|
1
|
Hutka B, Várallyay A, László SB, Tóth AS, Scheich B, Paku S, Vörös I, Pós Z, Varga ZV, Norman DD, Balogh A, Benyó Z, Tigyi G, Gyires K, Zádori ZS. A dual role of lysophosphatidic acid type 2 receptor (LPAR2) in nonsteroidal anti-inflammatory drug-induced mouse enteropathy. Acta Pharmacol Sin 2024; 45:339-353. [PMID: 37816857 PMCID: PMC10789874 DOI: 10.1038/s41401-023-01175-7] [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: 05/16/2023] [Accepted: 09/21/2023] [Indexed: 10/12/2023]
Abstract
Lysophosphatidic acid (LPA) is a bioactive phospholipid mediator that has been found to ameliorate nonsteroidal anti-inflammatory drug (NSAID)-induced gastric injury by acting on lysophosphatidic acid type 2 receptor (LPAR2). In this study, we investigated whether LPAR2 signaling was implicated in the development of NSAID-induced small intestinal injury (enteropathy), another major complication of NSAID use. Wild-type (WT) and Lpar2 deficient (Lpar2-/-) mice were treated with a single, large dose (20 or 30 mg/kg, i.g.) of indomethacin (IND). The mice were euthanized at 6 or 24 h after IND treatment. We showed that IND-induced mucosal enteropathy and neutrophil recruitment occurred much earlier (at 6 h after IND treatment) in Lpar2-/- mice compared to WT mice, but the tissue levels of inflammatory mediators (IL-1β, TNF-α, inducible COX-2, CAMP) remained at much lower levels. Administration of a selective LPAR2 agonist DBIBB (1, 10 mg/kg, i.g., twice at 24 h and 30 min before IND treatment) dose-dependently reduced mucosal injury and neutrophil activation in enteropathy, but it also enhanced IND-induced elevation of several proinflammatory chemokines and cytokines. By assessing caspase-3 activation, we found significantly increased intestinal apoptosis in IND-treated Lpar2-/- mice, but it was attenuated after DBIBB administration, especially in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. Finally, we showed that IND treatment reduced the plasma activity and expression of autotaxin (ATX), the main LPA-producing enzyme, and also reduced the intestinal expression of Lpar2 mRNA, which preceded the development of mucosal damage. We conclude that LPAR2 has a dual role in NSAID enteropathy, as it contributes to the maintenance of mucosal integrity after NSAID exposure, but also orchestrates the inflammatory responses associated with ulceration. Our study suggests that IND-induced inhibition of the ATX-LPAR2 axis is an early event in the pathogenesis of enteropathy.
Collapse
Affiliation(s)
- Barbara Hutka
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
- Pharmacological and Drug Safety Research, Gedeon Richter Plc, Budapest, Hungary
| | - Anett Várallyay
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Szilvia B László
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - András S Tóth
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Bálint Scheich
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Sándor Paku
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Imre Vörös
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
- HCEMM-SU Cardiometabolic Immunology Research Group, Semmelweis University, Budapest, Hungary
- MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Budapest, Hungary
- MTA-SE System Pharmacology Research Group, Budapest, Hungary
| | - Zoltán Pós
- Department of Genetics, Cell and Immunobiology, Semmelweis University, Budapest, Hungary
| | - Zoltán V Varga
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
- HCEMM-SU Cardiometabolic Immunology Research Group, Semmelweis University, Budapest, Hungary
- MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Budapest, Hungary
| | - Derek D Norman
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN, USA
| | - Andrea Balogh
- Institute of Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Zoltán Benyó
- Institute of Translational Medicine, Semmelweis University, Budapest, Hungary
- HUN-REN-SU Cerebrovascular and Neurocognitive Diseases Research Group, Budapest, Hungary
| | - Gábor Tigyi
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN, USA
- Institute of Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Klára Gyires
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Zoltán S Zádori
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
| |
Collapse
|
|
2
|
Feng Z, Wei Y, Zhang Z, Li M, Gu R, Lu L, Liu W, Qin H. Wheat peptides inhibit the activation of MAPK and NF-κB inflammatory pathways and maintain epithelial barrier integrity in NSAID-induced intestinal epithelial injury. Food Funct 2024; 15:823-837. [PMID: 38131381 DOI: 10.1039/d3fo03954d] [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: 12/23/2023]
Abstract
The use of non-steroidal anti-inflammatory drugs (NSAIDs) has negative effects on the gastrointestinal tract, but the proton pump inhibitors currently in use only protect against gastrointestinal disease and may even make NSAID-induced enteropathy worse. Therefore, new approaches to treating enteropathy are required. This study aimed to investigate the protective effect of wheat peptides (WPs) against NSAID-induced intestinal damage in mice and their mechanism. Here, an in vivo mouse model was built to investigate the protective and reparative effects of different concentrations of WPs on NSAID-induced intestinal injury. WPs ameliorated NSAID-induced weight loss and small intestinal tissue damage in mice. WP treatment inhibited NSAID-induced injury leading to increased levels of oxidative stress and expression levels of inflammatory factors. WPs protected and repaired the integrity and permeability injury of the intestinal tight junction induced by NSAIDs. An in vitro Caco-2 cell model was built with lipopolysaccharide (LPS). WP pretreatment inhibited LPS-induced changes in the Caco-2 cell permeability and elevated the levels of oxidative stress. WPs inhibited LPS-induced phosphorylation of NF-κB p65 and mitogen-activated protein kinase (MAPK) signaling pathways and reduced the expression of inflammatory factors. In addition, WPs increased tight junction protein expression, which contributed to improved intestinal epithelial dysfunction. Our results suggest that WPs can ameliorate NSAID-induced impairment of intestinal barrier functional integrity by improving intestinal oxidative stress levels and reducing inflammatory factor expression through inhibition of NF-κB p65 and MAPK signaling pathway activation. WPs can therefore be used as potential dietary supplements to reduce NSAID-induced injury of the intestine.
Collapse
Affiliation(s)
- Zhiyuan Feng
- Tianjin Key Laboratory of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin Economic and Technological Development Area, Tianjin, China.
- Beijing Engineering Research Center of Protein & Functional Peptides, China National Research Institute of Food and Fermentation Industries, Beijing, 100015, China
| | - Ying Wei
- Department of Food Science and Engineering, Beijing University of Agriculture, Beijing, China.
| | - Zhuoran Zhang
- Beijing Engineering Research Center of Protein & Functional Peptides, China National Research Institute of Food and Fermentation Industries, Beijing, 100015, China
| | - Mingliang Li
- Beijing Engineering Research Center of Protein & Functional Peptides, China National Research Institute of Food and Fermentation Industries, Beijing, 100015, China
| | - Ruizeng Gu
- Beijing Engineering Research Center of Protein & Functional Peptides, China National Research Institute of Food and Fermentation Industries, Beijing, 100015, China
| | - Lu Lu
- Beijing Engineering Research Center of Protein & Functional Peptides, China National Research Institute of Food and Fermentation Industries, Beijing, 100015, China
| | - Wenying Liu
- Department of Food Science and Engineering, Beijing University of Agriculture, Beijing, China.
| | - Huimin Qin
- Tianjin Key Laboratory of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin Economic and Technological Development Area, Tianjin, China.
| |
Collapse
|
|
3
|
D'Antongiovanni V, Antonioli L, Benvenuti L, Pellegrini C, Di Salvo C, Calvigioni M, Panattoni A, Ryskalin L, Natale G, Banni S, Carta G, Ghelardi E, Fornai M. Use of Saccharomyces boulardii CNCM I-745 as therapeutic strategy for prevention of nonsteroidal anti-inflammatory drug-induced intestinal injury. Br J Pharmacol 2023; 180:3215-3233. [PMID: 37519261 DOI: 10.1111/bph.16200] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 02/21/2023] [Accepted: 03/28/2023] [Indexed: 08/01/2023] Open
Abstract
BACKGROUND AND PURPOSE Nonsteroidal anti-inflammatory drugs (NSAIDs) can be associated with severe adverse digestive effects. This study examined the protective effects of the probiotic Saccharomyces boulardii CNCM I-745 in a rat model of diclofenac-induced enteropathy. EXPERIMENTAL APPROACH Enteropathy was induced in 40-week-old male rats by intragastric diclofenac (4 mg·kg-1 BID for 14 days). S. boulardii CNCM I-745 (3 g·kg-1 BID by oral gavage) was administered starting 14 days before (preventive protocol) or along with (curative protocol) diclofenac administration. Ileal damage, inflammation, barrier integrity, gut microbiota composition and toll-like receptors (TLRs)-nuclear factor κB (NF-κB) pathway were evaluated. KEY RESULTS Diclofenac elicited intestinal damage, along with increments of myeloperoxidase, malondialdehyde, tumour necrosis factor and interleukin-1β, overexpression of TLR2/4, myeloid differentiation primary response 88 (Myd88) and NF-κB p65, increased faecal calprotectin and butyrate levels, and decreased blood haemoglobin levels, occludin and butyrate transporter monocarboxylate transporter 1 (MCT1) expression. In addition, diclofenac provoked a shift of bacterial taxa in both faecal and ileal samples. Treatment with S. boulardii CNCM I-745, in both preventive and curative protocols, counteracted the majority of these deleterious changes. Only preventive administration of the probiotic counteracted NSAID-induced decreased expression of MCT1 and increase in faecal butyrate levels. Occludin expression, after probiotic treatment, did not significantly change. CONCLUSIONS AND IMPLICATIONS Treatment with S. boulardii CNCM I-745 prevents diclofenac-induced enteropathy through anti-inflammatory and antioxidant activities. Such effects are likely to be related to increased tissue butyrate bioavailability, through an improvement of butyrate uptake by the enteric mucosa.
Collapse
Affiliation(s)
| | - Luca Antonioli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Laura Benvenuti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Carolina Pellegrini
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Clelia Di Salvo
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Marco Calvigioni
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Adelaide Panattoni
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Larisa Ryskalin
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Gianfranco Natale
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Sebastiano Banni
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Gianfranca Carta
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Emilia Ghelardi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Matteo Fornai
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| |
Collapse
|
|
4
|
Farkas R, Mireisz T, Toumi M, Abbaszade G, Sztráda N, Tóth E. The Impact of Anti-Inflammatory Drugs on the Prokaryotic Community Composition and Selected Bacterial Strains Based on Microcosm Experiments. Microorganisms 2023; 11:1447. [PMID: 37374949 PMCID: PMC10303239 DOI: 10.3390/microorganisms11061447] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 05/24/2023] [Accepted: 05/26/2023] [Indexed: 06/29/2023] Open
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are increasingly recognized as potential environmental contaminants that may induce toxicity in aquatic ecosystems. This 3-week microcosm experiment explores the acute impacts of NSAIDs, including diclofenac (DCF), ibuprofen (IBU), and acetylsalicylic acid (ASA), on bacterial communities using a wide range of these substances (200-6000 ppm). The results showed that the NSAID-treated microcosms had higher cell count values than control samples, though the diversity of microbial communities decreased. The isolated heterotrophic bacteria mostly belonged to Proteobacteria, particularly Klebsiella. Next-generation sequencing (NGS) revealed that NSAIDs altered the structure of the bacterial community composition, with the proportion of Proteobacteria aligning with the selective cultivation results. Bacteria had higher resistance to IBU/ASA than to DCF. In DCF-treated microcosms, there has been a high reduction of the number of Bacteroidetes, whereas in the microcosms treated with IBU/ASA, they have remained abundant. The numbers of Patescibacteria and Actinobacteria have decreased across all NSAID-treated microcosms. Verrucomicrobia and Planctomycetes have tolerated all NSAIDs, even DCF. Cyanobacteria have also demonstrated tolerance to IBU/ASA treatment in the microcosms. The archaeal community structure was also impacted by the NSAID treatments, with Thaumarchaeota abundant in all microcosms, especially DCF-treated microcosms, while Nanoarchaeota is more typical of IBU/ASA-treated microcosms with lower NSAID concentrations. These results indicate that the presence of NSAIDs in aquatic environments could lead to changes in the composition of microbial communities.
