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Datta M, Majumder R, Banerjee A, Bandyopadhyay D, Chattopadhyay A. Melatonin protects against diclofenac induced oxidative stress mediated myocardial toxicity in rats: A mechanistic insight. Food Chem Toxicol 2024; 190:114813. [PMID: 38876380 DOI: 10.1016/j.fct.2024.114813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 05/31/2024] [Accepted: 06/10/2024] [Indexed: 06/16/2024]
Abstract
Diclofenac, a traditional non-steroidal anti-inflammatory drug, is commonly used for treating chronic pain and inflammation. Recently, a number of articles have highlighted the toxicities associated with diclofenac. The current study explores the molecular mechanism of diclofenac induced cardiac toxicity following oxidative stress. Diclofenac inhibits catalase, disrupts the redox balance in cardiac tissue, accelerates the monoamine oxidase induced hydroperoxide generation and eventually inhibits crucial mitochondrial enzyme, viz., aldehyde dehydrogenase, thereby causing myocardial injury. Melatonin, the pineal indoleamine with high antioxidative efficacy, is well known for its cardio-protective properties and its dietary consumption has profound impact on cardiac health. The present study demonstrates perhaps for the first time, that apart from ameliorating oxidative load in the cardiac tissue, melatonin also attenuates the inhibition of catalase and aldehyde dehydrogenase, and prevents stress mediated stimulation of monoamine oxidase. Moreover, favourable binding of diclofenac with melatonin may protect the myocardium from the deleterious effects of this drug. The results indicate toward a novel mechanism of protection by melatonin, having future therapeutic relevance.
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Affiliation(s)
- Madhuri Datta
- Department of Physiology, Vidyasagar College, 39, Sankar Ghosh Lane, Kolkata, 700006, India; Oxidative Stress and Free Radical Biology Laboratory, Department of Physiology, University of Calcutta, 92, APC Road, Kolkata, 700009, India
| | - Romit Majumder
- Department of Physiology, Vidyasagar College, 39, Sankar Ghosh Lane, Kolkata, 700006, India; Oxidative Stress and Free Radical Biology Laboratory, Department of Physiology, University of Calcutta, 92, APC Road, Kolkata, 700009, India
| | - Adrita Banerjee
- Department of Physiology, Vidyasagar College, 39, Sankar Ghosh Lane, Kolkata, 700006, India; Oxidative Stress and Free Radical Biology Laboratory, Department of Physiology, University of Calcutta, 92, APC Road, Kolkata, 700009, India
| | - Debasish Bandyopadhyay
- Oxidative Stress and Free Radical Biology Laboratory, Department of Physiology, University of Calcutta, 92, APC Road, Kolkata, 700009, India.
| | - Aindrila Chattopadhyay
- Department of Physiology, Vidyasagar College, 39, Sankar Ghosh Lane, Kolkata, 700006, India.
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Vielee ST, Isibor J, Buchanan WJ, Roof SH, Patel M, Meaza I, Williams A, Toyoda JH, Lu H, Wise SS, Kouokam JC, Young Wise J, Abouiessa AM, Cai J, Cai L, Wise JP. Employing a Toxic Aging Coin approach to assess hexavalent chromium (Cr[VI])-induced neurotoxic effects on behavior: Heads for age differences. Toxicol Appl Pharmacol 2024; 489:117007. [PMID: 38901695 PMCID: PMC11342792 DOI: 10.1016/j.taap.2024.117007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 06/05/2024] [Accepted: 06/14/2024] [Indexed: 06/22/2024]
Abstract
We are facing a rapidly growing geriatric population (65+) that will live for multiple decades and are challenged with environmental pollution far exceeding that of previous generations. Consequently, we currently have a poor understanding of how environmental pollution will impact geriatric health distinctly from younger populations. Few toxicology studies have considered age differences with geriatric individuals. Critically, all top ten most prevalent age-related diseases are linked to metal exposures. Hexavalent chromium [Cr(VI)] is a metal of major environmental health concern that can induce aging phenotypes and neurotoxicity. However, there are many knowledge gaps for Cr(VI) neurotoxicity, including how Cr(VI) impacts behavior. To address this, we exposed male rats across three ages (3-, 7-, and 18-months old) to Cr(VI) in drinking water (0, 0.05, 0.1 mg/L) for 90 days. These levels reflect the maximum contaminant levels determined by the World Health Organization (WHO) and the U.S. Environmental Protection Agency (US EPA). Here, we report how these Cr(VI) drinking water levels impacted rat behaviors using a battery of behavior tests, including grip strength, open field assay, elevated plus maze, Y-maze, and 3-chamber assay. We observed adult rats were the most affected age group and memory assays (spatial and social) exhibited the most significant effects. Critically, the significant effects were surprising as rats should be particularly resistant to these Cr(VI) drinking water levels due to the adjustments applied in risk assessment from rodent studies to human safety, and because rats endogenously synthesize vitamin C in their livers (vitamin C is a primary reducer of Cr[VI] to Cr[III]). Our results emphasize the need to broaden the scope of toxicology research to consider multiple life stages and suggest the current regulations for Cr(VI) in drinking water need to be revisited.
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Affiliation(s)
- Samuel T Vielee
- Pediatric Research Institute, the Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY 40292, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Jessica Isibor
- Pediatric Research Institute, the Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - William J Buchanan
- Pediatric Research Institute, the Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Spencer H Roof
- Pediatric Research Institute, the Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Maitri Patel
- Pediatric Research Institute, the Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Idoia Meaza
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Aggie Williams
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Jennifer H Toyoda
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Haiyan Lu
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Sandra S Wise
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - J Calvin Kouokam
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Jamie Young Wise
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | | | - Jun Cai
- Pediatric Research Institute, the Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY 40292, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Lu Cai
- Pediatric Research Institute, the Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY 40292, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - John P Wise
- Pediatric Research Institute, the Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY 40292, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA.
