Histamine-2 Receptor Research Articles

Dihydroergotamine Increases Histamine Brain Levels and Improves Memory in a Scopolamine-Induced Amnesia Model.

The beneficial effects of increasing histamine levels on memory have acquired special interest due to their applicability to psychiatric conditions that cause memory impairments. In addition, by employing drug repurposing approaches, it was demonstrated that dihydroergotamine (DHE), an FDA drug approved to treat migraines, inhibits Histamine N Methyl Transferase (HNMT), the enzyme responsible for the inactivation of histamine in the brain. For this reason, in the present work, the effect of DHE on histamine levels in the hippocampus and its effects on memory was evaluated, employing the scopolamine-induced amnesia model, the Novel Object Recognition (NOR) paradigm, and the Morris Water Maze (MWM). Furthermore, the role of histamine 1 receptor (H1R) and histamine 2 receptor (H2R) antagonists in the improvement in memory produced by DHE in the scopolamine-induced amnesia model was evaluated. Results showed that the rats that received DHE (10 mg/kg, i.p.) showed increased histamine levels in the hippocampus after 1 h of administration but not after 5 h. In behavioral assays, it was shown that DHE (1 mg/kg, i.p.) administered 20 min before the training reversed the memory impairment produced by the administration of scopolamine (2 mg/kg, i.p.) immediately after the training in the NOR paradigm and MWM. Additionally, the effects in memory produced by DHE were blocked by pre-treatment with pyrilamine (20 mg/kg, i.p.) administered 30 min before the training in the NOR paradigm and MWM. These findings allow us to demonstrate that DHE improves memory in a scopolamine-induced amnesia model through increasing histamine levels at the hippocampus due to its activity as an HNMT inhibitor.

Risk of circulatory diseases associated with proton-pump inhibitors: a retrospective cohort study using electronic medical records in Thailand.

Proton-pump inhibitors (PPIs) are prescribed to treat gastric acid-related diseases, while they may also have potential risks to population health. Recent studies suggested that a potential mechanism explaining the association between PPIs and cardiovascular diseases (CVD) includes the inhibition of the nitrate-nitrite-nitric oxide (NO) pathway. However, previous observational studies showed controversial results of the association. In addition, the inhibition of the NO pathway due to PPIs use may lead to peripheral vascular diseases (PVD); however, none of the studies explore the PPI-PVD association. Therefore, this study aimed to evaluate the association of PPIs with circulatory diseases (CVD, ischemic strokes or IS, and PVD). We conducted a retrospective hospital-based cohort study from Oct 2010 to Sep 2017 in Songkhla province, Thailand. PPIs and histamine 2-receptor antagonists (H2RAs) prescriptions were collected from electronic pharmacy records, while diagnostic outcomes were retrieved from electronic medical records at Songklanagarind hospital. Patients were followed up with an on-treatment approach. Cox proportional hazard models were applied to measure the association comparing PPIs vs H2RAs after 1:1 propensity-score-matching. Sub-group analysis, multi-bias E-values, and array-based sensitivity analysis for some covariates were used to assess the robustness of associations. A total of 3,928 new PPIs and 3,928 H2RAs users were included in the 1:1 propensity score-matched cohort. As compared with H2RAs, the association of PPIs with CVD, IS, and PVD, the hazard ratios were 1.76 95% CI = [1.40-2.20] for CVD, 3.53 95% CI = [2.21-5.64] for ischemic strokes, and 17.07 95% CI = [13.82-76.25] for PVD. The association between PPIs and each outcome was significant with medication persistent ratio of over 50%. In addition, the association between PPIs and circulatory diseases was robust to unmeasured confounders (i.e., smoking and alcohol). PPIs were associated with circulatory diseases, particularly ischemic strokes in this hospital-based cohort study, whereas, the strength of associations was robust to unmeasured confounders.

The Effect of Proton-Pump Inhibitors the on Development of Arrhythmia and Hypomagnesemia After Off-Pump Coronary Artery Bypass Surgery

