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1.
Ther Innov Regul Sci ; 58(1): 166-174, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37891390

RESUMO

OBJECTIVE: To estimate the incidence rates (IR) of prespecified outcomes of interest in pediatric patients (1 month to < 1 year) treated with intravenous (IV) pantoprazole using Optum's longitudinal electronic health records database (Optum Market Clarity) from the United States (US). METHODS: This real-world, non-interventional, retrospective cohort study was conducted from 01 January 2007 to 31 December 2020 in patients who received IV pantoprazole. Premature patients and those weighing < 2.36 kg were excluded. Patients were categorized based on diagnosis of gastroesophageal reflux disease (GERD) and erosive esophagitis (EE) into: Subgroup 1 (GERD and EE), Subgroup 2 (GERD and no EE), and Subgroup 3 (absence of GERD and EE). Overall IRs (per 1000 person-years [PY]) and 95% confidence intervals (CI) of outcomes were estimated (overall and subgroups) and stratified by duration of IV pantoprazole treatment (< 4 days versus ≥ 4 days). RESULTS: Of 1879 eligible patients, none were identified in Subgroup 1; 851 (45.3%) and 1028 (54.7%) patients were identified in Subgroups 2 and 3, respectively. IRs of outcomes of interest ranged from 0.0 to 742.8 per 1000 PY. IRs were highest for vomiting (742.80), diarrhea (377.77), abdominal distension (214.31), hyponatremia (204.99), and hypokalemia (203.49). IRs were comparable between Subgroups 2 and 3. For most outcomes, IRs were higher among patients treated with IV pantoprazole for ≥ 4 days versus those treated for < 4 days. CONCLUSION: These results are consistent with the known safety profile of pantoprazole and emphasize the utility of using real-world data from pediatric populations for assessment of safety outcomes.


Assuntos
Antiulcerosos , Refluxo Gastroesofágico , Humanos , Criança , Pantoprazol/uso terapêutico , Antiulcerosos/efeitos adversos , Omeprazol/efeitos adversos , 2-Piridinilmetilsulfinilbenzimidazóis/efeitos adversos , Estudos Retrospectivos , Benzimidazóis/efeitos adversos , Sulfóxidos/efeitos adversos , Refluxo Gastroesofágico/tratamento farmacológico , Refluxo Gastroesofágico/induzido quimicamente
3.
Eur J Pharm Sci ; 194: 106653, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38006986

RESUMO

As a widely used antidepressant that works by inhibiting the reuptake of serotonin, sertraline exerts an antidepressant effect depending on its concentration in the brain, which might be limited by the blood-brain barrier (BBB). It is highly possible to combine proton pump inhibitors (PPIs) with sertraline in clinical trials. Nevertheless, the role played by PPIs in regulating the transport of sertraline across the BBB remains unclear. Here, the impact of PPIs on the distribution of sertraline in the brain and the mechanisms involved were investigated. A mouse brain distribution study showed that Omeprazole (OME), Pantoprazole (PAN), Ilaprazole (ILA), and Esomeprazole (ESO) increased the area under the brain concentration-time curves (AUC) for sertraline by 2.02-, 3.18-, 3.04-, and 4.21-fold, respectively, after the 14-day administration of PPIs. Besides, PPIs significantly increased the permeability of sertraline in brain perfusion experiments, with PAN having the highest rank order, followed by ILA, OME, and ESO. In the tail suspension test (TST), co-administration PPI groups showed significantly shorter immobility time than the control group. In vitro, four PPIs inhibited sertraline efflux in breast cancer resistance protein (BCRP)-overexpressing MDCKII cells, and showed a mixed inhibition type. In this study, PPIs were further found to inhibit the mRNA and protein expression of brain BCRP. To sum up, the findings of this study revealed that PPIs could enhance the brain distribution and antidepressant effect of sertraline, which may be attributed to the inhibition of BCRP expression at the BBB by PPIs.


Assuntos
2-Piridinilmetilsulfinilbenzimidazóis , Inibidores da Bomba de Prótons , Sertralina , Animais , Camundongos , Inibidores da Bomba de Prótons/farmacologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Sertralina/farmacologia , Barreira Hematoencefálica/metabolismo , Proteínas de Neoplasias/metabolismo , Omeprazol/farmacologia , Esomeprazol , Antidepressivos/farmacologia , Pantoprazol/farmacologia
4.
Artigo em Inglês | MEDLINE | ID: mdl-38141290

