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Mohan M, Mannan A, Singh S, Singh TG. Unlocking the cellular mystery: how proton pump inhibitors may alter the dementia landscape. Brain Res 2025; 1861:149702. [PMID: 40368227 DOI: 10.1016/j.brainres.2025.149702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2025] [Revised: 04/30/2025] [Accepted: 05/10/2025] [Indexed: 05/16/2025]
Abstract
Proton pump inhibitors (PPIs) have become virtually the sole class of histamine-2 receptor antagonists due to their greater effectiveness and general availability. However, concern has been increasing about long-term use and some possible neurological adverse effects, including a link with dementia. Several studies indicate that long-term use of PPIs can raise the risk for both Alzheimer's disease (AD) and non-Alzheimer's dementia, though there is opposing evidence. Neurological side effects of PPIs are cognitive impairment, neuropathies, depression, anxiety, and hallucinations. The mechanisms are unknown but could be due to PPIs crossing the BBB and interfering with neuronal function or causing systemic deficiencies, e.g., vitamin B12 deficiency. Vitamin B12 is essential for cognitive function, and its deficiency has been linked to dementia. PPIs also cause B12 deficiency by inhibiting gastric acid secretion, which is required for B12 absorption. B12 deficiency causes hyperhomocysteinemia, which facilitates tau hyperphosphorylation and amyloid-β (Aβ) deposition, major pathological hallmarks of AD. PPIs have also been found to disrupt amyloid precursor protein processing, mitochondrial function, and neuroinflammation, further enhancing neurodegenerative processes. Experimental evidence indicates that PPIs affect brain homeostasis through inhibition of vacuolar ATPases, modulation of microglial Aβ phagocytosis, and induction of synaptic dysfunction. While the specific molecular mechanisms are unknown, findings suggest that long-term PPI exposure could contribute to neurodegeneration, especially in elderly patients. With increasing dementia prevalence, additional clinical research is needed to ascertain whether PPIs are a causative agent or a contributing factor to cognitive impairment.
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Affiliation(s)
- Maneesh Mohan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Ashi Mannan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Shareen Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
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Pu Q, Lai X, Peng Y, Wu Q. A controllable DNA: structural features and advanced applications of i-motif. Analyst 2025; 150:1726-1740. [PMID: 40183738 DOI: 10.1039/d4an01549e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2025]
Abstract
The i-motif consists of two parallel-stranded duplexes, stabilized by intercalated semi-protonated cytosine-cytosine (C·C+) pairing. Initially, the i-motif was thought to be unstable under physiological pH, which limited its biological interest. However, recent studies have demonstrated the presence of i-motifs in regulatory regions of the human genome at neutral pH, making their study biologically relevant. In addition, in the field of nanotechnology, the reversible pH-responsive properties of i-motif structures have been utilized to construct functional nanostructures for biomedical diagnostics and therapeutics. In this review, we present an overview of the structural features of i-motifs, the factors affecting their stability, and detection methods. Furthermore, we focus on summarizing recent advances in the application of i-motif-based functional nanostructures at the cellular level. The challenges and future prospects of i-motifs in nanomedicine are also discussed at the end of this paper.
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Affiliation(s)
- Qiumei Pu
- NHC Key Laboratory of Tropical Disease Control, School of Tropical Medicine & The Second Affiliated Hospital, Hainan Medical University, Haikou, 571199, China.
- Key Laboratory of Emergency and Trauma of Ministry of Education, The First Affiliated Hospital, Hainan Medical University, Haikou, 570102, China
| | - Xiangde Lai
- NHC Key Laboratory of Tropical Disease Control, School of Tropical Medicine & The Second Affiliated Hospital, Hainan Medical University, Haikou, 571199, China.
- Key Laboratory of Emergency and Trauma of Ministry of Education, The First Affiliated Hospital, Hainan Medical University, Haikou, 570102, China
| | - Yanan Peng
- Key Laboratory of Advanced Materials of Tropical Island Resources, Ministry of Education, School of Materials Science and Engineering, Hainan University, Haikou, 570228, China.
| | - Qiang Wu
- NHC Key Laboratory of Tropical Disease Control, School of Tropical Medicine & The Second Affiliated Hospital, Hainan Medical University, Haikou, 571199, China.
- Key Laboratory of Emergency and Trauma of Ministry of Education, The First Affiliated Hospital, Hainan Medical University, Haikou, 570102, China
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3
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Xie Y, Yan Y, Hong Q, Zheng H, Cao L, Li X, Liu S, Chen H. Heterogeneous treatment effects of stress ulcer prophylaxis among ICU patients at risk for gastrointestinal bleeding. BMC Med 2025; 23:206. [PMID: 40189498 PMCID: PMC11974205 DOI: 10.1186/s12916-025-04038-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 03/26/2025] [Indexed: 04/09/2025] Open
Abstract
BACKGROUND While randomized clinical trials of stress ulcer prophylaxis (SUP) have generally shown no overall benefit, subgroup analyses suggest the benefit or harm of SUP in specific patients, indicating heterogeneity of treatment effects (HTE). Understanding HTE is crucial for tailoring SUP to individual treatment. METHODS This cohort study included patients admitted to intensive care unit (ICU) with at least one risk factor for clinically important gastrointestinal bleeding (GIB). The primary exposure was the use of SUP within 48 h after ICU entry; the primary outcome was 28-day mortality. We employed conventional subgroup analysis, risk-based analysis, and effect-based analysis to explore the HTE of SUP. RESULTS A total of 25,475 patients were included, of whom 6199 (24.3%) received SUP, with famotidine being the most commonly prescribed (53.7%). Baseline characteristics were well-balanced between treatment groups after weighting. SUP was not associated with the 28-day mortality in the overall population (median value for the posterior distribution of the odds ratio (OR), 1.03; 95% credible interval (CrI), 0.96-1.11). In conventional subgroups, the impact of SUP on 28-day mortality varied substantially between patients with an age of higher than or equal to 77 years in comparison with other age subgroups (posterior probability of difference in OR, 99.3%), between patients with and without chronic liver disease (posterior probability of difference in OR, 99.9%), between patients with and without coagulopathy (posterior probability of difference in OR, 92.1%), and between patients with and without malignant cancer (posterior probability of difference in OR, 100%). In risk-based analysis, patients at high risk of death exhibited the highest propensity for benefit from SUP (posterior probability of an OR > 1, 1.9%). In effect-based analysis, patients with malignant cancer and a higher Charlson comorbidity index identified at high probability of benefit. CONCLUSIONS Among ICU patients with at least one risk factor for clinically important GIB, those who are younger, have chronic liver disease, coagulopathy, or malignant cancer are more likely to benefit from SUP.
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Affiliation(s)
- Yongpeng Xie
- Department of Emergency and Critical Care Medicine, the First Affiliated Hospital, The First People'S Hospital of Lianyungang, the Lianyungang Clinical College of Nanjing Medical University, Kangda College of Nanjing Medical University, the Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu, 222000, China
| | - Yao Yan
- Department of Emergency and Critical Care Medicine, the First Affiliated Hospital, The First People'S Hospital of Lianyungang, the Lianyungang Clinical College of Nanjing Medical University, Kangda College of Nanjing Medical University, the Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu, 222000, China
| | - Qixiang Hong
- Department of Emergency and Critical Care Medicine, the First Affiliated Hospital, The First People'S Hospital of Lianyungang, the Lianyungang Clinical College of Nanjing Medical University, Kangda College of Nanjing Medical University, the Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu, 222000, China
| | - Hui Zheng
- Department of Emergency and Critical Care Medicine, the First Affiliated Hospital, The First People'S Hospital of Lianyungang, the Lianyungang Clinical College of Nanjing Medical University, Kangda College of Nanjing Medical University, the Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu, 222000, China
| | - Lijuan Cao
- Department of Emergency and Critical Care Medicine, the First Affiliated Hospital, The First People'S Hospital of Lianyungang, the Lianyungang Clinical College of Nanjing Medical University, Kangda College of Nanjing Medical University, the Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu, 222000, China
| | - Xiaoming Li
- Department of Emergency and Critical Care Medicine, the First Affiliated Hospital, The First People'S Hospital of Lianyungang, the Lianyungang Clinical College of Nanjing Medical University, Kangda College of Nanjing Medical University, the Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu, 222000, China
| | - Songqiao Liu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, China.
- The First People's Hospital of Lianyungang, The Lianyungang Clinical College of Nanjing Medical University, The First Affiliated Hospital of Kangda College of Nanjing Medical University, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu, 222000, China.
- Department of Critical Care Medicine, Trauma Center, Nanjing Lishui People's Hospital, Zhongda Hospital Lishui Branch, Nanjing, Jiangsu, 211200, China.
| | - Hui Chen
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China.
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Ibrahim IA, Al-Qadhi HI. The anti ulcerogenic effect of sildenafil and moringa on ulcers in rats. Tissue Cell 2025; 93:102685. [PMID: 39765139 DOI: 10.1016/j.tice.2024.102685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 11/27/2024] [Accepted: 12/12/2024] [Indexed: 03/05/2025]
Abstract
BACKGROUND Moringa and Sildenafil oleifera (MO) have been shown to mitigate the ulcerogenic effects of medications that induce ulcers in rats. OBJECTIVE the goal of This research is to assess the combined protective effects of Sildenafil citrate and the Indian herb Moringa oleifera against indomethacin-induced gastric ulcers in rats. MATERIALS AND METHODS Gastric ulcers were induced in rats by oral administration of indomethacin. Forty-eight rats were randomly distributed into six groups: Group 1 (control); Group 2 (indomethacin 60 mg/kg); Group 3 (sildenafil 50 mg/kg prior to indomethacin); Group 4 (Moringa leaf powder 200 mg/kg prior to indomethacin); Group 5 (both sildenafil and Moringa prior to indomethacin); and Group 6 (omeprazole prior to indomethacin). RESULTS Indomethacin significantly increased gastric mucosal ulceration in comparison to the control group. Rats in the indomethacin group exhibited elevated levels of Caspase 3, tumor necrosis factor-α (TNF-α), and malondialdehyde (MDA), while nitric oxide (NO) levels were reduced. Pretreatment with omeprazole resulted in a reduction of MDA, TNF-α, and Caspase 3 levels, but had no effect on NO levels. Pretreatment with sildenafil and/or Moringa significantly impacting the ulcer scores and make it less, increased NO levels, and decreased tissue MDA and TNF-α levels. CONCLUSION The study concludes that Sildenafil and Moringa oleifera exhibit gastroprotective effects in experimentally induced gastric ulcer models in rats.
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Affiliation(s)
- Ihab Abdulwahid Ibrahim
- Department of Pharmacology, College of Medicine,University of Baghdad, Iraq; Department of Pharmacology, College of Medicine, University of Baghdad, Iraq.
| | - Huda I Al-Qadhi
- Department of Pharmacology, College of Medicine,University of Baghdad, Iraq; Department of Pharmacology, College of Medicine, University of Baghdad, Iraq.
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MAFFEZZOLI MICHELE, GIUDICE GIULIACLAIRE, IOVANE GIACOMO, MANINI MARTINA, RAPACCHI ELENA, CARUSO GIUSEPPE, SIMONI NICOLA, FERRETTI STEFANIA, PULIATTI STEFANO, CAMPOBASSO DAVIDE, BUTI SEBASTIANO. The effect of concomitant drugs on oncological outcomes in patients treated with immunotherapy for metastatic urothelial carcinoma: a narrative review. Oncol Res 2025; 33:741-757. [PMID: 40191722 PMCID: PMC11964881 DOI: 10.32604/or.2024.057278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 11/04/2024] [Indexed: 04/09/2025] Open
Abstract
Background immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic urothelial carcinoma (mUC), significantly improving survival outcomes. However, a subset of patients do not respond to ICIs, prompting research into potential predictive factors. Commonly prescribed medications such as corticosteroids, proton-pump inhibitors (PPIs), antibiotics (Abs), antihypertensives, and analgesics may influence ICI effectiveness. Methods we conducted a literature search on PubMed to investigate the impact of concomitant medications on the outcomes of patients with mUC, treated with ICIs. We selected the most relevant studies and performed a narrative review. Results corticosteroids, PPIs and Abs have been associated with reduced survival in ICI-treated patients, including those with mUC. In contrast, antihypertensive agents like renin-angiotensin system inhibitors and beta-blockers may enhance ICI efficacy, though evidence remains inconclusive. The impact of other medications, such as statins, metformin, and analgesics, on ICI outcomes is less clear, with some data suggesting a detrimental impact on immune response. Conclusions this narrative review synthesizes current evidence on how concomitant medications affect outcomes in mUC patients treated with ICIs.
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Affiliation(s)
- MICHELE MAFFEZZOLI
- Medical Oncology Unit, University Hospital of Parma, Parma, 43126, Italy
- Department of Medicine and Surgery, University of Parma, Parma, 43126, Italy
| | - GIULIA CLAIRE GIUDICE
- Medical Oncology Unit, University Hospital of Parma, Parma, 43126, Italy
- Department of Medicine and Surgery, University of Parma, Parma, 43126, Italy
| | - GIACOMO IOVANE
- Medical Oncology Unit, University Hospital of Parma, Parma, 43126, Italy
- Department of Medicine and Surgery, University of Parma, Parma, 43126, Italy
| | - MARTINA MANINI
- Medical Oncology Unit, University Hospital of Parma, Parma, 43126, Italy
- Department of Medicine and Surgery, University of Parma, Parma, 43126, Italy
| | - ELENA RAPACCHI
- Medical Oncology Unit, University Hospital of Parma, Parma, 43126, Italy
| | - GIUSEPPE CARUSO
- Medical Oncology Unit, University Hospital of Parma, Parma, 43126, Italy
| | - NICOLA SIMONI
- Radiotherapy Unit, University Hospital of Parma, Parma, 43126, Italy
| | - STEFANIA FERRETTI
- Department of Urology, University of Modena and Reggio Emilia, Modena, 41124, Italy
| | - STEFANO PULIATTI
- Department of Urology, University of Modena and Reggio Emilia, Modena, 41124, Italy
| | | | - SEBASTIANO BUTI
- Medical Oncology Unit, University Hospital of Parma, Parma, 43126, Italy
- Department of Medicine and Surgery, University of Parma, Parma, 43126, Italy
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Mohyeldeen D, Arafat W. Proton pump inhibitors reduce survival outcomes in patients treated with capecitabine: meta-analysis. Ecancermedicalscience 2025; 19:1868. [PMID: 40492211 PMCID: PMC12146577 DOI: 10.3332/ecancer.2025.1868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Indexed: 06/11/2025] Open
Abstract
Proton pump inhibitors (PPIs) are widely used over-the-counter drugs. The interaction between capecitabine and PPIs is still ambiguous within the literature, with some discrepancies still being present regarding the risks, or benefits, of their concomitant use. This meta-analysis aims to analyse data from the literature regarding both the risk of PPIs on survival in patients treated with capecitabine, as well as their benefits regarding the incidence of hand-foot syndrome (HFS). A total of 17 studies were included after searching PubMed, Medline and Cochrane until October 2022 for the effect of PPIs on the treatment efficacy and pharmacokinetics, and incidence of HFS. Revman Ver. 5.3 was used for all statistical analyses. Our data showed a significant HFS reduction at a relative risk of 0.77 (95% CI: 0.70-085; p < 0.00001) in the PPI-using groups compared to control. Meta-analysis of studies assessing survival, however, showed a reduction in almost all survival aspects, most notably within the recurrence-free survival, with a hazard ratio of 1.75; 95% CI: 1.21-2.53; p = 0.003. Individual data incriminating the use of PPIs with capecitabine is quite limited; however, our robust survival data on around 30,000 patients gave significantly worse survival outcomes, particularly in the (neo)adjuvant setting.
