Protocol implementation during the COVID-19 pandemic: experiences from a randomized trial of stress ulcer prophylaxis.

BACKGROUND: During the COVID-19 pandemic, many intensive care units (ICUs) halted research to focus on COVID-19-specific studies. OBJECTIVE: To describe the conduct of an international randomized trial of stress ulcer prophylaxis (Re-Evaluating the Inhibition of Stress Erosions in the ICU [REVISE]) during the pandemic, addressing enrolment patterns, center engagement, informed consent processes, data collection, a COVID-specific substudy, patient transfers, and data monitoring. METHODS: REVISE is a randomized trial among mechanically ventilated patients, comparing pantoprazole 40 mg IV to placebo on the primary efficacy outcome of clinically important upper gastrointestinal bleeding and the primary safety outcome of 90-day mortality. We documented protocol implementation status from March 11th 2020-August 30th 2022. RESULTS: The Steering Committee did not change the scientific protocol. From the first enrolment on July 9th 2019 to March 10th 2020 (8 months preceding the pandemic), 267 patients were enrolled in 18 centers. From March 11th 2020-August 30th 2022 (30 months thereafter), 41 new centers joined; 59 were participating by August 30th 2022 which enrolled 2961 patients. During a total of 1235 enrolment-months in the pandemic phase, enrolment paused for 106 (8.6%) months in aggregate (median 3 months, interquartile range 2;6). Protocol implementation involved a shift from the a priori consent model pre-pandemic (188, 58.8%) to the consent to continue model (1615, 54.1%, p < 0.01). In one new center, an opt-out model was approved. The informed consent rate increased slightly (80.7% to 85.0%, p = 0.05). Telephone consent encounters increased (16.6% to 68.2%, p < 0.001). Surge capacity necessitated intra-institutional transfers; receiving centers continued protocol implementation whenever possible. We developed a nested COVID-19 substudy. The Methods Centers continued central statistical monitoring of trial metrics. Site monitoring was initially remote, then in-person when restrictions lifted. CONCLUSION: Protocol implementation adaptations during the pandemic included a shift in the consent model, a sustained high consent rate, and launch of a COVID-19 substudy. Recruitment increased as new centers joined, patient transfers were optimized, and monitoring methods were adapted.

Efficacy and Safety of Vonoprazan-Based Quadruple Therapy for the Eradication of Helicobacter pylori in Patients with Peptic Ulcers: A Pooled Analysis of Two Randomized, Double-Blind, Double-Dummy, Phase 3 Trials.

Helicobacter pylori eradication is crucial in the treatment of peptic ulcers caused by H. pylori infection, a disease highly prevalent in Asia. We present a pooled analysis of two randomized, double-blind, double-dummy, phase 3 studies evaluating the efficacy and safety of vonoprazan-based bismuth-containing quadruple therapy for H. pylori eradication. Patients aged ≥18 years with endoscopically confirmed duodenal or gastric ulcers were randomized 1 : 1 to receive vonoprazan 20 mg or lansoprazole 30 mg once daily for up to 6 (duodenal ulcers) or 8 weeks (gastric ulcers). H. pylori-positive patients received vonoprazan- or lansoprazole-based bismuth-containing quadruple therapy for the first 2 weeks. H. pylori eradication was determined using the carbon-13 urea breath test at a follow-up visit 4 weeks post-treatment. The H. pylori eradication rate was 90.6% with vonoprazan vs. 85.2% with lansoprazole (difference: 5.4%; 95% confidence interval (CI): -0.1, 10.8). H. pylori eradication rates were 7.1% (95% CI: 1.4, 12.8) and 12.6% (95% CI: 3.9, 22.0) higher in patients aged <65 years and current smokers, respectively, with vonoprazan vs. lansoprazole. In the Chinese subpopulation, the H. pylori eradication rate was 92.0% with vonoprazan vs. 86.0% with lansoprazole (difference: 6.1%; 95% CI: 0.5, 11.7). Treatment-emergent adverse events occurred in 72.7 vs. 62.6% of H. pylori-positive patients at baseline in the vonoprazan vs. lansoprazole arm. H. pylori eradication with vonoprazan-based quadruple therapy was noninferior to lansoprazole-based quadruple therapy and exceeded 90%, a clinically relevant threshold for determining the efficacy of H. pylori eradication regimens (ClinicalTrials.gov identifier: NCT03050359; NCT03050307).

