Histamine Type-2 Receptor Antagonists Research Articles

Sleep disruption due to nocturnal heartburn: a review of the evidence and clinical implications

Nocturnal heartburn (NHB) is a symptom that affects up to 25% of the general population and has been shown to cause sleep disruption that adversely affects quality of life and psychomotor performance. Few studies have evaluated the association between occasional NHB and sleep disturbances; therefore, this connection may be underappreciated and left untreated by the primary care provider and patient, with potentially significant negative clinical consequences and effects on quality of life. This review sought to describe what is currently known about the interplay between occasional NHB and sleep disruption, and identify whether acid suppression therapy can improve symptoms of occasional NHB and associated sleep disruptions. The pathophysiology of heartburn-induced sleep disruption appears to follow a bidirectional cycle due to the normal physiologic changes that occur in the upper gastrointestinal tract during sleep and due to the potential for heartburn symptoms to cause sleep arousal. The majority of the identified studies suggested that pharmacologic interventions for acid reduction, including proton pump inhibitors or histamine type-2 receptor antagonists (H2RAs), improved objective and/or subjective sleep outcomes among individuals with gastroesophageal reflux disease (GERD) and NHB. Several studies specific to famotidine demonstrated that treatment with 10 mg or 20 mg reduced nighttime awakenings due to NHB. In conclusion, NHB symptoms can cause sleep dysfunction that can have a profound adverse downstream effect on quality of life, next-day functioning, and health-related outcomes. The current approach to managing occasional NHB is similar to that associated with GERD, highlighting the need for studies specific to the occasional heartburn population. Health care providers should investigate NHB as one of the potential causes of sleep complaints, and patients with heartburn should be questioned about sleep quality, recalled arousals, next-day vitality, early fatigue, and next-day functioning.

Proton pump inhibitor use and risk of pneumonia: a self-controlled case series study.

Recent research indicates that use of proton pump inhibitors (PPIs) is associated with pneumonia, but existing evidence is inconclusive because of methodological issues. This study aimed to answer whether PPI-use increases risk of pneumonia while taking the methodological concerns of previous research into account. This population-based and nationwide Swedish study conducted in 2005-2019 used a self-controlled case series design. Data came from national registries for medications, diagnoses, and mortality. Conditional fixed-effect Poisson regression provided incidence rate ratios (IRR) with 95% confidence intervals (CI) for pneumonia comparing PPI-exposed periods with unexposed periods in the same individuals, thus controlling for confounding. Analyses were stratified by PPI-treatment duration, sex, age, and smoking-related diseases. Use of histamine type-2 receptor antagonists (used for the same indications as PPIs) and risk of pneumonia was analysed for assessing the validity and specificity of the results for PPI-therapy and pneumonia. Among 519,152 patients with at least one pneumonia episode during the study period, 307,709 periods of PPI-treatment occurred. PPI-use was followed by an overall 73% increased risk of pneumonia (IRR 1.73, 95% CI 1.71-1.75). The IRRs were increased across strata of PPI-treatment duration, sex, age, and smoking-related disease status. No such strong association was found between histamine type-2 receptor antagonist use and risk of pneumonia (IRR 1.08, 95% CI 1.02-1.14). PPI-use seems to be associated with an increased risk of pneumonia. This finding highlights a need for caution in using PPIs in individuals with a history of pneumonia.

Efficacy of antacids for cisplatin-induced gastrointestinal symptoms in the treatment of lung cancer.

Chemotherapy-induced nausea and vomiting (CINV) and chemotherapy-associated dyspepsia syndrome (CADS) are frequently appearing adverse effects of cisplatin (CDDP)-containing chemotherapy. Antiemetic guidelines suggest that the administration of antacids such as proton pump inhibitors (PPIs) or histamine type-2 receptor antagonists be considered for CADS, although their efficacy for treating these symptoms remains unknown. This study aimed to reveal whether antacids attenuate gastrointestinal symptoms in CDDP-containing chemotherapy. In total, 138 patients with lung cancer who received ≥75 mg/m2 CDDP-containing regimens were enrolled in this retrospective study. Patients were divided into an antacid group including patients administered PPIs or vonoprazan during all chemotherapy periods and controls without antacid administration. The primary endpoint was the comparison of anorexia incidence during the first cycle of chemotherapy. Secondary endpoints were CINV evaluation and risk factor analysis for the incidence of anorexia using logistic regression analysis. The incidence of anorexia during the first cycle was 54.4% in the control group and 60.3% in the antacid group, without significant differences (p = 0.60). The incidence of nausea was also similar between the groups (p = 1.00). Multivariate analysis suggested that antacid administration was not associated with anorexia. Baseline antacid administration does not affect gastrointestinal symptoms associated with CDDP-containing treatment in lung cancer.

