriinfection by European gastroenterologists is heterogeneous, suboptimal and discrepant with current recommendations. Only quadruple therapies lasting at least 10 days are able to achieve over 90% eradication rates. European recommendations are being slowly and heterogeneously incorporated into routine clinical practice, which was associated with a corresponding increase in effectiveness.

Background:Many patients with moderate to severe Crohn’s disease (CD) are treated with infliximab (IFX). As most of these patients experience a long-lasting therapy, the outcome and withdrawal of IFX treatment are important clinical questions. Methods:In this retrospective study, we analyzed the treatment outcome in moderate to severe CD patients with a steroid-dependent/refractory disease course started on IFX. Withdrawal of IFX was evaluated in patients with deep remission defined as clinical (Harvey-Bradshaw Index ≤4), biochemical (fecal calprotectin [FC] ≤150 μg/g stool) over a period of 2 years, and endoscopic and histological remission before discontinuation of IFX. Results:After induction with IFX, clinical remission was observed in 45/109 patients (41.3%) and clinical response in 61/109 patients (56.0%). Only 8/109 patients (7.3%) achieved deep remission and therefore could be discontinued from IFX therapy. In 4 of these patients (50%), relapse was observed after discontinuation of IFX treatment. FC decreased in these 8 patients in deep remission from 652 ± 168 μg/g stool (mean ± SE) at baseline to 24.9 ± 8.1 μg/g stool at 14 weeks. When compared to patients in deep remission, FC had decreased significantly less at 14 weeks in patients in clinical remission after induction with IFX (n= 31; 154 ± 55 μg/g stool; p= 0.01), in patients with clinical response after induction achieving clinical remission during the maintenance phase (n= 11; 352 ± 67 μg/g stool; p= 0.004), or in patients with chronic active disease course on maintenance therapy (n= 50; 645 ± 93 μg/g stool; p< 0.001). Conclusion:A low discontinuation rate was observed for steroid-dependent/refractory moderate to severe CD patients with IFX treatment. As FC showed a more or less pronounced decrease depending on the response to the IFX treatment, monitoring of FC may become a noninvasive tool for tailoring biological therapy in CD patients.

Abstract: A randomized, double-blind, placebo-controlled, cross-over, dose-escalating, single-center study was conducted to evaluate the safety, tolerability, and pharmacokinetic (PK) profile of multiple once-daily (qd) subcutaneous (sc) doses of pasireotide in healthy male subjects. Subjects received pasireotide 50, 200, or 600 μg sc qd for 14 days and placebo in separate sequences. Thirty-three subjects were randomized. The most frequently reported drug-related adverse events were injection–site reactions (n = 18), diarrhea (n = 14) and nausea (n = 10), which were mostly mild or moderate in intensity. Pasireotide 600 μg sc was associated with pre- and post-prandial elevations in glucose levels relative to placebo; however, this effect was less pronounced on day 14 compared with day 1. PK steady state appeared to be achieved after 3 days of dosing and PK exposures had a moderate accumulation of 20–40 % across doses. Pasireotide demonstrated fast absorption (T max,ss: 0.25–0.5 h), low clearance (CL/F ss: 8.10–9.03 L/h), long effective half-life (T ½,eff: ~12 h, on average between 9.7 and 13.1 h for 50, 200, and 600 μg sc qd), and large volume of distribution (V z/F ss: 251–1,091 L) at steady state. Dose proportionality was confirmed for C max,ss; other PK parameters (C max, AUC0–24 h and AUCtau) were approximately dose proportional. Growth hormone inhibition was observed with pasireotide 200 and 600 μg sc qd. Gallbladder volume increased post-prandially with pasireotide 200 and 600 μg sc qd, which appeared to correlate with reduced levels of cholecystokinin at these doses. Pasireotide was generally well tolerated up to the tested dose of 600 μg qd, with a linear and time-independent PK profile after sc qd dosing in healthy subjects.