Quality-by-design driven approach in the formulation of an anti-ulcer and gastro-protective oral suspension.

OBJECTIVE: This work aims to present a Quality-by-Design (QbD) step-by-step methodology to formulate anti-ulcer and gastro-protective oral suspensions. METHODS: Sucralfate was used as a drug model. The Quality Target Product Profile was established early during preformulation. Viscosity, resuspendability, pH, and density were assessed through the screening of several suspension platforms based on different prototype compositions. A compatibility study between the active pharmaceutical ingredient and the excipients was performed by thermal analysis and infrared spectroscopy. An Ishikawa fishbone diagram and Failure Mode and Effect Analysis were employed to identify the Critical Material Attributes (CMAs), Critical Process Parameters (CPPs), and Critical Quality Attributes (CQAs). CMAs' and CPPs' impact on identified CQAs was further assessed through a 22 full factorial experimental design at normal conditions after manufacture and one month at super-accelerated stress conditions. Results: The lead prototype exhibited no physicochemical incompatibilities. The risk assessment tools revealed that the concentration of the wetting agent and the total concentration of thickening agents represented critical factors for the quality profile of the preparation in terms of viscosity. The optimized formulation comprising 1.125 w/v% total concentration of Natrosol 250 HX and Avicel RC 591 exhibited an enhanced performance according to the established profile. CONCLUSIONS: The analytical and physicochemical tests showed the robustness and compliance of the final preparation with the quality profile. The proposed step-by-step methodology based on QbD, Design of Experiments, and Quality Risk Management presented in our research holds practical implications for local industries and formulation scientists involved in the development of oral suspensions.

Ferulic acid nanoemulsion as a promising anti-ulcer tool: in vitro and in vivo assessment.

OBJECTIVE: Ferulic acid (FA) is a promising nutraceutical molecule which exhibits antioxidant and anti-inflammatory properties, but it suffers from poor solubility and bioavailability. In the presented study, FA nanoemulsions were prepared to potentiate the therapeutic efficacy of FA in prevention of gastric ulcer. METHODS: FA nanoemulsions were prepared, pharmaceutically characterized, and the selected nanoemusion was tested for its ulcer-ameliorative properties in rats after induction of gastric ulcer using ethanol, by examination of stomach tissues, assessment of serum IL-1ß and TNF-α, assessment of nitric oxide, prostaglandin E2, glutathione, catalase and thiobarbituric acid reactive substance in stomach homogenates, as well as histological and immunohistochemical evaluation. RESULTS: Results revealed that the selected FA nanoemulsion showed a particle size of 90.43 nm, sustained release of FA for 8 h, and better in vitro anti-inflammatory properties than FA. Moreover, FA nanoemulsion exhibited significantly better anti-inflammatory and antioxidant properties in vivo, and the gastric tissue treated with FA nanoemulsion was comparable to the normal control upon histological and immunohistochemical evaluation. CONCLUSION: Findings suggest that the prepared ferulic acid nanoemulsion is an ideal anti-ulcer system, which is worthy of further investigations.

Combined effect of pantoprazole and mesenchymal stem cells on experimentally induced gastric ulcer: implication of oxidative stress, inflammation and apoptosis pathways.

Gastric ulcer (GU) is one of the most common diseases of the upper gastrointestinal tract that affects millions of people worldwide. This study aimed to investigate the possible alleviating effect of a combined treatment of pantoprazole (PANTO) and adipose tissue-derived mesenchymal stem cells (ADSCs) in comparison with each treatment alone on the healing process of the experimentally induced GU in rats, and to uncover the involved pathways. Rats were divided into five groups: (1) Control, (2) GU, (3) PANTO, (4) ADSCs and (5) ADSCs + PANTO. Markers of oxidative stress, inflammation and apoptosis were assessed. The current data indicated that PANTO-, ADSCs- and ADSCs + PANTO-treated groups showed significant drop (p < 0.05) in serum advanced oxidation protein products (AOPPs) and advanced glycation end products (AGEPs) along with significant elevation (p < 0.05) in serum TAC versus the untreated GU group. Moreover, the treated groups (PANTO, ADSCs and ADSCs + PANTO) displayed significant down-regulation (p < 0.05) in gastric nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor alpha (TNF-α), cyclooxygenase-2 (COX-2), intercellular adhesion molecule-1 (ICAM-1), matrix metallopeptidase 9 (MMP-9) and caspase-3 along with significant up-regulation (p < 0.05) in vascular endothelial growth factor (VEGF) and peroxisome proliferator-activated receptor gamma (PPARγ) genes expression compared to the untreated GU group. Immunohistochemical examination of gastric tissue for transforming growth factor ß1 (TGF-ß1), epidermal growth factor (EGF) and proliferating cell nuclear antigen (PCNA) showed moderate to mild and weak immune reactions, respectively in the PANTO-, ADSCs- and ADSCs + PANTO-treated rat. Histopathological investigation of gastric tissue revealed moderate to slight histopathological alterations and almost normal histological features of the epithelial cells, gastric mucosal layer, muscularis mucosa and submucosa in PANTO-, ADSCs- and ADSCs + PANTO-treated rats, respectively. Conclusively, the co-treatment with ADSCs and PANTO evidenced sententious physiological protection against GU by suppressing oxidative stress, inhibiting inflammation and reducing apoptosis with consequent acceleration of gastric tissue healing process.

