H2 Blockers Research Articles

A Case Report of a Young Patient with Dysphagia: Eosinophillic Esophagitis, Achalasia or Atypical course of Gastroesophageal Reflux Disease ?

A 19 years old female patient presented with symptoms of dysphagia, esophageal retention and radiologic and endoscopic suspicion of esophageal stricture and achalasia in one other institution. After extensive diagnostic procedure including upper gastrointestinal endoscopy with narrow-band imaging and histology of esophageal mucosa, Magnetic resonance imaging (MRI) of the thorax and abdomen, the 24h esophageal impedance pH monitoring and esophageal high-resolution monitoring. We have excluced eosinophilic oesophagitis and achalasia, indicating to the atypical course of gastroesophageal reflux disease. The patient underwent the intense and combined pharmacologic (PPIs, H2 blockers, antacids) and endoscopic (repeated ballon-dilatation of of esophagogastric junction stricture) therapy, over a period of two years. With this combined and long-lasting therapy, the patient significantly improved, clinically. The esophageal peristaltic activity was also recovered, thus incompletely. The patient remained well and gaining weight with minimal symptoms of dysphagia to solids, occasionally. In presented case of a young female patient, we witnessed the overlapping nature of different criteria denoting the distinct entities, linked to esophageal dysphagia and esophageal motility disorder, such as achalasia, eosinophilic oesophagitis and gastroesophageal reflux disease. The complex diagnostic approach, including esophageal functional testing pointed to the presence of gastroesophageal reflux disease, as to underlying condition for this complex clinical situation. The combined therapeutic approach, including antisecretory agents and repeatied balloon dilatations led to significant clinical improvement.

A Risk Scoring System Utilizing Machine Learning Methods for Hepatotoxicity Prediction One Year After the Initiation of Tyrosine Kinase Inhibitors.

BackgroundThere is currently no method to predict tyrosine kinase inhibitor (TKI) -induced hepatotoxicity. The purpose of this study was to propose a risk scoring system for hepatotoxicity induced within one year of TKI administration using machine learning methods.MethodsThis retrospective, multi-center study analyzed individual data of patients administered different types of TKIs (crizotinib, erlotinib, gefitinib, imatinib, and lapatinib) selected in five previous studies. The odds ratio and adjusted odds ratio from univariate and multivariate analyses were calculated using a chi-squared test and logistic regression model. Machine learning methods, including five-fold cross-validated multivariate logistic regression, elastic net, and random forest were utilized to predict risk factors for the occurrence of hepatotoxicity. A risk scoring system was developed from the multivariate and machine learning analyses.ResultsData from 703 patients with grade II or higher hepatotoxicity within one year of TKI administration were evaluated. In a multivariable analysis, male and liver metastasis increased the risk of hepatotoxicity by 1.4-fold and 2.1-fold, respectively. The use of anticancer drugs increased the risk of hepatotoxicity by 6.0-fold. Patients administered H2 blockers or PPIs had a 1.5-fold increased risk of hepatotoxicity. The area under the receiver-operating curve (AUROC) values of machine learning methods ranged between 0.73-0.75. Based on multivariate and machine learning analyses, male (1 point), use of H2 blocker or PPI (1 point), presence of liver metastasis (2 points), and use of anticancer drugs (4 points) were integrated into the risk scoring system. From a training set, patients with 0, 1, 2-3, 4-7 point showed approximately 9.8%, 16.6%, 29.0% and 61.5% of risk of hepatotoxicity, respectively. The AUROC of the scoring system was 0.755 (95% CI, 0.706-0.804).ConclusionOur scoring system may be helpful for patient assessment and clinical decisions when administering TKIs included in this study.

Follow-Up Clinico-Endoscopic Study among Young Patients with Peptic Ulcer Perforation: A Prospective Analysis

Background: One of the most common difficulties in the operation fatality is perforation peritonitis. The goal of this study was to identify risk factors for peptic ulcer disease (PUD) in young patients. Materials and method: In this study, 70 patients were evaluated and clinical examinations and endoscopies were performed at 8 weeks and 6 months. Place and Duration: A population‐based cohort study was conducted at the Gastroenterology department of Sharif Medical College, Lahore for one-year duration from January 2021 to December 2021. Result: Six patients died, and 4 patients were not followed up on, out of a total of 80 patients. There were 62 men and 8 women among the remaining 70 patients. The majority of the patients were between the ages of 35 and 40. After eight weeks, 34 (50%) had no infections on endoscopy, with 34 patients (48.6%) on treatment and 1 (1.4%) not on any therapies. The residual 35 patients (50%) had active ulcers and other positive endoscopic outcomes. Six months after surgery, 56 patients (80%) had no ulcers on endoscopy, with 34 on treatment and 12 without treatment. The rest 14 had some positive endoscopic findings. The study also revealed other factors linked with peptic ulcer perforation and impacting healing in the postoperative phase. Preoperative PUD symptoms, alcohol consumption, comorbidities, chronic drug consumption (NSAIDs/steroids), smoking, postoperative treatment given and H. pylori infection were all variables. Conclusion: All patients with peptic ulcer perforation should receive H2 blockers or proton pump inhibitors as a post - operative therapies, as well as an anti-Helicobacter pylori regimen. Postoperative follow-up should include routine endoscopic examinations of these patients to detect ulcer healing. Keywords: peptic ulcer disease, endoscopies, chronic drug consumption.