Inflammatory bowel disease (IBD) is an inflammatory condition that affects the gastrointestinal tract. The solute carrier (SLC) superfamily of transporters comprise proteins involved in the uptake of drugs, hormones, and other biologically active compounds. The purpose of this study was to determine the mRNA expression levels of 15 solute carrier transporters in two regions of the intestine in IBD patients. Endoscopic biopsy specimens were taken from two locations (terminal ileum and colon) for histological examination and RNA extraction. We quantitatively measured the mRNA expression of 15 SLC transporters in 107 IBD patients (53 with Crohn's disease and 54 with ulcerative colitis) and 23 control subjects. mRNA expression was evaluated using the quantitative reverse transcription-polymerase chain reaction technique. We observed that in the ileum of IBD patients, mRNA levels for serotonin transporter, equilibrative nucleoside transporter (ENT) 1, ENT2, and organic anion-transporting polypeptide (OATP) 2B1 were significantly elevated, whereas levels for apical sodium-dependent bile acid transporter (ASBT) and organic zwitterion/cation transporter (OCTN) 2 were significantly lower. In colon, mRNA levels for ENT1, ENT2, concentrative nucleoside transporter (CNT) 2, OATP2B1, and OATP4A1 were significantly higher, whereas mRNA levels for OCTN2 were significantly decreased. In inflamed colon of IBD patients the mRNA expression levels of ENT1, ENT2, CNT2, OATP2B1, OATP4A1, and peptide transporter 1 were significantly higher. We conclude that intestinal SLC mRNA levels are dysregulated in IBD patients, which may be linked to the inflammation of the tissue and provides an indication about the role of inflammatory signaling in regulation of SLC expression.

ABSTRACTBAL8557 is the water-soluble prodrug of a novel antifungal triazole, BAL4815. BAL4815 is active against a broad spectrum of major opportunistic and pathogenic fungi, including strains that are resistant to other azoles. Cohorts of healthy male subjects received single-ascending oral (p.o.) doses of BAL8557 that were equivalent to 100, 200, or 400 mg of BAL4815 or single-ascending, 1-h constant-rate intravenous (i.v.) infusions of BAL8557 which were equivalent to 50, 100, or 200 mg of BAL4815. In each cohort, six subjects were randomly assigned to receive active drug and two subjects were assigned to receive the placebo. All doses were well tolerated, and no severe or serious adverse events occurred. Maximum plasma concentrations of BAL4815 were observed 1.5 to 3 h after p.o. drug intake or at the end of the 1-h infusion. After both routes of administration, values for maximum drug concentration observed in plasma and area under the concentration-time curve increased slightly more than proportionally to the administered dose. Mean elimination half-lives were particularly long (56 to 77 h after p.o. administration and 76 to 104 h after i.v. administration). The volume of distribution was large (155 to 292 liters after p.o. administration and 304 to 494 liters after i.v. administration) and systemic clearance was low (1.9 to 2.8 liter/h after p.o. administration and 2.8 to 5.0 liter/h after i.v. administration). Urinary recovery of BAL4815 was less than 0.4% of the infused dose. Based on the exposure data, oral bioavailability of BAL4815 is assumed to be very high. The pharmacokinetics of BAL4815 are well suited to maintaining concentrations of BAL4815 for a long period of time in the body and to enabling an effective treatment of systemic mycoses.

Efflux transporters such as P-glycoprotein and multidrug resistance-associated proteins (MRPs) in the intestinal wall restrict intestinal drug transport. To overcome this limitation for enteral drug absorption, galenical targeting approaches have been proposed for site-specific luminal drug release in segments of the gut, where expression of the respective absorption-limiting transporter is minimal. Therefore, expression of multidrug resistance gene 1 (MDR1) and MRP1-5 was systematically investigated in 10 healthy subjects. Biopsies were taken from different segments of the gastrointestinal tract (from duodenum and terminal ileum, as well as ascending, transverse, descending, and sigmoid colon). Gene expression was investigated by quantitative real-time PCR (TaqMan). MRP3 appeared to be the most abundantly expressed transporter in investigated parts of the human intestine, except for the terminal ileum, where MDR1 showed the highest expression. The ranking of transporter gene expression in the duodenum was MRP3 >> MDR1 > MRP2 > MRP5 > MRP4 > MRP1. In the terminal ileum, the ranking order was as follows: MDR1 > MRP3 >> MRP1 approximately MRP5 approximately MRP4 > MRP2. In all segments of the colon (ascending, transverse, descending, and sigmoid colon), the transporter gene expression showed the following order: MRP3 >> MDR1 > MRP4 approximately MRP5 > MRP1 >> MRP2. We have shown, for the first time, systematic site-specific expression of MDR1 and MRP mRNA along the gastrointestinal tract in humans. All transporters showed alterations in their expression levels from the duodenum to sigmoid colon. The most pronounced changes were observed for MRP2, with high levels in the small intestine and hardly any expression in colonic segments. This knowledge may be useful to develop new targeting strategies for enteral drug delivery.