Background: Long-term use of proton-pump inhibitors (PPI) can result in hypomagnesemia and arrhythmia. This study aimed to compare the effect of PPI and histamine 2-receptor antagonists (H2 RA) on the incidence of hypomagnesemia and arrhythmia in patients following off-pump coronary artery bypass surgery (CABG). Method: In this randomized-controlled clinical trial 290 patients admitted to the ICU after off-pump CABG were randomly divided into two groups of H2 RA (n=145) and PPI (n=145). For patients in the H2 RA group, 50 mg intravenous ranitidine was prescribed every 8 hours after the nothing by mouth (NPO) period, followed by 40 mg famotidine tablets after starting the oral regimen (PO). The PPI group received 40 mg pantozol IV injections every 12 hours during the NPO period and 40 mg pantozol tablets once daily after becoming PO. The patients were investigated for the development of hypomagnesemia and associated arrhythmia. Results: In total 271 patients with a mean age of 59.3±10 years completed the study (female/male=32.8%). Hypomagnesemia occurred in 60.1% of the patients, 76 (56.7%) in the H2 RA group and 87 (63.5%) in the PPI group (P=0.245), whereas arrhythmia had a prevalence of 12 (9.6%) and 15 (11.1%) cases, respectively (P=0.690). The mean time of occurrence of hypomagnesemia and arrhythmia was 1.75±1.08 and 3.0±0.9 days after the operation in the H2 RA group (P=0.111) and 1.47±0.7 and 2.9±1.5 days in the PPI group (P=0.897), respectively. Conclusion: Our study revealed that the short-term use of PPIs does not result in higher rates of hypomagnesemia and associated arrhythmia in comparison to H2 RA consumption after off-pump CABG.

Association between pazopanib exposure and safety in Japanese patients with renal cell carcinoma or soft tissue sarcoma

The safety and effectiveness of pazopanib are related to plasma trough concentrations in renal cell carcinoma (RCC); however, data on pazopanib plasma trough concentrations with soft tissue sarcoma (STS) are limited. This study investigated the relationship between plasma trough concentrations and pazopanib safety in 45 Japanese patients with RCC or STS. Among the 33 patients included, the median pazopanib trough concentration was 37.5 (range, 12.1–67.6) µg/mL, which was not significantly different between Japanese RCC and STS patients. The plasma trough concentrations showed significant and positive correlations with aspartate aminotransferase and alanine aminotransferase values in blood samples taken for pharmacokinetic measurements after the administration. The incidence of pazopanib treatment discontinuation were significantly higher in RCC patients (p = 0.027). The primary reason for treatment discontinuation was hepatic dysfunction (5/6, 83.3%). Furthermore, this study revealed that pazopanib trough concentration was affected significantly by proton pump inhibitors but not by histamine 2-receptor blockers. In conclusion, the observed pazopanib trough levels and their safety in the Japanese RCC and STS populations in this study were similar to those of the global population. This is the first study to correlate the hepatotoxicity and pharmacokinetic property of pazopanib plasma trough levels by comparing Japanese patients with RCC or STS.

558: RISK OF H2RA VERSUS PPI FOR DEVELOPING ICU DELIRIUM IN MECHANICALLY VENTILATED OLDER ADULTS

Introduction: Histamine 2-receptor antagonists (H2RA) and proton pump inhibitors (PPI), two acid suppressing drugs, are commonly prescribed for stress ulcer prophylaxis (SUP) in the intensive care unit (ICU). Although both exhibit equivalent effectiveness, recent data suggests a higher risk for ICU delirium with H2RA when compared to PPI. Methods: This was a single-center, retrospective, observational cohort. Mechanically ventilated ≥65 years old patients admitted to a Medical ICU between January 2020 and December 2021 were included if they received at least one dose of H2RA or PPI. Patients were excluded if they received both H2RA and PPI or had a positive Confusion Assessment Method (CAM-ICU) within 24 hours prior to the administration of the drug. Descriptive statistics were used for frequency, median, and mean. Associations between characteristics and the SUP were measured using chi-square, Fisher’s exact, and Wilcoxon rank-sum or t-test. The primary objective was to compare the rate of ICU delirium (≥1 day positive CAM-ICU) in mechanically ventilated older patients receiving H2RA vs. PPI for SUP. Secondary objectives were to compare the percentage of ICU days in delirium and compare the rate of ICU delirium stratified by age (65-75 years old and >75 years old). Results: We screened 236 patients and identified 60 patients for inclusion; 35.0% were female and 70.0% were 65 to 75 years old. Fifty-five percent of patients received H2RA and 45% received PPI. The incidence of delirium in groups was similar; 69.7% (23) for H2RA vs. 63.0% (17) for PPI (p=NS). The percentage of ICU days in delirium was also similar; 37.5% for H2RA vs. 28.2% for PPI (p=NS). Analysis stratified by age also did not show statistical differences between SUP therapies and incidence of delirium or percentage of ICU days in delirium. The relative risk in advanced elderly ICU patients was numerically higher with H2RA (28% greater risk in patients >75 years old vs. 2% greater risk in patients 65-75 years old). Conclusions: We found no association between choice of SUP and risk for ICU delirium development in mechanically ventilated older Medical ICU patients. Larger epidemiologic studies are needed to elucidate whether there is potentially a differential risk between H2RA and PPI in the advanced elderly population.