Efficacy and safety of proton pump inhibitors versus histamine-2 receptor blockers in the cardiac surgical population: insights from the PEPTIC trial.

The comparative effectiveness and safety of proton pump inhibitors (PPIs) versus histamine-2 receptor blockers for stress ulcer prophylaxis in the cardiac surgical intensive care unit population is uncertain. Although the Proton Pump Inhibitors versus Histamine-2 Receptor Blockers for Ulcer Prophylaxis Therapy in the Intensive Care Unit (PEPTIC) trial reported a higher risk of mortality in the PPI arm with no difference in gastrointestinal bleeding, detailed information on surgical variables and clinically relevant surgical subgroups was not available. The analysis included all Canadian cardiac surgery patients enrolled in the PEPTIC trial. Data were electronically linked using unique patient identifiers to a clinical information system. Outcomes of interest included in-hospital mortality, gastrointestinal bleeding, Clostridium difficile infections, ventilator-associated conditions and length of stay. We studied 823 (50.6%) randomized to PPIs and 805 (49.4%) to histamine-2-receptor blockers. In the intention-to-treat analysis, there were no differences in hospital mortality [PPI: 4.3% vs histamine-2 receptor blockers: 4.8%, adjusted odds ratio (aOR) 0.97, 95% confidence interval (CI) 0.55-1.70], gastrointestinal bleeding (3.9% vs 4.8%, aOR 1.09, 95% CI 0.66-1.81), C. difficile infections (0.9% vs 0.1%, aOR 0.18, 95% CI 0.02-1.59), ventilator-associated conditions (1.6% vs 1.7%, aOR 0.92, 95% CI 0.85-1.00) or median length of stay (9.2 vs 9.8 days, adjusted risk ratio 1.06, 85% CI 0.99-1.13). No significant treatment differences were observed among subgroups of interest or per-protocol populations. In a secondary analysis of cardiac surgery patients enrolled in the PEPTIC trial in Canada, no differences in effectiveness or safety were observed between use of PPIs and histamine-2 receptor blockers for stress ulcer prophylaxis. anzctr.org.au identifier: ACTRN12616000481471.

The role of histamine in anterior pituitary secretion

Objectives: The aim of the present study was to determine the effects of histamine on the anterior pituitary secretion in rats. Materials and Methods: In the first experiments rats were injected with histamine 5 mg/kg i.p., and blood samples were collected to determine the effect of histamine on serum level of adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), prolactin, FSH, and luteinizing hormone (LH) after 10, 20, and 30 min of histamine injection. In the second experiments, rats were treated with (H 1 blocker), chlorphenramine 10 mg/kg, i.p. or (H 2 blocker), cimetidine 80 mg/kg, i.p. respectively, and after 30 min they were injected with histamine and blood samples were taken 30 min after the injection of histamine to determine the same hormones. Results: Histamine significantly elevated serum ACTH and LH level, and these stimulatory effects were inhibited by both H1 and H2 receptor blockers. However, histamine significantly inhibited the serum level of thyroid-stimulating hormone and this inhibitory effect was blocked by H2 receptor blocker, while it showed no effect on the secretion of both prolactin and FSH, although H2 blocker significantly decreased prolactin level and H1 blocker significantly elevated FSH level. Conclusion: The results clearly indicated that histaminergic pathways were involved in the anterior pituitary secretion.

Predictors of Response to Oral Medications and Low-Histamine Diet in Patients with Chronic Urticaria.