RESUMO

There exist two enantiomers: (R)- and (S)-rabeprazole. (R)-rabeprazole offers specific pharmacokinetic advantages and enhanced therapeutic efficacy, warranting further investigation and development. Here, we developed a simple and rapid chiral liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to simultaneously quantify rabeprazole enantiomers and their metabolites (rabeprazole sulfoxide and desmethyl rabeprazole enantiomers) and a LC-MS to quantify rabeprazole thioether. As for the chiral LC-MS/MS method, Chiral-AGP column (150 × 4 mm, 5 µm) was used and its mobile phase was acetonitrile (mobile phase A) and 10 mmol/L ammonium acetate (mobile phase B) (linear gradient profile: 0 min, 10 % B; 5 min, 15 % B; 9 min, 15 % B; 9.01 min, 10 % B; 13 min, 10 % B). The multiple reactions monitoring transitions of m/z 360.3 â†’ 242.1, 376.2 â†’ 240.1, 346.2 â†’ 228.2 and 368.2 â†’ 190.2 were opted for quantifying rabeprazole enantiomers, rabeprazole sulfoxide, desmethyl rabeprazole enantiomers and internal standard omeprazole. The analyte samples were prepared by a simple liquid-liquid extraction method. As for the LC-MS method, analytes were separated on a Inertsil® ODS-3 column (4.6 × 150 mm, 5 µm). The mobile phase was acetonitrile-5 mmol/L ammonium acetate water solution (65:35, v/v). ESI+ was used and ion peaks with m/z 344.2 (rabeprazole thioether) and 285.1 (internal standard diazepam) were monitored. Both these 2 methods were validated for specificity, linearity, precision, accuracy, matrix effect and extraction recovery, and, particularly, the stability of analytes under various conditions. We successfully applied these methods to a 13-week toxicokinetic study of rabeprazole in rats after intravenous administration of (R)- (80, 20, 5 mg/kg/d) and racemic (80 mg/kg/d) rabeprazole sodium. The results showed that rabeprazole and its metabolites did not accumulate in rats. However, desmethyl rabeprazole and rabeprazole thioether showed higher exposure and lower clearance rate in the last administration than in the first one. (R)-rabeprazole showed a higher exposure and a slower elimination rate than (S)-rabeprazole in rats. These findings offer experimental evidence and a theoretical foundation for further preclinical investigations and clinical applications of (R)-rabeprazole.


Assuntos
2-Piridinilmetilsulfinilbenzimidazóis , Acetatos , Espectrometria de Massas em Tandem , Animais , Ratos , Rabeprazol/química , Rabeprazol/farmacocinética , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Toxicocinética , Sulfóxidos , Sulfetos , Acetonitrilas , Reprodutibilidade dos Testes
5.
Artigo em Inglês | MEDLINE | ID: mdl-38096743

RESUMO

Omeprazole (OME) is a widely used gastric proton pump inhibitor, marketed as a racemic mixture comprising (S)- and (R)-enantiomers, with distinct pharmacokinetic profiles. OME is primarily metabolized by the cytochrome P450 enzymes 2C19 (CYP2C19) and 3A4 (CYP3A4). OME is a conventional probe for CYP2C19 phenotyping. Accurate measurement of these enantiomers and their metabolites is essential for pharmacokinetic studies. This article presents a sensitive and accurate two-dimensional liquid chromatography-mass spectrometry (LC-MS/MS) method for the simultaneous quantification of OME enantiomers and its hydroxylated metabolite (5-hydroxyomeprazole) in human plasma. The method involves an online extraction using an achiral Discovery HS C18 trapping column for purification (20 × 2.1 mm ID, 5µm particle size, Supelco) and subsequent forward flush elution onto a chlorinated phenylcarbamate cellulose-based chiral column (150x2mm ID, 3 µm particle size, Lux Cellulose-4, Phenomenex). The assay was fully validated and met international validation criteria for accuracy, precision, and stability and ensured high selectivity and sensitivity within a short runtime (<8 min). Application of this method to clinical samples demonstrated its utility in studying OME enantiomer pharmacokinetics, particularly its potential for phenotyping the activity of the CYP2C19 isoenzyme. This robust analytical approach offers a valuable tool for clinicians and researchers studying OME's pharmacokinetics, providing insights into its metabolism and potential implications for personalized medicine.