Estimates of Chronic Kidney Diseases Associated with Proton-Pump Inhibitors Using a Retrospective Hospital-Based Cohort in Thailand.

Potential adverse outcomes of Proton pump inhibitors (PPIs) have increasingly been reported. The potential risks to PPIs include hypomagnesemia and chronic kidney disease (CKD). Unlike a real-world electronic medical record (RW-EMR) with active-comparator design, claim databases and special population cohort with non-user design, using in previous studies, resulted in a wide range of strength of association with indication bias. This study aimed to measure the total effect of association between PPIs use and CKD incidence using Thai RW-EMR. A retrospective hospital-based cohort was applied into this study. Electronic medical records and administrative data of out- and inpatient were retrieved from October 1st, 2010 to September 30th, 2017. On-treatment with grace period as well as propensity score matching was used in data analysis. Cox proportional hazard models were applied to evaluate the PPIs-CKD association. Of all 63,595 participants, a total of 59,477 new PPIs and 4118 Histamine 2-receptor antagonist (H2RA) users were eligible for follow-up. As compared with H2RA, the PPI users were non-elderly and more likely being female. The association of PPIs with CKD was statistically significant (adjusted hazard ratio [HR] = 3.753, 95% CI = 2.385-5.905). The HR were not statistically different by concomitant use PPIs with NSAIDs and by medication possession ratio levels. The association between PPIs and CKD incidence was statistically significant in this hospital-based cohort. However, self-treatment with over-the-counter PPIs, as well as, smoking, drinking alcohol and body mass index could not be fully retrieved, affecting the estimation of treatment effect.

Effects of CYP3A4/5 and ABC transporter polymorphisms on osimertinib plasma concentrations in Japanese patients with non-small cell lung cancer.

The effects of polymorphisms in CYP3A4 (20230G > A), CYP3A5 (6986A > G), ABCB1 (1236C > T, 2677G > T/A, 3435C > T), ABCG2 (421C > A), and ABCC2 (-24C > T) on the area under the concentration-time curve (AUC) of osimertinib in 23 patients with non-small cell lung cancer were investigated. Blood sampling was performed just prior to and at 1, 2, 4, 6, 8, 12, and 24h after osimertinib administration at the steady-state on day 15 after beginning therapy. The osimertinib AUC0-24 was significantly correlated with age (P = 0.038), serum albumin (P = 0.002), and serum creatinine (P = 0.012). Additionally, there were significant differences in the AUC0-24 of osimertinib among the groups administered vonoprazan, histamine 2-receptor antagonists or esomeprazole, and no acid suppressants (P = 0.021). By contrast, there were no significant differences in the AUC0-24 of osimertinib between genotypes of CYP3A4/5 or ABC transporters. Furthermore, there were no significant differences in the AUC0-24 of osimertinib between patients with diarrhea, skin rash, or hepatotoxicity and those without these conditions. In multivariate analysis, only serum albumin value was an independent factor predicting the AUC0-24 of osimertinib. Analysis of CYP3A4/5 and ABC transporter polymorphisms before osimertinib therapy may not predict the efficacy or side effects of osimertinib. The lower serum albumin values were associated with an increase in the AUC0-24 of osimertinib; however, further studies are needed to assess the factors contributing to the interindividual variability of osimertinib pharmacokinetics.

Proton-Pump Inhibitors and Risk of Calcium Pyrophosphate Deposition in a Population-Based Study.

There are no proven effective medical treatments to prevent calcium pyrophosphate crystal deposition (CPPD). Hypomagnesemia is a known CPPD risk factor. The present study was undertaken to carry out a real-world epidemiologic study on proton-pump inhibitor (PPI) use, which can cause hypomagnesemia, and CPPD risk. We conducted a time-stratified, propensity score (PS)-matched cohort study using the UK-based IQVIA Medical Research Data. We compared risk of incident CPPD among PPI users versus H2 blocker users using Cox proportional hazards models. We used greedy matching of incident PPI users 1:1 to incident histamine receptor 2 (H2 ) blocker users in 1-year cohort accrual blocks. Subjects were censored at time of drug switch. We evaluated incident use of PPI and H2 blockers prior to incident CPPD using a nested case-control study within the same cohort, matched 1:4 by age and sex using risk-set sampling. We identified 81,102 PPI and H2 blocker initiators, with 113 and 63 incident cases of CPPD, respectively. In the case-control study when compared with nonusers, both PPI and H2 B users had higher risk of incident CPPD, with odds ratios (ORs) of 1.79 (95% confidence interval [95% CI] 1.55-2.07) and 1.52 (95% CI 1.14-2.03), respectively. Incident PPI use was nonsignificantly associated with incident CPPD (hazard ratio 1.03 [95% CI 0.75-1.41]) compared with H2 blocker use. In this study using real-world data, incident use of PPIs was not associated with a higher risk of CPPD compared with incident H2 blocker use, although use of PPI and H2 blockers had higher risk compared with nonuse.

