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Han C, Wu Y, Rong J, Xia Q, Du D. Unveiling the Emerging Role of Xanthine Oxidase in Acute Pancreatitis: Beyond Reactive Oxygen Species. Antioxidants (Basel) 2025; 14:95. [PMID: 39857429 PMCID: PMC11759826 DOI: 10.3390/antiox14010095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 12/29/2024] [Accepted: 01/13/2025] [Indexed: 01/27/2025] Open
Abstract
Acute pancreatitis (AP) is a potentially fatal acute digestive disease that is widespread globally. Although significant progress has been made in the previous decade, the study of mechanisms and therapeutic strategies is still far from being completed. Xanthine oxidase (XO) is an enzyme that catalyzes hypoxanthine and xanthine to produce urate and is accompanied by the generation of reactive oxygen species (ROS) in purine catabolism. Considerable preclinical and clinical studies have been conducted over many decades to investigate the role of XO in the pathogenesis of AP and its potential targeting therapeutic value. There is no doubt that the ROS generated by irreversibly activated XO participates in the local pancreas and multiple organ failure during AP. However, the optimal timing and doses for therapeutic interventions targeting XO in animal studies and the clinic, as well as the additional molecular mechanisms through which XO contributes to disease onset and progression, including metabolic regulation, remain to be elucidated. This review summarized the benefits and contradictions of using XO inhibitors in animal models, offered mechanisms other than ROS, and discussed the difficulties faced in clinical trials. We hope to provide a perspective on the future worthwhile basic and clinical research on XO by analyzing its chemical and biological characteristics, as well as the progress of its regulatory mechanisms in AP.
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Affiliation(s)
- Chenxia Han
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yaling Wu
- Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Juan Rong
- Department of Gastroenterology, The Third People’s Hospital of Chengdu, Chengdu 610031, China
| | - Qing Xia
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Dan Du
- Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
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Xia CC, Chen HT, Deng H, Huang YT, Xu GQ. Reactive oxygen species and oxidative stress in acute pancreatitis: Pathogenesis and new therapeutic interventions. World J Gastroenterol 2024; 30:4771-4780. [PMID: 39649547 PMCID: PMC11606378 DOI: 10.3748/wjg.v30.i45.4771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 09/27/2024] [Accepted: 10/29/2024] [Indexed: 11/13/2024] Open
Abstract
Acute pancreatitis (AP) is a common acute gastrointestinal disorder affecting approximately 20% of patients with systemic inflammatory responses that may cause pancreatic and peripancreatic fat necrosis. This condition often progresses to multiple organ failure, significantly increasing morbidity and mortality. Oxidative stress, characterized by an imbalance between the body's reactive oxygen species (ROS) and antioxidants, activates the inflammatory signaling pathways. Although the pathogenesis of AP is not fully understood, ROS are increasingly recognized as critical in the disease's progression and development. Modulating the oxidative stress pathway has shown efficacy in mitigating the progression of AP. Despite numerous basic studies examining this pathway, comprehensive reviews of recent research remain sparse. This systematic review offers an in-depth examination of the critical role of oxidative stress in the pathogenesis and progression of AP and evaluates the therapeutic potential of antioxidant interventions in its management.
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Affiliation(s)
- Chuan-Chao Xia
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Hong-Tan Chen
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Hao Deng
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Yi-Ting Huang
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Guo-Qiang Xu
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
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Rojas-Victoria EJ, Hernández-Ruiz SI, García-Perdomo HA. Effectiveness of the pharmacological therapy to prevent post ERCP acute pancreatitis: a network meta-analysis. Expert Rev Gastroenterol Hepatol 2024; 18:203-215. [PMID: 38725175 DOI: 10.1080/17474124.2024.2345640] [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: 09/02/2023] [Accepted: 04/17/2024] [Indexed: 05/24/2024]
Abstract
OBJECTIVE To determine the effectiveness of the different pharmacological agents in preventing post-ERCP acute pancreatitis. METHODS We included clinical trials of pharmacological interventions for prophylaxis of acute post-ERCP pancreatitis. The event evaluated was acute pancreatitis. We conducted a search strategy in MEDLINE (OVID), EMBASE, and Cochrane Central Register of Controlled Trials from inception to nowadays. We reported the information in terms of relative risks (RR) with a 95% confidence interval. We assessed the heterogeneity using the I2 test. RESULTS We included 84 studies for analysis (30,463 patients). The mean age was 59.3 years (SD ± 7.01). Heterogeneity between studies was low (I2 = 34.4%) with no inconsistencies (p = 0.2567). Post ERCP pancreatitis was less in prophylaxis with NSAIDs (RR 0.65 95% CI [0.52 to 0.80]), aggressive hydration with Lactate Ringer (RR 0.32 95% CI [0.12-0.86]), NSAIDs + isosorbide dinitrate (RR 0.28 95% CI [0.11-0.71]) and somatostatin and analogues (RR 0.54 [0.43 to 0.68]) compared with placebo. CONCLUSIONS NSAIDs, the Combination of NSAIDs + isosorbide dinitrate, somatostatin and analogues, and aggressive hydration with lactate ringer are pharmacological strategies that can prevent post-ERCP pancreatitis when compared to placebo. More clinical trials are required to determine the effectiveness of these drugs.
