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American Journal of Translational... 2022To validate that dexlansoprazole, an anti-acid drug, can prevent pulmonary artery hypertension (PAH) in preclinical animal models and find the possible mechanism of...
OBJECTIVES
To validate that dexlansoprazole, an anti-acid drug, can prevent pulmonary artery hypertension (PAH) in preclinical animal models and find the possible mechanism of action of dexlansoprazole for this new indication.
METHODS
The efficacy of dexlansoprazole to attenuate PAH in vivo was evaluated in PAH animal models. Plasma guanosine 3', 5'-cyclic phosphate (cGMP) in PAH rats was measured by enzyme linked immunosorbent assay (ELISA). To investigate the anti-PAH effect of dexlansoprazole in vitro, proliferation and migration assays of primary cultured pulmonary artery smooth muscle cells (PASMCs) were performed. Furthermore, dexlansoprazole's function on fibroblast transition of vascular smooth muscle cells (VSMC) was explored by single cell ribonucleic acid (RNA) sequencing and RNAscope.
RESULTS
Dexlansoprazole could attenuate the pathologic process in monocrotaline (MCT)-, hypoxia-induced PAH rats and SU5416/hypoxia (SuHy)-induced PAH mice. The intervention with dexlansoprazole significantly inhibited elevated right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and pulmonary vascular wall thickness. Furthermore, plasma cGMP in MCT-induced PAH rats was restored after receiving dexlansoprazole. In vitro, dexlansoprazole could inhibit PASMCs' proliferation and migration stimulated by platelet derived growth factor-BB (PDGF-BB). Moreover, dexlansoprazole significantly ameliorated pulmonary vascular remodeling by inhibiting VSMC phenotypic transition to fibroblast-like cells in a VSMC-specific multispectral lineage-tracing mouse.
CONCLUSIONS
Dexlansoprazole can prevent PAH through promoting cGMP generation and inhibiting pulmonary vascular remodeling through restraining PASMCs' proliferation, migration, and phenotypic transition to fibroblast-like cells. Consequently, PAH might be a new indication for dexlansoprazole.
PubMed: 36105026
DOI: No ID Found -
BMC Nephrology May 2022The objective of this study was to evaluate the reported associations between the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and a variety of...
AIM
The objective of this study was to evaluate the reported associations between the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and a variety of proton pump inhibitors (PPI) through analysis of the reports extracted from the Food and Drug Administration Adverse Event Reporting System (FAERS).
METHODS
FAERS reports from January 2004 to March 2020 were used to conduct disproportionality and Bayesian analyses. The definition of SIADH relied on the preferred terms provided by the Medical Dictionary for Regulatory Activities. The time to onset, mortality, and hospitalization rates of PPI-related SIADH were also investigated.
RESULTS
The study identified a total of 273 reports of PPI-associated SIADH, which appeared to influence more elderly than middle-aged patients (71.1% vs. 12.5%). Women were more affected than men (48.7% vs. 41.8%). Rabeprazole had a stronger SIADH association than other PPIs based on the highest reporting odds ratio (reporting odds ratio = 13.3, 95% confidence interval (CI) = 7.2, 24.9), proportional reporting ratio (proportional reporting ratio = 13.3, χ = 113.7), and empirical Bayes geometric mean (empirical Bayes geometric mean = 13.3, 95% CI = 7.9). The median time to SIADH onset was 22 (interquartile range 6-692) days after PPI administration. PPI-associated SIADH generally led to a 2.95% fatality rate and a 79.7% hospitalization rate. The highest hospitalization death rate occurred in esomeprazole (91.2%).
CONCLUSION
According to our findings, more attention should be paid to SIADH within the first several months after the administration of PPIs. For women older than 65 years, dexlansoprazole may reduce the incidence of PPI-associated SIADH. Nonetheless, larger epidemiological studies are suggested to verify this conclusion.
Topics: Adverse Drug Reaction Reporting Systems; Aged; Bayes Theorem; Female; Humans; Inappropriate ADH Syndrome; Male; Middle Aged; Pharmacovigilance; Proton Pump Inhibitors; Vasopressins
PubMed: 35590283
DOI: 10.1186/s12882-022-02818-3 -
Frontiers in Cardiovascular Medicine 2022Proton pump inhibitors (PPIs) are among the most widely prescribed medications in clinical practice. However, there are also concerns about the potential risks of...
