Histamine Receptor Antagonists Research Articles

Gut homeostasis, injury, and healing: New therapeutic targets.

The integrity of the gastrointestinal mucosa plays a crucial role in gut homeostasis, which depends upon the balance between mucosal injury by destructive factors and healing via protective factors. The persistence of noxious agents such as acid, pepsin, nonsteroidal anti-inflammatory drugs, or Helicobacter pylori breaks down the mucosal barrier and injury occurs. Depending upon the size and site of the wound, it is healed by complex and overlapping processes involving membrane resealing, cell spreading, purse-string contraction, restitution, differentiation, angiogenesis, and vasculogenesis, each modulated by extracellular regulators. Unfortunately, the gut does not always heal, leading to such pathology as peptic ulcers or inflammatory bowel disease. Currently available therapeutics such as proton pump inhibitors, histamine-2 receptor antagonists, sucralfate, 5-aminosalicylate, antibiotics, corticosteroids, and immunosuppressants all attempt to minimize or reduce injury to the gastrointestinal tract. More recent studies have focused on improving mucosal defense or directly promoting mucosal repair. Many investigations have sought to enhance mucosal defense by stimulating mucus secretion, mucosal blood flow, or tight junction function. Conversely, new attempts to directly promote mucosal repair target proteins that modulate cytoskeleton dynamics such as tubulin, talin, Ehm2, filamin-a, gelsolin, and flightless I or that proteins regulate focal adhesions dynamics such as focal adhesion kinase. This article summarizes the pathobiology of gastrointestinal mucosal healing and reviews potential new therapeutic targets.

The effect of proton pump inhibitors and vonoprazan on the development of 'gastric mucosal redness'.

The safety of long-term proton pump inhibitor (PPI) and vonoprazan (VPZ) use is a relatively recent concern. Gastric mucosal redness was reported as a VPZ-associated lesion in a previous study. The aim of this study was to investigate the prevalence and risk factors for gastric mucosal redness. Between December 2020 and November 2021, 1,101 patients who underwent esophagogastroduodenoscopy were reviewed. The cohort was divided into four groups: Control (n=580), histamine-2 receptor antagonist (H2RA) (n=65), PPI (n=146) and VPZ groups (n=310). Gastric mucosal redness was present in 48/1,101 patients (4%). The prevalence in controls, H2RA, PPI and VPZ groups was 1.9% (11/580), 1.5% (1/65), 6.2% (9/146) and 8.7% (27/310), respectively. Both the PPI and VPZ groups had a significantly higher prevalence of gastric mucosal redness compared with the control group (P<0.001). In the multivariate analysis, PPI and VPZ use were significantly associated with gastric mucosal redness. Fundic gland polyps, gastric hyperplastic polyps, multiple white and flat elevated lesions, cobblestone-like mucosa, and stardust gastric mucosa were also significantly associated with PPI and VPZ use in the multivariate analysis. Back-to-back analysis showed that gastric mucosal redness was not seen before starting PPI/VPZ in most patients. The duration of treatment with VPZ was investigated to determine if it affected the prevalence of gastric mucosal redness. There were no significant differences in treatment duration among patients with and without gastric mucosal redness (mean ± standard deviation: 3.0±1.5 vs. 2.5±1.4 years, P=0.077). In conclusion, the prevalence of gastric mucosal redness was low but was associated with PPI and VPZ use.

Effects of Gastric Acid Secretion Inhibitors for Ventilator-Associated Pneumonia.

Objective: This study analyzed the association of gastric acid secretion inhibitors (GASIs) [including proton pump inhibitors (PPIs) and histamine 2 receptor antagonists (H2RAs)] with the occurrence of ventilator-associated pneumonia (VAP) and in-hospital mortality in patients who received invasive mechanical ventilation (IMV). Method: Patients who received IMV and used GASI were included based on records in the MIMIC-IV database. The relationships of GASIs with VAP and the in-hospital mortality were determined using univariate and multivariate logistic regression analyses. Also, the effects of GASIs in some subgroups of the population were further analyzed. Results: A total of 18,669 patients were enrolled, including 9191 patients on H2RAs only, 6921 patients on PPIs only, and 2557 were on a combination of the two drugs. Applying logistic regression to the univariate and multivariate models revealed that compared with H2RAs, PPIs had no significant effect on the incidence of VAP, and the combination of H2RAs and PPIs was a risk factor for VAP. Compared with H2RAs, univariate logistic regression revealed that, PPIs and combine the two drugs were both risk factors for in-hospital mortality, but multivariate logistic regression showed that they were not significantly associated with in-hospital mortality. In subgroup analysis, there were interaction in different subgroups of age, PCO2, myocardial infarct, congestive heart failure (P for interaction<0.05). Conclusion: Compared with H2RAs, PPIs did not have a significant association with either VAP or in-hospital mortality; the combination of H2RAs and PPIs was risk factor for VAP, but did not have a significantly associated with in-hospital mortality.