Collapse
Affiliation(s)
- Rózsa Farkas
- Department of Microbiology, Doctoral School of Biology, Institute of Biology, Eötvös Loránd University, Pázmány Péter stny., 1/C, 1117 Budapest, Hungary
- Department of Microbiology, Eötvös Loránd University, Pázmány Péter stny., 1/C, 1117 Budapest, Hungary
| | - Tamás Mireisz
- Department of Microbiology, Eötvös Loránd University, Pázmány Péter stny., 1/C, 1117 Budapest, Hungary
- Department of Microbiology, Doctoral School of Environmental Sciences, Institute of Biology, Eötvös Loránd University, Pázmány Péter stny., 1/C, 1117 Budapest, Hungary
| | - Marwene Toumi
- Department of Microbiology, Eötvös Loránd University, Pázmány Péter stny., 1/C, 1117 Budapest, Hungary
- Department of Microbiology, Doctoral School of Environmental Sciences, Institute of Biology, Eötvös Loránd University, Pázmány Péter stny., 1/C, 1117 Budapest, Hungary
| | - Gorkhmaz Abbaszade
- Department of Microbiology, Eötvös Loránd University, Pázmány Péter stny., 1/C, 1117 Budapest, Hungary
- Department of Microbiology, Doctoral School of Environmental Sciences, Institute of Biology, Eötvös Loránd University, Pázmány Péter stny., 1/C, 1117 Budapest, Hungary
| | - Nóra Sztráda
- Department of Microbiology, Eötvös Loránd University, Pázmány Péter stny., 1/C, 1117 Budapest, Hungary
| | - Erika Tóth
- Department of Microbiology, Eötvös Loránd University, Pázmány Péter stny., 1/C, 1117 Budapest, Hungary
| |
Collapse
|
|
5
|
Cañamares-Orbís P, Lanas Arbeloa Á. New Trends and Advances in Non-Variceal Gastrointestinal Bleeding-Series II. J Clin Med 2021; 10:3045. [PMID: 34300211 PMCID: PMC8303152 DOI: 10.3390/jcm10143045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 07/03/2021] [Accepted: 07/05/2021] [Indexed: 12/12/2022] Open
Abstract
The gastrointestinal tract is a long tubular structure wherein any point in the mucosa along its entire length could be the source of a hemorrhage. Upper (esophagel and gastroduodenal) and lower (jejunum, ileum, and colon) gastrointestinal bleeding are common. Gastroduodenal and colonic bleeding are more frequent than bleeding from the small bowel, but nowadays the entire gastrointestinal tract can be explored endoscopically and bleeding lesions can be locally treated successfully to stop or prevent further bleeding. The extensive use of antiplatelet and anticoagulants drugs in cardiovascular patients is, at least in part, the cause of the increasing number of patients suffering from gastrointestinal bleeding. Patients with these conditions are usually older and more fragile because of their comorbidities. The correct management of antithrombotic drugs in cases of gastrointestinal bleeding is essential for a successful outcome for patients. The influence of the microbiome in the pathogenesis of small bowel bleeding is an example of the new data that are emerging as potential therapeutic target for bleeding prevention. This text summarizes the latest research and advances in all forms of acute gastrointestinal bleeding (i.e., upper, small bowel and lower). Diagnosis is approached, and medical, endoscopic or antithrombotic management are discussed in the text in an accessible and comprehensible way.
Collapse
Affiliation(s)
- Pablo Cañamares-Orbís
- Gastroenterology, Hepatology and Nutrition Unit, San Jorge University Hospital, 22004 Huesca, Spain
| | - Ángel Lanas Arbeloa
- IIS Aragón, CIBERehd, 50009 Zaragoza, Spain;
- Service of Digestive Diseases, University Clinic Hospital Lozano Blesa, 50009 Zaragoza, Spain
- University of Zaragoza, 500009 Zaragoza, Spain
| |
Collapse
|
|
6
|
McEvoy L, Carr DF, Pirmohamed M. Pharmacogenomics of NSAID-Induced Upper Gastrointestinal Toxicity. Front Pharmacol 2021; 12:684162. [PMID: 34234675 PMCID: PMC8256335 DOI: 10.3389/fphar.2021.684162] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 05/11/2021] [Indexed: 12/19/2022] Open
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are a group of drugs which are widely used globally for the treatment of pain and inflammation, and in the case of aspirin, for secondary prevention of cardiovascular disease. Chronic non-steroidal anti-inflammatory drug use is associated with potentially serious upper gastrointestinal adverse drug reactions (ADRs) including peptic ulcer disease and gastrointestinal bleeding. A few clinical and genetic predisposing factors have been identified; however, genetic data are contradictory. Further research is needed to identify clinically relevant genetic and non-genetic markers predisposing to NSAID-induced peptic ulceration.
Collapse
Affiliation(s)
- L McEvoy
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom
| | - D F Carr
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom
| | - M Pirmohamed
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom
| |
Collapse
|
|
7
|
Hutka B, Lázár B, Tóth AS, Ágg B, László SB, Makra N, Ligeti B, Scheich B, Király K, Al-Khrasani M, Szabó D, Ferdinandy P, Gyires K, Zádori ZS. The Nonsteroidal Anti-Inflammatory Drug Ketorolac Alters the Small Intestinal Microbiota and Bile Acids Without Inducing Intestinal Damage or Delaying Peristalsis in the Rat. Front Pharmacol 2021; 12:664177. [PMID: 34149417 PMCID: PMC8213092 DOI: 10.3389/fphar.2021.664177] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 04/19/2021] [Indexed: 01/02/2023] Open
Abstract
Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) induce significant damage to the small intestine, which is accompanied by changes in intestinal bacteria (dysbiosis) and bile acids. However, it is still a question of debate whether besides mucosal inflammation also other factors, such as direct antibacterial effects or delayed peristalsis, contribute to NSAID-induced dysbiosis. Here we aimed to assess whether ketorolac, an NSAID lacking direct effects on gut bacteria, has any significant impact on intestinal microbiota and bile acids in the absence of mucosal inflammation. We also addressed the possibility that ketorolac-induced bacterial and bile acid alterations are due to a delay in gastrointestinal (GI) transit. Methods: Vehicle or ketorolac (1, 3 and 10 mg/kg) were given to rats by oral gavage once daily for four weeks, and the severity of mucosal inflammation was evaluated macroscopically, histologically, and by measuring the levels of inflammatory proteins and claudin-1 in the distal jejunal tissue. The luminal amount of bile acids was measured by liquid chromatography-tandem mass spectrometry, whereas the composition of microbiota by sequencing of bacterial 16S rRNA. GI transit was assessed by the charcoal meal method. Results: Ketorolac up to 3 mg/kg did not cause any signs of mucosal damage to the small intestine. However, 3 mg/kg of ketorolac induced dysbiosis, which was characterized by a loss of families belonging to Firmicutes (Paenibacillaceae, Clostridiales Family XIII, Christensenellaceae) and bloom of Enterobacteriaceae. Ketorolac also changed the composition of small intestinal bile by decreasing the concentration of conjugated bile acids and by increasing the amount of hyodeoxycholic acid (HDCA). The level of conjugated bile acids correlated negatively with the abundance of Erysipelotrichaceae, Ruminococcaceae, Clostridiaceae 1, Muribaculaceae, Bacteroidaceae, Burkholderiaceae and Bifidobacteriaceae. Ketorolac, under the present experimental conditions, did not change the GI transit. Conclusion: This is the first demonstration that low-dose ketorolac disturbed the delicate balance between small intestinal bacteria and bile acids, despite having no significant effect on intestinal mucosal integrity and peristalsis. Other, yet unidentified, factors may contribute to ketorolac-induced dysbiosis and bile dysmetabolism.
Collapse
Affiliation(s)
- Barbara Hutka
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Bernadette Lázár
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - András S Tóth
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Bence Ágg
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.,Pharmahungary Group, Szeged, Hungary
| | - Szilvia B László
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Nóra Makra
- Department of Medical Microbiology, Semmelweis University, Budapest, Hungary
| | - Balázs Ligeti
- Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, Hungary
| | - Bálint Scheich
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Kornél Király
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Mahmoud Al-Khrasani
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Dóra Szabó
- Department of Medical Microbiology, Semmelweis University, Budapest, Hungary
| | - Péter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.,Pharmahungary Group, Szeged, Hungary
| | - Klára Gyires
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Zoltán S Zádori
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| |
Collapse
|
|
8
|
Guo CG, Leung WK. Potential Strategies in the Prevention of Nonsteroidal Anti-inflammatory Drugs-Associated Adverse Effects in the Lower Gastrointestinal Tract. Gut Liver 2021; 14:179-189. [PMID: 31547642 PMCID: PMC7096237 DOI: 10.5009/gnl19201] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Accepted: 07/09/2019] [Indexed: 12/21/2022] Open
Abstract
With the increasing use of nonsteroidal anti-inflammatory drugs (NSAIDs), the incidence of lower gastrointestinal (GI) complications is expected to increase. However, unlike upper GI complications, the burden, pathogenesis, prevention and treatment of NSAID-associated lower GI complications remain unclear. To date, no cost-effective and safe protective agent has been developed that can completely prevent or treat NSAID-related lower GI injuries. Selective COX-2 inhibitors, misoprostol, intestinal microbiota modulation, and some mucoprotective agents have been reported to show protective effects on NSAID-induced lower GI injuries. This review aims to provide an overview of the current evidence on the prevention of NSAID-related lower GI injuries.
Collapse
Affiliation(s)
- Chuan-Guo Guo
- Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
| | - Wai K Leung
- Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
| |
Collapse
|
|
9
|
Wang X, Tang Q, Hou H, Zhang W, Li M, Chen D, Gu Y, Wang B, Hou J, Liu Y, Cao H. Gut Microbiota in NSAID Enteropathy: New Insights From Inside. Front Cell Infect Microbiol 2021; 11:679396. [PMID: 34295835 PMCID: PMC8290187 DOI: 10.3389/fcimb.2021.679396] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 06/10/2021] [Indexed: 12/15/2022] Open
Abstract
As a class of the commonly used drugs in clinical practice, non-steroidal anti-inflammatory drugs (NSAIDs) can cause a series of adverse events including gastrointestinal injuries. Besides upper gastrointestinal injuries, NSAID enteropathy also attracts attention with the introduction of capsule endoscopy and double balloon enteroscopy. However, the pathogenesis of NSAID enteropathy remains to be entirely clarified. Growing evidence from basic and clinical studies presents that gut microbiota is a critical factor in NSAID enteropathy progress. We have reviewed the recent data about the interplay between gut microbiota dysbiosis and NSAID enteropathy. The chronic medication of NSAIDs could change the composition of the intestinal bacteria and aggravate bile acids cytotoxicity. Meanwhile, NSAIDs impair the intestinal barrier by inhibiting cyclooxygenase and destroying mitochondria. Subsequently, intestinal bacteria translocate into the mucosa, and then lipopolysaccharide released from gut microbiota combines to Toll-like receptor 4 and induce excessive production of nitric oxide and pro-inflammatory cytokines. Intestinal injuries present in the condition of intestinal inflammation and oxidative stress. In this paper, we also have reviewed the possible strategies of regulating gut microbiota for the management of NSAID enteropathy, including antibiotics, probiotics, prebiotics, mucosal protective agents, and fecal microbiota transplant, and we emphasized the adverse effects of proton pump inhibitors on NSAID enteropathy. Therefore, this review will provide new insights into a better understanding of gut microbiota in NSAID enteropathy.
Collapse
Affiliation(s)
- Xianglu Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Qiang Tang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Huiqin Hou
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Wanru Zhang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Mengfan Li
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Danfeng Chen
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Yu Gu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Jingli Hou
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
- *Correspondence: Hailong Cao, ; Jingli Hou, ; Yangping Liu,
| | - Yangping Liu
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
- *Correspondence: Hailong Cao, ; Jingli Hou, ; Yangping Liu,
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
- *Correspondence: Hailong Cao, ; Jingli Hou, ; Yangping Liu,
| |
Collapse
|
|
10
|
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly used drugs in the world, and their side effects are very high. First of all, these are NSAID gastropathy, but in the long term, 5070% of NSAIDs cause damage to the small intestine (NSAID enteropathy), sometimes with serious consequences. To date, no drugs have been proposed with proven effectiveness to prevent this side effect. Apparently, this is not due to the fully clarified mechanism of pathogenesis. The most promising is the hypothesis of the participation of individual representatives of microflora in the development of enteropathy. Therefore, modulating the intestinal flora with the help of probiotics can be the basic therapeutic strategy for the prevention and treatment of such damage.