BACKGROUND
Proton pump inhibitors (PPIs) are among the most widely prescribed medications in clinical practice. However, there are also concerns about the potential risks of long-term PPI use. The present study aimed to examine the safety of PPIs and summarize their potential cardiac and vascular risks in a real-world setting.
METHODS
This pharmacovigilance study extracted records between January 2015 and December 2019 from the FDA Adverse Event Reporting System (FAERS) database. The association of seven PPI medications with cardiac and vascular events (CVEs) were evaluated. Two established pharmacovigilance methods, reporting odds ratio (ROR) and information components (IC) based statistical shrinkage, were used to measure disproportionality.
RESULTS
In total 62,140 CVE records associated with PPI use were investigated. Women showed a higher proportion (54.37%) of PPI-associated CVEs. The median time from PPI initiation to CVE onset was 97 [interquartile range (IQR): 8-491] days, with the shortest median time of 42 days (IQR: 2-277 days) for esomeprazole, and the longest time of 389 days (IQR: 0-525 days) for dexlansoprazole. Although PPIs were not associated with elevated CVE risks compared those of the whole database (IC/ROR = -0.39/0.74), various signals emerged. Despite some similarities exist between the PPIs, their cardiac and vascular safety profiles varied significantly. Pantoprazole showed the broadest spectrum of signals, from thrombotic thrombocytopenic purpura (IC/ROR = 0.01/1.08) to renal haemangioma (IC/ROR = 3.14/9.58). Esomeprazole showed the second-broadest spectrum of toxicities, ranging from duodenal ulcer hemorrhage (IC/ROR = 0.07/1.28) to hypertensive nephropathy (IC/ROR = 4.09/18.72). Vascular signals were more dominant than cardiac signals, suggesting that vascular function was more heavily affected. Hypertensive nephropathy, renal haemangioma, renal artery stenosis, and renal infarct had strong signals across most PPI regimens and merited further attention.
CONCLUSIONS
PPIs may inflict various CVEs, particularly those involving the vascular system, on the users. Given the wide range of onset times and different toxicity profiles for various PPI medications, they should be prescribed with caution.
PubMed: 35282344
DOI: 10.3389/fcvm.2022.767987 -
The Cochrane Database of Systematic... Jan 2022Upper gastrointestinal (GI) bleeding is a common reason for emergency hospital admission. Proton pump inhibitors (PPIs) reduce gastric acid production and are used to... (Review)
Review
BACKGROUND
Upper gastrointestinal (GI) bleeding is a common reason for emergency hospital admission. Proton pump inhibitors (PPIs) reduce gastric acid production and are used to manage upper GI bleeding. However, there is conflicting evidence regarding the clinical efficacy of proton pump inhibitors initiated before endoscopy in people with upper gastrointestinal bleeding.
OBJECTIVES
To assess the effects of PPI treatment initiated prior to endoscopy in people with acute upper GI bleeding.
SEARCH METHODS
We searched the CENTRAL, MEDLINE, Embase and CINAHL databases and major conference proceedings to October 2008, for the previous versions of this review, and in April 2018, October 2019, and 3 June 2021 for this update. We also contacted experts in the field and searched trial registries and references of trials for any additional trials.
SELECTION CRITERIA
We selected randomised controlled trials (RCTs) that compared treatment with a PPI (oral or intravenous) versus control treatment with either placebo, histamine-2 receptor antagonist (HRA) or no treatment, prior to endoscopy in hospitalised people with uninvestigated upper GI bleeding.