Reducing Unnecessary Acid Suppression Use in Hospitalized Patients: A Description of Targeted Strategies Implemented Across a Large Health System.

Ensuring the appropriate use of proton pump inhibitors (PPIs) and histamine type 2-receptor antagonists (H2RAs) is an important hospital patient safety and quality initiative because therapy may be inappropriately continued during transitions of care. In this article, we aim to describe the impact of targeted quality improvement strategies to reduce unnecessary acid suppression use in hospitalized patients across a large health system. Beginning January 1, 2018, focused quality improvement strategies to prevent unnecessary initiation and continuation of proton pump inhibitors (PPIs) and histamine type 2-receptor antagonists (H2RAs) were implemented throughout a large health system. Targeted strategies were initially tested as part of the PPI deprescribing Institute for Healthcare Improvement (IHI) International Innovators Network initiative and were expanded to include H2RAs for hospitalized patients. Strategies to decrease PPIs and H2RAs during hospitalization included standardization of stress ulcer prophylaxis care pathways, evidence-based order set modifications, technology-driven support, and clinical pharmacy metric performance to goal. PPI/H2RA days of therapy (DOT) per 1000 patient days were measured from the first quarter (1Q) of 2017 to the fourth quarter (4Q) of 2021 to determine if implemented strategies resulted in improvement. After quality improvement strategies were implemented, the number of PPI/H2RA DOT was reduced by 7.9 days per 1000 patient days each quarter over 4 years. The average PPI/H2RA DOT per 1000 patient days decreased from 592 (1Q 2017) to 439 (4Q 2021). In the fourth quarter of 2018, 45 hospitals (28%) achieved a 10% reduction in combined PPI/H2RA DOT per 1000 patient days, and 121 hospitals (97%) attained the goal of greater than 25% of eligible patients deprescribed PPI/H2RA for ICU patients in the fourth quarter of 2019. In the fourth quarter of 2020, 97 hospitals (87%) met the metric of 40% or more of eligible patients deprescribed from PPI/H2RA in or after an ICU stay, and 85 hospitals (87%) reached 50% or more of eligible patients deprescribed PPI/H2RA in or after an ICU stay in 4Q2021. Targeted quality improvement strategies decreased unnecessary PPI and H2RA use for a large health system over 4 years. Continually evaluating measured results along with establishing a new clinical pharmacy metric goal each year to encourage further improvement contributed to deprescribing success.

Influence of concomitant gastric acid suppressants use on the survival of patients with non-small cell lung cancer treated with programmed death-1/ligand-1 inhibitors: A meta-analysis

IntroductionInfluence of concomitant use of gastric acid suppressants (GAS) on survival of non-small cell lung cancer (NSCLC) patients receiving programmed death-1/ligand-1 (PD-1/PD-L1) inhibitors has rarely been comprehensively evaluated. A meta-analysis was performed to systematically evaluate the effect of concomitant GAS in NSCLC patients receiving PD-1/PD-L1inhibitors. MethodsRelevant observational studies were identified by search of Medline, Embase, and Web of Science databases from inception to May 26, 2022. A random-effect model which incorporates the possible between-study heterogeneity was used to combine the results. ResultsTen retrospective and one prospective cohort studies including 5892 patients were patients were included. Influence of concomitant proton pump inhibitors (PPIs) was evaluated in ten studies, and influence of GAS, including PPIs or histamine type-2 receptor antagonists were evaluated in one study. Pooled results showed that concomitant use of GAS was associated with worse progression-free survival (PFS, adjusted hazard ratio [HR]: 1.32, 95% confidence interval [CI]: 1.20 to 1.45, P < 0.001; I2 = 0%) and overall survival (OS, adjusted HR: 1.36, 95% CI: 1.26 to 1.48, P < 0.001; I2 = 0%) in NSCLC patients taking PD-1/PD-L1inhibitors. Subgroup analyses indicated that the association between concomitant use of GAS and poor survival in NSCLC patients taking PD-L1inhibitors was consistent in univariate and multivariate studies (P values for subgroup difference both > 0.05 for PFS and OS). ConclusionsThe meta-analysis by summarizing the up-to-date literatures showed that use of GAS, primarily PPIs, may be associated with poor survival outcomes in patients with NSCLC receiving PD-1/PD-L1inhibitors.