Collapse
Affiliation(s)
- E N Kareva
- Sechenov First Moscow State Medical University (Sechenov University).,Pirogov Russian National Research Medical University
| |
Collapse
|
|
11
|
Bielsa-Fernández M, Tamayo-de la Cuesta J, Lizárraga-López J, Remes-Troche J, Carmona-Sánchez R, Aldana-Ledesma J, Avendaño-Reyes J, Ballesteros-Amozorrutia M, De Ariño M, de Giau-Triulzi L, Flores-Rendón R, Huerta-Guerrero H, González-González J, Hernández-Guerrero A, Murcio-Pérez E, Jáquez-Quintana J, Meixueiro-Daza A, Nogueira-de Rojas J, Rodríguez-Hernández H, Santoyo-Valenzuela R, Solorzano-Olmos S, Uscanga-Domínguez L, Zamarripa-Dorsey F. Consenso mexicano sobre diagnóstico, prevención y tratamiento de la gastropatía y enteropatía por antiinflamatorios no esteroideos. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2020; 85:190-206. [DOI: 10.1016/j.rgmx.2019.11.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 10/27/2019] [Accepted: 11/27/2019] [Indexed: 02/07/2023]
|
|
12
|
Bielsa-Fernández M, Tamayo-de la Cuesta J, Lizárraga-López J, Remes-Troche J, Carmona-Sánchez R, Aldana-Ledesma J, Avendaño-Reyes J, Ballesteros-Amozorrutia M, De Ariño M, de Giau-Triulzi L, Flores-Rendón R, Huerta-Guerrero H, González-González J, Hernández-Guerrero A, Murcio-Pérez E, Jáquez-Quintana J, Meixueiro-Daza A, Nogueira-de Rojas J, Rodríguez-Hernández H, Santoyo-Valenzuela R, Solorzano-Olmos S, Uscanga-Domínguez L, Zamarripa-Dorsey F. The Mexican consensus on the diagnosis, treatment, and prevention of NSAID-induced gastropathy and enteropathy. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2020. [DOI: 10.1016/j.rgmxen.2019.11.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
|
|
13
|
Maseda D, Ricciotti E. NSAID-Gut Microbiota Interactions. Front Pharmacol 2020; 11:1153. [PMID: 32848762 PMCID: PMC7426480 DOI: 10.3389/fphar.2020.01153] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 07/15/2020] [Indexed: 12/21/2022] Open
Abstract
Nonsteroidal anti-inflammatory drugs (NSAID)s relieve pain, inflammation, and fever by inhibiting the activity of cyclooxygenase isozymes (COX-1 and COX-2). Despite their clinical efficacy, NSAIDs can cause gastrointestinal (GI) and cardiovascular (CV) complications. Moreover, NSAID use is characterized by a remarkable individual variability in the extent of COX isozyme inhibition, therapeutic efficacy, and incidence of adverse effects. The interaction between the gut microbiota and host has emerged as a key player in modulating host physiology, gut microbiota-related disorders, and metabolism of xenobiotics. Indeed, host-gut microbiota dynamic interactions influence NSAID disposition, therapeutic efficacy, and toxicity. The gut microbiota can directly cause chemical modifications of the NSAID or can indirectly influence its absorption or metabolism by regulating host metabolic enzymes or processes, which may have consequences for drug pharmacokinetic and pharmacodynamic properties. NSAID itself can directly impact the composition and function of the gut microbiota or indirectly alter the physiological properties or functions of the host which may, in turn, precipitate in dysbiosis. Thus, the complex interconnectedness between host-gut microbiota and drug may contribute to the variability in NSAID response and ultimately influence the outcome of NSAID therapy. Herein, we review the interplay between host-gut microbiota and NSAID and its consequences for both drug efficacy and toxicity, mainly in the GI tract. In addition, we highlight progress towards microbiota-based intervention to reduce NSAID-induced enteropathy.
Collapse
Affiliation(s)
- Damian Maseda
- Department of Microbiology, University of Pennsylvania, Philadelphia, PA, United States
| | - Emanuela Ricciotti
- Department of Systems Pharmacology and Translational Therapeutics, and Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, United States
- *Correspondence: Emanuela Ricciotti,
| |
Collapse
|
|
14
|
Karateev AE, Moroz EV, Kryukov EV. Small intestinal damage associated with the use of nonsteroidal anti-inflammatory drugs. ALMANAC OF CLINICAL MEDICINE 2019; 47:559-567. [DOI: 10.18786/2072-0505-2019-47-048] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
The use of nonsteroidal anti-inflammatory drugs (NSAID), even if short-term, may be associated to small intestinal complications, such as erosions, ulcers and chronic mucosal inflammation. Video capsule endoscopy allows for identification of such lesions in 20 to 55% of the patients who have taken nonselective NSAID for 2 to 4 weeks. The pathophysiology of NSAID-induced enteropathy is related to a reduced reparative potential of the mucosa and abnormalities of the microbial balance in the small intestine. In real world practice, NSAID enteropathy is commonly asymptomatic, and its manifestations, such as bleeding, perforation and ileus, are quite rare (about 0.3 episodes per 100 patient-years). The main manifestation of NSAID enteropathy is chronic iron deficient anemia. The use of rebamipide, sulfasalazine, mesalazine, and rifaximin has been discussed in the treatment of NSAID enteropathy, whereas its prevention implies preferential administration of coxibs, the use of rebamipide and probiotics.
Collapse
Affiliation(s)
- A. E. Karateev
- V.A. Nasonova Research Institute of Rheumatology, Russian Academy of Medical Sciences
| | - E. V. Moroz
- N.N. Burdenko Main Military Clinical Hospital
| | | |
Collapse
|
|
15
|
Scarpignato C, Bjarnason I. Drug-Induced Small Bowel Injury: a Challenging and Often Forgotten Clinical Condition. Curr Gastroenterol Rep 2019; 21:55. [PMID: 31720893 DOI: 10.1007/s11894-019-0726-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Most drugs are given by the oral route. Oral intake allows direct contact between the drug and the entire GI tract mucosa, exposing it to potential topical damage until absorption. Medication-induced GI symptoms and lesions are therefore commonly encountered in clinical practice. This review will examine the most common drugs or classes of drugs affecting small bowel function and/or structure. RECENT FINDINGS Since non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medicines, NSAID enteropathy is highly prevalent and brings about considerable morbidity. Antimicrobials and proton-pump inhibitors profoundly modify intestinal microbiota, affecting gut sensory and motor functions, while other drugs (like iron and gold derivatives) impair intestinal permeability. Olmesartan (and likely ACE inhibitors) induce villous atrophy and consequent malabsorption. Mycophenolate mofetil, cancer chemotherapeutic agents, and immune checkpoint inhibitors cause intestinal inflammation, abdominal pain, and diarrhea. Potassium chloride supplements may induce small bowel ulceration, stenosis, and perforation while the cotraceptive pill and anticoagulants are associated with intestinal ischemia and spontaneous intramural hematoma, respectively. In clinical practice, a deep knowledge of clinical pharmacology and toxicology and a high degree of suspicion of drug-related adverse events are mandatory. Only then, the practicing physician will be able to diagnose medication-induced small bowel lesions correctly and will implement the best strategies to treat them.
Collapse
Affiliation(s)
- Carmelo Scarpignato
- LUdeS Lugano Campus, Lugano, Switzerland.
- United Campus of Malta, Gzira, Malta.
- Faculty of Medicine, Chinese University of Hong Kong, ShaTin, Hong Kong.
- Department of Medicine & Surgery, University of Parma, Parma, Italy.
| | - Ingvar Bjarnason
- Department of Gastroenterology, King's College Hospital, London, UK
| |
Collapse
|
|
16
|
Fornai M, Pellegrini C, Benvenuti L, Tirotta E, Gentile D, Natale G, Ryskalin L, Colucci R, Piccoli E, Ghelardi E, Blandizzi C, Antonioli L. Protective effects of the combination Bifidobacterium longum plus lactoferrin against NSAID-induced enteropathy. Nutrition 2019; 70:110583. [PMID: 31739175 DOI: 10.1016/j.nut.2019.110583] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 08/29/2019] [Accepted: 08/30/2019] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Nonsteroidal anti-inflammatory drugs can exert detrimental effects in the lower digestive tract. The aim of this study was to examine the protective effects of a combination of the probiotic Bifidobacterium longum BB536 (Bifidobacterium) with the prebiotic lactoferrin in a rat model of diclofenac-induced enteropathy. METHODS Enteropathy was induced in 40-wk-old male rats by intragastric diclofenac (4 mg/kg twice daily for 14 d). Lactoferrin (100 mg/kg twice daily), Bifidobacterium (2.5 × 106 CFU/rat twice daily) or their combination were administered 1 h before diclofenac. At the end of treatments, the ileum was processed for the evaluation of histologic damage, myeloperoxidase (MPO) and malondialdehyde (MDA) levels, as well as the expression of Toll-like receptors 2 and 4 (TLR-2/-4) and the activation of downstream signaling molecules (MyD88 and nuclear factor [NF]-κB p65). Blood hemoglobin and fecal calprotectin were also assessed. RESULTS Diclofenac induced intestinal damage, along with increments of MPO and MDA, overexpression of TLR-2, TLR-4, MyD88, and NF-κB p65, increased fecal calprotectin and decreased blood hemoglobin levels. Lactoferrin or Bifidobacterium alone prevented diclofenac-induced enteric damage, and the changes in blood hemoglobin, MPO, MDA, fecal calprotectin, and NF-κB p65. Bifidobacterium, but not lactoferrin, decreased TLR-4 expression, although none of them affected MyD88 overexpression. TLR-2 expression was slightly enhanced by all treatments. The combined administration of lactoferrin and Bifidobacterium reduced further the intestinal damage, and restored MPO and blood hemoglobin levels. CONCLUSIONS Diclofenac induced ileal mucosal lesions by activation of inflammatory and pro-oxidant mechanisms. These detrimental actions were prevented by the combination of lactoferrin with Bifidobacterium likely through the modulation of TLR-2/-4/NF-κB proinflammatory pathways.
Collapse
Affiliation(s)
- Matteo Fornai
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
| | | | - Laura Benvenuti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Erika Tirotta
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Daniela Gentile
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Gianfranco Natale
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Larisa Ryskalin
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Rocchina Colucci
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Elena Piccoli
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Emilia Ghelardi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Corrado Blandizzi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Luca Antonioli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| |
Collapse
|
|
17
|
Abstract
Rheumatological diseases (RDs) represent a diverse group of diseases that are inherited or related to environmental factors. RDs frequently affect the gastrointestinal (GI) tract, and gastroenterologists are often asked to evaluate patients with symptoms thought to represent an underlying or coexisting RD. GI manifestations of RDs vary based on the organ involved as well as the extent and duration of involvement. Although most manifestations of RD are nonspecific and not life-threatening, the chronicity and severity of symptoms can be debilitating and may lead to serious injury. This narrative review discusses the most common RD encountered by gastroenterologists: systemic lupus erythematosus, systemic sclerosis (scleroderma), dermatomyositis/polymyositis, rheumatoid arthritis, Sjögren syndrome, overlap syndromes, mixed connective tissue disease, Ehlers-Danlos syndromes, and other vasculitides. Each section begins with a brief overview of the condition, followed by a discussion of the etiopathophysiology, physical examination findings, GI manifestations, diagnostic tools (i.e., serologic, imaging, endoscopic, and functional), and treatment options.