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Affiliation(s)
| | | | - Herney Andrés García-Perdomo
- Division of Urology/Urooncology, Department of Surgery, School of Medicine, Universidad del Valle, Cali, Colombia
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Akshintala VS, Kanthasamy K, Bhullar FA, Sperna Weiland CJ, Kamal A, Kochar B, Gurakar M, Ngamruengphong S, Kumbhari V, Brewer-Gutierrez OI, Kalloo AN, Khashab MA, van Geenen EJM, Singh VK. Incidence, severity, and mortality of post-ERCP pancreatitis: an updated systematic review and meta-analysis of 145 randomized controlled trials. Gastrointest Endosc 2023; 98:1-6.e12. [PMID: 37004815 DOI: 10.1016/j.gie.2023.03.023] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 03/01/2023] [Accepted: 03/21/2023] [Indexed: 04/04/2023]
Abstract
BACKGROUND AND AIMS The incidence, severity, and mortality of post-ERCP pancreatitis (PEP) largely remain unknown with changing trends in ERCP use, indication, and techniques. We sought to determine the incidence, severity, and mortality of PEP in consecutive and high-risk patients based on a systemic review and meta-analysis of patients in placebo and no-stent arms of randomized control trials (RCTs). METHODS The MEDLINE, Embase, and Cochrane databases were searched from the inception of each database to June 2022 to identify full-text RCTs evaluating PEP prophylaxes. The incidence, severity, and mortality of PEP from the placebo or no-stent arms of RCTs were recorded for consecutive and high-risk patients. A random-effects meta-analysis for a proportions model was used to calculate PEP incidence, severity, and mortality. RESULTS One hundred forty-five RCTs were found with 19,038 patients in the placebo or no-stent arms. The overall cumulative incidence of PEP was 10.2% (95% confidence interval [CI], 9.3-11.3), predominantly among the academic centers conducting such RCTs. The cumulative incidences of severe PEP and mortality were .5% (95% CI, .3-.7) and .2% (95% CI, .08-.3), respectively, across 91 RCTs with 14,441 patients. The cumulative incidences of PEP and severe PEP were 14.1% (95% CI, 11.5-17.2) and .8% (95% CI, .4-1.6), respectively, with a mortality rate of .2% (95% CI, 0-.3) across 35 RCTs with 3733 patients at high risk of PEP. The overall trend for the incidence of PEP among patients randomized to placebo or no-stent arms of RCTs has remained unchanged from 1977 to 2022 (P = .48). CONCLUSIONS The overall incidence of PEP is 10.2% but is 14.1% among high-risk patients based on this systematic review of placebo or no-stent arms of 145 RCTs; this rate has not changed between 1977 and 2022. Severe PEP and mortality from PEP are relatively uncommon.
