Challenges in Conducting Clinical Trials for Preeclampsia.

PURPOSE OF REVIEW: To review recent data describing the challenges and innovations in therapeutic research focused on the prevention and treatment of preeclampsia. RECENT FINDINGS: Pregnant individuals have traditionally been excluded from therapeutic research, resulting in a paucity of innovation in therapeutics for pregnancy-specific medical conditions, especially preeclampsia. With the increased awareness of maternal morbidity and mortality, there is significant interest among researchers to expand therapeutic research in pregnancy. Several medications, including aspirin, pravastatin, metformin, and esomeprazole, which are commonly used in non-pregnant populations, are now being investigated for preeclampsia prevention. However, given the historic precedent of exclusion, along with the regulatory, ethical, and feasibility concerns that accompany this population, the study of these and novel medications has been complicated by numerous challenges. While complex, and laden with challenges, there is great ongoing need for therapeutic research to address preeclampsia. Aspirin, pravastatin, metformin, and esomeprazole have all shown promise as potential therapeutic agents; however, their use remains to be optimized, and innovative therapeutics need to be developed.

Effectiveness of high-dose esomeprazole or pantoprazole 10-day sequential therapy empirically prescribed in Helicobacter pylori-infected naïve patients: a retrospective study.

BACKGROUND AND AIM: Helicobacter pylori infection is one of the most common bacterial infections affecting humans, causing gastroduodenal and extraintestinal diseases. Treatment of the infection remains challenging for the clinicians, and different factors are involved in the failure of the therapeutic approach. The importance of the intensity of acid secretion inhibition remains an unclear issue. The aim of this study is to assess whether 80 mg/day esomeprazole-based 10-day sequential therapy (esomeprazole-ST) achieved different eradication rates when compared to 80 mg/day pantoprazole-based analogous regimen (pantoprazole-ST). METHODS: This was a retrospective observational study where data of consecutive patients referred by their physicians to our unit to perform an upper gastrointestinal endoscopy were analyzed. RESULTS: Overall, 1,327 patients were available for the analysis: 599 and 728 patients received pantoprazole-ST and esomeprazole-ST, respectively. Eradication rate was significantly higher in patients receiving esomeprazole-ST (92.6%, 95% CI: 91-94.5) than pantoprazole-ST (89.3%, 95% CI: 86.7-91.7; difference: 3.3%; 95% CI: 0.2-6.5; P = 0.037). Even after a multivariate analysis, the esomeprazole-ST achieved a significantly higher eradiation (OR: 1.44; 95% CI: 1.1-2.17). CONCLUSIONS: This study showed that esomeprazole-ST achieved significantly higher H. pylori cure rates than pantoprazole-ST. Prospective and well-designed trials are demander to confirm this prelaminar finding.

Therapeutic efficacy and drug safety comparison of one-week Vonoprazan triple therapy with two-weeks Esomeprazole triple therapy in Helicobacter pylori infection: Findings from a single-centre randomized clinical trial in population of Pakistan.

OBJECTIVE: To compare the therapeutic efficacy and drug safety of Vonoprazan and Esomeprazole triple therapies in Helicobacter pylori infection. METHODS: The randomised clinical trial was conducted from December 2022 to January 2023 at the Department of Pharmacology, Army Medical College, National University of Medical Sciences, Rawalpindi, Pakistan, in collaboration with the Gastroenterology Department of Pak Emirates Military Hospital, Rawalpindi, and comprised patients found positive for Helicobacter pylori by stool antigen test. They were randomly distributed into two groups. The EAL group received twoweek triple therapy with Esomeprazole 20mgand Amoxicillin 1000mg twice daily with Levofloxacin 500mg once daily. The VAL group was prescribed one-week triple therapy with Vonoprazan 20mg and Amoxicillin 1000mg twice daily with Levofloxacin 500mg once daily. Eradication success was evaluated by stool antigen test 4 weeks after starting the treatment. Safety of the therapy was assessed by noting adverse effects at days 3 and 14 of the treatment. Data was analysed using SPSS 27. RESULTS: Of the 122 patients, there were 61(50%) in each of the 2 groups; 30(49.2%) males and 31(50.8%) females with mean age 38.40±12.25 years in group EAL, and 35(57.4%) males and 26(42.6%) females with mean age 40.98±12.13 years in VAL group. In the EAL group, 57(93.4%) patients were found to be free of Helicobacter pylori infection compared to 58(95%) in the VAL group. Nausea 14(23%), bitter taste 41(67.2%), abdominal pain 16(26.2%) and headache 20(32.8%) were the adverse effects that were significantly more common in the EAL group compared to the VAL group B. CONCLUSIONS: Vonoprazan-based triple therapy was found to be more effective with less reported adverse effects and potential benefits of better patient compliance due to shorter therapy duration. Clinical Trial Number: Iranian Registry of Clinical Trials: IRCT20221207056738N1.