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Dawra S, Behl P, Srivastava S, Manrai M, Chandra A, Kumar A, Kumar A, Tevatia MS. Non-neoplastic disorders in an aging gut: concise review. THE EGYPTIAN JOURNAL OF INTERNAL MEDICINE 2023. [DOI: 10.1186/s43162-023-00189-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
AbstractThe spectrum of gastrointestinal (GI) issues in the older population varies from common physiological age-related changes to devastating, less common sinister pathological illness. GI system has direct exposure to external environment. Thus, it is modeled to embrace the pathophysiological changes that occur due to interaction with external factors. Gastrointestinal tract (GIT) per se is more resilient to aging as compared to other organ systems. On the other hand, elderly may present with a large plethora of GI symptoms. This presents a challenge to all echelons of medical consultation for accurate attribution for the aging process or pathophysiological causation of GI symptoms. This dichotomy leads to hindrance in adequate and appropriate treatment of GI ailments. In GI system, non-neoplastic disorders are far more common than neoplastic disorders. Hence, it becomes imperative to understand the aging evolution of the GI system and management of GI disorders in the older population.
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Khan MS, Roberts MS. Challenges and innovations of drug delivery in older age. Adv Drug Deliv Rev 2018; 135:3-38. [PMID: 30217519 DOI: 10.1016/j.addr.2018.09.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Revised: 08/31/2018] [Accepted: 09/07/2018] [Indexed: 12/12/2022]
Abstract
Both drug delivery performance and various age-related physical, mental and physiological changes can affect drug effectiveness and safety in elderly patients. The many drug delivery systems developed over the years include recent novel transdermal, nasal, pulmonary and orally disintegrating tablets that provide consistent, precise, timely and more targeted drug delivery. Certain drug delivery systems may be associated with suboptimal outcomes in the elderly because of the nature of drug present, a lack of appreciation of the impact of age-related changes in drug absorption, distribution and clearance, the limited availability of pharmacokinetic, safety and clinical data. Polypharmacy, patient morbidity and poor adherence can also contribute to sub-optimal drug delivery systems outcomes in the elderly. The development of drug delivery systems for the elderly is a poorly realised opportunity, with each system having specific advantages and limitations. A key challenge is to provide the innovation that best meets the specific physiological, psychological and multiple drug requirements of individual elderly patients.
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Testosterone alleviates mitochondrial ROS accumulation and mitochondria-mediated apoptosis in the gastric mucosa of orchiectomized rats. Arch Biochem Biophys 2018; 649:53-59. [PMID: 29733810 DOI: 10.1016/j.abb.2018.05.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Revised: 04/28/2018] [Accepted: 05/03/2018] [Indexed: 01/25/2023]
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Ahluwalia A, Jones MK, Hoa N, Zhu E, Brzozowski T, Tarnawski AS. Reduced NGF in Gastric Endothelial Cells Is One of the Main Causes of Impaired Angiogenesis in Aging Gastric Mucosa. Cell Mol Gastroenterol Hepatol 2018; 6:199-213. [PMID: 29992182 PMCID: PMC6037903 DOI: 10.1016/j.jcmgh.2018.05.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 05/10/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Aging gastric mucosa has increased susceptibility to injury and delayed healing owing to impaired angiogenesis, but the mechanisms are not fully known. We examined whether impairment of angiogenesis in aging gastric mucosa is caused by deficiency of nerve growth factor (NGF) in gastric endothelial cells (ECs), and whether NGF therapy could reverse this impairment. METHODS In gastric mucosal ECs (GECs) isolated from young and aging rats we examined the following: (1) in vitro angiogenesis, (2) NGF expression, and (3) the effect of NGF treatment on angiogenesis, GEC proliferation and migration, and dependence on serum response factor. In in vivo studies in young and aging rats, we examined NGF expression in gastric mucosa and the effect of NGF treatment on angiogenesis and gastric ulcer healing. To determine human relevance, we examined NGF expression in gastric mucosal biopsy specimens of aging (≥70 y) and young (≤40 y) individuals. RESULTS In cultured aging GECs, NGF expression and angiogenesis were reduced significantly by 3.0-fold and 4.1-fold vs young GECs. NGF therapy reversed impairment of angiogenesis in aging GECs, and serum response factor silencing completely abolished this response. In gastric mucosa of aging rats, NGF expression in GECs was reduced significantly vs young rats. In aging rats, local NGF treatment significantly increased angiogenesis and accelerated gastric ulcer healing. In aging human subjects, NGF expression in ECs of gastric mucosal vessels was 5.5-fold reduced vs young individuals. CONCLUSIONS NGF deficiency in ECs is a key mechanism underlying impaired angiogenesis and delayed ulcer healing in aging gastric mucosa. Local NGF therapy can reverse these impairments.
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Key Words
- Aging
- Akt, serine threonine kinase signaling protein
- Angiogenesis
- BrdU, bromodeoxyuridine
- EC, endothelial cell
- Endothelial Cells
- FITC, fluorescein isothiocyanate
- GEC, gastric mucosal microvascular endothelial cells isolated from rats
- GU, gastric ulcer
- Gene Therapy
- LV-GFP, lentiviral green fluorescent protein
- LV-NGF, lentiviral nerve growth factor
- NGF, nerve growth factor
- NSAID, nonsteroidal anti-inflammatory drug
- Nerve Growth Factor
- PBS, phosphate-buffered saline
- PCNA, proliferating cell nuclear antigen
- PCR, polymerase chain reaction
- PI3, phosphoinositide-3
- SRF, serum response factor
- Ulcer Healing
- VEGF, vascular endothelial growth factor
- mRNA, messenger RNA
- mTOR, mammalian target of rapamycin
- siRNA, small interfering RNA
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Affiliation(s)
- Amrita Ahluwalia
- Medical and Research Services, Veterans Affairs Long Beach Healthcare System, Long Beach, California
| | - Michael K. Jones
- Medical and Research Services, Veterans Affairs Long Beach Healthcare System, Long Beach, California
- Department of Medicine, University of California, Irvine, California
| | - Neil Hoa
- Medical and Research Services, Veterans Affairs Long Beach Healthcare System, Long Beach, California
| | - Ercheng Zhu
- Medical and Research Services, Veterans Affairs Long Beach Healthcare System, Long Beach, California
| | - Tomasz Brzozowski
- Department of Physiology, Jagiellonian University Medical College, Krakow, Poland
| | - Andrzej S. Tarnawski
- Medical and Research Services, Veterans Affairs Long Beach Healthcare System, Long Beach, California
- Department of Medicine, University of California, Irvine, California
- Correspondence Address correspondence to: Andrzej S. Tarnawski, MD, PhD, AGAF, FACG, Veterans Affairs Long Beach Healthcare System, 5901 East 7th Street, 09/151, Long Beach, California 90822. fax: (562) 826-5675.