Gastroprotective effects of water extract of domesticated Amauroderma rugosum against several gastric ulcer models in rats.

CONTEXT: Amauroderma rugosum (Blume & T. Nees) Torrend (Ganodermataceae) is an edible mushroom with medicinal properties. However, the effects of A. rugosum on gastric ulcer remain unclear. OBJECTIVE: To investigate the gastroprotective efficacy of water extract of A. rugosum (WEA) on gastric ulcer. MATERIALS AND METHODS: Sprague-Dawley rats were randomly grouped as control, model, lansoprazole and 200, 100 and 50 mg/kg of WEA. After pre-treatment for seven days, ethanol- and indomethacin-induced gastric ulcer models were established. The gastric ulcer and histopathology were investigated. Enzyme-linked immunosorbent assay (ELISA), quantitative polymerase chain reaction (Q-PCR) and Western blot assays were conducted to explore the potential anti-inflammatory effect and mechanism of WEA. Additionally, the pyloric ligation model was used to explore the influence of WEA on gastric acid and mucus. RESULTS: Pre-treatment with WEA (200, 100 and 50 mg/kg) effectively reduced ulcerous area in both ethanol-induced (71%, 88% and 71%) and indomethacin-induced (77%, 65% and 86%) gastric ulcer model. The gastric levels of tumour necrosis factor-alpha (TNF-α) (34% and 50 mg/kg), interleukin-6 (IL-6) (32% and 100 mg/kg) and interleukin-1ß (IL-1ß) (36%, 45% and 41%) were reduced significantly (p < 0.05) by WEA. Serum nitric oxide was decreased significantly (p < 0.05) at 200 and 50 mg/kg and PGE2 concentration was increased remarkably (p < 0.05) at 100 mg/kg. Gene expression of inflammasome Nlrp3, and the nuclear translocation of nuclear factor-κB (NF-κB) P65 were significantly decreased by WEA pre-treatment. However, the pH of gastric acid and secretion of mucus did not show any significant change. CONCLUSIONS: The gastroprotective effect of WEA on gastric damage is attributed to anti-inflammation through the inhibition on NF-κB P65 nuclear migration and Nlrp3 gene expression.

Polaprezinc for prevention of oral mucositis in patients receiving chemotherapy followed by hematopoietic stem cell transplantation: A multi-institutional randomized controlled trial.

Oral mucositis is a common and distressing complication in patients receiving high-dose chemotherapy followed by hematopoietic stem cell transplantation (HSCT). We reported previously in a single-center retrospective analysis that zinc-L-carnosine (polaprezinc [PZ]) reduced the incidence of oral mucositis associated with HSCT. To verify the accuracy of the prophylactic effect of PZ against oral mucositis, we carried out a multi-institutional prospective randomized controlled study. Patients were randomly allocated to either the prevention group, in which PZ lozenge treatment was started before chemotherapy, or the control group, in which administration of PZ lozenges was initiated immediately after the onset of Grade 2 oral mucositis. Oral mucositis was evaluated daily from the start of chemotherapy to 35 days after transplantation. A total of 91 patients were enrolled, and 88 patients (47 in the control group and 41 in the prevention group) were eligible for data analysis. The incidence of Grade ≥2 but not Grade ≥3 oral mucositis was significantly reduced in the prevention group compared to the control group (44.7% in control group vs 22.0% in the prevention group, P = .025). There were no significant differences in the incidence rates of other adverse events or the rate of engraftment (95.6% vs 97.2%, P = .693) between the two groups. These findings suggest that PZ lozenge is effective for prophylaxis against Grade ≥2 oral mucositis associated with chemotherapy in patients undergoing HSCT without any influence on the HSCT outcome.