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Affiliation(s)
- Dina Mohyeldeen
- Oncology Department, Faculty of Medicine, Alexandria University, Alexandria 21526, Egypt
- https://orcid.org/0000-0002-4424-2648
| | - Waleed Arafat
- Oncology Department, Faculty of Medicine, Alexandria University, Alexandria 21526, Egypt
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Bioletto F, Calleris G, Aversa LS, Oderda M, Marra G, Parasiliti-Caprino M, Gesmundo I, Granata R, Gontero P, Ghigo E. Association between the use of proton pump inhibitors and serum PSA levels in the general U.S. population. World J Urol 2025; 43:133. [PMID: 39982526 PMCID: PMC11845559 DOI: 10.1007/s00345-025-05469-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Accepted: 01/15/2025] [Indexed: 02/22/2025] Open
Abstract
BACKGROUND Proton pump inhibitors (PPIs) are widely prescribed drugs that have been associated with increased prostate cancer (PCa) cell proliferation in vitro and worse oncological outcomes in vivo. However, data on their influence on PSA levels in the general population are lacking. METHODS We extracted individual participant data from the 2001-2010 cycles of the National Health and Nutrition Examination Survey (NHANES), in which PSA levels were measured in all male participants aged 40 years or older. The association of PPI use with total PSA levels and free/total PSA ratio was evaluated through multivariable linear regression analyses, adjusted for potential confounders. RESULTS A total of 7366 subjects were included (median age: 53 years; median serum PSA: 0.9 ng/mL), of whom 746 were receiving PPI treatment at the time of the study. After adjustment for potential confounders, ongoing PPI use was associated with lower total PSA levels (-0.24 ng/mL, 95%CI: [-0.37,-0.11], p < 0.001), while no significant association with free/total PSA ratio was found (p = 0.881). A significant effect modification was observed according to age, with the association being limited to older participants (≥ 60 years) at stratified analyses. CONCLUSIONS Contrary to the available data in the context of PCa, we found no evidence of increased PSA levels in PPI users with no prostate malignancy. Instead, PPI use was associated with a decrease of total PSA in older adults. This adds knowledge on how PPIs may influence PSA in population-based screening programs.
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Affiliation(s)
- Fabio Bioletto
- Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy.
| | - Giorgio Calleris
- Division of Urology, Department of Surgical Sciences, University of Turin, Turin, Italy
| | - Luigi Simone Aversa
- Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy
| | - Marco Oderda
- Division of Urology, Department of Surgical Sciences, University of Turin, Turin, Italy
| | - Giancarlo Marra
- Division of Urology, Department of Surgical Sciences, University of Turin, Turin, Italy
| | | | - Iacopo Gesmundo
- Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy
| | - Riccarda Granata
- Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy
| | - Paolo Gontero
- Division of Urology, Department of Surgical Sciences, University of Turin, Turin, Italy
| | - Ezio Ghigo
- Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy
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Tandoğan Yİ, Aydin O, Pehlivanli F, Aydinuraz K, Daphan ÇE, Kaplan İ. Therapeutic Effects of Esomeprazole on Pancreatic and Lung Injury in Acute Pancreatitis: An Experimental Study. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:200. [PMID: 40005317 PMCID: PMC11857347 DOI: 10.3390/medicina61020200] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 01/02/2025] [Accepted: 01/22/2025] [Indexed: 02/27/2025]
Abstract
Background and Objectives: During acute pancreatitis, leakage of pancreatic enzymes into the gland results in autolysis of the pancreas. The lungs are also involved in this process. This study aimed to investigate the therapeutic effects of esomeprazole on damaged pancreatic tissue and affected lung tissue in rats with acute pancreatitis. Materials and Methods: The 24 Wistar-Albino male rats were divided into three groups: Control group (2 mL 0.9% saline solution was given intraperitoneally, n = 8); PCT group (acute pancreatitis was induced and then 2 mL 0.9% saline solution was administered intraperitoneally, n = 8); ESM group (acute pancreatitis was induced and then 10 mg/kg esomeprazole was administered intraperitoneally, n = 8). Then, the lungs and pancreas were completely removed, and blood samples were taken from all rats for histopathological and biochemical examination. Results: Pancreatic edema, vacuolization, necrosis, and inflammation in the PCT group were higher than in the control and ESM groups. Alveolar edema, alveolar distension, alveolar PMNL infiltration, and alveolar wall thickness in the PCT group were higher than in the control and ESM groups. Furthermore, IL-β (F = 40.137, p < 0.001), TNF-α (F = 40.132, p < 0.001), MIP-2 (X2 = 19.245, p < 0.001), ICAM-1 (F = 14.312, p < 0.001), NO (F = 25.873, p < 0. 001), amylase (F = 30.333, p < 0.001), and lipase (X2 = 16.141, p < 0.001) values measured in serum were different among groups. Pairwise group comparisons revealed that IL-β, TNF-α, MIP-2, and amylase levels in the ESM group were lower than in the PCT group (p < 0.05). Conclusions: Esomeprazole could be recommended in clinical practice during acute pancreatitis treatment due to its therapeutic effects on damaged pancreatic and lung tissues secondary to pancreatitis in rats.
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Affiliation(s)
| | - Oktay Aydin
- Department of General Surgery, Kirikkale University School of Medicine, Kirikkale 71450, Turkey (K.A.)
| | - Faruk Pehlivanli
- Department of General Surgery, Kirikkale University School of Medicine, Kirikkale 71450, Turkey (K.A.)
| | - Kuzey Aydinuraz
- Department of General Surgery, Kirikkale University School of Medicine, Kirikkale 71450, Turkey (K.A.)
| | - Çağatay Erden Daphan
- Department of General Surgery, Kirikkale University School of Medicine, Kirikkale 71450, Turkey (K.A.)
| | - İlker Kaplan
- Department of General Surgery, Ermenek State Hospital, Karaman 70400, Turkey;
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Hong KJ, Wang TC, Tsui K. Association of acid-suppressive therapy and tuberculosis: A causal or coincidental link to the infection? Respir Investig 2025; 63:27-32. [PMID: 39615321 DOI: 10.1016/j.resinv.2024.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 10/16/2024] [Accepted: 11/12/2024] [Indexed: 01/13/2025]
Abstract
BACKGROUND Acid-suppressant proton-pump inhibitors (PPI) and histamine-2-receptor antagonists (H2RA) are associated with an increased risk of tuberculosis (TB). However, it remains unclear whether this association is causal or coincidental. METHODS Patients newly diagnosed with TB between 2000 and 2013 were identified from the Taiwan National Health Insurance Database. Each patient with TB was matched in a 1:10 ratio with patients without TB by age, sex, and index date. The time lags from the end of PPI or H2RA treatment to the index date, and respective cumulative doses in the 90 days before the index date, were analyzed for association with TB. RESULTS The age (mean [standard deviation] 60.8 [17.3] years) and sex ratio (69.4% males) were comparable between patients with TB (n = 6002) and patients without TB (n = 60,020). Previous PPI or H2RA treatment was more frequently observed in patients with TB (16.6% vs. 8.9%, p < 0.001). Concurrent antacid therapy posed the highest risk for TB (odds ratio [OR] 4.21 for PPI and 2.24 for H2RA, both p < 0.0001), and the closer to the end of the therapy, the more likely TB was detected (p for trend: 0.0077 for PPI and 0.0145 for H2RA). The cumulative doses of antacid in the 90 days before TB had an inverse relationship with TB risk. PPI, used either alone or in combination with H2RA, conferred a higher risk of TB than H2RA alone. CONCLUSIONS Tuberculosis should be considered in symptomatic patients receiving or recently ceased antacid therapy with PPI or H2RA in TB endemic areas.
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Affiliation(s)
- Kun-Jing Hong
- Department of Medical Research, Cathay General Hospital, No.280, Sec. 4, Renai Rd., Daan Dist., Taipei, 106438, Taiwan
| | - Ting-Chuan Wang
- Integrative medical database center, Department of Medical Research, National Taiwan University Hospital, No. 7, Zhongshan S. Rd., Zhongzheng Dist., Taipei, 100225, Taiwan
| | - Kochung Tsui
- Department of Medical Research, Cathay General Hospital, No.280, Sec. 4, Renai Rd., Daan Dist., Taipei, 106438, Taiwan; Division of Infectious Diseases, Department of Internal Medicine, Cathay General Hospital, No.280, Sec. 4, Renai Rd., Daan Dist., Taipei, 106438, Taiwan; Fu Jen Catholic University School of Medicine, No. 510, Zhongzheng Rd., Xinzhuang Dist., New Taipei City, 242062, Taiwan.
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Kim SY, Yoon JH, Jung DH, Kim GH, Kim CH, Lee SK. Fexuprazan safeguards the esophagus from hydrochloric acid-induced damage by suppressing NLRP1/Caspase-1/GSDMD pyroptotic pathway. Front Immunol 2024; 15:1410904. [PMID: 39737189 PMCID: PMC11682960 DOI: 10.3389/fimmu.2024.1410904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 11/22/2024] [Indexed: 01/01/2025] Open
Abstract
Introduction Proton pump inhibitors (PPIs) and potassium-competitive acid blockers (P-CABs) are widely used to manage gastric acid-related disorders by inhibiting hydrochloric acid (HCl) secretion from parietal cells in the stomach. Although PPIs are known to have anti-inflammatory properties beyond their role in inhibiting gastric acid secretion, research on P-CABs is lacking. In this study, we aimed to investigate whether all available P-CABs exhibit anti-inflammatory effects in gastroesophageal reflux-induced esophagitis and to elucidate the underlying mechanisms. Methods Het-1A cells, normal esophageal epithelial cells, were treated with HCl (pH 4) for 30 min. Esomeprazole, a representative PPI, and three currently marketed P-CABs (vonoprazan, tegoprazan, and fexuprazan) were used for pretreatment. Total RNA sequencing was performed using Het-1A cells pretreated with 1% DMSO or fexuprazan, followed by exposure to HCl. Pyroptosis was measured using lactate dehydrogenase (LDH) release and Annexin V-FITC/PI staining. Western blotting, qRT-PCR, and ELISA were used to determine the expression of the related genes. Results Pretreatment with esomeprazole, vonoprazan, tegoprazan, and fexuprazan significantly inhibited the HCl-induced pro-inflammatory cytokines, including IL-6, IL-8, IL-1β, and TNF-α. Fexuprazan and vonoprazan significantly attenuated the HCl-induced pyroptosis rate, as assessed by elevated LDH release and Annexin V-FITC/PI staining, whereas esomeprazole and tegoprazan did not. RNA sequencing revealed that NOD-like receptor (NLR) family pyrin domain-containing 1 (NLRP1) was significantly reduced in Het-1A cells pretreated with fexuprazan compared to those treated with DMSO. Fexuprazan and vonoprazan markedly reduced the HCl-induced transcriptional and translational expression of genes involved in the pyroptosis pathway, including NLRP1, Caspase-1, gasdermin D, and IL-1β. Notably, fexuprazan reduced the HCl-induced increase in pyroptosis and IL-1β using siRNA, even in the presence of NLRP1 knockdown. Fexuprazan, tested on inflammatory THP-1 macrophage cells, significantly reduced NLRP1 expression and inhibited lipopolysaccharide-induced pyroptosis. Conclusion Our findings reveal that all p-CABs exhibit anti-inflammatory properties, while fexuprazan inhibits inflammation and pyroptosis of esophageal cells caused by the gastric acid. Therefore, it is presumed to have additional benefits in gastroesophageal reflux disease in addition to suppressing gastric acid secretion.
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Affiliation(s)
- Seo Yeon Kim
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Department of Internal Medicine, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jung-Ho Yoon
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Da Hyun Jung
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Ga Hee Kim
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Chul Hoon Kim
- Department of Internal Medicine, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea
- Department of Pharmacology, BK21 PLUS Project for Medical Science, Brain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sang Kil Lee
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
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Borekci A, Kuru Bektasoglu P, Somay A, Hazneci J, Gürer B. Esomeprazole's Antifibrotic Effects on Rats With Epidural Fibrosis. Global Spine J 2024:21925682241306045. [PMID: 39622191 PMCID: PMC11613153 DOI: 10.1177/21925682241306045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 11/07/2024] [Accepted: 11/25/2024] [Indexed: 12/06/2024] Open
Abstract
STUDY DESIGN Rat subjects were randomly assigned to control, local, and systemic esomeprazole groups (n = 4-6 per group). OBJECTIVE Excessive scar formation after laminectomy can cause nerve entrapment and postoperative pain and discomfort. A rat laminectomy model determined whether topical application and systemic administration of esomeprazole can prevent epidural fibrosis. METHODS Laminectomy alone was performed in the control group. Topical esomeprazole was introduced to the laminectomy area in the local esomeprazole group. Intraperitoneal esomeprazole was introduced in the systemic esomeprazole group following laminectomy. Macroscopic and histopathologic examinations were performed four weeks after laminectomy. RESULTS In the systemic esomeprazole group, the macroscopic epidural fibrosis score was less than the control group (P < 0.001). Microscopic epidural fibrosis score and fibroblast cell density classification scores in local and systemic esomeprazole groups did not significantly differ. Fibrosis thickness was significantly lower in the local and systemic esomeprazole groups compared to the control group (P < 0.01, P < 0.001, respectively). CONCLUSIONS Esomeprazole reduced the formation of epidural fibrosis in the rat laminectomy model.
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Affiliation(s)
- Ali Borekci
- University of Health Sciences, Fatih Sultan Mehmet Education and Research Hospital, Department of Neurosurgery, Istanbul, Turkiye
| | - Pinar Kuru Bektasoglu
- University of Health Sciences, Fatih Sultan Mehmet Education and Research Hospital, Department of Neurosurgery, Istanbul, Turkiye
| | - Adnan Somay
- University of Health Sciences, Fatih Sultan Mehmet Education and Research Hospital, Department of Pathology, Istanbul, Turkiye
| | - Jülide Hazneci
- University of Health Sciences, Fatih Sultan Mehmet Education and Research Hospital, Department of Neurosurgery, Istanbul, Turkiye
| | - Bora Gürer
- Istinye University Faculty of Medicine, Department of Neurosurgery, Istanbul, Turkiye
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12
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Li J, Yao S, Zimny S, Koob D, Jin H, Wimmer R, Denk G, Tuo B, Hohenester S. The acidic microenvironment in the perisinusoidal space critically determines bile salt-induced activation of hepatic stellate cells. Commun Biol 2024; 7:1591. [PMID: 39609606 PMCID: PMC11605060 DOI: 10.1038/s42003-024-07192-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 10/31/2024] [Indexed: 11/30/2024] Open
Abstract
Cholestatic liver diseases, accompanied by the hepatic accumulation of bile salts, frequently lead to liver fibrosis, while underlying profibrogenic mechanisms remain incompletely understood. Here, we evaluated the role of extracellular pH (pHe) on bile salt entry and hepatic stellate cell (HSC) activation and proliferation. As modulators of intracellular pH (pHi), various proton pump inhibitors (PPI) were tested for their ability to prevent bile salt entry and HSC activation. Lastly, the PPI pantoprazole was employed in the 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine (DDC)-diet model of cholestatic liver fibrosis. We found in vitro, that slightly acidic pHe (7.2-7.3) enhanced bile salt accumulation in HSC and was a prerequisite to bile salt-induced HSC activation. Pantoprazole in the DDC model exhibited antifibrotic effects. We conclude that bile salt-induced activation of HSC may depend on the slightly acidic microenvironment present in the perisinusoidal space and modulation of pHi in HSC may offer a novel pharmacological target in cholestatic disease.