Collapse
|
|
18
|
Kim TJ, Kim ER, Hong SN, Kim YH, Lee YC, Kim HS, Kim K, Chang DK. Effectiveness of acid suppressants and other mucoprotective agents in reducing the risk of occult gastrointestinal bleeding in nonsteroidal anti-inflammatory drug users. Sci Rep 2019; 9:11696. [PMID: 31406189 PMCID: PMC6690955 DOI: 10.1038/s41598-019-48173-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 07/31/2019] [Indexed: 02/07/2023] Open
Abstract
Acid suppressants such as histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) are effective in preventing gastrointestinal (GI) bleeding in nonsteroidal anti-inflammatory drugs (NSAIDs) users. Despite widespread acid suppressant use, there remain concerns about several potential risks of long-term use. Therefore, we investigated whether gastroprotective agents (GPAs) other than acid suppression therapy are effective in preventing NSAID-related GI injury. To this end, we studied 9,133 patients with osteoarthritis or rheumatoid arthritis who used NSAIDs for ≥1 month. A decrease of 2 g/dL or more in the hemoglobin level was considered a GI injury indicator. The GPAs included acid suppressants and other mucoprotective agents. Acid suppressants included PPIs and H2RAs. Other mucoprotective agents included misoprostol, rebamipide, and eupatilin. During a median follow-up period of 27 (range, 4.3-51.3) weeks, occult GI bleeding occurred in 1,191 (13%) patients. A comparison of patients who used GPAs concomitantly with that of nonusers in a multivariable analysis revealed the hazard ratios (HRs; 95% confidence intervals [CIs]) for occult GI bleeding were 0.30 (0.20-0.44), 0.35 (0.29-0.43), 0.47 (0.23-0.95), 0.43 (0.35-0.51), and 0.98 (0.86-1.12) for PPIs, H2RAs, misoprostol, rebamipide, and eupatilin, respectively. Compared to PPI co-treatment, H2RA, misoprostol, rebamipide, and eupatilin co-treatments were associated with occult GI bleeding HRs (95% CIs) of 1.19 (0.79-1.79), 1.58 (0.72-3.46), 1.44 (0.96-2.16), and 3.25 (2.21-4.77), respectively. Our findings suggest that mucoprotective agents, such as rebamipide and misoprostol, as well as acid suppressants, are effective in reducing the risk for GI injury in NSAID users.
Collapse
Affiliation(s)
- Tae Jun Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Eun Ran Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Sung Noh Hong
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Young-Ho Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Yeong Chan Lee
- Department of Digital Health, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Hye Seung Kim
- Biostatistics and Clinical Epidemiology Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Kyunga Kim
- Biostatistics and Clinical Epidemiology Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
| | - Dong Kyung Chang
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
| |
Collapse
|
|
19
|
Petta I, Peene I, Elewaut D, Vereecke L, De Bosscher K. Risks and benefits of corticosteroids in arthritic diseases in the clinic. Biochem Pharmacol 2019; 165:112-125. [PMID: 30978323 DOI: 10.1016/j.bcp.2019.04.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 04/08/2019] [Indexed: 02/06/2023]
Abstract
Glucocorticoids (GCs) constitute a first line treatment for many autoimmune and inflammatory diseases. Due to their potent anti-inflammatory and immunosuppressive actions, GCs are added frequently to disease modifying antirheumatic drugs (DMARDs) in various arthritic diseases, such as rheumatoid arthritis. However, their prolonged administration or administration at high doses is associated with adverse effects that may be (quality of) life-threatening, including osteoporosis, metabolic, gastrointestinal and cardiovascular side effects. In this review, we summarize the clinical and pharmacological effects of GCs in different arthritic diseases, while documenting the current research efforts towards the identification of novel and more efficient GCs with reduced side effects.
Collapse
Affiliation(s)
- Ioanna Petta
- Department of Rheumatology, Faculty of Medicine and Health Sciences, Host-Microbiota Interaction Lab (HMI) and Laboratory for Molecular Immunology and Inflammation, Ghent University, Corneel Heymanslaan 10, 9000 Ghent, Belgium; VIB Center for Inflammation Research (IRC), Ghent University, Technologiepark 71 - Zwijnaarde, 9052 Ghent, Belgium; Ghent Gut Inflammation Group (GGIG), Ghent University, Ghent, Belgium
| | - Isabelle Peene
- Department of Rheumatology, Faculty of Medicine and Health Sciences, Host-Microbiota Interaction Lab (HMI) and Laboratory for Molecular Immunology and Inflammation, Ghent University, Corneel Heymanslaan 10, 9000 Ghent, Belgium; VIB Center for Inflammation Research (IRC), Ghent University, Technologiepark 71 - Zwijnaarde, 9052 Ghent, Belgium; Department of Rheumatology, AZ SintJan, Ruddershove 10, 8000 Brugge, Belgium
| | - Dirk Elewaut
- Department of Rheumatology, Faculty of Medicine and Health Sciences, Host-Microbiota Interaction Lab (HMI) and Laboratory for Molecular Immunology and Inflammation, Ghent University, Corneel Heymanslaan 10, 9000 Ghent, Belgium; VIB Center for Inflammation Research (IRC), Ghent University, Technologiepark 71 - Zwijnaarde, 9052 Ghent, Belgium; Ghent Gut Inflammation Group (GGIG), Ghent University, Ghent, Belgium
| | - Lars Vereecke
- Department of Rheumatology, Faculty of Medicine and Health Sciences, Host-Microbiota Interaction Lab (HMI) and Laboratory for Molecular Immunology and Inflammation, Ghent University, Corneel Heymanslaan 10, 9000 Ghent, Belgium; VIB Center for Inflammation Research (IRC), Ghent University, Technologiepark 71 - Zwijnaarde, 9052 Ghent, Belgium; Ghent Gut Inflammation Group (GGIG), Ghent University, Ghent, Belgium
| | - Karolien De Bosscher
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Translational Nuclear Receptor Research, VIB Center for Medical Biotechnology, Albert Baertsoenkaai 3, 9000, Ghent, Belgium.
| |
Collapse
|
|
20
|
Colucci R, Pellegrini C, Fornai M, Tirotta E, Antonioli L, Renzulli C, Ghelardi E, Piccoli E, Gentile D, Benvenuti L, Natale G, Fulceri F, Palazón-Riquelme P, López-Castejón G, Blandizzi C, Scarpignato C. Pathophysiology of NSAID-Associated Intestinal Lesions in the Rat: Luminal Bacteria and Mucosal Inflammation as Targets for Prevention. Front Pharmacol 2018; 9:1340. [PMID: 30555323 PMCID: PMC6281992 DOI: 10.3389/fphar.2018.01340] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Accepted: 10/31/2018] [Indexed: 12/11/2022] Open
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) can damage the small intestine, mainly through an involvement of enteric bacteria. This study examined the pathophysiology of NSAID-associated intestinal lesions in a rat model of diclofenac-enteropathy and evaluated the effect of rifaximin on small bowel damage. Enteropathy was induced in 40-week old male rats by intragastric diclofenac (4 mg/kg BID, 14 days). Rifaximin (delayed release formulation) was administered (50 mg/kg BID) 1 h before the NSAID. At the end of treatments, parameters dealing with ileal damage, inflammation, barrier integrity, microbiota composition, and TLR-NF-κB-inflammasome pathway were evaluated. In addition, the modulating effect of rifaximin on NLRP3 inflammasome was tested in an in vitro cell system. Diclofenac induced intestinal damage and inflammation, triggering an increase in tissue concentrations of tumor necrosis factor and interleukin-1β, higher expression of TLR-2 and TLR-4, MyD88, NF-κB and activation of caspase-1. In addition, the NSAID decreased ileal occludin expression and provoked a shift of bacterial phyla toward an increase in Proteobacteria and Bacteroidetes abundance. All these changes were counterbalanced by rifaximin co-administration. This drug was also capable of increasing the proportion of Lactobacilli, a genus depleted by the NSAID. In LPS-primed THP-1 cells stimulated by nigericin (a model to study the NLRP3 inflammasome), rifaximin reduced IL-1β production in a concentration-dependent fashion, this effect being associated with inhibition of the up-stream caspase-1 activation. In conclusion, diclofenac induced ileal mucosal lesions, driving inflammatory pathways and microbiota changes. In conclusion, rifaximin prevents diclofenac-induced enteropathy through both anti-bacterial and anti-inflammatory activities.
Collapse
Affiliation(s)
- Rocchina Colucci
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy
| | - Carolina Pellegrini
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Matteo Fornai
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Erika Tirotta
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Luca Antonioli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Cecilia Renzulli
- Reasearch & Development Department, Alfasigma SpA, Bologna, Italy
| | - Emilia Ghelardi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Elena Piccoli
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Daniela Gentile
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Laura Benvenuti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Gianfranco Natale
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Federica Fulceri
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Pablo Palazón-Riquelme
- Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester, United Kingdom
| | - Gloria López-Castejón
- Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester, United Kingdom
| | - Corrado Blandizzi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Carmelo Scarpignato
- Clinical Pharmacology & Digestive Pathophysiology Unit, Department of Clinical & Experimental Medicine, University of Parma, Parma, Italy
| |
Collapse
|
|
21
|
Zhu LP, Zhao JW, Chen X, Wang BM. Proton pump inhibitor usage and nonsteroidal anti-inflammatory drugs-associated small intestinal injury: How to balance risks and benefits. Shijie Huaren Xiaohua Zazhi 2018; 26:1334-1339. [DOI: 10.11569/wcjd.v26.i22.1334] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Proton pump inhibitors (PPIs) are widely used in the treatment of acid-related diseases and can effectively prevent upper gastrointestinal damage associated with nonsteroidal anti-inflammatory drugs (NSAIDs). However, recent studies have shown that PPIs cannot protect from NSAIDs-associated small bowel injury, and may even aggravate intestinal injury by altering the intestinal flora. This article will discuss the risks associated with the combined use of NSAIDs and PPIs, as well as how to balance risks and benefits of PPIs treatment, and provide a brief review of strategies for the prevention of NSAIDs-associated small bowel injury.
Collapse
Affiliation(s)
- Lan-Ping Zhu
- Department of Gastroenterology and Hepatology, General Hospital of Tianjin Medical University, Tianjin 300052, China
| | - Jing-Wen Zhao
- Department of Gastroenterology and Hepatology, General Hospital of Tianjin Medical University, Tianjin 300052, China
| | - Xin Chen
- Department of Gastroenterology and Hepatology, General Hospital of Tianjin Medical University, Tianjin 300052, China
| | - Bang-Mao Wang
- Department of Gastroenterology and Hepatology, General Hospital of Tianjin Medical University, Tianjin 300052, China
| |
Collapse
|
|
22
|
Jia L, Chopp M, Wang L, Lu X, Szalad A, Zhang ZG. Exosomes derived from high-glucose-stimulated Schwann cells promote development of diabetic peripheral neuropathy. FASEB J 2018; 32:fj201800597R. [PMID: 29932869 PMCID: PMC6219828 DOI: 10.1096/fj.201800597r] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 06/12/2018] [Indexed: 02/07/2023]
Abstract
Schwann cells actively interact with axons of dorsal root ganglia (DRG) neurons. Exosomes mediate intercellular communication by transferring their biomaterials, including microRNAs (miRs) into recipient cells. We hypothesized that exosomes derived from Schwann cells stimulated by high glucose (HG) exosomes accelerate development of diabetic peripheral neuropathy and that exosomal cargo miRs contribute to this process. We found that HG exosomes contained high levels of miR-28, -31a, and -130a compared to exosomes derived from non-HG-stimulated Schwann cells. In vitro, treatment of distal axons with HG exosomes resulted in reduction of axonal growth, which was associated with elevation of miR-28, -31a, and -130a and reduction of their target proteins of DNA methyltransferase-3α, NUMB (an endocytic adaptor protein), synaptosome associated protein 25, and growth-associated protein-43 in axons. In vivo, administration of HG exosomes to sciatic nerves of diabetic db/db mice at 7 wk of age promoted occurrence of peripheral neuropathy characterized by impairment of nerve conduction velocity and induction of mechanic and thermal hypoesthesia, which was associated with substantial decreases in intraepidermal nerve fibers. Our findings demonstrate a functional role of exosomes derived from HG-stimulated Schwann cells in mediating development of diabetic peripheral neuropathy.-Jia, L., Chopp, M., Wang, L., Lu, X., Szalad, A., Zhang, Z. G. Exosomes derived from high-glucose-stimulated Schwann cells promote development of diabetic peripheral neuropathy.
