Management of perforated diverticulitis with generalized peritonitis. A multidisciplinary review and position paper.

Perforated diverticulitis is an emergent clinical condition and its management is challenging and still debated. The aim of this position paper was to critically review the available evidence on the management of perforated diverticulitis and generalized peritonitis in order to provide evidence-based suggestions for a management strategy. Four Italian scientific societies (SICCR, SICUT, SIRM, AIGO), selected experts who identified 5 clinically relevant topics in the management of perforated diverticulitis with generalized peritonitis that would benefit from a multidisciplinary review. The following 5 issues were tackled: 1) Criteria to decide between conservative and surgical treatment in case of perforated diverticulitis with peritonitis; 2) Criteria or scoring system to choose the most appropriate surgical option when diffuse peritonitis is confirmed 3); The appropriate surgical procedure in hemodynamically stable or stabilized patients with diffuse peritonitis; 4) The appropriate surgical procedure for patients with generalized peritonitis and septic shock and 5) Optimal medical therapy in patients with generalized peritonitis from diverticular perforation before and after surgery. In perforated diverticulitis surgery is indicated in case of diffuse peritonitis or failure of conservative management and the decision to operate is not based on the presence of extraluminal air. If diffuse peritonitis is confirmed the choice of surgical technique is based on intraoperative findings and the presence or risk of severe septic shock. Further prognostic factors to consider are physiological derangement, age, comorbidities, and immune status. In hemodynamically stable patients, emergency laparoscopy has benefits over open surgery. Options include resection and anastomosis, Hartmann's procedure or laparoscopic lavage. In generalized peritonitis with septic shock, an open surgical approach is preferred. Non-restorative resection and/or damage control surgery appear to be the only viable options, depending on the severity of hemodynamic instability. Multidisciplinary medical management should be applied with the main aims of controlling infection, relieving postoperative pain and preventing and/or treating postoperative ileus. In conclusion, the complexity and diversity of patients with diverticular perforation and diffuse peritonitis requires a personalized strategy, involving a thorough classification of physiological derangement, staging of intra-abdominal infection and choice of the most appropriate surgical procedure.

Intermittent versus every-day mesalazine therapy in preventing complications of diverticular disease: a long-term follow-up study.

BACKGROUND: Mesalazine seems to be effective in preventing recurrence of acute uncomplicated diverticulitis (AUD), but the optimal mesalazine scheme to achieve these results is still debated. AIM: To assess the effectiveness of two different mesalazine-based treatments in preventing recurrence of AUD and the occurrence of other complications of diverticular disease (DD) during a long-term follow-up. PATIENTS AND METHODS: We reviewed 311 patients suffer from recent episode of AUD and undergoing to mesalazine treatment: 207 (group A, 105 males, median age 63 years, range 47-74 years) were treated with mesalazine 1.6 g for 10 days each month, whilst 104 (group B, 55 males, median age 65 years, range 50-72 years) were treated with mesalazine 1.6 g every day. Patients were followed-up every 6 months (median 7.5 months, range 5-13 months). RESULTS: Patients were followed-up for a mean time of 3 years (range 12-72 months). Overall, occurrence of complication recurred more frequently in group A than in group B (p = 0.030, log-rank test). Acute diverticulitis recurred in 17 (8.2%) patients in group A and in 3 (2.9%) in group B; diverticular bleeding occurred in 4 (1.9%) patients in group A and in 1 (0.96%) patient in group B; surgery was required in 3 (1.4%) patients in group A and in no (0%) patient in group B. CONCLUSIONS: This is the first study showing that long-term mesalazine treatment is significantly better that intermittent mesalazine treatment in preventing occurrence of DD complications after an attack of acute diverticulitis.

Pharmaceutical principles of acid inhibitors: unmet needs.

