Laryngopharyngeal reflux: A confounding cause of aerodigestive dysfunction.

BACKGROUND: Laryngopharyngeal reflux (LPR) is one of the most common and important disorders of upper airway inflammation. It causes significant impairment to quality of life, and can predict serious laryngeal and oesophageal pathology, yet it remains under-diagnosed and under-treated. OBJECTIVE: This paper attempts to unravel the diagnostic dilemma of LPR and provide a practical, discriminating approach to managing this common condition. DISCUSSION: Historical red flags mandating early referral for specialist review are identified, and pathophysiology, symptomatology and common signs are reviewed. In addition, a comprehensive treatment plan consisting of lifestyle modifications, counselling aids and empirical medical therapy is proposed. A strategy for tracking clinical improvement using Belfasky's validated symptom index is included to aid counselling, compliance and follow-up.

Cost-effectiveness of histamine receptor-2 antagonist versus proton pump inhibitor for stress ulcer prophylaxis in critically ill patients*.

OBJECTIVE: To examine the cost-effectiveness of using histamine receptor-2 antagonist or proton pump inhibitor for stress ulcer prophylaxis. DESIGN: Decision analysis model examining costs and effectiveness of using histamine receptor-2 antagonist or proton pump inhibitor for stress ulcer prophylaxis. Costs were expressed in 2012 U.S. dollars from the perspective of the institution and included drug regimens and the following outcomes: clinically significant stress-related mucosal bleed, ventilator-associated pneumonia, and Clostridium difficile infection. Effectiveness was the mortality risk associated with these outcomes and represented by survival. Costs, occurrence rates, and mortality probabilities were extracted from published data. SETTING: A simulation model. PATIENTS: A mixed adult ICU population. INTERVENTIONS: Histamine receptor-2 antagonist or proton pump inhibitor for 9 days of stress ulcer prophylaxis therapy. MAIN MEASUREMENTS AND RESULTS: Output variables were expected costs, expected survival rates, incremental cost, and incremental survival rate. Univariate sensitivity analyses were conducted to determine the drivers of incremental cost and incremental survival. Probabilistic sensitivity analysis was conducted using second-order Monte Carlo simulation. For the base case analysis, the expected cost of providing stress ulcer prophylaxis was $6,707 with histamine receptor-2 antagonist and $7,802 with proton pump inhibitor, resulting in a cost saving of $1,095 with histamine receptor-2 antagonist. The associated mortality probabilities were 3.819% and 3.825%, respectively, resulting in an absolute survival benefit of 0.006% with histamine receptor-2 antagonist. The primary drivers of incremental cost and survival were the assumptions surrounding ventilator-associated pneumonia and bleed. The probabilities that histamine receptor-2 antagonist was less costly and provided favorable survival were 89.4% and 55.7%, respectively. A secondary analysis assuming equal rates of C. difficile infection showed a cost saving of $908 with histamine receptor-2 antagonists, but the survival benefit of 0.0167% favored proton pump inhibitors. CONCLUSIONS: Histamine receptor-2 antagonist therapy appears to reduce costs with survival benefit comparable to proton pump inhibitor therapy for stress ulcer prophylaxis. Ventilator-associated pneumonia and bleed are the variables most affecting these outcomes. The uncertainty in the findings justifies a prospective trial.

Optogenetic inhibition of cocaine seeking in rats.

Inhibitory optogenetics was used to examine the roles of the prelimbic cortex (PL), the nucleus accumbens core (NAcore) and the PL projections to the NAcore in the reinstatement of cocaine seeking. Rats were microinjected into the PL or NAcore with an adeno-associated virus containing halorhodopsin or archaerhodopsin. After 12 days of cocaine self-administration, followed by extinction training, animals underwent reinstatement testing along with the presence/absence of optically induced inhibition via laser light. Bilateral optical inhibition of the PL, NAcore or the PL fibers in the NAcore inhibited the reinstatement of cocaine seeking.

Diagnosing gastro-oesophageal reflux disease or lactose intolerance in babies who cry a lot in the first few months overlooks feeding problems.

