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Molecular Biology Reports Jun 2024Vanillic acid (VA; 4-hydroxy-3-methoxybenzoic acid) is a flavouring agent found in various natural sources such as olives, fruits, and green tea. While VA exhibits...
BACKGROUND
Vanillic acid (VA; 4-hydroxy-3-methoxybenzoic acid) is a flavouring agent found in various natural sources such as olives, fruits, and green tea. While VA exhibits numerous pharmacological effects, its potential protective effects against gastric injury warrants further investigation. Therefore, the primary objective of this study is to elucidate investigate the gastroprotective properties of VA against ethanol-induced gastric injury.
METHODS AND RESULTS
Rats were orally administered either saline or VA at different doses (50, 100, and 200 mg/kg/day), with omeprazole (20 mg/kg) serving as a positive control, for fourteen consecutive days before ethanol administration. Blood and gastric tissue samples were collected one hour after ethanol administration for biochemical, molecular, and histological analyses. Pre-treatment with VA before ulcer induction alleviated both macroscopic and microscopic damage. It also increased antioxidant glutathione levels and decreased malondialdehyde and myeloperoxidase activity, along with reducing inflammatory markers such as tumour necrosis factor (TNF)-α, interleukin (IL)-6, and nuclear factor kappa B (NF-κB). Additionally, VA pre-treatment reversed the elevation of Bax mRNA expression and gastric caspase-3 levels induced by gastric damage. It also mitigated the reduction in Bcl-2 mRNA expression.
CONCLUSION
These findings suggest that VA exerts protective effects against ethanol-induced gastric injury in rats. It achieves this by augmenting gastric antioxidant capacity and mitigating oxidative, inflammatory, and apoptotic damage.
Topics: Animals; NF-kappa B; Ethanol; Rats; Apoptosis; Vanillic Acid; Signal Transduction; Male; Stomach Ulcer; Gastric Mucosa; Oxidative Stress; Antioxidants; Protective Agents; Rats, Wistar; Tumor Necrosis Factor-alpha; Glutathione
PubMed: 38874632
DOI: 10.1007/s11033-024-09672-6 -
Helicobacter 2024The optimal dosage of tetracycline remains unclear for Helicobacter pylori eradication. Frequent dosing requirements may decrease patient adherence and increase the... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy of Tetracycline Three Times Daily was Comparable to That of Four Times Daily for Helicobacter pylori Rescue Treatment: A Multicenter, Noninferiority, Randomized Controlled Trial.
BACKGROUND
The optimal dosage of tetracycline remains unclear for Helicobacter pylori eradication. Frequent dosing requirements may decrease patient adherence and increase the incidence of adverse events, potentially reducing treatment efficacy. This study aimed to compare the efficacy of different tetracycline dosages in rescue treatment for H. pylori infection.
METHODS
A total of 406 patients needing H. pylori rescue treatment were enrolled. Patients were randomized into two groups and received bismuth-containing quadruple therapies as follows: esomeprazole 40 mg twice daily, bismuth 220 mg twice daily, amoxicillin 1000 mg twice daily, and tetracycline 500 mg either three (TET-T group) or four (TET-F group) times daily. At least 6 weeks after treatment completion, a C-urea breath test was performed to evaluate H. pylori eradication.
RESULTS
The intention-to-treat (ITT) eradication rates were 91.13% (185/203) and 90.15% (183/203) (p = 0.733), the modified ITT (MITT) eradication rates were 94.87% (185/195) and 95.31% (183/192) (p = 0.841), and the per-protocol (PP) eradication rates were 94.79% (182/192) and 95.21% (179/188) (p = 0.851) in the TET-T group and TET-F group, respectively. The eradication rates for the TET-T group were not inferior to those of the TET-F group in ITT, MITT, and PP analyses. The incidence of adverse effects was significantly lower in the TET-T group than in the TET-F group (23.65% vs. 33.50%, p = 0.028). No significant differences were observed in treatment compliance between the groups.
CONCLUSIONS
The dose of tetracycline administered three times daily showed comparable efficacy to that administered four times daily, while significantly reducing the incidence of adverse events. The combination of tetracycline and amoxicillin in bismuth-containing quadruple therapy achieved a high eradication rate in H. pylori rescue treatment.
Topics: Humans; Helicobacter Infections; Tetracycline; Male; Female; Middle Aged; Anti-Bacterial Agents; Helicobacter pylori; Adult; Treatment Outcome; Aged; Drug Therapy, Combination; Amoxicillin; Drug Administration Schedule; Esomeprazole; Breath Tests; Bismuth
PubMed: 38873902
DOI: 10.1111/hel.13102 -
Alternative Therapies in Health and... Jun 2024This study aims to investigate the use of proton pump inhibitors (PPIs) among inpatients in a hospital and analyze the rationality of their use.