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Choi YJ, Kim N, Lee JY, Nam RH, Suh JH, Lee SM, Ham MH, Jo HJ, Shim YK, Park YH, Lee JC, Choi YJ, Lee HS, Lee DH. PMK-S005 Alleviates Age-Related Gastric Acid Secretion, Inflammation, and Oxidative Status in the Rat Stomach. Gut Liver 2017; 10:749-56. [PMID: 27172930 PMCID: PMC5003198 DOI: 10.5009/gnl15584] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Accepted: 12/05/2015] [Indexed: 12/12/2022] Open
Abstract
Background/Aims The aim of this study was to evaluate the effect of the synthetic S-allyl-l-cysteine (SAC) PMK-S005 on gastric acid secretion, inflammation, and antioxidant enzymes in aging rats. Methods The rats were divided into four groups at 31 weeks of age and were continuously fed a diet containing a vehicle control, PMK-S005 (5 or 10 mg/kg), or lansoprazole (5 mg/kg). Gastric acid secretion and connective tissue thickness of the lamina propria were evaluated at 74 weeks and 2 years of age. Tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and COX-2 levels were measured by using enzyme-linked immunosorbent assays (ELISAs) or Western blot assays. Levels of antioxidant enzymes, including heme oxyganase 1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO-1), were also measured. Results As the rats aged, gastric acid secretion significantly decreased, and the connective tissue of the lamina propria increased. However, 74-week-old rats in the PMK-S005 group exhibited greater levels of gastric acid secretion than those of the control and lansoprazole groups. The increase of TNF-α, IL-1β, and COX-2 expression in 74-week and 2-year-old control rats were inhibited by PMK-S005. In addition, the decrease in HO-1 and NQO-1 protein expression that occurred with aging was inhibited by PMK-S005 in the 74-week-old rats. Conclusions These results suggest that PMK-S005 has therapeutic potential as an antiaging agent to ameliorate age-related gastric acid secretion, inflammation, and oxidative stress in the stomach.
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Affiliation(s)
- Yoon Jeong Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Ju Yup Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Ryoung Hee Nam
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Ji Hyung Suh
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Sun Min Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Min Hee Ham
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hyun Jin Jo
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Young Kwang Shim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Yo Han Park
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jong-Chan Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Yoon Jin Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Decreased vascular endothelial growth factor expression is associated with cell apoptosis in low-dose aspirin-induced gastric mucosal injury. Am J Med Sci 2015; 349:110-6. [PMID: 25607509 DOI: 10.1097/maj.0000000000000409] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND The use of low-dose aspirin (LDA) has emerged as an important cause of gastrointestinal ulcers. The aim of this study was to investigate the association between LDA-induced gastric mucosal injury and the expression of vascular endothelial growth factor (VEGF) and cell apoptosis in elderly Chinese patients. METHODS A total of 136 patients aged 60 to 80 years with LDA-induced (100 mg/d for at least 1 month) gastric mucosal injury and 48 age-matched healthy subjects were enrolled in this study. The patients were divided into a low-severity group and a high-severity group based on their modified Lanza scale scores. Biopsy specimens of gastric mucosa from all participants were subjected to immunohistochemical staining for VEGF expression and terminal deoxynucleotidyl transferase dUTP nick end labeling staining for cell apoptosis. Staining indices and apoptotic indices were applied to assess VEGF expression level and the extent of cell apoptosis. RESULTS VEGF expression decreased significantly in the 2 patient groups, whereas the extent of cell apoptosis significantly increased compared with the control group. Furthermore, Spearman's correlation coefficients suggest that VEGF expression levels and the extent of cell apoptosis in gastric mucosae shared a significant correlation with the severity of LDA-induced gastric mucosal injury. Receiver operating characteristics analysis further confirmed these results. CONCLUSIONS Our findings provide important clues as to the underlying molecular mechanism behind gastric mucosal injury resulting from exposure to LDA in elderly adults, and also suggest that interventions specifically targeting the pathways associated with angiogenesis and apoptosis may help facilitate the healing process.
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Razavi F, Gross S, Katz S. Endoscopy in the elderly: risks, benefits, and yield of common endoscopic procedures. Clin Geriatr Med 2014; 30:133-47. [PMID: 24267608 DOI: 10.1016/j.cger.2013.10.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
There has been limited research examining the risks, benefits, and use of common endoscopic procedures in the elderly. Furthermore, gastroenterology training programs do not routinely incorporate elderly concerns when dealing with common gastrointestinal issues. There exists a broad array of endoscopic procedures with varying inherent risks that must be weighed with each elderly patient in mind. This article discusses the benefits and drawbacks of the most common procedures and indications for endoscopy including upper endoscopy, colonoscopy, endoscopic retrograde cholangiopancreatography, endoscopic ultrasound, percutaneous endoscopic gastrostomy, and deep enteroscopy.
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Affiliation(s)
- Farid Razavi
- Division of Gastroenterology, Langone Medical Center, New York University, 550 1st Avenue, New York, NY 10016, USA.