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Affiliation(s)
- Venkata S Akshintala
- Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Kavin Kanthasamy
- Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Furqan A Bhullar
- Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | | | - Ayesha Kamal
- Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Bharati Kochar
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Merve Gurakar
- Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | | | - Vivek Kumbhari
- Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | | | - Anthony N Kalloo
- Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Mouen A Khashab
- Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Erwin-Jan M van Geenen
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Vikesh K Singh
- Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
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Mansour-Ghanaei F, Joukar F, Khalesi AA, Naghipour M, Sepehrimanesh M, Mojtahedi K, Yeganeh S, Saedi HS, Asl SF. Naproxen, isosorbide dinitrate and co-administration cannot prevent post-endoscopic retrograde cholangiopancreatography pancreatitis: Randomized controlled trial. Ann Hepatobiliary Pancreat Surg 2020; 24:259-268. [PMID: 32843590 PMCID: PMC7452799 DOI: 10.14701/ahbps.2020.24.3.259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 04/30/2020] [Accepted: 04/30/2020] [Indexed: 11/17/2022] Open
Abstract
Backgrounds/Aims Acute pancreatitis is the most widespread complication of endoscopic retrograde cholangiopancreatography. Here, we investigated the efficacy of rectal suppository naproxen, sublingual isosorbide dinitrate and their co-administration in the prevention of post-ERCP pancreatitis. Methods This double-blind randomized clinical trial carried out from June 2015 to February 2016 at the Gastrointestinal and Liver Diseases Research Center in Rasht, Iran. A total of 585 patients were selected from candidates for diagnostic or therapeutic ERCP by using the simple sampling method. Patients divided into three groups. Group A received 500 mg naproxen, group B took 5 mg isosorbide dinitrate, and group C was co-administrated both agents before ERCP. The primary outcome measure was the development of pancreatitis onset of pain in the upper abdomen and increase of serum amylase activity more than 3 times over the upper normal limit (60-100 IU/L) within first the 24 h post-ERCP. Results Totally, 80 patients developed PEP included 29 (4.9%), 24 (4.1%), and 27 (4.6%) patients in groups A, B, and C, respectively (p=0.845). Longer ERCP time (p=0.041), using diazepam (p=0.033), a higher number of pancreatic ducts cannulation (p<0.001), pancreatic duct injection (p=0.013), and using pancreatic stent (p=0.004) were the predisposing factors for PEP. Conclusions Our findings indicated that prophylactic naproxen suppository or isosorbide dinitrate sublingually or co-administration had no significant difference in the prevention and severity of PEP, however, enhancing the endoscopist’s skills can be effective. Departments and educational hospitals should develop their assessment and quality assurance measures for the training of fellows’ not only technical training but also an understanding of the diagnostic and therapeutic roles of the procedure.
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Affiliation(s)
- Fariborz Mansour-Ghanaei
- GI Cancer Screening and Prevention Research Center, Rasht, Iran.,Caspian Digestive Disease Research Center, Rasht, Iran
| | - Farahnaz Joukar
- GI Cancer Screening and Prevention Research Center, Rasht, Iran.,Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | | | | | - Masood Sepehrimanesh
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran.,New Iberia Research Center, University of Louisiana, Lafayette, LA, USA
| | - Kourosh Mojtahedi
- Caspian Digestive Disease Research Center, Rasht, Iran.,Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Sara Yeganeh
- GI Cancer Screening and Prevention Research Center, Rasht, Iran.,Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
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Parekh PJ, Majithia R, Sikka SK, Baron TH. The "Scope" of Post-ERCP Pancreatitis. Mayo Clin Proc 2017; 92:434-448. [PMID: 28160947 DOI: 10.1016/j.mayocp.2016.10.028] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Revised: 10/22/2016] [Accepted: 10/31/2016] [Indexed: 12/14/2022]
Abstract
Pancreatitis is the most common adverse event of endoscopic retrograde cholangiopancreatography, with the potential for clinically significant morbidity and mortality. Several patient and procedural risk factors have been identified that increase the risk of post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP). Considerable research efforts have identified several pharmacologic and procedural interventions that can drastically affect the incidence of PEP. This review article addresses the underlying mechanisms at play for the development of PEP, identifying patient and procedural risk factors and meaningful use of risk-stratification information, and details current interventions aimed at reducing the risk of this complication.
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Affiliation(s)
- Parth J Parekh
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tulane University, New Orleans, LA
| | - Raj Majithia
- Division of Gastroenterology and Hepatology, University of North Carolina-Johnston Healthcare, Smithfield
| | - Sanjay K Sikka
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tulane University, New Orleans, LA
| | - Todd H Baron
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill.