The impact of a 1-hour time interval between pazopanib and subsequent intake of gastric acid suppressants on pazopanib exposure.

Co-treatment with gastric acid suppressants (GAS) in patients taking anticancer drugs that exhibit pH-dependant absorption may lead to decreased drug exposure and may hamper drug efficacy. In our study, we investigated whether a 1-hour time interval between subsequent intake of pazopanib and GAS could mitigate this negative effect on drug exposure. We performed an observational study in which we collected the first steady-state pazopanib trough concentration (Cmin ) levels from patients treated with pazopanib 800 mg once daily (OD) taken fasted or pazopanib 600 mg OD taken with food. All patients were advised to take GAS 1 hour after pazopanib. Patients were grouped based on the use of GAS and the geometric (GM) Cmin levels were compared between groups for each dose regimen. Additionally, the percentage of patients with exposure below the target threshold of 20.5 mg/L and the effect of the type of PPI was explored. The GM Cmin levels were lower in GAS users vs non-GAS users for both the 800 and 600 mg cohorts (23.7 mg/L [95% confidence interval [CI]: 21.1-26.7] vs 28.2 mg/L [95% CI: 25.9-30.5], P = .015 and 26.0 mg/L [95% CI: 22.4-30.3] vs 33.5 mg/L [95% CI: 30.3-37.1], P = .006). Subtherapeutic exposure was more prevalent in GAS users vs non-GAS users (33.3% vs 19.5% and 29.6% vs 14%). Sub-analysis showed lower GM pazopanib Cmin in patients who received omeprazole, while minimal difference was observed in those receiving pantoprazole compared to non-users. Our research showed that a 1-hour time interval between intake of pazopanib and GAS did not mitigate the negative effect of GAS on pazopanib exposure and may hamper pazopanib efficacy.

Acid Suppression Does Not Improve Laryngomalacia Outcomes but Treatment for Oropharyngeal Dysphagia Might Be Protective.

OBJECTIVE: To determine whether the use of acid suppression and thickened feeds impact laryngomalacia outcomes in infants, including supraglottoplasty risk, time to supraglottoplasty, and hospitalization risk. STUDY DESIGN: We performed a retrospective cohort study to compare risk and time with supraglottoplasty and frequency and duration of hospitalizations for infants diagnosed with laryngomalacia at Boston Children's Hospital between January 1 and December 31, 2017. The primary outcomes were supraglottoplasty requirement, time to supraglottoplasty, and hospitalization risk. Multivariate analyses were performed to determine predictors of supraglottoplasty and hospitalization risk after adjusting for laryngomalacia severity and comorbidities in addition to propensity score adjustment. Kaplan-Meier curves were created to determine the impact of acid suppression use on time to supraglottoplasty. RESULTS: In total, 236 subjects with mean age 62.6 ± 4 days were included in the analysis; 55% were treated with acid suppression. Subjects treated with acid suppression had a greater risk of supraglottoplasty (hazard ratio 3.36, 95% CI 1.36-8.29, P = .009), shorter time to supraglottoplasty (5.64 ± 0.92 vs 7.98 ± 1.92 months, P = .006), and increased respiratory hospitalization risk (relative risk 1.97, 95% CI 1.01-3.85, 0.047), even after adjustment for covariates. Subjects receiving thickening had fewer respiratory hospitalization nights and longer time to supraglottoplasty (9.3 ± 1.7 vs 4.56 ± 0.73 months, P = .004), even after adjustment. CONCLUSIONS: Acid suppression use does not reduce the frequency of supraglottoplasty and related hospitalizations compared with untreated subjects. However, patients treated with thickening have decreased hospitalization and longer time to supraglottoplasty, suggesting that thickening of feeds may be a preferred intervention over acid suppression.

Silk industry waste protein: isolation, purification and fabrication of electrospun silk protein nanofibers as a possible nanocarrier for floating drug delivery.