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Tarnawski AS, Ahluwalia A, Jones MK. Increased susceptibility of aging gastric mucosa to injury: The mechanisms and clinical implications. World J Gastroenterol 2014; 20:4467-4482. [PMID: 24782600 PMCID: PMC4000484 DOI: 10.3748/wjg.v20.i16.4467] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
This review updates the current views on aging gastric mucosa and the mechanisms of its increased susceptibility to injury. Experimental and clinical studies indicate that gastric mucosa of aging individuals-“aging gastropathy”-has prominent structural and functional abnormalities vs young gastric mucosa. Some of these abnormalities include a partial atrophy of gastric glands, impaired mucosal defense (reduced bicarbonate and prostaglandin generation, decreased sensory innervation), increased susceptibility to injury by a variety of damaging agents such as ethanol, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), impaired healing of injury and reduced therapeutic efficacy of ulcer-healing drugs. Detailed analysis of the above changes indicates that the following events occur in aging gastric mucosa: reduced mucosal blood flow and impaired oxygen delivery cause hypoxia, which leads to activation of the early growth response-1 (egr-1) transcription factor. Activation of egr-1, in turn, upregulates the dual specificity phosphatase, phosphatase and tensin homologue deleted on chromosome ten (PTEN) resulting in activation of pro-apoptotic caspase-3 and caspase-9 and reduced expression of the anti-apoptosis protein, survivin. The imbalance between pro- and anti-apoptosis mediators results in increased apoptosis and increased susceptibility to injury. This paradigm has human relevance since increased expression of PTEN and reduced expression of survivin were demonstrated in gastric mucosa of aging individuals. Other potential mechanisms operating in aging gastric mucosa include reduced telomerase activity, increase in replicative cellular senescence, and reduced expression of vascular endothelial growth factor and importin-α-a nuclear transport protein essential for transport of transcription factors to nucleus. Aging gastropathy is an important and clinically relevant issue because of: (1) an aging world population due to prolonged life span; (2) older patients have much greater risk of gastroduodenal ulcers and gastrointestinal complications (e.g., NSAIDs-induced gastric injury) than younger patients; and (3) increased susceptibility of aging gastric mucosa to injury can be potentially reduced or reversed pharmacologically.
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Ahluwalia A, Jones MK, Tarnawski AS. Key role of endothelial importin-α in VEGF expression and gastric angiogenesis: novel insight into aging gastropathy. Am J Physiol Gastrointest Liver Physiol 2014; 306:G338-45. [PMID: 24356884 DOI: 10.1152/ajpgi.00382.2013] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Recent in vivo studies demonstrated that aging gastric mucosa has impaired angiogenesis and reduced expression of vascular endothelial growth factor (VEGF). Angiogenesis is triggered by hypoxia and VEGF gene activation, and the latter requires transport of transcription factor(s) into endothelial cell nuclei. We focused on gastric mucosal endothelial cells (GMEC), which are key targets and effectors of gastric angiogenesis, and determined whether and to what extent importin-α, a nuclear transport protein, regulates VEGF gene activation and gastric angiogenesis and the possible role of importin-α in aging gastropathy. GMEC were isolated from rats 3 and 24 mo of age, young (YGEC) and aging (AGEC), respectively. We examined in these cells 1) in vitro angiogenesis, 2) expression of VEGF and importin-α, 3) nuclear transport of hypoxia-inducible factor (HIF)-1α by importin-α, 4) binding of HIF-1α to the VEGF gene promoter, and 5) effects of importin-α silencing in YGEC and its upregulation in AGEC on angiogenesis and VEGF expression. AGEC exhibited significantly impaired in vitro angiogenesis by fourfold and decreased expression of VEGF, importin-α, and nuclear HIF-1α by 1.4-fold, 1.6-fold, and 2.9-fold, respectively, vs. YGEC. Upregulation of importin-α in AGEC significantly reversed all these abnormalities. In YGEC, knockdown of importins-α1 and -α3 significantly reduced in vitro angiogenesis by 93% and 73% and VEGF expression by 48% and 52%, respectively. The above findings demonstrate that importin-α is a novel and critical regulator of gastric angiogenesis. Its reduced expression in AGEC is the key mechanism for impaired angiogenesis and reduced VEGF.
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Affiliation(s)
- Amrita Ahluwalia
- Medical and Research Services, Veterans Affairs Long Beach Healthcare System (VALBHS) and Southern California Institute for Research and Education
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Ahluwalia A, Jones MK, Deng X, Sandor Z, Szabo S, Tarnawski AS. An imbalance between VEGF and endostatin underlies impaired angiogenesis in gastric mucosa of aging rats. Am J Physiol Gastrointest Liver Physiol 2013; 305:G325-32. [PMID: 23788612 DOI: 10.1152/ajpgi.00127.2013] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Gastric mucosa of aging individuals exhibits increased susceptibility to injury and delayed healing. Our previous studies in young rats showed that healing of mucosal injury depends on and is critically dependent on VEGF and angiogenesis. Since angiogenesis in aging gastric mucosa has not been examined before, in this study we examined the extent to which angiogenesis is impaired in gastric mucosa of aging vs. young rats and determined the underlying mechanisms with a focus on mucosal expression of VEGF (proangiogenic factor) and endostatin (antiangiogenic factor). Aging rats had significantly impaired gastric angiogenesis by ~12-fold, 5-fold, 4-fold, and 3-fold, respectively (vs. young rats; all P < 0.001) at 24, 48, 72, and 120 h following ethanol-induced gastric injury and reduced and delayed healing of mucosal erosions. In gastric mucosa of aging (vs. young) rats at baseline, VEGF expression was significantly reduced, whereas endostatin levels were significantly increased (P < 0.05 and P < 0.01, respectively). In contrast to young rats, gastric mucosal VEGF levels did not increase following ethanol-induced injury in aging rats. MMP-9 enzyme activity was significantly higher in gastric mucosa of aging vs. young rats both at baseline (2.7-fold) and 24 h (3.8-fold) after ethanol injury (both P < 0.001). Since endostatin is generated from collagen XVIII by MMP-9, this finding can explain the mechanism of increased endostatin expression in aging gastric mucosa. The above findings demonstrate that reduced VEGF and increased endostatin result in the impaired angiogenesis and delayed injury healing in gastric mucosa of aging rats.
