[Diagnosis of oesophageal reflux by PH, impedance, and bilirubin measurement: recommendations of the German Society of Neurogastroenterology and of the working group for neurogastroenterology of the German Society for Digestive and Metabolic Diseases]. / Ösophageale Refluxdiagnostik - pH-Metrie, Impedanzmessung, Bilirubin-Messung: Empfehlungen der Deutschen Gesellschaft für Neurogastroenterologie und Motilität und der Arbeitsgruppe Neurogastroenterologie der Deutschen Gesellschaft für Verdauungs- und Stoffwechselkrankheiten.

The current recommendations on indications, technical performance, and interpretation of diagnostic techniques for oesophageal reflux update the German recommandations about 24 hour pH measurement of 2003. The recommendations encompass conventional pH measurement, wireless pH measurement, pH and impedance measurements, and bilirubin measurement (duodenogastro-oesophageal reflux).

Bioavailability of amoxicillin and clavulanic acid from extended release tablets depends on intragastric tablet deposition and gastric emptying.

The rate and extent of amoxicillin and clavulanic acid absorption from pharmacokinetically enhanced extended release (ER) tablets is strongly influenced by the intake conditions. In order to investigate the cause of the food effects, a pharmacokinetic study with simultaneous imaging of the in vivo behaviour of the ER tablets by magnetic marker monitoring (MMM) was performed. Under fasting conditions the amoxicillin AUC (1854+/-280microg min ml(-1)) was significantly lower than after intake at the beginning of the breakfast (2452+/-354microg min ml(-1)) or after the breakfast (2605+/-446microg min ml(-1)). In contrast, clavulanic acid AUC was well comparable after tablet intake under fasting conditions and intake at the beginning of a breakfast (191+/-46 and 189+/-44microg min ml(-1), respectively) but significantly lower following a breakfast (126+/-71microg min ml(-1)). The localization data showed that the reduced bioavailability of amoxicillin under fasting conditions is due to early gastric emptying in combination with poor absorption from deeper parts of the small intestine. Prolonged gastric residence of clavulanic acid caused by intragastric tablet deposition in the proximal stomach was identified as the reason for the decreased bioavailability of clavulanic acid after tablet intake following the meal.

Do we need gastric acid?

Evidence from comparative anatomy and physiology studies indicates that gastric acid secretion developed during the evolution of vertebrates approximately 350 million years ago. The cellular mechanisms that produce gastric acid have been conserved over the millennia and therefore proton pump inhibitors have pharmacological effects in almost all relevant species. These observations suggest that gastric acid provides an important selective advantage; however, in modern-day humans the need for gastric acid can be questioned in light of the widespread use of safe and effective pharmacologic acid suppression. The Kandahar Working Group addressed questions concerning the need, production and effects of gastric acid, specifically: (1) motility in the upper gastrointestinal (GI) tract; (2) neuroendocrine factors; (3) digestive and mucosal processes; (4) microbiology, and (5) central processes and psychological involvement. We addressed each topic with the individual models available to answer our questions including animal versus human studies, pharmacologic, surgical as well as pathophysiologic states of acid suppression.

Systematic review: do we need a new gastro-oesophageal reflux disease questionnaire?

BACKGROUND: Gastro-oesophageal reflux disease (GERD) is highly prevalent in Western countries. Because the majority of patients do not present with endoscopic abnormalities, the assessment of the symptom severity and quality of life, and their response to treatment, has become increasingly important. Self-assessed symptom questionnaires are now key instruments in clinical trials. AIM: To evaluate the validity of available GERD measurement tools. METHODS: An ideal GERD symptom assessment instrument, suitable as a primary end-point for clinical trials, should possess the following characteristics: (i) be sensitive in patients with GERD; (ii) cover the frequency and intensity of typical and atypical GERD symptoms; (iii) be multidimensional (cover all symptom dimensions); (iv) have proven psychometric properties (validity, reliability and responsiveness); (v) be practical and economical; (vi) be self-assessed; (vii) use 'word pictures' which are easy to understand for patients; (viii) respond rapidly to changes (responsiveness over short time intervals); (ix) be used daily to assess changes during and after therapy; and (x) be valid in different languages for international use. RESULTS: A literature review revealed five scales that met some of the above characteristics, but did not fulfil all criteria. CONCLUSION: There is a need for a new evaluative tool for the assessment of GERD symptoms and their response to therapy.