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Gooshe M, Abdolghaffari AH, Nikfar S, Mahdaviani P, Abdollahi M. Antioxidant therapy in acute, chronic and post-endoscopic retrograde cholangiopancreatography pancreatitis: An updated systematic review and meta-analysis. World J Gastroenterol 2015; 21:9189-9208. [PMID: 26290647 PMCID: PMC4533052 DOI: 10.3748/wjg.v21.i30.9189] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Revised: 04/15/2015] [Accepted: 06/15/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the efficacy and adverse effects of antioxidant therapy in acute pancreatitis (AP), chronic pancreatitis (CP) and post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP). METHODS PubMed, Scopus, Google Scholar, Cochrane library database, and Evidence-based medicine/clinical trials published before August 2014 were searched. Clinical and laboratory outcomes of randomized trials of antioxidant therapy in patients with AP, CP and PEP were included. The methodological quality of the trials was assessed by the Jadad score based on the description of randomization, blinding, and dropouts (withdrawals). The results of the studies were pooled and meta-analyzed to provide estimates of the efficacy of antioxidant therapy. RESULTS Thirty four trials out of 1069 potentially relevant studies with data for 4898 patients were eligible for inclusion. Antioxidant therapy significantly reduced the length of hospital stay in AP patients {mean difference -2.59 d (95%CI: -4.25-(-0.93)], P = 0.002}. Although, antioxidant therapy had no significant effect on serum C reactive protein (CRP) after 5-7 d in AP patients [mean difference -9.57 (95%CI: -40.61-21.48, P = 0.55], it significantly reduced serum CRP after 10 d {mean difference -45.16 [95%CI: -89.99-(-0.33)], P = 0.048}. In addition, antioxidant therapy had no significant effect on CP-induced pain [mean difference -2.13 (95%CI: -5.87-1.6), P = 0.26]. Antioxidant therapy had no significant effects on the incidence of all types of PEP [mean difference 1.05 (95%CI: 0.74-1.5), P = 0.78], severe PEP [mean difference 0.92 (95%CI: 0.43-1.97), P = 0.83], moderate PEP [mean difference 0.82 (95%CI: 0.54-1.23), P = 0.33], and mild PEP [mean difference 1.33 (95%CI: 0.99-1.78), P = 0.06]. Furthermore, while antioxidant therapy had no significant effect on serum amylase after less than 8 h sampling [mean difference -20.61 (95%CI: -143.61-102.39), P = 0.74], it significantly reduced serum amylase close to 24-h sampling {mean difference -16.13 [95%CI: -22.98-(-9.28)], P < 0.0001}. CONCLUSION While there is some evidence to support antioxidant therapy in AP, its effect on CP and PEP is still controversial.
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Romagnuolo J. Risk assessment and reduction. ERCP 2015:41-58. [DOI: 10.1002/9781118769409.ch5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Incidence, severity, and mortality of post-ERCP pancreatitis: a systematic review by using randomized, controlled trials. Gastrointest Endosc 2015; 81:143-149.e9. [PMID: 25088919 DOI: 10.1016/j.gie.2014.06.045] [Citation(s) in RCA: 321] [Impact Index Per Article: 32.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2013] [Accepted: 06/26/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND Data regarding the incidence and severity of post-ERCP pancreatitis (PEP) are primarily from nonrandomized studies. OBJECTIVE To determine the incidence, severity, and mortality of PEP from a systematic review of the placebo or no-stent arms of randomized, controlled trials (RCTs). DESIGN MEDLINE, EMBASE, and Cochrane databases were searched to identify RCTs evaluating the efficacy of drugs and/or pancreatic stents to prevent PEP. SETTING Systematic review of patients enrolled in RCTs evaluating agents for PEP prophylaxis. PATIENTS Patients in the placebo or no-stent arms of the RCTs INTERVENTION ERCP. MAIN OUTCOME MEASUREMENTS Incidence, severity, and mortality of PEP. RESULTS There were 108 RCTs with 13,296 patients in the placebo or no-stent arms. Overall, the PEP incidence was 9.7% and the mortality rate was 0.7%. Severity of PEP was reported for 8857 patients: 5.7%, 2.6%, and 0.5% of cases were mild, moderate, and severe, respectively. The incidence of PEP in 2345 high-risk patients was 14.7% and the severity of PEP was mild, moderate, and severe in 8.6%, 3.9%, and 0.8%, respectively, with a 0.2% mortality rate. The incidence of PEP was 13% in North American RCTs compared with 8.4% in European and 9.9% in Asian RCTs. ERCPs conducted before and after 2000 had a PEP incidence of 7.7% and 10%, respectively. LIMITATIONS Difference in PEP risk among patients in the included RCTs. CONCLUSION The incidence of PEP and severe PEP is similar in high-risk patients and the overall cohort. Discrepancies in the incidence of PEP across geographic regions require further study.