This paper explores two areas in which the translation of research into practice may be improved in the management of cry-fuss behaviours in the first few months of life. Firstly, babies who cry excessively are often prescribed proton pump inhibitors, despite evidence that gastro-oesophageal reflux disease is very rarely a cause. The inaccuracy of commonly used explanatory mechanisms, the side-effects of acid-suppressive medications, and the failure to identify treatable problems, including feeding difficulty when the diagnosis of 'reflux' is applied, are discussed. Secondly, crying breastfed babies are still prescribed lactase or lactose-free formula, despite evidence that the problem of functional lactose overload is one of breastfeeding management. The mechanisms and management of functional lactose overload are discussed. These two problems of research translation need to be addressed because failure to identify and manage other causes of cry-fuss problems, including feeding difficulty, may have adverse outcomes for a small but significant minority of families.

Increasing the duration of dual amoxicillin plus omeprazole Helicobacter pylori eradication to 6 weeks: a pilot study.

BACKGROUND AND AIM: Helicobacter pylori infections have become increasingly difficult to treat as antimicrobial resistance has increased. The aim of this study was to test the hypothesis that a 6-week dual regimen of amoxicillin 1 gm and omeprazole 20 gm therapy b.i.d. would cure at least 90% of treatment-naïve H. pylori infections. METHODS: This was an open-label prospective pilot study in which treatment-naïve subjects with active H. pylori infection (positive by two tests) received dual amoxicillin 1 g and omeprazole 20 mg, b.i.d. daily for 6 weeks. Success was accessed by urea breath test 4-6 weeks later. A tentatively effective therapy was defined as a per-protocol treatment success of 90% or greater; treatment success of 80% or less was prespecified as unacceptable. RESULTS: Sixteen patients were included in the study (14 men, two women) with an average age of 49 years. At 16 patients, the prespecified stopping rule of six treatment failures was achieved (i.e. the 95% confidence interval excluded achieving the required 90% success rate even if 50 patients were entered). As per protocol, enrollment was stopped. Per-protocol and intention-to-treat treatment success were both 62.5% (95% confidence interval, 35-84%). Compliance was greater than 99%. Five patients (31%) reported side-effects, all of which were mild and none interrupted therapy. CONCLUSION: Despite the theory and pre-existing data from Japan, in the USA, prolonging the duration of dual amoxicillin-PPI therapy did not improve treatment outcome in 90% or more of our patients.

Cisapride and ventricular arrhythmia.

AIMS: We aimed to examine the association between cisapride and ventricular arrhythmia, and examine the relationship to dose and CYP3A4 inhibitors. METHODS: A nested case-control study was conducted in Medicaid beneficiaries exposed to cisapride, metoclopramide or a proton pump inhibitor (PPI) from 1999 to 2000. Cases were hospitalized with a principal International Classification of Diseases-9 code indicating sudden cardiac death or ventricular arrhythmia. Controls had at least as much event-free person time following the study prescription as its matched case. RESULTS: A total of 145 cases and 7250 controls were identified. The unadjusted rate ratio for cisapride vs. PPIs was 1.49 (95% confidence interval 0.96, 2.25). The adjusted odds ratio (OR) for cisapride vs. PPIs was 2.10 (1.34, 3.28). Excluding persons in managed care, the adjusted OR for cisapride was 2.92 (1.55, 5.49). In the initial prescription period, the adjusted OR for cisapride vs. PPIs was 7.85 (1.95, 31.60). Non-arrhythmogenic CYP3A4 inhibitors were not associated with an increased risk in users of cisapride or PPI inhibitors. The OR for potentially arrhythmogenic CYP3A4 inhibitors was 3.79 (1.76, 8.15) in cisapride users and 3.47 (2.06, 5.83) in PPI users. CONCLUSIONS: Cisapride was associated with a doubling to tripling of the risk of hospitalization for ventricular arrhythmia, and a nearly eightfold risk in the initial prescription period. Although use of potentially arrhythmogenic CYP3A4 inhibitors was associated with an increased risk, this appears to be due to a direct effect of the drugs themselves rather than an interaction with cisapride.

Systematic review: maintenance treatment of gastro-oesophageal reflux disease with proton pump inhibitors taken 'on-demand'.

