Background: The optimal management of patients with reflux-associated laryngitis is unclear. We performed a placebo-controlled crossover trial in patients with proven reflux disease and associated laryngitis to determine the effect of pantoprazole and to gain information on the natural course of the disease. Methods: Sixty-two consecutive non-smoking patients with hoarseness and proven laryngitis were examined. Scores with respect to the larynx and for subjective complaints were determined and 24-h pH-metry to assess acid reflux in the lower oesophagus and pharynx was performed. Patients with pathologic reflux were given the chance to enter a double-blinded randomized crossover trial with pantoprazole 40 mg b.i.d. and placebo for a duration of 3 months each, separated by a 2-week washout period. Results: Twenty-four of 62 patients showed pathological reflux; 21 patients were included in the study and 14 concluded all parts of the study. Both pantoprazole and placebo resulted in a marked improvement in laryngitis scores (decrease of 8.0 +/- 1.4 versus 5.6 +/- 2.6; no significant difference between the 2 treatments) and symptoms after the first 3 months (decrease of oesophageal symptom score of 2.2 +/- 1.4 versus 5.4 +/- 2.8; decrease of laryngeal scores of 8.3 +/- 3.6 versus 10.3 +/- 3.9; also no significant difference between the 2 treatments). A second pH-metry 2 weeks thereafter proved the persistence of reflux in most of these patients. Switching to pantoprazole led to a further improvement of scores. In the group switched to placebo there was recurrence only in a minority of patients. Conclusions: The self-limited nature of reflux-associated laryngitis in non-smokers is largely underestimated. Laryngitis improves despite the persistence of reflux. Pantoprazole may be helpful especially in relieving acute symptoms, but the advantage of long-term treatment over placebo has been greatly overestimated.

OBJECTIVES: Nitric oxide, a neurotransmitter in the noncholinergic, nonadrenergic nervous system, is a mediator of relaxation of GI smooth muscle and of visceral nociception mainly studied in vitro. Sildenafil stimulates the nitric oxide guanosine 3', 5'-cyclic monophosphate (NO-cGMP) pathway through inhibition of phosphodiesterase 5. The aims of this study were to evaluate in vivo the effect of stimulation of the NO-cGMP pathway on rectal tone, distensibility, and perception in healthy individuals and in patients with irritable bowel syndrome (IBS).METHODS: In eight healthy subjects and four patients with IBS rectal tone, distensibility and perception thresholds were measured with an electronic barostat both before and 60 min after administration of sildenafil (50 mg p.o.). Perception was scored on a graded scale of 0-6. At the end of a distension series an anatomic questionnaire was filled out by the subjects.RESULTS: Sildenafil significantly reduced rectal tone in healthy subjects (intrabag volume predrug: 145.5 +/- 18.7 ml vs postdrug: 164.4 +/- 16.9 ml, p = 0.01) and IBS (111.3 +/- 25.2 ml vs 136.5 +/- 33.3 ml; p = 0.01) but did not alter rectal compliance (healthy subjects: 5.8 +/- 0.4 vs 6.3 +/- 0.6 ml/mm Hg, p > 0.05; IBS subjects: 6.1 +/- 0.6 vs 7.1 +/- 1.0 ml/mm Hg, p > 0.05). Intrabag pressure and rectal wall tension to reach perception thresholds for initial sensation, sensation of stool, and urgency were not altered by sildenafil. However, intrabag volumes to reach these thresholds were significantly increased by sildenafil both in healthy subjects and in patients with IBS. Viscerosomatic referral was unchanged.CONCLUSIONS: Stimulation of the NO-cGMP pathway decreases rectal tone but does not influence rectal distensibility. Relaxation of the rectum is accompanied by an increase in rectal volumes to reach perception thresholds in healthy subjects and in patients with IBS, but no direct effect on rectal perception can be demonstrated.