Despite the well-established benefits of currently approved delayed-release proton pump inhibitors (PPIs) in the treatment of acid-related diseases, the unmet needs are still present and although often frustrating, they challenge clinicians. The unmet needs relate to the lack of complete control of acid secretion with oral PPI administration in the management of patients with gastroesophageal symptoms. These substantial groups of patients, who do not respond completely to standard doses of PPIs, are nonresponders, and their lack of response should be considered as PPI failure. Several mechanisms could explain PPI failure: differences in pharmacokinetics, PPI formulation, dosing time and diet, noncompliance, transient lower esophageal sphincter relaxations, esophageal hypersensitivity, and nocturnal acid breakthrough. To increase the quality of life of these patients and avoid multiple medical consultations and unnecessary investigations, we have to go one step forward and use combined therapy or look towards new treatments beyond acid suppression.

[Functional endoscopy : the physiological and pathophysiological basis of reflux disease, diagnosis and therapy]. / Funktionelle Endoskopie : Physiologische und pathophysiologische Grundlagen der Refluxerkrankung, ihre Diagnostik und Therapie.

ENT specialists and gastroenterologists are increasingly confronted with the question of how to recognize and evaluate extra-esophageal complications of reflux. Both specialities need to collaborate, since they are connected via the esophagus, and both need to know more about the speciality of their neighbor than was hitherto usual. This publication presents the observations and measurements of little-known physiological functions. This is followed by an attempt to define the border between healthy and diseased. Finally, the possible consequences of functional disorders are described. The leap from observation of function to the microcosm of biochemical links is discussed and supported using experimental work. This overview highlights the limitations of our current knowledge. The success of functional endoscopy in terms of therapeutic approaches is immense. The required therapy is finally based on a clear diagnostic concept; probatory therapy is a waste of money.

Impact of primary antibiotic resistance on the effectiveness of sequential therapy for Helicobacter pylori infection: lessons from a 5-year study on a large number of strains.

BACKGROUND: The increasing prevalence of strains resistant to antimicrobial agents is a critical issue in the management of Helicobacter pylori (H. pylori) infection. AIMS: (1) To evaluate the prevalence of primary resistance to clarithromycin, metronidazole and levofloxacin (2) to assess the effectiveness of sequential therapy on resistant strains (3) to identify the minimum number of subjects to enrol for evaluating the effectiveness of an eradication regimen in patients harbouring resistant strains. METHODS: Consecutive 1682 treatment naïve H. pylori-positive patients referred for upper GI endoscopy between 2010 and 2015 were studied and resistances assessed by E-test. Sequential therapy was offered, effectiveness evaluated and analysed. RESULTS: H. pylori-primary resistance to antimicrobials tested was high, and increased between 2010 and 2015. Eradication rates were (estimates and 95% CIs): 97.3% (95.6-98.4) in strains susceptible to clarithromycin and metronidazole; 96.1% (91.7-98.2) in strains resistant to metronidazole but susceptible to clarithromycin; 93.4% (88.2-96.4) in strains resistant to clarithromycin but susceptible to metronidazole; 83.1% (77.7-87.3) in strains resistant to clarithromycin and metronidazole. For any treatment with a 75%-85% eradication rate, some 98-144 patients with resistant strains need to be studied to get reliable information on effectiveness in these patients. CONCLUSIONS: H. pylori-primary resistance is increasing and represents the most critical factor affecting effectiveness. Sequential therapy eradicated 83% of strains resistant to clarithromycin and metronidazole. Reliable estimates of the effectiveness of a given regimen in patients harbouring resistant strains can be obtained only by assessing a large number of strains.

Determinants of the short-term gastric damage caused by NSAIDs in man.

BACKGROUND: The short-term gastric damage seen with non-steroidal anti-inflammatory drugs (NSAIDs) in man may involve inhibition of cyclooxygenase (COX-1) and COX-2 as well as the topical irritancy, which is dependant on the acidity (pKa) and/or lipophilicity (log P(7.4)). AIM: To study the quantitative relationship between NSAID-induced short-term gastric damage, their physicochemical properties and contrasting roles of COX-1 and COX-2 inhibition. METHODS: We identified studies that allowed a qualitative comparison of the gastric injury (Lanza scores) induced by NSAIDs with their pKa and log P(7.4). Damage was correlated with gastric COX inhibition and potency to inhibit COX-1 and 2 and their COX-2/COX-1 selectivity ratio. RESULTS: The gastric damage correlates significantly with pKa (r = -0.69; P < 0.01), log P (r = -0.58, P < 0.05) and potency of the NSAIDs to inhibit COX-1 (r = -0.61, P < 0.02), but not with COX-2 inhibition or COX-2/COX-1 selectivity. CONCLUSION: Against a background of COX-1 and COX-2 inhibition, the physicochemical properties of NSAID appear to play an important role in short-term gastric damage.