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Affiliation(s)
- Jingguo Li
- Department of Medicine II, LMU University Hospital, LMU Munich, Munich, Germany
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Shun Yao
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Sebastian Zimny
- Department of Medicine II, LMU University Hospital, LMU Munich, Munich, Germany
| | - Dennis Koob
- Department of Medicine II, LMU University Hospital, LMU Munich, Munich, Germany
| | - Hai Jin
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Ralf Wimmer
- Department of Medicine II, LMU University Hospital, LMU Munich, Munich, Germany
| | - Gerald Denk
- Department of Medicine II, LMU University Hospital, LMU Munich, Munich, Germany
| | - Biguang Tuo
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
| | - Simon Hohenester
- Department of Medicine II, LMU University Hospital, LMU Munich, Munich, Germany.
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13
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Cui X, Yin L, Zhang Y, Jiang X, Li L, Bi X. Salivary microbiota composition before and after use of proton pump inhibitors in patients with laryngopharyngeal reflux: a self-control study. BMC Oral Health 2024; 24:1194. [PMID: 39379876 PMCID: PMC11460238 DOI: 10.1186/s12903-024-05000-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 10/01/2024] [Indexed: 10/10/2024] Open
Abstract
BACKGROUND Issues associated with proton pump inhibitor (PPI) usage have been documented. PPIs affect the gastrointestinal microbiome, as well as the saliva microbiota of healthy individuals. However, the alterations in the saliva microbiota of laryngopharyngeal reflux (LPR) patients remain unclear. This study aims to examine the composition of saliva microbiota in LPR patients before and after PPI usage through a self-controlled study. METHODS Thirty-two adult LPR patients participated in the study. Saliva samples were collected before and after an 8-week regimen of twice-daily administration of 20-mg esomeprazole. The impact of PPI administration on bacterial communities was assessed using 16 S rRNA gene sequencing. The functional and metabolic changes in saliva microbial communities after PPI usage were analyzed using PICRUSt2 based on our 16 S rRNA gene sequencing results. RESULTS The alpha diversity within the salivary microbiota, as measured by the PD-whole-tree index, exhibited a significant difference between samples collected before and after PPI application (P = 0.038). Additionally, PCoA analysis of unweighted UniFrac distances (beta diversity) revealed distinct separation of saliva sample microbiota structures before and after PPI application in LPR patients, with statistical significance (Adonis test, R2 = 0.063, P< 0.010). Taxon-based analysis indicated that PPI administration increased the abundance of Epsilonproteobacteria, Campylobacterales, Campylobacteraceae, Campylobacter, and Campylobacter_gracilis, while reducing the abundance of Lactobacillaceae and Lactobacillus in salivary samples ( P< 0.050). Using LEfSe to compare bacterial abundances, Bacillaceae and Anoxybacillus were found to be enriched before PPI usage in LPR patients. Furthermore, the proportion of genes responsible for indole alkaloid biosynthesis in the salivary microbiota of LPR patients significantly increased after PPI therapy (P< 0.050). CONCLUSIONS These findings indicate that PPIs induce alterations in the salivary microbiota of LPR patients. CHINESE CLINICAL TRIAL REGISTRY No. ChiCTR2300067507. Registered on January 10,2023 retrospectively. LEVEL OF EVIDENCE: 4
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Affiliation(s)
- Xiaohuan Cui
- Senior Department of Otolaryngology Head and Neck Surgery, the Sixth Medical Center, Chinese PLA General Hospital, Chinese PLA Medical School, Beijing, 100048, China
- State Key Laboratory of Hearing and Balance Science, Beijing, 100853, China
- National Clinical Research Center for Otolaryngologic Diseases, Beijing, 100853, China
- Key Laboratory of Hearing Science, Ministry of Education, Beijing, 100853, China
- Beijing Key Laboratory of Hearing Impairment Prevention and Treatment, Beijing, 100853, China
- Department of Otorhinolaryngology Head and Neck Surgery, the Eighth Medical Center, Chinese PLA General Hospital, Beijing, 100091, China
| | - Longlong Yin
- Hebei North University, Zhangjiakou, 075051, China
| | - Yanping Zhang
- Senior Department of Otolaryngology Head and Neck Surgery, the Sixth Medical Center, Chinese PLA General Hospital, Chinese PLA Medical School, Beijing, 100048, China.
- State Key Laboratory of Hearing and Balance Science, Beijing, 100853, China.
- National Clinical Research Center for Otolaryngologic Diseases, Beijing, 100853, China.
- Key Laboratory of Hearing Science, Ministry of Education, Beijing, 100853, China.
- Beijing Key Laboratory of Hearing Impairment Prevention and Treatment, Beijing, 100853, China.
- Department of Otorhinolaryngology Head and Neck Surgery, the Eighth Medical Center, Chinese PLA General Hospital, Beijing, 100091, China.
| | - Xingwang Jiang
- Senior Department of Otolaryngology Head and Neck Surgery, the Sixth Medical Center, Chinese PLA General Hospital, Chinese PLA Medical School, Beijing, 100048, China
- State Key Laboratory of Hearing and Balance Science, Beijing, 100853, China
- National Clinical Research Center for Otolaryngologic Diseases, Beijing, 100853, China
- Key Laboratory of Hearing Science, Ministry of Education, Beijing, 100853, China
- Beijing Key Laboratory of Hearing Impairment Prevention and Treatment, Beijing, 100853, China
- Department of Otorhinolaryngology Head and Neck Surgery, the Eighth Medical Center, Chinese PLA General Hospital, Beijing, 100091, China
| | - Lina Li
- Senior Department of Otolaryngology Head and Neck Surgery, the Sixth Medical Center, Chinese PLA General Hospital, Chinese PLA Medical School, Beijing, 100048, China
- State Key Laboratory of Hearing and Balance Science, Beijing, 100853, China
- National Clinical Research Center for Otolaryngologic Diseases, Beijing, 100853, China
- Key Laboratory of Hearing Science, Ministry of Education, Beijing, 100853, China
- Beijing Key Laboratory of Hearing Impairment Prevention and Treatment, Beijing, 100853, China
- Department of Otorhinolaryngology Head and Neck Surgery, the Eighth Medical Center, Chinese PLA General Hospital, Beijing, 100091, China
| | - Xinxin Bi
- Senior Department of Otolaryngology Head and Neck Surgery, the Sixth Medical Center, Chinese PLA General Hospital, Chinese PLA Medical School, Beijing, 100048, China
- State Key Laboratory of Hearing and Balance Science, Beijing, 100853, China
- National Clinical Research Center for Otolaryngologic Diseases, Beijing, 100853, China
- Key Laboratory of Hearing Science, Ministry of Education, Beijing, 100853, China
- Beijing Key Laboratory of Hearing Impairment Prevention and Treatment, Beijing, 100853, China
- Department of Otorhinolaryngology Head and Neck Surgery, the Eighth Medical Center, Chinese PLA General Hospital, Beijing, 100091, China
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Schlager H, Baumann-Durchschein F, Steidl K, Häfner M, Dinkhauser P, Weitersberger M, Holzinger J, Mader M, Gröchenig HP, Madl C, Schreiner P. Diagnosis and management of eosinophilic esophagitis and esophageal food impaction in adults : A position paper issued by the Austrian Society of Gastroenterology and Hepatology (ÖGGH). Wien Klin Wochenschr 2024; 136:479-499. [PMID: 39230674 PMCID: PMC11387459 DOI: 10.1007/s00508-024-02401-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 06/21/2024] [Indexed: 09/05/2024]
Abstract
This position paper deals with an expert consensus on diagnosis and management of eosinophilic esophagitis and esophageal food impaction issued by the Austrian Eosinophilic Esophagitis Network, a working group under the patronage of the Austrian Society of Gastroenterology and Hepatology (ÖGGH). In need of a standardized approach on the management of EoE, recommendations were made based on international guidelines and landmark studies.
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Affiliation(s)
- Hansjörg Schlager
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, University Hospital Graz, Auenbruggerplatz 15, 8036, Graz, Austria.
| | - Franziska Baumann-Durchschein
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, University Hospital Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Karin Steidl
- Department of Internal Medicine, Barmherzige Brüder St. Veit/Glan, St. Veit, Austria
| | - Michael Häfner
- 2nd Medical Department, Barmherzige Schwestern Krankenhaus, Vienna, Austria
| | - Patrick Dinkhauser
- Department of Internal Medicine I, Division of Gastroenterology and Hepatology, Endocrinology and Rheumatology, Klinikum Wels-Grieskirchen, Wels, Austria
| | - Michael Weitersberger
- Department of Gastroenterology and Hepatology, Ordensklinikum Linz Barmherzige Schwestern, Linz, Austria
| | - Josef Holzinger
- Department of Surgery, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria
| | - Markus Mader
- Department of Internal Medicine II, Universitätsklinikum St. Pölten-Karl Landsteiner Privatuniversität, St. Pölten, Austria
| | - Hans Peter Gröchenig
- Department of Internal Medicine, Barmherzige Brüder St. Veit/Glan, St. Veit, Austria
| | - Christian Madl
- Division of Gastroenterology and Hepatology, Krankenanstalt Rudolfstiftung, Krankenanstaltenverbund Wien (KAV), Vienna, Austria
| | - Philipp Schreiner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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15
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Pu L, Jia T, Su S, Yang L, Yao H, Su Y, Chen Z. Proton Pump Inhibitors Versus Histamine-2 Receptor Blockers for Stress Ulcer Prophylaxis on In-hospital Mortality Among Intensive Care Unit Patients Hospitalized for Major Adverse Cardiovascular and Cerebrovascular Events: Retrospective Cohort Study. Clin Ther 2024; 46:677-682. [PMID: 39068058 DOI: 10.1016/j.clinthera.2024.06.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Accepted: 06/27/2024] [Indexed: 07/30/2024]
Abstract
PURPOSE Patients in the intensive care unit (ICU) commonly receive stress ulcer prophylaxis drugs, either proton pump inhibitors (PPIs) or histamine-2 receptor blockers (H2RBs). The goal of this research was to evaluate the impact of these drugs on mortality among ICU patients hospitalized for major adverse cardiovascular and cerebrovascular events (MACCEs). METHODS ICU patients hospitalized for MACCEs were sourced from the Medical Information Mart for Intensive Care-III database. We performed a propensity score matching analysis to match patients treated with PPIs to those treated with H2RBs for stress ulcer prophylaxis. The outcome was 90-day mortality. We used multivariable Cox regression analyses to compare the effect. Hazard ratio (HR), 95% CIs, and P values were reported from the model. FINDINGS From 2001 to 2012, a total of 3577 patients hospitalized for MACCEs (1997 received PPIs and 1580 received H2RBs) were admitted. The 90-day mortality was 23.7% (848/3577); it was 27% (540/1997) and 19.5% (308/1580) for PPIs and H2RBs users, respectively. The PPI group exhibited a greater 90‑day mortality in comparison to the H2RBs group (relative risk = 1.17; P = 0.036), after conditioning on potential confounder. The results remained robust in propensity score matching, sensitivity analyses, and subgroup analyses. IMPLICATIONS PPIs for stress ulcer prophylaxis were linked to an increased risk of in-hospital mortality than H2RBs in patients hospitalized for MACCEs. Further investigation of this association and validation of its clinical significance is needed.
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Affiliation(s)
- Lanxiang Pu
- Department of Pharmacy, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, China
| | - Ting Jia
- Centre for Reproductive Medicine, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, China
| | - Shili Su
- Department of Gynaecology and Obstetrics, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, China
| | - Liang Yang
- Department of Pharmacy, Second Affiliated Hospital, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Hong Yao
- Department of Pharmacy, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, China
| | - Yujie Su
- Department of Gynaecology and Obstetrics, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, China
| | - Zhaowen Chen
- Department of Gynaecology and Obstetrics, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, China.
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Liang Y, Meng Z, Ding XL, Jiang M. Effects of proton pump inhibitors on inflammatory bowel disease: An updated review. World J Gastroenterol 2024; 30:2751-2762. [PMID: 38899331 PMCID: PMC11185295 DOI: 10.3748/wjg.v30.i21.2751] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 04/26/2024] [Accepted: 05/15/2024] [Indexed: 06/03/2024] Open
Abstract
Inflammatory bowel disease (IBD) is believed to be caused by various factors, including abnormalities in disease susceptibility genes, environmental factors, immune factors, and intestinal bacteria. Proton pump inhibitors (PPIs) are the primary drugs used to treat acid-related diseases. They are also commonly prescribed to patients with IBD. Recent studies have suggested a potential association between the use of certain medications, such as PPIs, and the occurrence and progression of IBD. In this review, we summarize the potential impact of PPIs on IBD and analyze the underlying mechanisms. Our findings may provide insights for conducting further investigations into the effects of PPIs on IBD and serve as an important reminder for physicians to exercise caution when prescribing PPIs to patients with IBD.
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Affiliation(s)
- Yu Liang
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Zhen Meng
- Department of Intervention, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Xue-Li Ding
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Man Jiang
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
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Ayoub M, Tomanguillo J, Faris C, Anwar N, Chela H, Daglilar E. Use of proton pump inhibitors improves outcomes in mild acute pancreatitis: A nationwide cohort study. Medicine (Baltimore) 2024; 103:e37694. [PMID: 38579028 PMCID: PMC10994513 DOI: 10.1097/md.0000000000037694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Accepted: 03/01/2024] [Indexed: 04/07/2024] Open
Abstract
Previous studies showed a potential anti-inflammatory effect of proton pump inhibitors (PPI) as well as possible inhibition of pancreatic secretion. This presents the question of their possible use in acute pancreatitis (AP). Current clinical evidence does not address the role of PPI and the present review for possible therapeutic use and safety is lacking. Therefore, our study aims to address the role of PPI in the management of AP and their association with the different outcomes of AP. We queried the Diamond Network through TriNetX-Research Network. This network included 92 healthcare organizations. Patients with mild AP with Bedside Index of Severity in Acute Pancreatitis (BISAP) score of Zero regardless of etiology were divided into 2 cohorts; 1st cohort included patients on PPI, and 2nd cohort included patients not on any PPI. Patients with BISAP score equal to or more than 1 or on PPI prior to the study date were excluded. Two well-matched cohorts were created using 1:1 propensity-scored matching model between cohorts. We compared the incidence of intensive care unit admission, mortality, and other associated complications. A total of 431,571 patients met the inclusion criteria. Of those, 32.9% (n = 142,062) were on PPI, and 67% (n = 289,509) were not on any PPI. After propensity matching, the sample included 115,630 patients on PPI vs 115,630 patients not on PPI. The PPI group had a lower rate of mortality (3.7% vs 4.4%, P < .001), a lower rate of intensive care unit admission (3.9% vs 5.5%, P < .001), a lower rate of necrotizing pancreatitis (1.1% vs 1.9%, P < .001), a lower rate of Hospital-Acquired Pneumonia (3.6% vs 4.9%, P < .001), a lower rate of respiratory failure (2.8% vs 4.2%, P < .001), and a lower rate of acute kidney injury (6.9% vs 10.1%, P < .001). There was no statistical difference in the rate of Clostridium difficile infection between the 2 cohorts (0.9% vs 0.8%, P = .5). The use of PPI in mild AP with a BISAP-score of zero is associated with reduced pancreatitis-related complications and improved mortality. Prospective studies are needed to confirm these findings.