Famotidine activates the vagus nerve inflammatory reflex to attenuate cytokine storm

BackgroundSevere COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and clinical studies suggest famotidine, a histamine 2 receptor (H2R) antagonist widely used to treat gastroesophageal reflux disease, attenuates the clinical course of COVID-19. Because evidence is lacking for a direct antiviral activity of famotidine, a proposed mechanism of action is blocking the effects of histamine released by mast cells. Here we hypothesized that famotidine activates the inflammatory reflex, a brain-integrated vagus nerve mechanism which inhibits inflammation via alpha 7 nicotinic acetylcholine receptor (α7nAChR) signal transduction, to prevent cytokine storm.MethodsThe potential anti-inflammatory effects of famotidine and other H2R antagonists were assessed in mice exposed to lipopolysaccharide (LPS)-induced cytokine storm. As the inflammatory reflex is integrated and can be stimulated in the brain, and H2R antagonists penetrate the blood brain barrier poorly, famotidine was administered by intracerebroventricular (ICV) or intraperitoneal (IP) routes.ResultsFamotidine administered IP significantly reduced serum and splenic LPS-stimulated tumor necrosis factor (TNF) and IL-6 concentrations, significantly improving survival. The effects of ICV famotidine were significantly more potent as compared to the peripheral route. Mice lacking mast cells by genetic deletion also responded to famotidine, indicating the anti-inflammatory effects are not mast cell-dependent. Either bilateral sub-diaphragmatic vagotomy or genetic knock-out of α7nAChR abolished the anti-inflammatory effects of famotidine, indicating the inflammatory reflex as famotidine’s mechanism of action. While the structurally similar H2R antagonist tiotidine displayed equivalent anti-inflammatory activity, the H2R antagonists cimetidine or ranitidine were ineffective even at very high dosages.ConclusionsThese observations reveal a previously unidentified vagus nerve-dependent anti-inflammatory effect of famotidine in the setting of cytokine storm which is not replicated by high dosages of other H2R antagonists in clinical use. Because famotidine is more potent when administered intrathecally, these findings are also consistent with a primarily central nervous system mechanism of action.

Activation of histamine type 2 receptors enhances intrinsic excitability of medium spiny neurons in the nucleus accumbens.

Histaminergic neurons are exclusively located in the hypothalamic tuberomammillary nucleus, from where they project to many brain areas including the nucleus accumbens (NAc), a brain area that integrates diverse monoaminergic inputs to coordinate motivated behaviours. While the NAc expresses various histamine receptor subtypes, the mechanisms by which histamine modulates NAc activity are still poorly understood. Using whole‐cell patch‐clamp recordings, we found that pharmacological activation of histamine 2 (H2) receptors elevates the excitability of NAc medium spiny neurons (MSNs), while activation of H1 receptors failed to significantly affect MSN excitability. The evoked firing of MSNs increased after seconds of local H2 agonist administration and remained elevated for minutes. H2 receptor (H2R) activation accelerated subthreshold depolarization in response to current injection, reduced the latency to fire, diminished action potential afterhyperpolarization and increased the action potential half‐width. The increased excitability was protein kinase A‐dependent and associated with decreased A‐type K+ currents. In addition, selective pharmacological inhibition of the Kv4.2 channel, the main molecular determinant of A‐type K+ currents in MSNs, mimicked and occluded the increased excitability induced by H2R activation. Our results indicate that histaminergic transmission in the NAc increases MSN intrinsic excitability through H2R‐dependent modulation of Kv4.2 channels. Activation of H2R will significantly alter spike firing in MSNs in vivo, and this effect could be an important mechanism by which these receptors mediate certain aspects of goal‐induced behaviours.Key points Histamine is synthesized and released by hypothalamic neurons of the tuberomammillary nucleus and serves as a general modulator for whole‐brain activity including the nucleus accumbens.Histamine receptors type 2 (HR2), which are expressed in the nucleus accumbens, couple to Gαs/off proteins which elevate cyclic adenosine monophosphate levels and activate protein kinase A.Whole‐cell patch‐clamp recordings revealed that H2R activation increased the evoked firing in medium spiny neurons of the nucleus accumbens via protein kinase A‐dependent mechanisms.HR2 activation accelerated subthreshold depolarization in response to current injection, reduced the latency to fire, diminished action potential medium after‐hyperpolarization and increased the action potential half‐width. HR2 activation also reduced A‐type potassium current.Selective pharmacological inhibition of the Kv4.2 channel mimicked and occluded the increased excitability induced by H2R activation.