Collapse
Affiliation(s)
- Longfei Jia
- Inovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA; and
| | - Michael Chopp
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA; and
- Department of Physics, Oakland University, Rochester, Michigan, USA
| | - Lei Wang
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA; and
| | - Xuerong Lu
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA; and
| | - Alexandra Szalad
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA; and
| | - Zheng Gang Zhang
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA; and
| |
Collapse
|
|
23
|
Edogawa S, Peters SA, Jenkins GD, Gurunathan SV, Sundt WJ, Johnson S, Lennon RJ, Dyer RB, Camilleri M, Kashyap PC, Farrugia G, Chen J, Singh RJ, Grover M. Sex differences in NSAID-induced perturbation of human intestinal barrier function and microbiota. FASEB J 2018; 32:fj201800560R. [PMID: 29897814 PMCID: PMC6219825 DOI: 10.1096/fj.201800560r] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 05/21/2018] [Indexed: 12/12/2022]
Abstract
Intestinal barrier function and microbiota are integrally related and play critical roles in maintenance of host physiology. Sex is a key biologic variable for several disorders. Our aim was to determine sex-based differences in response to perturbation and subsequent recovery of intestinal barrier function and microbiota in healthy humans. Twenty-three volunteers underwent duodenal biopsies, mucosal impedance, and in vivo permeability measurement. Permeability testing was repeated after administration of indomethacin, then 4 to 6 wk after its discontinuation. Duodenal and fecal microbiota composition was determined using 16S rRNA amplicon sequencing. Healthy women had lower intestinal permeability and higher duodenal and fecal microbial diversity than healthy men. Intestinal permeability increases after indomethacin administration in both sexes. However, only women demonstrated decreased fecal microbial diversity, including an increase in Prevotella abundance, after indomethacin administration. Duodenal microbiota composition did not show sex-specific changes. The increase in permeability and microbiota changes normalized after discontinuation of indomethacin. In summary, women have lower intestinal permeability and higher microbial diversity. Intestinal permeability is sensitive to perturbation but recovers to baseline. Gut microbiota in women is sensitive to perturbation but appears to be more stable in men. Sex-based differences in intestinal barrier function and microbiome should be considered in future studies.-Edogawa, S., Peters, S. A., Jenkins, G. D., Gurunathan, S. V., Sundt, W. J., Johnson, S., Lennon, R. J., Dyer, R. B., Camilleri, M., Kashyap, P. C., Farrugia, G., Chen, J., Singh, R. J., Grover, M. Sex differences in NSAID-induced perturbation of human intestinal barrier function and microbiota.
Collapse
Affiliation(s)
- Shoko Edogawa
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Stephanie A. Peters
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Gregory D. Jenkins
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Wendy J. Sundt
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Stephen Johnson
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Ryan J. Lennon
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
| | - Roy B. Dyer
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Michael Camilleri
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Purna C. Kashyap
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Gianrico Farrugia
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA
| | - Jun Chen
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
| | - Ravinder J. Singh
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Madhusudan Grover
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| |
Collapse
|
|
24
|
Davids M, Gudra D, Radovica-Spalvina I, Fridmanis D, Bartkevics V, Muter O. The effects of ibuprofen on activated sludge: Shift in bacterial community structure and resistance to ciprofloxacin. JOURNAL OF HAZARDOUS MATERIALS 2017; 340:291-299. [PMID: 28719845 DOI: 10.1016/j.jhazmat.2017.06.065] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Revised: 05/10/2017] [Accepted: 06/27/2017] [Indexed: 06/07/2023]
Abstract
Ibuprofen (IBP) is ranked at the 4th place among 57 pharmaceutical compounds according to the number of citations in prioritization documents. The response of microbial community of activated sludge to IBP was studied at the concentrations of 50-5000mg/L. Batch incubation was performed in an OxiTop® device for 21days. The reduction of biological oxygen demand depended on the IBP concentration and varied in the range from 321 to 107mg O2/L. Massive DNA sequencing analysis of the activated sludge revealed that Proteobacteria became more dominant when grown in the presence of IBP. Microbial diversity was reduced in the presence of 500-1000mg/L IBP, but increased again in the presence of 5000mg/L IBP, despite the domination of Enterobacteriales (48.1%) in this sample. Incubation of activated sludge in the presence of 1000mg/L IBP led to an increased occurrence of ciprofloxacin-resistant bacteria. The use of Eosin Methylene Blue Agar for disc diffusion assay was shown to be more appropriate in order to reveal the changes in antibiotic resistance. The predominance of Enterobacteriales in the activated sludge is suggested as one of the possible explanations of the enhanced resistance to ciprofloxacin.
Collapse
Affiliation(s)
- Madars Davids
- Institute of Microbiology & Biotechnology, University of Latvia, Jelgavas Str. 1, Riga LV-1004, Latvia
| | - Dita Gudra
- Latvian Biomedical Research and Study Centre, Ratsupites Str. 1, Riga LV-1067, Latvia
| | | | - Davids Fridmanis
- Latvian Biomedical Research and Study Centre, Ratsupites Str. 1, Riga LV-1067, Latvia
| | - Vadims Bartkevics
- Faculty of Chemistry, University of Latvia, Jelgavas Str. 1, Riga LV-1004, Latvia
| | - Olga Muter
- Institute of Microbiology & Biotechnology, University of Latvia, Jelgavas Str. 1, Riga LV-1004, Latvia.
| |
Collapse
|
|
25
|
Utzeri E, Usai P. Role of non-steroidal anti-inflammatory drugs on intestinal permeability and nonalcoholic fatty liver disease. World J Gastroenterol 2017; 23:3954-3963. [PMID: 28652650 PMCID: PMC5473116 DOI: 10.3748/wjg.v23.i22.3954] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 01/19/2017] [Accepted: 02/08/2017] [Indexed: 02/06/2023] Open
Abstract
The use of non-steroidal anti-inflammatory drugs (NSAIDs) is widespread worldwide thanks to their analgesic, anti-inflammatory and antipyretic effects. However, even more attention is placed upon the recurrence of digestive system complications in the course of their use. Recent data suggests that the complications of the lower gastro-intestinal tract may be as frequent and severe as those of the upper tract. NSAIDs enteropathy is due to enterohepatic recycling of the drugs resulting in a prolonged and repeated exposure of the intestinal mucosa to the compound and its metabolites. Thus leading to so-called topical effects, which, in turn, lead to an impairment of the intestinal barrier. This process determines bacterial translocation and toxic substances of intestinal origin in the portal circulation, leading to an endotoxaemia. This condition could determine a liver inflammatory response and might promote the development of non-alcoholic steatohepatitis, mostly in patients with risk factors such as obesity, metabolic syndrome and a high fat diet, which may induce a small intestinal bacterial overgrowth and dysbiosis. This alteration of gut microbiota may contribute to nonalcoholic fatty liver disease and its related disorders in two ways: firstly causing a malfunction of the tight junctions that play a critical role in the increase of intestinal permeability, and then secondly leading to the development of insulin resistance, body weight gain, lipogenesis, fibrogenesis and hepatic oxidative stress.
Collapse
|
|
26
|
Lué A, Lanas A. Protons pump inhibitor treatment and lower gastrointestinal bleeding: Balancing risks and benefits. World J Gastroenterol 2016; 22:10477-10481. [PMID: 28082800 PMCID: PMC5192259 DOI: 10.3748/wjg.v22.i48.10477] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Revised: 09/28/2016] [Accepted: 11/13/2016] [Indexed: 02/06/2023] Open
Abstract
Proton pump inhibitors (PPIs) represent a milestone in the treatment of acid-related diseases, and are the mainstay in preventing upper gastrointestinal bleeding in high-risk patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin. However, this beneficial effect does not extend to the lower gastrointestinal tract. PPIs do not prevent NSAID or aspirin-associated lower gastrointestinal bleeding (LGB). PPIs may increase both small bowel injury related to NSAIDs and low-dose aspirin treatment and the risk of LGB. Recent studies suggested that altering intestinal microbiota by PPIs may be involved in the pathogenesis of NSAID-enteropathy. An increase in LGB hospitalization rates may occur more frequently in older patients with more comorbidities and are associated with high hospital resource utilization, longer hospitalization, and increased mortality. Preventive strategies for NSAID and aspirin-associated gastrointestinal bleeding should be directed toward preventing both upper and lower gastrointestinal damage. Future research should be directed toward identifying patients at low-risk for gastrointestinal events associated with the use of NSAIDs or aspirin to avoid inappropriate PPI prescribing. Alternatively, the efficacy of new pharmacologic strategies should be evaluated in high-risk groups, with the aim of reducing the risk of both upper and lower gastrointestinal bleeding in these patients.
Collapse
|
|
27
|
Eichstadt LR, Moore GE, Childress MO. Risk factors for treatment-related adverse events in cancer-bearing dogs receiving piroxicam. Vet Comp Oncol 2016; 15:1346-1353. [PMID: 27714960 DOI: 10.1111/vco.12276] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Revised: 09/12/2016] [Accepted: 09/13/2016] [Indexed: 01/02/2023]
Abstract
Piroxicam has antitumour effects in dogs with cancer, although side effects may limit its use. The purpose of this study was to retrospectively identify factors predisposing cancer-bearing dogs to adverse events (AEs) following piroxicam therapy. Medical records of dogs presented to the Purdue Veterinary Teaching Hospital between 2005 and 2015 were reviewed, and 137 dogs met the criteria for study inclusion. Toxic effects of piroxicam in these dogs were graded according to an established system. Multivariate logistic regression was used to estimate the extent to which certain factors affected the risk for AEs. Age [odds ratio (OR) 1.250, P = 0.009; 95% confidence interval (CI) 1.057-1.479] and concurrent use of gastroprotectant medications (OR 2.612, P = 0.025; 95% CI 1.127-6.056) significantly increased the risk for gastrointestinal AEs. The results of this study may help inform the risk versus benefit calculation for clinicians considering the use of piroxicam to treat dogs with cancer.
Collapse
Affiliation(s)
- L R Eichstadt
- Veterinary Teaching Hospital, Purdue University, West Lafayette, IN, USA
| | - G E Moore
- Department of Veterinary Administration, Purdue University, West Lafayette, IN, USA
| | - M O Childress
- Department of Veterinary Clinical Sciences, Purdue University, West Lafayette, IN, USA
| |
Collapse
|
|
28
|
Tachecí I, Kopáčová M, Rejchrt S, Bureš J. Non-steroidal Anti-inflammatory Drug Induced Injury to the Small Intestine. ACTA MEDICA (HRADEC KRÁLOVÉ) 2016. [DOI: 10.14712/18059694.2016.56] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Non-steroidal anti-inflammatory drug (NSAIDs) induced enteropathy represents an important complication of one of the most commonly used drugs worldwide. Due to previous diagnostics difficulties the real prevalence of this disease was underestimated for a long time. The pathogenesis of NSAID-enteropathy is more multifactorial and complex than formerly assumed but has still not been fully uncovered. A combination of the local and systemic effect plays an important role in pathogenesis. Thanks to novel enteroscopy methods (wireless capsule endoscopy, double balloon enteroscopy), small bowel lesions are described in a substantial section of NSAID users although most are clinically asymptomatic. The other non-invasive tests (small bowel permeability, faecal calprotectin, scintigraphy using faecal excretion of 111-indium-labelled leukocytes etc.) proposed for diagnostics are not generally used in clinical practice, mainly because of their non-specificity. Despite intensive research into possible treatment, the main measure for patients with NSAID-enteropathy is still withdrawal of NSAIDs. Double balloon enteroscopy plays an important role in the treatment of complications (bleeding, strictures).