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Affiliation(s)
- Mark Ayoub
- Internal Medicine Department, Charleston Area Medical Center, West Virginia University, Charleston, WV, USA
| | - Julton Tomanguillo
- Internal Medicine Department, Charleston Area Medical Center, West Virginia University, Charleston, WV, USA
| | - Carol Faris
- Department of General Surgery, Marshall University School of Medicine, Huntington, WV, USA
| | - Nadeem Anwar
- West Virginia University School of Medicine, Charleston Division, Gastroenterology, Charleston, WV, USA
| | - Harleen Chela
- West Virginia University School of Medicine, Charleston Division, Gastroenterology, Charleston, WV, USA
| | - Ebubekir Daglilar
- West Virginia University School of Medicine, Charleston Division, Gastroenterology, Charleston, WV, USA
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Bjurström O, Karling P. The association between drugs and repeated treatment with budesonide in patients with microscopic colitis: a retrospective observational study. Therap Adv Gastroenterol 2024; 17:17562848241240640. [PMID: 38510459 PMCID: PMC10953108 DOI: 10.1177/17562848241240640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 03/01/2024] [Indexed: 03/22/2024] Open
Abstract
Background Smoking and the use of non-steroidal anti-inflammatory drugs (NSAIDs) acetylsalicylic acid (ASA), proton pump inhibitors (PPIs), serotonin reuptake inhibitors (SSRIs), and statins have been associated with microscopic colitis (MC). Objectives We investigated whether these factors were associated with repeated budesonide treatments in patients diagnosed with MC. Design Retrospective observational study. Methods All patients with a histologically verified diagnosis of MC at our clinic between the years 2006 and 2022 were identified. Baseline factors and drugs prescribed before and after diagnosis were registered. The influence of risk factors on the odds of having a prescription of oral budesonide and the odds of having a second course of budesonide was studied. Results Patients with MC (n = 183) with a mean age of 62.3 years [standard deviation (SD): 13.3 years] were followed for a median of 5 years (25th-75th percentile 4-10 years) after diagnosis. In all, 138 patients (75%) had at least one prescription of budesonide after diagnosis, and 90 patients (49%) had at least one clinical relapse treated with budesonide. Patients who had been prescribed NSAIDs within 1 year before clinical relapse had higher odds for clinical relapse [odds ratio (OR): 3.70, 95% confidence interval (CI): 1.06-12.9] but there was no increased risk for clinical relapse for the use of ASA (OR: 0.99, 95% CI: 0.39-2.90), PPIs (OR: 1.09, 95% CI: 0.45-2.63), SSRI (OR: 1.41, 95% CI: 0.82-2.44), or statins (OR: 0.83, 95% CI: 0.35-1.99). No association was seen between being a smoker and/or being prescribed NSAID, ASA, PPI, SSRI, and statins at baseline and the odds of having a prescription of oral budesonide within 1 year after diagnosis. Conclusion The risk of being prescribed a second course of budesonide is associated with receiving a prescription of NSAIDs but not with the use of ASA, PPIs, SSRIs, and statins.
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Affiliation(s)
- Oliver Bjurström
- Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
| | - Pontus Karling
- Department of Public Health and Clinical Medicine, Umeå University, Umeå, 901 87, Sweden
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Dimitrov G, Aumar M, Duhamel A, Wanneveich M, Gottrand F. Proton pump inhibitors in esophageal atresia: A systematic review and meta-analysis. J Pediatr Gastroenterol Nutr 2024; 78:457-470. [PMID: 38262739 DOI: 10.1002/jpn3.12115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 12/09/2023] [Accepted: 12/18/2023] [Indexed: 01/25/2024]
Abstract
Gastroesophageal reflux disease (GERD) is frequent and prolonged in esophageal atresia (EA) pediatric patients requiring routine use of proton pump inhibitors (PPIs). However, there are still controversies on the prophylactic use of PPIs and the efficacy of PPIs on GERD and EA complications in this special condition. The aim of the study is to assess the prophylactic use of PPIs in pediatric patients with EA and its complications. We, therefore, performed a systematic review including all reports on the subject from 1980 to 2022. We conducted meta-analysis of the pooled proportion of PPI-and no PPI groups using random effect model, meta-regression, and estimate heterogeneity by heterogeneity index I2 . Thirty-eight reports on the topic met the criteria selection, representing a cumulative 6044 patients with EA. Prophylactic PPI prescription during the first year of life does not appear to prevent GERD persistence at follow-up and is not associated with a significantly reduced rate of antireflux surgical procedures (ARP). PPIs improve peptic esophagitis and induce remission of eosinophilic esophagitis at a rate of 50%. Their effect on other GERD outcomes is uncertain. Evidence suggests that PPIs do not prevent anastomotic stricture, Barrett's esophagus, or respiratory complications. PPI use in EA can improve peptic and eosinophilic esophagitis but is ineffective on the other EA complications. Side effects of PPIs in EA are almost unknown.
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Affiliation(s)
- Georges Dimitrov
- Unit of Pediatric Surgery, Unit of Pediatrics, Competence Centre for Rare Esophageal Diseases, University Hospital Center of Orléans, Orléans, France
| | - Madeleine Aumar
- Reference Centre for Rare Esophageal Diseases, University of Lille, CHU Lille, Lille, France
| | - Alain Duhamel
- Biostatistics Unit, University Hospital of Lille, Lille, France
| | | | - Frédéric Gottrand
- Reference Centre for Rare Esophageal Diseases, University of Lille, CHU Lille, Lille, France
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Banna S, Schenck C, Shahu A, Thomas A, Heck C, Tangredi R, Ali T, Miller PE. Stress Ulcer Prophylaxis in Mechanically Ventilated Patients With Acute Myocardial Infarction. JACC. ADVANCES 2024; 3:100750. [PMID: 38939822 PMCID: PMC11198220 DOI: 10.1016/j.jacadv.2023.100750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 10/10/2023] [Accepted: 11/03/2023] [Indexed: 06/29/2024]
Abstract
Background Proton pump inhibitors (PPIs) and histamine type 2-receptor blockers (H2Bs) are commonly used for stress ulcer prophylaxis among patients requiring invasive mechanical ventilation (IMV). Recent studies suggest an increased mortality associated with PPIs compared to H2Bs, but these studies poorly represent patients with cardiovascular disease or acute myocardial infarction (AMI). Objectives The aim of this study was to compare outcomes related to stress ulcer prophylaxis with PPIs compared to H2Bs in patients with AMI requiring IMV. Methods We queried the Vizient Clinical Data Base for adults aged ≥18 years admitted between October 2015 and December 2019 with a primary diagnosis of AMI and requiring IMV. Using multivariable logistic regression, we assessed for the association between stress ulcer prophylaxis and in-hospital mortality. Results Including 11,252 patients with AMI requiring IMV, 66.7% (n = 7,504) received PPIs and 33.3% (n = 3,748) received H2Bs. Age, sex, and the proportion of patients presenting with ST-segment elevation myocardial infarction or cardiogenic shock were similar between groups (all, P > 0.05). Compared to PPIs, patients receiving H2Bs had a lower mortality (41.5% vs 43.5%, P = 0.047), which was not statistically significant after multivariate adjustment (odds ratio 0.97; 95% confidence interval: 0.89-1.06, P = 0.49). In unadjusted and adjusted analyses, H2Bs use was associated with fewer ventilator days, less ventilator-associated pneumonia, and lower hospitalization cost but similar Clostridium difficile infections. Conclusions Among patients with AMI requiring IMV in this observation cohort study, there was no difference in mortality among patients receiving H2Bs vs PPIs for stress ulcer prophylaxis despite fewer ventilator days and lower ventilator-associated pneumonia in those receiving H2Bs.
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Affiliation(s)
- Soumya Banna
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Christopher Schenck
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Andi Shahu
- Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Alexander Thomas
- Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Cory Heck
- Heart and Vascular Medicine, Yale New Haven Hospital, New Haven, Connecticut, USA
| | - Rosanna Tangredi
- Heart and Vascular Medicine, Yale New Haven Hospital, New Haven, Connecticut, USA
| | - Tariq Ali
- Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - P. Elliott Miller
- Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, Connecticut, USA
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Zhang S, Tian J, Wang X, Liu C. PPIs therapy has a negative impact on the clinical outcomes of advanced SCLC patients treated with PD-L1 inhibitors. BMC Pulm Med 2023; 23:438. [PMID: 37951887 PMCID: PMC10638834 DOI: 10.1186/s12890-023-02754-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Accepted: 11/07/2023] [Indexed: 11/14/2023] Open
Abstract
BACKGROUND Programmed death-ligand 1 (PD-L1) inhibitors has emerged as a first-line therapeutic strategy for advanced small cell lung cancer (SCLC), which can stimulate T-cell activation, thereby preventing tumor avoidance of immunologic surveillance, whereas, proton pump inhibitors (PPIs) can play an important role in regulating immune function. This study assessed whether the concomitantly use of PPIs affected outcomes of immunotherapy in advanced SCLC. METHODS Data from advanced SCLC patients who firstly treated with PD-L1 inhibitors between July 2018 and February 2021 was retrospectively analyzed. The impact of concomitant medications (especially PPIs) on objective response rate, progression-free survival (PFS) and overall survival (OS) were evaluated. RESULTS Of 208 patients, 101 received immunotherapy concomitant PPIs. The median PFS of patients receiving PPIs (6.6 months) were significantly shorter than those without PPIs (10.6 months), and so was OS. There was associated with a 74.9% increased risk of progression and 58.3% increased risk of death. Both first-line and post-first-line immunotherapy, patients treated PPIs had poorer PFS. CONCLUSION PPIs therapy has a negative impact on the clinical outcomes of advanced SCLC patients treated with PD-L1 inhibitors.
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Affiliation(s)
- Sisi Zhang
- Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong, 250062, China
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Academy of Medical Sciences, Jinan, Shandong, 250117, China
| | - Jing Tian
- Department of Radiation Oncology, Jinan Zhangqiu District People's Hospital, Jinan, Shandong, 250200, China
| | - Xinwei Wang
- Department of Intensive Care Medical Center, Shandong Public Health Clinical Center, Shandong University, Jinan, Shandong, 250013, China
| | - Chengxin Liu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Academy of Medical Sciences, Jinan, Shandong, 250117, China.
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22
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Sophonsri A, Kelsom C, Lou M, Nieberg P, Wong-Beringer A. Risk factors and outcome associated with coinfection with carbapenem-resistant Klebsiella pneumoniae and carbapenem-resistant Pseudomonas aeruginosa or Acinetobacter baumanii: a descriptive analysis. Front Cell Infect Microbiol 2023; 13:1231740. [PMID: 37908764 PMCID: PMC10613969 DOI: 10.3389/fcimb.2023.1231740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 10/02/2023] [Indexed: 11/02/2023] Open
Abstract
Background Nearly 30% of patients infected with carbapenem-resistant Klebsiella pneumoniae (CRKP) were previously shown to be coinfected with carbapenem-resistant Pseudomonas aeruginosa (CRPA) or Acinetobacter baumannii (CRAB). Infections caused by multiple carbapenem-resistant pathogens present significant challenge to infection control and therapeutic management. The study objective was to identify risk factors for acquisition of multiple carbapenem-resistant pathogens and associated outcomes. Methods A descriptive analysis of adults infected with either CRKP alone or coinfected with CRPA or CRAB was performed. Patient groups were compared on demographics, clinical characteristics, treatment, and outcome. Results 86 patients with CRKP monoinfection and 60 patients with coinfections were evaluated. Respiratory tract was the predominant infection site for coinfected patients involving mostly CRPA whereas urinary tract was the primary site for CRKP-only group. More coinfected patients were severely debilitated, had prior carbapenem exposure (37% vs 13%, p<0.001) and history of pneumonia in the past year (67% vs 41%, p<0.01). More coinfected patients required direct ICU admission (45% vs 27%, p=0.02) and had prolonged length of stay (median 15 vs 10 days, p<0.01) than the CRKP-only group but mortality rates (18% vs 16%) were similar. Conclusions CRKP coinfection with another carbapenem-resistant pathogen adds significant morbidity and healthcare burden overall. Empiric therapy with reliable activity against both CRKP and carbapenem-resistant Pseudomonas aeruginosa may be prudent for at risk patients with pneumonia.
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Affiliation(s)
- Anthony Sophonsri
- Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, United States
| | - Corey Kelsom
- Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, United States
- Department of Pharmacy, Huntington Hospital, Pasadena, CA, United States
| | - Mimi Lou
- Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, United States
| | - Paul Nieberg
- Department of Infectious Diseases Medicine, Huntington Hospital, Pasadena, CA, United States
| | - Annie Wong-Beringer
- Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, United States
- Department of Pharmacy, Huntington Hospital, Pasadena, CA, United States
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Mekhail A, Young P, Mekhail AM, Tinawi G, Haran C, Clayton N, Galvin S. Stress Ulcer Prophylaxis in Cardiac Surgery: A Retrospective Cohort Study to Analyze the Effects of SUP Cessation. J Intensive Care Med 2023; 38:917-921. [PMID: 37093762 DOI: 10.1177/08850666231171327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2023]
Abstract
INTRODUCTION Upper gastrointestinal bleeding (UGIB) is an important complication among critically ill adults, especially those having cardiac surgery as management is complicated by the requirement for antiplatelet/anticoagulant therapy. As a result, stress ulcer prophylaxis (SUP) has become routine practice in many centers, utilizing either proton pump inhibitors (PPIs) or histamine-2 receptor blockers (H2RBs). Recent evidence from the PEPTIC trial indicated an increase in mortality risk among cardiac surgery patients receiving PPIs compared to H2RBs. Considering these findings, alongside practical difficulties surrounding the transition to H2RBs as a prophylactic agent in New Zealand, Wellington Hospital intensive care unit elected to discontinue routine PPI use for SUP in cardiac surgery patients. A retrospective study was conducted to assess patient outcomes following the discontinuation of routine SUP. METHOD A retrospective cohort study was conducted of all adult patients who underwent cardiac surgery at Wellington Hospital between February/2018 and January/2022, and divided patients into cohorts before and after the discontinuation of routine use of SUP on the 31st of January 2020. The primary outcomes were the rate of UGIB, oesophagogastroduodenoscopy (OGD) and 180-day postoperative mortality. Secondary outcomes included rates of postoperative Clostridium difficile enteritis, pneumonia, deep sternal wound infection, and length of stay of the index admission. RESULTS The rate of UGIB statistically significantly increased since the cessation of routine SUP in January 2020 (2.4% vs 5.4%, P-value = .004). This finding was mirrored with the increased rates of OGD (1.9% vs 4.0%, P-value = .005). There were no significant changes in 180-day mortality, hospital length of stay, or any of the postoperative infective complications analyzed, pneumonia, deep sternal wound infection, or C difficile enteritis. CONCLUSION This study suggests an association between routine use of SUP and reduced rates of clinically significant UGIB and OGD requirements in cardiac surgery patients without increasing risk of infective complications or postoperative mortality.