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Prevention effect of allopurinol on post-endoscopic retrograde cholangiopancreatography pancreatitis: a meta-analysis of prospective randomized controlled trials. PLoS One 2014; 9:e107350. [PMID: 25202907 PMCID: PMC4159328 DOI: 10.1371/journal.pone.0107350] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2014] [Accepted: 08/14/2014] [Indexed: 01/07/2023] Open
Abstract
Background Pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP) which can be severe and cause death in approximately 10% of cases. Up to now, six randomized controlled trials (RCTs) have been found relevant to the effect of allopurinol on prevention of Post-ERCP pancreatitis (PEP). However, these results remained controversial. Objective To conduct a meta-analysis with RCTs published in full text to determine the effectiveness of prophylactic allopurinol of different dosages and administration time in the incidence and severity of PEP. Methods Literature search was performed in PubMed, Embase, Web of Science and Cochrane Library from databases inception to May 2014. RCTs comparing the effect of allopurinol with placebo on prevention of PEP were included. Statistical heterogeneity was quantitatively evaluated byχ2 test with the significance set P<0.10 or I2>50%. Results Six RCTs consisting of 1974 participants were eventually included. The incidences of PEP in allopurinol group and placebo group were 8.4%(83/986) and 9.9%(98/988) respectively. Meta-analysis showed no evident prevention effect of allopurinol on the incidence of PEP (RR 0.75, 95%CI 0.39–1.42) with significant heterogeneity (I2 = 70.4%, P = 0.005). When studies were stratified according to the dosages and administration time of allopurinol they applied, there was still no evident prevention effect of allopurinol on mild, moderate or severe PEP. However, statistically substantial heterogeneity was presented in the subgroup of moderate PEP when the effect of high dose of allopurinol was analyzed (Imoderate2 = 82.3%, Pmoderate = 0.018). Statistically significant heterogeneity was also observed in subgroup of mild PEP, when the effect of long adminstration time of allopurinol was investigated (Imild2 = 62.8%, Pmild = 0.068). Conclusion The prophylactic use of allopurinol in different dosages and administration time had no effect in preventing incidence and severity of PEP.
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Ahmed Ali U, Jens S, Busch ORC, Keus F, van Goor H, Gooszen HG, Boermeester MA, Cochrane Upper GI and Pancreatic Diseases Group. Antioxidants for pain in chronic pancreatitis. Cochrane Database Syst Rev 2014; 2014:CD008945. [PMID: 25144441 PMCID: PMC10114264 DOI: 10.1002/14651858.cd008945.pub2] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Reduced intake and absorption of antioxidants due to pain and malabsorption are probable causes of the lower levels of antioxidants observed in patients with chronic pancreatitis (CP). Improving the status of antioxidants might be effective in slowing the disease process and reducing pain in CP. OBJECTIVES To assess the benefits and harms of antioxidants for the treatment of pain in patients with CP. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Conference Proceedings Citation Index from inception to October 2012. Two review authors performed the selection of trials independently. SELECTION CRITERIA We included all randomised controlled trials (RCTs) evaluating antioxidants for treatment of pain in CP. All trials were included irrespective of blinding, numbers of participants randomly assigned and language of the article. DATA COLLECTION AND ANALYSIS Two review authors extracted data independently. The risk of bias of included trials was assessed. Study authors were asked for additional information in the case of missing data. MAIN RESULTS Twelve RCTs with a total of 585 participants were included. Six trials were double-blinded, placebo-controlled studies, and the other six trials were of less adequate methodology. Most trials were small and had high rates of dropout. Eleven of the 12 included trials described the effects of antioxidants on chronic abdominal pain in chronic pancreatitis. Pain as measured on a visual analogue scale (VAS, scale range 0 to 10) after one to six months was less in the antioxidant group than in the control group (mean difference (MD) -0.33, 95% confidence interval (CI) -0.64 to -0.02, P value 0.04, moderate-quality evidence). The number of pain-free participants was not statistically significantly different (risk ratio (RR) 1.73, 95% CI 0.95 to 3.15, P value 0.07, low-quality evidence). More adverse events were observed in the antioxidant group, both in the parallel trials (RR 4.43, 95% CI 1.60 to 12.29, P value 0.0004, moderate-quality evidence) and in the cross-over trials (RR 5.80, 95% CI 1.56 to 21.53, P value 0.0009, moderate-quality evidence). Adverse events occurred in 16% of participants and were mostly mild (e.g. headache, gastrointestinal complaints), but were sufficient to make participants stop antioxidant use. Other important outcomes such as use of analgesics, exacerbation of pancreatitis and quality of life were rarely reported. One trial from 1991 evaluated the effects of antioxidants on acute pain during exacerbation of chronic pancreatitis and found that a significantly higher proportion of participants in the antioxidant group experienced pain relief. This trial was conducted more than 25 years ago and has not been reproduced since that time. Therefore, additional trials are needed before reliable conclusions can be drawn. AUTHORS' CONCLUSIONS Current evidence shows that antioxidants can reduce pain slightly in patients with chronic pancreatitis. The clinical relevance of this small reduction is uncertain, and more evidence is needed. Adverse events in one of six patients may prevent the use of antioxidants. Effects of antioxidants on other outcome measures, such as use of analgesics, exacerbation of pancreatitis and quality of life remain uncertain because reliable data are not available.