Collapse
|
|
29
|
Ricci A, Coppo E, Barbieri R, Debbia EA, Marchese A. The effect of sub-inhibitory concentrations of rifaximin on urease production and on other virulence factors expressed by Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa and Staphylococcus aureus. J Chemother 2016; 29:67-73. [DOI: 10.1080/1120009x.2016.1195069] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Annalisa Ricci
- Microbiology Section “C.A. Romanzi”, DISC, University of Genoa, Genoa, Italy
| | - Erika Coppo
- Microbiology Section “C.A. Romanzi”, DISC, University of Genoa, Genoa, Italy
| | - Ramona Barbieri
- Microbiology Section “C.A. Romanzi”, DISC, University of Genoa, Genoa, Italy
| | - Eugenio A. Debbia
- Microbiology Section “C.A. Romanzi”, DISC, University of Genoa, Genoa, Italy
| | - Anna Marchese
- Microbiology Section “C.A. Romanzi”, DISC, University of Genoa, Genoa, Italy
| |
Collapse
|
|
30
|
Affiliation(s)
- John L Wallace
- Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.
| |
Collapse
|
|
31
|
Fornai M, Antonioli L, Pellegrini C, Colucci R, Sacco D, Tirotta E, Natale G, Bartalucci A, Flaibani M, Renzulli C, Ghelardi E, Blandizzi C, Scarpignato C. Small bowel protection against NSAID-injury in rats: Effect of rifaximin, a poorly absorbed, GI targeted, antibiotic. Pharmacol Res 2015; 104:186-96. [PMID: 26747402 DOI: 10.1016/j.phrs.2015.12.031] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2015] [Revised: 12/17/2015] [Accepted: 12/25/2015] [Indexed: 12/22/2022]
Abstract
Nonsteroidal anti-inflammatory drugs, besides exerting detrimental effects on the upper digestive tract, can also damage the small and large intestine. Although the underlying mechanisms remain unclear, there is evidence that enteric bacteria play a pivotal role. The present study examined the enteroprotective effects of a delayed-release formulation of rifaximin-EIR (R-EIR, 50mg/kg BID, i.g.), a poorly absorbed antibiotic with a broad spectrum of antibacterial activity, in a rat model of enteropathy induced by indomethacin (IND, 1.5mg/kg BID for 14 days) administration. R-EIR was administered starting 7 days before or in concomitance with IND administration. At the end of treatments, blood samples were collected to evaluate hemoglobin (Hb) concentration (as an index of digestive bleeding). Small intestine was processed for: (1) histological assessment of intestinal damage (percentage length of lesions over the total length examined); (2) assay of tissue myeloperoxidase (MPO) and TNF levels, as markers of inflammation; (3) assay of tissue malondialdehyde (MDA) and protein carbonyl concentrations, as an index of lipid and protein peroxidation, respectively; (4) evaluation of the major bacterial phyla. IND significantly decreased Hb levels, this effect being significantly blunted by R-EIR. IND also induced the occurrence of lesions in the jejunum and ileum. In both intestinal regions, R-EIR significantly reduced the percentage of lesions, as compared with rats receiving IND alone. Either the markers of inflammation and tissue peroxidation were significantly increased in jejunum and ileum from IND-treated rats. However, in rats treated with R-EIR, these parameters were not significantly different from those observed in controls. R-EIR was also able to counterbalance the increase in Proteobacteria and Firmicutes abundance induced by INDO. To summarize, R-EIR treatment significantly prevents IND-induced intestinal damage, this enteroprotective effect being associated with a decrease in tissue inflammation, oxidative stress and digestive bleeding as well as reversal of NSAID-induced alterations in bacterial population.
Collapse
Affiliation(s)
- Matteo Fornai
- Division of Pharmacology, Department of Clinical & Experimental Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy
| | - Luca Antonioli
- Division of Pharmacology, Department of Clinical & Experimental Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy
| | - Carolina Pellegrini
- Division of Pharmacology, Department of Clinical & Experimental Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy
| | - Rocchina Colucci
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Deborah Sacco
- Division of Pharmacology, Department of Clinical & Experimental Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy
| | - Erika Tirotta
- Division of Pharmacology, Department of Clinical & Experimental Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy
| | - Gianfranco Natale
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy
| | - Alessia Bartalucci
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy
| | - Marina Flaibani
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy
| | - Cecilia Renzulli
- Department of Research & Development, Alfa Wassermann SpA, Via Ragazzi del'99, 5, 40133 Bologna, Italy
| | - Emilia Ghelardi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via San Zeno 37, 56127 Pisa, Italy
| | - Corrado Blandizzi
- Division of Pharmacology, Department of Clinical & Experimental Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy
| | - Carmelo Scarpignato
- Clinical Pharmacology & Digestive Pathophysiology Unit, Department of Clinical & Experimental Medicine, University of Parma, Via Gramsci 14, 43125 Parma, Italy.
| |
Collapse
|
|
32
|
Abstract
BACKGROUND/AIMS NSAID-induced enteropathy has been the focus of recent basic and clinical research subsequent to the development of the capsule endoscope and double-balloon endoscope. We review the possible pathogenic mechanisms underlying NSAID-induced enteropathy and discuss the role of the inhibition of COX-1/COX-2 and the influences of food as well as various prophylactic treatments on these lesions. METHODS Studies were performed in experimental animals. RESULTS Multiple factors, such as intestinal hypermotility, decreased mucus secretion, enterobacteria, and upregulation of iNOS/NO expression, are involved in the pathogenesis of NSAID-induced enteropathy, in addition to the decreased production of PGs due to the inhibition of COX. Enterobacterial invasion is the most important pathogenic event, and intestinal hypermotility, which was associated with this event, is essential for the development of these lesions. NSAIDs also upregulate the expression of COX-2, and the inhibition of both COX-1 and COX-2 is required for the intestinal ulcerogenic properties of NSAIDs to manifest. NSAID-induced enteropathy is prevented by PGE2, atropine, ampicillin, and aminoguanidine as well as soluble dietary fiber, and exacerbated by antisecretory drugs such as proton pump inhibitors. CONCLUSION These findings on the pathogenesis of NSAID-induced enteropathy will be useful for the future development of intestinal-sparing alternatives to standard NSAIDs.
Collapse
Affiliation(s)
- Koji Takeuchi
- Department of Pharmacology and Experimental Therapeutics, Division of Pathological Sciences, Kyoto Pharmaceutical University, Misasagi, Yamashina, Japan
| | | |
Collapse
|
|
33
|
Chang SS, Hu HY. Long-term use of steroids protects from the development of symptomatic diverticulitis requiring hospitalization in the Asian population. PLoS One 2015; 10:e0124598. [PMID: 25919040 PMCID: PMC4412717 DOI: 10.1371/journal.pone.0124598] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Accepted: 11/30/2014] [Indexed: 11/18/2022] Open
Abstract
OBJECTIVE The pathophysiology of diverticulitis is poorly understood. Factors such as physical inactivity, constipation, obesity, smoking, and the use of nonsteroidal antiinflammatory drugs (NSAIDs) have been associated with an increased risk of diverticular disease. To evaluate whether patients exhibiting long-term steroid use are at increased risk of colonic diverticulitis. METHOD We conducted a population-based, nested case-control study. Data were retrospectively collected from the National Health Insurance Research Database. The study cohort comprised patients diagnosed with diverticulitis, identified using inpatient discharge records using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes (562.11 and 562.13), and those who were administered one or more prescriptions for corticosteroids for systemic use. Control patients were matched to cases by age, sex, NSAID use, laxative drug use, and index date. We enrolled 690 patients with colonic diverticulitis and 2760 in the control group. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. RESULTS Compared with steroid nonusers, the adjusted ORs were 0.60 (95% CI = 0.35-1.06) and 0.80 (95% CI = 0.64-1.008) in current steroid users and previous steroid users, respectively. In addition, the adjusted ORs were 0.55 (95% CI = 0.31-0.98), 0.57 (95% CI = 0.31-0.98), and 0.44 (95% CI = 0.22-0.86) for steroid use duration more than half time by an exposure period of 90 days, 180 days, and 365 days before the claim date of colonic diverticulitis, respectively. CONCLUSIONS The results indicated that long-term steroid use within one year is associated with lower risk of colonic diverticulitis.
Collapse
Affiliation(s)
- Shen-Shong Chang
- Division of Gastroenterology, Taipei City Hospital Yang-Ming Branch, Taipei, Taiwan
- Department of Internal Medicine, Taipei City Hospital Yang-Ming Branch, Taipei, Taiwan
- School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Hsiao-Yun Hu
- Institute of Public Health and Department of Public Health, National Yang-Ming University, Taipei, Taiwan
- Department of Education and Research, Taipei City Hospital, Taipei, Taiwan
- * E-mail:
| |
Collapse
|
|
34
|
Goldstein JL, Cryer B. Gastrointestinal injury associated with NSAID use: a case study and review of risk factors and preventative strategies. DRUG HEALTHCARE AND PATIENT SAFETY 2015; 7:31-41. [PMID: 25653559 PMCID: PMC4310346 DOI: 10.2147/dhps.s71976] [Citation(s) in RCA: 87] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective anti-inflammatory and analgesic agents and are among the most commonly used classes of medications worldwide. However, their use has been associated with potentially serious dose-dependent gastrointestinal (GI) complications such as upper GI bleeding. GI complications resulting from NSAID use are among the most common drug side effects in the United States, due to the widespread use of NSAIDs. The risk of upper GI complications can occur even with short-term NSAID use, and the rate of events is linear over time with continued use. Although gastroprotective therapies are available, they are underused, and patient and physician awareness and recognition of some of the factors influencing the development of NSAID-related upper GI complications are limited. Herein, we present a case report of a patient experiencing a gastric ulcer following NSAID use and examine some of the risk factors and potential strategies for prevention of upper GI mucosal injuries and associated bleeding following NSAID use. These risk factors include advanced age, previous history of GI injury, and concurrent use of medications such as anticoagulants, aspirin, corticosteroids, and selective serotonin reuptake inhibitors. Strategies for prevention of GI injuries include anti-secretory agents, gastroprotective agents, alternative NSAID formulations, and nonpharmacologic therapies. Greater awareness of the risk factors and potential therapies for GI complications resulting from NSAID use could help improve outcomes for patients requiring NSAID treatment.
Collapse
Affiliation(s)
- Jay L Goldstein
- Department of Medicine, NorthShore University HealthSystem, Evanston, IL, USA
| | - Byron Cryer
- Division of Gastroenterology, University of Texas Southwestern Medical Center and Dallas VA Medical Center, Dallas, TX, USA
| |
Collapse
|
|
35
|
Marlicz W, Loniewski I, Grimes DS, Quigley EM. Nonsteroidal anti-inflammatory drugs, proton pump inhibitors, and gastrointestinal injury: contrasting interactions in the stomach and small intestine. Mayo Clin Proc 2014; 89:1699-709. [PMID: 25440891 DOI: 10.1016/j.mayocp.2014.07.015] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Revised: 07/20/2014] [Accepted: 07/28/2014] [Indexed: 02/06/2023]
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors (PPIs) are among the most frequently prescribed groups of drugs worldwide. The use of NSAIDs is associated with a high number of significant adverse effects. Recently, the safety of PPIs has also been challenged. Capsule endoscopy studies reveal that even low-dose NSAIDs are responsible for gut mucosal injury and numerous clinical adverse effects, for example, bleeding and anemia, that might be difficult to diagnose. The frequent use of PPIs can exacerbate NSAID-induced small intestinal injury by altering intestinal microbiota. Thus, the use of PPI is considered to be an independent risk factor associated with NSAID-associated enteropathy. In this review, we discuss this important clinical problem and review relevant aspects of epidemiology, pathophysiology, and management. We also present the hypothesis that even minor and subclinical injury to the intestinal mucosa can result in significant, though delayed, metabolic consequences, which may seriously affect the health of an individual. PubMed was searched using the following key words (each key word alone and in combination): gut microbiota, microbiome, non-steroidal anti inflammatory drugs, proton pump inhibitors, enteropathy, probiotic, antibiotic, mucosal injury, enteroscopy, and capsule endoscopy. Google engine search was also carried out to identify additional relevant articles. Both original and review articles published in English were reviewed.