Is there any benefit with pantoprazole treatment in infantile hypertrophic pyloric stenosis?

Context:Previous studies demonstrated faster correction of metabolic derangement associated with hypertrophic pyloric stenosis with pre-operative intravenous (IV) histamine-2 receptor antagonists.Aims:We investigated if similar outcomes are achieved with IV pantoprazole, a proton-pump inhibitor (PPI), including the subgroup of delayed presenters in the South African setting.Settings and Design:A 5-year retrospective record review (January 2014–December 2018) compared the rate of metabolic correction in patients with hypertrophic pyloric stenosis at two tertiary centres.Subjects and Methods:One centre routinely administers IV pantoprazole (1 mg/kg daily) preoperatively (PPI group) and the other does not (non-PPI group). Fluid administration, chloride supplementation and post-operative emesis were evaluated.Statistical Analysis:Spearman's rank correlation coefficient was used to calculate statistical significance for discrete dependent variables. Continuous variables were compared between the groups using the Student t-test. Fisher's exact contingency tables were used to classify categorical data and to assess the significance of outcome between two treatment options. P < 0.05 was considered statistically significant.Results:Forty-two patients received IV pantoprazole and 24 did not. The mean time of metabolic correction was 8 h shorter in the PPI group (P = 0.067). Total pre-operative chloride administration correlated to the rate of metabolic correction in both cohorts (P < 0.0001). Profound hypochloraemia (chloride <85 mmol/l) was corrected 23 h faster in the PPI group (P < 0.004). Post-operative emesis was noted: 0.45 episodes/patient in the PPI group and 0.75 episodes/patient in the non-PPI group (P = 0.01).Conclusions:Pre-operative IV pantoprazole administration showed a faster correction of metabolic derangements, and in profound hypochloraemia, the correction occurred substantially faster in the PPI group. Post-operative emesis was significantly less frequent in the PPI group.

Physiological effects of histamine on renal function in salt‐sensitive hypertension

Introduction . Histamine is a regulatory agent involved in the immune response, neurotransmission, and gastric acid secretion, and is produced and released from the mast cells and basophils. Elevated histamine levels and increased expression of histamine metabolizing enzymes have been reported in kidney diseases. The goal of this study is to provide insight into the physiological importance of the histamine-related pathways in salt-sensitive hypertension (SSH), a disease accompanied with inflammation-driven kidney damage. Methods . SSH was induced in Dahl Salt-Sensitive (DSS) rats by a 3-week long high salt diet challenge (HS, 4% NaCl); age-matched normal salt diet (NS, 0.4% NaCl) fed rats were used as a control group. To characterize the expression of histamine receptors, mast cells markers, and histamine metabolism-related enzymes, Western blot or IHC were performed on renal tissues collected from DSS rats maintained on HS or NS diets for 3 weeks. In order to test the effects of histamine receptor 2 (HR2) inhibition, he DSS rats were injected with a single daily i.p. dose of an HR2 blocker, ranitidine (RAN, 25mg/kg in saline) or saline (VEH), for 3 consecutive days before the switch to a HS diet, and at the end of the 21-day long HS challenge. Urine and water consumption were assessed in metabolic cages during hours 0-8 (acute), and 8-24 post-injections. At the end of the protocol, GFR was measured, and tissues were harvested. Results . Western blots revealed similar expression of the mast cell markers’ (FCER1A and tryptase) in NS and HS diet fed rats, however, we observed significantly lower histamine decarboxylase (HDC, p=0.002), and higher histamine N-methyltransferase (HNMT, p=0.035) levels in HS diet fed rats. Renal IHC revealed that expression of HR2 was downregulated, while HR3 and HR4 were upregulated in the collecting ducts of HS diet fed rats. In vivo experiments showed that RAN-administered rats on NS diet exhibited an acute (8-24 hr period) decrease in urine output and 24 h water intake on day 1 of injections (p=0.01). We observed trends for an increase in urinary electrolytes, and an overall increase in the excretion of osmolesin RAN vs VEH animals 24 hours post day 1 injection on the NS diet. Post HS challenge, electrolyte excretion, urine flow and water intake were similar between RAN and VEH animals. At the endpoint on HS, GFR between the groups was similar on day 3 post-injection. Conclusions . Differential expression of HRs, as well as changes in the enzymes responsible for histamine synthesis and metabolism between HS and NS fed rats, indicate a shift in the renal histaminergic tone during SSH development. Similar mast cell levels suggest an alternate, perhaps intrarenal, source of histamine. Our in vivo data show that inhibition of HR2 has effects on urine output and water consumption in SSH. Further research is required to discern the molecular pathways downstream of specific HRs, as well as the consequences of chronic administration of HR-specific pharmacology, in renal pathophysiology.