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Affiliation(s)
- Andrew Mekhail
- Department of Cardiothoracic Surgery, Wellington Hospital, Wellington, New Zealand
| | - Paul Young
- Department of Intensive Care Medicine, Wellington Hospital, Wellington, New Zealand
| | - Ann-Marie Mekhail
- Department of Intensive Care Medicine, Wellington Hospital, Wellington, New Zealand
| | - Georges Tinawi
- Department of Cardiothoracic Surgery, Wellington Hospital, Wellington, New Zealand
| | - Cheyaanthan Haran
- Department of Cardiothoracic Surgery, Wellington Hospital, Wellington, New Zealand
| | - Nicholas Clayton
- Department of Cardiothoracic Surgery, Wellington Hospital, Wellington, New Zealand
| | - Sean Galvin
- Department of Cardiothoracic Surgery, Wellington Hospital, Wellington, New Zealand
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Triadafilopoulos G, Mashimo H, Tatum R, O'Clarke J, Hawn M. Mixed Esophageal Disease (MED): A New Concept. Dig Dis Sci 2023; 68:3542-3554. [PMID: 37470896 DOI: 10.1007/s10620-023-08008-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 06/15/2023] [Indexed: 07/21/2023]
Abstract
We define mixed esophageal disease (MED) as a disorder of esophageal structure and/or function that produces variable signs or symptoms, simulating-fully or in part other well-defined esophageal conditions, such as gastroesophageal reflux disease, esophageal motility disorders, or even neoplasia. The central premise of the MED concept is that of an overlap syndrome that incorporates selected clinical, endoscopic, imaging, and functional features that alter the patient's quality of life and affect natural history, prognosis, and management. In this article, we highlight MED scenarios frequently encountered in medico-surgical practices worldwide, posing new diagnostic and therapeutic challenges. These, in turn, emphasize the need for better understanding and management, aiming towards improved outcomes and prognosis. Since MED has variable and sometimes time-evolving clinical phenotypes, it deserves proper recognition, definition, and collaborative, multidisciplinary approach, be it pharmacologic, endoscopic, or surgical, to optimize therapeutic outcomes, while minimizing iatrogenic complications. In this regard, it is best to define MED early in the process, preferably by teams of clinicians with expertise in managing esophageal diseases. MED is complex enough that is increasingly becoming the subject of virtual, multi-disciplinary, multi-institutional meetings.
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Affiliation(s)
- George Triadafilopoulos
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, 430 Broadway Street 3rd floor, MC6341, Redwood City, CA, 94063, USA.
| | - Hiroshi Mashimo
- Section of Gastroenterology, Harvard Medical School, VA Boston Healthcare - Roxbury, 1400 VFW Pkwy, West Roxbury, MA, 02132, USA
| | - Roger Tatum
- Department of General Surgery, University of Washington, 1660 S. Columbian Way, Seattle, WA, 98108, USA
| | - John O'Clarke
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Mary Hawn
- Department of Surgery, Stanford University School of Medicine, Stanford, CA, 94305, USA
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25
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Sakowicz A, Bralewska M, Rybak-Krzyszkowska M, Grzesiak M, Pietrucha T. New Ideas for the Prevention and Treatment of Preeclampsia and Their Molecular Inspirations. Int J Mol Sci 2023; 24:12100. [PMID: 37569476 PMCID: PMC10418829 DOI: 10.3390/ijms241512100] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 07/25/2023] [Accepted: 07/26/2023] [Indexed: 08/13/2023] Open
Abstract
Preeclampsia (PE) is a pregnancy-specific disorder affecting 4-10% of all expectant women. It greatly increases the risk of maternal and foetal death. Although the main symptoms generally appear after week 20 of gestation, scientific studies indicate that the mechanism underpinning PE is initiated at the beginning of gestation. It is known that the pathomechanism of preeclampsia is strongly related to inflammation and oxidative stress, which influence placentation and provoke endothelial dysfunction in the mother. However, as of yet, no "key players" regulating all these processes have been discovered. This might be why current therapeutic strategies intended for prevention or treatment are not fully effective, and the only effective method to stop the disease is the premature induction of delivery, mostly by caesarean section. Therefore, there is a need for further research into new pharmacological strategies for the treatment and prevention of preeclampsia. This review presents new preventive methods and therapies for PE not yet recommended by obstetrical and gynaecological societies. As many of these therapies are in preclinical studies or under evaluation in clinical trials, this paper reports the molecular targets of the tested agents or methods.
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Affiliation(s)
- Agata Sakowicz
- Department of Medical Biotechnology, Medical University of Lodz, Zeligowskiego 7/9, 90-752 Lodz, Poland; (M.B.); (T.P.)
| | - Michalina Bralewska
- Department of Medical Biotechnology, Medical University of Lodz, Zeligowskiego 7/9, 90-752 Lodz, Poland; (M.B.); (T.P.)
| | - Magda Rybak-Krzyszkowska
- Department of Obstetrics and Perinatology, University Hospital in Krakow, 31-501 Krakow, Poland;
| | - Mariusz Grzesiak
- Department of Perinatology, Obstetrics and Gynecology, Polish Mother’s Memorial Hospital-Research Institute in Lodz, 93-338 Lodz, Poland;
- Department of Gynecology and Obstetrics, Medical University of Lodz, 93-338 Lodz, Poland
| | - Tadeusz Pietrucha
- Department of Medical Biotechnology, Medical University of Lodz, Zeligowskiego 7/9, 90-752 Lodz, Poland; (M.B.); (T.P.)
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Abstract
Eosinophilic gastrointestinal disorders are a group of rare diseases characterized by the infiltration of eosinophils in the gastrointestinal wall in a greater amount than in homeostatic conditions. 'Non-esophageal eosinophilic gastrointestinal disorders' is the umbrella term for all eosinophilic gastrointestinal disorders outside of the well known eosinophilic esophagitis. This includes eosinophilic gastritis, eosinophilic enteritis and eosinophilic colitis. The clinical presentation is atypical and not very different for the three disorders. The depth of infiltration has a bigger influence on the presenting symptoms than the disease location. Although the frequency of diagnosis and research in this subject is increasing over time, non-esophageal eosinophilic disorders are rare and high quality evidence is limited to date. In this narrative review, we provide an overview of the latest insights in the pathophysiology, diagnostic approach and available treatment options. Transcriptome studies have found the pathogenesis to be T helper type 2 driven. Various laboratory findings can be used to trigger raised suspicion and investigation with endoscopy. As the endoscopic appearance of the mucosa is normal in most cases, multiple biopsies in each segment are needed to quantify the amount of eosinophils in the tissue. Eosinophilic cut-offs for diagnosis are a controversial topic and a consensus is still lacking. A recently developed tissue based diagnostic platform which measures differentially expressed genes might be available in the future to classify patients with intermediate eosinophilic tissue levels under the cut-off. For the treatment, corticosteroids are still the cornerstone of treatment but promising research suggests a role of biologicals, such as Lirentelimab (anti-siglec 8) in particular.
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Affiliation(s)
- J Janssens
- Faculty of Medicine, KULeuven, Leuven, Belgium
| | - T Vanuytsel
- Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
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Ghosh N, Kesh K, Singh PK, Sharma U, Chupikova I, Ramakrishnan S, Roy S. Morphine use induces gastric microbial dysbiosis driving gastric inflammation through TLR2 signalling which is attenuated by proton pump inhibition. Br J Pharmacol 2023; 180:1582-1596. [PMID: 36585367 PMCID: PMC10175111 DOI: 10.1111/bph.16025] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 09/29/2022] [Accepted: 10/28/2022] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND AND PURPOSE Opioids are the standard drug for pain management; however, their effects on gastric dysfunction are relatively understudied. Opioid users have a higher incidence of gastric pathology leading to increased hospitalization. Herein, we investigated the consequences of morphine use on gastric pathology and the underlying mechanisms. We further investigated the therapeutic benefit of proton pump inhibition to overcome morphine-mediated gastric inflammation. EXPERIMENTAL APPROACH Mice were implanted with 25 mg slow-release morphine and placebo pellets. Gastric microbiome analyses were performed. Gastric damage was assayed. Gastric pH was measured. Germ-free and TLR2KO mice were used to investigate the mechanisms. Gastroprotective studies were performed with the proton pump inhibitor (PPI) omeprazole. KEY RESULTS Chronic morphine treatment alters gastric microbial composition and induces preferential expansion of pathogenic bacterial communities such as Streptococcus and Pseudomonas. Morphine causes disruption of the gastric mucosal layer, increases apoptosis, and elevates inflammatory cytokines. Moreover, morphine-mediated gastric pathology was significantly attenuated in germ-free mice, and reconstitution of morphine gastric microbiome in germ-free mice resulted gastric inflammation. In addition, morphine-mediated gastric inflammation was attenuated in TLR2KO mice. Morphine causes a decrease in gastric pH, which contributes to gastric dysbiosis leads to gastric inflammation. Omeprazole treatment inhibits gastric acidity, rescuing morphine-induced gastric dysbiosis and preventing inflammation. CONCLUSION AND IMPLICATIONS This study attributes morphine-induced gastric acidity as a driver of gastric dysbiosis and pathology and proposes the therapeutic use of PPI as an inexpensive approach for the clinical management of morphine-associated pathophysiology.
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Affiliation(s)
- Nillu Ghosh
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Kousik Kesh
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Praveen Kumar Singh
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Umakant Sharma
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Irina Chupikova
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Sundaram Ramakrishnan
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
- Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Sabita Roy
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
- Sylvester Comprehensive Cancer Center, Miami, FL, USA
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Saka Y, Naruse T, Chikamatsu T, Mitani K, Hayashi M, Matsumoto J, Yosizawa Y, Mimura T, Takahashi H, Watanabe Y. Long-Term Proton Pump Inhibitor Therapy Increases the Risk of Infection in Patients with Incident Hemodialysis. Nephron Clin Pract 2023; 147:608-615. [PMID: 37231855 DOI: 10.1159/000531028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Accepted: 04/12/2023] [Indexed: 05/27/2023] Open
Abstract
BACKGROUND Infection is one of the most common causes of death in patients with chronic kidney disease (CKD). Proton pump inhibitors (PPIs) are not only widely used in patients with CKD but also represent a known risk factor for infection in the general population. Here, we investigated associations between PPIs and infection events in patients with incident hemodialysis. METHODS We analyzed data from 485 consecutive patients with CKD who started hemodialysis at our hospital between January 2013 and December 2019. We analyzed associations between infection events and long-term (≥6 months) PPI use before and after propensity score-matched analysis. RESULTS Of the 485 patients, PPIs were administered to 177 patients (36.5%). During 24 months of follow-up, infection events occurred in 53 patients (29.9%) with PPIs and 40 patients (13.0%) without PPIs (p < 0.001). Patients with PPIs had a significantly higher cumulative incidence rate of infection events than those without PPIs (hazard ratio [HR] 2.13, 95% confidence interval [CI]: 1.36-3.32; p < 0.001). Even after propensity score-matched analysis (132 patients matched in each), the rate of infection events was higher for patients with PPIs (28.8% vs. 12.1%, HR 2.88, 95% CI: 1.61-5.16; p < 0.001). Similar results were obtained for severe infection events in both unmatched (14.1% vs. 4.5%, HR 2.97, 95% CI: 1.47-6.00; p = 0.002) and propensity score-matched analyses (14.4% vs. 3.8%, HR 4.54, 95% CI: 1.85-11.13; p < 0.001). CONCLUSIONS In patients with incident hemodialysis, long-term PPI use increases the risk of infection. Clinicians should be wary of unnecessarily prolonging PPI therapy.
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Affiliation(s)
- Yosuke Saka
- Department of Nephrology, Kasugai Municipal Hospital, Kasugai, Japan
| | - Tomohiko Naruse
- Department of Nephrology, Kasugai Municipal Hospital, Kasugai, Japan
| | - Taiki Chikamatsu
- Department of Nephrology, Kasugai Municipal Hospital, Kasugai, Japan
| | - Kotaro Mitani
- Department of Nephrology, Kasugai Municipal Hospital, Kasugai, Japan
| | - Mako Hayashi
- Department of Nephrology, Kasugai Municipal Hospital, Kasugai, Japan
| | - Jun Matsumoto
- Department of Nephrology, Kasugai Municipal Hospital, Kasugai, Japan
| | - Yuka Yosizawa
- Department of Nephrology, Kasugai Municipal Hospital, Kasugai, Japan
| | - Tetsushi Mimura
- Department of Nephrology, Kasugai Municipal Hospital, Kasugai, Japan
| | - Hiroshi Takahashi
- Department of Nephrology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Yuzo Watanabe
- Department of Nephrology, Kasugai Municipal Hospital, Kasugai, Japan
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Lin MH, Wu WT, Chen YC, Lin TK, Chou YC, Sun CA. Association between clinical use of lansoprazole and the risk of type 2 diabetes mellitus: a pharmacoepidemiological cohort study. Diabetol Metab Syndr 2023; 15:96. [PMID: 37165435 PMCID: PMC10170833 DOI: 10.1186/s13098-023-01051-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 03/31/2023] [Indexed: 05/12/2023] Open
Abstract
BACKGROUND Proton pump inhibitors (PPIs) are common and widely used for gastrointestinal-related disorders. Lansoprazole is one of PPIs with potential benefits of anti-inflammation, reduced oxidative stress, and anti-diabetes. The aims of this study are to determine whether lansoprazole imparts differential risk of type 2 diabetes as compared with other PPIs. METHODS A population-based retrospective cohort study was conducted using the National Health Insurance Research Database in Taiwan. Patients who received lansoprazole more than 90 days and without records of use of other PPIs between January 1, 2000 and December 31, 2005 (the exposure period) were considered as the exposed cohort (n = 1668). In comparison, patients who received other PPIs more than 90 days and without use of lansoprazole in the exposure period were treated as the comparison cohort (n = 3336).The primary outcome was the new-onset of type 2 diabetes mellitus (T2DM). The association between use of lansoprazole and the risk of T2DM was determined by hazard ratios (HRs) and 95% confidence intervals (CIs) derived from multivariable Cox proportional hazards models. RESULTS The lansoprazole cohort showed a significantly reduced risk of T2DM with an adjusted HR of 0.65 (95% CI 0.56-0.76). Interestingly, the inverse association between use of lansoprazole and risk of T2DM was observed in both genders and in various age groups. CONCLUSION The present study findings suggest that lansoprazole was associated with a reduced risk of T2DM compared with other PPIs. Further studies are needed to determine the clinical implications of the present study.
