Comparisons of the distribution of oesophageal acid exposure throughout the sleep period among the different gastro-oesophageal reflux disease groups

BACKGROUND: Nocturnal gastro-oesophageal reflux diseases (GERD) can lead to oesophageal mucosal injury and extra-oesophageal complications. AIM: To compare distribution of oesophageal acid exposure during sleep time among patients with non-erosive reflux disease and abnormal pH test (NERD-positive), erosive oesophagitis (EO) and Barrett's oesophagus (BO). METHODS: Patients underwent endoscopy followed by 24-h oesophageal pH testing. Oesophageal acid exposure was assessed every 2 h of the sleep period (0-2, 2-4, 4-6 and 6-8 h). Each period of 2 h was evaluated for acid reflux parameters. All groups were matched by age, time from last meal and duration of sleep time. RESULTS: Thirty-eight patients were enrolled (NERD-positive, 16; EO, 1.4; and BO, 8). All GERD groups demonstrated higher oesophageal acid exposure in the first vs. second half of the sleep period as determined by percent time pH <4 (BO: 34.7 vs.11.6, EO: 13.5 vs. 6.9, NERD-positive: 8.8 vs. 2.5, all P < 0.01). In general, patients with BO had a significantly higher distribution of oesophageal acid exposure than those with NERD-positive and EO. CONCLUSIONS: Oesophageal acid exposure generally declines throughout the sleep period regardless of GERD group, but BO patients demonstrated the greatest decline during the sleep period.     

Azathioprine or mercaptopurine‐induced acute pancreatitis is not a disease‐specific phenomenon

Aliment Pharmacol Ther 31 , 1322–1329

Summary

Background Several reports suggest an increased rate of adverse reactions to azathioprine in patients with Crohn’s disease. Aim To compare the incidence of thiopurine‐induced acute pancreatitis in patients with inflammatory bowel disease (IBD) with that in patients with vasculitis. Methods This retrospective analysis was performed using data collected in three databases by two university hospitals (241 patients with IBD and 108 patients with vasculitis) and one general district hospital (72 patients with IBD). Results The cumulative incidence of thiopurine‐induced acute pancreatitis in Crohn’s disease equalled that of ulcerative colitis (UC) (2.6% vs. 3.7%) and this did not differ from vasculitis patients (2.6% vs.1.9%). In addition, the cumulative incidence of thiopurine‐induced acute pancreatitis in UC patients was not different from that in vasculitis patients. In the IBD group, 100% of thiopurine‐induced acute pancreatitis patients were women, whereas in the vasculitis group the two observed thiopurine‐induced acute pancreatitis cases (n = 2 of 2) concerned were men (P = 0.012). Conclusions In this study, the alleged higher cumulative incidence of thiopurine‐induced acute pancreatitis in Crohn’s disease compared with vasculitis or UC patients was not confirmed. Female gender appears to be a risk factor for developing thiopurine‐induced acute pancreatitis in IBD patients.     

A comparative study of cisapride and ranitidine at controlling oesophageal acid exposure in erosive oesophagitis

Background: The severity of gastro-oesophageal reflux disease is generally considered to be related to the extent of oesophageal acid exposure. Current therapies include antisecretory and prokinetic agents. We compared two of these, ranitidine and cisapride, in their ability to lower oesophageal acid exposure in patients with erosive oesophagitis. Methods: Seven patients with Savary–Miller's grade II–IV oesophagitis and with oesophageal contact time ± 8% were studied. Mean lower oesophageal sphincter pressure was 4.6 mmHg. Oesophageal acid contact time was 25.6 ± 5.6%. Each patient received ranitidine 150 mg b.d., ranitidine 150 mg q.d.s., or cisapride 10 mg q.d.s. in a randomized 3-way cross-over design. Intra-oesophageal pH was monitored during 24 h for each of these treatments in a controlled hospital environment, while consuming a high fat, high calorie diet. Results: Cisapride and ranitidine at both doses decreased the acid contact time and the number of reflux episodes. However, a minority of patients treated with ranitidine, and none with cisapride, diminished their oesophageal acid contact time to a normal value of < 5%. No treatment significantly decreased nocturnal acid exposure. Conclusion: In patients with severe gastro-oesophageal reflux disease both cisapride and ranitidine demonstrably lower oesophageal acid exposure, but neither therapy predictably normalizes it.     