MO525: Iron absorption and phosphate-lowering effects of ferric citrate hydrate are not influenced by gastric secretion inhibitors in patients with chronic kidney disease

Abstract BACKGROUND AND AIMS Ferric citrate hydrate (FC, Riona®), an oral iron-based phosphate binder in chronic kidney disease (CKD) patients, is also approved as an iron preparation for iron-deficiency anemia (IDA) in Japan. In the USA, ferric citrate (Auryxia®) is approved as a phosphate binder for dialysis-dependent CKD and an iron replacement product for the treatment of IDA in patients with CKD not on dialysis. Ingested iron is dissolved at a low pH of the secreted gastric acid in the stomach, which is an important process for its effective absorption [1]. Patients taking gastric acid secretion inhibitors (GASI), such as proton pump inhibitors and histamine-2 receptor antagonists, showed decreased iron absorption and increased risk of iron deficiency, which were dose- and treatment-duration-dependent [2]. The increase in the intragastric pH by concomitantly use of GASI might be affected on FC's iron absorption effect. METHOD We have conducted a retrospective study using data from two previous clinical studies to investigate FC in CKD patients with hyperphosphatemia. A 12-week, phase 3, multicenter, randomized, double-blind, placebo-controlled study in non–dialysis-dependent (ND) CKD patients (FC, n = 60, ; placebo, n = 30) (CTI-111 435) [3], and a 52-week, phase 3, multicenter, open-label, dose-titration study in CKD patients undergoing hemodialysis (HD) (FC, n = 180) (CTI-111 437) [4] were divided into with or without GASI, and levels of iron and phosphate related parameters were analyzed. RESULTS In ND patients, approximately 25% in FC (n = 14) and 50% (n = 14) in placebo used GASI. Mean [standard deviation (SD)] changes from baseline to end of treatment (EOT) in serum ferritin (ng/mL) were 109.83 (104.46) in FC with GASI, 142.68 (94.28) in FC without GASI, −22.49 (74.85) in placebo with GASI, and −3.43 (43.58) in placebo without GASI (Fig. 1a). Those in transferrin saturation (TSAT, %) were 16.64 (30.13) in FC with GASI, 17.07 (17.56) in FC without GASI, 2.86 (14.68) in placebo with GASI, and 1.31 (9.75) in placebo without GASI (Figure 1b). The mean (SD) dose of FC with or without GASI were 3240 mg/day (approximately 778 mg ferric iron) with GASI (n = 14) and 3445 mg/day (approximately 827 mg ferric iron) without GASI (n = 46), respectively. In HD patients, approximately 50% (n = 95) used GASI. Mean changes (SD) from baseline to EOT in serum ferritin (ng/mL) were 166.32 (153.70) with GASI and 155.16 (139.47) without GASI, and in TSAT (%) were 16.60 (19.44) with GASI and 16.02 (18.81) without GASI, respectively. The mean (SD) dose of FC with or without GASI were 2619 mg/day (approximately 629 mg of ferric iron) with GASI (n = 95) and 2854 mg/day (approximately 685 mg or ferric iron) without GASI (n = 85), respectively. In both studies, there were no differences in the changes from baseline to EOT in serum phosphate between with or without GASI. CONCLUSION GASI did not interfere with iron absorption and phosphate-lowering effects of FC in CKD patients with hyperphosphatemia.