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Affiliation(s)
- Ming-Hsun Lin
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei City, 114, Taiwan
| | - Wen-Tung Wu
- Department of Pharmacy, Tri-Service General Hospital, National Defense Medical Center, Taipei City, 114, Taiwan
| | - Yong-Chen Chen
- Department of Public Health, College of Medicine, Fu-Jen Catholic University, No.510, Zhongzheng Road, Xinzhuang District, New Taipei City, 242, Taiwan
- Department of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, 242, Taiwan
| | - Tsung-Kun Lin
- School of Pharmacy, National Defense Medical Center, Taipei City, 114, Taiwan
| | - Yu-Ching Chou
- School of Public Health, National Defense Medical Center, Taipei City, 114, Taiwan
| | - Chien-An Sun
- Department of Public Health, College of Medicine, Fu-Jen Catholic University, No.510, Zhongzheng Road, Xinzhuang District, New Taipei City, 242, Taiwan.
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30
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Kiecka A, Szczepanik M. Proton pump inhibitor-induced gut dysbiosis and immunomodulation: current knowledge and potential restoration by probiotics. Pharmacol Rep 2023:10.1007/s43440-023-00489-x. [PMID: 37142877 PMCID: PMC10159235 DOI: 10.1007/s43440-023-00489-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 04/20/2023] [Accepted: 04/21/2023] [Indexed: 05/06/2023]
Abstract
Proton pump inhibitors (PPIs) are the most commonly prescribed drugs for the treatment of non-erosive reflux disease (NERD), ulcers associated with non-steroidal anti-inflammatory drugs (NSAIDs), esophagitis, peptic ulcer disease (PUD), Zollinger-Ellison syndrome (ZES), gastroesophageal reflux disease (GERD), non-ulcer dyspepsia, and Helicobacter pylori eradication therapy. The drugs have the effect of inhibiting acid production in the stomach. According to research, PPIs can affect the composition of gut microbiota and modulate the immune response. Recently, there has been a problem with the over-prescription of such drugs. Although PPIs do not have many side effects, their long-term use can contribute to small intestinal bacterial overgrowth (SIBO) or C. difficile and other intestinal infections. Probiotic supplementation during PPIs therapy may provide some hope in the reduction of emerging therapy side effects. This review aims to present the most important effects of long-term PPI use and provides critical insights into the role of probiotic intervention in PPI therapy.
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Affiliation(s)
- Aneta Kiecka
- Chair of Biomedical Sciences, Institute of Physiotherapy, Faculty of Health Sciences, Jagiellonian University Medical College, Kopernika 7a, 31-034, Kraków, Poland.
| | - Marian Szczepanik
- Chair of Biomedical Sciences, Institute of Physiotherapy, Faculty of Health Sciences, Jagiellonian University Medical College, Kopernika 7a, 31-034, Kraków, Poland
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31
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Horváth IL, Bunduc S, Hankó B, Kleiner D, Demcsák A, Szabó B, Hegyi P, Csupor D. No evidence for the benefit of PPIs in the treatment of acute pancreatitis: a systematic review and meta-analysis. Sci Rep 2023; 13:2791. [PMID: 36797320 PMCID: PMC9935541 DOI: 10.1038/s41598-023-29939-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 02/13/2023] [Indexed: 02/18/2023] Open
Abstract
Although current guidelines do not recommend the use of proton pump inhibitors (PPIs) in the standard of care of acute pancreatitis (AP), they are often prescribed in clinical practice, mainly for ulcer stress prophylaxis. In this systematic review and meta-analysis we evaluated the association between the use of PPIs in the management of AP and various clinical outcomes. We conducted the systematic research in six databases without restrictions on January 24th, 2022. We investigated adult patient with AP, who were treated with PPI compared to conventional therapy. The pooled odds ratios, mean differences, and corresponding 95% confidence intervals were calculated with random effect model. We included six RCTs and three cohort studies, consisting of 28,834 patients. We found a significant decrease in the rate of pancreatic pseudocyst formation in patients who received PPI treatment. PPI use was associated with a higher risk of GI bleeding, however this finding could be due to the patients' comorbid conditions. We found no significant difference in the rates of 7-day mortality, length of hospital stay, and acute respiratory distress syndrome between the groups. The available data on this topic are limited; therefore, further well designed RCTs are needed to evaluate the potential benefits and adverse effects of PPIs in AP.
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Affiliation(s)
- István László Horváth
- Centre for Translational Medicine, Semmelweis University, Üllői út 26, 1085, Budapest, Hungary
- University Pharmacy Department of Pharmacy Administration, Hőgyes Endre utca 7-9, 1092, Budapest, Hungary
| | - Stefania Bunduc
- Centre for Translational Medicine, Semmelweis University, Üllői út 26, 1085, Budapest, Hungary
- Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, Baross út 22-24, 1085, Budapest, Hungary
- Carol Davila University of Medicine and Pharmacy, Dionisie Lupu Street 37, 020021, Bucharest, Romania
- Fundeni Clinical Institute, Fundeni Street 258, 022328, Bucharest, Romania
| | - Balázs Hankó
- University Pharmacy Department of Pharmacy Administration, Hőgyes Endre utca 7-9, 1092, Budapest, Hungary
| | - Dénes Kleiner
- Centre for Translational Medicine, Semmelweis University, Üllői út 26, 1085, Budapest, Hungary
- University Pharmacy Department of Pharmacy Administration, Hőgyes Endre utca 7-9, 1092, Budapest, Hungary
| | - Alexandra Demcsák
- Department of Surgery, University of California Los Angeles, 675 Charles E Young Dr. S MRL 2220, Los Angeles, CA, 90095, USA
| | - Bence Szabó
- Centre for Translational Medicine, Semmelweis University, Üllői út 26, 1085, Budapest, Hungary
| | - Péter Hegyi
- Centre for Translational Medicine, Semmelweis University, Üllői út 26, 1085, Budapest, Hungary
- Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, Baross út 22-24, 1085, Budapest, Hungary
- Institute for Translational Medicine, Medical School, University of Pécs, Szigeti út 12, 7624, Pécs, Hungary
| | - Dezső Csupor
- Centre for Translational Medicine, Semmelweis University, Üllői út 26, 1085, Budapest, Hungary.
- Institute for Translational Medicine, Medical School, University of Pécs, Szigeti út 12, 7624, Pécs, Hungary.
- Institute of Clinical Pharmacy, University of Szeged, Szikra utca 8, 6725, Szeged, Hungary.
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32
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Raoul JL, Moreau-Bachelard C, Gilabert M, Edeline J, Frénel JS. Drug-drug interactions with proton pump inhibitors in cancer patients: an underrecognized cause of treatment failure. ESMO Open 2023; 8:100880. [PMID: 36764092 PMCID: PMC10024146 DOI: 10.1016/j.esmoop.2023.100880] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/03/2023] [Accepted: 01/12/2023] [Indexed: 02/11/2023] Open
Abstract
New concepts and drugs have revolutionized medical treatment for cancers. These drugs, which are very expensive and usually well tolerated, have dramatically improved cancer prognosis. We must use them wisely for patients to fully benefit. Gastric acid antisecretory drugs and particularly proton pump inhibitors (PPIs) revolutionized the treatment of gastroduodenal ulcers and severe gastroesophageal reflux, but are frequently overused for symptomatic treatment of epigastric pain or heartburn. Long-term acid suppression may alter the efficacy of many anticancer drugs, such as tyrosine kinase inhibitors (TKIs), cyclin-dependent kinase (CDK) 4/6 inhibitors and immune checkpoint inhibitors (ICIs), by either decreasing gastric acid secretion and thus drug absorption, or by modifying the gut microbiome that modulates the response to ICIs. Oncologists thus need to pay particular attention to the concomitant use of PPIs and anticancer drugs. These interactions translate into major clinical impacts, with demonstrated loss of efficacy for some TKIs (erlotinib, gefitinib, pazopanib), and conflicting results with many other oral drugs, including capecitabine and CDK 4/6 inhibitors. Furthermore, the profound changes in the gut microbiome due to using PPIs have shown that the benefit of using ICIs may be suppressed in patients treated with PPIs. As the use of PPIs is not essential, we must apply the precautionary principle. The first sentence of a recent Comment in Nature was "Every day, millions of people are taking medications that will not help them". We fear that every day millions of cancer patients are taking medications that harm them. While this may well be only association and not causation, there is enough to make us pause until we reach a clear answer. All these data should encourage medical oncologists to refrain from prescribing PPIs, explaining to patients the risks of interaction in order to prevent inappropriate prescription by another physician.
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Affiliation(s)
- J L Raoul
- Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Saint-Herblain, France.
| | - C Moreau-Bachelard
- Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Saint-Herblain, France
| | - M Gilabert
- Department of Medical Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - J Edeline
- Department of Medical Oncology, Centre Eugène Marquis, Rennes, France
| | - J S Frénel
- Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Saint-Herblain, France
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Effect of Antacid Use on Immune Checkpoint Inhibitors in Advanced Solid Cancer Patients: A Systematic Review and Meta-analysis. J Immunother 2023; 46:43-55. [PMID: 36301729 DOI: 10.1097/cji.0000000000000442] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 09/08/2022] [Indexed: 11/07/2022]
Abstract
The influence of antacids use on immune checkpoint inhibitor (ICI) efficacy remains unclear. A systematic review and meta-analysis was performed to evaluate the effect of proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs) on ICI efficacy in advanced solid cancer patients. A systematic literature search in PubMed, EMBASE, and Web of Science was performed to retrieve studies investigating the effect of antacid use on ICI efficacy. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and immune-related adverse events were measured using hazard ratios (HRs) or odds ratios (ORs). Thirty studies enrolling 16,147 advanced cancer patients receiving ICI treatment were included. The pooled analysis indicated that PPI use was associated with shorter OS (HR=1.40, 95% CI, 1.25-1.57) and PFS (HR=1.34, 95% CI, 1.19-1.52) in advanced cancer patients treated with ICIs. PPI use did not show effect on ORR or immune-related adverse event of advanced cancer patients receiving ICI treatment. OS, PFS, and ORR did not differ between H2RA users and non-H2RA users. In subgroup analyses, PPI use was associated with shorter OS and PFS in NSCLC and urothelial carcinoma patients and in patients treated with anti-programmed cell death 1 or anti-programmed cell death ligand 1 monotherapy. In addition, ICI efficacy was different in the antacid exposure time frame subgroups. In conclusion, PPI use has a negative effect on OS and PFS among advanced cancer patients receiving ICI treatment. PPIs should be cautiously administered among advanced cancer patients treated with ICI. The safety of H2RAs and the influence of H2RAs on ICI efficacy need further investigation.
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Ebrahimpour A, Ahir M, Wang M, Jegga AG, Bonnen MD, Eissa NT, Montesi SB, Raghu G, Ghebre YT. Combination of esomeprazole and pirfenidone enhances antifibrotic efficacy in vitro and in a mouse model of TGFβ-induced lung fibrosis. Sci Rep 2022; 12:20668. [PMID: 36450789 PMCID: PMC9712660 DOI: 10.1038/s41598-022-24985-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 11/23/2022] [Indexed: 12/03/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown etiology. Currently, pirfenidone and nintedanib are the only FDA-approved drugs for the treatment of IPF and are now the standard of care. This is a significant step in slowing down the progression of the disease. However, the drugs are unable to stop or reverse established fibrosis. Several retrospective clinical studies indicate that proton pump inhibitors (PPIs; FDA-approved to treat gastroesophageal reflux) are associated with favorable outcomes in patients with IPF, and emerging preclinical studies report that PPIs possess antifibrotic activity. In this study, we evaluated the antifibrotic efficacy of the PPI esomeprazole when combined with pirfenidone in vitro and in vivo. In cell culture studies of IPF lung fibroblasts, we assessed the effect of the combination on several fibrosis-related biological processes including TGFβ-induced cell proliferation, cell migration, cell contraction, and collagen production. In an in vivo study, we used mouse model of TGFβ-induced lung fibrosis to evaluate the antifibrotic efficacy of esomeprazole/pirfenidone combination. We also performed computational studies to understand the molecular mechanisms by which esomeprazole and/or pirfenidone regulate lung fibrosis. We found that esomeprazole significantly enhanced the anti-proliferative effect of pirfenidone and favorably modulated TGFβ-induced cell migration and contraction of collagen gels. We also found that the combination significantly suppressed collagen production in response to TGFβ in comparison to pirfenidone monotherapy. In addition, our animal study demonstrated that the combination therapy effectively inhibited the differentiation of lung fibroblasts into alpha smooth muscle actin (αSMA)-expressing myofibroblasts to attenuate the progression of lung fibrosis. Finally, our bioinformatics study of cells treated with esomeprazole or pirfenidone revealed that the drugs target several extracellular matrix (ECM) related pathways with esomeprazole preferentially targeting collagen family members while pirfenidone targets the keratins. In conclusion, our cell biological, computational, and in vivo studies show that the PPI esomeprazole enhances the antifibrotic efficacy of pirfenidone through complementary molecular mechanisms. This data supports the initiation of prospective clinical studies aimed at repurposing PPIs for the treatment of IPF and other fibrotic lung diseases where pirfenidone is prescribed.
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Affiliation(s)
- Afshin Ebrahimpour
- Department of Radiation Oncology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
| | - Manisha Ahir
- Department of Radiation Oncology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
| | - Min Wang
- Department of Radiation Oncology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
| | - Anil G Jegga
- Division of Biomedical Informatics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA
| | - Mark D Bonnen
- Department of Radiation Oncology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA
| | - N Tony Eissa
- Department of Medicine, University of California, Irvine School of Medicine, Irvine, CA, 92697, USA
| | - Sydney B Montesi
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Ganesh Raghu
- Division of Pulmonary and Critical Care Medicine, Center for Interstitial Lung Disease, University of Washington, Seattle, WA, 98195, USA
| | - Yohannes T Ghebre
- Department of Radiation Oncology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
- Department of Radiation Oncology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
- Department of Medicine, Section on Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, 77030, USA.
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.
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Jeong SH, Molloy L, Ang E, Helsby N. Re-thinking the possible interaction between proton pump inhibitors and capecitabine. Cancer Chemother Pharmacol 2022; 90:381-388. [PMID: 36098758 PMCID: PMC9556389 DOI: 10.1007/s00280-022-04473-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 09/05/2022] [Indexed: 12/02/2022]
Abstract
Proton Pump Inhibitors (PPI) rank within the top ten most prescribed medications in Europe and USA. A high frequency of PPI use has been reported amongst patients undergoing chemotherapy, to mitigate treatment-induced gastritis or gastro-oesophageal reflux. Several recent, mostly retrospective, observational studies have reported inferior survival outcomes among patients on capecitabine who concomitantly use PPI. Whilst this association is yet to be definitively established, given the prominence of capecitabine as an anti-cancer treatment with multiple indications, these reports have raised concern within the oncological community and drug regulatory bodies worldwide. Currently, the leading mechanism of interaction postulated in these reports has focussed on the pH altering effects of PPI and how this could diminish capecitabine absorption, leading to a decrease in its bioavailability. In this discourse, we endeavour to summarise plausible pharmacokinetic interactions between PPI and capecitabine. We provide a basis for our argument against the currently proposed mechanism of interaction. We also highlight the long-term effects of PPI on health outcomes, and how PPI use itself could lead to poorer outcomes, independent of capecitabine.