Concomitant Gastric Acid Suppressants on the Survival of Patients with Non-Small-Cell Lung Cancer Treated with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: A Meta-Analysis.

Background The influence of concomitant use of gastric acid suppressants (AS) on survival of patients with non-small-cell lung cancer (NSCLC) treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inconsistent according to previous studies. We performed a meta-analysis to evaluate the effect of additional AS in patients with NSCLC taking TKIs. Methods Relevant observational studies were identified by a search of Medline, Embase, and Web of Science databases. Only studies with multivariate analyses were included. A random-effect model was used to combine the results. Results Thirteen retrospective studies with 12259 patients were included. Pooled results showed that concomitant use of AS was associated with worse progression-free survival (PFS, adjusted hazard ratio (HR): 1.57, 95% confidence interval (CI): 1.31 to 1.89, P < 0.001; I2 = 65%) and overall survival (OS, adjusted HR: 1.38, 95% CI: 1.19 to 1.61, P < 0.001; I2 = 70%) in NSCLC patients taking TKIs. Sensitivity analysis limited to studies including NSCLC with EGFR mutation showed consistent results (HR for PFS: 1.53, P=0.003; HR for OS: 1.43, P=0.001). Subgroup analyses indicated that the association between concomitant use of AS and poor survival was not significantly affected by the category of AS used (proton pump inhibitors or histamine type-2 receptor antagonists) or the country of the study (Asian or non-Asian, P for subgroup analysis all >0.05). Conclusions Concomitant use of AS in patients with NSCLC taking TKIs may be associated with poor survival outcomes.

STRESS ULCER PROPHYLAXIS USING PROTON PUMP INHIBITORS OR HISTAMINE TYPE-2 RECEPTOR ANTAGONISTS IN MECHANICALLY VENTILATED PATIENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS

TOPIC: Critical Care TYPE: Original Investigations PURPOSE: The use of stress ulcer prophylaxis (SUP) is routine in the intensive care unit (ICU) to prevent serious deleterious effects of gastrointestinal bleeding (GIB). There is debate over which choice of drug is safest in the ICU setting for SUP. This literature review looks at the role of proton pump inhibitors (PPIs) compared to histamine type-2 receptor antagonists (H2RAs) and the efficacy of each drug class in regards to clinically significant/overt GIB (CS/O-GIB), ventilator associated pneumonia (VAP), ICU mortality, and ICU length of stay. METHODS: A thorough search of the literature was conducted to perform a meta-analysis of the available studies that investigated the efficacy of PPIs compared to H2RAs in the ICU for SUP among mechanically ventilated patients. This search was performed using PubMed, Embase, and Cochrane for data on the subject matter of study from inception to April 20, 2021. We considered only randomized controlled trials for this analysis. From each study, we collected the number of patients who underwent treatment with either a PPI or H2RA while intubated. The primary outcome was the occurrence of CS/O-GIB. Secondary outcomes were the occurrence of VAP, ICU mortality, and ICU length of stay. The random-effects model was used to calculate the risk ratios (RR), mean differences (MD), and confidence intervals (CIs). A p-value <0.05 was considered statistically significant. Heterogeneity was assessed using Higgins I2 index. RESULTS: Seven randomized controlled trials involving 27905 patients were including in the meta-analysis. The rate of CS/O-GIB was significantly lower in patients receiving PPIs when compared to those receiving H2RAs while intubated (1.6% vs. 2.5%, RR 0.59, 95% CI 0.45-0.79, p= 0.0003, I2= 31%). Five studies reported the rate of VAP, which was not significantly lower in either the PPIs group or the H2RAs group (12.1% vs. 11.4%, RR 1.10, 95% CI 0.74-1.62, p= 0.64, I2= 0%). Five studies reported the rates of ICU mortality in intubated patients, which was not significantly lower in patients receiving PPIs or H2RAs (0.73% vs. 0.70%, RR 1.05, 95% CI 0.86-1.30, p= 0.62, I2= 0%). Four studies reported ICU length of stay, which was found to be similar in both patients receiving PPIs or H2RAs (MD= 0.02 days, 95% CI -0.12-0.16, p= 0.70, I2= 32%). CONCLUSIONS: Our meta-analysis demonstrates that the use of PPIs for mechanically ventilated patients when compared to H2RAs, significantly reduced the rate of CS/O-GIB. The rate of VAP is not significantly lower in either the PPI or H2RA group. Also, there is no significant reduction in the ICU mortality or ICU length of stay when PPIs are used instead of H2RAs. Further data should be collected to confirm our findings. CLINICAL IMPLICATIONS: The use of PPIs in mechanically ventilated patients is effective in preventing CS/O-GIB when compared to H2RAs, without leading to a significant increase in the rate of VAP or ICU mortality. DISCLOSURES: No relevant relationships by Hyder Ali, source=Web Response No relevant relationships by Modar Alom, source=Web Response No relevant relationships by Mohammed Awad, source=Web Response No relevant relationships by Azizullah Beran Beran, source=Web Response No relevant relationships by prabath herath mudiyanselage, source=Web Response No relevant relationships by Saffa Iftikhar, source=Web Response No relevant relationships by Nithin Kesireddy, source=Web Response No relevant relationships by Waleed Khokher, source=Web Response No relevant relationships by Rakin Rashid, source=Web Response