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Affiliation(s)
- Amrita Ahluwalia
- Veterans Affairs Long Beach Healthcare System, and Univ. of California, Irvine, 5901 E. 7th St., 09/151, Bldg. 162, Rm. 115, Long Beach, CA 90822. or
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Jarupongprapa S, Ussavasodhi P, Katchamart W. Comparison of gastrointestinal adverse effects between cyclooxygenase-2 inhibitors and non-selective, non-steroidal anti-inflammatory drugs plus proton pump inhibitors: a systematic review and meta-analysis. J Gastroenterol 2013. [PMID: 23208017 DOI: 10.1007/s00535-012-0717-6] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND There are conflicting and inconsistent data regarding the gastrointestinal (GI) protective effect of cyclooxygenase-2 (COX-2) inhibitors and of non-steroidal anti-inflammatory drugs (NSAIDs) plus proton-pump inhibitors (PPI). AIM To compare the adverse GI effects between COX-2 inhibitors and NSAIDs plus PPI. METHODS We performed a systematic review of randomized trials comparing GI adverse effects between COX-2 inhibitors and NSAID plus PPI. Trials were identified in MEDLINE, EMBASE, and the Cochrane Library. Primary outcomes were major GI complications including hemorrhage, perforation, and obstruction. RESULTS A total of nine trials involving 7,616 participants from 2002 to 2011 were included. All trials were randomized, double blinded, and placebo-controlled with moderate to high quality. COX-2 inhibitors were found to have significantly reduced the risk of major GI events, including perforation, obstruction, and bleeding (relative risk or RR 0.38, 95 % confidence interval or CI 0.25-0.56, p < 0.001); however, the benefit was significant only for patients who were at high risk for NSAID-related GI complications and long-term users. Additionally, the risk of diarrhea (RR 0.56, 95 % CI 0.35-0.9, p 0.02) and withdrawal (RR 0.77, 95 % CI 0.62-0.94, p 0.01) was significantly lower in use of COX-2 inhibitors, while the rate of dyspepsia was higher (RR 1.58, 95 % CI 1.26-1.98, p < 0.001). CONCLUSIONS COX-2 inhibitors significantly reduced the risk of perforation, obstruction, bleeding, diarrhea, and withdrawal due to GI adverse events, while the risk of dyspepsia was lower with NSAIDs plus PPI.
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Seo PJ, Kim N, Kim JH, Lee BH, Nam RH, Lee HS, Park JH, Lee MK, Chang H, Jung HC, Song IS. Comparison of Indomethacin, Diclofenac and Aspirin-Induced Gastric Damage according to Age in Rats. Gut Liver 2012; 6:210-7. [PMID: 22570750 PMCID: PMC3343159 DOI: 10.5009/gnl.2012.6.2.210] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2011] [Revised: 09/17/2011] [Accepted: 10/10/2011] [Indexed: 12/26/2022] Open
Abstract
Background/Aims Aging gastric mucosa is known to have decreased mucosal defenses and increased susceptibility to injury by nonsteroidal anti-inflammatory drugs. Depending on the type of nonsteroidal anti-inflammatory drug (NSAID), the underlying mechanisms and the extent of damage to the stomach or intestine may differ. This study was performed to evaluate the acute gastric damage caused by different doses of indomethacin, diclofenac and aspirin in rats of various ages. Methods For the acute models, indomethacin (10, 20 or 40 mg/kg), diclofenac (40 or 80 mg/kg) or aspirin (100 mg/kg) was given to 7- and 25-week-old and 1-year-old Sprague-Dawley rats by intragastric gavage. The gross ulcer index, damage area as assessed by imaging, histological index, myeloperoxidase (MPO) activity, and cytosolic phospholipase A2 (cPLA2) levels were measured after 24 hours. Results The gross ulcer index and damage area increased with age in the presence of three NSAIDs (p<0.05). The increases in MPO levels induced by diclofenac and aspirin were significantly higher in 1-year-old than 7-week-old rats (p<0.05). cPLA2 expression induced by indomethacin (10 and 40 mg/kg) was greater in the 1-year-old rats, compared with 7-week-old rats (p<0.05). Conclusions NSAID-induced acute gastric damage increased in a dose- and age-dependent manner.
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Affiliation(s)
- Pyoung Ju Seo
- Department of Internal Medicine Seoul National University Bundang Hospital, Seongnam, Korea
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Kang JM, Kim N, Kim JH, Oh E, Lee BY, Lee BH, Shin CM, Park JH, Lee MK, Nam RH, Lee HE, Lee HS, Kim JS, Jung HC, Song IS. Effect of aging on gastric mucosal defense mechanisms: ROS, apoptosis, angiogenesis, and sensory neurons. Am J Physiol Gastrointest Liver Physiol 2010; 299:G1147-53. [PMID: 20724528 DOI: 10.1152/ajpgi.00218.2010] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Aging changes in the stomach lead to a decreased capacity for tissue repair in response to gastric acid. The aim of this study was to determine the mechanism associated with the increased susceptibility to injury of aging mucosa including reactive oxygen species (5), apoptosis, angiogenesis, and sensory neuron activity. Fischer 344 rats at four different ages (6, 31, 74 wk, and 2 yr of age) were studied. The connective tissue indicators [salt-soluble collagen and sulfated glycosaminoglycan (sGAG)], lipid hydroperoxide (LPO), myeloperoxidase (MPO), and hexosamine were assessed. We also evaluated the expression of early growth response-1 (Egr-1), phosphatase and tension homologue deleted on chromosome 10 (PTEN), caspase-9 (index of apoptosis), VEGF (index of angiogenesis), calcitonin gene-related peptide (CGRP, index of sensory neurons), and neuronal nitric oxide synthase (nNOS). The histological connective tissue area in the lower part of rat gastric mucosa increased with aging, with increase of salt-soluble collagen and sGAG. LPO and MPO in old rats were significantly greater than in the young rats, whereas hexosamine was significantly reduced. The old gastric mucosa had increased expression of Egr-1, PTEN, and caspase-9, whereas the VEGF, CGRP, and nNOS expression were significantly reduced. These results indicate that the lower part of rat gastric mucosa was found to be replaced by connective tissue with accumulation of oxidative products with aging. In addition, impairment of apoptosis, angiogenesis, and sensory neuron activity via the activation of Egr-1 and PTEN might increase the susceptibility of gastric mucosa to injury during aging.
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Affiliation(s)
- Jung Mook Kang
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Mármol F, Sánchez J, López D, Martínez N, Mitjavila MT, Puig-Parellada P. Oxidative stress, nitric oxide and prostaglandin E2 levels in the gastrointestinal tract of aging rats. J Pharm Pharmacol 2010. [DOI: 10.1211/jpp.61.02.0009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Abstract
Objectives
To evaluate the presence of oxidative stress and alterations in the levels of two cytoprotective agents, prostaglandin E2 and nitric oxide, in the gastrointestinal tract of aging rats.
Methods
The production of superoxide anion, lipid peroxides, levels of superoxide dismutase and catalase, and production of prostaglandin E2 and nitric oxide in the stomach and duodenum of rats were determined at 1.5, 3, 12, 18 and 24 months of age.