The diagnosis and treatment of gastro-oesophageal reflux disease (GERD) presents many problems, despite the fact that significant advances have been made in recent years in the understanding of its pathogenesis and symptomatology. GERD affects many people and has a significant negative impact on patient quality of life. Heartburn is the most common symptom of GERD which occurs with and without oesophagitis. The predominant causative factor for symptoms is prolonged contact of oesophageal mucosa with refluxed acid and pepsin. Proton pump inhibitors (PPIs) are the most effective treatment for GERD: overall proportions of patients with healing and complete heartburn relief are markedly higher with PPIs than with alternative treatment strategies. Furthermore, the speed of healing and heartburn relief with PPIs is almost twice as rapid as with any other form of therapy. The present review focuses on the effectiveness and safety of the PPI, pantoprazole. The data show that the compound is highly effective in GERD patients with and without oesophagitis. Pantoprazole has an excellent safety record and shows only minor interaction with other drugs.

Background: Somatostatin is a naturally occurring peptide advocated for the management of hemodynamic complications of chronic liver diseases. The route of administration (bolus application or constant infusion) has been a question of debate.Aim: Our aim was to explore the effects of the somatostatin analog lanreotide, given as a bolus injection or continuous infusion, on food-stimulated hemodynamics in humans.Methods: Twelve healthy subjects (6 men and 6 women) were studied in a double-blind, double-dummy, randomized, crossover study. After a baseline period of 60 minutes, each subject received either a placebo bolus injection and an intravenous infusion of 100 μg/h lanreotide over a period of 8 hours or a placebo infusion over a period of 8 hours and an 800-μg lanreotide bolus injection. Simultaneously, a liquid test meal (Ensure Plus, 6.3 kJ/mL; Abbott Laboratories, Abbott Park, Ill) was perfused intraduodenally at 3 mL/min over a period of 8 hours. Diastolic blood pressure, heart rate, and superior mesenteric arterial and portal venous volume flows were measured at regular intervals by use of echo-Doppler technology. Plasma lanreotide levels were determined at defined intervals.Results: Lanreotide as a 100-μg/h infusion for 8 hours was bioequivalent with lanreotide as an 800-μg bolus injection (mean area under the plasma concentration–time curve [AUC] extrapolated to infinity [AUC∞], 1844.3 ng · min/L versus 1971.0 ng · min/L; AUC∞ratios, 0.99; confidence interval, 0.95-1.02), and clearance was identical (479.2 mL/min versus 413.4 mL/min, P > .05). As expected, significant differences were observed in maximum plasma concentrations (75.58 ng/mL versus 4.85 ng/mL, P < .001) after infusion and bolus injections, respectively. Lanreotide at 100 μg/h over a period of 8 hours was well tolerated and abolished food-stimulated splanchnic hyperemia in both the superior mesenteric artery and the portal vein (mean AUC above baseline values [AUCab], 37.25 L/min · min and 0.51 L/min · min, respectively). In contrast, the same dose of lanreotide given as a bolus injection only temporarily blunted postprandial hyperemia (mean AUCabfor superior mesenteric artery, 251.4 L/min · min, P < .001; mean AUCabfor portal vein, 194.95 L/min · min, P < .001), and subjects had significantly more side effects.Conclusion: On the basis of tolerability and hemodynamic effects, an intravenous infusion of lanreotide seems superior to a bolus injection of the same dose.Clinical Pharmacology & Therapeutics (2004) 75, 70–79; doi: 10.1016/j.clpt.2003.09.006

Background:Conscious sedation is standard for GI endoscopy. Propofol increasingly is used as an alternative drug to avoid unwanted effects of the commonly used benzodiazepines. Although propofol in the hands of nonanesthesiologists is still controversial, this study characterized the safety profile of propofol administered by nurses under supervision of the gastroenterologist. Methods:All patients undergoing any endoscopic procedure between September 2000 and December 2001 in the gastroenterology department of an academic tertiary medical center were eligible for inclusion in this prospective observational study. Sedation was voluntary. Demographic data, type of endoscopic procedure, and clinical features were recorded. A structured personal history led to a 5-class risk stratification based on the criteria of the American Society of Anesthesiologists. A total of 3475 procedures were performed in 2574 patients using propofol administered by registered nurses. Results:No major complications occurred because of the use of propofol, but overall decreases in the mean values for oxygen saturation (−2%), arterial pressure (−18%), and pulse rate (−10%) were observed. Severe respiratory depression requiring intervention occurred in less than 0.3% of all patients given propofol. Conclusion:The administration of propofol by registered nurses, with careful monitoring under the supervision of the gastroenterologist, is safe for conscious sedation during GI endoscopic procedures. (Gastrointest Endosc 2003;57:664-71.)