Amongst assorted regio-selective and targeted oral drug delivery strategies accepted for the gastro-retentive drug delivery system (GRDDS), the floating drug delivery system (FDDS) holds a major share as clinically accepted formulations. The major objective of the present investigation was to explore the silk industry waste protein, silk fibroin (SF) as a possible electrospun nanocarrier for the FDDS. In a nutshell, electrospinning (ES) is one of the flexible and astonishing strategies for the fabrication of porous electrospun nanofibers (NFs), which offers the potential to amend the floating profile, dissolution rate, solubility, and release patterns of the drug, etc as per compendial requirements. Looking at the prospects of floating SF-NFs preparation, we have isolated and lyophilized the SF from industrial waste cocoons and prepared drug-loaded SF single polymer nanofibers (SPN). Lafutidine (LF) being a good candidate for GRDDS selected as a model drug, which is an excellent proton pump inhibitor, mainly used in the treatment of gastric ulcers. Finally, the obtained LF loaded SF-NFs (LF-SF-NFs) were successfully analyzed for physicochemical characteristics, porosity, swelling index, antioxidant activity, mucoadhesion strength, floating properties, enzymatic degradation, and accelerated stability study, etc. Further, these LF-SF-NFs were evaluated for percent drug content, weight variation, in-vitro dissolution in 0.1 N hydrochloric acid (HCl, pH:1.2) and fasted state simulated gastric fluid (FSSGF), and accelerated stability study. It has shown significant floating time >18 h, about 99% ± 0.58% floating buoyancy with sustained release up to 24 h. LF-SF-NFs showed good compatibility, entrapment efficiency, antioxidant activity, mucoadhesion strength, enzymatic degradation, and long term stability. Soon, the essential floating and drug release profiles can claim single polymer (SF) based electrospun protein NFs as a possible novel oral nanocarrier for FDDS.

Sucralfate as an Adjunct to Analgesia to Improve Oral Intake in Children With Infectious Oral Ulcers: A Randomized, Double-Blind, Placebo-Controlled Trial.

STUDY HYPOTHESIS: We hypothesized that sucralfate along with oral analgesics (acetaminophen or ibuprofen) administered in the emergency department leads to a clinically significant improvement in oral intake in children with acute infectious oral ulcers. METHODS: This was a randomized, double-blind, placebo-controlled trial of sucralfate versus placebo conducted between 2017 and 2018 in an urban pediatric emergency department. Children aged 6 months to 5 years with acute, infectious oral ulcers and poor oral intake received either acetaminophen at 15 mg/kg or ibuprofen at 10 mg/kg and were then randomized to receive sucralfate at 20 mg/kg per dose up to 1 g or a placebo solution. The primary outcome was oral fluid intake within 60 minutes of medication administration. The secondary outcomes were repeat ED visits, length of stay in ED, intravenous hydration rate, admission rate, adverse event rate, and emergency physician's determination of the adequacy of oral intake. RESULTS: One hundred subjects with mild dehydration (clinical dehydration score of 1) and a median age of 1.38 years were enrolled and analyzed (49 in the sucralfate group and 51 in the placebo group). Oral intake 1 hour after drug administration was similar in both the groups: the median intake in the sucralfate group was 9.7 mL/kg and 10.7 mL/kg in the placebo group (difference -1 mL/kg; 95% confidence interval [CI] -2.0 to 4.8). According to the emergency physician's report, the secondary outcomes were significant only for adequate oral intake: 71% in the sucralfate group versus 88% in the placebo group (difference -16.8%; 95% CI -32.2 to -1.4). CONCLUSION: Sucralfate as an adjunct to oral analgesics was not superior to placebo in improving oral intake in children with acute oral infectious ulcers.

Mucoadhesive gastroretentive microparticulate system for programmed delivery of famotidine and clarithromycin.