The burden of constipation on quality of life: results of a multinational survey.

BACKGROUND: The impact of constipation on quality of life (QoL) may vary in different cultural or national settings. AIM: We studied QoL in a multinational survey to compare different social and demographic groups with and without constipation (defined according to Rome III criteria) and to detect country-specific differences among the groups studied. METHODS: Health-related QoL (HRQoL) was assessed with the Short Form 36 (SF-36) questionnaire in 2870 subjects in France, Germany, Italy, UK, South Korea, Brazil and USA. Results Respondents were mainly middle-aged, married or living together and part- or full-time employed. General health status, measured by the SF-36 questionnaire, was significantly worse in the constipated vs. non-constipated populations. RESULTS: were comparable in all countries. QoL scores correlated negatively with age. Constipated women reported more impaired HRQoL than constipated men. Brazilians were most affected by constipation as to their social functioning (35.8 constipated vs. 51.3 non-constipated) and general health perception (29.4 constipated vs. 54.4 non-constipated). CONCLUSIONS: There are significant differences in HRQoL between constipated and non-constipated individuals and a significant, negative correlation between the number of symptoms and complaints and SF-36 scores. The study detected a correlation of constipation with QoL and the influence of social and demographic factors on HRQoL in constipated people.

Systematic review with meta-analysis: rifaximin is effective and safe for the treatment of small intestine bacterial overgrowth.

BACKGROUND: Small intestinal bacterial overgrowth (SIBO) is a heterogeneous syndrome, characterised by an increased number and/or abnormal type of bacteria in the small bowel. Over the past decades, rifaximin has gained popularity for this indication despite its use is not evidence based. AIM: To perform a systematic review and meta-analysis to summarise evidence about the efficacy and safety of rifaximin to eradicate SIBO in adult patients. METHODS: MEDLINE, EMBASE, CCRCT, Scopus and Web of Science were searched from inception to March 16, 2015 for RCTs and observational studies. Furthermore, abstract books of major European, American and Asian gastroenterological meetings were also examined. RESULTS: Thirty-two studies involving 1331 patients were included. The overall eradication rate according to intention-to-treat analysis was 70.8% (95% CI: 61.4-78.2; I2 = 89.4%) and to per protocol analysis 72.9% (95% CI: 65.5-79.8; I2 = 87.5%). Meta-regression identified three covariates (drug dose, study design and co-therapy) independently associated with an increased eradication rate. The overall rate of adverse events was 4.6% (95% CI: 2.3-7.5; I2 = 63.6%). In the subset of studies (n= 10) allowing the analysis, improvement or resolution of symptoms in patients with eradicated SIBO was found to be 67.7% (95% CI: 44.7-86.9; I2 = 91.3%). CONCLUSIONS: Rifaximin treatment seems to be effective and safe for the treatment of SIBO. However, the quality of the available studies is generally poor. Well-designed RCTs are needed to substantiate these findings and to establish the optimal regimen.

Randomised clinical trial: mucosal protection combined with acid suppression in the treatment of non-erosive reflux disease - efficacy of Esoxx, a hyaluronic acid-chondroitin sulphate based bioadhesive formulation.