Colon carcinoma cell lines are used widely as screening models for intestinal absorption of drugs. However, the expression of important transport systems and of metabolic enzymes is not completely characterized yet. The expression and inducibility of multidrug resistance gene 1 (MDR1) and cytochrome P450 isoform 3A4 (CYP3A4) was investigated in Caco-2 parental, Caco-2 TC-7 (TC-7) and LS180 cell lines. In the same three cell lines, we investigated the expression of isoforms of the multidrug resistance associated protein family (MRP1–MRP5) and the human pregnane × receptor (hPXR), which may be important for MDR1 and CYP3A4 induction. Cells were treated with rifampicin or 1α, 25-dihydroxycholecalciferol (1,25(OH)2D3) for 72 h and the total RNA was extracted. Afterwards reverse transcription real-time polymerase chain reaction (TaqMan) assay was performed to determine the mRNA expression level. We have shown that in LS180 cells, MDR1 and CYP3A4 were inducible with both inducers. In Caco-2 parental and TC-7 cells, CYP3A4 was only inducible with 1,25(OH)2D3. Furthermore, differences were shown in gene expression of several transport proteins (MDR1 and MRP1–MRP5) and CYP3A4 in different human colon carcinoma derived cell lines. hPXR mRNA was expressed in all three cell lines but the amount of mRNA detected was significantly higher in LS180 cells than in Caco-2 and TC-7 cells. We concluded that LS180 cells were a suitable model to study MDR1 and CYP3A4 induction, but for drug transport studies Caco-2 parental and TC-7 cells would be preferred as the more physiological model.

Colon carcinoma cell lines are used widely as screening models for intestinal absorption of drugs. However, the expression of important transport systems and of metabolic enzymes is not completely characterized yet. The expression and inducibility of multidrug resistance gene 1 (MDR1) and cytochrome P450 isoform 3A4 (CYP3A4) was investigated in Caco‐2 parental, Caco‐2 TC‐7 (TC‐7) and LS180 cell lines. In the same three cell lines, we investigated the expression of isoforms of the multidrug resistance associated protein family (MRP1–MRP5) and the human pregnane × receptor (hPXR), which may be important for MDR1 and CYP3A4 induction. Cells were treated with rifampicin or 1α, 25‐dihydroxycholecalciferol (1,25(OH)2D3) for 72 h and the total RNA was extracted. Afterwards reverse transcription real‐time polymerase chain reaction (TaqMan) assay was performed to determine the mRNA expression level. We have shown that in LS180 cells, MDR1 and CYP3A4 were inducible with both inducers. In Caco‐2 parental and TC‐7 cells, CYP3A4 was only inducible with 1,25(OH)2D3. Furthermore, differences were shown in gene expression of several transport proteins (MDR1 and MRP1–MRP5) and CYP3A4 in different human colon carcinoma derived cell lines. hPXR mRNA was expressed in all three cell lines but the amount of mRNA detected was significantly higher in LS180 cells than in Caco‐2 and TC‐7 cells. We concluded that LS180 cells were a suitable model to study MDR1 and CYP3A4 induction, but for drug transport studies Caco‐2 parental and TC‐7 cells would be preferred as the more physiological model.