AIM: The present research was aimed to develop thiolated polyacrylic acid (TPA) based microspheres (MSPs) containing famotidine (FX) and clarithromycin (CLX). METHODS: TPA was synthesised from polyacrylic acid and l-cysteine in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDAC). The prepared TPA was characterised using FT-IR (Fourier transform-infra red), 1H-NMR (proton nuclear magnetic resonance) spectroscopy, P-XRD (powder X ray diffraction) method, and zeta potential. The analytical tools have supported the formation of TPA. The thiolated microspheres were prepared by emulsion solvent evaporation method using 0.75% w/v polymer concentration and stirring at 400 rpm for 8 hr. RESULTS: The average particle size and zeta potential of optimised formulation was found to be 25.2 ± 1.87 µm and -26.68 mV, respectively. The entrapment efficiency of the optimised formulation was obtained 67.20% for FX and 70.20% for CLX. The developed microspheres were swelled only in 4 h from 0.5 to 0.9. The in vitro mucoadhesive study and in vitro drug release studies demonstrated that microspheres showed mucoadhesive property. In in vitro drug release studies, the release of FX and CLX were observed to be 58.68% and 60.48%, respectively from microspheres in 8 h. The thiolated microspheres showed higher adhesion time (7.0 ± 0.8 h) in comparison to the plain microspheres (2.6 ± 0.4 h). CONCLUSION: The prepared TPA based mucoadhesive microspheres can be utilised as carriers for the treatment of peptic ulcer caused by Helicobacter pylori which will offer enhanced residence time for the rational drug combination in the gastric region.

Evaluation of antioxidant and anti-ulcerogenic effects of Eremurus persicus (Jaub & Spach) Boiss leaf hydroalcoholic extract on ethanol-induced gastric ulcer in rats.

This study aimed to investigate the antioxidant and protective effect of E. persicus leaf hydroalcoholic extract (EPE) in preventing gastric ulcers induced by ethanol in rats. Wistar rats weighing 180-220 g were randomly divided into five groups. These groups included negative control (normal) group, positive control (ethanolic) group, comparative control (ranitidine recipient) group, group recipient the dose of 250 mg/kg plant extract, and group recipient the dose of 500 mg/kg plant extract. One hour after gavage of the drug and extract, the gastric ulcer was induced by feeding 1 ml of 96% ethanol to each animal except the rats of the negative control group. After one hour, the rats were killed, and their stomachs were separated. Then, the gastric Ulcer index (UI), pH, oxidative stress parameters, and histopathological changes in the stomach of all groups were measured. Pre-treatment of ethanol-induced rats with the EPE reduced (P < 0.05) the ulcer index and gastric juice pH, compared to ethanolic group rats. Furthermore, pre-treatment with EPE at a dose-dependent manner, alleviated the gastric oxidative stress injury in rats through increase the activity of CAT, tissue NO· and GSH levels. EPE also was able to decrease the levels of ROS, MDA, PCO and serum NO·. According to the results, it can be concluded that pre-treatment with EPE prevents the formation of gastric ulcers caused by ethanol, which can be attributed to the antioxidant activity of plant polyphenols compounds.

Chemical constituents and gastro-protective potential of Pachira glabra leaves against ethanol-induced gastric ulcer in experimental rat model.

Gastric ulcer is a very common illness that adversely affects a significant number of people all over the globe. Phytochemical investigation of P. glabra leaf alcohol extract (PGLE) resulted in the isolation and Characterization of a new nature compound, quercetin-3- O-α -L-rhamnosyl-(1'''-6'')-(4''- O -acetyl)-ß -D-galactoside (4), in addition to seven known compounds. They are ferulic acid (1), p- coumaric acid (2), quercetin 3-O-α-L-rhamnoside-3'-O-ß-D-glucoside (3), quercetin-3- O-α -L-rhamnosyl-(1'''-6'')-(4''- O -acetyl)- ß -Dgalactoside (4), quercetin-3- O-ß -D-galactoside (5), 7-hydroxy maltol-3-O-ß-D-glucoside (6), maltol-3- O-ß -D-glucoside (7), and methyl coumarate (8) that were first to be isolated from the genus Pachira. PGLE demonstrated in vitro anti-Helicobacter pylori activity. Moreover, the in vivo gastroprotective assessment of PGLE at different dosses, 100, 200, and 400 mg/kg against ethanol induced ulceration revealed a dose-dependent gastroprotection comparable to omeprazole. PGLE attenuated gastric lesions and histopathological changes triggered by ethanol. Interestingly, PGLE exhibited an anti-inflammatory effect through down-regulating the expression of nuclear factor-ĸB and pro-inflammatory enzyme cyclooxygenase-2 in the ulcer group. It also hindered apoptosis through decreasing Bax and increasing Bcl-2 expression hence decreasing Bax/Bcl2 ratio with a subsequent reduction in caspase 3 expression. Collectively, P. glabra is a rich reservoir of various phytochemicals reflecting a promising potential for alleviation of gastric ulcer through the mediation of inflammatory and apoptotic cascades.