Background Chronic urticaria (CU) is comprised of diverse phenotypes, and thus, a shift towards a precision medical approach is warranted in its management. Methods This study enrolled 78 patients with CU. Serum erythrocyte sedimentation rate, hemoglobin, hematocrit, eosinophil count, IgE, antinuclear antibody (ANA), and serum diamine oxidase (DAO) levels of the patients were measured and were compared according to the patient's response to second-generation antihistamines (sgAH), corticosteroids, leukotriene receptor antagonist (LTRA), H2 blockers, and low-histamine diet. Results Age- and sex-adjusted logistic regression analysis showed that patients with duration of CU > 3 years (adjusted odd ratio [aOR] = 4.39) and a DAO level < 10 U/mL (aOR = 3.90) were significantly associated with a good sgAH response. Age > 50 years (aOR = 0.02), duration of chronic urticaria > 3 years (aOR =0.06), and an ANA titer ≥ 1 : 80 (aOR = 0.03) were significantly and inversely associated with corticosteroid response. A low-histamine diet response was significantly associated with LTRA response (aOR = 67.29). In addition, a DAO level < 5.4 U/mL (aOR = 71.95) was significantly associated with H2 blocker response. Furthermore, concomitant angioedema (aOR = 10.56), multiple food triggers (aOR = 11.69), and a DAO level < 5.4 U/mL (aOR = 3.78) were significantly associated with a low-histamine diet response. Conversely, dermatographic urticaria and a hematocrit level < 36% were significantly and inversely associated with low-histamine diet response. Conclusions Several promising biomarkers were identified in this study to predict the efficacy of chronic urticaria treatment. DAO could be a novel biomarker for predicting the efficacy not only of dietary intervention but also for antagonists of H1 and H2 receptors.

Pharmacological screening of Acalypha indica L.: Possible role in the treatment of asthma

Ethnopharmacological relevanceAcalypha indica Linn (Euphorbiaceae), a popular traditional medicine, is an erect herb found throughout various parts of India. In Ayurveda, Acalypha indica was commonly used in asthma and allergy. However, no attempts were made in past to validate the antiasthmatic potential of Acalypha indica.Aim of the study: The present study was aimed to assess the anti-asthmatic potential of ethanolic extracts of Acalypha indica leaves (EAIL) using various experimental animal models. Materials and methodsEAIL was analyzed using different screening methods such as acetylcholine and histamine-induced contraction of goat tracheal chain, clonidine-induced catalepsy in mice, milk-induced leucocytosis and eosinophilia in mice, clonidine-induced mast cell degranulation in rats, passive paw anaphylaxis in rats, histamine-induced bronchoconstriction in guinea pigs, and ovalbumin (OVA)-induced histopathological alterations in mice. ResultsData received in the present study showed that EAIL drastically antagonized acetylcholine and histamine-induced contraction of goat tracheal chain, suggesting its anticholinergic and antihistaminic activity respectively. The duration of immobility, produced by clonidine, was found to be decreased in mice which showed its H1 receptor blocking activity. In milk-induced leucocytosis and eosinophilia in mice, EAIL significantly reduced the number of leucocytes and eosinophils suggesting its adaptogenic and anti-allergic potential. Inhibition of clonidine-induced mast cell degranulation in rats displayed its mast cell stabilizing potential. Reduction of paw edema in passive paw anaphylaxis exhibited antianaphylactic activity of EAIL. Guinea pigs were protected from histamine-induced bronchoconstriction by EAIL which revealed its bronchodilator potential. Furthermore, the histopathological architecture of lung tissue was near to normal. ConclusionOur results contribute towards validation of the traditional use of Acalypha indica in the treatment of asthma due to the presence of a wide range of phytoconstituents. Hence our investigation revealed that EAIL possessed strong antiasthmatic property by virtue of various mechanisms.

De-Prescribing Proton Pump Inhibitors in Patients With End Stage Kidney Disease: A Quality Improvement Project.

Background:Proton pump inhibitors (PPIs) are widely prescribed and may be associated with harm; hypomagnesemia and reduced effectiveness of calcium carbonate phosphate binders may be important in end-stage kidney disease (ESKD).Objectives:Our objectives included (1) discontinuing PPIs and H2 blockers and (2) assessing the impact on serum magnesium and markers of mineral metabolism.Design:Prospective cohort.Setting:Satellite hemodialysis unit of a tertiary care hospital.Patients:Incident and prevalent patients with ESKD treated with hemodialysis.Measurements:We assessed the impact of stopping PPI/H2 blockers in patients who did not have an absolute indication as per guidelines in the general population; serum magnesium, calcium, and phosphate were measured before and approximately 8 weeks later. Analysis of variance (ANOVA) test and Kruskal-Wallis was used to describe the population. Wilcoxon signed rank test for the paired change scores (from pre to post)Methods:The electronic medical record (EMR) was extensively searched for absolute indications for a PPI. Results were reviewed with the primary nephrology team before approaching patients about stopping the PPI. Basic demographic information and select medications were also collected.Results:Electronic medical records were reviewed for 179 patients, 74 had a PPI or H2 antagonist or both on their medication list (43%); 23 (31%) were assessed as appropriate. After primary team and patient review, 29 patients agreed to a trial of PPI withdrawal. Fourteen patients restarted their PPI, most for gastroesophageal reflux disease. Three patients had a GI bleed, 1 fatally. Serum calcium (P = .17) and the dose of phosphate binders (P = .075) did not change but serum phosphate increased (1.55 [0.29] to 1.85 [0.34] mmol/L; P = .0005). Serum magnesium also increased (1.01 [0.16] to 1.06 [0.14] mmol/L; P = .01).Limitations:Small patient numbers and observational nature of the study does not establish causation in this population at high risk to experience a gastrointestinal bleed.Conclusions:Our results suggest that PPI deprescribing as recommended in the general population may be associated with harm in patients with ESKD and requires further study.Trial Registration:Not registered.