BACKGROUND: Several studies have shown that patients with non-erosive reflux disease (NERD) are less responsive to proton pump inhibitors (PPIs) than those with erosive disease as they belong to different subgroups, in whom factors other than acid can trigger symptoms. AIM: To evaluate whether combined therapy (mucosal protection plus acid suppression) would improve symptom relief compared to PPI treatment alone. METHODS: In a multicenter, randomised, double-blind trial, 154 patients with NERD were randomised to receive Esoxx (Alfa Wassermann, Bologna, Italy), a hyaluronic acid-chondroitin sulphate based bioadhesive formulation, or placebo, in addition to acid suppression with standard dose PPIs for 2 weeks. Symptoms (heartburn, acid regurgitation, retrosternal pain and acid taste in the mouth) and health-related quality of life (HRQL) were evaluated before and after treatment. The primary endpoint was the proportion of patients with at least a 3-point reduction in the total symptom score. RESULTS: At the end of treatment, the primary endpoint was reached by 52.6% of patients taking Esoxx compared to 32.1% of those given placebo (P < 0.01). The same was true also for HRQL, evaluated by means of the Short Form-36 questionnaire, which improved with both treatments, but some items were significantly better after Esoxx plus PPI therapy. CONCLUSION: The synergistic effect of Essox with PPI treatment suggests that mucosal protection added to acid suppression could improve symptoms and HRQL in NERD patients.

An expert consensus definition of failure of a treatment to provide adequate relief (F-PAR) for chronic constipation - an international Delphi survey.

BACKGROUND: As treatments for constipation become increasingly available, it is important to know when to progress along the treatment algorithm if the patient is not better. AIM: To establish the definition of failure of a treatment to provide adequate relief (F-PAR) to support this management and referral process in patients with chronic constipation. METHODS: We conducted an international Delphi Survey among gastroenterologists and general practitioners with a special interest in chronic constipation. An initial questionnaire based on recognised rating scales was developed following a focus group. Data were collected from two subsequent rounds of questionnaires completed by all authors. Likert scales were used to establish a consensus on a shorter list of more severe symptoms. RESULTS: The initial focus group yielded a first round questionnaire with 84 statements. There was good consensus on symptom severity and a clear severity response curve, allowing 67 of the symptom-severity pairings to be eliminated. Subsequently, a clear consensus was established on further reduction to eight symptom statements in the final definition, condensed by the steering committee into five diagnostic statements (after replicate statements had been removed). CONCLUSIONS: We present an international consensus on chronic constipation, of five symptoms and their severities, any of which would be sufficient to provide clinical evidence of treatment failure. We also provide data representing an expert calibration of commonly used rating scales, thus allowing results of clinical trials expressed in terms of those scales to be converted into estimates of rates of provision of adequate relief.

Review article: the opportunities and benefits of extended acid suppression.

Acid suppression therapy with proton pump inhibitors is associated with well-established benefits in the management of gastro-oesophageal reflux (GERD) and other acid-related disorders. However, a number of issues still remain unsettled. Despite their clinical efficacy, when given once daily, currently available proton pump inhibitors may not adequately control intragastric acidity during the night in a significant proportion of both healthy subjects and GERD patients, in whom symptom relief remains suboptimal. Although some novel proton pump inhibitors have been synthesized, only few reached clinical testing. Amongst them, tenatoprazole represents a true advance displaying a long half-life (five to seven times longer than that of currently available drugs) and extended acid suppression covering both day and night. All the available clinical studies suggest both pharmacokinetic and pharmacodynamic advantages of tenatoprazole over esomeprazole. As this last compound provides - amongst the members of the class - the most effective control of intragastric pH whatever the parameter considered, it is conceivable that tenatoprazole could similarly be better than the other existing proton pump inhibitors. Tenatoprazole appears to be a promising proton pump inhibitor for the treatment of acid-related diseases, where it has the potential to address unmet clinical needs.

Dysphagia aortica: a neglected symptom of aortoesophageal fistula.

Aortoesophageal fistula, secondary to thoracic aortic aneurysm, is an uncommon cause of gastrointestinal bleeding that is uniformly fatal without surgical intervention. Typical symptoms are midthoracic pain and/or dysphagia followed by a usually short, albeit unpredictable, symptom-free interval and by a 'herald' haemorrhage, which is observed in 80% of patients before fatal exsanguinations. Dysphagia is present in 45% of patients, sometimes for several weeks, before the first bleeding occurs. However, dysphagia aortica is rarely considered in the differential diagnosis of dysphagia and lack of awareness, as well as symptom's underevaluation, both contribute to a significant diagnostic and therapeutic delay. We present a case of a 77-year-old woman who died for a bleeding AEF consequent to a thoracic aortic aneurysm and whose main symptom during the past 2 months was dysphagia, which was not taken seriously into consideration by her general practitioner. This case report emphasises that primary care physicians should be alerted to evaluate carefully the alarming symptoms like dysphagia -- especially in elderly patients -- before life threatening complications occur, as they are the ones who could suspect early the diagnosis and make a proper referral.