DATA COLLECTION AND ANALYSIS
At least two review authors independently assessed study eligibility, extracted study data and assessed risk of bias. Outcomes assessed at 30 days were: mortality (our primary outcome), rebleeding, surgery, high-risk stigmata of recent haemorrhage (active bleeding, non-bleeding visible vessel or adherent clot) at index endoscopy, endoscopic haemostatic treatment at index endoscopy, time to discharge, blood transfusion requirements and adverse effects. We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
We included six RCTs comprising 2223 participants. No new studies have been published after the literature search performed in 2008 for the previous version of this review. Of the included studies, we considered one to be at low risk of bias, two to be at unclear risk of bias, and three at high risk of bias. Our meta-analyses suggest that pre-endoscopic PPI use may not reduce mortality (OR 1.14, 95% CI 0.76 to 1.70; 5 studies; low-certainty evidence), and may reduce rebleeding (OR 0.81, 95% CI 0.62 to 1.06; 5 studies; low-certainty evidence). In addition, pre-endoscopic PPI use may not reduce the need for surgery (OR 0.91, 95% CI 0.65 to 1.26; 6 studies; low-certainty evidence), and may not reduce the proportion of participants with high-risk stigmata of recent haemorrhage at index endoscopy (OR 0.80, 95% CI 0.52 to 1.21; 4 studies; low-certainty evidence). Pre-endoscopic PPI use likely reduces the need for endoscopic haemostatic treatment at index endoscopy (OR 0.68, 95% CI 0.50 to 0.93; 3 studies; moderate-certainty evidence). There were insufficient data to determine the effect of pre-endoscopic PPI use on blood transfusions (2 studies; meta-analysis not possible; very low-certainty evidence) and time to discharge (1 study; very low-certainty evidence). There was no substantial heterogeneity amongst trials in any analysis.
AUTHORS' CONCLUSIONS
There is moderate-certainty evidence that PPI treatment initiated before endoscopy for upper GI bleeding likely reduces the requirement for endoscopic haemostatic treatment at index endoscopy. However, there is insufficient evidence to conclude whether pre-endoscopic PPI treatment increases, reduces or has no effect on other clinical outcomes, including mortality, rebleeding and need for surgery. Further well-designed RCTs that conform to current standards for endoscopic haemostatic treatment and appropriate co-interventions, and that ensure high-dose PPIs are only given to people who received endoscopic haemostatic treatment, regardless of initial randomisation, are warranted. However, as it may be unrealistic to achieve the optimal information size, pragmatic multicentre trials may provide valuable evidence on this topic.
Topics: Acute Disease; Endoscopy; Gastrointestinal Hemorrhage; Histamine H2 Antagonists; Humans; Proton Pump Inhibitors
PubMed: 34995368
DOI: 10.1002/14651858.CD005415.pub4 -
Frontiers in Medicine 2021Non-cardiac chest pain is common with two-thirds due to gastroesophageal reflux disease (GERD). To evaluate the effectiveness and safety of guided vs. empirical...
Non-cardiac chest pain is common with two-thirds due to gastroesophageal reflux disease (GERD). To evaluate the effectiveness and safety of guided vs. empirical therapy in non-cardiac chest pain. Adults with normal angiogram or stress test were randomized into either a guided or empirical group. In the guided group, after the ambulatory pH-impedance test, if GERD then dexlansoprazole 30 mg/day for 8 weeks, but if functional or hypersensitive chest pain, then theophylline SR 250 mg/day for 4 weeks. In the empirical group, dexlansoprazole 60 mg/day was given for 2 weeks. The primary outcome was global chest pain visual analog score (VAS) and secondary outcomes were Quality of Life in Reflux and Dyspepsia (QOLRAD), GERD questionnaire (GERDQ), and pH parameters, all determined at baseline, 2nd and 8th weeks. Of 200 screened patients, 132 were excluded, and of 68 randomized per-protocol, 33 were in the guided group and 35 in the empirical group. For between-group analysis, mean global pain scores were better with guided vs. empirical group at 8th week ( = 0.005) but not GERDQ or QOLRAD or any of pH measures (all > 0.05). For within-group analysis, mean QOLRAD improved earliest at 8th week vs. baseline ( = 0.006) in the guided group and 2nd week vs. baseline ( = 0.011) in the empirical group but no differences were seen in other secondary outcomes ( > 0.05). No serious adverse events were reported. Guided approach may be preferred over short-term empirical therapy in symptom response, however QOLRAD, acid-related symptoms, or pH measures are not significantly different (trial registration ID no. NCT03319121).
PubMed: 33659261
DOI: 10.3389/fmed.2021.605647 -
Scientific Reports Feb 2021Proton pump inhibitors (PPIs) were widely used. Observational studies suggested increasing risk of kidney injury in patients with PPIs treatment. We gathered six PPI...