Effects of a single dose of rabeprazole 20 mg and pantoprazole 40 mg on 24‐h intragastric acidity and oesophageal acid exposure: a randomized study in gastro‐oesophageal reflux disease patients with a history of nocturnal heartburn

Aliment Pharmacol Ther 31 , 991–1000

Summary

Background Nocturnal heartburn is common in patients with gastro‐oesophageal reflux disease (GERD). Aim To compare the effects of single doses of rabeprazole 20 mg and pantoprazole 40 mg on 24‐h intragastric acidity and oesophageal acid exposure (OAE). Methods A total of 52 subjects with GERD and a ≥6‐month history of heartburn were randomized into a blinded, 2 × 2 crossover trial. Subjects’ intragastric pH was monitored in two 48‐h study periods with 6‐ to 13‐day washout between periods. Patients received placebo on day 1, a single dose of rabeprazole 20 mg or pantoprazole 40 mg on day 2, and standardized meals throughout. Results The mean percentage time with intragastric pH >4 was significantly greater with rabeprazole vs. pantoprazole for the 24‐h postdose interval (44.0% vs. 32.8%; P < 0.001). Significant differences were observed in the daytime (51.0% vs. 42.2%; P < 0.001) and nighttime (32.0% vs. 16.9%; P < 0.001). Rabeprazole was also significantly superior in other intragastric pH parameters. There was no statistical difference for OAE between treatments. Conclusions In GERD patients with nocturnal heartburn, rabeprazole 20 mg was significantly more effective than pantoprazole 40 mg in percentage time with intragastric pH >4 during the nighttime, daytime, and 24‐h periods. Differences between treatments in OAE were not demonstrated. This trial is registered with http://clinicaltrials.gov , number NCT00237367.     

Increased expression of miR‐34a in mouse spleen one day after exposure to N‐ethyl‐N‐nitrosourea

MicroRNAs (miRNAs) are a class of single‐stranded small RNA molecules (~22 nucleotides) that are not translated into proteins and function as regulators of gene expression. Many miRNAs are involved in carcinogenesis. One of them, miR‐34a, is associated with various p53‐initiated biological processes and may act as a tumor suppressor miRNA. Its expression is generally down‐regulated in tumor tissues and up‐regulated in tissues exposed to carcinogens chronically or subchronically. However, the response of this miRNA to acute exposure of a genotoxic carcinogen is little known. In this study, miR‐34a expression was evaluated in spleen tissues of mice treated with a dose of 120 mg kg^?1 body weight N‐ethyl‐N‐nitrosourea (ENU), a potent mutagenic carcinogen. Real‐time PCR analysis showed that the ENU exposure resulted in a 5.5‐fold increase of miR‐34a expression over the control one day after the treatment. The result suggests that miR‐34a expression responds sensitively to genotoxic insults within a short period after exposure of the mutagen, and therefore, this gene has the potential to be used as an indicator for genotoxin exposure.     

Decreasing oesophageal acid exposure in patients with GERD: a comparison of rabeprazole and omeprazole

BACKGROUND: Rabeprazole has been shown to be more potent and faster than other proton pump inhibitors in in vitro studies and highly effective in decreasing oesophageal acid exposure in patients with gastro-oesophageal reflux disease (GERD). AIM: This study was a multicentre, double-blind, placebo-controlled, randomized, parallel-group comparison of three active treatment regimens utilizing two different proton pump inhibitors, or placebo, administered over 7 days in patients with GERD. METHODS: Eighty-two patients with symptomatic GERD were given placebo, rabeprazole 10 mg b.d., rabeprazole 20 mg o.m., or omeprazole 20 mg o.m. for 7 days. Twenty-four hour oesophageal pH monitoring was performed at baseline and repeated at the conclusion of the treatment period. RESULTS: At the end of study, the percentage time (mean +/- s.d.) with pH < 4 over a 24-h period was significantly decreased by the three active regimens but without significant difference between them (9.27 +/- 4.77; 2.53 +/- 4.27; 2.02 +/- 1.71 and 2.91 +/- 4.06 for placebo, rabeprazole 10 mg b.d., rabeprazole 20 mg o.m. and omeprazole 20 mg o.m., respectively). Acid exposure was normalized in 90% of patients treated with rabeprazole 10 mg b.d., 95% treated with rabeprazole 20 mg o.m., 78% treated with omeprazole 20 mg o.m., and only 9.5% of patients treated with placebo. Both rabeprazole and omeprazole were well-tolerated. CONCLUSIONS: Although rabeprazole 20 mg o.m. showed greater activity numerically, this study demonstrates that rabeprazole 10 mg b.d. and 20 mg o.m. are equivalent to omeprazole 20 mg o.m. in decreasing oesophageal acid exposure.     