Evaluation of GERD symptoms during therapy. Part I. Development of the new GERD questionnaire ReQuest.

BACKGROUND/AIMS: The changes in gastroesophageal reflux disease (GERD)-related symptoms on treatment are variously described, but currently available questionnaires have shortcomings. We therefore developed a self-assessment reflux questionnaire (ReQuest). This article describes the process of development and testing. MATERIALS AND METHODS: For the first version of ReQuest the symptom spectrum of GERD and the various symptom descriptions were investigated. The 67 identified symptom descriptions were condensed empirically into 6 dimensions, to which a 7th dimension on general well-being was added. The symptom burden of the dimensions was measured by frequency and/or intensity. ReQuest was translated into different languages and then tested in focus groups. The initial validation was based on data from a clinical trial of patients with erosive GERD, treated with pantoprazole 20 or 40 mg daily for 28 days. Factor analyses determined the contribution of each symptom to the different dimensions. Additionally, correlation analyses between the identified factors and the dimensions were performed. RESULTS: On the basis of factor analyses, ReQuest was reduced to a 60-item scale. The factors generated correlated strongly with the dimensions and confirmed the empirical process mathematically. CONCLUSION: ReQuest provides a valuable, self-assessment tool for evaluating the daily treatment response in patients with erosive GERD.

International validation of ReQuest in patients with endoscopy-negative gastro-oesophageal reflux disease.

BACKGROUND: Reflux Questionnaire (ReQuest), a newly developed gastro-oesophageal reflux disease-sensitive scale, can be used to reliably evaluate the effect of treatment on gastro-oesophageal reflux disease symptoms. AIM: International validation of this scale, in patients suffering from endoscopy-negative gastro-oesophageal reflux disease. METHODS: In this open, multicentre and multinational clinical trial 840 endoscopy-negative gastro-oesophageal reflux disease patients received pantoprazole 20 mg daily for 28 days. The long and short versions of ReQuest were completed both in the pre-treatment and treatment phases. For scale development an item reduction analysis was performed. Internal consistency, test-retest reliability and responsiveness were calculated for psychometric analysis. Construct validity was evaluated by comparison with the Gastrointestinal Symptom Rating Scale and the Psychological General Well-being questionnaire by means of correlation coefficients. RESULTS: Factor analyses confirmed the content validity of both long and short version of ReQuest. Psychometric calculations proved high internal consistency (Cronbach's alpha: 0.9), test-retest reliability [Intraclass Correlation Coefficient: 0.9 (long vs. long) and 0.8 (short vs. short)], and responsiveness (Responsiveness Index 320.3) of the scale, for which also good construct validity was achieved (correlation coefficient: Gastrointestinal Symptom Rating Scale 0.6; Psychological General Well-being -0.4). CONCLUSION: ReQuest proved valid, reliable, and responsive in this multinational clinical trial to evaluate treatment response in endoscopy-negative gastro-oesophageal reflux disease patients.

Evaluation of GERD symptoms during therapy. Part II. Psychometric evaluation and validation of the new questionnaire ReQuest in erosive GERD.

BACKGROUND/AIMS: Evaluation of the response of gastroesophageal reflux disease (GERD) symptoms to treatment would be facilitated by a brief, valid, reliable and responsive, self-assessed GERD-sensitive scale. We therefore developed the Reflux Questionnaire (ReQuest). This publication describes the psychometric evaluation and validation of ReQuest. METHODS: This second phase of development was based on data from a clinical trial of patients with erosive GERD who received pantoprazole 20 or 40 mg daily for 28 days and completed weekly the long, and daily the short version of ReQuest. The psychometric analyses of ReQuest included internal consistency, test-retest reliability and responsiveness. Construct validity was evaluated by comparison with the Gastrointestinal Symptom Rating Scale (GSRS) and the Psychological General Well-Being (PGWB) scale. RESULTS: Validation of ReQuest indicated very high internal consistency (Cronbach's alpha = 0.90) and test-retest reliability (intraclass correlation coefficient 0.94 (long-long) and 0.86 (short-short)). This was also the case for the two subscales ReQuest-GI and ReQuest-WSO with Cronbach's alpha coefficients of 0.84 and 0.81. Responsiveness was high with a responsiveness index of >0.8 at day 28. Construct validity was good. CONCLUSION: ReQuest is a highly reliable, valid and responsive self-assessment tool for evaluating treatment response in patients with erosive GERD, and can be applied daily.

Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging.

AIM: The gastrointestinal transit of sequentially administered capsules was investigated in relation to the availability of fluid along the intestinal lumen by magnetic resonance imaging. METHODS: Water-sensitive magnetic resonance imaging was performed on 12 healthy subjects during fasting and 1 h after a meal. Specifiable non-disintegrating capsules were administered at 7, 4 and 1 h prior to imaging. RESULTS: While food intake reduced the mean fluid volumes in the small intestine (105 +/- 72 mL vs. 54 +/- 41 mL, P < 0.01) it had no significant effect on the mean fluid volumes in the colon (13 +/- 12 mL vs. 18 +/- 26 mL). The mean number of separated fluid pockets increased in both organs after meal (small intestine: 4 vs. 6, P < 0.05; large intestine: 4 vs. 6, P < 0.05). The distribution of capsules between the small and large intestine was strongly influenced by food (colon: 3 vs. 17 capsules, P < 0.01). CONCLUSIONS: The results show that fluid is not homogeneously distributed along the gut, which likely contributes to the individual variability of drug absorption. Furthermore, transport of fluid and solids through the ileocaecal valve is obviously initiated by a meal-induced gastro-ileocaecal reflex.

Brain activation responses to subliminal or supraliminal rectal stimuli and to auditory stimuli in irritable bowel syndrome.

Visceral hypersensitivity in irritable bowel syndrome (IBS) has been associated with altered cerebral activations in response to visceral stimuli. It is unclear whether these processing alterations are specific for visceral sensation. In this study we aimed to determine by functional magnetic resonance imaging (fMRI) whether cerebral processing of supraliminal and subliminal rectal stimuli and of auditory stimuli is altered in IBS. In eight IBS patients and eight healthy controls, fMRI activations were recorded during auditory and rectal stimulation. Intensities of rectal balloon distension were adapted to the individual threshold of first perception (IPT): subliminal (IPT -10 mmHg), liminal (IPT), or supraliminal (IPT +10 mmHg). IBS patients relative to controls responded with lower activations of the prefrontal cortex (PFC) and anterior cingulate cortex (ACC) to both subliminal and supraliminal stimulation and with higher activation of the hippocampus (HC) to supraliminal stimulation. In IBS patients, not in controls, ACC and HC were also activated by auditory stimulation. In IBS patients, decreased ACC and PFC activation with subliminal and supraliminal rectal stimuli and increased HC activation with supraliminal stimuli suggest disturbances of the associative and emotional processing of visceral sensation. Hyperreactivity to auditory stimuli suggests that altered sensory processing in IBS may not be restricted to visceral sensation.

Central neuropeptide Y and the sigma ligand, JO 1784, reverse corticotropin-releasing factor-induced inhibition of gastric acid secretion in rats.