BACKGROUND: Proton pump inhibitors (PPI) therapy 'on-demand' is often used as an alternative to continuous maintenance therapy in gastro-oesophageal reflux disease (GERD). AIM: We conducted a systematic review with the specific objectives to ascertain whether on-demand PPI therapy was effective in preventing symptomatic relapse and to assess the relative efficacy of on-demand vs. continuous PPI maintenance strategy. METHODS: Randomized-controlled clinical trials comparing on-demand PPI vs. placebo or on-demand vs. continuous PPI therapy in GERD patients were identified by searching the Medline database and the Cochrane Controlled Trials Register. RESULTS: Seventeen studies were found which met inclusion criteria. Out of the 17 studies: five investigated exclusively patients with non-erosive reflux disease (NERD), four patients with NERD and mild oesophagitis, two patients with erosive oesophagitis only, and two patients with uninvestigated GERD symptoms, respectively. Four further studies were not investigating the effectiveness of the therapies but primarily pharmacoeconomic or quality of life parameters. CONCLUSIONS: On the basis of the analysis of 17 studies, we can conclude that on-demand therapy with currently available PPI appears to be effective in the long-term management of patients with NERD or mild and uninvestigated forms of GERD, but not in patients with (severe) erosive oesophagitis.

Predictors of inappropriate utilization of intravenous proton pump inhibitors.

BACKGROUND: Inappropriate use of intravenous proton pump inhibitors is prevalent. AIM: To assess appropriateness of intravenous proton pump inhibitor prescribing. METHODS: Retrospective review of in-patient prescribing of intravenous pantoprazole over a 2-month period in 2004, in an academic centre. Prescribing was deemed appropriate before and after endoscopic haemostasis, and in fasting individuals requiring a proton pump inhibitor. RESULTS: Amongst 107 patients, 49 (46%) had upper gastrointestinal bleeding. Overall, 33 (31%, 95% CI: 22-41%) received appropriate therapy (indication, dose and duration), 61 (57%, 95% CI: 47-67%) had an inappropriate indication, and 13 (12%, 95% CI: 7-20%) had an incorrect treatment dose or duration. Therapy was appropriate in 20 (41%, 95% CI: 27-55%) with upper gastrointestinal bleeding, and 13 (22%, 95% CI: 12-33%) in the non-upper gastrointestinal bleeding group. Appropriate prescribing rates decreased (from 41% to 16%, 95% on difference CI: 14-38%) when considering intravenous proton pump inhibitor use while awaiting endoscopy as inappropriate. Significant predictors of inappropriate use were increasing age and decreasing mean daily dose, with a trend for prescriptions written during evening shifts. CONCLUSION: Inappropriate intravenous proton pump inhibitor utilization was most frequent in the non-upper gastrointestinal bleeding group, mostly for unrecognized indications. Educational interventions to optimize utilization should target prescribing in older patients, those receiving lower mean daily doses, and, perhaps, prescribing outside regular hours.

An in vitro comparison of different providers to deliver four proton pump inhibitor products through a feeding tube.

BACKGROUND: It is unclear how delivery through a feeding tube compares between esomeprazole in water, lansoprazole oral disintegrating tablet in water, omeprazole/NaHCO(3) in water and simplified lansoprazole suspension. AIM: This in vitro study compared delivery through a narrow calibre (8F) feeding tube among four proton pump inhibitors when given by skilled [nurse; (n = 8)] or unskilled [lay; (n = 8)] providers. METHODS: Following standard instruction, subjects were observed delivering each proton pump inhibitor in a sequential, but random, fashion to evaluate administration quality and time. Delivery was quantified using high-performance liquid chromatography methods and subject preferences were evaluated. RESULTS: Delivery (%), similar between lansoprazole oral disintegrating tablet (95.7 +/- 3.2) and omeprazole/NaHCO(3) (96.1 +/- 3.0), was both greater for lansoprazole oral disintegrating tablet than esomeprazole in water (88.9 +/- 8.6; P = 0.006) or simplified lansoprazole suspension (86.1 +/- 9.5; P = 0.0001) and omeprazole/NaHCO(3) than esomeprazole in water (P = 0.004) or simplified lansoprazole suspension (P < 0.001), and was not affected by prior subject experience. Quality was higher with both omeprazole/NaHCO(3) and lansoprazole oral disintegrating tablet than simplified lansoprazole suspension. Administration was quicker for lansoprazole oral disintegrating tablet than esomeprazole in water. Subjects preferred lansoprazole oral disintegrating tablet and omeprazole/NaHCO(3). CONCLUSIONS: When given through an in vitro feeding tube, omeprazole/NaHCO(3) and lansoprazole oral disintegrating tablet lead to greater drug delivery, improved administration quality and higher user satisfaction, than either esomeprazole in water or simplified lansoprazole suspension.