Gastrointestinal safety of amtolmetin guacyl in comparison with celecoxib in patients with rheumatoid arthritis.

OBJECTIVE: Selective inhibitors of cyclo-oxygenase-2 (COX-2) appear to be safer than conventional NSAIDs on the gastrointestinal (GI) tract. Amtolmetin guacyl (AMG), a NSAID that inhibits both COX-1 and COX-2, has an anti-inflammatory effect comparable to that of traditional NSAIDs, with a better GI safety profile. The primary end-point of this study was to evaluate the gastrointestinal safety of amtolmetin guacyl in comparison with celecoxib in patients affected with rheumatoid arthritis. The assessment of efficacy was the secondary end-point. METHODS: This study was a 24-week, randomized, parallel group, double-blind, double dummy, multicentre trial; 235 patients were enrolled and 180 patients (85 in the AMG group and 95 in the celecoxib group) completed the study. Each patient received twice daily amtolmetin guacyl 600 mg or celecoxib 200 mg. Assessment of safety was performed by upper GI endoscopy, gastrointestinal symptoms evaluation, electrocardiography, blood and urine laboratory tests, adverse events recording. Assessment of efficacy was performed by using the American College of Rheumatology (ACR-20) responder index. RESULTS: Neither amtolmetin guacyl nor celecoxib determined a worsening of baseline gastro-duodenal endoscopy findings. The percentage of patients with normal findings did not significantly change after treatment with both drugs, being virtually identical with AMG (i.e. 75.29%) and increasing from 75.79% to 77.66% with celecoxib. Moreover an evaluation of the other safety parameters did not reveal any difference between the two treatment groups. Therapeutic efficacy was equivalent in both groups, with no statistical difference between the two drugs at all time intervals. CONCLUSIONS: In patients affected with rheumatoid arthritis, AMG and celecoxib proved to be equivalent, showing comparable gastrointestinal safety and therapeutic efficacy of treatment.

Histamine H2-antagonists modify gastric emptying in the rat.

1 Histamine H2-receptor antagonists were tested for their effect on gastric emptying in the rat. 2 At low doses all the compounds were inactive except for burimamide which delayed and ranitidine which accelerated gastric emptying. 3 At high doses burimamide, metiamide, cimetidine and oxmetidine delayed, whereas ranitidine accelerated gastric emptying; tiotidine remained ineffective. 4 Changes in emptying rate were not accompanied by changes in emptying pattern which, with all the compounds examined, proceeded, as in the controls, by apparent first order kinetics. 5 The mechanism of the ranitidine-induced acceleration of gastric emptying seemed to be connected with an interference with the cholinergic system, whereas the mechanism of cimetidine- and oxmetidine-induced slowing of gastric emptying was apparently related to cholinolytic and possibly also relaxant effects of the compounds. 6 These different effects of the various H2-blockers are consistent with the idea that changes in emptying rate are independent of H2-receptor blockade.

Antisecretory and antiulcer effect of the H2-receptor antagonist famotidine in the rat: comparison with ranitidine.

1 The effects of the new H2-receptor antagonist famotidine, administered orally, on gastric secretion and emptying as well as on experimentally-induced gastric and duodenal ulcers were studied in the rat. Ranitidine was used as a reference compound. 2 Both compounds inhibited acid secretion in a dose-dependent manner. Calculated ED50 values were 0.80 and 6.84 mg kg-1 for famotidine and ranitidine, respectively. However, the duration of the antisecretory action was the same for both drugs. 3 The effect of the two drugs, administered at equiactive antisecretory doses, on gastric emptying was different. Ranitidine significantly accelerated the emptying rate whereas famotidine had no effect. 4 Famotidine reduced, in a dose-dependent manner, ulcer incidence in stomachs of dimaprit-treated rats and in duodena of cysteamine-treated animals with a potency respectively 2 and 7 times higher than that of ranitidine. 5 Famotidine is therefore an effective antisecretory and untiulcer compound. Its potency, but not its efficacy, is higher than that of ranitidine. Moreover, the duration of the antisecretory action is virtually the same for both drugs.