Variation in Fatty Acid Synthase, Ki67 and p53 Esophageal Mucosa Expressions in Barrett's Esophagus Patients Treated for One Year with Two Esomeprazole Different Regimens.

Barrett's esophagus (BE) is an acquired pre-malignant condition that results from chronic gastroesophageal reflux. The malignant transformation occurred in 0.5% of patients/year and was independent of medical and endoscopic conservative treatments. Fatty acid synthase (FAS) is a multifunctional enzyme that catalyzes the synthesis of long-chain fatty acids from acetyl-coenzyme A, malonyl-coenzyme A, a reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), and adenosine triphosphate. Activation of FAS is closely linked to malignant transformation. The aim of the present study was to evaluate the variation of FAS, p53, and Ki67 expressions in two groups of 21 BE patients each, after one year of continuous (group A) or discontinuous (group B) treatment with esomeprazole 40 mg/day in comparison to the initial expression. In both the two groups of BE patients, biopsies were taken from pathologic sites of the mucosa for histological and immuno-histochemical detection of FAS, Ki67, and p53 at entry and after one year of Esomeprazole 40 mg treatment. FAS expression was positive when a strong granular cytoplasmic staining was observed in esophageal cells. Ki67 and p53 were defined as positive when nuclear staining was clearly detected at ×10 magnification. FAS expression was reduced in 43% of patients treated with Esomeprazole continuously in comparison to the 10% of patients treated with Esomeprazole on demand (p = 0.002). Ki67 expression was reduced in 28% of continuously treated patients in comparison to 5% of patients treated on demand (p = 0.001). The p53 expression decreased in 19% of continuously treated patients in comparison to an increase in 2 patients (9%) treated on demand (p = 0.05). Continuously Esomeprazole treatment could help in the diminution of metabolic and proliferative activities in the esophageal columnar epithelium and in part it can help prevent the oxidative damage against cellular DNA, resulting in a diminution in p53 expression.

Structural characterization of the optical isomers esomeprazole and omeprazole using the JADER and FAERS databases.

BACKGROUND: It is unclear whether the s (-) form of esomeprazole (EPZ) has an improved safety profile when compared with its racemic form omeprazole (OPZ). We assessed the potential complications of these optical isomers when combined with cilostazol, clopidogrel, and prasugrel, which are frequently used concomitant medications. METHODS: Using two adverse event spontaneous reporting databases, Japanese Adverse Drug Event Report (JADER) and FDA Adverse Event Reporting System (FAERS), adverse event names for hemorrhage, venous/arterial embolization, and thrombus were obtained from the Medical Dictionary for Regulatory Activities. Reported odds ratios were calculated using a 2 × 2 contingency table, and a signal was considered present if the lower limit of the 95% confidence interval was >1. RESULTS: In combination with cilostazol, a hemorrhagic signal for OPZ in JADER and arterial emboli and thrombus signals for EPZ were detected in both databases. In combination with clopidogrel, OPZ showed arterial emboli and thrombus signals in JADER and venous/arterial emboli and thrombus signals in FAERS, while EPZ displayed arterial emboli and thrombus signals in FAERS. In contrast, when in combination with prasugrel, there were no adverse event signals in either database. CONCLUSION: This study has confirmed using big data, that EPZ, the optical isomer and racemic form of omeprazole, has the beneficial characteristics of being less sensitive to CYP, as was intended by its design.

Network meta-analysis of different dosages of esomeprazole and rabeprazole for the treatment of Helicobacter pylori.