BACKGROUND AND AIMS:Sildenafil blocks phosphodiesterase type 5 which degrades nitric oxide (NO) stimulated 3'5'-cyclic monophosphate (cGMP), thereby relaxing smooth muscle cells in various organs. We used sildenafil as a tool to investigate the role of the NO-cGMP pathway in the oesophagus of healthy volunteers and patients with hypercontractile oesophageal motility disorders.METHODS:Six healthy male volunteers participated in a randomised double blind study on two separate days before and one hour after oral intake of either sildenafil 50 mg or placebo. Oesophageal manometry was performed to determine vector volume of the lower oesophageal sphincter (LOS) and pressure amplitudes of the oesophageal body. Four of the volunteers underwent 12 hour ambulatory oesophageal manometry on two separate days, once with sildenafil 50 mg and once with placebo. An activity index for spontaneous swallowing was calculated for every hour of the study. Eleven patients with hypercontractile oesophageal motility disorders took part in an open study of the effect of 50 mg sildenafil on manometric features of their disorder and on the clinical response to sildenafil taken as required.RESULTS:In healthy subjects, sildenafil significantly reduced LOS pressure vector volume and pressure amplitudes in the distal half of the oesophageal body. In three of four subjects the inhibitory effect of sildenafil lasted at least eight hours. In nine of 11 patients, manometric improvement after sildenafil was observed but only four had an improvement in oesophageal symptoms with sildenafil taken as required. Two of these four patients however experienced side effects and did not want to continue treatment.CONCLUSIONS:Sildenafil lowers LOS pressure and propulsive forces in the body of the oesophagus of healthy subjects as well as in patients with nutcracker oesophagus, hypertensive LOS, and achalasia. The effect of sildenafil on the oesophageal body may last for up to eight hours in healthy volunteers. A subset of patients with hypertensive LOS or nutcracker oesophagus may benefit from sildenafil but side effects are a limiting factor.

Although adenocarcinoma of the cardia is extremely rare in adolescent patients, the endoscopist should be alert to this disease in patients of any age with dysphagia, even if symptoms, and results of a barium study, upper endoscopy, and esophageal manometry are suggestive of primary achalasia, especially if family history is negative for achalasia. In addition, secondary achalasia should be suspected in patients who do not respond to therapy with botulinum toxin within 2 months. Because none of the mentioned tests can distinguish between primary achalasia and secondary forms due to carcinoma of the cardia, biopsy specimens should be obtained. It appears that, although there is a minimal risk for complications, a diagnostic procedure such as biopsy would be appropriate when the information obtained could be essential. In some cases EUS can be an additional diagnostic tool, because lesions of the submucosa and the surrounding area can be identified by EUS.