Influence of Proton Pump Inhibitors and Histamine Receptor 2 Antagonists on Blastocystis ST3 and Selected Microorganisms of Intestinal Microbiota In Vitro.

INTRODUCTION:Proton pump inhibitors (PPIs) and histamine receptor 2 (H2) antagonists are commonly prescribed medications. Association between PPIs and alteration of the gut microbiota has been reported. Blastocystis, the most common intestinal protozoan worldwide, occurs in both healthy and symptomatic people with gastrointestinal or cutaneous disorders, with controversial pathogenicity. The current study was aimed to investigate the influence of PPIs and H2 blockers on the in vitro proliferation of selected intestinal bacteria, fungi, and protozoa.METHODS:Cultures of Lactobacillus rhamnosus, Escherichia coli, Enterococcus faecium, Candida albicans, and Blastocystis subtype 3 were treated with different concentrations of respective medications in vitro, and the numbers of microorganisms were quantified and compared.RESULTS:Pantoprazole and esomeprazole exerted a significant inhibition on Blastocystis and C. albicans, especially at higher concentrations, which were even more effective than metronidazole. On the other hand, treatment with pantoprazole caused an increase in proliferation of L. rhamnosus and E. coli. There was no influence of H2 blockers on the examined microorganisms.DISCUSSION:PPIs, such as pantoprazole, can be a potential treatment in the prophylaxis or eradication of Blastocystis and C. albicans.

Peptic Ulcer Disease: An Overview of Aetiology, Pathophysiology, Clinical Presentation, Diagnosis and Treatment Options

Introduction: Peptic ulcer disease (PUD) is endemic in all parts of the world. It is estimated that as high as 5-10% of the world’s population is affected by PUD. Disruption in the gastric protective factors within the gastrointestinal lumen is responsible for the development of PUD. Aggravating factors that promote formation of peptic ulcers include gastric acids, decreased bicarbonate and general decrease in mucosal defences. Non-steroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori (H. pylori) infection are the two major aetiologic factors contributing to damages to the mucosal defence. The major clinical symptom of PUD is epigastric pain. Others includes bloating, heartburn, nausea or vomiting. Testing for H. pylori is important in treatment of PUD. The major complications of H pylori-associated and NSAID-induced ulcers include upper gastrointestinal bleeding, perforation, penetration, gastric outlet obstruction and gastric adenocarcinoma. Purpose: The purpose of this review is to present a general overview of the aetiology, pathophysiology, clinical presentation, diagnosis and treatment options for peptic ulcer disease (PUD). Conclusion: PUD remains a global health challenge requiring that all patients should be treated. Conventional treatments include gastric acid suppressing agents such as proton pump inhibitors (PPIs) and histamine-2 (H2) receptor antagonists as well as mucosal protective agents. Eradication of H. Pylori is critical in pharmacotherapy of H. pylori associate PUD. New approaches to treatments may include the use of antioxidants containing medicinal plants.

Influence of proton pump inhibitor or rebamipide use on gut microbiota of rheumatoid arthritis patients

Patients with RA commonly use gastrointestinal (GI) protective drugs for treatment and prevention of drug-associated GI injuries. However, how these drugs affect the gut microbiota in RA patients remains unknown. The objective of this study was to examine the gut microbiota of RA patients according to use of GI protective drugs such as proton pump inhibitors (PPIs), histamine 2-receptor antagonists and rebamipide. Faecal samples were obtained from 15 healthy controls and 32 RA patients who were receiving PPI, histamine 2-receptor antagonist or rebamipide. Bacterial DNA was extracted from the faecal samples and 16S rRNA sequencing was performed. Microbial composition and function were analysed using Quantitative Insights Into Microbial Ecology and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States. RA patients exhibited reduced diversity and altered composition of the gut microbiota compared with healthy controls. The gut microbiota of RA patients receiving acid-suppressing drugs, particularly PPIs, was distinct from that of RA patients receiving rebamipide (PPI vs rebamipide, P = 0.005). Streptococcus was enriched in RA patients receiving PPI, while Clostridium bolteae was enriched in RA patients receiving rebamipide. The gut microbiota of PPI users was abundant with microbial functional pathway involved in the production of virulence factors. This featured microbial function was positively correlated with relative abundance of Streptococcus, the differentially abundant taxa of PPI users. The gut microbiota of RA patients receiving PPIs was distinguishable from that of those receiving rebamipide. The enriched virulent function in the gut microbiota of PPI users suggests that inappropriate PPI use may be harmful in RA patients.