OBJECTIVE
This study aims to investigate the use of proton pump inhibitors (PPIs) among inpatients in a hospital and analyze the rationality of their use.
METHODS
We analyzed the medication records of 1986 inpatients from January 2023 to June 2023, focusing on patients using PPIs under the "Internet + medical service" model. Additionally, we compared and analyzed the drug use patterns, including dosage form, dosage, medication frequency, average daily cost, and sales amount, between two groups: those treated before and after the implementation of the "Internet + medical service" model. The control group comprised 1962 inpatients treated with PPIs from July 2022 to December 2022. We also compared drug inventory time, account coincidence rate, error rate, and nursing satisfaction between the two periods.
RESULTS
Among the hospitalized patients using PPIs, 892 cases were male (44.91%) and 1094 cases were female (55.09%). Regarding age distribution, 456 cases were aged 18-45 (22.96%), 845 cases were aged 46-65 (42.55%), and 685 cases were over 65 years old (34.49%). The top 10 departments with the highest frequency of PPI use included gastroenterology (8.36%), oncology, hematology, trauma orthopedics (6.95% each), cardiovascular medicine, neurology (6.39% each), general surgery (6.29%), respiratory, critical care (5.84%), renal rheumatology, immunology (5.79%), and spine surgery (5.59%). Omeprazole enteric-coated capsules accounted for the highest proportion (25.08%), followed by rabeprazole enteric-coated tablets (22.96%) and pantoprazole sodium enteric-coated tablets (20.04%). After implementing the "Internet + medical service" model, there was a reduction in irrational PPI use, medication error rates, and inventory time. Moreover, the account coincidence rate and satisfaction rate increased significantly (P < .05).
CONCLUSION
The utilization of PPIs in hospitals is notably high. Implementing the "Internet + medical service" model can effectively improve the rationality of PPI use. Clinicians should adhere to relevant indications when prescribing PPIs and conduct drug interventions to prevent overuse.
PubMed: 38870506
DOI: No ID Found -
Zhongguo Zhen Jiu = Chinese Acupuncture... Jun 2024To observe the effect of acupuncture on gastroesophageal reflux disease (GERD) based on the "heart-stomach connection" theory, and to explore its possible mechanisms. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To observe the effect of acupuncture on gastroesophageal reflux disease (GERD) based on the "heart-stomach connection" theory, and to explore its possible mechanisms.
METHODS
Seventy patients with GERD were randomly divided into an acupuncture group (35 cases, 2 cases dropped out) and a medication group (35 cases, 1 case dropped out). The patients in the acupuncture group received acupuncture at bilateral Shenmen (HT 7), Neiguan (PC 6), Burong (ST 19), Tianshu (ST 25), Zusanli (ST 36), Gongsun (SP 4), and Zhongwan (CV 12), with needles retained for 30 min, every other day, three times a week. The patients in the medication group were treated with oral omeprazole capsules, once daily, 20 mg each time. Both groups were treated for 8 weeks. Before and after treatment, the GERD questionnaire (GERDQ), GERD-quality of life scale (GERD-QOL), Hamilton depression scale-24 (HAMD-24), Zung self-rating depression scale (SDS), and Zung self-rating anxiety scale (SAS) scores were observed. Serum levels of gastrointestinal hormones (gastrin [GAS], motilin [MTL], and vasoactive intestinal peptide [VIP]) were measured, and the clinical efficacy of both groups was evaluated. Correlation between pre-treatment GERDQ score and GERD-QOL score, HAMD-24 score, SDS score, and SAS score was analyzed.
RESULTS
After treatment, the scores of GERDQ, HAMD-24, SDS, and SAS were decreased (<0.001) and the scores of GERD-QOL were increased (<0.001), serum levels of GAS and MTL were increased (<0.001) in both groups, while the serum level of VIP in the acupuncture group was decreased (<0.001) compared with those before treatment. The acupuncture group had higher GERD-QOL score and lower SAS score than the medication group (<0.05), with lower serum VIP level (<0.05). The total effective rate was 75.8% (25/33) in the acupuncture group, and 76.5% (26/34) in the medication group, with no significant difference between the two groups (>0.05). GERDQ score was negatively correlated with GERD-QOL scores ( =-0.762, <0.01) and positively correlated with HAMD-24 score, SDS score, and SAS score ( =0.709, 0.649, 0.689, <0.01) before treatment.