Assuntos
2-Piridinilmetilsulfinilbenzimidazóis , Hidrocarboneto de Aril Hidroxilases , Omeprazol , Humanos , Cromatografia Líquida , Hidrocarboneto de Aril Hidroxilases/metabolismo , Citocromo P-450 CYP2C19 , Espectrometria de Massas em Tandem , Celulose
6.
BMC Gastroenterol ; 23(1): 249, 2023 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-37488516

RESUMO

OBJECTIVES: This study aimed to evaluate the efficacy, adverse events, patient compliance, and cost of dual therapy with Ilaprazole-amoxicillin (IA) at high dose versus Ilaprazole-amoxicillin-furazolidone-bismuth (IAFB) quadruple therapy for the Helicobacter pylori (H.pylori) infection among Chinese patients. METHODS: 200 patients who had tested positive for H. pylori and undergoing upper gastrointestinal endoscopy after being diagnosed with chronic gastritis participated in this open-label randomized controlled clinical trial. Patients were randomized to Group A and Group B: the 14-day IA dual treatment group (101) and IAFB quadruple treatment group (99). The 13 C urea breath test was conducted to determine whether H. pylori had been eliminated 4-6 weeks after the treatment. Eradication rates, drug-related adverse events, patient compliance, and drug costs were compared between the two treatment groups. RESULTS: Eradication rates in group A were 92.1% and 94.9%, depending on the intention-to-treat (ITT), per-protocol (PP), respectively, which was similar to group B (91.9% and 93.6%). There was no significant difference observed in adverse events between the two groups (P = 0.518). Interestingly, compliance was significantly higher in group A compared to the group B (P = 0.031). In addition, drug costs were significantly lower for group A in comparison to the group B. CONCLUSIONS: IA dual therapy was found to be equally effective, safer and less costly than IAFB quadruple therapy. Therefore, these therapies can be potentially considered as first-line regimens for empirical treatment.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Humanos , Amoxicilina , 2-Piridinilmetilsulfinilbenzimidazóis , Bismuto , Furazolidona
7.
Sci Rep ; 13(1): 7623, 2023 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-37165049

RESUMO

Breast cancer and diabetes are significant health challenges, and effective treatments for both diseases are lacking. Proton pump inhibitors (PPIs) have demonstrated anticancer and hypoglycemic effects, but their mechanisms of action are not yet fully understood. We used the GeneCards and PharmMapper databases to identify therapeutic targets for diabetes,  breast cancer and PPIs. We identified common targets and constructed a regulatory network of diseases and drugs using the STRING database and Cytoscape software. We also explored the binding between small molecule ligands and protein receptors using Discovery Studio software. We identified 33 shared targets for breast cancer, diabetes, and PPIs including lansoprazole, omeprazole, and pantoprazole, which play a critical role in fatty acid transport, insulin resistance, apoptosis, and cancer-related signaling pathways. Our findings demonstrated that PPIs had a strong affinity for AKT1 and MMP9. This study provides insights into the mechanisms of action of PPIs in breast cancer and diabetes and identifies AKT1 and MMP9 as critical targets for future drug development. Our findings highlight the potential of PPIs as a novel therapeutic approach for these challenging diseases.


Assuntos
Antiulcerosos , Neoplasias da Mama , Diabetes Mellitus , Humanos , Feminino , Inibidores da Bomba de Prótons/farmacologia , Inibidores da Bomba de Prótons/uso terapêutico , Metaloproteinase 9 da Matriz , Antiulcerosos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Farmacologia em Rede , Diabetes Mellitus/tratamento farmacológico , 2-Piridinilmetilsulfinilbenzimidazóis
8.
Turk J Gastroenterol ; 34(5): 533-541, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37158535

RESUMO

BACKGROUND: Gastroesophageal reflux disease is a common condition worldwide. There is no curative treatment for gastroesophageal reflux disease. Endoplasmic reticulum stress leads to the activation of the unfolded protein response and has an important role in inflammation. The aim is to determine the role of endoplasmic reticulum stress in the follow-up of individuals with gastroesophageal reflux disease and the temporal changes of endoplasmic reticulum stress markers with treatment. METHODS: Twenty-four subjects in total were recruited prospectively, of whom 15 had nonerosive reflux disease. Two biopsies from 2 cm above the esophagogastric junction, 2 biopsies from gastric antrum mucosa, and 2 biopsies from gastric corpus mucosa were taken. Simultaneously, 2 tubes of venous blood samples were drawn from each individual (1 tube for studying the genetic markers and 1 tube for analyzing the CYP2C19 polymorphism). RESULTS: The mean age was 42.3 ± 17.6 for women and 34.66 ± 11.2 for men. Pantoprazole, esomeprazole, rabeprazole, and lansoprazole preparations were used for treatment. There was no significant difference between tissue and blood samples for panel genes ATF-6, XBP-1, DDIT-3, DNAJC-10, and EIF-2-AK before treatment. There was a significant decrease in the level of ATF-6, XBP-1, DNAJC-9, EIF2-AK, and NF-2L-2 genes in blood after treatment. In the comparison of proton pump inhibitors, significant decreases in the expression of the ATF-6, XBP-1, and DNAJC-9 mRNAs were detected in blood from individuals after treatment. CONCLUSION: Endoplasmic reticulum stress can be for evaluating the clinical improvement and the effectiveness of treatment in gastroesophageal reflux disease.