BACKGROUND: The optimal dosage of new generation proton pump inhibitors (PPIs) in increasing cure rate of Helicobacter pylori (H. pylori) infection remains unclear. This network meta-analysis aimed to comprehensively evaluate the comparative efficacy and safety of different dosages of esomeprazole and rabeprazole in treating H. pylori infection. MATERIALS AND METHODS: We searched PubMed, Cochrane Central Registry for Controlled Trials (CENTRAL), and EMBASE for randomized controlled trials (RCTs) involving esomeprazole and rabeprazole with different dosages from their inception through 31 March, 2022. After data extraction and risk of bias assessment, network meta-analyses were conducted using STATA 14.0. We calculated the surface under the cumulative ranking (SUCRA) to rank all regimens. RESULTS: Thirteen studies including 14 reports were included. Six dosages including rabeprazole 10 mg (R10bid), 20 mg (R20bid), and 40 mg (R40bid) twice daily and esomeprazole 20 mg (E20bid) and 40 mg (E40bid) twice daily as well as 40 mg once daily (E40qd) were identified. Network meta-analysis suggested that R40bid ranked highest in the cure rate (83.8%), followed by E40bid (82.6%), E20bid (54.5%), R20bid (34.2%), R10bid (22.8%), and E40qd (22.0%); however, E40qd ranked highest in adverse events (91.1%), followed by R20bid (57.8), R10bid (57.6%), E20bid (38.9%), E40bid (34.2%), and R40bid (20.4%). Sensitivity analyses confirmed the robustness of these results. CONCLUSIONS: Based on the available evidence, R40bid and E40bid might be the optimum dosage to increase the cure rate; however, E40qd was superior for adverse events. Nevertheless, future studies should validate the results from this network meta-analysis.

Efficacy and safety of HIP1601 (dual delayed-release esomeprazole) 40 mg in erosive esophagitis compared to HGP1705 (delayed-release esomeprazole) 40 mg: a multicenter, randomized, double-blind, non-inferiority study.

BACKGROUND: Proton-pump inhibitors (PPIs) are the most effective drugs for treating acid-related disorders. However, once-daily dosing with conventional PPIs fail to fully control acid secretion over 24 h. This study aimed to compare the efficacy and safety of HIP1601 (dual delayed-release esomeprazole) and HGP1705 (delayed-release esomeprazole) in patients with erosive esophagitis (EE). METHODS: We enrolled 213 patients with EE randomized in a 1:1 ratio to receive 40 mg HIP1601 (n = 107) or HGP1705 (n = 106) once daily for 4 or 8 weeks. The primary endpoint was the EE healing rate, confirmed by endoscopy up to week 8. GERD-related symptoms and treatment-emergent adverse events were compared between both groups. RESULTS: By week 8, the estimated healing rates of EE were 97.8% and 96.8% in the HIP1601 and HGP1705 groups, respectively, with a 95% confidence interval of -4.7 to 7.2. After 4 or 8 weeks of treatment, the EE healing rate at week 4, complete resolution rate of symptoms, time to sustained resolution of symptoms, and number of rescue medications used were similar in both groups. The proportion of heartburn- and acid regurgitation-free nights by week 4 were higher in the HIP1601 group compared to the HGP1705 group, but the difference did not reach clinical significance (87.7% vs. 85.8%, P = 0.514, 87.5% vs. 85.8%, P = 0.774). The number of adverse events did not differ significantly between the two groups. CONCLUSIONS: The efficacy and safety of HIP1601 40 mg were comparable to those of HGP1705 40 mg for the treatment of EE and symptomatic improvement of GERD. TRIAL REGISTRATION: NCT04080726 ( https://classic. CLINICALTRIALS: gov/ct2/show/NCT04080726 ), registration date: 25/10/2018.

Time-dependent association between omeprazole and esomeprazole and hospitalization due to hyponatremia.