A comparative study of intragastric acidity during post-breakfast and pre-dinner administration of low-dose proton pump inhibitors: a randomized three-way crossover study.

BACKGROUND: The absorption and bioavailability of proton pump inhibitors is influenced by food intake. Proton pump inhibitors bind to the parietal cell active proton pump, which is maximally stimulated after dinner: usually the largest meal of the day. However, it has not been fully clarified whether the efficacy of proton pump inhibitors differs between post-breakfast and pre-dinner dosing. AIM: To perform a pH-monitoring study to clarify this issue for two low-dose proton pump inhibitors. SUBJECTS AND METHODS: The subjects were 20 healthy male volunteers (seven Helicobacter pylori-positive and 13 H. pylori-negative), who were divided into two groups of 10 and administered 15 mg lansoprazole or 10 mg rabeprazole, respectively. All subjects underwent ambulatory intragastric 24-h pH- monitoring under three conditions allocated randomly: (i) without medication, (ii) seventh day of post-breakfast administration and (iii) eighth day of pre-dinner administration of each drug. RESULTS: There was no significant difference in the percentage time during which pH > or =4.0 in the 24-h period between post-breakfast and pre-dinner administration of both drugs (56.6% vs. 55.8%; P = 0.557), although intragastric acidity during administration of both drugs was significantly lower than that without medication. CONCLUSIONS: The timing of drug administration does not significantly influence the efficacy of low-dose proton pump inhibitors.

Gastroesophageal reflux disease and physical activity.

Gastroesophageal reflux disease (GERD) is one of the most common disorders in the general population. In recent years, a marked increase in the occurrence of the disease worldwide has been noted. Intense exercise belongs to factors that are known to exacerbate symptoms of GERD. Episodes of reflux seem to be associated with the length and the intensity of the physical activity undertaken. Experimental studies suggest that the gastroesophageal reflux may be increased in athletes due to: decreased gastrointestinal blood flow; alterations of hormone secretion; changes in the motor function of the oesophagus and the ventricle; and the constrained body position during exercise. Disturbances of the balance between two areas of opposite pressure: intra-abdominal and intrathoracic, have also been proven to influence GERD events. GERD is found in sportspeople of various disciplines, but specific types of exercise may have significantly different impacts on the gastroesophageal reflux.Basic prevention of GERD comprise lifestyle and dietary interventions. Adjustments of the exercise load and avoiding meals and drinks about the time of physical effort may ease the symptoms. Unfortunately, in most patients, pharmacological measures are necessary. These include occasional application of antacids and blockers of histamine H2 receptors in mild forms of the disease, and a regular therapy with proton pump inhibitors (PPI) in the majority of other cases. An average dose of PPI varies from 20 to 40 mg/day and should be continued for 4-8 weeks. Unfortunately, symptoms of GERD frequently return and in these situations long-term acid suppression with PPI is usually necessary. As regular physical activity exerts beneficial health effects, the necessity of establishing associations between moderate, recreational exercise and GERD is needed.

Cardioprotective effects and gastrointestinal risks of aspirin: maintaining the delicate balance.