Somatostatin analogs labeled with radionuclides are of considerable interest in the diagnosis and therapy of SSTR-expressing tumors, such as gastroenteropancreatic, small cell lung, breast and frequently nervous system tumors. In view of the favorable physical characteristics of the Ga isotopes ⁶⁷Ga and ⁶⁸Ga, enabling conventional tumor scintigraphy, PET and possibly internal radiotherapy, we focused on the development of a Ga-labeled somatostatin analog suitable for targeting SSTR-expressing tumors. For this purpose, 3 somatostatin analogs, OC, TOC and TATE were conjugated to the metal chelator DOTA and labeled with the radiometals ¹¹¹In, ⁹⁰Y and ⁶⁷Ga. They were then evaluated for their performance in the AR4-2J pancreatic tumor model by testing SSTR2-binding affinity, internalization/externalization in isolated cells and biodistribution in tumor-bearing nude mice. Surprisingly, we found that, compared to ¹¹¹In or ⁹⁰Y, labeling with ⁶⁷Ga considerably improved the biologic performance of the tested somatostatin analogs with respect to SSTR2 affinity and tissue distribution. ⁶⁷Ga-labeled DOTA-somatostatin analogs were rapidly excreted from nontarget tissues, leading to excellent tumor-to-nontarget tissue uptake ratios. Of interest for radiotherapeutic application, [⁶⁷Ga]DOTATOC was strongly internalized by AR4-2J cells. Furthermore, our results suggest a link between the radioligand charge and its kidney retention. The excellent tumor selectivity of Ga-DOTA somatostatin analogs together with the different applications of Ga in nuclear oncology suggests that Ga-DOTA somatostatin analogs will become an important tool in the management of SSTR-positive tumors. © 2002 Wiley-Liss, Inc.

A 68-year-old male presented with abdominal pain and obstructive jaundice. CT revealed a large mass in the pancreatic head that was initially interpreted as pancreatic carcinoma. Needle biopsy revealed only fibrous tissue with signs of chronic inflammation. Together with typical findings of an idiopathic retroperitoneal fibrosis, the final diagnosis of multifocal idiopathic fibrosclerosis with focal pseudotumorous pancreatic head fibrosis could be made.

Background & Aims:This study was designed to characterize [D-F5Phe6D-Ala11]Bn(6-13)OMe (BIM26226) as a gastrin-releasing peptide (GRP)-preferring bombesin receptor antagonist and to determine whether GRP physiologically regulates gastrointestinal motility. Intravenous BIM26226 (5–500 μg · kg−1· h−1) inhibits GRP-induced gallbladder contraction and plasma cholecystokinin (CCK) release in a dose-dependent fashion. Methods:Gastric emptying and small bowel transit of a solid meal were quantified using scintigraphy. Meal-stimulated gallbladder contraction was measured by sonography in a 2-period crossover design. Results:Intravenous BIM26226 potently inhibited gastric lag time (114 ± 7 vs. 41 ± 6 minutes [control]) and gastric emptying rate (0.11 ± 0.02%/min vs. 0.26 ± 0.04%/min [control]), whereas concomitant infusion of BIM26226 accelerated small bowel transit time (153 ± 41 vs. 262 ± 20 minutes [control]). A continuous liquid meal perfusion into the duodenum induced complete gallbladder contraction (t50%, 35 ± 4 minutes), which BIM26226 inhibited significantly (t50%, 64 ± 8 minutes). BIM26226 did not alter plasma CCK response, indicating that circulating CCK did not mediate these effects. Conclusions:These data show that BIM26226 is a potent antagonist of exogenous and endogenous GRP and suggest that GRP is a major physiologic regulator of gastric emptying, small bowel transit, and gallbladder contraction.

CD66a is an adhesion molecule member of the carcinoembryonic antigen immunoglobulin-like family present on the surface of epithelial cells, granulocytes and IL-2 activated T cells. We studied whether CD66a is expressed in vivo by T lymphocytes and whether it affects TCR-mediated activation. CD66a was detected by histochemistry, flow cytometry analysis, reverse transcription PCR and Western blot on fresh colon biopsies and T cell clones. A fraction of T cells in the lamina propria express CD66a, which is induced by IL-7 and IL-15 cytokines. T cells express four different CD66a splice variants and at least two forms of the protein are glycosylated in a cell type-specific manner. Triggering of CD66a on T cells with physiological ligands or with specific mAb increases TCR-mediated lymphokine release, in an antigen dose-independent manner. This effect requires the presence of the CD66a intracytoplasmic domain, which contains two immunoglobulin receptor family tyrosine-based inhibitory motif-like domains, as shown by stimulation of Jurkat cells transfected with different CD66a isoforms and is associated with increased induction of AP1 and NFκB transcription factors. These data indicate that CD66a amplifies T cell activation and thus could facilitate crosstalk between epithelial cells and T lymphocytes in intestinal immune response.