A pragmatic assessment of proton pump inhibitors vs. histamine type 2 receptor antagonists on clinically important gastrointestinal bleeding and mortality when used for stress ulcer prophylaxis in the ICU.

Approximately 1%-5% of critically ill patients experience clinically important gastrointestinal bleeding (CIGB). This study assessed the effectiveness and safety of proton pump inhibitors (PPIs) compared to histamine type 2 receptor antagonists (H2RAs) for prevention of CIGB in mechanically ventilated patients. This is a retrospective, single-center, pharmacoepidemiologic study. This study was carried out in six intensive care units (ICUs). Critically ill adults admitted between 9/1/14 and 9/1/19 who received PPIs or H2RAs within 24h of intubation and for ≥48h were included in this study. PPIs or H2RAs for stress ulcer prophylaxis. Primary outcomes were CIGB occurring 48h after ICU admission and hospital mortality. Secondary outcomes were pneumonia, Clostridioides difficile infection (CDI), acute kidney injury, myocardial infarction/ischemia, thrombocytopenia, and delirium. Outcomes were defined using International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10)-codes with manual cross-reference for a hemoglobin drop, transfusion, or hemodynamic compromise to further define CIGB. Of 3873 patients, 2061 (53.2%) received PPIs. CIGB was rare but higher in the PPI group (0.34% vs. 0%, RR=1, 95% CI, 1-1; p=0.013); however, substantial group differences existed possibly predisposing the PPI group to CIGB. Hospital mortality was higher in the PPI group (42.1% vs. 29.1%, RR=1.23, 95% CI, 1.17-1.29; p<0.0001). PPIs remained an independent risk factor for mortality after multivariate adjustment (RR=1.61, 95% CI, 1.39-1.88; p<0.0001). Rates of secondary outcomes were similar between groups except thrombocytopenia (4.3% vs. 2.2%, RR=1.02, 95% CI, 1.01-1.03; p=0.0003) and delirium (83.7% vs. 78.1%, RR=1.34, 95% CI, 1.18-1.53; p<0.0001) that were higher in the PPI group. Proton pump inhibitors were associated with CIGB; however, the overall rate of CIGB was low. Compared to H2RAs, PPIs were associated with hospital mortality. Further identification of appropriate selection criteria for ulcer prophylaxis and comparisons of pharmacologic prevention strategies are warranted.

Acid-Suppressive Drugs and Risk of Fracture in Children and Young Adults: A Meta-Analysis of Observational Studies.