PD46-09 LIPOPOLYSACCHARIDE FROM DYSBIOTIC GUT MICROBIOTA PROMOTES INFLAMMATORY PROSTATE CANCER GROWTH THROUGH HISTAMINE H1 RECEPTOR SIGNALING

PD46-09 LIPOPOLYSACCHARIDE FROM DYSBIOTIC GUT MICROBIOTA PROMOTES INFLAMMATORY PROSTATE CANCER GROWTH THROUGH HISTAMINE H1 RECEPTOR SIGNALING

Proton pump inhibitors reduce the survival of advanced lung cancer patients with therapy of gefitinib or erlotinib

Gefitinib and erlotinib are the first-line tyrosine kinase inhibitors (TKI) for advanced non-small-cell lung cancer. However, co-administration of either drug with proton pump inhibitors (PPI) or histamine-2 receptor antagonists (H2RA) may reduce TKI’s bioavailability. Therefore, we aimed to investigate the effects of these drug–drug interactions. We surveyed nationwide population-based databases between Jan 1, 2010, and Dec 30, 2018. Newly diagnosed patients with advanced lung adenocarcinoma who received first-line gefitinib or erlotinib were identified. Effects on overall survival (OS) and time to next treatment (TTNT) association between PPIs or H2RAs and co-administrated gefitinib or erlotinib were evaluated. PPIs or H2RAs users were defined if the period overlapped with TKIs by ≥ 20%. A total of 4340 gefitinib and 1635 erlotinib users were included. PPI group had the shortest median OS and TTNT compared to the H2RA and non-user groups (in gefitinib cohort: OS: 14.35 vs. 17.67 vs. 21.87 months; P < 0.0001, TTNT: 8.47 vs. 10.78 vs. 10.33 months; P < 0.0001); (in erlotinib cohort: OS: 16.97 vs. 20.07 vs. 23.92 months; P < 0.0001, TTNT: 9.06 vs. 11.85 vs. 10.90 months; P = 0.0808). Compared with the non-user group, the adjusted hazard ratio (aHR) of the PPI group in the gefitinib was 1.58 on OS (95% CI 1.42–1.76), 1.37 on TTNT (95% CI 1.24–1.52); in the erlotinib was 1.54 on OS (95% CI 1.30–1.82) and 1.19 on TTNT (95% CI 1.01–1.39). Concurrent use of PPIs with first-line gefitinib or erlotinib therapy was associated with a worse OS and TTNT in patients with lung adenocarcinoma harboring EGFR mutations.

Comprehensive Analysis of N6-Methyladenosine Regulators in the Subcluster Classification and Drug Candidates Prediction of Severe Obstructive Sleep Apnea.

Background: Obstructive sleep apnea (OSA) is the most common type of sleep apnea that impacts the development or progression of many other disorders. Abnormal expression of N6-methyladenosine (m6A) RNA modification regulators have been found relating to a variety of human diseases. However, it is not yet known if m6A regulators are involved in the occurrence and development of OSA. Herein, we aim to explore the impact of m6A modification in severe OSA. Methods: We detected the differentially expressed m6A regulators in severe OSA microarray dataset GSE135917. The least absolute shrinkage and selection operator (LASSO) and support vector machines (SVM) were used to identify the severe OSA-related m6A regulators. Receiver operating characteristic (ROC) curves were performed to screen and verify the diagnostic markers. Consensus clustering algorithm was used to identify m6A patterns. And then, we explored the character of immune microenvironment, molecular functionals, protein-protein interaction networks and miRNA-TF coregulatory networks for each subcluster. Finally, the Connectivity Map (CMap) tools were used to tailor customized treatment strategies for different severe OSA subclusters. An independent dataset GSE38792 was used for validation. Results: We found that HNRNPA2B1, KIAA1429, ALKBH5, YTHDF2, FMR1, IGF2BP1 and IGF2BP3 were dysregulated in severe OSA patients. Among them, IGF2BP3 has a high diagnostic value in both independent datasets. Furthermore, severe OSA patients can be accurately classified into three m6A patterns (subcluster1, subcluster2, subcluster3). The immune response in subcluster3 was more active because it has high M0 Macrophages and M2 Macrophages infiltration and up-regulated human leukocyte antigens (HLAs) expression. Functional analysis showed that representative genes for each subcluster in severe OSA were assigned to histone methyltransferase, ATP synthesis coupled electron transport, virus replication, RNA catabolic, multiple neurodegeneration diseases pathway, et al. Moreover, our finding demonstrated cyclooxygenase inhibitors, several of adrenergic receptor antagonists and histamine receptor antagonists might have a therapeutic effect on severe OSA. Conclusion: Our study presents an overview of the expression pattern and crucial role of m6A regulators in severe OSA, which may provide critical insights for future research and help guide appropriate prevention and treatment options.