Assuntos
Refluxo Gastroesofágico , Omeprazol , Masculino , Feminino , Humanos , Adulto Jovem , Adulto , Pessoa de Meia-Idade , 2-Piridinilmetilsulfinilbenzimidazóis , Resultado do Tratamento , Inibidores da Bomba de Prótons/uso terapêutico , Refluxo Gastroesofágico/tratamento farmacológico , Lansoprazol , Rabeprazol , Estresse do Retículo Endoplasmático
9.
BMC Gastroenterol ; 23(1): 139, 2023 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-37127558

RESUMO

BACKGROUND: VISION is a randomised, phase 4, open-label, parallel-group, multicentre study conducted in 33 centres in Japan. The aim of this study was to assess the long-term safety of vonoprazan for maintenance treatment of healed erosive oesophagitis versus lansoprazole. METHODS: Patients with endoscopically diagnosed erosive oesophagitis were randomised 2:1 to once-daily vonoprazan 20 mg or lansoprazole 30 mg, for a 4- to 8-week healing phase. Patients with endoscopically confirmed healing entered a 260-week maintenance phase with a once-daily starting dose of vonoprazan 10 mg or lansoprazole 15 mg. Primary endpoint was change in gastric mucosal histopathology. RESULTS: Of 208 patients (vonoprazan, n = 139; lansoprazole, n = 69) entering the healing phase, 202 entered the maintenance phase (vonoprazan, n = 135; lansoprazole, n = 67). At 3 years, 109 vonoprazan-treated and 58 lansoprazole-treated patients remained on treatment. Histopathological evaluation of gastric mucosa showed that hyperplasia of parietal, foveolar and G cells was more common with vonoprazan than lansoprazole at week 156 of the maintenance phase. There was no marked increase in the occurrence of parietal, foveolar and G cell hyperplasia among patients in the vonoprazan group from week 48 to week 156. Histopathological evaluation of the gastric mucosa also showed no neoplastic changes in either group. No new safety issues were identified. CONCLUSIONS: In this interim analysis of VISION, no new safety concerns were identified in Japanese patients with healed erosive oesophagitis receiving vonoprazan or lansoprazole as maintenance treatment for 3 years. (CT.gov identifier: NCT02679508; JapicCTI-163153; Japan Registry of Clinical Trials: jRCTs031180040).


Assuntos
Antiulcerosos , Esofagite , Úlcera Péptica , Humanos , Inibidores da Bomba de Prótons/uso terapêutico , Hiperplasia , Lansoprazol/efeitos adversos , Resultado do Tratamento , 2-Piridinilmetilsulfinilbenzimidazóis/uso terapêutico , Antiulcerosos/uso terapêutico , Método Duplo-Cego
10.
Clin Exp Pharmacol Physiol ; 50(6): 516-526, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36897043

RESUMO

Rabeprazole is a representative of proton pump inhibitors and widely used in anti-ulcer treatment. However, the effect of Rabeprazole on gut barrier function remains to be identified. In this study, we show that ZO-1 expression is decreased in patients receiving Rabeprazole by immunofluorescence (IF) analysis. Western blotting (WB) and real-time PCR (qPCR) results demonstrate that Rabeprazole treatment leads to a significant downregulation of ZO-1 expression through inhibition of the FOXF1/STAT3 pathway, leading to destroy barrier function, which illustrates a novel pathway that Rabeprazole regulates barrier function in gastric epithelial cells. Mechanistically, Rabeprazole treatment led to a downregulation of STAT3 and FOXF1 phosphorylation, leading to inhibit nuclear translocation and decrease the binding of STAT3 and FOXF1 to ZO-1 promoter, respectively. Most important, endogenous FOXF1 interacted with STAT3, and this interaction was dramatically abolished by Rabeprazole stimulation. Overexpression of STAT3 and FOXF1 in GES-1 cells reversed the inhibitory effect of Rabeprazole on ZO-1 expression, respectively. These finding extended the function of Rabeprazole and established a previously unappreciated mechanism by which the Rabeprazole/FOXF1/STAT3 axis facilitated ZO-1 expression to regulate barrier function, and a comprehensive consideration and evaluation was required in treatment of patients.