1. The central interactions between the sigma ligand, JO 1784, [(+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethylbut-3- en-1-ylamine hydrochloride], or neuropeptide Y (NPY) and corticotropin-releasing factor (CRF)-induced inhibition of gastric acid secretion were investigated in rats anaesthetized with urethane. Drugs were injected intracisternally (i.c.) or into specific hypothalamic nuclei. Gastric acid secretion was measured by the flushed technique under basal and pentagastrin (10 micrograms kg-1 h-1, i.v.) stimulated conditions. 2. Intracisternal injection of CRF (10 micrograms), bombesin (0.1 microgram) and human recombinant interleukin-1 beta (hIL-1 beta, 0.1 microgram) inhibited gastric acid response to pentagastrin by 72%, 56% and 62%, respectively. NPY (0.5 microgram) or JO 1784 (0.5 microgram) injected i.c. did not alter acid secretion but completely prevented the inhibitory effect of CRF. The antagonistic effect of NPY and JO 1784 against CRF was dose-related (0.01-0.5 microgram) and peptide-specific since NPY and JO 1784 did not alter the antisecretory action of bombesin or hIL-1 beta. 3. The putative sigma receptor antagonist, BMY 14802, (1 mg kg-1, s.c.) did not influence pentagastrin-stimulated acid secretion nor CRF-induced inhibition of gastric acid secretion; however, BMY 14802 administered s.c. 20 min before JO 1784 or NPY, abolished the antagonistic effect of both JO 1784 and NPY. 4. CRF (3 micrograms) microinjected into the hypothalamic paraventricular nucleus (PVN) and the lateral hypothalamus (LH) inhibited pentagastrin-stimulated gastric acid secretion by 61% and 51%; NPY (0.03 micrograms) or JO 1784 (0.03 micrograms) microinjected into the PVN had no effect by themselves but blocked CRF antisecretory action.There were more VPBs (220 +/- 75), a higher incidence of VT (60%) and more episodes of VT (11.5 +/- 6.0 compared to 0.7 +/- 0.3 episodes in the preconditioned dogs not given L-NAME); none of the animals survived reperfusion (incidence of VF 100%). The improvement in the severity of the degree of inhomogeneity which resulted from preconditioning was abolished by L-NAME administration.5. L-NAME itself elevated blood pressure (from 96 +/- 5 mmHg diastolic to 119 +/- 7 mmHg), reduced heart rate (from 155 +/- 7 to 144 +/- 4 beats min-') but did not change LVEDP, LVdP/dt,,,,, coronary blood flow, ST-segment elevation or the degree of inhomogeneity of conduction. When given 10 min before the prolonged coronary artery occlusion in dogs not subjected to preconditioning, L-NAME had no significant effect on the severity of arrhythmias except for more periods of VT (a mean of 11.7 +/- 4.7 episodes per dog).6. It is concluded from these studies that the generation of nitric oxide contributes to the marked antiarrhythmic effects of preconditioning in the canine myocardium, probably through elevation of cyclic GMP.

Systematic review: do we need a new gastro-oesophageal reflux disease questionnaire?

BACKGROUND: Gastro-oesophageal reflux disease (GERD) is highly prevalent in Western countries. Because the majority of patients do not present with endoscopic abnormalities, the assessment of the symptom severity and quality of life, and their response to treatment, has become increasingly important. Self-assessed symptom questionnaires are now key instruments in clinical trials. AIM: To evaluate the validity of available GERD measurement tools. METHODS: An ideal GERD symptom assessment instrument, suitable as a primary end-point for clinical trials, should possess the following characteristics: (i) be sensitive in patients with GERD; (ii) cover the frequency and intensity of typical and atypical GERD symptoms; (iii) be multidimensional (cover all symptom dimensions); (iv) have proven psychometric properties (validity, reliability and responsiveness); (v) be practical and economical; (vi) be self-assessed; (vii) use 'word pictures' which are easy to understand for patients; (viii) respond rapidly to changes (responsiveness over short time intervals); (ix) be used daily to assess changes during and after therapy; and (x) be valid in different languages for international use. RESULTS: A literature review revealed five scales that met some of the above characteristics, but did not fulfil all criteria. CONCLUSION: There is a need for a new evaluative tool for the assessment of GERD symptoms and their response to therapy.

International validation of ReQuest in patients with endoscopy-negative gastro-oesophageal reflux disease.