Association of Early Life Prescriptions for Antibiotics and Acid Suppressants with Childhood Psychotropic Prescriptions

To examine the association between antibiotic and acid suppressant prescriptions in the first 2years of life and subsequent treatment for childhood psychiatric disorders. This was a retrospective cohort study of children born between October 2001 and September 2012 in the Military Health System enrolled in TRICARE past age 2years and within 35days of birth, with an initial hospital stay <7days, and without psychotropic agents dispensed during the first 2years of life. Exposure was defined as a filled prescription for an antibiotic or acid suppressant before age 2years, and the outcome was defined as a filled prescription for a psychotropic agent after age 2years. For the 804 920 patients (51% males and 49% female) composing the study population, the mean age at first psychotropic prescription was 6.8years. A total of 24 176 children (3%) were prescribed a proton pump inhibitor (PPI), 79 243 (10%) were prescribed a histamine-2 receptor antagonist (H2RA), and 607 348 (76%) were prescribed an antibiotic during the first 2years of life. The adjusted hazard ratio (aHR) of a psychotropic prescription was significantly increased in children prescribed any H2RA (1.79; 95% CI, 1.63-1.96), PPI (1.47; 95% CI, 1.26-1.71), or antibiotic (1.71; 95% CI, 1.59-1.84). The aHR of psychotropic prescriptions increased commensurately with each additional antibiotic class added and with each additional class of medication (H2RA, PPI, or antibiotics) prescribed. Children prescribed antibiotic and acid suppressants in the first 2years of life have a significant increase in future prescriptions for psychotropics, with a dose-related effect observed. This association represents a potential risk of early exposure to antibiotics and acid suppressants.

Ranitidine decreases human sperm motility and vitality and increases the activity of seminal creatine kinase.

Ranitidine (brand name: Zantac), an acid reducer, belongs to histamine-2 receptor antagonists. Since 1981, even though several adverse effects of this drug were reported in the body, still, its effects on human sperm parameters have yet to be confirmed. In this work, we attempted to measure sperm motility, sperm vitality and activity of seminal creatine kinase in the ejaculated human semen (n= 31) in the presence of ranitidine at a range of concentrations (0.1, 0.3, 0.6, 0.9 and 1.2μg/ml) compared with control (without ranitidine). Sperm motility was measured using the Makler counter, whilst sperm vitality was assessed using the Eosin test. Creatine kinase activity was measured using the kinetic spectrophotometric method. Sperm motility (total and progressive) as well as sperm vitality was significantly (p < .05) reduced in the presence of ranitidine in human semen, particularly at the higher tested concentrations (0.6-1.2 μg/ml) compared with the control. On the other hand, creatine kinase activity was significantly increased (p < .05) in the presence of ranitidine at 0.6, 0.9 and 1.2 μg/ml. In conclusion, ranitidine at 0.6-1.2 μg/ml reduced sperm motility and vitality, but increased the activity of creatine kinase in ejaculated human semen.

The Difference in Serum Pepsinogen I, Pepsinogen II, Carcinoembryonic Antigen, and Carcinoma Antigen 72-4 Levels between Children with and without Helicobacter Pylori Infection

BACKGROUND: Helicobacter pylori (H. pylori) is a common infection in human. The infection is mainly acquired in childhood with global prevalence of 32.3%. Several markers such as pepsinogen I, pepsinogen II, carcinoembryonic antigen (CEA), and carcinoma antigen (CA) 72-4 are associated with H. pylori infection and its complications.&#x0D; OBJECTIVE: To determine the difference in serum pepsinogen I, pepsinogen II, CEA, and CA 72-4 levels in children with and without H. pylori infection.&#x0D; METHODS: A cross sectional study was conducted in Samosir Island, Indonesia. Inclusion criteria were children aged 2 to 18 years who did not take antibiotics, bismuth containing drugs, histamine-2 receptor antagonists, proton pump inhibitors, and immunomodulator for the last 4 weeks before the study. All subjects were divided into 2 groups: H. pylori positive and negative. Demographic and anthropometric data were gathered. Serum pepsinogen I, pepsinogen II, CEA, and CA 72-4 levels were evaluated. The differences were determined using Mann Whitney U-test.&#x0D; RESULTS: A total of 74 subjects were enrolled in this study. H. pylori positive and negative subjects were 38 and 36, respectively. Females were dominant in both groups. No difference was observed in gender, age, anthropometric characteristics, serum CEA level, and CA 72-4 level between both groups. Serum pepsinogen I and pepsinogen II levels were higher in H. pylori positive group compared to their counterparts (p= 0.013 and p= 0.001, respectively).&#x0D; CONCLUSION: There are significant differences in serum pepsinogen I and II levels between children with and without H. pylori infection.