Purpose. Secretory systems contribute to drug absorption in the gastrointestinal tract. The purpose of this study was the identification of members of the ATP binding cassette superfamily of secretory transport proteins that may potentially modulate drug absorption in Caco-2 cells, which are an important cellular model predicting enteral absorption of drugs. Methods. Kinetic studies as well as PCR- and Western blot studies with confluent epithelial layers of human Caco-2 cells. Results. The study demonstrates functional expression of multidrug resistance related protein (MRP) and P-glycoprotein (P-gp) in Caco-2 cells: 1) Efflux studies with the MRP specific substrate glutathion-methylfluorescein (GS-MF) showed functional activity of MRP in Caco-2 cells preloaded with the metabolic precursor of GS-MF, chloro-methylfluoresceine-diacetate, CMFDA. Excretion of GS-MF was decreased in presence of the MRP-blocker MK-571.2) Transport experiments with cyclosporin A demonstrated the functional activity of P-gp. Cellular accumulation was increased in presence of the P-gp blocking agent SDZ-PSC 833.3) The expression of the 190 kDa protein MRP and the 170 kDa protein P-gp in Caco-2 cells was shown by Western blot analysis with specific monoclonal antibodies. 4) The expression of MRP-mRNA in Caco-2 cells was detected by RT-PCR and compared with the MRP over-expressing cell line H69AR. MRP primers recognize specifically human MRP1 (GenBank accession number L05628), but not all other published sequences of MRP (MRP2-MRP6). P-gp expression on mRNA-level was also confirmed by RT-PCR. Conclusions. The data demonstrate that besides P-gp, multidrug resistance related protein (MRP) is functionally expressed in Caco-2 cells and contributes to the active excretion of substrates in this cell line.

Objective: To investigate the gastrointestinal effects of intravenous lanreotide.Methods: Twenty healthy male subjects participated in 2 subsequent placebo-controlled, double-blind crossover studies. The effects of 3 doses of lanreotide (50, 100, and 200 μg/h) were investigated on 24-hour intragastric acidity (study I), food-stimulated gallbladder contraction, and plasma cholecystokinin release (study II).Results: Lanreotide showed linear pharmacokinetics. It raised median intragastric pH significantly and in a dose-dependent manner: from 1.4 ± 0.2 (placebo) to 2.5 ± 0.8 (P < .002) during administration of 50 μg/h lanreotide, to 3.2 ± 0.7 (P < .001) during 100 μg/h lanreotide, and to 4.3 ± 0.7 (P < .001) during 200 μg/h lanreotide. However, no significant inhibition of gastrin secretion could be established. All doses completely inhibited postprandial gallbladder contraction.Conclusion: Intravenous administration of lanreotide at rates applied in this study was able to significantly inhibit intragastric acid secretion and postprandial gallbladder contraction; under these conditions few untoward effects were noted.

Abstract: Mainly because of the loss of reservoir function, loss of sphincter function, and exclusion of the duodenal route, patients who undergo gastrectomy suffer from many adverse effects postoperatively. The ileocecal interpositional graft is an attractive method to use as a gastric substitute after gastrectomy and distal esophagectomy. A pedunculated ileocecal graft is placed between the esophagus and the duodenum. The cecum acts as a reservoir while the ileocecal valve protects against enteroesophageal reflux. The duodenal passage is also preserved. Fourteen patients underwent this operation. The technique-related morbidity was low and the quality of life was good. During a mean follow-up of 6 months, no evidence of severe dumping syndrome or reflux esophagitis was observed. Further prospective randomized studies are warranted to compare this technique with the standard methods of gastric reconstruction.

By means of loxiglumide, a potent and highly specific antagonist for cholecystokinin (CCK), the effects of blocking CCK receptors on gastrointestinal motility were investigated in a placebo-controlled study in healthy young men (aged 21-39, mean 24 years). Gallbladder contraction stimulated by ingestion of a liquid test meal was completely abolished by oral administration of loxiglumide 30 min before the test meal. Gastric emptying of radio-opaque markers ingested with the test meal was significantly accelerated by loxiglumide (area under the curve [markers × h] 33·3 [SEM 3·8] vs17·9 [2·7] after placebo). No effect of loxiglumide was found on small-bowel transit time, but 7 days' treatment with oral loxiglumide (800 mg three times daily) significantly shortened colonic transit time (29·4 [4·1] h after placebo, 15·0 [3·4] h after loxiglumide). It is concluded that CCK is an important mediator of meal-induced gallbladder contraction and is involved in the regulation of gastrointestinal motility in man.