A major drawback of endoscopic desobliteration procedures such as laser - or argon - plasma - desobliteration in enteral malignancies is the need for repeated treatments. Endoscopic implantation of metallic stents ( SEMS ) is a short time and single step procedure. The aim of this study was to evaluate whether SEMS are superior to desobliteration treatment preventing enteral obstruction. 35 patients ( 16f/19m, mean age 73y, 61y - 88y ) were treated by endoscopic desobliteration therapy with a continuous - wave Nd:Yag laser or an argon - plasma - coagulator. Mean treatment number was 2.6 ( 1 - 4 ), mean treatment duration was 50.5 min ( 25 - 85 ). The mean patency rate after desobliteration was estimated with 24.3 days (11 - 40). As a major complication perforation occured in 4 patients ( 11% ). Two died from peritonitis/ mediastinitis, the other patients recovered under conservative treatment. 38 patients ( 18f/20m, mean age 74y, 59y - 89y ) were treated by implantation of SEMS ( coated Wallstent®, Boston Scientific Inc. and Endocoil®, Euromed Inc. ). 22 patients had esophageal strictures, 2 patients duodenal stenoses caused by invasive pancreatic cancer and 14 patients had malignant colonic stricures. A total number of 51 SEMS ( 24 Wallstents, 17 Endocoils ) was implanted for complete desobliteration of the strictures. Mean duration of the implantation was 18 min (8 - 34 min ). After marking the stent position at the oral and distal end of the stenosis a guide wire was placed through the endoscope over the stricture. If the passage for the endoscope was impossible, only the oral/ distal end of the stricture was marked. After withdrawal of the endoscope the SEMS was positioned over the guide wire and deployed under fluoroscopic control. The succes rate of implantation was 100%, in 13 patients a second stent had to be implanted for optimal bridging the whole sticture. The mean patency rate was estimated with 89 days ( 33 - 161 ). In most cases stent occlusion occurred by tumor overgrowth at the ends of the SEMS. There was seen no major complication in the stent group. Since endoscopic desobliteration of malignant enteral obstruction is a time consumpting procedure with a high need of re - treatments and a remarkable complication rate there is strong evidence, that endoscopic implantation of SEMS may be superior. The implantation is an easy to perform and safe endoscopic procedure, patency rate and life quality are superior to the laser group. More data of larger trials are necessary to confirm these data of a small group. A major drawback of endoscopic desobliteration procedures such as laser - or argon - plasma - desobliteration in enteral malignancies is the need for repeated treatments. Endoscopic implantation of metallic stents ( SEMS ) is a short time and single step procedure. The aim of this study was to evaluate whether SEMS are superior to desobliteration treatment preventing enteral obstruction. 35 patients ( 16f/19m, mean age 73y, 61y - 88y ) were treated by endoscopic desobliteration therapy with a continuous - wave Nd:Yag laser or an argon - plasma - coagulator. Mean treatment number was 2.6 ( 1 - 4 ), mean treatment duration was 50.5 min ( 25 - 85 ). The mean patency rate after desobliteration was estimated with 24.3 days (11 - 40). As a major complication perforation occured in 4 patients ( 11% ). Two died from peritonitis/ mediastinitis, the other patients recovered under conservative treatment. 38 patients ( 18f/20m, mean age 74y, 59y - 89y ) were treated by implantation of SEMS ( coated Wallstent®, Boston Scientific Inc. and Endocoil®, Euromed Inc. ). 22 patients had esophageal strictures, 2 patients duodenal stenoses caused by invasive pancreatic cancer and 14 patients had malignant colonic stricures. A total number of 51 SEMS ( 24 Wallstents, 17 Endocoils ) was implanted for complete desobliteration of the strictures. Mean duration of the implantation was 18 min (8 - 34 min ). After marking the stent position at the oral and distal end of the stenosis a guide wire was placed through the endoscope over the stricture. If the passage for the endoscope was impossible, only the oral/ distal end of the stricture was marked. After withdrawal of the endoscope the SEMS was positioned over the guide wire and deployed under fluoroscopic control. The succes rate of implantation was 100%, in 13 patients a second stent had to be implanted for optimal bridging the whole sticture. The mean patency rate was estimated with 89 days ( 33 - 161 ). In most cases stent occlusion occurred by tumor overgrowth at the ends of the SEMS. There was seen no major complication in the stent group. Since endoscopic desobliteration of malignant enteral obstruction is a time consumpting procedure with a high need of re - treatments and a remarkable complication rate there is strong evidence, that endoscopic implantation of SEMS may be superior. The implantation is an easy to perform and safe endoscopic procedure, patency rate and life quality are superior to the laser group. More data of larger trials are necessary to confirm these data of a small group.