Collapse
Affiliation(s)
- Wojciech Marlicz
- Department of Gastroenterology, Pomeranian Medical University, Szczecin, Poland.
| | - Igor Loniewski
- International Pharmaceutical Consulting, Szczecin, Poland
| | | | - Eamonn M Quigley
- Division of Gastroenterology and Hepatology, Houston Methodist Hospital, and Weill Cornell Medical College, Houston, TX
| |
Collapse
|
|
36
|
Suthar SK, Sharma M. Recent Developments in Chimeric NSAIDs as Safer Anti-Inflammatory Agents. Med Res Rev 2014; 35:341-407. [DOI: 10.1002/med.21331] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Sharad Kumar Suthar
- Department of Pharmacy; Jaypee University of Information Technology; Waknaghat 173234 India
| | - Manu Sharma
- Department of Pharmacy; Jaypee University of Information Technology; Waknaghat 173234 India
| |
Collapse
|
|
37
|
Liu C, Chen S, Wang X, Chen Y, Tang N. 15d-PGJ2 decreases PGE2 synthesis in HBx-positive liver cells by interfering EGR1 binding to mPGES-1 promoter. Biochem Pharmacol 2014; 91:337-47. [DOI: 10.1016/j.bcp.2014.07.032] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2014] [Revised: 07/27/2014] [Accepted: 07/29/2014] [Indexed: 01/05/2023]
|
|
38
|
Potgieter W, Samuels CS, Snyman JR. Potentiated clinoptilolite: artificially enhanced aluminosilicate reduces symptoms associated with endoscopically negative gastroesophageal reflux disease and nonsteroidal anti-inflammatory drug induced gastritis. Clin Exp Gastroenterol 2014; 7:215-20. [PMID: 25061329 PMCID: PMC4087055 DOI: 10.2147/ceg.s51222] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Purpose The cation exchanger, a potentiated clinoptilolite (Absorbatox™ 2.4D), is a synthetically enhanced aluminosilicate. The aim of this study was to evaluate the possible benefits of a potentiated clinoptilolite as a gastroprotective agent in reducing the severity of clinical symptoms and signs associated with 1) endoscopically negative gastroesophageal reflux disease (ENGORD) and 2) nonsteroidal anti-inflammatory drug (NSAID) medication. Methods and patients Two randomized, double-blind, placebo-controlled, pilot studies, the ENGORD and NSAID studies, were conducted. After initial negative gastroscopy, a total of 25 patients suffering from ENGORD were randomized to receive either placebo capsules or 750 mg Absorbatox twice daily for 14 days. The NSAID study recruited 23 healthy patients who received orally either 1,500 mg Absorbatox or placebo three times daily, plus 500 mg naproxen twice daily. Patients underwent gastroscopic evaluation of their stomach linings prior to and on day 14 of the study. Gastric biopsies were obtained and evaluated via the upgraded Sydney system, whereas visible gastric events and status of the gastric mucosa were evaluated via a 0–3 rating scale. During both studies, patients recorded gastric symptoms in a daily symptom diary. Results In the ENGORD study, patients who received the potentiated clinoptilolite reported a significant reduction (P≤0.05) in severity of symptoms including reduction in heartburn (44%), discomfort (54%), and pain (56%). Symptom-free days improved by 41% compared to the group who received placebo (not significant). This was over and above the benefits seen with the proton pump inhibitor. In the NSAID study, the reduction in gastric symptom severity was echoed in the group who received the potentiated clinoptilolite. Treatment with the potentiated clinoptilolite resulted in significant prevention (P≤0.05) of mucosal erosion severity as graded by the gastroenterologist. Conclusion Absorbatox is a nonabsorbable aluminosilicate with potential gastroprotective benefits as it protected against ENGORD symptoms and NSAID-induced gastric events. The exact mechanism of action is not clear but may be due to its binding to hydrogen ions and biologically active amines and nitrates.
Collapse
Affiliation(s)
- Wilna Potgieter
- Department of Pharmacology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, Gauteng, South Africa
| | - Caroline Selma Samuels
- Department of Pharmacology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, Gauteng, South Africa
| | - Jacques Renè Snyman
- Department of Pharmacology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, Gauteng, South Africa
| |
Collapse
|
|
39
|
Scarpignato C. Piroxicam-β-cyclodextrin: a GI safer piroxicam. Curr Med Chem 2013; 20:2415-37. [PMID: 23394552 PMCID: PMC3664509 DOI: 10.2174/09298673113209990115] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2012] [Revised: 12/28/2012] [Accepted: 01/11/2013] [Indexed: 02/06/2023]
Abstract
Although NSAIDs are very effective drugs, their use is associated with a broad spectrum of adverse reactions in the liver, kidney, cardiovascular (CV) system, skin and gut. Gastrointestinal (GI) side effects are the most common and constitute a wide clinical spectrum ranging from dyspepsia, heartburn and abdominal discomfort to more serious events such as peptic ulcer with life-threatening complications of bleeding and perforation. The appreciation that CV risk is also increased further complicates the choices of physicians prescribing anti-inflammatory therapy. Despite prevention strategies should be implemented in patients at risk, gastroprotection is often underused and adherence to treatment is generally poor. A more appealing approach would be therefore to develop drugs that are devoid of or have reduced GI toxicity. Gastro-duodenal mucosa possesses many defensive mechanisms and NSAIDs have a deleterious effect on most of them. This results in a mucosa less able to cope with even a reduced acid load. NSAIDs cause gastro-duodenal damage, by two main mechanisms: a physiochemical disruption of the gastric mucosal barrier and systemic inhibition of gastric mucosal protection, through inhibition of cyclooxygenase (COX, PG endoperoxide G/H synthase) activity of the GI mucosa. However, against a background of COX inhibition by anti-inflammatory doses of NSAIDs, their physicochemical properties, in particular their acidity, underlie the topical effect leading to short-term damage. It has been shown that esterification of acidic NSAIDs suppresses their gastrotoxicity without adversely affecting anti-inflammatory activity. Another way to develop NSAIDs with better GI tolerability is to complex these molecules with cyclodextrins (CDs), giving rise to so-called “inclusion complexes” that can have physical, chemical and biological properties very different from either those of the drug or the cyclodextrin. Complexation of NSAIDs with β-cyclodextrin potentially leads to a more rapid onset of action after oral administration and improved GI tolerability because of minimization of the drug gastric effects. One such drug, piroxicam-β-cyclodextrin (PBC), has been used in Europe for 25 years. Preclinical and clinical pharmacology of PBC do show that the β-cyclodextrin inclusion complex of piroxicam is better tolerated from the upper GI tract than free piroxicam, while retaining all the analgesic and anti-inflammatory properties of the parent compound. In addition, the drug is endowed with a quick absorption rate, which translates into a faster onset of analgesic activity, an effect confirmed in several clinical studies. An analysis of the available trials show that PBC has a GI safety profile, which is better than that displayed by uncomplexed piroxicam. Being an inclusion complex of piroxicam, whose CV safety has been pointed out by several observational studies, PBC should be viewed as a CV safe anti-inflmmatory compound and a GI safer alternative to piroxicam. As a consequence, it should be considered as a useful addition to our therapeutic armamentarium.
Collapse
Affiliation(s)
- C Scarpignato
- Clinical Pharmacology & Digestive Pathophysiology Unit, Department of Clinical & Experimental Medicine, University of Parma, Italy.
| |
Collapse
|
|
40
|
Mani S, Boelsterli UA, Redinbo MR. Understanding and modulating mammalian-microbial communication for improved human health. Annu Rev Pharmacol Toxicol 2013; 54:559-80. [PMID: 24160697 DOI: 10.1146/annurev-pharmtox-011613-140007] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The fact that the bacteria in the human gastrointestinal (GI) tract play a symbiotic role was noted as early as 1885, well before we began to manage microbial infections using antibiotics. However, even with the first antimicrobial compounds used in humans, the sulfa drugs, microbes were recognized to be critically involved in the biotransformation of these therapeutics. Thus, the roles played by the microbiota in physiology and in the management of human health have long been appreciated. Detailed examinations of GI symbiotic bacteria that started in the early 2000s and the first phases of the Human Microbiome Project that were completed in 2012 have ushered in an exciting period of granularity with respect to the ecology, genetics, and chemistry of the mammalian-microbial axes of communication. Here we review aspects of the biochemical pathways at play between commensal GI bacteria and several mammalian systems, including both local-epithelia and nonlocal responses impacting inflammation, immunology, metabolism, and neurobiology. Finally, we discuss how the microbial biotransformation of therapeutic compounds, such as anticancer or nonsteroidal anti-inflammatory drugs, can be modulated to reduce toxicity and potentially improve therapeutic efficacy.
Collapse
Affiliation(s)
- Sridhar Mani
- Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, New York 10461
| | | | | |
Collapse
|
|
41
|
Mani S, Boelsterli UA, Redinbo MR. Understanding and modulating mammalian-microbial communication for improved human health. Annu Rev Pharmacol Toxicol 2013; 3. [PMID: 27942535 PMCID: PMC5145265 DOI: 10.11131/2016/101199] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The molecular basis for the regulation of the intestinal barrier is a very fertile research area. A growing body of knowledge supports the targeting of various components of intestinal barrier function as means to treat a variety of diseases, including the inflammatory bowel diseases. Herein, we will summarize the current state of knowledge of key xenobiotic receptor regulators of barrier function, highlighting recent advances, such that the field and its future are succinctly reviewed. We posit that these receptors confer an additional dimension of host-microbe interaction in the gut, by sensing and responding to metabolites released from the symbiotic microbiota, in innate immunity and also in host drug metabolism. The scientific evidence for involvement of the receptors and its molecular basis for the control of barrier function and innate immunity regulation would serve as a rationale towards development of non-toxic probes and ligands as drugs.
Collapse
Affiliation(s)
- Sridhar Mani
- Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, New York 10461
| | | | | |
Collapse
|
|
42
|
Kim MS, Morales W, Hani AA, Kim S, Kim G, Weitsman S, Chang C, Pimentel M. The effect of rifaximin on gut flora and Staphylococcus resistance. Dig Dis Sci 2013; 58:1676-82. [PMID: 23589147 DOI: 10.1007/s10620-013-2675-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Accepted: 03/27/2013] [Indexed: 12/11/2022]
Abstract
AIM Rifaximin is a non-absorbed antibiotic relative of rifampicin. The location of effect and staphylococcal resistance are two recent potential concerns with rifaximin. In this study we evaluate the location of effect of rifaximin as well as the development of staphylococcal rifampicin resistance. METHODS Rats were divided into three groups. Group 1 gavaged for 10 days with PBS, group 2 gavaged with rifaximin for 10 days, and group 3 gavaged with rifaximin for 10 days and housed for 30 days. In each group, stool was collected daily for quantitative culture of Staphylococcus spp. and coliforms. After euthanasia luminal bacterial counts were determined at multiple gut locations by qPCR. Rifampicin susceptibility was tested on Staphylococcus pre and post rifaximin. RESULTS At baseline, rats had a median of 2.90 × 10(6) cfu/ml Staphylococcus spp. in stool. After 10 days of rifaximin, this dropped to 1.20 × 10(5) cfu/ml (P < 0.01). With coliform counts, rats had a median of 1.86 × 10(4) cfu/ml at baseline which dropped to 2.2 × 10(3) cfu/ml (P < 0.01) after rifaximin. After cessation of rifaximin, coliform counts recovered within 3 days. When examining the total bacterial counts by qPCR, rifaximin reduced small bowel bacterial levels, but not colon. This reduction was sustained for 30 days. No colonies of Staphylococcus became resistant and only one colony was intermediate. The mean inhibitory concentration for rifampicin was not different before and after rifaximin. CONCLUSION Staphylococcal spp. fail to demonstrate resistance to rifampicin after rifaximin. The transient reductions in stool coliform counts recover while rifaximin appears to produce durable reductions in duodenal bacteria.
Collapse
Affiliation(s)
- Mi-Sung Kim
- Division of Gastroenterology, Cheongju St. Mary's Hospital, Cheongju, Korea
| | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in the world; nevertheless, about 50-70% of patients on long-term NSAIDs develop small intestine injury, namely NSAID enteropathy, sometimes with serious outcomes. No medications with proven efficacy are yet available to prevent NSAID enteropathy. A series of therapeutic strategies targeting the different mechanisms involved in small bowel injury have been investigated, but without definitive results. Intestinal bacteria and their degradation products are essential for the development of NSAID-induced small bowel lesions, because "germ-free" animals were found to be resistant to indomethacin injuries. Therefore, it has been suggested that modulating the intestinal flora, for example by using probiotics, could protect against NSAID enteropathy. In this work, we reviewed the main therapeutic strategies for NSAID enteropathy, in particular analyzing the available studies relating to the eventual protective role of probiotics. We found that results are not all concordant; nevertheless, the more recent studies provide better understanding about pathogenetic mechanisms involved in small intestinal injury and the role of probiotics, and show encouraging results. Larger and well-designed studies should be performed to evaluate the actual role of probiotics in NSAID enteropathy, the eventual differences among probiotic strains, dose-responses, and optimal duration of therapy.