Pancreatic enzyme secretion is regulated in humans by the cholinergic system and by cholecystokinin (CCK). The interaction between both regulatory systems in response to exogenous and endogenous stimulation was analyzed in the present study using the cholinergic antagonist atropine and the CCK antagonist loxiglumide. A dose-dependent stimulation of pancreatic enzyme output was achieved either by duodenal perfusion of graded caloric loads or by IV infusion of increasing doses of cerulein. Prestimulated pancreatic secretion was inhibited by atropine and loxiglumide. Atropine furthermore almost completely blocked meal-stimulated pancreatic secretion, whereas loxiglumide caused 60% inhibition. The enzyme response to graded doses of exogenous CCK was significantly inhibited by atropine and loxiglumide. Plasma levels of CCK were not altered by atropine but increased with infusion of loxiglumide. This study supports the concept that pancreatic enzyme secretion is predominantly dependent on a cholinergic tone and that CCK modulates the enzyme-secretory response.

The role of cholecystokinin (CCK) in the regulation of gastric emptying and pancreatic enzyme secretion was evaluated by infusing the CCK-receptor antagonist loxiglumide. Gastric emptying rates and pancreatic secretory outputs were measured in five healthy volunteers by the double-indicator perfusion technique using a multiple-lumen tube in the duodenum. Placebo or loxiglumide (22 μmol · kg−1· h−1) was infused throughout each experiment. Five hundred-milliliter liquid intragastric meals of (a) fat, protein, and glucose (Ensure; Abbott, Chicago, IL); (b) glucose, 20 g/dL; and (c) guar gum, 1.1 g/dL, were given in random order. In addition, the effect of a physiologic CCK-8 dose (20 pmol · kg−1· h−1) after an intragastric 500-mL saline meal (0.154 mol/L) was tested. Intravenous CCK-8 induced a marked retardation of the gastric emptying rate of the saline solution (P< 0.05) while stimulating pancreatic secretory outputs; both effects were completely abolished by the infusion of loxiglumide. Loxiglumide markedly accelerated the gastric emptying rates (by ~ 40%) and simultaneously diminished lipase (by ~ 75%) and trypsin (by ~ 50%) outputs of both the mixed meal (P< 0.01) and the pure glucose meal (P< 0.05). Additional experiments using gamma camera scintigraphy confirmed the accelerating effect of loxiglumide on gastric emptying of the mixed meal (P< 0.01). The gastric emptying rate of the guar meal, which did not release CCK, was not influenced by the infusion of loxiglumide. Loxiglumide distinctly augmented plasma CCK levels after the mixed (2.6 times) and the pure glucose (2.1 times) meals while markedly reducing (~ 76%) pancreatic polypeptide release (P< 0.02). It is concluded that endogenous CCK exerts a major role in the regulation of both gastric liquid emptying and pancreatic secretion in humans.

Background/Aims:Bombesin and gastrin-releasing peptide (GRP) are closely related peptides. Both have been proposed to serve as a satiety signal in animals. Methods:To explore further the role of GRP in humans, its effects on satiety and eating behavior were investigated by infusion of GRP into healthy men at three dosages (10, 40, and 160 pmol/kg per hour) and compared with saline infusions. Results:GRP produced a significant reduction in calorie intake (P< 0.05) but only a 19% (nonsignificant) reduction in food intake. Fluid ingestion was not affected by GRP. No overt side effects were produced by GRP, but subjects experienced less hunger and early fullness in the premeal period during GRP infusion but not when receiving saline (P< 0.05−0.01). Conclusions:This study shows that intravenous infusions of GRP can decrease spontaneous food intake at concentrations that produce physiological effects, such as stimulation of acid or pancreatic secretion or gallbladder contraction. The data imply that GRP-like peptides can act as satiety signals in humans, confirming data previously reported in animals.

Nasal sprays containing different concentrations of the somatostatin analogue octreotide and sodium tauro-24,25-dihydrofusidate (STDHF) as an absorption promoter were evaluated in two consecutive pharmacokinetic studies in healthy volunteers to characterize their bioavailability and local tolerability. The concentrations of STDHF were selected on the basis of a phase diagram generated by a dynamic laser light-scattering technique to ensure that the mixture was above the critical micellar concentrations. Compared to a 50-µg subcutaneous injection, the nasal spray formulation without STDHF had a mean relative bioavailability of 17.9%. For nasal formulations containing 3 and 1.65% (w/v) of STDHF, the bioavailability increased to 29.0 and 25.7%, respectively. The enhancement of nasal absorption was dependent on the STDHF concentrations as shown by decreasing the amounts to 1.2 and 0.8% (w/v) for tolerability reasons; the bioavailability was reduced to 15.3 and 20.5% in these cases, respectively. The local tolerability of all STDHF-containing sprays was poor, leading to stinging sensations and lacrimation. The poor local tolerability of the octreotide nasal spray containing different concentrations of STDHF required for effective nasal absorption enhancement appears to be impractical for further clinical development. These findings clearly stress the necessity to investigate tolerability and safety issues of new drug delivery systems in early developmental phases.