Key findings
Oxidative stress was present in the stomach of the old rats (24 months), whereas prostaglandin E2 and nitric oxide production remained stable at 18 and 24 months. In the duodenum, no oxidative stress was observed at 24 months, but at 18 months, an increase in superoxide anion levels was detected. Prostaglandin E2 remained constant in the aged rats but nitric oxide decreased significantly at 24 months.
Conclusions
The absence of macroscopic gastric injury throughout the gastrointestinal tract indicates that the oxidative stress in the stomach and the significant decrease of nitric oxide in the duodenum in the old rats are not sufficient to disrupt the mucosal defence network. The results support the notion that the disruption of the mucosal network is essentially regulated by the cytoprotective agents prostaglandin E2 and nitric oxide, and that injury appears only when both substances are concurrently reduced.
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Affiliation(s)
- Frederic Mármol
- Unitat de Farmacologia, Facultat de Medicina, IDIBAPS, Universitat de Barcelona, Barcelona, Spain
| | - Juan Sánchez
- Unitat de Farmacologia, Facultat de Medicina, IDIBAPS, Universitat de Barcelona, Barcelona, Spain
| | - Diego López
- Departament de Fisiologia, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
| | - Nuria Martínez
- Departament de Fisiologia, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
| | - Maria Teresa Mitjavila
- Departament de Fisiologia, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
| | - Pere Puig-Parellada
- Unitat de Farmacologia, Facultat de Medicina, IDIBAPS, Universitat de Barcelona, Barcelona, Spain
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Arora G, Singh G, Triadafilopoulos G. Proton pump inhibitors for gastroduodenal damage related to nonsteroidal anti-inflammatory drugs or aspirin: twelve important questions for clinical practice. Clin Gastroenterol Hepatol 2009; 7:725-35. [PMID: 19306941 DOI: 10.1016/j.cgh.2009.03.015] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2008] [Revised: 03/06/2009] [Accepted: 03/11/2009] [Indexed: 02/07/2023]
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin are among the most commonly used medications worldwide. Their use is associated with significant gastroduodenal adverse effects, including dyspepsia, bleeding, ulcer formation, and perforation. Given their long-term use by millions of patients, there is a substantial impact at the population level of these complications. In this evidence-based review, we have endeavored to answer 12 commonly encountered questions in clinical practice that deal with the following: extent of the problem of NSAID/aspirin-induced gastroduodenal damage and its impact on public health; role of proton pump inhibitors (PPIs) in the primary prevention, healing, and secondary prevention of NSAID/aspirin-induced gastroduodenal ulceration as assessed by using endoscopic end points; role of PPIs in the prevention of adverse clinical outcomes related to NSAID/aspirin use; whether PPIs are effective in NSAID-induced dyspepsia; comparison of PPI co-therapy with selective cyclooxygenase-2 inhibitors for risk reduction of adverse clinical outcomes; role of PPIs in preventing rebleeding from aspirin +/- clopidogrel therapy in high-risk patients; identifying high-risk patients who can benefit from PPI co-therapy; the role of other gastroprotective agents for prevention of NSAID/aspirin-induced gastroduodenal damage; and the cost-effectiveness of and limitations to the use of PPIs for prevention of gastroduodenal damage related to the use of NSAIDs or aspirin. We then summarized our recommendations on the use of PPIs for the clinical management of patients using NSAIDs or aspirin.
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Affiliation(s)
- Gaurav Arora
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California 94305-5187, USA
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Laine L, Takeuchi K, Tarnawski A. Gastric mucosal defense and cytoprotection: bench to bedside. Gastroenterology 2008; 135:41-60. [PMID: 18549814 DOI: 10.1053/j.gastro.2008.05.030] [Citation(s) in RCA: 448] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2008] [Revised: 04/07/2008] [Accepted: 05/05/2008] [Indexed: 02/06/2023]
Abstract
The gastric mucosa maintains structural integrity and function despite continuous exposure to noxious factors, including 0.1 mol/L HCl and pepsin, that are capable of digesting tissue. Under normal conditions, mucosal integrity is maintained by defense mechanisms, which include preepithelial factors (mucus-bicarbonate-phospholipid "barrier"), an epithelial "barrier" (surface epithelial cells connected by tight junctions and generating bicarbonate, mucus, phospholipids, trefoil peptides, prostaglandins (PGs), and heat shock proteins), continuous cell renewal accomplished by proliferation of progenitor cells (regulated by growth factors, PGE(2) and survivin), continuous blood flow through mucosal microvessels, an endothelial "barrier," sensory innervation, and generation of PGs and nitric oxide. Mucosal injury may occur when noxious factors "overwhelm" an intact mucosal defense or when the mucosal defense is impaired. We review basic components of gastric mucosal defense and discuss conditions in which mucosal injury is directly related to impairment in mucosal defense, focusing on disorders with important clinical sequelae: nonsteroidal anti-inflammatory drug (NSAID)-associated injury, which is primarily related to inhibition of cyclooxygenase (COX)-mediated PG synthesis, and stress-related mucosal disease (SRMD), which occurs with local ischemia. The annual incidence of NSAID-associated upper gastrointestinal (GI) complications such as bleeding is approximately 1%-1.5%; and reductions in these complications have been demonstrated with misoprostol, proton pump inhibitors (PPIs) (only documented in high-risk patients), and COX-2 selective inhibitors. Clinically significant bleeding from SRMD is relatively uncommon with modern intensive care. Pharmacologic therapy with antisecretory drugs may be used in high-risk patients (eg, mechanical ventilation >or=48 hours), although the absolute risk reduction is small, and a decrease in mortality is not documented.
