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Molecules (Basel, Switzerland) Feb 2024is an important edible and medicinal plant, with the polysaccharide (DOP) being its primary active constituent, known for its diverse biological activities. In this...
is an important edible and medicinal plant, with the polysaccharide (DOP) being its primary active constituent, known for its diverse biological activities. In this study, DOP was extracted and characterized for its structural properties. The potential of DOP to ameliorate gastric ulcers (GUs) was investigated using an acetic-acid-induced GU model in rats. The results demonstrated that DOP exerted a multifaceted protective effect against GU, mitigating the deleterious impact on food intake and body weight in rats. DOP exhibited its protective action by attenuating cellular damage attributed to oxidative stress and inflammatory reactions mediated by enhanced activities of SOD, GSH, and GSH-PX, coupled with a downregulation in the expression of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α. Furthermore, DOP effectively inhibited apoptosis in gastric mucosa cells of acetic-acid-induced GU rat models and facilitated the self-repair of damaged tissues. Remarkably, the DOP-200 and DOP-400 groups outperformed omeprazole in reducing the expression of IL-6 and malondialdehyde (MDA) in tissues, as well as IL-1β, IL-6, and TNF-α in serum. These groups also exhibited an improved expression of SOD in tissues and SOD, GSH, and GSH-PX in serum. A Western blot analysis of gastric mucosa demonstrated that the DOP-200 and DOP-400 groups significantly reduced the expression of NF-κBp65, phosphorylated NF-κBp65, FoxO3a, and Bim. The observed antagonism to GU appeared to be associated with the NF-κB cell pathway. Additionally, qRT-PCR results indicate that DOP reduced the mRNA transcription levels of IL-6, and TNF-α, which shows that the healing of GU is related to the reduction in the inflammatory reaction by DOP. However, the expression of EGF and VEGF decreased, suggesting that the mechanism of DOP inhibiting GU may not be directly related to EGF and VEGF, or there is an uncertain competitive relationship between them, so further research is needed.
Topics: Rats; Animals; Dendrobium; Acetic Acid; Tumor Necrosis Factor-alpha; Stomach Ulcer; Epidermal Growth Factor; Interleukin-6; Vascular Endothelial Growth Factor A; Polysaccharides; Superoxide Dismutase
PubMed: 38398633
DOI: 10.3390/molecules29040880 -
Clinical Pharmacokinetics Apr 2024We investigated the effect of a 5-day low-dose ritonavir therapy, as it is used in the treatment of COVID-19 with nirmatrelvir/ritonavir, on the pharmacokinetics of... (Clinical Trial)
Clinical Trial
Time Course of the Interaction Between Oral Short-Term Ritonavir Therapy with Three Factor Xa Inhibitors and the Activity of CYP2D6, CYP2C19, and CYP3A4 in Healthy Volunteers.
BACKGROUND
We investigated the effect of a 5-day low-dose ritonavir therapy, as it is used in the treatment of COVID-19 with nirmatrelvir/ritonavir, on the pharmacokinetics of three factor Xa inhibitors (FXaI). Concurrently, the time course of the activities of the cytochromes P450 (CYP) 3A4, 2C19, and 2D6 was assessed.
METHODS
In an open-label, fixed sequence clinical trial, the effect and duration of a 5-day oral ritonavir (100 mg twice daily) treatment on the pharmacokinetics of three oral microdosed FXaI (rivaroxaban 25 µg, apixaban 25 µg, and edoxaban 50 µg) and microdosed probe drugs (midazolam 25 µg, yohimbine 50 µg, and omeprazole 100 µg) was evaluated in eight healthy volunteers. The plasma concentrations of all drugs were quantified using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods and pharmacokinetics were analysed using non-compartmental analyses.
RESULTS
Ritonavir increased the exposure of apixaban, edoxaban, and rivaroxaban, but to a different extent the observed area under the plasma concentration-time curve (geometric mean ratio 1.29, 1.46, and 1.87, respectively). A strong CYP3A4 inhibition (geometric mean ratio > 10), a moderate CYP2C19 induction 2 days after ritonavir (0.64), and no alteration of CYP2D6 were observed. A CYP3A4 recovery half-life of 2.3 days was determined.