To elucidate the role of hormones in the control of pancreatic secretion, we developed, in seven dogs, a model of total extrinsic denervation of the jejunoileum by autotransplanting this segment of bowel. A Thomas-like cannula was placed into the stomach, the duodenum (to collect pure pancreatic juice), and the proximal part of the jejunum. Thus, intestinal stimulants could only stimulate the pancreas via release of humoral (= hormonal) mediators. Seven control dogs received only the three fistulas. After recovery, dose-response curves of pancreatic bicarbonate and protein response to perfusion of the extrinsically denervated or innervated jejunoileum with HC1 (1.5 to 48 mmol h−1) were performed with and without atropine (14 nmol kg−1h−1i.v.). Plasma levels of secretin were determined by radioimmunoassay. The maximal bicarbonate output occurred in response to 24 mmol h−1of HC1 and was significantly (p < 0.05) higher in intact as compared to denervated animals. Atropine only significantly depressed the bicarbonate response to HC1 in dogs with a denervated jejunoileum. HC1 caused a dose-dependent increase in plasma levels of secretin, which was not altered by denervation and/or atropine. Irrespective of the innervation of the small bowel, pancreatic protein output was only significantly stimulated above basal when high loads (12–48 mmol h−1) of HC1 were given. Atropine significantly reduced these responses. We conclude that (a) intrajejunal HC1 stimulates pancreatic bicarbonate and protein secretion via release of hormones; (b) extrinsic denervation of the jejunoileum lowers the maximal pancreatic bicarbonate response to intrajejunal HC1; (c) cholinergic extrinsic nerves of the jejunoileum are probably not involved in the control of pancreatic bicarbonate response to HC1; (d) release of secretin by HC1 does not depend on the extrinsic and intrinsic cholinergic nerves of the jejunoileum; and (e) high loads of HC1 stimulate pancreatic protein output by an atropine-sensitive mechanism that is independent of the integrity of the extrinsic nerves of the jejunoileum.

We measured pancreatic enzyme and bicarbonate responses to graded doses of intravenous secretin or cerulein alone or together in healthy human subjects. Bicarbonate responses were steady and well maintained during the last 3.5 h of the 4 h of infusions of secretagogues, giving evidence for a constant pancreatic flow rate. Potentiation (more-than-additive response) was observed between secretin and cerulein for bicarbonate secretion, but not for enzyme secretion. Secretin stimulated pancreatic enzyme secretion. The effect was most pronounced with amylase secretion and less prominent with lipase, trypsin, and chymotrypsin secretion. Changes in the proportion of enzymes were seen over time, with trypsin and chymotrypsin output declining towards the end of cerulein infusion. We conclude that in humans the effects of secretin on pancreatic enzyme secretion are complex and include timedependent changes in the enzyme mixture, but potentiation between secretin and cerulein does not occur for enzyme output.

The action of synthetic human secretin, which differs in two amino acid residues from porcine secretin, was compared with synthetic porcine secretin in 6 healthy volunteers. Pancreatic secretion was assessed by a marker perfusion technique and plasma secretin concentrations were assessed by a specific radioimmunoassay. Increasing doses of either human or porcine secretin produced increasing bicarbonate output (p < 0.01), whereas trypsin and lipase were not stimulated over basal. The highest doses of secretin induced a significant increase in pancreatic amylase secretion. The two secretin preparations were found to be equipotent with respect to pancreatic secretion and plasma kinetics. Significant increases of plasma secretin were observed after a steak meal in 15 volunteers (p < 0.001). When human secretin was infused at postprandial concentrations, significant increases in pancreatic bicarbonate output were observed (p < 0.05). We conclude (a) that the substitution of two amino acids in human secretin does not affect biologic activity and plasma metabolism of the compound; (b) secretin does not stimulate pancreatic enzyme secretion at physiologic concentrations; and (c) the stimulatory effects of secretin on pancreatic amylase remain to be elucidated. The study suggests that human secretin is a true hormone.