Proton pump inhibitors (PPIs) were widely used. Observational studies suggested increasing risk of kidney injury in patients with PPIs treatment. We gathered six PPI regimens and adverse reports of acute kidney injury (AKI) and chronic kidney disease (CKD) based on US FDA Adverse Event Reporting System (FAERS) database from 2004 to 2019. We employed reporting odds ratio (ROR) to detect signals. Finally, we identified 3187 PPIs-associated AKI cases and 3457 PPIs-associated CKD cases. We detected significant signals between PPIs and AKI as well as CKD. The signal strength was stronger for CKD (ROR = 8.80, 95% CI 8.49-9.13) than AKI (ROR = 3.95, 95% CI 3.81-4.10), while dexlansoprazole performed stronger association for CKD (ROR = 34.94, 95% CI 30.89-39.53) and AKI (ROR = 8.18, 95% CI 7.04-9.51) than the other five PPIs. The median time from PPIs use to event occurrence was 23 days for AKI and 177 days for CKD. PPIs-associated AKI resulted larger proportion of death, life-threatening, hospitalization and disability events than PPIs-associated CKD. By mining the FAERS big data, we provided more information between PPIs use and the AKI and CKD events. PPIs rational use should be repeatedly stressed.
Topics: Acute Kidney Injury; Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Data Mining; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Proton Pump Inhibitors; Renal Insufficiency, Chronic; United States; United States Food and Drug Administration; Young Adult
PubMed: 33574396
DOI: 10.1038/s41598-021-83099-y -
Medicine Dec 2020Randomized trials and observation studies have revealed conflicting results regarding the interaction between clopidogrel and proton pump inhibitors (PPIs). The aim of... (Observational Study)
Observational Study
BACKGROUND
Randomized trials and observation studies have revealed conflicting results regarding the interaction between clopidogrel and proton pump inhibitors (PPIs). The aim of our study was to provide laboratory evidence regarding whether PPIs blunt the antiplatelet reactivity of clopidogrel.
METHODS
We included records of Asian patients who received clopidogrel treatment for cardiovascular or cerebrovascular events and the VerifyNow P2Y12 assay for platelet reactivity monitoring. The responsiveness of antiplatelet effect to clopidogrel was analyzed according to 3 criteria:Results: Patients treated without PPIs did not differ significantly from those concomitantly treated with PPIs in terms of levels of PI (25.7% ± 24.3% vs 23.0 ± 25.3%, P = .4315), PRU (187.3 ± 74.0 vs 197.4 ± 77.3, P = .3373), or responsiveness to antiplatelet (adjusted absolute risk, 3.5%; 95% confidence interval, - 10.7 to 17.7%; P = .6297). Patients treated with lansoprazole, esomeprazole, pantoprazole, and rabeprazole exhibited no significant differences in PRU or PI levels compared with those treated without PPIs. By contrast, patients treated with dexlansoprazole exhibited a significantly decreased level of PI (25.7% ± 24.3% vs 14.0% ± 21.6%, P = .0297) and responsiveness to clopidogrel under the criterion PI > 20% (adjusted absolute risk: 10.5%; 95% confidence interval: 2.6% to 43.6%; P = .0274).
CONCLUSION
No robust interaction between clopidogrel and PPIs was found, but caution should be exercised in the concomitant use of dexlansoprazole and clopidogrel in Asians.
Topics: Age Factors; Aged; Aged, 80 and over; Asian People; Clopidogrel; Comorbidity; Drug Interactions; Female; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Proton Pump Inhibitors; Receptors, Purinergic P2Y12; Sex Factors
PubMed: 33327360
DOI: 10.1097/MD.0000000000023695 -
Indian Journal of Pharmacology 2020Levofloxacin-based triple therapies are considered the standard regimen for eradication of Helicobacter pylori (H. pylori) due to decreased sensitivity to clarithromycin... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Levofloxacin-based triple therapies are considered the standard regimen for eradication of Helicobacter pylori (H. pylori) due to decreased sensitivity to clarithromycin and the optimal duration of therapy is still controversial. Besides, there is no complete evidence about dexlansoprazole efficacy in the eradication of H. pylori.
AIM
Our study aimed to determine the effectiveness of triple therapy based on levofloxacin-dexlansoprazole as a standard treatment for H. pylori infection and estimate the effect of H. pylori on lipid profile and hemoglobin (Hb).