CONCLUSION
This trial with three microdosed FXaI suggests that at most the rivaroxaban dose should be reduced during short-term ritonavir, and only in patients receiving high maintenance doses. Thorough time series analyses demonstrated differential effects on three different drug-metabolising enzymes over time with immediate profound inhibition of CYP3A4 and only slow recovery after discontinuation.
CLINICAL TRIAL REGISTRATION
EudraCT number: 2021-006643-39.
Topics: Humans; Ritonavir; Male; Adult; Factor Xa Inhibitors; Cytochrome P-450 CYP3A; Healthy Volunteers; Pyridones; Drug Interactions; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2C19; Administration, Oral; Female; Rivaroxaban; Young Adult; Pyridines; Pyrazoles; Thiazoles; Midazolam; Omeprazole
PubMed: 38393578
DOI: 10.1007/s40262-024-01350-x -
Heliyon Feb 2024The current research proposed a highly sensitive and selective spectrofluorometric approach for the assay of gastrointestinal medications omeprazole (OMZ) and...
The current research proposed a highly sensitive and selective spectrofluorometric approach for the assay of gastrointestinal medications omeprazole (OMZ) and domperidone (DOM). Green synthesis of metal oxide nanoparticles such as zinc oxide (ZnONPs) and cerium oxide (CeONPs) using and extract was used as fluorescence emission catalysts for the determination of OMZ and DOM. Due to their unique optical properties, nanoparticles (NPs) form the basis for spectrofluorimetric quantification of the selected drugs. The detection studies were performed under λex/λem 350/450 nm and 284/392 nm for OMZ and DOM in the presence of ZnONPs and CeONPs, respectively. Under ideal conditions, fluorescence intensities (FI) were linearly with correlation coefficient (r = 0.999) over concentration ranges of 0.1-100 and 0.01-200 μg mL for OMZ, 0.01-100 and 0.01-300 g mL for DOM in the presence of ZnONPs and CeONPs, respectively. Method validation was carried out to guarantee the accuracy, suitability, and precision of the proposed fluorescence (FL) systems for the determination of OMZ and DOM. Analytical method guidelines and requirements were followed. The designed procedure was used effectively to identify the determined drugs in both their pure and commercial versions.
PubMed: 38390119
DOI: 10.1016/j.heliyon.2024.e26164 -
Experimental and Clinical... Jan 2024We aimed to present a drug monitoring profile of tacrolimus and proton pump inhibitor coadministration in a 23-year-old male patient with a history of high blood...
We aimed to present a drug monitoring profile of tacrolimus and proton pump inhibitor coadministration in a 23-year-old male patient with a history of high blood pressure who underwent kidney transplant. The patient's serum trough levels of tacrolimus were in the therapeutic range until omeprazole 20 mg daily was prescribed. Tacrolimus trough serum level increased to 29.5 ng/mL under the same daily dose and to 13.9 ng/mL after tacrolimus daily dose was decreased to 6 mg/day. This increase in tacrolimus serum level was behind a renal function alteration. After withdrawal of omeprazole, tacrolimus trough serum level returned to the therapeutic range. Because interactions between tacrolimus and omeprazole could result in toxicities, careful monitoring of tacrolimus serum levels should be considered to adjust the dosage.
Topics: Male; Humans; Young Adult; Adult; Tacrolimus; Proton Pump Inhibitors; Immunosuppressive Agents; Kidney Transplantation; Omeprazole; Drug Interactions
PubMed: 38385426
DOI: 10.6002/ect.MESOT2023.P89 -
Gut and Liver Mar 2024: Tegoprazan is a novel potassium-competitive acid blocker that has beneficial effects on acid-related disorders such as gastroesophageal reflux and peptic ulcer... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND/AIMS
: Tegoprazan is a novel potassium-competitive acid blocker that has beneficial effects on acid-related disorders such as gastroesophageal reflux and peptic ulcer diseases. This study aimed to validate the effect of tegoprazan on endoscopic submucosal dissection (ESD)-induced artificial ulcers.