Collapse
|
|
44
|
Zhang S, Chao GQ, Lu B. Proton pump inhibitors are not the key for therapying non-steroidal anti-inflammatory drugs-induced small intestinal injury. Rheumatol Int 2013; 33:2513-21. [PMID: 23604681 DOI: 10.1007/s00296-013-2756-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2012] [Accepted: 04/10/2013] [Indexed: 12/17/2022]
Abstract
The ability of non-steroidal anti-inflammatory drugs (NSAIDs) to injure the small intestine has been well established in humans and animals. Proton pump inhibitors (PPIs) are frequently prescribed to reduce gastric and duodenal injury caused in high-risk patients taking NSAIDs. However, scarce information is available concerning the effects of PPIs on intestinal damage induced by NSAIDs, and the suppression of gastric acid secretion by PPIs is hard to provide any protection against the damage caused by NSAIDs in the small intestine. The present study was designed to examine the effects of intragastric treatment of two PPIs widely used in clinical practice, namely omeprazole and pantoprazole, on the intestinal damage induced by administration of diclofenac in rat. Male SD rats were treated with omeprazole or pantoprazole for 9 days, with concomitant treatment with anti-inflammatory doses of diclofenac on the final 5 days. The anatomical lesion, villous height, the thickness, and the section area of small intestine were quantitatively analyzed. The change of ultrastructural organization was observed. Endotoxin level in blood was measured by photometry. Epidermal growth factor was observed by immunohistochemistry. Omeprazole and pantoprazole didn't decrease the macroscopic and histologic damage induced by diclofenac in the rat's small intestine. In the two PPI groups, villous height was (89.6 ± 11.8 and 92.6 ± 19.3 μm) lower than which of the control group (P < 0.05). The thickness became thinning, and the section area became small. LPS levels in the portal blood of omeprazole and pantoprazole were (4.36 ± 1.26 and 4.25 ± 1.17 EU/ml), significantly higher than in controls (P < 0.05). The EFG of PPI group descended significantly compared with the control group (P < 0.05). Omeprazole and pantoprazole cannot protect the small intestine from the damage induced by diclofenac in the conscious rat. PPIs cannot repair NSAID-induced intestinal damage at least in part because of significant lesion in mechanical barrier function and reduction in epidermal growth factor.
Collapse
Affiliation(s)
- Shuo Zhang
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou Youdian Road No. 54, Hangzhou, 310006, China
| | | | | |
Collapse
|
|
45
|
Zhang Z, Xiang Y, Wang B, Chen H, Cai X, Wang X, Mei L, Zheng Y. Intestinal mucosal permeability of children with cefaclor-associated serum sickness-like reactions. Eur J Pediatr 2013; 172:537-43. [PMID: 23296953 DOI: 10.1007/s00431-012-1926-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2012] [Revised: 12/16/2012] [Accepted: 12/24/2012] [Indexed: 11/24/2022]
Abstract
Although the serum sickness-like reaction (SSLR) in children after the administration of cefaclor has long been recognized, the exact mechanism of cefaclor-associated SSLR remains unclear. This study aims to investigate the association between intestinal mucosal permeability and cefaclor-associated SSLR in children. A total of 82 pediatric patients with upper respiratory tract infection following the cefaclor therapy was divided into cefaclor-associated SSLR positive group and negative group based on the presence or absence of SSLR after taking cefaclor, and 30 healthy volunteers served as control group. Urinary lactulose/mannitol (L/M) ratios and serum diamine oxidase (DAO) levels were determined in all cases on days 7, 9, 11, 13, and 15 after oral administration of cefaclor. The children in the control group were given the same measurements after enrollment in this study. From days 7 to 13, the urinary L/M ratio of children with cefaclor SSLR gradually increased and reached to the highest level of 0.38 ± 0.14 on day 13. Compared with the cefaclor-associated SSLR negative group and control group, urinary L/M ratios increased significantly in the cefaclor SSLR positive group on days 7, 9, 11, 13, and 15 after taking cefaclor, and serum levels of DAO following the treatment of cefaclor increased significantly in children with cefaclor SSLR on days 9, 11, 13, and 15. No significant difference in urinary L/M ratios and serum levels of DAO between SSLR negative group and control group through the entire experiment was observed. In conclusion, administration of cefaclor may induce SSLR in children by increasing the intestinal mucosal permeability and/or affecting the integrity of the intestinal mucosa. Determinations of urinary L/M ratios and serum DAO levels may be helpful for observing or predicting the occurrence of SSLR after administration of cefaclor, which will encourage physicians to proceed with extreme caution when prescribing cefaclor for pediatric patients.
Collapse
Affiliation(s)
- Zhen Zhang
- Department of Laboratory Medicine, Wuhan Medical and Health Center for Women and Children, Tongji Medical College, Huazhong University of Science and Technology, 100 Xianggang Rd., Jiang An District, Wuhan, Hubei 430016, People's Republic of China
| | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Wallace JL. Mechanisms, prevention and clinical implications of nonsteroidal anti-inflammatory drug-enteropathy. World J Gastroenterol 2013; 19:1861-1876. [PMID: 23569332 PMCID: PMC3613102 DOI: 10.3748/wjg.v19.i12.1861] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2013] [Revised: 02/23/2013] [Accepted: 03/08/2013] [Indexed: 02/06/2023] Open
Abstract
This article reviews the latest developments in understanding the pathogenesis, detection and treatment of small intestinal damage and bleeding caused by nonsteroidal anti-inflammatory drugs (NSAIDs). With improvements in the detection of NSAID-induced damage in the small intestine, it is now clear that this injury and the associated bleeding occurs more frequently than that occurring in the stomach and duodenum, and can also be regarded as more dangerous. However, there are no proven-effective therapies for NSAID-enteropathy, and detection remains a challenge, particularly because of the poor correlation between tissue injury and symptoms. Moreover, recent studies suggest that commonly used drugs for protecting the upper gastrointestinal tract (i.e., proton pump inhibitors) can significantly worsen NSAID-induced damage in the small intestine. The pathogenesis of NSAID-enteropathy is complex, but studies in animal models are shedding light on the key factors that contribute to ulceration and bleeding, and are providing clues to the development of effective therapies and prevention strategies. Novel NSAIDs that do not cause small intestinal damage in animal models offer hope for a solution to this serious adverse effect of one of the most widely used classes of drugs.
Collapse
|
|
47
|
Abimosleh SM, Tran CD, Howarth GS. Emu oil reduces small intestinal inflammation in the absence of clinical improvement in a rat model of indomethacin-induced enteropathy. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2013; 2013:429706. [PMID: 23573127 PMCID: PMC3612469 DOI: 10.1155/2013/429706] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Revised: 02/04/2013] [Accepted: 02/13/2013] [Indexed: 12/13/2022]
Abstract
Nonsteroidal-anti-inflammatory-drug (NSAID) enteropathy is characterized by small intestinal damage and ulceration. Emu Oil (EO) has previously been reported to reduce intestinal inflammation. Aim. We investigated EO for its potential to attenuate NSAID-enteropathy in rats. Methods. Male Sprague Dawley rats (n = 10/group) were gavaged with Water, Olive Oil (OO), or EO (0.5 mL; days 0-12) and with 0.5 mL Water or the NSAID, Indomethacin (8 mg/kg; days 5-12) daily. Disease activity index (DAI), 13C-sucrose breath test (SBT), organ weights, intestinal damage severity (IDS), and myeloperoxidase (MPO) activity were assessed. P < 0.05 was considered significant. Results. In Indomethacin-treated rats, DAI was elevated (days 10-12) and SBT values (56%) and thymus weight (55%) were decreased, relative to normal controls. Indomethacin increased duodenum (68%), colon (24%), SI (48%), caecum (48%), liver (51%) and spleen (88%) weights, IDS scores, and MPO levels (jejunum: 195%, ileum: 104%) compared to normal controls. Jejunal MPO levels were decreased (64%) by both EO and OO, although only EO decreased ileal MPO (50%), compared to Indomethacin controls. Conclusions. EO reduced acute intestinal inflammation, whereas other parameters of Indomethacin-induced intestinal injury were not affected significantly. Increased EO dose and/or frequency of administration could potentially improve clinical efficacy.
Collapse
Affiliation(s)
- Suzanne M. Abimosleh
- Department of Gastroenterology, Women's and Children's Hospital, North Adelaide, SA 5006, Australia
- Discipline of Physiology, School of Medical Sciences, Faculty of Health Sciences, The University of Adelaide, Adelaide, SA 5005, Australia
| | - Cuong D. Tran
- Department of Gastroenterology, Women's and Children's Hospital, North Adelaide, SA 5006, Australia
- Discipline of Physiology, School of Medical Sciences, Faculty of Health Sciences, The University of Adelaide, Adelaide, SA 5005, Australia
| | - Gordon S. Howarth
- Department of Gastroenterology, Women's and Children's Hospital, North Adelaide, SA 5006, Australia
- Discipline of Physiology, School of Medical Sciences, Faculty of Health Sciences, The University of Adelaide, Adelaide, SA 5005, Australia
- School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy Campus, Roseworthy, SA 5371, Australia
| |
Collapse
|
|
48
|
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are some of the most commonly used drugs worldwide; however, they are not innocuous. The spectrum of upper gastrointestinal (GI) tract damage caused by NSAIDs has been well established, and strategies to prevent this have been widely studied and implemented. Removing modifiable risk factors, the selection of less toxic NSAIDs and treatment with gastroprotective drugs, if necessary, are the main strategies employed. However, injury of the NSAIDs-related lower GI tract remains poorly characterized. In the last decade, there has been an increasing interest in this field and the search for effective preventive treatments is under way. Use of cyclooxygenase-2 inhibitor, prostaglandin, antibiotic or drugs that are not yet commercially available such as nitric oxide-releasing and hydrogen sulfide (H(2) S)-releasing NSAIDs compounds seem to reduce lower GI injury, but more evidence are needed before any of them are recommended in high-risk patients.
Collapse
Affiliation(s)
- Carla J Gargallo
- Service of Digestive Diseases, Lozano Blesa University Hospital, Zaragoza, Spain
| | | |
Collapse
|
|
49
|
Abstract
Detailed knowledge regarding the influence of hepatic transport proteins on drug disposition has advanced at a rapid pace over the past decade. Efflux transport proteins located in the basolateral and apical (canalicular) membranes of hepatocytes play an important role in the hepatic elimination of many endogenous and exogenous compounds, including drugs and metabolites. This review focuses on the role of these efflux transporters in hepatic drug excretion. The impact of these proteins as underlying factors for disease is highlighted, and the importance of hepatic efflux proteins in the efficacy and toxicity of drugs is discussed. In addition, a brief overview of methodology to evaluate the function of hepatic efflux transport proteins is provided. Current challenges in predicting the impact of altered efflux protein function on systemic, intestinal, and hepatocyte exposure to drugs and metabolites are highlighted.
Collapse
|
|
50
|
Patrignani P, Tacconelli S, Bruno A, Sostres C, Lanas A. Managing the adverse effects of nonsteroidal anti-inflammatory drugs. Expert Rev Clin Pharmacol 2012; 4:605-21. [PMID: 22114888 DOI: 10.1586/ecp.11.36] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Conventional medical treatment for rheumatoid arthritis and osteoarthritis includes the use of NSAIDs (traditional and selective inhibitors of cyclooxygenase [COX]-2), because they provide unmistakable and significant health benefits in the treatment of pain and inflammation. However, they are associated with an increased risk of serious gastrointestinal (GI) and cardiovascular (CV) adverse events. Both beneficial and adverse effects are due to the same mechanism of action, which is inhibition of COX-dependent prostanoids. Since CV and GI risk are related to drug exposure, a reduction in the administered dose is recommended. However, this strategy will not eliminate the hazard owing to a possible contribution of individual genetic background. Further studies will be necessary to develop genetic and/or biochemical markers predictive of the CV and GI risk of NSAIDs.
Collapse
Affiliation(s)
- Paola Patrignani
- Department of Medicine and Center of Excellence on Aging, G. d'Annunzio University, and CeSI, Via dei Vestini 31, 66100 Chieti, Italy.
| | | | | | | | | |
Collapse
|