Background: Recent studies have suggested that proton pump inhibitors (PPIs) and histamine type 2 receptor antagonists (H2RAs) may increase the risk of fracture. We performed a meta-analysis to evaluate the risk of fracture with PPIs and H2RAs use in children and young adults.Methods: PubMed, EMBASE database, Cochrane Library, and Web of Science for relevant articles published before May 2021 were searched. We included all the observational studies reporting on the risk of fracture with acid-suppressive drug (PPIs and H2RAs) use in children and young adults. We calculated pooled risk ratios (RRs) for fracture using random-effects models and conducted subgroup analyses.Results: A total of six studies were included in our analysis. Pooled analysis of PPIs use showed significant risk for fracture (RR = 1.23; 95% CI, 1.12–1.34; I 2 = 79.3), but not significant for PPIs combined with H2RAs use (RR = 1.22; 95% CI, 0.94–1.60; I 2 = 44.0%), as well as for H2RAs use alone (RR = 1.08; 95% CI, 0.94-1.24; I 2 = 84.1%). Grouping of studies by region showed a significantly increased fracture risk with PPIs use in North America (RR = 1.24; 95% CI, 1.16–1.32; I 2 =0.0%) than in Europe (RR = 1.23; 95% CI, 1.00–1.52; I 2 = 94.6%) and Asia (RR = 1.10; 95% CI, 0.96–1.25). However, there was no significant association between the H2RAs use and the fracture risk in North America (RR = 1.08; 95% CI, 1.00–1.09; I 2 = 0.0%). Moreover, PPIs use showed an increased risk of fracture in women (RR = 1.13; 95% CI, 1.07–1.19; I 2 = 0.0%), whereas there was no significant association between the PPIs use and the risk of fracture in men (RR = 0.93; 95% CI, 0.66–1.31; I 2 = 0.0%).Conclusion: PPIs use alone could increase the risk of fracture in children and young adults, but not for PPIs combined with H2RAs use or H2RAs use alone. Clinicians should exercise caution when prescribing PPIs for patients.

Use of gastric acid-suppressive agents increases the risk of dementia in patients with upper gastrointestinal disease: A population-based retrospective cohort study.

BackgroundPrescriptions for gastric acid–suppressive agents, including proton-pump inhibitors (PPIs) and histamine type-2 receptor antagonists (H2RAs), are rising. However, little data exist regarding their association with dementia in the Asian population. The objective of this study was thus to investigate the impact of the use of PPIs and H2RAs on the risk of dementia in an Asian population with upper gastrointestinal disease (UGID).MethodsWe conducted a population-based retrospective cohort study with a 10-year follow-up using data from 2000 to 2015 derived from Taiwan’s Longitudinal Health Insurance Database. We included 6711 patients with UGID receiving gastric acid–suppressive agents, 6711 patients with UGID not receiving agents, and 6711 patients without UGID or treatment thereof, all at least 20 years of age. Groups were matched for age, sex, and index date. The association between gastric acid–suppressive agent use and dementia was analyzed using a Cox proportional hazards regression model adjusted for potential confounders.ResultsThe adjusted hazard ratio (aHR) of dementia for patients with UGID receiving gastric acid–suppressive agents compared with patients with UGID without gastric acid–suppressive agents was 1.470 (95% confidence interval [CI] 1.267–1.705, p < 0.001). Both PPIs and H2RAs increase the risk of dementia (PPIs: aHR 1.886 [95% CI 1.377–2.582], p < 0.001; H2RAs: aHR 1.357 [95% CI 1.098–1.678], p < 0.01), with PPIs exhibiting significantly greater risk (aHR 1.456 [95% CI 1.022–2.075], p < 0.05).ConclusionsOur results demonstrate an increased risk of dementia in patients with UGID receiving gastric acid–suppressive agents, including PPIs and H2RAs, and the use of PPIs was associated with a significantly greater risk than H2RA use.

Impact of histamine type-2 receptor antagonists on the anticancer efficacy of gefitinib in patients with non-small cell lung cancer.