Assuntos
Células Epiteliais , Rabeprazol , Transdução de Sinais , Humanos , 2-Piridinilmetilsulfinilbenzimidazóis/metabolismo , Células Epiteliais/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Rabeprazol/efeitos adversos , Rabeprazol/metabolismo , Fator de Transcrição STAT3/metabolismo , Estômago , Proteína da Zônula de Oclusão-1/efeitos dos fármacos , Proteína da Zônula de Oclusão-1/metabolismo
11.
Int J Mol Sci ; 24(2)2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36674704

RESUMO

Proton-pump inhibitors (PPI), e.g., omeprazole or pantoprazole, are the most widely used drugs for various gastrointestinal diseases. However, more and more side effects, especially an increased risk of infections, have been reported in recent years. The underlying mechanism has still not yet been fully uncovered. Hence, in this study, we analyzed the T cell response after treatment with pantoprazole in vitro. Pantoprazole preincubation reduced the production and secretion of interferon (IFN)-γ and interleukin (IL)-2 after the T cells were activated with phytohemagglutinin (PHA)-L or toxic shock syndrome toxin-1 (TSST-1). Moreover, a lower zinc concentration in the cytoplasm and a higher concentration in the lysosomes were observed in the pantoprazole-treated group compared to the untreated group. We also tested the expression of the zinc transporter Zrt- and Irt-like protein (Zip)8, which is located in the lysosomal membrane and plays a key role in regulating intracellular zinc distribution after T cell activation. Pantoprazole reduced the expression of Zip8. Furthermore, we measured the expression of cAMP-responsive element modulator (CREM) α, which directly suppresses the expression of IL-2, and the expression of the phosphorylated cAMP response element-binding protein (pCREB), which can promote the expression of IFN-γ. The expression of CREMα was dramatically increased, and different isoforms appeared, whereas the expression of pCREB was downregulated after the T cells were treated with pantoprazole. In conclusion, pantoprazole downregulates IFN-γ and IL-2 expression by regulating the expression of Zip8 and pCREB or CREMα, respectively.


Assuntos
Interleucina-2 , Inibidores da Bomba de Prótons , Inibidores da Bomba de Prótons/farmacologia , Pantoprazol/farmacologia , 2-Piridinilmetilsulfinilbenzimidazóis/farmacologia , Zinco/farmacologia , Linfócitos T , Ácidos
12.
Int J Mol Sci ; 23(18)2022 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-36142643

RESUMO

Proton pump inhibitors (PPIs) are an antacid drug often used in acid-related disorders. They decrease acid secretion in the stomach by blocking an enzyme called H+/K+ ATPase which controls acid production. Introduced to the market in 1989, their use has increased rapidly worldwide and they are now among the top 10 most prescribed drugs in the United States. As of 2015, the FDA has already approved six drugs of this class (omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole and rabeprazole). Recently, the risks and benefits of long-term PPI use were questioned and many studies indicated that their use should be carefully considered, especially in young patients, whose treatment with these drugs could last many years. Even greater concerns have been raised about a potential positive association between PPIs and osteoporotic fracture risk including the hip, spine and wrist. Although based on observational studies, there is substantial evidence associating the long-term use of PPIs and fracture. This relationship is only partially admitted due to the lack of consistent effects of PPIs on bone mineral density loss. Therefore, this narrative review aimed to discuss the recent findings pertaining to the risk of osteoporotic fracture associated with PPIs, in particular prolonged use, and to call for further research to elucidate the mechanisms associated with this bone fragility.


Assuntos
Fraturas por Osteoporose , Inibidores da Bomba de Prótons , 2-Piridinilmetilsulfinilbenzimidazóis , Adenosina Trifosfatases , Antiácidos , Densidade Óssea , Dexlansoprazol , Esomeprazol , Humanos , Lansoprazol , Omeprazol/farmacologia , Fraturas por Osteoporose/tratamento farmacológico , Pantoprazol , Inibidores da Bomba de Prótons/efeitos adversos , Rabeprazol , Estados Unidos
13.
J Gastroenterol Hepatol ; 37(11): 2060-2066, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36068945