CONCLUSION
Based on the "heart-stomach connection" theory, acupuncture could effectively improve clinical symptoms, quality of life, and negative emotions in patients with GERD. Its mechanism may be related to the regulation of gastrointestinal hormone levels, thereby promoting the contraction of the lower esophageal sphincter.
Topics: Humans; Gastroesophageal Reflux; Acupuncture Therapy; Male; Female; Middle Aged; Adult; Aged; Gastrointestinal Hormones; Acupuncture Points; Young Adult; Stomach; Heart; Motilin
PubMed: 38867622
DOI: 10.13703/j.0255-2930.20230818-0004 -
Cell Communication and Signaling : CCS Jun 2024KRAS-mutant non-small cell lung cancer (NSCLC) shows a relatively low response rate to chemotherapy, immunotherapy and KRAS-G12C selective inhibitors, leading to short...
BACKGROUND
KRAS-mutant non-small cell lung cancer (NSCLC) shows a relatively low response rate to chemotherapy, immunotherapy and KRAS-G12C selective inhibitors, leading to short median progression-free survival, and overall survival. The MET receptor tyrosine kinase (c-MET), the cognate receptor of hepatocyte growth factor (HGF), was reported to be overexpressed in KRAS-mutant lung cancer cells leading to tumor-growth in anchorage-independent conditions.
METHODS
Cell viability assay and synergy analysis were carried out in native, sotorasib and trametinib-resistant KRAS-mutant NSCLC cell lines. Colony formation assays and Western blot analysis were also performed. RNA isolation from tumors of KRAS-mutant NSCLC patients was performed and KRAS and MET mRNA expression was determined by real-time RT-qPCR. In vivo studies were conducted in NSCLC (NCI-H358) cell-derived tumor xenograft model.
RESULTS
Our research has shown promising activity of omeprazole, a V-ATPase-driven proton pump inhibitor with potential anti-cancer properties, in combination with the MET inhibitor tepotinib in KRAS-mutant G12C and non-G12C NSCLC cell lines, as well as in G12C inhibitor (AMG510, sotorasib) and MEK inhibitor (trametinib)-resistant cell lines. Moreover, in a xenograft mouse model, combination of omeprazole plus tepotinib caused tumor growth regression. We observed that the combination of these two drugs downregulates phosphorylation of the glycolytic enzyme enolase 1 (ENO1) and the low-density lipoprotein receptor-related protein (LRP) 5/6 in the H358 KRAS G12C cell line, but not in the H358 sotorasib resistant, indicating that the effect of the combination could be independent of ENO1. In addition, we examined the probability of recurrence-free survival and overall survival in 40 early lung adenocarcinoma patients with KRAS G12C mutation stratified by KRAS and MET mRNA levels. Significant differences were observed in recurrence-free survival according to high levels of KRAS mRNA expression. Hazard ratio (HR) of recurrence-free survival was 7.291 (p = 0.014) for high levels of KRAS mRNA expression and 3.742 (p = 0.052) for high MET mRNA expression.
CONCLUSIONS
We posit that the combination of the V-ATPase inhibitor omeprazole plus tepotinib warrants further assessment in KRAS-mutant G12C and non G12C cell lines, including those resistant to the covalent KRAS G12C inhibitors.
Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Proto-Oncogene Proteins p21(ras); Cell Line, Tumor; Animals; Proto-Oncogene Proteins c-met; Mutation; Omeprazole; Mice; Pyridines; Pyrimidines; Xenograft Model Antitumor Assays; Mice, Nude; Pyrimidinones; Female; Triazines; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Piperazines; Piperidines; Pyridazines; Pyridones
PubMed: 38867255
DOI: 10.1186/s12964-024-01667-x -
The AAPS Journal Jun 2024Gefapixant is a weakly basic drug which has been formulated as an immediate release tablet for oral administration. A physiologically based biopharmaceutics model (PBBM)...
Gefapixant is a weakly basic drug which has been formulated as an immediate release tablet for oral administration. A physiologically based biopharmaceutics model (PBBM) was developed based on gefapixant physicochemical properties and clinical pharmacokinetics to aid formulation selection, bioequivalence safe space assessment and dissolution specification settings. In vitro dissolution profiles of different free base and citrate salt formulations were used as an input to the model. The model was validated against the results of independent studies, which included a bioequivalence and a relative bioavailability study, as well as a human ADME study, all meeting acceptance criteria of prediction errors ≤ 20% for both Cmax and AUC. PBBM was also applied to evaluate gastric pH-mediated drug-drug-interaction potential with co-administration of a proton pump inhibitor (PPI), omeprazole. Model results showed good agreement with clinical data in which omeprazole lowered gefapixant exposure for the free base formulation but did not significantly alter gefapixant pharmacokinetics for the citrate based commercial drug product. An extended virtual dissolution bioequivalence safe space was established. Gefapixant drug product batches are anticipated to be bioequivalent with the clinical reference batch when their dissolution is > 80% in 60 minutes. PBBM established a wide dissolution bioequivalence space as part of assuring product quality.