Relaxant effect of the H2-receptor antagonist oxmetidine on guinea-pig and human airways.

The effects of three different H2-receptor antagonists (cimetidine, ranitidine and oxmetidine) were tested on isolated preparations of guinea-pig trachea and human bronchus against contractions induced by acetylcholine, histamine and potassium chloride (KCl). In addition, their influence on calcium concentration-response curves in guinea-pig tracheal spirals was examined in a potassium-rich solution (30 mM). Finally, their effects were studied in vivo against acetylcholine and histamine-induced bronchoconstriction in anaesthetized guinea-pigs. In guinea-pig isolated trachea, oxmetidine--in contrast to cimetidine and ranitidine, which were completely inactive--induced a concentration-dependent relaxation regardless of the excitatory stimulus: its--log EC50 values (i.e. the negative log concentration that caused a 50% relaxation) were 3.46 +/- 0.11, 4.61 +/- 0.09 and 4.20 +/- 0.12 against acetylcholine, histamine and KCl, respectively. In Ca2+-free, K+-enriched solution, the compound was able to inhibit Ca2+-induced contractions at concentrations close to those needed to counteract the spasmogenic effect of histamine in normal Krebs solution. Results obtained in the human bronchus preparation were similar to those observed in guinea-pig tracheal spirals. When tested against acetylcholine or histamine-induced bronchoconstriction in vivo, oxmetidine (10 and 30 mg Kg-1 intravenously) significantly reduced the increase in pulmonary airway resistance (Raw) induced by both agents. Once again, cimetidine and ranitidine were completely ineffective. In summary, oxmetidine displayed non-specific antispasmogenic activity on guinea-pig and human airways. This effect, which is independent of H2-receptor blockade, represents a side-effect of the drug which may be connected to its interference with Ca2+ influx and the action or release of intracellular Ca2+.

Effect of a new potent CCK antagonist, lorglumide, on caerulein- and bombesin-induced pancreatic secretion and growth in the rat.

1. The effect of lorglumide, a new potent cholecystokinin (CCK) antagonist, on pancreatic secretion and growth induced by caerulein and bombesin was studied in the rat. 2. Pancreatic exocrine secretion was studied both in vitro (isolated and perfused pancreatic segments) and in vivo (anaesthetized animals with cannulation of the common bile duct) whereas the trophic effect was investigated after short-term (5 days) administration of the peptides and/or lorglumide. 3. Both caerulein and bombesin stimulated amylase release from in vitro pancreatic segments in a concentration-dependent manner. Although the efficacy of both peptides was virtually identical, the potency of caerulein was higher than that of bombesin. Lorglumide displaced the concentration-response curves to caerulein to the right without affecting the maximum response, suggesting a competitive antagonism. The Schild plot analysis of data gave a straight line with a slope not significantly different from unity. The calculated pA2 for lorglumide was 7.31 +/- 0.45. The antagonist, however, was completely ineffective when tested against bombesin-induced amylase release. 4. In vivo experiments confirmed results from in vitro studies since lorglumide (5 and 10 mg kg-1) significantly reduced pancreatic exocrine secretion induced by caerulein without affecting the response to bombesin. 5. Administration of either peptide increased the weight of the pancreas, the total pancreatic protein and DNA, trypsin and amylase content. Lorglumide (10 mg kg-1), administered together with caerulein, reduced the peptide-induced increase in pancreatic weight, protein and enzyme content. On the contrary, when lorglumide was given together with bombesin, all the parameters that were examined were not altered by concomitant administration of the antagonist. 6. These results have demonstrated the ability of lorglumide to antagonize the effects on the pancreas of a CCK-analogue, caerulein, and its inability to affect bombesin-induced pancreatic secretion and growth, suggesting that lorglumide is a potent and selective antagonist of CCK-receptors in the pancreas.