BACKGROUND AND AIMS: In our previous studies, we showed that glucagon inhibits cholinergic motor activities in the gastric antrum through postganglionic cholinergic motor neurons.However, the exact physiological roles of it have not yet been elucidated.The purpose of this study was to investigate the effects of glucagon on contractions and relaxations of the pyloric ring and antro-pyloro-duodenal coordinative contractions.SUB-JECTS AND METHODS: Experiments were performed on conscious dogs.In the gastric antrum, pyloric ring, and duodenum, the contractile activities were measured by means of strain gauge force transducers.RESULTS: 1) During migrating motor contractions (phase 3), relaxations of the pyloric ring (i.e.pyloric ring opening) were obviously observed at the same time as when intense phasic contractions occured in the antrum.In contrast, when phasic contractions were observed in the pyloric ring (i.e.pyloric ring closure), bursts of contractions occured in the duodenum.2) In the pyloric ring, glucagon (20-50ILglkg, drip infusion for 5 minutes) did not affect contractions, but strongly inhibited relaxations.At the same time, it significantly inhibited phasic contractions in the antrum, and did not affect these contractions in the duodenum.3) During the interdigestive quiescent phase, administration of erythromycin (0.15mglkg, drip infusion for 10 minutes) induced phase 3-like contractions with negative deflection of the pyloric ring, synchronized with strong contractions of the antrum, which were similar to spontaneous phase 3 contractions.Glucagon strongly inhibited relaxations in the pyloric ring, but never affected contractions.CONCLUSION: These results probably suggests that glucagon itself inhibits duodeno-gastric refluxes after bursts of contractions in the duodenum induced by glucagon, by means of inhibition of pyloric ring relaxations.

Background —Stimulation of sensory nerves with capsaicin regulates ion transport in the small intestine in animal experiments. Aim —To investigate whether sensory nerves that are stimulated by capsaicin administration influence fluid and electrolyte absorption in the human jejunum in vivo. Method —Intestinal perfusion studies were performed in 12 healthy subjects using a four lumen tube with a proximal occlusion balloon and a plasma-like electrolyte solution. After an initial control period, 5 (n = 3), 10 (n = 8), or 50 (n = 1) μg/ml capsaicin was added to the perfusate, and this was followed by a final control period. Rates of absorption of water, sodium, potassium, chloride, and bicarbonate were determined in a 30 cm segment of jejunum using a non-absorbable volume marker. Results —At all three concentrations of capsaicin there were no significant changes in water and electrolyte absorption as compared with control periods. Two subjects who received 10 μg/ml and the subject receiving 50 μg/ml experienced crampy abdominal pain. Conclusion —The results do not support the hypothesis that capsaicin sensitive afferent nerves are involved in the physiological regulation of net absorption or secretion across the human jejunal mucosa. Chemical stimulation of these nerves, however, gives rise to abdominal pain.

OBJECTIVE:Quantitative assessment of intestinal absorption of total and single amino acids in a hydrolysed bovine serum albumin solution over a 6-h period.DESIGN:Ten healthy volunteers underwent segmental jejunal perfusion using a multi-lumen tube assembly with a proximal occluding balloon. Prehydrolysed bovine serum albumin served as protein source. In one set of experiments we used a washout phase before the equilibration period to eliminate any contents present in the test segment. In another set we started directly with the equilibration period. Absorption rates of total and single amino acids were measured over a period of 6 h.RESULTS:Absorption rates remained constant throughout this period and there was no significant difference in absorption rates whether a washout phase was used or not. Absorption rates of total amino acids ranged from 6.4 +/- 1.9 (mean +/- SEM) to 10.7 +/- 0.7 g/h and 30 cm, when a washout phase was used. Percentage absorption of the perfusion load per hour was 24 +/- 7% to 40 +/- 2% with a washout phase. Although a highly concentrated perfusion load was used there was a correlation (r = 0.66, P < 0.05) between absolute concentration in the perfusion solution and the amount of individual amino acid absorbed. Individual amino acids showed a wide range of percentage absorption. Percentage absorption of 50% or more of the perfusion load was seen for alanine, phenylalanine, arginine, leucine, methionine and tyrosine. The highest absorption rate was seen for methionine with 86%, the lowest for cysteine with 3%.CONCLUSION:When hydrolysed bovine serum albumin is used, amino acid absorption is constant over a period of 6 h in the human jejunum. A washout phase has no influence on total and single amino acid absorption.