The extent of oesophageal acid exposure overlap among the different gastro-oesophageal reflux disease groups

BACKGROUND: Studies have demonstrated that patients with Barrett's oesophagus have the highest oesophageal acid exposure profile, followed by erosive oesophagitis and non-erosive reflux disease patients, but the exact extent of overlap remains unknown. AIM: To determine the extent of overlap in oesophageal acid exposure among the different gastro-oesophageal reflux disease groups. METHODS: A total of 121 patients with gastro-oesophageal reflux disease underwent an upper endoscopy and were classified as having Barrett's oesophagus, erosive oesophagitis and non-erosive reflux disease-all (non-erosive reflux disease-positive and functional heartburn). Subsequently, patients underwent pH testing and overlap in oesophageal acid exposure among the different gastro-oesophageal reflux disease groups was determined. RESULTS: Of those enrolled, 24 had Barrett's oesophagus, 30 erosive oesophagitis and 28 were non-erosive reflux disease-positive. Mean oesophageal acid exposure time was 224.8 +/- 35, 134.3 +/- 21.9 and 141.3 +/- 19.8 min for Barrett's oesophagus, erosive oesophagitis and non-erosive reflux disease-positive respectively. Per cent overlap for total, upright and supine time between non-erosive reflux disease-positive and erosive oesophagitis was 47.4%, 64.7% and 81.8%, between Barrett's oesophagus and erosive oesophagitis was 47.8%, 40.7% and 24%, and between Barrett's oesophagus and non-erosive reflux disease-positive was 31.6%, 37.5% and 20.8% respectively. CONCLUSIONS: Our study demonstrated a high oesophageal acid exposure overlap between patients with non-erosive reflux disease-positive and erosive oesophagitis, Barrett's oesophagus and erosive oesophagitis, as well as Barrett's oesophagus and non-erosive reflux disease-positive patients.     

Gestational retinoic acid exposure in the rat: effects of sex, strain and exposure period

Effects of gestational exposure to all-trans retinoic acid (RA) were assessed in the Long-Evans (hooded) and Sprague-Dawley (albino) rat strains. Two exposure periods were evaluated against vehicle controls. Both involved three consecutive daily per os doses of either 2.5 mg/kg RA on gestational days (GD) 11 through 13 or 10 mg/kg RA on GD 14 through 16. All assessments were conducted on at least one male and one female per litter. Substantial main effects of sex, strain and treatment were obtained, but with few significant interactions. Main effects of strain were found on surface righting, neonatal mortality, litter weight and postnatal day (PND) 35 regional brain weight. Among strain effects, the most interesting was the finding that weights of whole brain, frontal cortex, brainstem and cerebellar vermis were lower in hooded than in albino rats. These strain effects seldom interacted with treatment. Among the treatment effects was the finding that GD 11-13 but not GD 14-16 RA exposure impaired the righting reflex in both strains. Moreover, GD 11-13 exposure reduced weight of the cerebellar vermis more than did GD 14-16 RA exposure, while GD 14-16 RA exposure had greater impact on the weight of the cerebellar hemispheres than did GD 11-13 exposure. Covariate analysis suggested that these effects were independent of reductions in body weight. It is concluded that there are few strain or sex differences in the effects of gestational RA exposure, at least for the rat strains evaluated in this study.     

Prevalence and determinants of uptake of folic acid in peri‐conceptional period in a rural lower‐middle‐income country,Ghana

Folate is a vitamin B‐related substance needed by expectant mothers during the period right before and after conception (peri‐conceptional period) to help protect foetuses against neural tube defects (NTDs). Despite efforts to promote the peri‐conceptional uptake of folic acid (FA), adherence remains low. The aim of this study was to assess the prevalence and determinants of peri‐conceptional FA uptake among childbearing women in northern Ghana. In a cross‐sectional study, data from 303 women accessing antenatal care services in the Upper East Region of Ghana between February and July 2017 were collected and analysed in Stata (Version 12.1). Chi‐square and logistic regression analysis were used to identify the independent determinants of peri‐conceptional uptake of FA. The mean age of the study population was 27.4 (±5.73) years. The prevalence of uptake of peri‐conceptional FA was 28.7% (95% confidence interval: 26.7%‐34.2%); 66% of the women were aware of FA and 52% had acceptable knowledge about FA. Initiating ANC after 3 months of pregnancy was associated with 91% less chance of peri‐conceptional FA use [adjusted odds ratio (AOR) 0.09; 95% confidence interval (CI) 0.04‐0.22; P < .001]. Not knowing the frequency of dosing of FA was associated with a 58% less likelihood of uptake of peri‐conceptional FA (AOR 0.42; 95% CI 0.23‐0.76; P = .004). There is low uptake of peri‐conceptional FA among women of childbearing age accessing antenatal services in Northern Ghana, and this uptake is determined by the time of initiation of ANC visit and knowledge of dosage regimen of FA.     