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Affiliation(s)
- Usama Ahmed Ali
- University Medical Center UtrechtDepartment of SurgeryHeidelberglaan 100P.O. Box 85500UtrechtUtrechtNetherlands3508 GA
| | - Sjoerd Jens
- Academic Medical Centre, University of AmsterdamDepartment of RadiologyAmsterdamNetherlands
| | - Olivier RC Busch
- University of AmsterdamDepartment of Surgery, Academic Medical CenterAmsterdamNetherlands
| | - Frederik Keus
- University of Groningen, University Medical Center GroningenDepartment of Critical CareHanzeplein 1GroningenNetherlands9713 GZ
| | - Harry van Goor
- Radboud University Nijmegen Medical CentreDepartment of SurgeryPO Box 9101NijmegenNetherlands6500 HB
| | - Hein G Gooszen
- Radboud University Nijmegen Medical CenterCentre of Evidence‐based SurgeryPO Box 9101Huispost 630, route 631NijmegenNetherlands6500 HB
| | - Marja A Boermeester
- University of AmsterdamDepartment of Surgery, Academic Medical CenterAmsterdamNetherlands
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Gu WJ, Wei CY, Yin RX. Antioxidant supplementation for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: a meta-analysis of randomized controlled trials. Nutr J 2013; 12:23. [PMID: 23398675 PMCID: PMC3575286 DOI: 10.1186/1475-2891-12-23] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2012] [Accepted: 01/25/2013] [Indexed: 02/07/2023] Open
Abstract
Background Acute pancreatitis remains the most common major complication of endoscopic retrograde cholangiopancreatography (ERCP). The pathogenesis of post-ERCP acute pancreatitis may be mediated by oxygen-derived free radicals, which could be ameliorated by antioxidants. Antioxidant supplementation may potentially prevent post-ERCP pancreatitis. We performed a meta-analysis of randomized controlled trials to evaluate the effect of prophylactic antioxidant supplementation compared with control on the prevention of post-ERCP pancreatitis. Methods PubMed and Embase databases were searched to identify relevant trials. A standardized Excel file was used to extract data by two independent authors. Results were expressed as risk ratio (RR) with accompanying 95% confidence interval (CI). The meta-analysis was performed with the fixed-effects model or random-effects model according to heterogeneity. Results Eleven studies involving 3,010 patients met our inclusion criteria. Antioxidant supplementation did not significantly decrease the incidence of post-ERCP pancreatitis (RR, 0.92; 95% CI, 0.65-1.32; P = 0.665). There was also no statistical difference in the severity grades between the antioxidant group and control group. Conclusions Based on current evidence, antioxidant supplementation shows no beneficial effect on the incidence and the severity of post-ERCP pancreatitis; thus, there is currently a lack of evidence to support using antioxidants for the prevention of post-ERCP pancreatitis.
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Affiliation(s)
- Wan-Jie Gu
- Department of Anaesthesiology, The First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, People's Republic of China
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Romagnuolo J. Quality measurement and improvement in advanced procedures. TECHNIQUES IN GASTROINTESTINAL ENDOSCOPY 2012. [DOI: 10.1016/j.tgie.2011.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Abstract
Pancreatitis is the most common complication of ERCP. It can be associated with substantial morbidity. Hence, the minimization of both the incidence and severity of post-ERCP pancreatitis is paramount. Considerable efforts have been made to identify factors that may be associated with an increased risk of this complication. In addition, both procedure- and pharmacological-related interventions have been proposed that may prevent this complication. This paper outlines these interventions and presents the evidence to support their use in the prevention of post-ERCP pancreatitis.