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Affiliation(s)
- Soo Hee Jeong
- Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
| | - Lara Molloy
- Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Edmond Ang
- Cancer and Blood Research, Auckland District Health Board, Auckland, New Zealand
| | - Nuala Helsby
- Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
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36
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Thakkar KP, Fowler M, Keene S, Iuga A, Dellon ES. Long-term efficacy of proton pump inhibitors as a treatment modality for eosinophilic esophagitis. Dig Liver Dis 2022; 54:1179-1185. [PMID: 35410852 PMCID: PMC9427674 DOI: 10.1016/j.dld.2022.03.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 03/12/2022] [Accepted: 03/15/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND Proton pump inhibitors (PPIs) are a first-line treatment for EoE, but data are limited concerning response durability. We aimed to determine long-term outcomes in EoE patients responsive to PPI-therapy. METHODS We conducted a retrospective cohort study of newly diagnosed adults with EoE who had initial histologic response (<15 eosinophils per high-power-field) to PPI-only therapy. We extracted data regarding their subsequent clinical course and outcomes. We compared findings between the initial PPI-response endoscopy and the final endoscopy, and assessed factors associated with loss of PPI response. RESULTS Of 138 EoE patients with initial histologic response to PPI, 50 had long-term endoscopic follow-up, 40 had clinical follow-up, 10 changed treatments, and 38 had no long-term follow-up. Of those with endoscopic follow-up, mean follow-up-time was 3.6 ± 2.9 years; 30 and 32 patients (60%; 64%) maintained histologic and symptom responses, respectively. However, fibrotic endoscopic findings of EoE were unchanged. Younger age (aOR 1.05, 95% CI: 1.01-1.11) and dilation prior to PPI treatment (aOR 0.21, 95% CI: 0.05-0.83) were the only factors associated with long-term loss of PPI response. CONCLUSIONS Long-term histologic and clinical response rates for PPI therapy were 60% and 64%, respectively. Younger age and dilation at baseline were associated with histologic loss of response. These data can inform long-term EoE treatment selection.
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Affiliation(s)
- Kisan P Thakkar
- Center for Esophageal Diseases and Swallowing, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina School of Medicine, CB#7080 Bioinformatics Building, 130 Mason Farm Rd. UNC-CH, Chapel Hill, NC 27599-7080, USA
| | - Mark Fowler
- Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Staci Keene
- Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Alina Iuga
- Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Evan S Dellon
- Center for Esophageal Diseases and Swallowing, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina School of Medicine, CB#7080 Bioinformatics Building, 130 Mason Farm Rd. UNC-CH, Chapel Hill, NC 27599-7080, USA; Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
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37
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Do proton pump inhibitors affect the biomechanical efficiency of implant?- a systematic review. J Oral Biol Craniofac Res 2022; 12:656-661. [PMID: 36052118 DOI: 10.1016/j.jobcr.2022.08.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 08/13/2022] [Indexed: 11/24/2022] Open
Abstract
Purpose This systematic review was executed to determine the influence of proton pump inhibitors on biomechanical efficiency of dental implants. Materials and methods The comprehensive online literature search was conducted on digital database of Pubmed, Cochrane database and EBSCO host, Web of Science and Scopus from 2010 to 2021(Dec).The studies included in our research comprised of randomized controlled trials and animal studies. Literature review, Letter to the editor, short communication and studies not related to the dental implants were excluded. A total of 6 studies were finalized and included in the systemic review. Result The proton pump inhibitors have a negative influence on the bone metabolism and adversely affect the Osseointegration of the dental implants. Further they reduce the biomechanical efficiency of dental implant which ultimately results in their failure. Conclusion Proton pump inhibitors are a risk factor for dental implant survival. This conclusion has been drawn from the limited research available. Hence well designed prospective randomized controlled trials should be carried out on a large population including the users and non-users, to more thoroughly elucidate the effect of proton pump inhibitor on osseointegration process of dental implants.
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Ghosh N, Kesh K, Ramakrishnan S, Roy S. Opioid Use in Murine Model Results in Severe Gastric Pathology that May Be Attenuated by Proton Pump Inhibition. THE AMERICAN JOURNAL OF PATHOLOGY 2022; 192:1136-1150. [PMID: 35605643 PMCID: PMC9379687 DOI: 10.1016/j.ajpath.2022.04.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 04/14/2022] [Accepted: 04/27/2022] [Indexed: 06/15/2023]
Abstract
Opioids are the gold standard for chronic and acute pain management; however, their consequence on gastric function is relatively understudied. Opioid users have a higher incidence of gastric dysfunction, worse quality of life, increased hospitalizations, and increased use of antiemetic and pain modulator medications. The current study shows that morphine treatment in the murine model results in greater disruption of gastric epithelial cell morphology, increased gastric cell apoptosis, elevated inflammatory cytokines, and matrix metallopeptidase-9 secretion. Morphine treatment also increases gastric acid secretion and causes delays in gastric emptying. Moreover, morphine treatment causes an increase in systemic IL-6 level, which plays an important role in morphine-induced delayed gastric emptying and gastric damage. IL-6 knockout mice show a significant level of reduction in morphine-induced gastric delaying, acid retention, and gastric damage. Thus, morphine-mediated gastric damage is a consequence of the accumulation of acid in the stomach due to increased gastric acid secretion and delayed gastric emptying. Treatment with a proton pump inhibitor resulted in a significant reduction in morphine-induced gastric inflammation, gastric delaying, and improved morphine tolerance. Hence, these studies attribute morphine-mediated induction in gastric acidity and inflammatory cytokines as drivers for morphine-associated gastric pathology and show the therapeutic use of proton pump inhibitors as an inexpensive approach for clinical management of morphine-associated pathophysiology and analgesic tolerance.
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Affiliation(s)
- Nillu Ghosh
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida
| | - Kousik Kesh
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida
| | - Sundaram Ramakrishnan
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida
| | - Sabita Roy
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida; Sylvester Comprehensive Cancer Center, Miami, Florida.
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Abstract
Oesophageal adenocarcinoma (OAC) develops from columnar metaplasia of the distal oesophagus, Barrett's oesophagus (BO), secondary to chronic gastro-oesophageal reflux disease (GORD). In the present review, the stepwise development of GORD, BO and OAC is presented and the evidence of OAC prevention, including treatment with proton pump inhibitors (PPIs). PPIs are the main treatment of GORD and BO, with some evidence of prevention of OAC in these patients. However, as about 40% of OAC patient do not report a history of GORD and fewer than 15% of OAC cases are detected in individuals during BO surveillance, prevention of OAC is limited by PPI use in GORD and BO patients.
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Affiliation(s)
- Eivind Ness-Jensen
- HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway.,Department of Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway.,Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
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40
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Affiliation(s)
- Christopher Sawyer
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, United States of America
| | - Rinarani Sanghavi
- Division Pediatric Gastroenterology, Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, United States of America
| | - Eric B Ortigoza
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, United States of America.
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Eosinophilic Esophagitis in Esophageal Atresia: Is It Really a New Disease? CHILDREN (BASEL, SWITZERLAND) 2022; 9:children9071032. [PMID: 35884016 PMCID: PMC9317458 DOI: 10.3390/children9071032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 07/04/2022] [Accepted: 07/07/2022] [Indexed: 11/17/2022]
Abstract
Eosinophilic esophagitis (EoE) is a chronic, immune-mediated esophageal disease. Symptoms are related to mucosal eosinophilic-predominant inflammation that leads to esophageal dysfunction. Recent data suggest that esophageal atresia (EA) patients may have an increased incidence of EoE compared to the general population. As EoE symptoms may be confused with EA-related symptoms, they may significantly worsen morbidity in this specific group of patients. We investigated specific characteristics of patients with AE and EoE compared to those with EoE only. We conducted an observational retrospective monocentric study including all patients diagnosed with EoE from 1 January 2010 to 31 December 2021. For each patient, demographic, clinical and histopathological data were collected and then compared between the two cohorts (EA-EoE vs. EoE only). During the study period, 62 patients were included: 17 children were in the follow-up because of EA (18.1% of 94 EA patients screened in that period), while the other 45 presented EoE only. The demographic and clinical features of EA-EoE patients demonstrate a lower prevalence of allergic subjects (23.5% vs. 80%, p < 0.05), a lower age of presentation (3.1 vs. 12.2 years, p < 0.05), non-specific symptoms and a higher resolution rate with PPI therapy (64.7% vs. 17.8%, p < 0.05) compared to EoE-only patients. Our data confirm that EA patients are at high risk for developing EoE. As symptoms may overlap with the EA spectrum, early recognition of EoE may prevent patients from receiving unnecessary invasive therapeutic interventions and from developing complications from untreated EoE.
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Choi HG, Min C, Yoo DM, Tan BK, Kim JH, Kim HI, Park JY, Park S, Hwang YI, Jang SH, Jung KS. Associations Between Asthma Diagnosis/Asthma Exacerbation and Previous Proton-Pump Inhibitor use: A Nested Case-Control Study Using a National Health Screening Cohort. Front Pharmacol 2022; 13:888610. [PMID: 35847037 PMCID: PMC9279665 DOI: 10.3389/fphar.2022.888610] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 05/09/2022] [Indexed: 11/25/2022] Open
Abstract
Background: Proton-pump inhibitors (PPIs) block acid secretion from gastric parietal cells; however, recent studies have reported that PPIs have antioxidant and anti-inflammatory properties in various cells. Newer PPIs are stronger inhibitors of acid secretion; however, the anti-inflammatory effects of these drugs have not been assessed. We evaluated anti-inflammatory effect of PPIs on the development of asthma/asthma exacerbation (AE) in a national health screening cohort. Methods: This case-control study comprised 64,809 participants with asthma who were 1:1 matched with controls from the Korean National Health Insurance Service-Health Screening Cohort. Conditional logistic regression analysis was used to evaluate the effect of previous PPI use on an asthma diagnosis in all participants. Unconditional logistic regression was used to assess the effect of PPI use on AE in participants with asthma. These relationships were estimated in a subgroup analysis according to PPI generation. Results: Overall, PPI use increased the risk of asthma diagnosis [adjusted odds ratio (aOR) = 1.29, 95% confidence interval (CI) = 1.23–1.35, p < 0.001]. Use of the first-generation PPIs was associated with asthma (aOR = 1.34, 95% CI = 1.18–1.52, p < 0.001), while use of second-generation PPIs was not (aOR = 0.97, 95% CI = 0.82–1.15, p = 0.748). In contrast, overall PPI use decreased the risk of AE in participants with asthma (aOR = 0.79, 95% CI = 0.75–0.84, p < 0.001), although this effect was observed only for second-generation PPIs (aOR = 0.76, 95% CI = 0.65–0.89, p = 0.001). Conclusion: PPI use increased the risk for subsequent asthma diagnosis. However, this effect was confined to first-generation PPIs. Second-generation PPIs decreased the risk of AE.
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Affiliation(s)
- Hyo Geun Choi
- Departments of Otorhinolaryngology-Head and Neck Surgery, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, South Korea
| | - Chanyang Min
- Hallym Data Science Laboratory, Hallym University College of Medicine, Anyang, South Korea
| | - Dae Myoung Yoo
- Hallym Data Science Laboratory, Hallym University College of Medicine, Anyang, South Korea
| | - Bruce K. Tan
- Department of Otolaryngology – Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Joo-Hee Kim
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, South Korea
- *Correspondence: Joo-Hee Kim,
| | - Hwan Il Kim
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, South Korea
| | - Ji-Young Park
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, South Korea
| | - Sunghoon Park
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, South Korea
| | - Yong Il Hwang
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, South Korea
| | - Seung Hun Jang
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, South Korea
| | - Ki-Suck Jung
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, South Korea
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Identification of novel and potential PPARγ stimulators as repurposed drugs for MCAO associated brain degeneration. Toxicol Appl Pharmacol 2022; 446:116055. [PMID: 35550883 DOI: 10.1016/j.taap.2022.116055] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 04/30/2022] [Accepted: 05/02/2022] [Indexed: 12/14/2022]
Abstract
Peroxisome proliferator-activated receptor-gamma (PPARγ) has been shown to have therapeutic promise in the treatment of ischemic stroke and is supported by several studies. To identify possible PPARγ activators, the current study used an in silico technique in conjunction with molecular simulations and in vivo validation. FDA-approved drugs were evaluated using molecular docking to determine their affinity for PPARγ. The findings of molecular simulations support the repurposing of rabeprazole and ethambutol for the treatment of ischemic stroke. Adult Sprague Dawley rats were subjected to transient middle cerebral artery occlusion (t-MCAO). Five groups were made as a sham-operated, t-MCAO group, rabeprazole +t-MCAO, ethambutol +t-MCAO, and pioglitazone +t-MCAO. The neuroprotective effects of these drugs were evaluated using the neurological deficit score and the infarct area. The inflammatory mediators and signaling transduction proteins were quantified using Western blotting, ELISA, and immunohistochemistry. The repurposed drugs mitigated cerebral ischemic injury by PPARγ mediated downregulation of nods like receptor protein 3 inflammasomes (NLRP3), tumor necrosis factor-alpha (TNF-α), cyclooxygenase 2 (COX-2), nuclear factor kappa-light-chain-enhancer of activated B cells (p-NF-kB), and c-Jun N-terminal kinase (p-JNK). Our data demonstrated that rabeprazole and ethambutol have neuroprotective potential via modulating the cytoprotective stress response, increasing cellular survival, and balancing homeostatic processes, and so may be suitable for future research in stroke therapy.
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Gupta V, Hammond CL, Roztocil E, Gonzalez MO, Feldon SE, Woeller CF. Thinking inside the box: Current insights into targeting orbital tissue remodeling and inflammation in thyroid eye disease. Surv Ophthalmol 2022; 67:858-874. [PMID: 34487739 PMCID: PMC8891393 DOI: 10.1016/j.survophthal.2021.08.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 08/24/2021] [Accepted: 08/30/2021] [Indexed: 12/21/2022]
Abstract
Thyroid eye disease (TED) is an autoimmune disorder that manifests in the orbit. In TED, the connective tissue behind the eye becomes inflamed and remodels with increased fat accumulation and/or increased muscle and scar tissue. As orbital tissue expands, patients develop edema, exophthalmos, diplopia, and optic neuropathy. In severe cases vision loss may occur secondary to corneal scarring from exposure or optic nerve compression. Currently there is no cure for TED, and treatments are limited. A major breakthrough in TED therapy occurred with the FDA approval of teprotumumab, a monoclonal insulin-like growth factor 1 receptor (IGF1R) blocking antibody. Yet, teprotumumab therapy has limitations, including cost, infusion method of drug delivery, variable response, and relapse. We describe approaches to target orbital fibroblasts and the complex pathophysiology that underlies tissue remodeling and inflammation driving TED. Further advances in the elucidation of the mechanisms of TED may lead to prophylaxis based upon early biomarkers as well as lead to more convenient, less expensive therapies.