RESUMO

BACKGROUND AND AIM: Considering the limitation of varying acid suppression of proton pump inhibitors, this study was aimed to assess the efficacy, safety, and dose-effect relationship of keverprazan, a novel potassium-competitive acid blocker, in the treatment of duodenal ulcer (DU) compared with lansoprazole. METHODS: A randomized, double-blind, double-dummy, multicenter, low-dose, high-dose, and positive-drug parallel-controlled study was conducted to verify the non-inferiority of keverprazan (20 or 30 mg) to lansoprazole of 30 mg once daily for 4 to 6 weeks and dose-effect relationship of keverprazan in the treatment of patients with active DU confirmed by endoscopy. RESULTS: Of the 180 subjects randomized, including 55 cases in the keverprazan_20 mg group, 61 cases in the keverprazan_30 mg group, and 64 cases in the lansoprazole_30 mg group, 168 subjects (93.33%) completed the study. The proportions of healed DU subjects in the keverprazan_20 mg, keverprazan_30 mg, and lansoprazole_30 mg groups were respectively 87.27%, 90.16%, and 79.69% at week 4 (P = 0.4595) and were respectively 96.36%, 98.36%, and 92.19% at week 6 (P = 0.2577). The incidence of adverse events in the keverprazan_20 mg group was lower than that in the lansoprazole_30 mg (P = 0.0285) and keverprazan_30 mg groups (P = 0.0398). CONCLUSIONS: Keverprazan was effective and non-inferior to lansoprazole in healing DU. Based on the comparable efficacy and safety data, keverprazan of 20 mg once daily is recommended for the follow-up study of acid-related disorders. (Trial registration number: ChiCTR2100043455.).


Assuntos
Antiulcerosos , Úlcera Duodenal , Humanos , Úlcera Duodenal/tratamento farmacológico , Úlcera Duodenal/induzido quimicamente , Antiulcerosos/uso terapêutico , Seguimentos , Lansoprazol/efeitos adversos , Inibidores da Bomba de Prótons/efeitos adversos , Método Duplo-Cego , 2-Piridinilmetilsulfinilbenzimidazóis/efeitos adversos
14.
J Gastroenterol Hepatol ; 37(10): 1935-1945, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35938741

RESUMO

BACKGROUND AND AIM: The influence of gastric acid inhibitors (GAIs) on nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy is controversial. Herein, the influences of different GAIs on NSAID-induced intestinal injury and the underlying mechanisms are clarified. METHODS: Indomethacin (IND; 10 mg/kg/day) was administered to mice to induce small intestinal injury. Disease activity was examined macroscopically and histologically. The permeability of small intestine was evaluated by measuring plasma lipopolysaccharide levels. 16S rDNA sequencing was performed to determine the composition of intestinal flora. RESULTS: Among the four GAIs, ilaprazole (IPZ) significantly attenuated IND-induced small intestinal injury and maintained the integrity of the mucosal barrier. Omeprazole (OPZ) and vonoprazan (VPZ) ameliorated ulceration without significant differences, while rabeprazole (RPZ) failed to protect against the injury. To explore the potential mechanism, we investigated changes in the gut microbiota mediated by GAIs. After 5-day administration, GAIs significantly altered the composition of the gut microbiota. The IND group had a significant decrease in alpha diversity compared with the control group, and this decrease was reversed by OPZ and IPZ treatment, respectively. After IPZ treatment, the community membership was more assembled in the control group than the IND group. Further, we found that Lactobacillus was significantly increased in the groups of OPZ, IPZ, and VPZ, while Bacteroides was significantly increased in the RPZ group. CONCLUSION: Our results indicated that GAIs have different influences on the mucosal barrier, possibly by altering the composition of intestinal microbiota, and the impacts mediated by various GAIs in the IND-induced intestinal damage model seem different.


Assuntos
Indometacina , Enteropatias , 2-Piridinilmetilsulfinilbenzimidazóis , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , DNA Ribossômico , Indometacina/efeitos adversos , Enteropatias/patologia , Mucosa Intestinal/patologia , Intestino Delgado/patologia , Lipopolissacarídeos , Camundongos , Omeprazol/efeitos adversos , Potássio , Inibidores da Bomba de Prótons/efeitos adversos , Pirróis , Rabeprazol/efeitos adversos , Sulfonamidas
15.
Artigo em Inglês | MEDLINE | ID: mdl-35868653

RESUMO

OBJECTIVE: Management of erosive oesophagitis (EE) remains suboptimal, with many patients experiencing incomplete healing, ongoing symptoms, and relapse despite proton pump inhibitor (PPI) treatment. The Study of Acid-Related Disorders investigated patient burden of individuals with EE in a real-world setting. DESIGN: US gastroenterologists (GIs) or family physicians (FPs)/general practitioners (GPs) treating patients with EE completed a physician survey and enrolled up to four patients with EE for a patient survey, with prespecified data extracted from medical records. RESULTS: 102 GIs and 149 FPs/GPs completed the survey; data were available for 73 patients (mean age at diagnosis, 45.4 years). Omeprazole was healthcare professional (HCP)-preferred first-line treatment (60.8% GIs; 56.4% FPs/GPs), and pantoprazole preferred second line (29.4% and 32.9%, respectively). Price and insurance coverage (both 55.5% HCPs) and familiarity (47.9%) key drivers for omeprazole; insurance coverage (52.0%), price (50.0%), familiarity (48.0%), initial symptom relief (46.0%), and safety (44.0%) key drivers for pantoprazole. Only 49.3% patients took medication as instructed all the time; 56.8% independently increased medication frequency some of the time. Despite treatment, 57.5% patients experienced heartburn and 30.1% regurgitation; heartburn was the most bothersome symptom. 58.9% patients believed that their symptoms could be better controlled; only 28.3% HCPs were very satisfied with current treatment options. 83.6% patients wanted long-lasting treatment options. Fast symptom relief for patients was a top priority for 66.1% HCPs, while 56.6% would welcome alternatives to PPIs. CONCLUSION: This real-world multicentre study highlights the need for new, rapidly acting treatments in EE that reduce symptom burden, offer durable healing and provide symptom control.