Use of histamine-2 receptor antagonists and risk of inflammatory bowel diseases: A systematic review and meta-analysis of observational studies.

The effect of histamine-2 receptor antagonists (H2RAs) use causing inflammatory bowel diseases (IBD) has been reported in few isolated observational studies; however, pooled estimation of IBD risk has not been done. The present study was conducted to estimate the risk of IBD [Crohn's disease (CD), ulcerative colitis (UC) and microscopic colitis (MC)], among H2RAs users. Databases such as MEDLINE/PubMed, Scopus and Cochrane Library were searched from inception to January 2021. A bibliographic search of selected articles, random search in Google Scholar and ResearchGate were also performed for any additional studies. The observational studies which assessed the incidence or risk of IBD in H2RA users published in the English language were considered. Modified Downs and Black Checklist was used for quality assessment. Two independent reviewers were involved in study selection, data extraction and quality assessment; any discrepancies were settled through consensus or by consulting a third reviewer. Four studies out of 2,658 articles were included for this meta-analysis. The meta-analysis of 4studies with 8939 participants revealed a significantly higher risk of IBD (OR: 2.27; 95% CI: 1.70-3.02; p<0.0001) in H2RA users compared to non-users. Similar significant relationships were observed in the subgroup analysis of adults (p<0.0001) and paediatrics (p=0.04). The quality of included studies was observed to be fair to good. Our findings indicate a significantly higher IBD risk among those who used H2RA compared to non-users both in adults and in paediatrics. Further observational studies involving large populations are required to strengthen these results and to generalize these findings.

Meta-analysis of the effectiveness of histamine-2 receptor antagonists as prophylaxis for gastrointestinal bleeding in intensive care unit patients

Background: The risk of upper gastrointestinal bleeding increases in critically ill patients admitted to an intensive care unit (ICU), with 50–77% mortality. Histamine-2 receptor antagonists (H2RAs) are frequently used to prevent gastrointestinal bleeding in ICU patients, but the tests on its effectiveness and safety are still conflicting. Objective: To determine the effectiveness and safety of H2RA in preventing gastrointestinal bleeding in ICU patients. Methods: Data on randomised controlled trials (RCTs) were collected from the MEDLINE database, ScienceDirect, ClinicalKey, and The Cochrane Library. Two investigators assessed the quality of the trials using the critical appraisal skills program (CASP) checklist for RCT studies, and fixed-effects meta-analysis was carried out using Review Manager software. Results: The 12 RCTs showed a reduced risk of gastrointestinal bleeding (RR = 0.40; 95% CI = 0.30 ‒ 0.53; I-square = 38%; p &lt;0.00001) and a decreased number of patients requiring blood transfusion in H2RA group (RR = 0.44; 95% CI = 0.23 ‒ 0.82; I-square = 8%; p = 0.01), and these effects were significantly different from the placebo group. However, there was no significant difference in mortality between the two groups (RR = 0.99; 95% CI = 0.74 ‒ 1.33; I-square = 0%; p = 0.96). Regarding its safety, the administration of H2RAs did not affect the incidence of nosocomial pneumonia (RR = 1.13; 95% CI = 0.82 ‒ 1.55; I-square = 30%; p = 0.46). A sensitivity analysis with a random-effects model was also performed on eight articles with a low risk of bias. The statistical analyses of eight and 12 articles showed the same results—that H2RAs significantly reduced the risk of gastrointestinal bleeding. Conclusion: H2RA proves effective and safe in reducing the incidence of gastrointestinal bleeding, but not reducing the mortality in ICU patients.

A Quality by Design and green LC technique for the determination of mast cell stabilizer and histamine receptor antagonist (Olopatadine HCl) in multiple formulations.