A survey on the incidence of common musculoskeletal side effects among the patients taking long-term anti-ulcerant therapies in Bangladesh

BackgroundProton pump inhibitors (PPIs) and H2 blockers are commonly prescribed medications to treat ulcers in the stomach and the upper part of the small intestine and prescribed for some other common gastrointestinal complications such as gastroesophageal reflux disease, esophagitis, irritable bowel syndrome, and dyspepsia. Previous studies claimed that, apart from other side effects, these anti-ulcerant therapies significantly altered bone mineral density by interfering with intestinal reabsorption of minerals and vitamin B12, and the most widely prescribed PPIs were significantly associated with increased risks of hip and spine fractures. However, the potential skeletal side effects of these antiulcerants are unknown in Bangladesh. MethodsTo examine safety concerns of anti-ulcer therapies and their impact on musculoskeletal health among patients in Bangladesh, the present work surveyed 200 patients in five different hospitals from December 2019 to February 2020. ResultsThe current study revealed that most respondents (95 %) received PPIs for gastrointestinal indications while the rest were taking H2 receptor antagonists for their gastric ailments. Most patients taking PPIs alone (> 3 years; 95 % of respondents) claimed some unusual musculoskeletal side effects, such as weakness, flank pain, spasm of hands and feet, muscle aches, numbness, and tremor. About 61 % of patients taking PPIs experienced low back pain whereas the respondents with neck pain and knee joint pain were 10 % and 7 %, respectively. However, few osteopenia and osteoporotic incidences have been also recorded. Although further studies are required to confirm the impact of these antiulcerants on the bone, these patient responses suggest that these musculoskeletal side effects might have some links with altered bone metabolism. ConclusionsIt is possible that anti-ulcerant therapies may worsen the bone metabolism of patients suffering from osteoporosis or other bone disorders, and awareness and precautions should be raised among the patients and clinicians for the careful administration of PPIs to patients suffering from bone disorders.

N-Nitrosodimethylamine-contaminated ranitidine and risk of cancer in South Korea: a nationwide cohort study

Objective: On September 2019, the United States Food and Drug Administration announced that some ranitidine products were contaminated with unacceptable levels of N-nitrosodimethylamine (NDMA). We aimed to determine whether the use of ranitidine that was potentially contaminated with NDMA, rather than another histamine H2-receptor antagonist (H2 blocker), increased the risk of overall cancer. Methods: We performed a Korean population-based nationwide cohort study with propensity score matching of 95,656 adults (unmatched) and 55,584 adults (matched) who initiated treatment with H2 blockers between January 2005 and December 2014, and were followed until December 2015. Incident overall cancer was the primary outcome and all-cause mortality was the secondary outcome. Results: The unweighted cohort had 30,335 new users of ranitidine and 65,321 new users of other H2 blockers. The weighted cohort had 27,792 new users of ranitidine and 27,792 new users of other H2 blockers (median age, 55.0 years [interquartile range, 45-63]; 21,186 men [38.3%]). During follow-up (median of 6.8 years for ranitidine vs. 6.6 years for other H2 blockers), there were 2,840 new diagnoses of cancers and 1,758 deaths among users of other H2 blockers, and 2,113 new diagnoses of cancers and 1,933 deaths among users of ranitidine. The adjusted hazard ratio (aHR) for overall cancer in ranitidine users was 1.01 (95% confidence interval [CI], 0.95 to 1.06), with no evidence of a dose-response relationship (Ptrend=0.429) and no evidence of a duration-response relationship (Ptrend=0.549). The aHR for all-cause death in ranitidine users was 1.04 (95% CI, 0.97 to 1.11), with no significant association. The results from the unweighted cohort were similar to the primary results in the weighted cohort. Conclusions: Although our findings do not reassure keep using ranitidine, but those suggest that use of contaminated ranitidine was not markedly dangerous of cancer risk at short-term follow-up period. However, future studies are needed to investigate the long-term cancer risk and the risk of cancer in pediatric populations.