Topics: Therapeutic Equivalency; Humans; Models, Biological; Solubility; Proton Pump Inhibitors; Biological Availability; Biopharmaceutics; Drug Liberation; Omeprazole; Administration, Oral; Hydrogen-Ion Concentration; Tablets; Drug Interactions; Chemistry, Pharmaceutical; Cross-Over Studies; Drug Compounding
PubMed: 38862807
DOI: 10.1208/s12248-024-00938-2 -
Helicobacter 2024Potassium-competitive acid blockers have demonstrated enormous potential in the eradication treatment of Helicobacter pylori infection, with tegoprazan being one of the... (Randomized Controlled Trial)
Randomized Controlled Trial
Fourteen-Day Tegoprazan-Amoxicillin Dual Therapy as the First-Line Treatment of Helicobacter pylori Infection (SHARE2301): A Multicenter, Noninferiority, Randomized Clinical Trial.
BACKGROUND
Potassium-competitive acid blockers have demonstrated enormous potential in the eradication treatment of Helicobacter pylori infection, with tegoprazan being one of the representatives. The available data on the safety and efficacy of tegoprazan in dual therapy are limited.
MATERIALS AND METHODS
The multicenter, noninferiority, randomized-controlled trial was conducted from May 2023 to March 2024. Treatment-naive subjects were randomly assigned (1:1) to enter either the tegoprazan-amoxicillin (TA) group (tegoprazan 50 mg twice daily and amoxicillin 750 mg four times daily) or the esomeprazole-amoxicillin (EA) group (esomeprazole 20 mg and amoxicillin 750 mg all four times daily), with a duration for 14 days. The primary outcome was eradication rate as determined by C-urea breath test, including per-protocol (PP) analysis and intention-to-treat (ITT) analysis. Secondary outcomes were adverse events and compliance.
RESULTS
A total of 368 individuals were included in the randomization. The eradication rates in the EA group and the TA group were 84.2% and 85.8%, respectively, according to an ITT analysis (p = 0.77), and 88.5% and 88.2%, respectively, according to PP analysis (p = 1.00). The eradication rates for the TA group were not inferior to those of the EA group in both PP (p = 0.0023) and ITT analyses (p = 0.0009). There were no significant statistical differences in the incidence of adverse events and compliance between the two groups. The multivariate logistic regression analysis revealed that poor compliance increased the risk of eradication failure (p < 0.001).
CONCLUSIONS
Dual therapy containing tegoprazan is safe and effective to be considered as a clinical first-line treatment option, but further optimization involving antimicrobial susceptibility testing and adjustments in dosage and frequency is warranted.
TRIAL REGISTRATION
ClinicalTrials.gov ID: NCT05870683.
Topics: Humans; Helicobacter Infections; Male; Female; Amoxicillin; Middle Aged; Helicobacter pylori; Anti-Bacterial Agents; Drug Therapy, Combination; Adult; Treatment Outcome; Proton Pump Inhibitors; Aged; Breath Tests; Esomeprazole; Pyrroles; Sulfonamides
PubMed: 38853394
DOI: 10.1111/hel.13098 -
Drug Metabolism and Disposition: the... Jun 2024Arsenite is an important heavy metal. Some Chinese traditional medicines contain significant amounts of arsenite. The aim of this study was to investigate subacute...
Arsenite is an important heavy metal. Some Chinese traditional medicines contain significant amounts of arsenite. The aim of this study was to investigate subacute exposure of arsenite on activities of cytochrome P450 enzymes and pharmacokinetic behaviors of drugs in rats. Midazolam, tolbutamide, metoprolol, omeprazole, caffeine, and chlorzoxazone, the probe substrates for CYPs3A2, 2C6, 2D2, 2C11, 1A2, and 2E1, were selected as model drugs for the pharmacokinetic study. Significant decreases in AUCs of probe substrates were observed in rats after consecutive 30 day exposure at 12 mg/kg. Microsomal incubation study showed that the subacute exposure to arsenite resulted in little changes in effects on the activities of P450 enzymes examined. However, everted gut sac study demonstrated that such exposure induced significant decreases in intestinal absorption of these drugs by both passive diffusion and carrier-mediated transport. In addition, study showed that the arsenite exposure decreased the rate of peristaltic propulsion. The decreases in intestinal permeability of the probe drugs and peristaltic propulsion rate most likely resulted in the observed decreases in the internal exposure of the probe drugs. Exposure to arsenite may lead to the reduction of the efficiencies of pharmaceutical agents co-administered resulting from the observed drug-drug interactions. Exposure to arsenite may lead to the reduction of the efficiencies of pharmaceutical agents co-administered resulting from the observed drug-drug interactions. In this study, we found that P450 enzyme probe drug exposure was reduced in arsenic-exposed animals (AUCs) and the intestinal absorption of the drug was reduced in the animals. Subacute arsenic exposure tends to cause damage to intestinal function, which leads to reduced drug absorption.