BACKGROUND: Reflux Questionnaire (ReQuest), a newly developed gastro-oesophageal reflux disease-sensitive scale, can be used to reliably evaluate the effect of treatment on gastro-oesophageal reflux disease symptoms. AIM: International validation of this scale, in patients suffering from endoscopy-negative gastro-oesophageal reflux disease. METHODS: In this open, multicentre and multinational clinical trial 840 endoscopy-negative gastro-oesophageal reflux disease patients received pantoprazole 20 mg daily for 28 days. The long and short versions of ReQuest were completed both in the pre-treatment and treatment phases. For scale development an item reduction analysis was performed. Internal consistency, test-retest reliability and responsiveness were calculated for psychometric analysis. Construct validity was evaluated by comparison with the Gastrointestinal Symptom Rating Scale and the Psychological General Well-being questionnaire by means of correlation coefficients. RESULTS: Factor analyses confirmed the content validity of both long and short version of ReQuest. Psychometric calculations proved high internal consistency (Cronbach's alpha: 0.9), test-retest reliability [Intraclass Correlation Coefficient: 0.9 (long vs. long) and 0.8 (short vs. short)], and responsiveness (Responsiveness Index 320.3) of the scale, for which also good construct validity was achieved (correlation coefficient: Gastrointestinal Symptom Rating Scale -0.6; Psychological General Well-being -0.4). CONCLUSION: ReQuest proved valid, reliable, and responsive in this multinational clinical trial to evaluate treatment response in endoscopy-negative gastro-oesophageal reflux disease patients.

Role of CRF in stress-related alterations of gastric and colonic motor function.

Major advances have been made in the understanding of the pathophysiology of stress-related alteration of gut function. A wealth of information indicates that CRF is involved in the central mechanisms by which stress inhibits gastric emptying while stimulating colonic motor function. CRF acts in the PVN to trigger both the inhibition of gastric emptying and the stimulation of colonic motor function in response to stress, in addition to previously established endocrine and behavioral responses. Preliminary evidence exists that CRF acts in the locus coeruleus to induce a selective stimulation of colonic transit without influencing gastric emptying. The central actions of CRF to alter gastric and colonic motor function are conveyed by autonomic pathways and are unrelated to the associated stimulation of pituitary hormone secretion. The demonstration that central CRF plays a role in mediating gastric stasis resulting from surgery, peritonitis or high levels of central interleukin-1 provides new insight into the mechanisms involved in gastric ileus induced postoperatively or by infectious disease. Likewise, the demonstration that CRF in the PVN and locus coeruleus induce the anxiogenic and colonic motor responses to stress and that colonic distention activates neurons in the locus coeruleus opens new avenues for the understanding of the pathogenesis of a subset of IBS patients with colonic hypersensitivity associated with psychopathological disturbance and diarrhea-predominant symptoms.

CRF in the paraventricular nucleus of the hypothalamus stimulates colonic motor activity in fasted rats.

The influence of corticotropin releasing factor (CRF) microinjected into the paraventricular nucleus of the hypothalamus (PVN) on colonic motility was investigated in conscious, fasted rats. Rats were chronically implanted with a bilateral guide cannula into the PVN and a catheter into the proximal colon to record motor activity manometrically. Microinjection of CRF (0.6 nmol/rat) into the PVN increased both phasic and tonic motor activity in the proximal colon. Atropine sulfate (1 mg/kg, IP) completely abolished the colonic motor response to CRF. Microinjection of CRF (0.6 nmol/rat) into sites outside of the PVN did not modify colonic motor activity. These data show that CRF acts in the PVN to stimulate tonic and phasic motor activity in the proximal colon. Corticotropin releasing factor action is site specific and mediated through cholinergic pathways.

Low hepatic clearance of peptide YY (PYY) in the perfused rat liver.

The hepatic clearance rate and secretion rate mainly determine peripheral plasma concentrations of regulatory peptides released from the gastrointestinal tract. In the present study hepatic extraction of peptide YY (PYY) during a single passage was investigated in the in situ perfused rat liver excluding modulating actions of circulating hormones. During perfusion of low amounts of PYY (50, 100, 500 pmol l-1), peptide concentrations in the portal vein (5.1 +/- 4.6, 98.1 +/- 2.6, 558 +/- 13.6 pmol l-1) and in the hepatic vein (50.2 +/- 1.4, 88.6 +/- 2.2, 503 +/- 18.1 pmol l-1 was only 22.1%. PYY had no influence on hepatic glucose and lactate production, portal flow as well as bile flow and bile acid secretion at these concentrations. PYY seems to traverse the liver almost intact and reaches the target organs without any significant hepatic extraction. Concomitant studies on metabolic and excretory functions of the liver showed no effect of PYY.