METHODS
: Patients from 16 centers in Korea who underwent ESD for gastric neoplasia were enrolled. After ESD, pantoprazole was administered intravenously for 48 hours. The patients were randomly allocated to either the tegoprazan or esomeprazole group. Tegoprazan 50 mg or esomeprazole 40 mg were administered for 4 weeks, after which gastroscopic evaluation was performed. If the artificial ulcer had not healed, the same dose of tegoprazan or esomeprazole was administered for an additional 4 weeks, and a gastroscopic evaluation was performed.
RESULTS
: One hundred sixty patients were enrolled in this study. The healing rates of artificial ulcers at 4 weeks were 30.3% (23/76) and 22.1% (15/68) in the tegoprazan and esomeprazole groups, respectively (p=0.006). At 8 weeks after ESD, the cumulative ulcer healing rates were 73.7% (56/76) and 77.9% (53/68) in the tegoprazan and esomeprazole groups, respectively (p=0.210). Delayed bleeding occurred in two patients in the tegoprazan group (2.6%) and in one patient in the esomeprazole group (1.5%). Other adverse events were negligible in both groups.
CONCLUSIONS
: Tegoprazan showed similar effects on post-ESD artificial ulcer healing in comparison with esomeprazole.
Topics: Humans; Esomeprazole; Ulcer; Proton Pump Inhibitors; Stomach Ulcer; Stomach Neoplasms; Endoscopic Mucosal Resection; Benzene Derivatives; Imidazoles
PubMed: 38384180
DOI: 10.5009/gnl230242 -
Drug Metabolism and Disposition: the... Feb 2024The regulation of drug-metabolizing enzymes and transporters by cytokines has been extensively studied, in vitro and in clinic. Cytokine-mediated suppression of CYPs or...
The regulation of drug-metabolizing enzymes and transporters by cytokines has been extensively studied, in vitro and in clinic. Cytokine-mediated suppression of CYPs or drug transporters may increase or decrease the systemic clearance of drug substrates that are primarily cleared via these pathways; neutralization of cytokines by therapeutic proteins may thereby alter systemic exposures of such drug substrates. The FDA recommends evaluating such clinical drug interactions during clinical development and has provided labeling recommendations for therapeutic proteins. To determine the clinical relevance of these drug interactions to dose adjustments, trends in steady-state exposures (AUC) of CYP-sensitive substrates co-administered with cytokine modulators as reported in the UW DIDB were extracted and examined for each of the CYPs. Co-administration of CYP3A (midazolam/simvastatin), CYP2C19 (omeprazole), or CYP1A2 (caffeine/tizanidine) substrates with anti-IL-6 and with anti-IL-23 therapeutics led to changes in systemic exposures of CYP substrates ranging from ~ -58% to ~35%; no significant trends were observed for CYP2D6 (dextromethorphan) and CYP2C9 (warfarin) substrates. Although none of these changes in systemic exposures have been reported as clinically meaningful, dose adjustment of midazolam for optimal sedation in acute care settings has been reported. Simulated concentration-time profiles of midazolam under conditions of elevated cytokine levels when co-administered with tocilizumab, suggest a ~6-7 fold increase in midazolam clearance suggesting potential implications of cytokine- CYP drug interactions on dose adjustments of sensitive CYP3A substrates in acute care settings. Additionally, this article also provides a brief overview of non-clinical and clinical assessments of cytokine-CYP drug interactions, in drug discovery and development. There has been significant progress in understanding cytokine-mediated drug interactions for CYP-sensitive substrates. This article provides an overview of the progress in this field, including a trend analysis of systemic exposures of CYP-sensitive substrates co-administered with anti-IL-x therapeutics. In addition, the review also provides a perspective of current methods used to assess these drug interactions during drug development, and a focus on individualized medicine, particularly in acute care settings.