Tablet of Spondias mombin L. Developed from Nebulized Extract Prevents Gastric Ulcers in Mice via Cytoprotective and Antisecretory Effects.

Spondias mombin L. (Anacardiaceae) has a worldwide distribution and is present in all regions of Brazil. Its leaves, flowers and bark are used as teas in folk medicine to treat diseases of the digestive system. This study aimed to evaluate the acute non-clinical toxicity, gastroprotective activity, and the related mechanisms of action of nebulized extract and tablets based on dried Spondias mombin (SmNE). SmNE screening showed the presence of flavonoids (0.65%), polyphenols (25.50%), where the major compound is gallic acid. In the acute oral toxicity assay, a dose of 2000 mg/kg of SmNE administered orally in Swiss mice did not induce any behavioral changes. SmNE (250 or 500 mg/kg p.o) significantly reduced the ulcerative lesion area when compared to the control group in ethanol and non-steroidal anti-inflammatory drug (NSAIDs) models. Results showed that treatment with SmNE (250 mg/kg) reduced acid secretion and gastric content, accompanied with an increase in pH. Previous administration of indomethacin and glibenclamide reversed the protection provided by SmNE, confirming the participation of prostaglandins (PGs) and ATP-sensitive potassium channels (KATP) in its gastroprotective effect. The SmNE tablets met the pharmacopeial quality requirements with gastroprotective activity and similar protection in comparison to the isolated extract administrated. In conclusion, SmNe has a gastroprotective activity related to cytoprotective mechanisms, such as the participation of endogenous prostaglandins and KATP channels, having an anti-secretory effect with systemic action. The formulation obtained presented gastroprotective effects similar to the administration of the extract, the tablets showed favorable compression characteristics by the direct route and met the pharmacopeial quality requirements.

Efficacy and safety of twice a day, bismuth-containing quadruple therapy using high-dose tetracycline and metronidazole for second-line Helicobacter pylori eradication.

BACKGROUND/AIMS: Conventional second-line, bismuth-containing quadruple therapy is administered four times a day. We aimed to evaluate the efficacy and safety of twice a day administration compared to the four times a day therapy. METHODS: Medical records of consecutive patients with positive 13 C-urea breath tests (UBTs) after first-line eradication were reviewed. From December 2018 to June 2019, 100 consecutive 13 C-UBT-positive patients received tetracycline 1 g, metronidazole 750 mg, bismuth subcitrate 300 mg, and pantoprazole 20 mg twice a day for one week. The same number of consecutive13 C-UBT-positive patients before December 2018 was included as controls. The control group received tetracycline 500 mg and bismuth subcitrate 300 mg four times a day, metronidazole 500 mg three times a day, and pantoprazole 20 mg twice a day for one week. Eradication was confirmed based on a 13 C-UBT performed in the 5th week after taking quadruple therapy. RESULTS: Ninety-eight patients from the twice a day group and 99 patients from the four times a day group were analyzed. The eradication rate did not differ between the twice a day group (92/98, 93.9%) and the four times a day group (92/99, 92.9%). Adverse drug effects were found in 36 patients from the twice a day group and 50 patients from the four times a day group (P = .051). Abdominal pain, discomfort, and distention were more common with four times a day intake (13.1%) than with twice a day intake (4.1%; P = .024). CONCLUSIONS: We determined for the first time that twice a day intake of bismuth-containing quadruple therapy using 2 g/d of tetracycline, 1.5 g/d of metronidazole, and 600 mg/d of bismuth subcitrate for one week is effective and safe as the conventional four times a day therapy. Twice a day intake decreased abdominal pain, discomfort, and distention.

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

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: There were substantial differences in the use of GARD medicines in Australia and Korea over 14 years. 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.

Pre-dialysis serum creatinine as an independent predictor of responsiveness to zinc supplementation among patients on hemodialysis.