Gefitinib is one of the standard treatments for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor mutations. It has been reported that acid suppressants (AS) decrease the anti-tumor effect of gefitinib by reducing its solubility. AS is sometimes necessary in cancer patients; however, previous reports have not shown the most compatible AS with gefitinib administration in cancer patients. This study was conducted to determine if histamine type 2 receptor antagonists (H2RAs) can affect the anti-tumor efficacy of gefitinib. Eighty-seven patients with NSCLC who were administered gefitinib were retrospectively investigated. Patients who were co-administered H2RA were compared with non-AS control patients. H2RA was administered once a day at about 3-5 or 8-12h after gefitinib intake. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints were overall survival (OS), overall response rate (ORR), and adverse effects. Median PFS in H2RA group and control group was 8.0months and 9.0months, respectively, with no significant difference (p = 0.82). The incidence of liver dysfunction was significantly less in patients administered H2RA, whereas there were no differences between the two groups with regard to skin toxicity and diarrhea. Multivariate analysis suggested that H2RA co-administration is not a risk factor for worse PFS and OS (hazard ratio of 0.95, 0.86; 95% confidence interval of 0.60-1.48, 0.52-1.43; p = 0.82 and 0.60, respectively). This study demonstrated that concomitant administration of H2RA with gefitinib does not affect the efficacy of gefitinib.

No Time to Waste: Real-World Repurposing of Generic Drugs as a Multifaceted Strategy Against COVID-19.

Real-world drug repurposing—the immediate “off-label” prescribing of drugs to address urgent clinical needs—is an indispensable strategy gaining rapid traction in the current COVID-19 crisis. Although off-label prescribing (ie, for a nonapproved indication) is legal in most countries, it tends to shift the burden of liability and cost to physicians and patients, respectively. Nevertheless, in urgent public health crises, it is often the only realistic source of a meaningful potential solution. To be considered for real-world repurposing, drug candidates should ideally have a track record of safety, affordability, and wide accessibility. Although thousands of such drugs are already available, the absence of a central repository of off-label uses presents a barrier to the immediate identification and selection of the safest, potentially useful interventions. Using the current COVID-19 pandemic as an example, we provide a glimpse at the extensive literature that supports the rationale behind six generic drugs, in four classes, all of which are affordable, supported by decades of safety data, and pleiotropically target the underlying pathophysiology that makes COVID-19 so dangerous. Having previously fast-tracked this paper to publication in summary form, we now expand on why cimetidine/famotidine (histamine type-2 receptor antagonists), dipyridamole (antiplatelet agent), fenofibrate/bezafibrate (cholesterol/triglyceride-lowering agents), and sildenafil (phosphodiesterase-5 inhibitor) are worth considering for patients with COVID-19 based on their antiviral, anti-inflammatory, renoprotective, cardioprotective, and anticoagulation properties. These examples also reveal the unlimited opportunity to future-proof public health by proactively mining, synthesizing, and cataloging the off-label treatment opportunities of thousands of safe, well-established, and affordable generic drugs.

ACVIM consensus statement: Support for rational administration of gastrointestinal protectants to dogs and cats.

The gastrointestinal (GI) mucosal barrier is continuously exposed to noxious toxins, reactive oxygen species, microbes, and drugs, leading to the development of inflammatory, erosive, and ultimately ulcerative lesions. This report offers a consensus opinion on the rational administration of GI protectants to dogs and cats, with an emphasis on proton pump inhibitors (PPIs), histamine type‐2 receptor antagonists (H2RAs), misoprostol, and sucralfate. These medications decrease gastric acidity or promote mucosal protective mechanisms, transforming the management of dyspepsia, peptic ulceration, and gastroesophageal reflux disease. In contrast to guidelines that have been established in people for the optimal treatment of gastroduodenal ulcers and gastroesophageal reflux disease, effective clinical dosages of antisecretory drugs have not been well established in the dog and cat to date. Similar to the situation in human medicine, practice of inappropriate prescription of acid suppressants is also commonplace in veterinary medicine. This report challenges the dogma and clinical practice of administering GI protectants for the routine management of gastritis, pancreatitis, hepatic disease, and renal disease in dogs and cats lacking additional risk factors for ulceration or concerns for GI bleeding. Judicious use of acid suppressants is warranted considering recent studies that have documented adverse effects of long‐term supplementation of PPIs in people and animals.