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Affiliation(s)
- Vardaan Gupta
- Flaum Eye Institute, University of Rochester, 210 Crittenden Boulevard, Rochester, New York 14642, USA
| | - Christine L Hammond
- Flaum Eye Institute, University of Rochester, 210 Crittenden Boulevard, Rochester, New York 14642, USA
| | - Elisa Roztocil
- Flaum Eye Institute, University of Rochester, 210 Crittenden Boulevard, Rochester, New York 14642, USA
| | - Mithra O Gonzalez
- Flaum Eye Institute, University of Rochester, 210 Crittenden Boulevard, Rochester, New York 14642, USA
| | - Steven E Feldon
- Flaum Eye Institute, University of Rochester, 210 Crittenden Boulevard, Rochester, New York 14642, USA
| | - Collynn F Woeller
- Flaum Eye Institute, University of Rochester, 210 Crittenden Boulevard, Rochester, New York 14642, USA.
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Abu El-Ella SS, El-Mekkawy MS, Mohamed Selim A. Stress ulcer prophylaxis for critically ill children: routine use needs to be re-examined. ANALES DE PEDIATRÍA (ENGLISH EDITION) 2022; 96:402-409. [PMID: 35701033 DOI: 10.1016/j.anpede.2021.03.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 12/11/2020] [Indexed: 10/21/2022] Open
Abstract
INTRODUCTION Stress ulcer prophylaxis (SUP) is commonly used in Paediatric Intensive Care Units (PICUs). However, strong evidence for this practice is lacking and there is a dire need for paediatric randomized controlled trials (RCTs). Our aim was to assess the usefulness of SUP with omeprazole in critically ill children. PATIENTS AND METHODS We conducted a randomized, controlled open-label trial, including 144 children admitted into a PICU with a paediatric Sequential Organ Failure Assessment (pSOFA) score of less than 16. We randomly allocated patients to SUP with omeprazole or no SUP. The primary outcome was development of upper gastrointestinal bleeding or nosocomial infection. RESULTS The incidence of gastrointestinal bleeding was 27.1%, but clinically significant bleeding developed in only 5.6% of patients. We did not find a significant difference in the incidence of bleeding between the prophylaxis and control groups (27.8% vs 26.4%; P = .85). We also did not find a significant difference between the groups in the incidence of ventilator-associated pneumonia (VAP) (9.6% vs 8.3%; P = .77). The incidence of central line-associated bloodstream infection (CLABSI) was higher in the prophylaxis group compared to the control group (30.6% vs 12.5%; P = .014). None of the patients developed Clostridium difficile-associated diarrhoea. We did not find significant differences in mortality, length of PICU stay or duration of mechanical ventilation. Mechanical ventilation was an independent predictor of bleeding (OR, 6.4; 95%CI, 2.73-14.9). CONCLUSION In PICU patients with mild to moderate organ dysfunction, omeprazole does not seem to be useful for prevention of gastrointestinal bleeding while at the same time increasing the risk of CLABSI. Thus, we recommend restricting SUP to mechanically ventilated children.
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Affiliation(s)
| | | | - Ali Mohamed Selim
- Departamento de Pediatría, Facultad de Medicina, Universidad de Menufia, Shibin el-Kom, Egypt
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Liu YB, Chen MK. The impact of proton pump inhibitors in liver diseases and the effects on the liver. J Dig Dis 2022; 23:196-208. [PMID: 35357775 DOI: 10.1111/1751-2980.13093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 03/09/2022] [Accepted: 03/29/2022] [Indexed: 12/11/2022]
Abstract
In this systematic and comprehensive overview, we aimed to evaluate the impact of proton pump inhibitors (PPIs) on chronic liver diseases, especially on cirrhosis. A manual and comprehensive search of the PubMed database was conducted to obtain relevant literatures. PPIs altered the composition and function of the intestinal microflora and might lead to small intestinal bacterial overgrowth and bacterial translocation, which were associated with adverse effects in liver diseases. They might increase the risk of hepatic encephalopathy, spontaneous bacterial peritonitis, infections, and are related to an increased mortality in cirrhosis. PPIs might lead to an increased risk of hepatocellular carcinoma, although the mechanism is unknown, and the results are controversial. PPIs also had an impact on the direct-acting antiviral regimen in patients with chronic hepatitis C. They were associated with an increased risk of liver abscess and increased mortality. Additionally, PPIs might lead to metabolic risk events, such as liver steatosis and weight gain. PPIs are associated with several adverse outcomes in liver diseases. Cautious use of PPIs is recommended and clinicians should be aware of the indications for their use in patients with liver diseases.
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Affiliation(s)
- Yuan Bin Liu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Ming Kai Chen
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
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Repurposing Multiple-Molecule Drugs for COVID-19-Associated Acute Respiratory Distress Syndrome and Non-Viral Acute Respiratory Distress Syndrome via a Systems Biology Approach and a DNN-DTI Model Based on Five Drug Design Specifications. Int J Mol Sci 2022; 23:ijms23073649. [PMID: 35409008 PMCID: PMC8998971 DOI: 10.3390/ijms23073649] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/22/2022] [Accepted: 03/23/2022] [Indexed: 02/04/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) epidemic is currently raging around the world at a rapid speed. Among COVID-19 patients, SARS-CoV-2-associated acute respiratory distress syndrome (ARDS) is the main contribution to the high ratio of morbidity and mortality. However, clinical manifestations between SARS-CoV-2-associated ARDS and non-SARS-CoV-2-associated ARDS are quite common, and their therapeutic treatments are limited because the intricated pathophysiology having been not fully understood. In this study, to investigate the pathogenic mechanism of SARS-CoV-2-associated ARDS and non-SARS-CoV-2-associated ARDS, first, we constructed a candidate host-pathogen interspecies genome-wide genetic and epigenetic network (HPI-GWGEN) via database mining. With the help of host-pathogen RNA sequencing (RNA-Seq) data, real HPI-GWGEN of COVID-19-associated ARDS and non-viral ARDS were obtained by system modeling, system identification, and Akaike information criterion (AIC) model order selection method to delete the false positives in candidate HPI-GWGEN. For the convenience of mitigation, the principal network projection (PNP) approach is utilized to extract core HPI-GWGEN, and then the corresponding core signaling pathways of COVID-19-associated ARDS and non-viral ARDS are annotated via their core HPI-GWGEN by KEGG pathways. In order to design multiple-molecule drugs of COVID-19-associated ARDS and non-viral ARDS, we identified essential biomarkers as drug targets of pathogenesis by comparing the core signal pathways between COVID-19-associated ARDS and non-viral ARDS. The deep neural network of the drug–target interaction (DNN-DTI) model could be trained by drug–target interaction databases in advance to predict candidate drugs for the identified biomarkers. We further narrowed down these predicted drug candidates to repurpose potential multiple-molecule drugs by the filters of drug design specifications, including regulation ability, sensitivity, excretion, toxicity, and drug-likeness. Taken together, we not only enlighten the etiologic mechanisms under COVID-19-associated ARDS and non-viral ARDS but also provide novel therapeutic options for COVID-19-associated ARDS and non-viral ARDS.
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Chawla BK, Cohen RE, Yerke LM. Association between proton pump inhibitors and periodontal disease severity. Clin Exp Dent Res 2022; 8:395-401. [PMID: 34545705 PMCID: PMC8874058 DOI: 10.1002/cre2.495] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 09/02/2021] [Accepted: 09/05/2021] [Indexed: 01/07/2023] Open
Abstract
OBJECTIVES Proton pump inhibitors (PPIs) are commonly prescribed for the management of acid-related gastrointestinal disorders. PPIs modulate osteoclast function, reduce gastric acid secretion, and are associated with the establishment of a more diverse gastrointestinal microbiota. Periodontitis is characterized by microbe-associated host-mediated inflammation that results in loss of periodontal attachment. The aim of this study was to assess whether a relationship exists between PPIs and periodontal disease. MATERIALS AND METHODS A retrospective analysis was performed using patient records from a faculty periodontal practice. The proportion of elevated probing depths was used to measure periodontitis severity. Statistical analysis was performed using independent sample t-tests, and Chi-square tests of independence. RESULTS Records from 1093 patients were initially assessed. Fourteen percent of teeth were associated with ≥6 mm probing depths among PPI users, in contrast to 24% for patients not using PPIs (P = 0.030). Similarly, 27% of teeth exhibited ≥5 mm probing depths among PPI users versus 40% for non-PPI users (P = 0.039). CONCLUSIONS The results suggest that PPIs are associated with a reduced proportion of elevated probing depths. Future prospective studies are indicated to elucidate possible mechanisms through which PPIs might affect, and potentially be used in the treatment of, periodontitis.
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Affiliation(s)
- Bhavneet K. Chawla
- Department of Periodontics and Endodontics, School of Dental Medicine, The State University of New YorkUniversity at BuffaloBuffaloNew YorkUSA
| | - Robert E. Cohen
- Department of Periodontics and Endodontics, School of Dental Medicine, The State University of New YorkUniversity at BuffaloBuffaloNew YorkUSA
| | - Lisa M. Yerke
- Department of Periodontics and Endodontics, School of Dental Medicine, The State University of New YorkUniversity at BuffaloBuffaloNew YorkUSA
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Feo-Ortega S, Lucendo AJ. Evidence-based treatments for eosinophilic esophagitis: insights for the clinician. Therap Adv Gastroenterol 2022; 15:17562848211068665. [PMID: 35069803 PMCID: PMC8777364 DOI: 10.1177/17562848211068665] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 12/03/2021] [Indexed: 02/04/2023] Open
Abstract
Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder characterized by symptoms of esophageal dysfunction and eosinophil-predominant inflammation. Left untreated, EoE progresses to fibrous remodeling and stricture formation that impairs quality of life. Therefore, EoE requires either repeated treatments or maintenance therapy. Current guidelines recommend swallowed topical corticosteroids (STCs), proton-pump inhibitors (PPIs), or dietary intervention as initial options to induce and maintain long-term disease remission. Impractical exclusive elemental diets and suboptimal allergy testing-directed food avoidance paved the way for empirical elimination diets. These are moderately effective and highly reproducible in inducing EoE remission and allow for identification of specific food triggers. Step-up strategies, including two- and four-food rather than six-food elimination diets, should be considered as initial approaches for dietary treatment in patients of all ages, as they reduce the need for endoscopic procedures, shorten diagnostic processing time, and avoid unnecessary restrictions. Formulations of STC originally designed for asthma therapy are suboptimal for EoE treatment, with new effervescent orodispersible tablets and viscose formulations designed to coat the esophageal mucosa providing increased effectiveness at reduced doses. The anti-inflammatory effects of PPI in EoE are independent from gastric acid secretion inhibition; despite evidence from observational research, PPIs are the most commonly prescribed first-line therapy for EoE due to their accessibility, low cost, and safety profile. Double doses of PPI only induce remission in half of EoE patients, irrespective of the drug used or patients' age. Inflammatory rather than stricturing EoE phenotype and treatment duration up to 12 weeks increase chances of achieving EoE remission. Most responders effectively maintain long-term remission with standard PPI doses. Finally, endoscopic dilation should be considered in patients with reduced esophageal caliber or persistent dysphagia despite histological remission. This article provides a state-of-the-art review and updated discussion of current therapies and newly developed options for EoE.
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Affiliation(s)
- Sara Feo-Ortega
- Pediatric Gastroenterology Unit, Hospital
General de Tomelloso, Tomelloso, Spain, and Instituto de Investigación
Sanitaria de Castilla-La Mancha (IDISCAM)
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Yao H, Wang L, Li H, Xu S, Bai Z, Wu Y, Chen H, Goyal H, Qi X. Proton pump inhibitors may reduce the risk of high-grade dysplasia and/or esophageal adenocarcinoma in Barrett's esophagus: a systematic review and meta-analysis. Expert Rev Clin Pharmacol 2022; 15:79-88. [PMID: 34806503 DOI: 10.1080/17512433.2022.2008909] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 10/27/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Barrett's esophagus (BE) is an important risk factor for high-grade dysplasia (HGD) and/or esophageal adenocarcinoma (EAC). The effect of proton pump inhibitors (PPIs) on the chemoprevention of HGD and/or EAC arising from BE remains controversial. RESEARCH DESIGN AND METHODS PubMed, EMBASE, and Cochrane Library databases were systematically searched. Risk ratios (RRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were pooled by a random-effect model. Heterogeneity and its potential source were assessed. RESULTS Fifteen studies with 26,291 BE patients were included. Meta-analysis of eight cohort studies showed that PPIs can significantly reduce the risk of HGD and/or EAC in BE patients (RR = 0.46; P < 0.001), but meta-analysis of six case-control studies showed no significant benefit of PPIs (OR = 0.64; P = 0.334). Heterogeneity was significant among both cohort and case-control studies, which might be attributed to the information sources of PPIs. There was no significant protective effect of high-dose PPIs on HGD and/or EAC in one RCT (RR = 0.84; P = 0.21), meta-analysis of two cohort studies (RR = 0.61; P = 0.28), or meta-analysis of two case-control studies (OR = 0.32; P = 0.08). CONCLUSIONS Chemoprevention of HGD and/or EAC by PPIs may be considered in BE patients. However, there might not be further preventive effect of high-dose PPIs.
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Affiliation(s)
- Haijuan Yao
- Department of Gastroenterology, General Hospital of Northern Theater Command (formerly called General Hospital of Shenyang Military Area), Shenyang, China
- Postgraduate College, Liaoning University of Traditional Chinese Medicine, Shenyang, P.R. China
| | - Le Wang
- Department of Gastroenterology, General Hospital of Northern Theater Command (formerly called General Hospital of Shenyang Military Area), Shenyang, China
- Postgraduate College, Dalian Medical University, Dalian, China
- Postgraduate College, China Medical University, Shenyang, China
| | - Hongyu Li
- Department of Gastroenterology, General Hospital of Northern Theater Command (formerly called General Hospital of Shenyang Military Area), Shenyang, China
| | - Shixue Xu
- Department of Gastroenterology, General Hospital of Northern Theater Command (formerly called General Hospital of Shenyang Military Area), Shenyang, China
- Postgraduate College, China Medical University, Shenyang, China
| | - Zhaohui Bai
- Department of Gastroenterology, General Hospital of Northern Theater Command (formerly called General Hospital of Shenyang Military Area), Shenyang, China
- Postgraduate College, Shenyang Pharmaceutical University, Shenyang, China
| | - Yanyan Wu
- Department of Gastroenterology, General Hospital of Northern Theater Command (formerly called General Hospital of Shenyang Military Area), Shenyang, China
- Postgraduate College, Jinzhou Medical University, Jinzhou, China
| | - Hongxin Chen
- Department of Gastroenterology, General Hospital of Northern Theater Command (formerly called General Hospital of Shenyang Military Area), Shenyang, China
- Postgraduate College, Liaoning University of Traditional Chinese Medicine, Shenyang, P.R. China
| | - Hemant Goyal
- Department of Medicine, The Wright Center for Graduate Medical Education, Scranton, PA, USA
| | - Xingshun Qi
- Department of Gastroenterology, General Hospital of Northern Theater Command (formerly called General Hospital of Shenyang Military Area), Shenyang, China
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