Nizatidine interacts with ct-DNA causing genotoxicity and cytotoxicity: an assessment by in vitro, in vivo, and in silico studies

H2 receptor antagonists are the medication given for treating stomach ulcers, but lately, reports have shown their role in healing several malignant ulcers. The present work entails the interaction of H2 blocker nizatidine with calf thymus (ct)-DNA for determining the binding mode and energetics of the interaction. Multi-spectroscopic, calorimetric, viscometric and bioinformatic analysis revealed that nizatidine interacted with ct-DNA via groove-binding mode and is characterised by exothermic reaction. Moreover, assessment of genotoxic potential of nizatidine in vitro was carried out in peripheral human lymphocytes by alkaline comet assay. DNA damage occurred at high concentrations of nizatidine. Genotoxicity of nizatidine was also evaluated in vivo by assessing cytogenetic biomarkers viz. micronuclei formation and chromosomal aberration test. Nizatidine was able to induce micronuclei formation and chromosomal damage at high dose. Additionally, cytotoxic activity of nizatidine was determined in cancer cell lines, namely HeLa and HCT-116 and compared with the normal human cell line HEK-293 employing MTT assay. It was observed that nizatidine was more toxic towards HeLa and HCT-116 than HEK-293. Cell morphology analysis by compound inverted microscopy further strengthens the finding obtained through MTT assay.

Sleep disorders and their correction in patients with chronic back pain

Back pain and insomnia (insomnia) significantly impair the quality of life of patients. Pain contributes to the development of sleep disorders and vice versa, poor quality sleep increases pain. Sleep disorders are widespread in the population, and in chronic pain syndrome, almost 70% of patients suffer from insomnia. The National Sleep Association singles out pain as one of the leading causes of sleep disorders. The article discusses a typical clinical case of the combination and interaction of chronic pain syndrome and insomnia. A patient with acute back pain developed a sleep disorder for which therapy was not carried out. The prescribed standard therapy for back pain, which included a non-steroidal anti-inflammatory drug, muscle relaxant, made it possible to relieve pain in a short time. However, the patient’s insomnia not only persisted, but also progressed, which led to the appearance of symptoms of asthenia in the form of fatigue, irritability, decreased performance, and ultimately significantly reduced the quality of life. In order to normalize sleep, the patient was prescribed a histamine H1 receptor blocker from the ethanolamine group, namely the drug Doxylamine. Follow-up observation for 1 year showed no exacerbation of back pain and sleep disturbances. In the treatment of patients with chronic back pain, it is necessary to pay attention to the presence of sleep disturbances and provide appropriate therapy. Today, three groups of hypnotics are used in clinical practice: melatonin receptor agonists (insufficient effectiveness in acute sleep disorders), benzodiazepines (addictive and addictive), and antihistamines. The modern drug Doxylamin belongs to the group of antihistamine hypnotics, has a good efficacy and safety profile and is included in the domestic recommendations for the treatment of insomnia.

Research Into the Effect of Proton Pump Inhibitors on Lungs and Leukocytes.

Proton pump inhibitors (PPI) are the most commonly used medication in the world. They are prescribed as an effective treatment choice for gastrointestinal system diseases linked to hyperacidity, especially. Additionally, non-indication and unnecessary use are very common. Many publications in recent times have reported significant side effects. However, there are insufficient studies about the mechanism for these side effects. Twenty-four Wistar albino rats were used in this study. Rats were divided into 3 groups of control, group-administered H2 receptor blockers and a group-administered PPI. Medications were administered for 30 days intraperitoneal. After 30 days, rats were euthanized and lung tissue was obtained. Lung was stained for immunohistochemical catalase, superoxide dismutase, Glutathione peroxidase, myeloperoxidase, and toluidine blue and investigated with a light microscope. Transmission electron microscopy (TEM) was used to investigate lung tissues and neutrophil leukocytes. Additionally, lung tissue had biochemical hydrogen peroxide (H2O2) levels researched. H2O2 amounts, produced by lysosomes with important duties for neutrophil functions in lung tissues, were found to be statistically significantly reduced in the group-administered PPI. Results from investigations of specimens obtained with immunohistochemical staining observed increases in antioxidant amounts in the PPI group. Investigation with TEM identified more inflammation findings in the lung tissue from the group-administered PPI compared to the control group and the group-administered H2 receptors. In conclusion, we identified long-term PPI use disrupts neutrophil leukocyte functions in the lung. All clinicians should be much more careful about PPI use.

Connections between Immune-Derived Mediators and Sensory Nerves for Itch Sensation.

Although histamine is a well-known itch mediator, histamine H1-receptor blockers often lack efficacy in chronic itch. Recent molecular and cellular based studies have shown that non-histaminergic mediators, such as proteases, neuropeptides and cytokines, along with their cognate receptors, are involved in evocation and modulation of itch sensation. Many of these molecules are produced and secreted by immune cells, which act on sensory nerve fibers distributed in the skin to cause itching and sensitization. This understanding of the connections between immune cell-derived mediators and sensory nerve fibers has led to the development of new treatments for itch. This review summarizes current knowledge of immune cell-derived itch mediators and neuronal response mechanisms, and discusses therapeutic agents that target these systems.