Mast cell stabilizer and histamine receptor antagonist olopatadine hydrochloride (OPT) assay method predicated on LC have been established for the analysis in multiple formulations. The current method dealt with ophthalmic solution, nasal spray, and tablet formulation products. The isocratic chromatography method was optimized and validated with a Boston green C8 column (150 × 4.6 mm, 5μm i.d.). Sodium dihydrogen phosphate buffer (pH3.5) with acetonitrile in the ratio of 75:25 (v/v) was used as a mobile phase at a flow rate of 1.0mL min-1 and at the column temperature of 30°C, and the detection was done at 299 nm. The method was validated as per International Council for Harmonisation (ICH) guidelines and United States Pharmacopoeia (USP). The accuracy results ranged from 99.9 to 100.7%, % relative standard deviation (RSD) from the precision was 0.5, and correlation coefficient from the linearity experiment was > 0.999. Solution stability was established for 24 h at room temperature and refrigerator conditions, and it was found that the solutions were stable. Using quality by design-based experiment designs, critical quality attributes were studied and it was found that the method was robust. In all the forced degradation studies peak purity was passed, and no interference was found at the retention time of the active component. The method validation data demonstrated that the developed method is linear, precise, accurate, specific, robust, and stable for the determination of OPT from multiple formulations. Analytical eco-scale tool, Green Analytical Procedure Index (GAPI) tool, and the National Environmental Method Index (NEMI) were used to evaluate the greenness of the method, and the analytical eco-score of 77 for the presented method was found to be excellent.

Impact of Proton Pump Inhibitors and Histamine-2-Receptor Antagonists on Non-Small Cell Lung Cancer Immunotherapy: A Systematic Review and Meta-Analysis.

Simple SummaryThe current meta-analysis highlighted that proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs) could impact immune checkpoint inhibitors (ICIs) efficacy in NSCLC patients, highlighting the need for a deeper comprehension of factors involved in treatment response or resistance. Since the number of indications and NSCLC patients receiving ICIs is supposed to increase further soon, identifying the impact of these agents on NSCLC immunotherapy represents a compelling and urgent need regarding NSCLC.(1) Background: In recent years, immunotherapy has revolutionized the treatment landscape of non-small cell lung cancer (NSCLC), representing a therapeutic breakthrough in this field. Antacid agents such as proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs) are commonly prescribed for extended periods in NSCLC patients, and these drugs have the potential to modify the efficacy of immune checkpoint inhibitors (ICIs). (2) Materials and Methods: Herein, we conducted a systematic review and meta-analysis to investigate the impact of PPIs and H2RAs on progression-free survival (PFS) and overall survival (OS) among patients receiving immunotherapy for metastatic NSCLC. Effect measures for OS were Hazard Ratios (HRs) and 95% Confidence Intervals (CIs), which were extracted from available studies. Forest plots were used to assess HRs to describe the relationship between treatment and OS in the specified cohorts of patients. (3) Results: Six studies were included in the analysis, involving 2267 patients. The pooled HRs for OS and PFS were 1.4 (95% CI, 1.25–1.58) and 1.29 (95% CI, 1.17–1.43), respectively, suggesting that PPIs and H2RAs administration was negatively associated with PFS and OS. (4) Conclusion: Concomitant antacid use could modify the activity of ICIs in NSCLC patients.

Votucalis, a Novel Centrally Sparing Histamine-Binding Protein, Attenuates Histaminergic Itch and Neuropathic Pain in Mice.