PubMed: 38849209
DOI: 10.1124/dmd.124.001772 -
Naunyn-Schmiedeberg's Archives of... Jun 2024Gastric ulcer disease is associated with significant morbidity and mortality rates. The most two common causes of the ulcer are Helicobacter pylori infection and...
Gastric ulcer disease is associated with significant morbidity and mortality rates. The most two common causes of the ulcer are Helicobacter pylori infection and non-steroidal anti-inflammatory drugs. In the past few decades, a significant decrease in the morbidity and mortality rate has been observed probably due to the discovery of proton pump inhibitors. However, the medications used to treat gastric ulcers impose several nauseous side effects. Therefore, recent studies focus on the use of natural products to treat gastric ulcers. In the current study, gastric ulcer was effectively induced using indomethacin, and the protective effect of apigenin, a potent antioxidant flavonoid, was assessed in comparison to omeprazole. The administration of a single oral indomethacin (50 mg/kg) induced gastric ulcer as manifested by hemorrhagic lesions in the gastric mucosa, increased ulcer index, and histopathological alterations. Indomethacin also increased lipid peroxidation, decreased the activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase, increased the immunoreactivity of the inflammatory markers cyclo-oxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-α), and nuclear factor-kappa B (NF-κB), increased the transcription of the apoptotic marker, Bax, and decreased that of the antiapoptotic Bcl-2. Indomethacin also decreased the immunoreactivity of transforming growth factor-beta 1 (TGF-β1). On the other hand, pretreatment with apigenin (10 and 20 mg/kg) resulted in a dose-dependent improvement in the macroscopic and microscopic features of the gastric mucosa in a manner comparable to that of omeprazole. The gastroprotective effects of apigenin may be attributed to its anti-inflammatory, anti-antioxidant, and anti-apoptotic activities as well as enhancing the expression of TGF-β1. Further experimental and clinical research is required to confirm activity of apigenin as anti-ulcer agent.
PubMed: 38842560
DOI: 10.1007/s00210-024-03200-w -
CPT: Pharmacometrics & Systems... Jun 2024Cytokine release syndrome (CRS) was associated with teclistamab treatment in the phase I/II MajesTEC-1 study. Cytokines, especially interleukin (IL)-6, are known...
Cytokine release syndrome (CRS) was associated with teclistamab treatment in the phase I/II MajesTEC-1 study. Cytokines, especially interleukin (IL)-6, are known suppressors of cytochrome P450 (CYP) enzymes' activity. A physiologically based pharmacokinetic model evaluated the impact of IL-6 serum levels on exposure of substrates of various CYP enzymes (1A2, 2C9, 2C19, 3A4, 3A5). Two IL-6 kinetics profiles were assessed, the mean IL-6 profile with a maximum concentration (C) of IL-6 (21 pg/mL) and the IL-6 profile of the patient presenting the highest IL-6 C (288 pg/mL) among patients receiving the recommended phase II dose of teclistamab in MajesTEC-1. For the mean IL-6 kinetics profile, teclistamab was predicted to result in a limited change in exposure of CYP substrates (area under the curve [AUC] mean ratio 0.87-1.20). For the maximum IL-6 kinetics profile, the impact on omeprazole, simvastatin, midazolam, and cyclosporine exposure was weak to moderate (mean AUC ratios 1.90-2.23), and minimal for caffeine and s-warfarin (mean AUC ratios 0.82-1.25). Maximum change in exposure for these substrates occurred 3-4 days after step-up dosing in cycle 1. These results suggest that after cycle 1, drug interaction from IL-6 effect has no meaningful impact on CYP activities, with minimal or moderate impact on CYP substrates. The highest risk of drug interaction is expected to occur during step-up dosing up to 7 days after the first treatment dose (1.5 mg/kg subcutaneously) and during and after CRS.
PubMed: 38831634
DOI: 10.1002/psp4.13144