PURPOSE: The aim of this study was to explore the time-course of hospitalization due to hyponatremia associated with omeprazole and esomeprazole. METHODS: In this register-based case-control study, we compared patients hospitalized with a main diagnosis of hyponatremia (n = 11,213) to matched controls (n = 44,801). We used multiple regression to investigate time-related associations between omeprazole and esomeprazole and hospitalization because of hyponatremia. RESULTS: The overall adjusted OR (aOR) between proton pump inhibitor (PPI) exposure, regardless of treatment duration and hospitalization with a main diagnosis of hyponatremia, was 1.23 (95% confidence interval CI 1.15-1.32). Exposure to PPIs was associated with a prompt increase in risk of hospitalization for hyponatremia from the first week (aOR 6.87; 95% CI 4.83-9.86). The risk then gradually declined, reaching an aOR of 1.64 (0.96-2.75) the fifth week. The aOR of ongoing PPI treatment was 1.10 (1.03-1.18). CONCLUSION: The present study shows a marked association between omeprazole and esomeprazole and hyponatremia related to recently initiated treatment. Consequently, newly initiated PPIs should be considered a potential culprit in any patient suffering from hyponatremia. However, if the patient has had this treatment for a longer time, the PPI should be considered a less likely cause.

Separation and identification of degradation impurities of esomeprazole sodium.

Drug impurities are important factors that affect drug safety and efficacy. The aim of this study is to separate and confirm the structure of two degradation impurities of esomeprazole sodium, designated X and Y. The impurities X and Y were successfully isolated using preparative HPLC by developing separation methods with the help of ACD/Labs AutoChrom software. There was a steady increase in X and Y impurities in forced esomeprazole sodium degradation. Impurity X was confirmed as 6-methoxy-1h-benzo[d]imidazole-2-yl-4-amino-3,5-dimethylpyridinecarboxylate and impurity Y as 6-methoxy-1h-benzo[d]imidazole-2-yl-4-hydroxy-3,5-dimethylpyridinecarboxylate using nuclear magnetic resonance spectrometry, infrared spectroscopy, and high-resolution mass spectrometry. These findings provide a comprehensive understanding of the impurity profile of esomeprazole sodium because these impurities are reported for the first time. Based on our results, active pharmaceutical ingredient manufacturers can further control process parameters to reduce impurity generation, and drug production manufacturers can optimize the packaging and storage conditions of esomeprazole sodium.

Development of Delayed Release Oral Formulation Comprising Esomeprazole Spray Dried Dispersion Utilizing Design of Experiment As An Optimization Strategy.

Solid dispersion (SD) technology is one of the most widely preferred solubility enhancement methods, especially for Biopharmaceutics classification system class II and IV drugs. Since the last decade, its application for the dual purpose of solubility hike and modified release using novel carriers has been in demand for its added advantages. Spray drying is a commercially accepted technique with high aspects of scalability and product characteristics. The current study used spray-dried dispersion to design delayed release capsule for the proton pump inhibitor esomeprazole. The SD carrier hydroxypropyl methylcellulose acetate succinate-medium grade (HPMCAS-MF) enhanced solubility, inhibited precipitation of saturated drug solutions, and allowed enteric release owing to its solubility above pH 6. The proposed approach avoided compression, coating with enteric polymers, and the development of multi-particulate pellet-based formulations, improving manufacturing feasibility. The formulation was optimized using Box-Behnken design, considering significant formulation variables like HPMCAS-MF proportion and critical process parameters like feed flow rate and inlet temperature. The optimized spray-dried dispersion were characterized based on Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM) and also evaluated for solubility, in vitro drug release, residual solvent content, and stability testing. Response surface methodology optimization anticipated that formulation variables affected solubility and release profile, whereas CPPs affected yield. The design space was developed via overlay plot based on constraints specified to attain the desired response and validated using three checkpoint batches with desirability 1. FTIR showed active pharmaceutical ingredient-polymer compatibility. Particle size and SEM studies showed spherical particles with an average Z-value of 1.8 µ. DSC and PXRD confirmed SD's amorphous nature. The drug release investigation and release kinetics prediction utilizing DD-solver software showed a 2-h lag time with > 90% cumulative drug release up to 4 h for the DR formulation. ESM SDD were prepared by spray drying technique using the novel solid dispersion carrier HPMCAS-MF to serve the dual purpose of solubility enhancement and delayed release. The ratio of API:carrier and process variables like feed flow rate and inlet temperature were varied using the Box-Behnken Design to determine the design space of optimized product to procure the desired characteristics of solubility improvement compared to crystalline API and delayed release of PPI to avoid the degradation in the gastric environment. The developed formulation represents several benefits over the already existing marketed products.