Increased palatability of ethanol after prenatal ethanol exposure is mediated by the opioid system

Previous studies have shown that prenatal exposure to a moderate dose of ethanol (2 g/kg) during the last days of gestation of the rat (17-20) not only increases postnatal intake of the drug but also enhances the palatability of ethanol's taste when measured with a taste reactivity test. Prenatal administration of the opioid antagonist naloxone, together with ethanol, reduces ethanol intake. The aim of the present study was to analyze whether this decreased intake of ethanol after the administration of naloxone is accompanied by a reduction in ethanol's palatability. Results show that preweanling rats exposed prenatally to ethanol alone displayed more ethanol intake and more ingestive responses in reaction to its taste than non-exposed pups. Simultaneous prenatal administration of naloxone with ethanol prevented both the increased intake of ethanol and the higher amount of appetitive responses to its taste. These results indicate that the opioid system plays an important role in the effect of enhanced palatability of ethanol's taste after its prenatal exposure. Results also support the hypothesis of a conditioned response established in utero as a consequence of the association between ethanol's chemosensory and reinforcing aspects, the latter mediated by the opioid system.     

Meta‐analysis: the effects of placebo treatment on gastro‐oesophageal reflux disease

Aliment Pharmacol Ther 2010; 32: 29–42

Summary

Background There appears to be a significant placebo response rate in clinical trials for gastro‐oesophageal reflux disease. Little is known about the determinants and the circumstances associated with placebo response in the treatment of gastro‐oesophageal reflux disease (GERD). Aims To estimate the magnitude of the placebo response rate in randomized controlled trials for GERD and to identify factors that influence this response. Methods A meta‐analysis of randomized, double‐blind, placebo‐controlled trials, published in English language, which included >20 patients with GERD, treated with either a proton pump inhibitor or H₂‐receptor antagonist for at least 2 weeks. Medline, Cochrane and EMBASE databases were searched, considering only studies that reported a global response for ‘heartburn’. Results A total of 24 studies included 9989 patients with GERD. The pooled odds ratio (OR) for response to active treatment vs. placebo was 3.71 (95% CI: 2.78–4.96). The pooled estimate of the overall placebo response was 18.85% (range 2.94%–47.06%). Patients with erosive oesophagitis had a non‐significantly lower placebo response rate than patients without it (11.87% and 18.31%, respectively; P = 0.246). Placebo response was significantly lower in studies of PPI therapy vs. studies of H₂ RAs ( 14.51% vs. 24.69%, respectively; P = 0.05). Conclusions The placebo response rate in randomized controlled trials for GERD is substantial. A lower placebo response was associated with the testing of PPIs, but not the presence of erosive oesophagitis.     

Development and validation of a disease‐specific quality of life questionnaire for gastro‐oesophageal reflux disease: the GERD‐QOL questionnaire

Aliment Pharmacol Ther 31 , 452–460

Summary

Background A simple and meaningful health‐related quality of life (HRQoL) questionnaire for gastro‐oesophageal reflux disease (GERD) patients is lacking. Aim To develop and validate a disease‐specific HRQoL instrument (GERD‐QOL) for GERD patients. Methods An 18‐item questionnaire was generated to measure the impact of GERD on sleep, exercise, diet, need for medication, sex life, work, social activity and psychological well‐being. GERD patients were invited to complete the GERD‐QOL, a visual analogue scale (VAS) and a validated Chinese generic QoL (SF‐36) questionnaire before and after esomeprazole treatment. Factor analysis was performed for item selection and psychometric properties were measured. An English version was developed by a forward‐backward translation process. Results A final 16‐item GERD‐QOL questionnaire was developed. The items were grouped into four subscales (Daily activity, Treatment effect, Diet, and Psychological well‐being) after factor analysis. GERD‐QOL had good item‐internal consistency (Cronbach’s alpha: 0.64–0.88), high test‐retest reliability (intraclass correlation coefficient: 0.73–0.94, P < 0.001). Its subscale scores were correlated with SF‐36 and VAS, which demonstrated high construct validity (P < 0.001). Discriminant validity was verified by correlating GERD‐QOL scores with symptom severity (P < 0.001). Responsiveness after esomeprazole treatment was significant (paired‐t‐test P < 0.001). An English version of GERD‐QOL was developed. Conclusion The instrument, GERD‐QOL, is valid and reliable.