BACKGROUND: To investigate whether pre-dialysis level of serum creatinine (SCre) could indicate the responsiveness to zinc supplementation of patients on maintenance hemodialysis (MHD). METHODS: We retrospectively reviewed the results of our previous randomized study of 91 patients who had been on MHD and received zinc supplementation with either zinc acetate hydrate (ZAH; zinc, 50 mg/day) or polaprezinc (PPZ; zinc, 34 mg/day). A late response to zinc supplementation was defined as a serum zinc level of < 80 µg/dL three months after the study began. Patients were divided into two groups: late response (serum zinc level < 80 µg/dL) and early response (serum zinc level ≥ 80 µg/dL). Factors independently associated with a late response to zinc supplementation were determined using inverse probability of treatment weighting (IPTW) multivariate logistic analysis. RESULTS: Of 91 patients, 86 continued to receive zinc supplementation after three months. The mean pre-dialysis SCre level was 10.0 mg/dL. The number of patients with a late response and response to zinc supplementation was 32 and 54, respectively. There was a significant negative correlation between the pre-dialysis SCre and the Δserum zinc change for 3 months. (r = - 0.284, P = 0.008). IPTW multivariate analysis showed that a pre-dialysis SCre level ≥ 10.0 mg/dL (odds ratio, 3.71; 95% confidence interval; 1.24-11.1, P = 0.022) was an independent factor associated with a late response to zinc supplementation. CONCLUSIONS: Pre-dialysis SCre level was independently associated with responsiveness to zinc supplementation after three months in patients on MHD.

Influence of co-initiation of antiulcer drugs on persistence and adherence to low-dose aspirin: A retrospective cohort study using a Japanese claims database
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OBJECTIVE: The purpose of this study was to examine whether co-initiation of antiulcer drugs (AUDs) and low-dose aspirin (LDA) therapy is beneficial for good adherence to LDA therapy. MATERIALS AND METHODS: A retrospective cohort study was conducted using the JMDC claims database. Patients for whom LDA therapy was newly initiated between January 2005 and April 2016 were selected from the JMDC database. The selected patients were divided into LDA and LDA+AUD groups and were followed up from the first prescription of LDA or LDA+AUD until the earliest of the following events: discontinuation or the end of the observation period. Unadjusted and multivariable Cox proportional hazards models controlling for all demographic and clinical characteristics were applied to examine whether the addition of an AUD to LDA improved adherence. A 1 : 1 propensity score matching analysis was conducted to balance confounders between the two groups. RESULTS: After the propensity score matching analysis, 4,089 patients were matched in each therapy group. The Kaplan-Meier curves for the rate of LDA continuation showed a sharp decline just after the initiation of LDA therapy. A significant difference was observed in the incidence of LDA therapy discontinuation between the LDA+AUD and LDA groups (HR: 0.87, 95% CI: 0.82 - 0.92), and the median duration of LDA therapy in the LDA+AUD and LDA groups were 18 and 11 months (log-rank test: p < 0.0001), respectively. CONCLUSION: The therapy persistence rate in the LDA+AUD group was significantly higher than that in the LDA group.

Comparing proton pump inhibitors with histamin-2 receptor blockers regarding the risk of osteoporotic fractures: a nested case-control study of more than 350,000 Korean patients with GERD and peptic ulcer disease.

BACKGROUND: Patients with peptic ulcer disease (PUD) and gastroesophageal reflux disease (GERD) are more likely to receive long-term therapy with proton pump inhibitors (PPIs). This study aimed to investigate the risk of osteoporotic fractures in PPI users compared to histamine-2 receptor antagonist (H2RA) users and the association between fractures and the duration and regular use of PPI. METHODS: A population-based, nationwide nested case-control study from January 2006 to December 2015 was performed using Korean National Health Insurance Service claims data. We included patients ≥50 years of age, without previous fractures, newly prescribed with PPI or H2RA, and diagnosed with PUD or GERD from 2006 to 2015. Patients with osteoporotic fracture (n = 59,240) were matched with the non-fracture control group (n = 296,200) at a 1:5 ratio based on sex, age, cohort entry date, follow-up duration, and bisphosphonate use. The osteoporotic fractures were defined using the diagnostic codes of claims data (M80, M81, M82, M484, M485, S220, S221, S320, S327, S422, S423, S525, S526, S72). RESULTS: The higher the cumulative use of PPIs, the higher the osteoporotic fracture risk (P for trend < 0.001). The risk of osteoporotic fracture in the patients whose cumulative use of PPI was more than 1 year was higher than that of others (OR: 1.42, 95% CI: 1.32-1.52). Patients who regularly used PPI in the recent 1 year had a higher risk of osteoporotic fracture than exclusive H2RA users (OR: 1.37, 95% CI: 1.26-1.50). CONCLUSIONS: The risk of osteoporotic fracture increased with the duration of PPI use, especially when PPI was used for ≥1 year and regularly in the recent 1 year.