Systematic evaluation of the pre-eclampsia drugs, dietary supplements and biologicals pipeline using target product profiles.

BACKGROUND: The Accelerating Innovation for Mothers (AIM) project established a database of candidate medicines in research and development (R&D) between 2000 and 2021 for five pregnancy-related conditions, including pre-eclampsia. In parallel, we published target product profiles (TPPs) that describe optimal characteristics of medicines for use in preventing/treating pre-eclampsia. The study objective was to use systematic double screening and extraction to identify all candidate medicines being investigated for pre-eclampsia prevention/treatment and rank their potential based on the TPPs. METHODS: Adis Insight, Pharmaprojects, WHO international clinical trials registry platform (ICTRP), PubMed and grant databases were searched (Jan-May 2021). The AIM database was screened for all candidates being investigated for pre-eclampsia. Candidates in clinical development were evaluated against nine prespecified criteria from TPPs identified as key for wide-scale implementation, and classified as high, medium or low potential based on matching to the TPPs. Preclinical candidates were categorised by product type, archetype and medicine subclass. RESULTS: The AIM database identified 153 candidates for pre-eclampsia. Of the 87 candidates in clinical development, seven were classified as high potential (prevention: esomeprazole, L-arginine, chloroquine, vitamin D and metformin; treatment: sulfasalazine and metformin) and eight as medium potential (prevention: probiotic lactobacilli, dalteparin, selenium and omega-3 fatty acid; treatment: sulforaphane, pravastatin, rosuvastatin and vitamin B3). Sixty-six candidates were in preclinical development, the most common being amino acid/peptides, siRNA-based medicines and polyphenols. CONCLUSIONS: This is a novel, evidence-informed approach to identifying promising candidates for pre-eclampsia prevention and treatment - a vital step in stimulating R&D of new medicines for pre-eclampsia suitable for real-world implementation.

Esomeprazole inhibits hypoxia/endothelial dysfunction-induced autophagy in preeclampsia.

Preeclampsia (PE) affects 3 to 5% of pregnant women worldwide and is associated with fetal and maternal morbidity and mortality. Although a complete understanding of PE remains elusive, it has been widely accepted that a dysfunction of the placenta plays a key role in the pathogenesis of PE. In this study, we investigated the role of excessive placental autophagy during PE pathogenesis and explored whether esomeprazole ameliorates PE by inhibiting the autophagy in the placenta. The PE cellular model was established by treating the cells' L-NAME and hypoxia. The PE mice model was established by L-NAME administration and was confirmed by the increased systolic blood pressure (SBP) and urinary protein detected. The autophagy and key proteins were detected in human placental tissue, in cells, and in the mice model by Western blot and immunofluorescence staining. Results showed that excessive autophagy could be detected in human PE placental tissue, in the PE cellular model, and in the PE mice model. Hypoxia induces autophagy by activating AMPKα and inhibiting mTOR in vivo and in vitro. Esomeprazole inhibits L-NAME-induced autophagy in mice by inhibiting AMPKα and activating mTOR. In conclusion, this study demonstrates that the excessive autophagy induced by the SIRT1/AMPKα-mTOR pathway plays a significant role in the pathogenesis of PE. However, esomeprazole treatment inhibits AMPKα but activates mTOR, resulting in the inhibition of autophagy in the placenta and, therefore, mitigates PE symptoms.

Legumain affects the PI3K/AKT tumor progression pathway in retinoblastoma.