First-in-Human Dose-Finding Study of AAVhu37 Vector-Based Gene Therapy: BAY 2599023 Has Stable and Sustained Expression of FVIII over 2 Years

▪BackgroundGene therapy for hemophilia A has the potential to reduce the treatment burden for patients and their care providers by eliminating the need for regular factor VIII (FVIII) prophylaxis through long-term expression of endogenous FVIII at levels sufficient to provide bleed protection. Ongoing phase 3 gene therapy trials for hemophilia A show promise but can result in unpredictable FVIII expression of uncertain durability. Gene therapy must evolve to meet patient expectations of a durable, efficacious and safe treatment.BAY 2599023 (AAVhu37.hFVIIIco) is the first, clinical stage adeno-associated virus (AAV) gene therapy vector, based on the AAVhu37 serotype. BAY 2599023 is a non-replicating AAV vector and contains a single-stranded DNA genome encoding a B-domain-deleted FVIII, under the control of a liver-specific promoter/enhancer combination, optimized for transgenic expression. The AAVhu37 capsid is a member of the hepatotropic clade E family and was selected based on preclinical studies demonstrating efficient, liver-directed FVIII gene transfer, favorable biodistribution and durable FVIII expression. Here, we report safety and FVIII activity levels achieved to date in this first-in-human, dose-finding study of BAY 2599023.MethodsThe ongoing BAY 2599023 phase 1/2, open-label, dose-finding study (NCT03588299) included male patients aged ≥18 years with severe hemophilia A, no history of FVIII inhibitors, no detectable neutralizing immunity against AAVhu37 (neutralizing antibody titer ≤5), and ≥150 exposure days to FVIII products. Patients received a single intravenous infusion of BAY 2599023 and were enrolled sequentially into three dose cohorts (0.5 × 10 13 GC/kg, 1.0 × 10 13 GC/kg and 2.0 × 10 13 GC/kg), each comprising at least two patients. Patients to be enrolled in a fourth cohort will receive a single infusion of 4 × 10 13 GC/kg (Figure 1). Primary endpoints were adverse events (AEs), serious AEs (SAEs) and AEs/SAEs of special interest (S/AESIs). The secondary endpoint was FVIII activity over time. Informed patient consent and ethics committee approval were obtained.ResultsThree cohorts of ≥2 patients each (N = 9) were enrolled sequentially (Figure 1). At the data cutoff (May 2021), FVIII activity data were available for the first eight patients.BAY 2599023 delivered sustained FVIII expression levels for up to >23 months, with evidence of bleed protection. Patients in Cohorts 2 and 3 have all been off prophylaxis with FVIII products since approximately 6-12 weeks after gene transfer. To date, it has been observed that no spontaneous bleeds requiring treatment have been reported once FVIII levels >11 IU/dL were achieved. Of the 9 patients treated, 5 patients developed an AESI: mild/moderate alanine aminotransferase (ALT) elevations observed in Cohort 2 (n =1) and Cohort 3 (n = 3) were managed with corticosteroid treatment; another ALT elevation was reported as study-drug-related SAE in Cohort 3 (n = 1) but returned to normal a few weeks after interruption of the H2 blocker famotidine. The latest follow-up data for up to 28 months will be presented.ConclusionsBAY 2599023 was designed to enhance efficacy and durability of FVIII expression with a favorable safety profile. Sustained FVIII levels allowed suspension of FVIII prophylaxis in the majority of patients, with asymptomatic ALT elevations that respondedto corticosteroids, making BAY 2599023 a key candidate in the evolution of gene therapy in hemophilia A. [Display omitted] DisclosuresPipe: Genventiv: Consultancy; Regeneron/ Intellia: Consultancy; uniQure: Consultancy, Other; Spark Therapeutics: Consultancy; Takeda: Consultancy; Sanofi: Consultancy, Other; Sangamo Therapeutics: Consultancy; Roche/Genentech: Consultancy, Other; Pfizer: Consultancy; Novo Nordisk: Consultancy; Freeline: Consultancy, Other: Clinical trial investigator; HEMA Biologics: Consultancy; CSL Behring: Consultancy; Catalyst Biosciences: Consultancy; Biomarin: Consultancy, Other: Clinical trial investigator; Bayer: Consultancy; ASC Therapeutics: Consultancy; Apcintex: Consultancy; Grifols: Consultancy; Octapharma: Consultancy; Shire: Consultancy. Sheehan: BioMarin: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Bayer: Consultancy, Research Funding. Coppens: Portola/Alexion: Research Funding; CSL Behring: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Roche: Research Funding; Daiichi Sankyo: Research Funding; Sanquin Blood Supply: Research Funding; uniQure: Research Funding; Medcon International: Consultancy; MEDtalks: Consultancy; Novo Nordisk: Consultancy; Pfizer: Consultancy; Sobi: Consultancy. Eichler: Takeda: Consultancy, Honoraria; BioMarin: Consultancy, Research Funding; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Pfizer: Research Funding; Novo Nordisk: Consultancy, Research Funding; Biotest: Consultancy, Honoraria; Bayer: Consultancy, Research Funding. Linardi: Bayer: Current Employment. Wiegmann: Bayer: Current Employment. Hay: Pfizer: Consultancy, Research Funding; Inspiration: Consultancy, Honoraria; BioMarin: Consultancy, Honoraria; Roche: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Spark Therapeutics: Consultancy, Research Funding. Lissitchkov: Bayer: Other: Principal Investigator of Clinical Trials; Catalist: Other: Principal Investigator of Clinical Trials; Grifols: Other: Principal Investigator of Clinical Trials.