Abstract In rats, the combined administration of the 5‐HT2 antagonist ketanserin and the 5‐HT3 antagonist tropisetron inhibits cholera toxin‐induced intestinal secretion. We investigated whether these agents and the 5‐HT3 antagonist ondansetron can inhibit cholera toxin‐induced secretion in the human jejunum using a segmental perfusion technique. In a first control period the subjects' jejunums were perfused continuously with a plasma‐like electrolyte solution. In a second control period they either received a combination of tropisetron plus ketanserin, or tropisetron or ondansetron alone. Cholera toxin 6·25 μg was then administered intrajejunally and the experiments were continued for 4 h. Net water movements during the 4th hour after CT administration minus net water movement during the first control period was used for further calculation and was referred to as net luminal gain. In perfusion studies with tropisetron plus ketanserin resp. ondansetron the net luminal gain of water (+161 ± 26 resp. 189 ± 28 ml 30 cm‐1 h‐1, mean ± SEM) was significantly higher compared to perfusion studies with cholera toxin alone (+94 ± 30). Treatment with tropisetron did not change the CT‐induced net luminal gain of water (+108 ± 41). Movements of sodium, chloride, bicarbonate and potassium paralleled the movement of water. In agreement with these observations we found a deterioration of clinical parameters after the end of the perfusion studies in four of five subjects treated with CT 25 μg plus ketanserin and tropisetron. Contrary to what has been observed in animal experiments the results in humans indicate enhancement rather than inhibition of CT‐induced secretion by administration of 5‐HT antagonists. Our results do not support the contention that the intravenous administration of ketanserin, tropisetron or ondansetron might be of potential therapeutic value in patients with Asiatic cholera.

Animal experiments have shown that acute respiratory acidosis stimulates water, Na and Cl absorption and HCO3 secretion in the ileum. The aim of this study was to investigate whether the human ileum also responds to changes in systemic acid-base balance. Seven healthy volunteers (mean age 24, range 21-29 years) underwent segmental ileal perfusion using a multi-lumen tube assembly with a proximal occluding balloon. A 30 cm test segment was perfused under steady state conditions with a plasma-like electrolyte solution containing PEG as a non-absorbable volume marker. After a control period, respiratory acidosis (blood pCO2 56.2 mmHg, pH 7.29 and [HCO3] 26.4 mmol l-1) was induced by CO2-breathing over a period of 50 min. Acute respiratory acidosis stimulated net HCO3 secretion in patients secreting HCO3 and reduced absorption in patients exhibiting net HCO3 absorption. These changes were immediate and appeared to be at least partly reversible. Net water, Na, K and Cl movement were not affected. The data suggest that HCO3 transport in the human ileum responds to acute respiratory acidosis.

In order to develop a model for secretory diarrhoea and to confirm the in vitro effects of cholera toxin in man in vivo the effect of intrajejunally administered cholera toxin was investigated in healthy volunteers. An intestinal perfusion technique with an occluding balloon proximal to the infusion site was used. The jejunum was perfused under steady state conditions with a plasma like electrolyte solution containing polyethylene glycol as a non-absorbable volume marker. After two control periods of one hour each, during which water was absorbed at a rate of 104 (14) (mean (SEM), n = 15) and 94 (15) ml/30 cm/h, respectively, three different doses of cholera toxin (6.25 micrograms, 12.5 micrograms, 25 micrograms) were administered by bolus into the lumen of the jejunum. Cholera toxin reduced absorption of water and electrolytes progressively over four hours and induced secretion in a dose dependent fashion. In the fourth hour net secretion amounted to 22 (23), 36 (24), and 88 (40) ml/30 cm/h (each n = five) with doses of 6.25, 12.5, and 25 micrograms cholera toxin, respectively. The movement of sodium, chloride, and bicarbonate paralleled water movement. Our results suggest that cholera toxin may serve as a secretory model in the human jejunum which might allow testing of new antisecretory agents.