Effect of substance P and its natural analogues on gastric emptying of the conscious rat.

1 Substance P and its natural analogues were tested for their effect on gastric emptying in the rat. 2 Substance P and kassinin were virtually inactive even at the maximum dose tests. 3 The other tachykinins significantly delayed gastric emptying their effect being quite remarkable with 100 micrograms/kg. The lowest doses (30 microgram/kg) caused a slight and non-significant increase in emptying rate. 4 The effect on gastric emptying was most probably correlated with a spasmogenic effect on the gastroduodenal junction, as pointed out in previous work.

Different effects of bombesin on glucose- and tolbutamide-induced insulin release in man.

1. The effect of bombesin, a neurogastrointestinal peptide, on basal and stimulated insulin release was studied in man. 2. Two different stimuli were used, hyperglycaemic (20 g glucose) and hypoglycaemic (1 g tolbutamide). They were injected intravenously to two groups of male healthy volunteers during saline or bombesin (5 ng kg-1 min-1 for 60 min) infusion. 3. The peptide had no significant effect on basal levels of glucose and insulin. However, the insulin response to intravenous glucose was strongly potentiated by bombesin, the integrated insulin response being 2.23 +/- 0.59 mu ml-1 . 90 min and 0.98 +/- 0.19 mu ml-1 . 90 min during infusion of bombesin and saline, respectively (P less than 0.05). The behaviour of plasma glucose was not significantly modified by the peptide. Indeed, the glucose disappearance rate (K of Conard, mg min 10(-2)) changed from 2.5 +/- 0.3 during saline to 2.4 +/- 0.4 during bombesin infusion. 4. When the hypoglycaemic stimulus (i.e. tolbutamide) was used, no effect of the peptide on insulin release could be detected. Here again, the drop in plasma glucose (expressed as Marigo's coefficient) was not affected by the peptide, with a value of 92.8 +/- 12.6 and 84.0 +/- 10.9 during bombesin and saline administration. 5. These data therefore show that, at normal or low blood glucose levels, the dose of bombesin used is unable to modify insulin release and suggest that this peptide might be regarded as a glucose-dependent insulinotropic peptide.

Different actions of CCK on pancreatic and gastric growth in the rat: effect of CCK(A) receptor blockade.

1. It is now well established that cholecystokinin (CCK) has a major physiological role in the regulation of pancreatic secretion and gastro-intestinal (GI) motility. Both these actions are mediated by stimulation of CCK(A)-receptors located on pancreatic acini and GI smooth muscle cells. While chronic administration of CCK-like peptides invariably causes pancreatic hypertrophy and hyperplasia, their action on gastric growth remains controversial. 2. In the present investigation the action of exogenous and endogenous CCK on both pancreatic and gastric growth was studied in the same animal. In addition, the ability of dexloxiglumide, a new potent and selective CCK(A)-receptor antagonist, to counteract CCK-mediated effects was evaluated. 3. The amphibian peptide caerulein (1 microg kg(-1) intraperitoneally three times daily) was used as a CCK agonist, while camostate (200 mg kg(-1) intragastrically once daily), a synthetic protease inhibitor, was used to release endogenous CCK. They were administered to rats for seven days with or without dexloxiglumide (25 mg kg(-1) subcutaneously 15 min before the stimulus). On the eighth day, animals were killed, the pancreas and stomach excised, weighed, homogenized and their protein and DNA content measured. 4. Both exogenous and endogenous CCK increased the weight of the pancreas as well as the total pancreatic protein and DNA content. Dexloxiglumide, which alone did not affect pancreatic size and composition, was able to counteract both caerulein- and camostate-induced pancreatic changes. Neither stimuli affected gastric growth in respect of weight and composition of the oxyntic gland area and the antrum. 5. These results show different effects of CCK on pancreatic and gastric growth. The CCK-induced pancreatic hypertrophy and hyperplasia are blocked by the potent and specific CCK(A)-receptor antagonist, dexloxiglumide. This compound therefore represents a useful tool to investigate CCK-receptor interactions in peripheral organs.