Risk and protective factors of acute kidney injury in decompensated cirrhotic patients with ascites on tolvaptan.

Background and AimAcute kidney injury (AKI) is a life‐threatening complication of liver cirrhosis. Here, we evaluated the risk factors and characteristics of AKI in cirrhosis.Patients/MethodsThis was a single‐center retrospective study. A total of 199 Japanese patients with decompensated liver cirrhosis (104 men, median age 61 years) were enrolled and received tolvaptan orally. Survival rates and new onset of AKI were monitored, and risk factors were evaluated.ResultsForty‐six patients (23.1%) suffered an AKI complication and exhibited significantly poorer survival (P < 0.01). The rates of hepatic encephalopathy (P < 0.01) and chronic kidney disease (CKD; P = 0.02) were significantly increased in patients with AKI. The rate of proton pump inhibitor (PPI)/H2 blocker treatment (P = 0.04) was significantly lower, whereas that of ascites drainage was significantly higher in the AKI cases (P < 0.01). The AKI risk was significantly increased in patients with hepatic encephalopathy (HR 4.18, 95% CI 1.618–10.771). In contrast, the incidence of AKI was significantly lower in patients with a higher serum albumin level (HR 0.36, 95% CI 0.142–0.914, P = 0.03). Treatment with PPI/H2 blockers (HR 0.30, 95% CI 0.126–0.711, P < 0.01) or kanamycin/rifaximin (HR 0.26, 95% CI 0.075–0.929, P = 0.04) was significantly associated with a reduced risk of AKI development.ConclusionsAKI incidence was increased in patients with decreased liver function and was associated with poor survival. PPI/H2 blocker or kanamycin/rifaximin treatment may reduce the risk of AKI.

101 National Trends in Emergency Department Ondansetron Use and Clinical Outcomes Among Children with Acute Gastroenteritis

Abstract Primary Subject area Emergency Medicine - Paediatric Background Acute gastroenteritis (AGE) is among the most common illnesses for which children are evaluated in the Emergency Department (ED). Among children with AGE, ondansetron has been shown to reduce vomiting, intravenous (IV) fluid administration and hospitalizations when administered in the ED. Objectives To determine whether increasing ondansetron administration is associated with a concomitant decline in IV rehydration and hospitalization among children presenting with AGE in a broad, nationally representative ED sample. Design/Methods This was a cross-sectional analysis of the US Centers for Disease Control and Prevention (CDC) National Hospital Ambulatory Medical Care Survey (NHAMCS) database from 2006 to 2015. Children &amp;lt; 18 years old with a discharge diagnosis of AGE were included for analysis. Survey weighting procedures were applied to generate population-level estimates and to perform multivariable logistic regression to identify factors associated with ondansetron administration. Results There were an estimated 15.1 million (95% CI 13.5-16.7) visits for AGE during the 10-year study period. AGE visits increased as a proportion of all pediatric ED visits over time (4.6% in 2006, 5.7% in 2015; p-trend=0.013). The mean patient age was 4.7 (95% CI 4.5-5.0) years, and most visits were to non-teaching (86.6%, 95% CI 83.3-89.3%) and non-pediatric (83.4%, 95% CI 78.2-87.5%) hospitals. The proportion of patients receiving ondansetron increased over time (11.8% in 2006, 62.5% in 2015; p-trend &amp;lt; 0 .001), both in the ED (10.6% in 2006, 55.5% in 2015; p-trend &amp;lt; 0 .001) and as outpatient prescriptions (3.3% in 2006, 45.3% in 2015; p-trend &amp;lt; 0 .001). Over the same period, there was no change in hospitalizations (2.9% overall, 95% CI 2.2-3.7%; p-trend=0.144). IV hydration for AGE decreased (31.8% in 2006, 24.9% in 2015; p-trend &amp;lt; 0 .048), as did IV fluid administration across all other pediatric ED visits (10.3% in 2006, 7.8% in 2015; p-trend &amp;lt; 0 .023). After adjustment for patient- and hospital-level factors, the odds ratio for IV rehydration among children with AGE was 0.97 (95% CI 0.92-1.01). Multivariable analysis found younger age (aOR 0.94, 95% CI 1.04-1.09), Medicaid/Medicare insurance (aOR 0.74; 95% CI 0.57-0.97), and presentation to a teaching hospital (aOR 0.74; 95% CI 0.54-0.99) were inversely associated with ondansetron administration. Other antiemetics most commonly used were promethazine (7.4%, 95% CI 5.9-9.2%), metoclopramide (1.8%, 95% CI 1.3-2.5%) and trimethobenzamide (1.5%, 95% CI 1.1-2.1%). Antimotility agents, H2-receptor blockers, and probiotics were infrequently used. Conclusion Both ED and outpatient prescribing of ondansetron for children with AGE increased; however, no concomitant decline was observed in hospitalizations or IV rehydration. Guidelines and quality improvement efforts are needed to target ondansetron administration to children most likely to benefit to minimize adverse events and costs associated with overuse.