Known as a common malignant tumor among children, retinoblastoma (RB) is highly malignant and has poor prognosis, damages children's vision and degrades quality of life. To identify a potential molecular mechanism of RB, we conducted this study on legumain (LGMN), which is highly expressed in multiple tumors. In this study, we found that LGMN was significantly upregulated in RB cells and was positively expressed in RB tissues. We confirmed that LGMN overexpression (LGMN-OE) can promote RB cell proliferation and inhibit cell apoptosis through CCK8 experiments and flow cytometry. In addition, real-time quantitative polymerase chain reaction (RT‒qPCR) and Western blot results showed that LGMN-OE could regulate the expression of epithelial-mesenchymal transformation-related genes and proteins, related to tumor invasion and metastasis. Moreover, after LGMN knock down, the result was the opposite., RNA sequence analysis revealed 1159 differentially expressed genes between LGMN-OE and the negative control (NCOE), of which 564 were upregulated and 595 were downregulated. The first 10 genes were verified by RT‒qPCR based on P value and fold change. Interestingly, we found that LGMN could regulate the expression of recoverin (RCVRN)through a gene responsible for cancer-related retinopathy. We also screened and verified that LGMN partially activated the PI3K/AKT pathway in RB. Furthermore, we evaluated the effect of legumain inhibitors (e.g., esomeprazole) on RB, and the results suggest that esomeprazole may provide a reference for the clinical adjuvant treatment of RB. In conclusion, legumain can serve as an attractive target for RB therapy and hopefully provide new insights and ideas for the development of targeted drugs and precise personalized clinical therapy.

Pravastatin, proton-pump inhibitors, metformin, micronutrients, and biologics: new horizons for the prevention or treatment of preeclampsia.

There has been increasing research momentum to identify new therapeutic agents for the prevention or treatment of preeclampsia, drugs that can affect the underlying disease pathophysiology. Molecular targets of candidate treatments include oxidative stress, antiangiogenic factors, and the angiotensin, nitric oxide, and proinflammatory pathways. The proposed treatments undergoing preclinical and clinical trial evaluation are thought to act on placental or endothelial disease or both. Most have adopted the pragmatic strategy of repurposing drugs. Of all the therapeutic agents proposed, pravastatin has received the most interest. There are preclinical studies showing that it has pleiotropic actions that favorably impact on multiple molecular targets and can resolve a preeclampsia phenotype in many animal models. An early phase clinical trial suggests that it may have therapeutic activity. Several large prevention trials are planned or ongoing and, when completed, could definitively address whether pravastatin can prevent preeclampsia. Proton-pump inhibitors, metformin, and sulfasalazine are other drugs with preclinical evidence of multiple molecular actions that could resolve the pathophysiology of preeclampsia. These agents are also currently being evaluated in clinical trials. There have been many recent preclinical studies identifying the potential of numerous natural compounds to treat preeclampsia, such as plant extracts and micronutrients that have potent anti-inflammatory or antioxidant activity. Recent preclinical studies have also proposed novel molecular-targeted strategies, such as monoclonal antibodies targeting tumor necrosis factor alpha, placental growth factor, and short interfering RNA technology, to silence the gene expression of soluble fms-like tyrosine kinase-1 or angiotensinogen. Other treatment approaches that have transitioned to human trials (ranging from single-arm to phase III trials that have been completed or are ongoing) include folic acid, nitric oxide donors (such as L-arginine), recombinant antithrombin III, digoxin immune antigen-binding fragment, and melatonin. There have been case series showing the removal of circulating soluble fms-like tyrosine kinase-1 may help stabilize the disease and prolong pregnancy. Interestingly, there are case reports suggesting that monoclonal antibody eculizumab (complement inhibitor) may have therapeutic potential. If new agents are discovered that are proven to be effective in preventing or treating preeclampsia, the potential to improve global maternal and perinatal health will be significant.

Esomeprazole alleviates fibrosis in systemic sclerosis by modulating AhR/Smad2/3 signaling.

Systemic sclerosis (SSc) is a connective tissue disease with the involvement of complex signaling pathways, such as TGF-ß/Smad2/3. SSc can lead to severe multiple organ fibrosis, but no effective therapy is currently available because of its unclear pathogenesis. Exploring new treatments is the focus of recent research on SSc. Recent studies have implied a potential antifibrotic role of esomeprazole (ESO), but with currently unidentified mechanisms. Signaling of AhR, a ligand-dependent transcription factor, has been described as a key controller of fibrosis, tumorigenesis, and immune balance. Recently, it has been reported that ESO may be an exogenous agonist of AhR signaling, while no previous study has revealed the effects of ESO on SSc and its underlying mechanisms. In this study, we demonstrate that ESO suppresses the migration of SSc dermal fibroblasts, downregulates profibrotic markers, including COLIA1, α-SMA CTGF and MMP1, and limits collagen production potentially via the activation of AhR signaling. More importantly, ESO could block Smad2/3 phosphorylation concurrently with the reduction in collagen via AhR signaling. Moreover, our results from the bleomycin (BLM)-induced SSc model in skin and lung shows that ESO ameliorates fibrosis in vivo, which in keeping with our in vitro results. We conclude that ESO is a potential therapeutic drug for SSc fibrosis.