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Affiliation(s)
- Loren Laine
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
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20
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Tarnawski A, Pai R, Deng X, Ahluwalia A, Khomenko T, Tanigawa T, Akahoshi T, Sandor Z, Szabo S. Aging gastropathy-novel mechanisms: hypoxia, up-regulation of multifunctional phosphatase PTEN, and proapoptotic factors. Gastroenterology 2007; 133:1938-47. [PMID: 18054565 DOI: 10.1053/j.gastro.2007.08.037] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2006] [Accepted: 07/19/2007] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Aging gastric mucosa has impaired mucosal defense and increased susceptibility to injury. Our aims were to determine the mechanisms responsible for above abnormalities. METHODS We used Fisher F-344 rats, 3 and 24 months of age. We measured gastric mucosal blood flow; visualized mucosal hypoxia; examined expression of early growth response-1 transcription factor and phosphatase and tensin homologue deleted on chromosome 10 (PTEN); assessed apoptosis; and determined expression of caspase-3, caspase-9, and survivin. We also examined susceptibility of gastric mucosa of young and aging rats to ethanol injury and whether down-regulation of PTEN affects susceptibility of aging gastric mucosa to injury. To determine human relevance, we examined expression of PTEN and survivin in human gastric specimens of young and aging individuals. RESULTS Gastric mucosa of aging (vs young) rats has a 60% reduction in mucosal blood flow; prominent hypoxia; and increased early growth response-1 transcription factor and PTEN messenger RNAs, and proteins. It also has increased expression of proapoptotic proteins caspase-3 and capase-9, reduced survivin, and a 6-fold increased apoptosis vs mucosa of young rats. Ethanol-induced gastric mucosal injury in aging (vs young) rats was significantly increased. The down-regulation of PTEN in gastric mucosa of aging rats completely reversed its increased susceptibility to ethanol injury. In aging human gastric mucosa, PTEN expression was significantly increased, whereas survivin was significantly reduced. CONCLUSIONS (1) Gastric mucosa of aging rats has significantly reduced blood flow, tissue hypoxia, activation of Egr-1, PTEN; increased caspases; and reduced survivin. (2) These changes increase susceptibility of aging gastric mucosa to injury.
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Affiliation(s)
- Andrzej Tarnawski
- Department of Medicine, VA Long Beach Healthcare System and the University of California, Irvine, California, USA.
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Abstract
Interventions to reduce mortality and disability in older people are vital. Aspirin is cheap and effective and known to prevent cardiovascular and cerebrovascular disease, many cancers, and Alzheimer dementia. The widespread use of aspirin in older people is limited by its gastrointestinal side effects. Understanding age-related changes in gastrointestinal physiology that could put older people at risk of the side effects of aspirin may direct strategies to improve tolerance and hence lead to greater numbers of older people being able to take this effective intervention.
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Affiliation(s)
- Julia L Newton
- Institute for Ageing and Health, University of Newcastle upon Tyne, Care of the Elderly Offices, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
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22
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Newton JL. Effect of age-related changes in gastric physiology on tolerability of medications for older people. Drugs Aging 2005; 22:655-61. [PMID: 16060716 DOI: 10.2165/00002512-200522080-00003] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Studies specifically examining the effect of age upon the stomach are limited and frequently uncontrolled for the high prevalence of Helicobacter pylori in this age group. Age-related changes in gastric physiology such as reduced mucosal protection, gastric blood flow and impaired repair mechanisms may all impact upon gastrointestinal adverse effects and how older people tolerate medicines. Understanding how the upper gastrointestinal tract changes with advancing age could allow interventions that lead to more appropriate prescribing for older people, potentially reduce adverse effects, increase compliance with treatment regimens, and may allow older people to take medications that they would not otherwise tolerate. This review emphasises how the stomach changes with age, and how understanding this will aid clinicians when prescribing medications with potential gastrointestinal adverse effects to older people.
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Affiliation(s)
- Julia L Newton
- Institute for Ageing and Health, University of Newcastle, Newcastle, UK.
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23
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Singh G, Triadafilopoulos G. Appropriate choice of proton pump inhibitor therapy in the prevention and management of NSAID-related gastrointestinal damage. Int J Clin Pract 2005; 59:1210-7. [PMID: 16178990 DOI: 10.1111/j.1368-5031.2005.00660.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with gastrointestinal adverse effects, ranging from dyspepsia and peptic ulcer disease to more serious complications such as haemorrhage or perforation. NSAID-induced gastrointestinal toxicity is a significant medical problem worldwide. Misoprostol is effective in reducing NSAID-induced mucosal damage, but patient compliance is limited by poor tolerance. Histamine receptor antagonists are relatively effective against duodenal ulcers but offer no significant protection against gastric ulcers. Proton pump inhibitors (PPIs), such as pantoprazole, omeprazole and lansoprazole, have been shown to be effective in preventing the development of gastric and duodenal ulcers in high-risk patients taking NSAIDs. PPI therapy is also beneficial in healing NSAID-induced ulcers and preventing their recurrence in patients requiring ongoing NSAID therapy. PPIs have an excellent safety profile, and pantoprazole--with its low potential for drug-drug interactions--is particularly suitable for administration to elderly patients who often require concomitant treatment with other medications.
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Affiliation(s)
- G Singh
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94062, USA.
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24
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Hall KE, Proctor DD, Fisher L, Rose S. American gastroenterological association future trends committee report: effects of aging of the population on gastroenterology practice, education, and research. Gastroenterology 2005; 129:1305-38. [PMID: 16230084 DOI: 10.1053/j.gastro.2005.06.013] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Karen E Hall
- Veterans Affairs Healthcare System, Geriatric Research, Education and Clinical Center, Ann Arbor, Michigan, USA
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25
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Abstract
Ankylosing spondylitis is the prototype of related diseases commonly called spondylarthropathies which include reactive arthritis, psoriatic arthritis, arthritis associated with inflammatory bowel diseases (enteropathic arthritis) and undifferentiated spondylarthropathies. Ankylosing spondylitis and spondylarthropathies are generally observed in young patients but can be observed later in life or in persons >50 years of age. All the spondylarthropathy subgroups are represented in the elderly with some features particular to this age group. Indeed, radiological aspects of ankylosing spondylitis may be difficult to interpret because of the radiological changes induced by aging. Late-onset peripheral spondylarthropathies are characterised by severe disease, marked elevation of laboratory parameters of inflammation, oligoarthritis involving the lower limbs and oedema of the extremities. Psoriatic arthritis is more severe in the elderly and is associated with worse outcomes than in young patients. The clinical presentation of undifferentiated spondylarthropathy is as varied in the elderly as in young and middle-aged adults. Reactive arthritis and enteropathic arthritis are observed in the elderly more rarely. The effects of aging on drug metabolism and pharmacokinetics, together with the existence of co-morbidities and polypharmacy, are responsible for difficulties in the therapeutic management of late-onset ankylosing spondylitis or spondylarthropathies. Indeed, NSAIDs should be used with caution in older patients because of the high risk of serious gastrointestinal complications. Sulfasalazine and methotrexate have been used as disease-controlling drugs but did not prove very effective. Pamidronate and tumour necrosis factor (TNF)-alpha antagonists offer a therapeutic alternative but have not been specifically tested in the elderly. Pamidronate has been tested in young-onset ankylosing spondylitis and spondylarthropathies with conflicting results but can be used in older patients without risk of major adverse effects. TNFalpha antagonists have been adequately evaluated in ankylosing spondylitis and spondylarthropathies and are associated with dramatic improvement in clinical and biological parameters of disease activity. However, the safety profile of these agents in the elderly is not currently known and careful surveillance, in particular for the risk of infection such as tuberculosis, and/or exacerbation of chronic heart failure, is thus required when using these drugs in this age group.