PubMed: 38383116
DOI: 10.1124/dmd.123.001499 -
Pharmacopsychiatry Mar 2024CYP2D6 and CYP2C19 functional status as defined by genotype is modulated by phenoconversion (PC) due to pharmacokinetic interactions. As of today, there is no data on...
INTRODUCTION
CYP2D6 and CYP2C19 functional status as defined by genotype is modulated by phenoconversion (PC) due to pharmacokinetic interactions. As of today, there is no data on the effect size of PC for CYP2C19 functional status. The primary aim of this study was to investigate the impact of PC on CYP2C19 functional status.
METHODS
Two patient cohorts (total n=316; 44.2±15.4 years) were investigated for the functional enzyme status of CYP2C19 applying two different correction methods (PC, PC) as well as serum concentration and metabolite-to-parent ratio of venlafaxine, amitriptyline, mirtazapine, sertraline, escitalopram, risperidone, and quetiapine.
RESULTS
There was a decrease in the number of normal metabolizers of CYP2C19 and an increase in the number of poor metabolizers. When controlled for age, sex, and, in the case of amitriptyline, venlafaxine, and risperidone, CYP2D6 functional enzyme status, an association was observed between the CYP2C19 phenotype/functional enzyme status and serum concentration of amitriptyline, sertraline, and escitalopram.
DISCUSSION
PC of CYP2C19 changes phenotypes but does not improve correlations with serum concentrations. However, only a limited number of patients received perturbators of CYP2C19. Studies with large numbers of patients are still lacking, and thus, it cannot be decided if there are minor differences and which method of correction to use. For the time being, PC is relevant in individual patients treated with CYP2C19-affecting drugs, for example, esomeprazole. To ensure adequate serum concentrations in these patients, this study suggests the use of therapeutic drug monitoring.
Topics: Humans; Cytochrome P-450 CYP2D6; Venlafaxine Hydrochloride; Amitriptyline; Pharmacogenetics; Sertraline; Risperidone; Escitalopram; Cytochrome P-450 CYP2C19; Genotype
PubMed: 38354747
DOI: 10.1055/a-2248-6924 -
Scientific Reports Feb 2024The aim of this study was to investigate the potential of Ipomoea carnea flower methanolic extract (ICME) as a natural gastroprotective therapy against ethanol-induced...
The aim of this study was to investigate the potential of Ipomoea carnea flower methanolic extract (ICME) as a natural gastroprotective therapy against ethanol-induced gastric ulcers, particularly in individuals exposed to ionizing radiation (IR). The study focused on the Nrf2/HO signaling pathway, which plays a crucial role in protecting the gastrointestinal mucosa from oxidative stress and inflammation. Male Wistar rats were divided into nine groups, the control group received distilled water orally for one week, while other groups were treated with ethanol to induce stomach ulcers, IR exposure, omeprazole, and different doses of ICME in combination with ethanol and/or IR. The study conducted comprehensive analyses, including LC-HRESI-MS/MS, to characterize the phenolic contents of ICME. Additionally, the Nrf2/HO pathway, oxidative stress parameters, gastric pH, and histopathological changes were examined. The results showed that rats treated with IR and/or ethanol exhibited histopathological alterations, increased lipid peroxidation, decreased antioxidant enzyme activity, and reduced expression levels of Nrf2 and HO. However, pretreatment with ICME significantly improved these parameters. Phytochemical analysis identified 39 compounds in ICME, with flavonoids, hydroxybenzoic acids, and fatty acids as the predominant compounds. Virtual screening and molecular dynamics simulations suggested that ICME may protect against gastric ulceration by inhibiting oxidative stress and inflammatory mediators. In conclusion, this study demonstrates the potential of ICME as a natural gastroprotective therapy for preventing gastric ulcers. These findings contribute to the development of novel interventions for gastrointestinal disorders using natural plant extracts particularly in individuals with a history of radiation exposure.