Votucalis is a biologically active protein in tick (R. appendiculatus) saliva, which specifically binds histamine with high affinity and, therefore, has the potential to inhibit the host’s immunological responses at the feeding site. We hypothesized that scavenging of peripherally released endogenous histamine by Votucalis results in both anti-itch and anti-nociceptive effects. To test this hypothesis, adult male mice were subjected to histaminergic itch, as well as peripheral nerve injury that resulted in neuropathic pain. Thus, we selected models where peripherally released histamine was shown to be a key regulator. In these models, the animals received systemic (intraperitoneal, i.p.) or peripheral transdermal (subcutaneous, s.c. or intraplantar, i.pl.) administrations of Votucalis and itch behavior, as well as mechanical and thermal hypersensitivity, were evaluated. Selective histamine receptor antagonists were used to determine the involvement of histamine receptors in the effects produced by Votucalis. We also used the spontaneous object recognition test to confirm the centrally sparing properties of Votucalis. Our main finding shows that in histamine-dependent itch and neuropathic pain models peripheral (s.c. or i.pl.) administration of Votucalis displayed a longer duration of action for a lower dose range, when compared with Votucalis systemic (i.p.) effects. Stronger anti-itch effect was observed after co-administration of Votucalis (s.c.) and antagonists that inhibited peripheral histamine H1 and H2 receptors as well as central histamine H4 receptors indicating the importance of these histamine receptors in itch. In neuropathic mice, Votucalis produced a potent and complete anti-nociceptive effect on mechanical hypersensitivity, while thermal (heat) hypersensitivity was largely unaffected. Overall, our findings further emphasize the key role for histamine in the regulation of histaminergic itch and chronic neuropathic pain. Given the effectiveness of Votucalis after peripheral transdermal administration, with a lack of central effects, we provide here the first evidence that scavenging of peripherally released histamine by Votucalis may represent a novel therapeutically effective and safe long-term strategy for the management of these refractory health conditions.

Is acid suppression associated with the increased length of stay in diabetic ketoacidosis patients? A nationwide analysis.

BackgroundDiabetic ketoacidosis (DKA) patients present with low serum bicarbonate (HCO3−), and an increase in its level to ≥15 mEq/L is considered one of the criteria for DKA resolution. Both proton pump inhibitors and histamine‐2 receptor antagonists inhibit downstream functioning of H+/K+ ATPase in the gastric parietal cells, which results in the decreased secretion of HCO3− into the bloodstream.ObjectivesWe aimed to introduce the hypothesis that DKA patients on acid‐suppressive medications may have a delayed rise in serum HCO3− to >15 mEq/L that may cause increased hospital length of stay (LOS) and sought to compare the outcomes of such patients. For the sake of simplicity, conditions requiring acid suppression are grouped under the term peptic ulcer disease (PUD) in this study.MethodsThis is a retrospective study using Nationwide Inpatient Sample employing International Classification of Diseases (ICD‐10) codes for adult patients with a primary diagnosis of DKA. Analyses were performed using STATA, proportions were compared using Fisher exact test, and continuous variables using Student's t‐test. Confounding variables were adjusted using propensity matching, multivariate logistic, and linear regression analyses.ResultsDKA patients with PUD had higher adjusted LOS, intensive care unit admission, and total hospital costs. Mortality and morbidity indicators were similar in both groups. The variables found to be independent predictors of increased LOS were malnutrition, Clostridium difficile infection, pneumonia, Glasgow Coma Scale score of 3–8, and higher Charlson comorbidity score.ConclusionWe found that Clostridium difficile and pneumonia predicted longer LOS in DKA patients with concomitant PUD, hinting at the possible role of acid suppression in prolonging the LOS in such patients. However, further studies are needed to examine the effect of lesser HCO3− generation on LOS.

Neurotransmitters of sleep and wakefulness in flatworms.

Study ObjectivesSleep is a prominent behavioral and biochemical state observed in all animals studied, including platyhelminth flatworms. Investigations into the biochemical mechanisms associated with sleep—and wakefulness—are important for understanding how these states are regulated and how that regulation changed with the evolution of new types of animals. Unfortunately, beyond a handful of vertebrates, such studies on invertebrates are rare.MethodsWe investigated the effect of seven neurotransmitters, and one pharmacological compound, that modulate either sleep or wakefulness in mammals, on flatworms (Girardia tigrina). Flatworms were exposed via ingestion and diffusion to four neurotransmitters that promote wakefulness in vertebrates (acetylcholine, dopamine, glutamate, histamine), and three that induce sleep (adenosine, GABA, serotonin) along with the H1 histamine receptor antagonist pyrilamine. Compounds were administered over concentrations spanning three to five orders of magnitude. Flatworms were then transferred to fresh water and video recorded for analysis.ResultsDopamine and histamine decreased the time spent inactive and increased distance traveled, consistent with their wake-promoting effect in vertebrates and fruit flies; pyrilamine increased restfulness and GABA showed a nonsignificant trend towards promoting restfulness in a dose-dependent manner, in agreement with their sleep-inducing effect in vertebrates, fruit flies, and Hydra. Similar to Hydra, acetylcholine, glutamate, and serotonin, but also adenosine, had no apparent effect on flatworm behavior.ConclusionsThese data demonstrate the potential of neurotransmitters to regulate sleep and wakefulness in flatworms and highlight the conserved action of some neurotransmitters across species.