Aspirin is a very useful medication for the prevention of cardiovascular thrombotic events in patients with or those at risk for cardiovascular disease (CVD). Aspirin, however, carries an increased risk for gastrointestinal (GI) injury (e.g., ulceration) and its complications (e.g., hemorrhage), which may be caused by its antiplatelet and gastric mucosal effects. In those with established CVD, aspirin use has been documented to decrease the risk of a first myocardial infarction (MI). Its effects on stroke and vascular death are less conclusive. The use of aspirin in these individuals is recommended only for those whose risk for cardiovascular events (based on coronary risk assessment tools) is sufficiently high that it outweighs the risk for GI complications. Secondary prevention refers to the use of aspirin to prevent cardiovascular events in patients with established CVD such as an MI, stroke, or angina. The use of aspirin in these individuals is recommended based on a documented decrease in future cardiovascular events and mortality. The risk for GI events with aspirin is at least additive to the risk for these events in those who also are receiving therapy with a nonsteroidal anti-inflammatory drug. Patients being treated with aspirin, even at 81 mg/day for cardioprotection, should be assessed for factors that increase the risk for GI injury. Studies have confirmed that co-therapy with a proton pump inhibitor (PPI) or misoprostol decreases the risk for GI injury and complications. Although both classes of such gastroprotective agents are effective, treatment with a PPI is tolerated better, with fewer patients discontinuing the drug because of side effects such as diarrhea.

High-dose intravenous proton pump inhibition following endoscopic therapy in the acute management of patients with bleeding peptic ulcers in the USA and Canada: a cost-effectiveness analysis.

BACKGROUND: The efficacy of high-dose intravenous proton pump inhibition has recently been shown, yet its cost-effectiveness remains poorly studied. AIM: To assess the cost-effectiveness of this approach separately for American and Canadian health care settings. METHODS: A validated decision model included patients with bleeding ulcers after successful endoscopic haemostasis. Probabilities were determined from the literature, and charges and lengths of stay from national databases. A third-party payer perspective was adopted over a 30-day time horizon. RESULTS: Re-bleeding rates were 5.9% for patients who received high-dose intravenous proton pump inhibition and 22.9% for those who did not. Hospitalization costs for patients with and without re-bleeding were 11,802 US dollars and 7993 US dollars, and 5220 Canadian dollars and 2696 Canadian dollars, respectively. High-dose intravenous proton pump inhibition was more effective and less costly than the alternative of not administering it. The cost-effectiveness ratios for high-dose and no high-dose intravenous proton pump inhibition were 9112 US dollars and 11,819 US dollars (3293 dollars and 4284 dollars for the Canadian case), respectively. Sensitivity and threshold analyses showed that the results were robust across a wide range of clinically relevant assumptions. CONCLUSION: In the USA and Canada, administering high-dose intravenous proton pump inhibition for 3 days is both more effective and less costly than not doing so for patients with bleeding ulcers after successful endoscopic haemostasis.

Benefits of different drug formulations in psychopharmacology.

Adequate dosage forms are essential for achieving successful pharmacotherapy. Innovative dosage forms or delivery systems may direct a drug to its specific site of action, optimize the timing of the drug release, or increase comfort or convenience for the patient. Thus, such innovations may improve efficacy and tolerability and lead to improvements in health-related quality of life. Specialized dosage forms (e.g., depot injections, extended-release formulations) of several psychiatric agents have been extensively used. The latest addition is an orally disintegrating formulation of the antidepressant mirtazapine. This dosage form dissolves rapidly in the mouth and is convenient for the large proportion of patients who have difficulty in swallowing tablets.

The influence of feeding on gastric acid suppression in Helicobacter pylori-positive patients treated with a proton pump inhibitor or an H2-receptor antagonist after bleeding from a gastric ulcer.