Recent Advances in the Pharmacological Management of Gastroesophageal Reflux Disease

The management of proton pump inhibitor-refractory GERD (rGERD) is a challenge in clinical practice. Since up to one-third of patients with typical GERD symptoms (heartburn and/or acid regurgitation) are not satisfied with proton pump inhibitor (PPI) therapy, new drug development targeting different pathophysiologies of GERD is imperative. At present, no other drugs serve as a more potent acid suppression agent than PPIs. As an add-on therapy, histamine type-2 receptor antagonists, alginates, prokinetics and transient lower esophageal sphincter relaxation inhibitors have some impact on the subgroups of rGERD, but greater effectiveness and fewer adverse effects for widespread use are required. Visceral hypersensitivity also contributes to the perception of GERD symptoms, and neuromodulators including antidepressants play a role in this category. Esophageal pH-impedance monitoring helps to distinguish functional heartburn from true GERD, and psychologic medication and cognitive behavior therapy are further therapy options instead of PPIs.

Prescription audit of NSAIDs and gastroprotective strategy in elderly in primary care.

The use of non-steroidal anti-inflammatory drug (NSAIDs) is deemed amajor risk factor for peptic ulcer disease in elderly population that requires concomitant therapy with gastroprotective agents (GPAs). This study evaluated the rational prescribing of NSAIDs and GPAs, and extent of adherence to the guideline recommendations in primary care. Nationwide audit of prescriptions issued to elderly patients (≥65 years) with hypertension or diabetic hypertension in primary care. Among 2090 elderly, 45.9% were on low-dose aspirin, and 13.5% on other NSAIDs. Diclofenac-XR was the most frequently prescribed NSAIDs to three-quarter patients whereas naproxen, the safest NSAID for patients with high cardiovascular (CV) risk, was rarely prescribed. Among those on NSAID, 82.9% were on ascheduled dosing regimen; of these 78.8% received long-term NSAID therapy (3.9±0.9 months). The prescription rate of GPAs was low: 29.2% for aspirin and 33.3% for other NSAIDs. Aquarter of the patients on histamine type-2 receptor antagonists received ranitidine at subtherapeutic single-dose for gastroprotection. Approximately half of the patients on proton pump inhibitors (PPIs) were prescribed supra-therapeutic double-dose regimen: omeprazole and esomeprazole accounted for 63.2% of overall prescribed PPIs. The rational choice of NSAIDs and physicians' adherence to gastroprotective measures was suboptimal in primary care. The choice of NSAIDs and gastroprotective strategy in elderly be guided by the CV and gastrointestinal adverse events likelihood due to the NSAIDs and risk profile of patients for such adverse events.

Acid-suppressing therapies and subsite-specific risk of stomach cancer

Background:Associations of stomach cancer risk with histamine type-2 receptor antagonists (H2RA) and proton-pump inhibitors (PPI) are controversial. We hypothesised that proximal extension of Helicobacter pylori infection from acid suppression would disproportionately increase cancers at proximal subsites.Methods:A total of 1 563 860 individuals in the Danish Prescription Drug Registry first prescribed acid-suppressive drugs 1995–2011 were matched to unexposed population-based controls. Hazard ratios (HR) were calculated by Cox proportional hazard regression for stomach cancers diagnosed more than one year after first prescription.Results:There were 703 stomach cancers among H2RA-exposed individuals and 1347 among PPI-exposed. Restricted to individuals with five or more prescriptions, subsite-specific HRs for H2RA and PPI were 4.1 and 6.4 for proximal subsites vs 8.0 and 10.3 for distal subsites, respectively.Conclusions:Moderate exposures to acid-suppressive drugs did not favour proximal tumour localisation. Given confounding by indication, these findings do not resolve potential contribution to gastric carcinogenesis overall.

Hypomagnesemia Induced by Long-Term Treatment with Proton-Pump Inhibitors.