Topics: Animals; Rats; Antioxidants; Ethanol; Gastric Mucosa; Methanol; NF-E2-Related Factor 2; Plant Extracts; Rats, Wistar; Stomach Ulcer; Tandem Mass Spectrometry; Ulcer
PubMed: 38342928
DOI: 10.1038/s41598-024-53336-1 -
Healthcare (Basel, Switzerland) Jan 2024We present the case of a 42-year-old female whose escitalopram use potentially contributed to a diagnosis of collagenous colitis. The patient presented with significant...
We present the case of a 42-year-old female whose escitalopram use potentially contributed to a diagnosis of collagenous colitis. The patient presented with significant watery, nonbloody diarrhea, abdominal cramping and pain, and weight loss. Established risk factors of microscopic colitis in this patient include a history of smoking and female gender. The patient underwent a colonoscopy, which confirmed histological changes consistent with collagenous colitis. Prescribed therapy included oral budesonide and omeprazole, continued for eight and twelve weeks, respectively. Escitalopram was continued, with a discussion regarding changing to an alternative therapy. Based on the patient's history of escitalopram use, this case suggests a relationship between escitalopram and microscopic colitis. Though case reports of patients diagnosed with microscopic colitis after antidepressant use are published, this case appears to be the only report of collagenous colitis without macroscopic complications following escitalopram use. This case adds further support in that antidepressants may contribute to microscopic colitis. Despite an undefined frequency of association, healthcare providers who prescribe antidepressants should be cognizant of the theorized association and understand risk factors, screening, and treatment approaches.
PubMed: 38338214
DOI: 10.3390/healthcare12030330 -
BMC Microbiology Feb 2024Resistance mechanisms are a shelter for Acinetobacter baumannii to adapt to our environment which causes difficulty for the infections to be treated and WHO declares...
Resistance mechanisms are a shelter for Acinetobacter baumannii to adapt to our environment which causes difficulty for the infections to be treated and WHO declares this organism on the top of pathogens priority for new drug development. The most common mechanism that develops drug resistance is the overexpression of the efflux pump, especially Resistance-nodulation-cell division (RND) family, to almost most antibiotics. The study is designed to detect RND efflux pump genes in A. baumannii, and its correlation to multidrug resistance, in particular, the carbapenems resistance Acinetobacter baumannii (CRAB), and using different inhibitors that restore the antibiotic susceptibility of imipenem. Clinical A. baumannii isolates were recovered from different Egyptian hospitals in Intensive care unit (ICU). The expression of genes in two strains was analyzed using RT-PCR before and after inhibitor treatment. About 100 clinical A. baumannii isolates were recovered and identified and recorded as MDR strains with 75% strains resistant to imipenem. adeB, adeC, adeK, and adeJ were detected in thirty- seven the carbapenems resistance Acinetobacter baumannii (CRAB) strains. Cinnamomum verum oil, Trimethoprim, and Omeprazole was promising inhibitor against 90% of the carbapenems resistance Acinetobacter baumannii (CRAB) strains with a 2-6-fold decrease in imipenem MIC. Downregulation of four genes was associated with the addition of those inhibitors to imipenem for two the carbapenems resistance Acinetobacter baumannii (CRAB) (ACN15 and ACN99) strains, and the effect was confirmed in 24 h killing kinetics. Our investigation points to the carbapenems resistance Acinetobacter baumannii (CRAB) strain's prevalence in Egyptian hospitals with the idea to revive the imipenem activity using natural and chemical drugs as inhibitors that possessed high synergistic activity.
Topics: Humans; Trimethoprim; Acinetobacter baumannii; Cinnamomum zeylanicum; Bacterial Proteins; Acinetobacter Infections; Anti-Bacterial Agents; Imipenem; Microbial Sensitivity Tests; Drug Resistance, Multiple, Bacterial
PubMed: 38331716
DOI: 10.1186/s12866-024-03194-8