Consumption of medicines used for gastric acid-related disorders in Australia and South Korea: a cross-country comparison

The study's aim was to compare the use of proton pump inhibitors (PPIs), histamine 2-receptor antagonists (H2RAs) and mucoprotective medicines (MPs) used for gastric acid-related disorders (GARD) in Australia and South Korea (Korea) from 2004 to 2017. Prescription data for PPIs, H2RAs and MPs for Australian outpatients were extracted from the Australian Statistics on Medicines annual reports, with dose-specific and expenditure data obtained from Medicare. Similar data were obtained from Korean National Health Insurance Service claims data. We analysed the volume and expenditure of medicines use annually using the defined daily dose per 1,000 population per day. We calculated which medicines accounted for 90% of use and estimated the proportions of use for low- and high-dose PPIs. While total utilisation for GARD medicines increased over time in both countries, patterns of use differed. Overall, use was somewhat higher in Australia but increased more rapidly in Korea. PPIs were used more extensively in Australia, while more MPs and H2RAs were used in Korea. Expenditure and use of low-dose PPIs is escalating in Korea. There were substantial differences in the use of GARD medicines in Australia and Korea over 14years. Both countries face similar challenges to promote rational medicines use and contain medical care costs. The discrepant prescribing patterns can be attributed to differences in healthcare systems, pharmaceutical policies and demographics. This study provides a baseline to influence more rational use of these medicines. It provides insight into medicines policies for other countries that face similar challenges.

Machine learning analysis to identify the association between risk factors and onset of nosocomial diarrhea: a retrospective cohort study.

BackgroundAlthough several risk factors for nosocomial diarrhea have been identified, the detail of association between these factors and onset of nosocomial diarrhea, such as degree of importance or temporal pattern of influence, remains unclear. We aimed to determine the association between risk factors and onset of nosocomial diarrhea using machine learning algorithms.MethodsWe retrospectively collected data of patients with acute cerebral infarction. Seven variables, including age, sex, modified Rankin Scale (mRS) score, and number of days of antibiotics, tube feeding, proton pump inhibitors, and histamine 2-receptor antagonist use, were used in the analysis. We split the data into a training dataset and independant test dataset. Based on the training dataset, we developed a random forest, support vector machine (SVM), and radial basis function (RBF) network model. By calculating an area under the curve (AUC) of the receiver operating characteristic curve using 5-fold cross-validation, we performed feature selection and hyperparameter optimization in each model. According to their final performances, we selected the optimal model and also validated it in the independent test dataset. Based on the selected model, we visualized the variable importance and the association between each variable and the outcome using partial dependence plots.ResultsTwo-hundred and eighteen patients were included. In the cross-validation within the training dataset, the random forest model achieved an AUC of 0.944, which was higher than in the SVM and RBF network models. The random forest model also achieved an AUC of 0.832 in the independent test dataset. Tube feeding use days, mRS score, antibiotic use days, age and sex were strongly associated with the onset of nosocomial diarrhea, in this order. Tube feeding use had an inverse U-shaped association with the outcome. The mRS score and age had a convex downward and increasing association, while antibiotic use had a convex upward association with the outcome.ConclusionWe revealed the degree of importance and temporal pattern of the influence of several risk factors for nosocomial diarrhea, which could help clinicians manage nosocomial diarrhea.

P1.14-59 Clinical Implications of the Pharmacokinetics of Dacomitinib Co-Administration with H2-Receptor Antagonists in Cancer Patients

Dacomitinib (Vizimpro®) is a competitive, irreversible, small-molecule inhibitor of epidermal growth factor receptor (EGFR) and is currently approved for first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR activating mutations. Similar to other EGFR inhibitors, the aqueous solubility of dacomitinib is pH dependent, with its highest solubility observed at acidic pH. Therefore, it is important to evaluate the potential impact of gastric pH-elevating agents on the pharmacokinetics (PK) of dacomitinib. Co-administration of a proton pump inhibitor (rabeprazole 40 mg once daily for 4 days) resulted in approximately a 40-50% decrease in dacomitinib exposure after a single 45-mg dose of dacomitinib. There was no effect on the extent of absorption of dacomitinib during treatment with a short-acting antacid (Maalox Maximum Strength). This report evaluated the effect of co-administration of histamine 2-receptor antagonists (H2RA) on dacomitinib PK based on a retrospective analysis of pooled PK data collected from clinical studies in patients treated with dacomitinib. Data were drawn from 11 Phase 1, 2 and 3 clinical studies in advanced NSCLC or solid tumor patients. For each patient, steady-state trough concentrations (Ctrough, ss) of dacomitinib after ≥14 days of consecutive dacomitinib dosing at a dose level of 15, 30, 45 or 60 mg once daily were measured at various times during the treatment period. Within-patient comparison of a 45-mg dose of normalized dacomitinibCtrough, ss between dacomitinib dosing alone and dacomitinib co-administered with an H2RA (cimetidine, famotidine, nizatidine and ranitidine) consecutively for ≥3 days was performed using a linear mixed effects model with time and treatment as fixed effects and patient within time as a random effect. A total of 86 (5.9%) patients from the pooled patient studies received an H2RA. In this analysis, 16 patients had dacomitinib Ctrough,ss for both dacomitinib dosing alone and dacomitinib co-administered with an H2RA. The adjusted geometric mean ratio of a 45-mg dose of normalized dacomitinib Ctrough,ss following co-administration with an H2RA was 85.9% (90% confidence interval [CI]: 72.9%, 101.1%) relative to dacomitinib dosing alone. The 90% CI for the ratio includes 100%, suggesting no statistically significant difference between the reference and test groups (P>0.05). Co-administration of an H2RA is not expected to have a clinically relevant effect on dacomitinib exposure. In accordance with knowledge derived from other EGFR inhibitors, it is recommended that the time of dacomitinib dosing with an H2RA should be staggered to allow dacomitinib absorption at the time of lowest gastric pH and to minimize any potential impact from the concomitant use of an H2RA.