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Romagnuolo J, Cotton PB, Eisen G, Vargo J, Petersen BT. Identifying and reporting risk factors for adverse events in endoscopy. Part II: noncardiopulmonary events. Gastrointest Endosc 2011; 73:586-97. [PMID: 21353858 DOI: 10.1016/j.gie.2010.11.023] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2010] [Accepted: 11/16/2010] [Indexed: 02/08/2023]
Affiliation(s)
- Joseph Romagnuolo
- Medical University of South Carolina, Charleston, South Carolina 29425, USA
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Woods KE, Willingham FF. Endoscopic retrograde cholangiopancreatography associated pancreatitis: A 15-year review. World J Gastrointest Endosc 2010; 2:165-78. [PMID: 21160744 PMCID: PMC2998911 DOI: 10.4253/wjge.v2.i5.165] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2010] [Revised: 04/29/2010] [Accepted: 05/06/2010] [Indexed: 02/06/2023] Open
Abstract
The aim of this article is to review the literature regarding post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. We searched for and evaluated all articles describing the diagnosis, epidemiology, pathophysiology, morbidity, mortality and prevention of post-ERCP pancreatitis (PEP) in adult patients using the PubMed database. Search terms included endoscopic retrograde cholangiopancreatography, pancreatitis, ampulla of vater, endoscopic sphincterotomy, balloon dilatation, cholangiography, adverse events, standards and utilization. We limited our review of articles to those published between January 1, 1994 and August 15, 2009 regarding human adults and written in the English language. Publications from the reference sections were reviewed and included if they were salient and fell into the time period of interest. Between the dates queried, seventeen large (> 500 patients) prospective and four large retrospective trials were conducted. PEP occurred in 1%-15% in the prospective trials and in 1%-4% in the retrospective trials. PEP was also reduced with pancreatic duct stent placement and outcomes were improved with endoscopic sphincterotomy compared to balloon sphincter dilation in the setting of choledocholithiasis. Approximately 34 pharmacologic agents have been evaluated for the prevention of PEP over the last fifteen years in 63 trials. Although 22 of 63 trials published during our period of review suggested a reduction in PEP, no pharmacologic therapy has been widely accepted in clinical use in decreasing the development of PEP. In conclusion, PEP is a well-recognized complication of ERCP. Medical treatment for prevention has been disappointing. Proper patient selection and pancreatic duct stenting have been shown to reduce the complication rate in randomized clinical trials.
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Affiliation(s)
- Kevin E Woods
- Kevin E Woods, Department of Medicine, Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
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Monfared SSMS, Vahidi H, Abdolghaffari AH, Nikfar S, Abdollahi M. Antioxidant therapy in the management of acute, chronic and post-ERCP pancreatitis: a systematic review. World J Gastroenterol 2009; 15:4481-4490. [PMID: 19777606 PMCID: PMC2751992 DOI: 10.3748/wjg.15.4481] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2009] [Revised: 08/03/2009] [Accepted: 08/10/2009] [Indexed: 02/06/2023] Open
Abstract
We systematically reviewed the clinical trials which recruited antioxidants in the therapy of pancreatitis and evaluated whether antioxidants improve the outcome of patients with pancreatitis. Electronic bibliographic databases were searched for any studies which investigated the use of antioxidants in the management of acute pancreatitis (AP) or chronic pancreatitis (CP) and in the prevention of post-endoscopic retrograde cholangio-pancreatography (post-ERCP) pancreatitis (PEP) up to February 2009. Twenty-two randomized, placebo-controlled, clinical trials met our criteria and were included in the review. Except for a cocktail of antioxidants which showed improvement in outcomes in three different clinical trials, the results of the administration of other antioxidants in both AP and CP clinical trials were incongruent and heterogeneous. Furthermore, antioxidant therapy including allopurinol and N-acetylcysteine failed to prevent the onset of PEP in almost all trials. In conclusion, the present data do not support a benefit of antioxidant therapy alone or in combination with conventional therapy in the management of AP, CP or PEP. Further double blind, randomized, placebo-controlled clinical trials with large sample size need to be conducted.
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DiMagno MJ, Wamsteker EJ, DeBenedet AT. Advances in managing acute pancreatitis. F1000 MEDICINE REPORTS 2009; 1:59. [PMID: 20539749 PMCID: PMC2881482 DOI: 10.3410/m1-59] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
This review highlights advances in acute pancreatitis (AP) made in the past year. We focus on clinical aspects of AP - severe disease especially - and risk stratification tools to guide the clinical care of patients. Most patients with AP have mild disease that requires a diagnostic evaluation, self-limited supportive care, and a short hospital stay. In patients with potentially severe AP, it is important for clinicians to use available risk-stratifying tools to identify high-risk patients and initiate timely interventions such as aggressive fluid resuscitation, close monitoring, early initiation of enteral nutrition, and appropriate use of endoscopic retrograde cholangio-pancreatography. This approach decreases morbidity and possibly mortality and is supported by evidence drawn from recent clinical guidelines, historical literature, and the highest quality studies published in the last year.