"Nonpolarity paving" in substrate tunnel of a Limnobacter sp. Phenylacetone monooxygenase for efficient single whole-cell synthesis of esomeprazole.

Baeyer-Villiger monooxygenase (BVMO) mediated sulfoxidation is a sustainable approach for the synthesis of esomeprazole. In this work, a novel phenylacetone monooxygenase from Limnobacter sp. (LnPAMO) was found to have trace activity for synthesis of enantiopure esomeprazole. Through engineering in the substrate tunnel using a mutagenesis strategy called "nonpolarity paving" and some modifications in cofactor binding domains, a mutant harboring 15 mutations (LnPAMO Mu15) was obtained with 6.6 × 103-fold higher activity to convert omeprazole sulfide into esomeprazole. The activities of the mutant for synthesis of (S)-methyl phenyl sulfoxide and (S)-pantoprazole also increased much, indicating the versatility of the mutant for sulfoxide synthesis. Importantly, no over-oxidation byproduct omeprazole sulfone was detected in the sulfoxidation products by both mass spectrometry and HPLC analysis. Then NADP-dependent Burkholderia stabili formate dehydrogenase was ligated behind Mu15 along with a ribosome binding site sequence in pET-28a for co-expression. By single whole-cell of recombinant Escherichia coli BL21 coexpressing Mu15 and formate dehydrogenase, omeprazole sulfide was efficiently converted into esomeprazole without production of sulfone (16 g/L substrate, enantiomeric excess > 99.9% (S) and > 99% conversion) and the space-time-yield reached 1.67 g product/L/h.

Administering esomeprazole subcutaneously via a syringe driver in the palliative demographic: A case series.

WHAT IS KNOWN AND OBJECTIVE: Proton pump inhibitors are potent suppressors of gastric acid secretion, and are commonly prescribed in palliative medicine. Despite multiple relevant indications in patients at the end-of-life, their use is often precluded as oral and intravenous administration is frequently inappropriate or not possible. Limited anecdotal evidence suggests proton pump inhibitors may be administered subcutaneously. Our objective was to investigate the tolerability and effectiveness of the administration of esomeprazole as a continuous subcutaneous infusion over 24 h via a syringe driver. METHODS: Case series (n = 7) design assessing sequential patients admitted to a specialist inpatient centre for palliative care, who required parenteral proton pump inhibitor therapy. RESULTS AND DISCUSSION: Four patients reported complete resolution of dyspeptic and reflux symptoms post commencement of esomeprazole. Two patients developed upper gastrointestinal bleeding, which via observation of vomitus and stools, resolved with the initiation of esomeprazole. A single patient, deemed high risk of gastrointestinal bleeding, was commenced on esomeprazole and no bleeding events occurred. WHAT IS NEW AND CONCLUSION: Esomeprazole when administered via a syringe driver over 24 h appears well tolerated and effective for the symptomatic management of dyspepsia and treatment of gastrointestinal bleeding. Overall, this series adds to the limited evidence base for using subcutaneous proton pump inhibitors in the palliative demographic.

US FDA-validated TLC method with four greenness assessment evaluations for simultaneous determination of prednisolone and esomeprazole in spiked human plasma.