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Affiliation(s)
- Eric Toussirot
- Department of Rheumatology, University Hospital Jean Minjoz, Besançon, France.
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Abstract
Aspirin has a role in the prevention of cardiovascular and cerebrovascular disease, Alzheimer's dementia and several cancers. Encouraging all 50 year olds to take low-dose aspirin doubles their chances of living a healthy life into their nineties. The widespread use of aspirin, however, is limited as many older subjects are currently unable to take aspirin because of gastrointestinal side-effects. This review explores why gastrointestinal events occur with aspirin use and how a net benefit from prophylactic aspirin might be achieved in older subjects. It is suggested that, by understanding the age-related changes in upper gastrointestinal physiology and the mechanisms by which aspirin leads to the risk reductions associated with its use, it may be possible to direct interventions to improve tolerability in older subjects. This would allow greater numbers of older subjects to gain the benefits associated with aspirin use.
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Affiliation(s)
- J L Newton
- Institute for Ageing and Health, University of Newcastle upon Tyne, Care of the Elderly Offices, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
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Hsu PI, Lai KH, Lo GH, Tseng HH, Lo CC, Chen HC, Tsai WL, Jou HS, Peng NJ, Chien CH, Chen JL, Hsu PN. Risk factors for ulcer development in patients with non-ulcer dyspepsia: a prospective two year follow up study of 209 patients. Gut 2002; 51:15-20. [PMID: 12077085 PMCID: PMC1773281 DOI: 10.1136/gut.51.1.15] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS A subset of non-ulcer dyspepsia (NUD) disorders can evolve into peptic ulcer disease. This prospective study attempted to determine the independent risk factors for ulcer formation in NUD patients, and compared the natural history of Helicobacter pylori positive and negative NUD subjects. METHODS From May 1997 to April 1999, consecutive NUD patients were enrolled into the study. Endoscopy was performed routinely on enrolment, at the end of the second and 12th months, and whenever there was a dyspepsia attack. Patients were prospectively followed up for two years. RESULTS Peptic ulcers occurred in 16 of 209 NUD patients during the two year follow up period. Multivariate analysis of 13 host and bacterial factors demonstrated that advanced age (odds ratio 2.90), H pylori infection (odds ratio 3.59), and use of non-steroidal anti-inflammatory drugs (NSAID; odds ratio 4.46) were independently significant in predicting subsequent peptic ulcer development. NUD patients with all three risk factors had a 75% (3/4) risk of developing peptic ulcer but the ulcer incidence in patients without any of the risk parameters was only 1.2% (1/84). The resolution rate of symptoms in the H pylori positive NUD patients was similar to the H pylori negative patients (57.9% v 49.1%; 95% confidence interval (CI) -5 to 22). However, rates for subsequent peptic ulcer and erosion development were significantly higher in H pylori positive patients than in H pylori negative patients (ulcer 12.6% v 3.5%, 95% CI 1-16; erosion 23.2% v 12.3%, 95% CI 1-21). CONCLUSION A small but significant proportion of NUD patients develop peptic ulcer after long term follow up. H pylori infection, NSAID use, and advanced age are independent risk factors for subsequent ulcer formation. Follow up endoscopy is strongly indicated for an NUD patient with multiple risk factors for ulcer formation when symptoms recur.
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Affiliation(s)
- P-I Hsu
- Division of Gastroenterology, Kaohsiung Veterans General Hospital, Taiwan, ROC
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Jones JI, Hawkey CJ. Physiology and organ-related pathology of the elderly: stomach ulcers. Best Pract Res Clin Gastroenterol 2001; 15:943-61. [PMID: 11866486 DOI: 10.1053/bega.2001.0251] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Peptic ulcer disease, particularly as a result of its complications, is a burden that is focused on the elderly through their higher Helicobacter pylori prevalence and use of non-steroidal anti-inflammatory drugs (NSAIDs). In these patients, senescence may further increase ulcer susceptibility, particularly in the stomach, by the loss of mucosal protection and repair mechanisms. Age is mainly a marker for the increased prevalence of other complicated ulcer risk factors such as previous ulcer history and use of anti-coagulants, steroids and aspirin. The development of selective cyclo-oxygenase inhibitors (coxibs) has reduced the specific risk of NSAID ulceration, but the residual incidence in high risk patients remains substantially higher than that in young patients without other risk factors. The argument for early surgery versus endoscopic therapy in high risk patients with bleeding ulcers has not been resolved, both having a high mortality. There is still potential for the development of new strategies to prevent primary and secondary ulcers, either by new drug development or by expanding existing co-prescription strategies.
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Affiliation(s)
- J I Jones
- Divison of Gastroenterology, University Hospital, Nottingham NG7 2UH, UK
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Abstract
Nutrition is a prime concern for the optimal health of older persons. Nutritional requirements for older persons must take into account the physiologic changes that occur with aging. The gastrointestinal tract is the site of key structural and functional changes that affect nutrient intake and assimilation. A working knowledge of nutritional screening, assessment, and interventions can assist the practitioner in providing quality care for the older patient.
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Affiliation(s)
- G L Jensen
- Vanderbilt Center for Human Nutrition, Vanderbilt, University Medical Center, Nashville, Tennessee, USA.
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