Assuntos
Antiulcerosos , Esofagite , Refluxo Gastroesofágico , Úlcera Péptica , Médicos , 2-Piridinilmetilsulfinilbenzimidazóis/uso terapêutico , Antiulcerosos/efeitos adversos , Benzimidazóis/efeitos adversos , Esofagite/induzido quimicamente , Esofagite/tratamento farmacológico , Esofagite/epidemiologia , Refluxo Gastroesofágico/tratamento farmacológico , Refluxo Gastroesofágico/epidemiologia , Azia/induzido quimicamente , Azia/tratamento farmacológico , Humanos , Omeprazol/uso terapêutico , Pantoprazol/uso terapêutico , Úlcera Péptica/induzido quimicamente , Úlcera Péptica/tratamento farmacológico , Inibidores da Bomba de Prótons/uso terapêutico
16.
Expert Opin Drug Metab Toxicol ; 18(5): 337-346, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35787720

RESUMO

INTRODUCTION: Proton pump inhibitors (PPIs) block the gastric H/K-ATPase, therefore inhibiting acid gastric secretion, leading to an increased pH (>4). They account for an extremely high number of prescriptions worldwide. Numerous drug-drug interactions have been described with PPIs, but all the described interactions do not have clinical significance. AREAS COVERED: This review will discuss the latest updates on drug-drug interactions with PPIs, focusing on the last 10-year publications in the following areas: anti-infective agents, anticancer drugs, antiplatelet agents and anticoagulants, and antidiabetics. EXPERT OPINION: Although pharmacokinetic interactions of PPIs have been described with many drugs, their clinical relevance remains controversial. However, given the extremely high number of people being treated with PPIs, clinicians should remain vigilant for interactions that may be clinically significant and require dose adjustment or therapeutic monitoring. Interestingly, not all PPIs have the same pharmacokinetic and pharmacodynamic profile, with some having a strong potential to inhibit CYP2C19, such as omeprazole, esomeprazole, and lansoprazole, while others, pantoprazole, rabeprazole, and dexlansoprazole, are weak CYP2C19 inhibitors. These may be preferred depending on co-prescribed treatments.In addition, new formulations have been developed to prevent some of the gastric pH-dependent drug interactions and should be evaluated in further large-scale prospective comparative studies.


Assuntos
Omeprazol , Inibidores da Bomba de Prótons , 2-Piridinilmetilsulfinilbenzimidazóis/farmacologia , Interações Medicamentosas , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Esomeprazol/farmacologia , Humanos , Omeprazol/farmacocinética , Estudos Prospectivos , Inibidores da Bomba de Prótons/farmacocinética
17.
Aliment Pharmacol Ther ; 55(12): 1524-1533, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35505467

RESUMO

BACKGROUND: Keverprazan is a novel potassium-competitive acid blocker (P-CAB) with a strong acid-suppressive capacity that may provide clinical benefit in acid-related diseases. AIMS: This study aimed to explore the non-inferior efficacy and safety of keverprazan to lansoprazole in treating erosive oesophagitis (EO). METHODS: This was a phase III, randomised, double-blind multicentre study. Patients were randomised to receive keverprazan 20 mg once daily or lansoprazole 30 mg once daily for 4-8 weeks. EO healing rates and adverse events (AEs) were compared between the keverprazan group and the lansoprazole group. RESULTS: A total of 238 patients comprised the full analysis set (FAS) while 221 patients comprised the per-protocol set (PPS). For FAS analysis, the EO healing rates at week 8 were 95.8% (114/119) and 89.9% (107/119) for keverprazan and lansoprazole respectively. For PPS analysis, the EO healing rates at week 8 were 99.1% (110/111) and 92.7% (102/110) for keverprazan and lansoprazole respectively. Non-inferiority of keverprazan compared with lansoprazole according to EO healing rates at 8 weeks was demonstrated in both FAS (difference: 5.8% [95% CI: -0.6% to 12.3%]; p = 0.081) and PPS (difference: 6.1% [95% CI: 1.1%-11.2%]; p = 0.018) analysis. Drug-related AEs were reported in 34.5% (41/119) patients of the keverprazan group and 25.2% (30/119) patients of the lansoprazole group with no significant difference (p = 0.156). No severe AE happened in the keverprazan group. CONCLUSIONS: This study demonstrated the non-inferior efficacy of keverprazan to lansoprazole in treating EO. The incidences of drug-related AEs were comparable between keverprazan and lansoprazole.