MATERIALS AND METHODS
A pilot prospective randomized trial of a triple therapy based on levofloxacin-dexlansoprazole for H. pylori eradication was conducted at Damanhour Medical National Institute, Egypt; 66 participants with H. pylori infection received levofloxacin (500 mg/day) plus amoxicillin (1 g/12 h) plus dexlansoprazole (60 mg/day). All medications administrated orally for either 7 days or 10 days. Four weeks after treatment, the eradication was assessed by the stool antigen test.
RESULTS
The rate of eradication was 63.6% in levofloxacin, amoxicillin, and dexlansoprazole (LAD) 7-day group, and 90.9% in LAD 10-day group. In addition, laboratory test results showed a significant difference in Hb, low-density lipoprotein, high-density lipoprotein, triglyceride, and total cholesterol levels before and after treatment (P < 0.05).
CONCLUSION
LAD 10 days is the least duration that provides maximum efficacy for H. pylori in Egyptian participants. In addition, successful treatment of H. pylori infection may reduce the risk of anemia and dyslipidemia. Furthermore, all members of the patient's family should be screened for H. pylori to prevent recurrent infection.
Topics: Adolescent; Adult; Amoxicillin; Anti-Bacterial Agents; Dexlansoprazole; Drug Therapy, Combination; Female; Helicobacter Infections; Helicobacter pylori; Humans; Levofloxacin; Male; Middle Aged; Pilot Projects; Prospective Studies; Proton Pump Inhibitors; Time Factors; Treatment Outcome; Young Adult
PubMed: 33283766
DOI: 10.4103/ijp.IJP_364_19 -
Clinical and Translational Science Jan 2021There is limited evidence to support pharmacogenetic (PGx) testing in children. We conducted a retrospective review of PGx testing among 452 patients at an academic...
There is limited evidence to support pharmacogenetic (PGx) testing in children. We conducted a retrospective review of PGx testing among 452 patients at an academic children's hospital to determine the potential utility of PGx in diseases of childhood and to identify targets for future pediatric pharmacogenetic research. An actionable gene-drug pair associated with the 28 genes tested (Clinical Pharmacogenetics Implementation Consortium (CPIC) level A or B, Pharmacogenomics Knowledge Base (PharmGKB) level 1A or B, or US Food and Drug Administration (FDA) recommendation and a PharmGKB level) was present in 98.7% of patients. We identified 203 actionable gene-drug-diagnosis groups based on the indications for each actionable drug listed in Lexicomp. Among patients with an actionable gene-drug-diagnosis group, 49.3% had a diagnosis where the drug was a therapeutic option and PGx could be used to guide treatment selection. Among patients with an associated diagnosis, 30.9% had a prescription for the actionable drug allowing PGx guided dosing. Three genes (CYP2C19, CYP2D6, and CYP3A5) accounted for all the gene-drug-diagnosis groups with matching diagnoses and prescriptions. The most common gene-drug-diagnosis groups with matching diagnoses and prescriptions were CYP2C19-citalopram-escitalopram-depression 3.3% of patients tested; CYP2C19-dexlansoprazole-gastritis-esophagitis 3.1%; CYP2C19-omeprazole-gastritis-esophagitis 2.4%; CYP2D6-atomoxetine-attention deficit hyperactivity disorder 2.2%; and CYP2C19-citalopram-escitalopram-obsessive-compulsive disorder 1.5%. PGx could be used to guide selection of current treatment options or medication dosing in almost half (48.7%) of pediatric patients tested. Mood disorders and gastritis/esophagitis are promising targets for future study of PGx testing because of the high prevalence of these diagnoses and associated actionable gene-drug pairs in the pediatric population.
Topics: Academic Medical Centers; Adolescent; Attention Deficit Disorder with Hyperactivity; Child; Clinical Decision-Making; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Depression; Dose-Response Relationship, Drug; Drug Prescriptions; Esophagitis; Feasibility Studies; Female; Gastritis; Hospitals, Pediatric; Humans; Male; Obsessive-Compulsive Disorder; Pharmacogenomic Testing; Pharmacogenomic Variants; Prescription Drugs; Retrospective Studies
PubMed: 33048453
DOI: 10.1111/cts.12895