BACKGROUND: This study investigated the influence of feeding on gastric acid suppression in Helicobacter pylori-positive patients treated with intravenous infusions of proton pump inhibitors (PPIs) or with H2-receptor antagonists (H2-RAs) after bleeding from a gastric ulcer. METHODS: Forty-nine H. pylori-positive patients with bleeding gastric ulcers (44 men and 5 women) were divided into four groups: one group received an H2-RA while fasting, one group received an H2-RA while eating regularly, one group received a PPI while fasting, and one group received a PPI while eating regularly. Intragastric pH was monitored during fasting and nonfasting to calculate the pH 3 and pH 4 holding times and the mean pH. RESULTS: During a 24-h fast, the pH 3 and pH 4 holding times and the mean pH were significantly higher in patients administered omeprazole (PPI; 93.2 +/- 9.2%, 90.6 +/- 11.1%, and 6.9 +/- 0.6, respectively) than in those administered ranitidine (H2-RA; 61.0 +/- 27.5%, 55.8 +/- 29.1%, and 4.8 +/- 1.3, respectively; P<0.001 for all). Results were similar during feeding (PPI meal, 98.9 +/- 2.6%, 98.3 +/- 3.7%, and 6.9 +/- 0.3; H2-RA meal, 59.8 +/- 17.6%, 49.7 +/- 18.0%, and 4.3 +/- 0.7, respectively; P<0.001 for all). In addition, the pH 3 and pH 4 holding times and the mean pH in the H2-RA meal group were not significantly lower than those in the H2-RA group (P=0.999, P=0.865, and P=0.687, respectively). The values in the PPI and PPI meal groups were similar (P=0.872, P=0.777, and P>0.999, respectively). CONCLUSIONS: Gastric acid suppression during the administration of an H2-RA or a PPI soon after the cessation of gastric bleeding was scarcely affected by feeding. It may well be that H. pylori-positive patients with bleeding gastric ulcer can resume a regular diet and return to work soon after bleeding ceases.

Influence of anti-ulcer drugs used in Japan on the result of (13)C-urea breath test for the diagnosis of Helicobacter pylori infection.

BACKGROUND: The (13)C-urea breath test (UBT) is a simple breath test for the diagnosis of Helicobacter pylori infection, but several factors have been reported to affect the results of this test. In this study, the effects of the antiulcer drugs used in Japan on the results of UBT were determined. METHODS: The subjects of the study were 64 adult volunteers who tested positive for H. pylori infection by the serum antibody method. Eight classes of anti-ulcer drugs used in Japan were administered at their usual doses to these subjects: lansoprazole, a proton pump inhibitor (PPI); nizatidine, an H(2)-receptor antagonist (H(2)RA); and polaprezinc, ecabet sodium, rebamipide, teprenone, cetraxate hydrochloride, and sucralfate, all mucoprotective agents. The study drugs were randomized for administration to the subjects, and each of the drugs was administered for 14 consecutive days. The UBT was performed on days 0, 14, and 21. RESULTS: The mean Delta(13)C per thousand in the lansoprazole group was significantly decreased on day 14, to below 10 per thousand, in 4 of 16 subjects, and in 1 of the 4 subjects, the test result was negative, with the Delta(13)C per thousand falling to 1.7 per thousand. The value returned to baseline 1 week after the discontinuation of lansoprazole. The other drugs administered had no significant effect on the result of the UBT, except that the mean Delta(13)C per thousand showed a tendency to decrease after the administration of ecabet sodium and rebamipide. CONCLUSIONS: Administration of a PPI may produce a false-negative UBT result, while other anti-ulcer drugs, for the most part, have little effect on the result of the UBT when used alone. The (13)C-urea breath test (UBT) is a simple test for the diagnosis of Helicobacter pylori infection, but several factors have been reported to affect the results of this test. In this study, the effects of the anti-ulcer drugs used in Japan on the results of the UBT were determined.

Clinical efficacy of proton pump inhibitor therapy in neurologically impaired children with gastroesophageal reflux: prospective study.

OBJECTIVE: To study the effects of proton pump inhibitors in reducing vomiting, gastrointestinal bleeding, and chest infections in institutionalised neurologically impaired children with gastroesophageal reflux. DESIGN: Prospective study. SETTING: A regional hospital, Hong Kong. PATIENTS: Neurologically impaired children with refractory gastroesophageal reflux. MAIN OUTCOME MEASURES: Episodes of vomiting, gastrointestinal bleeding, and pneumonia in the baseline and proton pump inhibitor treatment periods. RESULTS: Nine children received proton pump inhibitor therapy for a median duration of 81 days. Mean reflux index was 9.3% (standard deviation, 5%). Dosage of omeprazole used was 1.0-2.3 mg/kg/d. Vomiting was reduced significantly with proton pump inhibitor treatment (median vomiting index [baseline]=0.4, median vomiting index [proton pump inhibitors]=0.2; P<0.05). No significant decrease in gastrointestinal bleeding or chest infection was observed. CONCLUSION: Proton pump inhibitors significantly reduced vomiting episodes in neurologically impaired children with gastroesophageal reflux.