Association of histamine with hypertension-induced cardiac remodeling and reduction of hypertrophy with the histamine-2-receptor antagonist famotidine compared with the beta-blocker metoprolol

The association of histamine with adverse cardiac remodeling in chronic pressure overload has not received much attention. A pilot study in spontaneously hypertensive rats (SHRs) indicated a reduction of left ventricular hypertrophy (LVH) with a histamine-2-receptor (H2R) antagonist (famotidine). This finding prompted a detailed investigation of temporal variation in myocardial histamine and H2R expression and the cardiovascular response to H2R antagonism compared with that of the conventional beta-blocker metoprolol. Reduction of LVH is known to reduce the risk of adverse cardiovascular events. The myocardial histamine content and H2R expression increased with age in SHRs but not in normotensive Wistar rats. The cardiovascular response to famotidine (30 mg kg-1) was compared with that of metoprolol (50 mg kg-1) in 6-month-old male SHRs treated for 60 days. The decrease in diastolic blood pressure and improvement in cardiac function induced by famotidine and metoprolol were comparable. Both treatments caused the regression of LVH as assessed from the hypertrophy index, histomorphometry, B type natriuretic peptide (BNP), pro-collagen 1, and hydroxyproline levels. Calcineurin-A expression (marker of pathological remodeling) decreased, and Peroxiredoxin-3 expression (mitochondrial antioxidant) increased in response to the treatments. The myocardial histamine levels decreased with the treatments. The age-dependent increase in myocardial histamine and H2R in the SHRs signifies their association with progressive cardiac remodeling. The regression of LVH and improvement in cardiac function by famotidine further demonstrates the role of histamine in cardiac remodeling. Hypertrophy of cultured cardiac cells upon exposure to histamine and the H2R agonist amthamine substantiates the role of histamine in cardiac remodeling. The cardiovascular response to famotidine is comparable to that of metoprolol, suggesting repurposing of H2R antagonists for the management of hypertensive heart disease.

Risks versus benefits of medication use during pregnancy: what do women perceive?

BackgroundUnderstanding perception of risks and benefits is essential for informed patient choices regarding medical care. The primary aim of this study was to evaluate the perception of risks and benefits of 9 drug classes during pregnancy and associations with women’s characteristics.MethodsQuestionnaires were distributed to pregnant women who attended a Dutch Obstetric Care facility (first- and second-line care). Mean perceived risk and benefit scores were computed for 9 different drug classes (paracetamol, antacids, antibiotics, antifungal medication, drugs against nausea and vomiting, histamine-2 receptor antagonists/proton pump inhibitors, antidepressants, nonsteroidal anti-inflammatory drugs, and sedatives/anxiolytics). For each participant, we computed weighted risk and benefit sum scores with principal component analysis. In addition, major concerns regarding medication use were evaluated.ResultsThe questionnaire was completed by 136 women (response rate 77%). Pregnant women were most concerned about having a child with a birth defect (35%), a miscarriage (35%), or their child developing an allergic disease (23%), respectively, as a result of drug use. The majority of studied drug classes were perceived relatively low in risk and high in benefit. Higher risk scores were reported if women were in their first trimesters of pregnancy (p=0.007). Lower benefit scores were reported if women were single (p=0.014), smoking (p=0.028), nulliparous (p=0.006), or did not have a family history of birth defects (p=0.005).ConclusionPregnant women’s concerns regarding potential drug adverse effects were not only focused on congenital birth defects but also included a wider range of adverse outcomes. This study showed that most of the studied drug classes were perceived relatively low in risk and high in benefit.