In 2006, hypomagnesemia was first described as a complication of proton-pump inhibitors. To address this issue, we systematically reviewed the literature. Hypomagnesemia, mostly associated with hypocalcemic hypoparathyroidism and hypokalemia, was reported in 64 individuals on long-term proton-pump inhibitors. Hypomagnesemia recurred following replacement of one proton-pump inhibitor with another but not with a histamine type-2 receptor antagonist. The association between proton-pump inhibitors and magnesium metabolism was addressed in 14 case-control, cross-sectional studies. An association was found in 11 of them: 6 reports found that the use of proton-pump inhibitors is associated per se with a tendency towards hypomagnesemia, 2 found that this tendency is more pronounced in patients concurrently treated with diuretics, carboplatin, or cisplatin, and 2 found a relevant tendency to hypomagnesemia in patients with poor renal function. Finally, findings likely reflecting decreased intestinal magnesium uptake were observed on treatment with proton-pump inhibitors. Three studies did not disclose any relationship between magnesium metabolism and treatment with histamine type-2 receptor antagonists. In conclusion, proton-pump inhibitors may cause hypomagnesemia. In these cases, switching to a histamine type-2 receptor antagonist is advised.

Risk Factors for Falls with Use of Acid-Suppressive Drugs

Some recent reports suggest an increased risk of fractures with use of proton pump inhibitors (PPIs) and histamine type 2 receptor antagonists (H2RAs), although results are inconsistent and a causal relationship has yet to be proven. As these acid-suppressive drugs may have uncommon adverse effects on the central nervous system (CNS), such as dizziness, we investigated whether their use is associated with falls as a possible mechanism for increasing fracture risk. A cohort study with nested case-control analysis and two validation strategies was performed using data from UK patients (aged 40-89 years) included in The Health Improvement Network database (2000-2008). Due to the large number of falls, a random sample of 20,000 cases was used for the analysis. The overall incidence of falls per 1000 person-years was 13.0 (95% confidence interval [CI] = 12.9-13.1). After adjustment for potential confounders, there was no relationship between falls and current use of single PPIs (odds ratio [OR] = 0.95; 95% CI = 0.89-1.02) or H2RAs (OR = 1.01; 95% CI = 0.90-1.14); there was no relationship with dose or duration of treatment. Falls were associated with CNS disorders and treatment with various pharmacological agents including antiparkinson drugs (OR = 2.7; 95% CI = 2.2-3.3) and antiepileptics (OR = 2.1; 95% CI = 1.8-2.3). There was no association between falls and use of PPIs or H2RAs. Any potential increase in the risk of fractures proposed to be associated with the use of acid-suppressive drugs is not via an increased risk of falls.

Current Pharmacological Management of Gastroesophageal Reflux Disease

Gastroesophageal reflux disease (GERD), a common disorder with troublesome symptoms caused by reflux of gastric contents into the esophagus, has adverse impact on quality of life. A variety of medications have been used in GERD treatment, and acid suppression therapy is the mainstay of treatment for GERD. Although proton pump inhibitor is the most potent acid suppressant and provides good efficacy in esophagitis healing and symptom relief, about one-third of patients with GERD still have persistent symptoms with poor response to standard dose PPI. Antacids, alginate, histamine type-2 receptor antagonists, and prokinetic agents are usually used as add-on therapy to PPI in clinical practice. Development of novel therapeutic agents has focused on the underlying mechanisms of GERD, such as transient lower esophageal sphincter relaxation, motility disorder, mucosal protection, and esophageal hypersensitivity. Newer formulations of PPI with faster and longer duration of action and potassium-competitive acid blocker, a newer acid suppressant, have also been investigated in clinical trials. In this review, we summarize the current and developing therapeutic agents for GERD treatment.

The use of H2 antagonists in treating and preventing NSAID-induced mucosal damage

Pain affects the quality of life for millions of individuals and is a major reason for healthcare utilization. As populations age, medical personnel will need to manage more and more patients suffering from pain associated with degenerative and inflammatory musculoskeletal disorders. Nonsteroidal anti-inflammatory drugs (NSAIDs) are an effective treatment for both acute and chronic musculoskeletal pain; however, their use is associated with potentially significant gastrointestinal (GI) toxicity. Guidelines suggest various strategies to prevent problems in those at risk for NSAID-associated GI complications. In this article, we review the data supporting one such strategy - the use of histamine type-2 receptor antagonists (H2RAs) - for the prevention of GI adverse events in NSAID users. Older studies suggest that high-dose H2RAs are effective in preventing upper GI ulcers and dyspepsia. This suggestion was recently confirmed during clinical trials with a new ibuprofen/famotidine combination that reduced the risk of ulcers by 50% compared with ibuprofen alone.