ISPD peritonitis guideline recommendations: 2022 update on prevention and treatment.

Peritoneal dialysis (PD)-associated peritonitis is a serious complication of PD and prevention and treatment of such is important in reducing patient morbidity and mortality. The ISPD 2022 updated recommendations have revised and clarified definitions for refractory peritonitis, relapsing peritonitis, peritonitis-associated catheter removal, PD-associated haemodialysis transfer, peritonitis-associated death and peritonitis-associated hospitalisation. New peritonitis categories and outcomes including pre-PD peritonitis, enteric peritonitis, catheter-related peritonitis and medical cure are defined. The new targets recommended for overall peritonitis rate should be no more than 0.40 episodes per year at risk and the percentage of patients free of peritonitis per unit time should be targeted at >80% per year. Revised recommendations regarding management of contamination of PD systems, antibiotic prophylaxis for invasive procedures and PD training and reassessment are included. New recommendations regarding management of modifiable peritonitis risk factors like domestic pets, hypokalaemia and histamine-2 receptor antagonists are highlighted. Updated recommendations regarding empirical antibiotic selection and dosage of antibiotics and also treatment of peritonitis due to specific microorganisms are made with new recommendation regarding adjunctive oral N-acetylcysteine therapy for mitigating aminoglycoside ototoxicity. Areas for future research in prevention and treatment of PD-related peritonitis are suggested.

Mast Cells in Atopic Diseases: More Than Just Histamine

Mast cells are present in all tissues and are able to release multiple mediators in response to allergic, autoimmune, environmental, neurohormonal and pathogenic triggers. Histamine has received most of the attention in terms of pathophysiology and drug development, while tryptase remains to this date with no clear function and no known inhibitor. Mast cells can also release pro-inflammatory and pruritogenic molecules, such as IL-6 and IL-31, selectively without degranulation. One such critical molecule is platelet activating factor (PAF), which is vasoactive, can cause wheal and flare on ita own, but can also stimulate eosinophils and mast cells that are critical in the pathogenesis of chronic spontaneous urticaria (CSU) and rhinitis. Mast cell-derived cytokines and PAF have also been implicated in inflammatory processes including COVID-19. Among the second generation histamine-1 receptor antagonists, rupatadine is more effective overall, it has potent anti-PAF activity, and also inhibits activation of human mast cells and eosinophils. Rupatadine could, therefore, serve as a first-line drug for CSU and rhinitis, but may also be used, especially for patients resistant to antihistamines.

A multicenter cohort analysis of fractures in histamine-2-receptor antagonist treated pediatric patients

Background Histamine 2 receptor antagonists (H2RA) are amongst the most entrenched antacid therapies available including over-the-counter. They have an excellent safety profile including no known teratogenic risk. Fracture risk is generally recognized with chronic proton pump inhibitor (PPI) therapy in adults and children although the related mechanism is poorly understood. The analogous risk in H2RAs, including in children, is unclear. We studied the fracture risk and characteristics among hospitalized pediatric patients exposed to H2RA compared to an untreated cohort. Methods The Pediatric Health Information System (PHIS) multicenter database was queried for hospital encounters of children aged 6 months − 15.5 years and between 7/2016 and 8/2017. Patients with comorbidities and medications including PPI that predispose for fractures were excluded from the cohort and a propensity-matched control was identified. The subjects and controls were followed for 2 years for hospitalization with fracture diagnoses. Results Our cohort included 3526 patients with exposure to H2RA and matched controls. Fractures were reported in 1% of patients (67) with no statistical difference between the groups. Upper, then lower extremity fractures were the most common in both groups. Axial skeleton fractures were the least frequently encountered fractures among both groups. Conclusion H2RA exposure is not associated with an increased risk of fracture in hospitalized children exposed to H2RA when compared with a matched untreated cohort, further studies are needed to determine if long-term exposure to H2RA may be associated with fracture risk in both those with and without comorbidities or on fracture predisposing medication.