Assuntos
Antiulcerosos , Esofagite , Úlcera Péptica , 2-Piridinilmetilsulfinilbenzimidazóis/efeitos adversos , Método Duplo-Cego , Esofagite/tratamento farmacológico , Humanos , Lansoprazol/efeitos adversos , Úlcera Péptica/tratamento farmacológico , Potássio , Inibidores da Bomba de Prótons/efeitos adversos , Resultado do Tratamento
18.
Electrophoresis ; 43(13-14): 1446-1454, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35353923

RESUMO

In this work, a new open-tubular capillary electrochromatography (OT-CEC) column was prepared using ß-cyclodextrin covalent organic framework (ß-CD COF) as a stationary phase. Polydopamine was used to assist fabrication of ß-CD COF on an inner wall of a fused-silica capillary. The coating layer on the capillary was characterized by scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). Electroosmotic flow (EOF) was also studied to evaluate the variation of the inner wall of immobilized columns. Furthermore, the chiral separation effectiveness of the fabricated capillary column was evaluated by CEC using enantiomers of several related proton pump inhibitors as model analytes, including omeprazole, lansoprazole, pantoprazole and tenatoprazole. The effects of bonding time and concentration of ß-CD COF, the type, concentration and pH of buffer, applied voltage were investigated to obtain satisfactory enantioselectivity. In the optimum conditions, the enantiomers of four analytes were resolved within 15 min with resolutions of 1.63-2.62. The relative standard deviation values for migration times and resolutions of the analytes representing intraday and interday were less than 6.75% and 4.24%, respectively. The results reveal that ß-CD COF has great potential as chiral-stationary phases for enantioseparation in CEC.


Assuntos
Eletrocromatografia Capilar , beta-Ciclodextrinas , 2-Piridinilmetilsulfinilbenzimidazóis/análise , Eletrocromatografia Capilar/métodos , Indóis , Polímeros , Estereoisomerismo , beta-Ciclodextrinas/química
19.
Clin Transl Sci ; 15(5): 1155-1166, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35099109

RESUMO

The 13 C-pantoprazole breath test (PAN-BT) is a safe, noninvasive, in vivo CYP2C19 phenotyping probe for adults. Our objective was to evaluate PAN-BT performance in children, with a focus on discriminating individuals who, according to guidelines from the Clinical Pharmacology Implementation Consortium (CPIC), would benefit from starting dose escalation versus reduction for proton pump inhibitors (PPIs). Children (n = 65, 6-17 years) genotyped for CYP2C19 variants *2, *3, *4, and *17 received a single oral dose of 13 C-pantoprazole. Plasma concentrations of pantoprazole and its metabolites, and changes in exhaled 13 CO2 (termed delta-over-baseline or DOB), were measured 10 times over 8 h using high performance liquid chromatography with ultraviolet detection and spectrophotometry, respectively. Pharmacokinetic parameters of interest were generated and DOB features derived using feature engineering for the first 180 min postadministration. DOB features, age, sex, and obesity status were used to run bootstrap analysis at each timepoint (Ti ) independently. For each iteration, stratified samples were drawn based on genotype prevalence in the original cohort. A random forest was trained, and predictive performance of PAN-BT was evaluated. Strong discriminating ability for CYP2C19 intermediate versus normal/rapid metabolizer phenotype was noted at DOBT30 min (mean sensitivity: 0.522, specificity: 0.784), with consistent model outperformance over a random or a stratified classifier approach at each timepoint (p < 0.001). With additional refinement and investigation, the test could become a useful and convenient dosing tool in clinic to help identify children who would benefit most from PPI dose escalation versus dose reduction, in accordance with CPIC guidelines.


Assuntos
Testes Respiratórios , Inibidores da Bomba de Prótons , 2-Piridinilmetilsulfinilbenzimidazóis/farmacocinética , Adulto , Testes Respiratórios/métodos , Criança , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Genótipo , Humanos , Pantoprazol , Inibidores da Bomba de Prótons/farmacocinética
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