Pediatric Mastocytosis: An Update.

Mastocytosis is a rare clonal disorder characterized by excessive proliferation and accumulation of mast cells (MC) in various organs and tissues. Cutaneous mastocytosis (CM), the most common form in children, is defined when MC infiltration is limited to the skin. In adults, the most common form is systemic mastocytosis (SM), characterized by MC proliferation and accumulation in organs, such as bone marrow, lymph nodes, liver, and spleen.1 Genetic aberrations, mainly the KIT D816V mutation, play a crucial role in the pathogenesis of mastocytosis, enhancing MC survival and subsequent accumulation in organs and tissues.2,3 CM includes three forms: solitary mastocytoma, maculopapular cutaneous mastocytosis (MPCM), and diffuse cutaneous mastocytosis (DCM). In most children with CM, skin lesions regress spontaneously around puberty; unfortunately, it is not always a self-limiting disease.4 Even if SM occurs occasionally, all children with mastocytosis require planned follow-up over time. Children with mastocytosis often suffer from MC mediator-related symptoms, the most common of which is itching, often triggered by rubbing the lesions. Management of pediatric mastocytosis is mainly based on strict avoidance of triggers. Treatment with H1 and H2 histamine receptor blockers on demand and the availability of epinephrine auto-injectors for the patients to use in case of severe anaphylactic reactions are recommended.

AYURVEDIC MANAGEMENT OF AMLAPITTA (GASTRITIS) - A CASE REPORT

Amlapitta is the most typical illness in the present era. In a rapidly growing civilization, Amlapitta is the outer- most common disorder within the current society, because of indulgence in incompatible food habits and activi- ties. Materialistic lifestyle provokes people to run behind a busy, tremendous stressful life which is the least con- cern towards proper food habits. "Hurry", “Worry” &amp; “Curry” are the main causes of Amlapitta disease. The us- age of synthetic drugs like H2 receptor blockers &amp; proton pump inhibitors has decreased due to their side effects. The signs and symptoms of Amlapitta are very comparable to Gastritis or Hyperacidity. The ruling features of Amlapitta are Avipaka (indigestion), Urodaha (Burning in the chest), Utklesha (Nausea) Aruchi (Anorexia) and Tikta-Amlodgara (sour and bitter belching) have been described in Ayurvedic classical texts. A 42-year-old male patient came in OPD with the following complaints Tikta-Amlodgara, Urodaha, Utklesha, Aruchi, Praseka. Dur- ing Examination, the vitals are normal. The patient was treated with Sutshekar rasa 1 tab. BD, Avipattikar chura- na 3gm BD, Drakshavaleha 5gm BD on the basis. The patient was advised to follow up every 15th day. Along with medication, the patient was also advised to follow diet and lifestyle restrictions. Keywords: Agni, Amlapitta, Annavahasrotas, Hyperacidity.

A CONCEPTUAL STUDY ON THE EFFECT OF NARIKELA KHANDA IN AMLAPITTA

Nowadays due to unawareness about Prakriti (psychosomatic constitution) people are practising inappropriate diet and lifestyle which leads to disturbances in the digestive system. The core principles in Ayurveda give prime im- portance to Agni, Prakriti, Ahara (food) and Vihara (lifestyle) in maintaining health. In the present era, people are scheduled to one or the other works due to which they are following unwholesome food and habits which may lead to the manifestation of many diseases. One of the common disorders which troubles a person a lot is Amlapitta. It is composed of the word Amla and Pitta. Amlapitta is a very common disease caused by Vidagdha Pitta with features like Amlaudgara, Tiktaudgara, Hrud Kantha Daha etc. It is the GI disorder described in Ayurvedic texts that closely resembles Gastritis in modern science. In the chronic stage, it may lead to ulcerative colitis. In modern medical science, they give some anta-acids, H2 blockers, Proton pump inhibitors, some steroids which have high prevalence costs and side effects. Today there is a need for a potent herbal formulation that can cure hyperacidity and ulcers. The present study is being undertaken to approach the disease Amlapitta through the formulation of Narikela Khanda. Keywords: Ayurveda, Amlapitta, Narikela Khanda.