Recently, prednisolone has been used in treating many medical conditions, such as autoimmune diseases and cancer. It is also prescribed to mitigate the respiratory complications caused by COVID-19 infection. It can cause some health complications, such as GIT ulcers, so it should be co-administered with proton-pump inhibitors, such as esomeprazole, to prevent the risk of ulcers. This work aims to develop an ecofriendly and sensitive TLC method for simultaneous determination of esomeprazole and prednisolone in their binary mixtures and spiked human plasma. Separation was performed using a mixture of ethyl acetate, methanol, and ammonia (9.5:0.5:0.1, v/v/v) as an eluting system with UV scanning at 245 nm. Dapoxetine was used as an internal standard to correct the variation during sampling. The resulting Rf values for plasma, esomeprazole, prednisolone, and dapoxetine were 0.03, 0.51, 0.72 and 0.85, respectively. Four greenness assessment tools-national environmental method index, eco-scale assessments, analytical greenness metric approach (AGREE), and green analytical procedure index (GAPI)-were used to evaluate the greenness characteristics of the proposed method to the environment, and the results were acceptable and satisfactory. Validation parameters were checked according to the US FDA guidelines to achieve the international requirements for bioanalytical method validation, and the results were within the accepted ranges.

Enantioselective recognition of esomeprazole with a molecularly imprinted sol-gel-based electrochemical sensor.

A simple, selective, and accurate electrochemical chiral sensor based on molecularly imprinted polymer (MIP) has been developed for sensitive and selective detection of esomeprazole (ESOM). For this purpose, the porous MIP sensor was prepared using tetraethyl orthosilicate (TEOS) and cetyltrimethylammonium bromide (CTAB) in the presence of ß-cyclodextrin (ß-CD) as a chiral recognizing element on a glassy carbon electrode (GCE). The changes in the MIP-layer related to removal and rebinding of the target ESOM were performed via differential pulse voltammetry (DPV) and cyclic voltammetry (CV) by using [Fe(CN)6]3-/4- as the redox probe. The structures of the developed sensor surface were characterized by using scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). Electrochemical impedance spectroscopy (EIS) was also utilized for a complementary electrochemical characterization. The calibration curve was obtained in the range 1.0 × 10-14-2.0 × 10-13 M with a limit of detection (LOD) of 1.9 × 10-15 M. The developed method has improved the accessibility of binding sites by producing the porous material via hydrolysis/condensation reaction of TEOS in presence of CTAB. The selectivity tests of the developed SiO2-ß-CD@MIP/GCE sensor indicated a high specificity towards ESOM compared with structurally related competitor molecules such as R-omeprazole (R-OM), R-lansoprazole, and S-lansoprazole. The developed sensor was successfully used to determine ESOM in tablets and commercial human serum samples with satisfactory recoveries (100.25 to 100.60%) and precision (RSD 0.46 to 0.66%).

Broad transcriptional response of the human esophageal epithelium to proton pump inhibitors.

BACKGROUND: Proton pump inhibitors (PPIs) have been recognized as a primary treatment of eosinophilic esophagitis (EoE), an allergic inflammatory disease of the esophageal mucosa. The mechanisms underlying esophageal epithelial responses to PPIs remain poorly understood. OBJECTIVE: We hypothesized that PPIs can counteract IL-13-mediated esophageal epithelial responses that are germane for EoE pathogenesis. METHODS: Transcriptional responses of human esophageal cells to IL-13 and the PPIs omeprazole and esomeprazole were assessed by RT-PCR and RNA sequencing. Cytokine secretion was measured by multiplex analysis and ELISA. RESULTS: Human esophageal epithelial cells robustly responded to PPI stimulation by inducing a set of 479 core genes common between omeprazole and esomeprazole treatments. The transcriptional response to PPIs was partially mediated through the aryl hydrocarbon receptor signaling pathway, as the aryl hydrocarbon receptor antagonist GNF-351 modified approximately 200 genes, particularly those enriched in metabolic processes and regulation of cell death. PPI treatment reversed approximately 20% of the IL-13 transcriptome. Functional analysis of the PPI-responsive, upregulated genes revealed enrichment in metabolic and oxidation processes, and the unfolded protein response. In contrast, downregulated genes were overrepresented in functional terms related to cell division and cytoskeletal organization, which were also enriched for the genes in the EoE transcriptome reversed by PPIs. Furthermore, PPI treatment decreased the IL-13-induced proliferative response of esophageal epithelial cells. CONCLUSIONS: These results demonstrate broad effects of PPIs on esophageal epithelium, including their ability to curtail transcriptomic processes involved in cellular proliferation and IL-13-induced responses, and they highlight the importance of AHR signaling in mediating these responses.