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Affiliation(s)
- Matthew J DiMagno
- Department of Internal Medicine, University of Michigan School of Medicine1500 East Medical Center Drive, Ann Arbor, MI 48109USA
- Division of Gastroenterology and Hepatology, University of Michigan School of Medicine1500 East Medical Center Drive, Ann Arbor, MI 48109USA
| | - Erik-Jan Wamsteker
- Department of Internal Medicine, University of Michigan School of Medicine1500 East Medical Center Drive, Ann Arbor, MI 48109USA
- Division of Gastroenterology and Hepatology, University of Michigan School of Medicine1500 East Medical Center Drive, Ann Arbor, MI 48109USA
| | - Anthony T DeBenedet
- Department of Internal Medicine, University of Michigan School of Medicine1500 East Medical Center Drive, Ann Arbor, MI 48109USA
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Martinez-Torres H, Rodriguez-Lomeli X, Davalos-Cobian C, Garcia-Correa J, Maldonado-Martinez JM, Medrano-Muñoz F, Fuentes-Orozco C, Gonzalez-Ojeda A. Oral allopurinol to prevent hyperamylasemia and acute pancreatitis after endoscopic retrograde cholangiopancreatography. World J Gastroenterol 2009; 15:1600-6. [PMID: 19340902 PMCID: PMC2669944 DOI: 10.3748/wjg.15.1600] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the efficacy of allopurinol to prevent hyperamylasemia and pancreatitis after endoscopic retrograde cholangiopancreatography (PEP).
METHODS: One hundred and seventy patients were enrolled and randomized to two groups: a study group (n = 85) who received 300 mg of oral allopurinol at 15 h and 3 h before endoscopic retrograde cholangiopancreatography (ERCP) and a control group (n = 85) receiving an oral placebo at the same times. Main Outcome Measurements included serum amylase levels and the number severity of the episodes of pancreatitis. Serum amylase levels were classified as normal (< 150 IU/L) or hyperamylasemia (> 151 IU/L). Episodes of PEP were classified following Ranson’s criteria and CT severity index.
RESULTS: Gender distribution was similar between groups. Mean age was 53.5 ± 18.9 years for study group and 52.8 ± 19.8 years for controls. Also, the distribution of benign pathology was similar between groups. Hyperamylasemia was more common in the control group (P = 0.003). Mild PEP developed in two patients from the study group (2.3%) and eight (9.4%) from control group (P = 0.04), seven episodes were observed in high-risk patients of the control group (25%) and one in the allopurinol group (3.3%, P = 0.02). Risk factors for PEP were precut sphincterotomy (P = 0.02), pancreatic duct manipulation (P = 0.002) and multiple procedures (P = 0.000). There were no deaths or side effects.
CONCLUSION: Oral allopurinol before ERCP decreased the incidences of hyperamylasemia and pancreatitis in patients submitted to high-risk procedures.
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Choi CW, Kang DH, Kim GH, Eum JS, Lee SM, Song GA, Kim DU, Kim ID, Cho M. Nafamostat mesylate in the prevention of post-ERCP pancreatitis and risk factors for post-ERCP pancreatitis. Gastrointest Endosc 2009; 69:e11-e18. [PMID: 19327467 DOI: 10.1016/j.gie.2008.10.046] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2008] [Accepted: 10/22/2008] [Indexed: 02/08/2023]
Abstract
BACKGROUND Pancreatitis is a major complication of ERCP. OBJECTIVE To determine whether nafamostat mesylate prophylaxis decreases the incidence of post-ERCP pancreatitis (PEP). DESIGN A single-center, randomized, double-blinded, controlled trial. SETTING A large tertiary-referral center. PATIENTS From January 2005 to December 2007, a total of 704 patients who underwent ERCP were analyzed. INTERVENTION Patients received continuous infusion of 500 mL of 5% dextrose solution with 20 mg of nafamostat mesylate (354 patients) or without 20 mg of nafamostat mesylate (350 patients). Serum amylase and lipase levels were checked before ERCP, 4 and 24 hours after ERCP, and when clinically indicated. MAIN OUTCOME MEASUREMENTS The incidence of PEP and risk factors associated with the development of PEP. RESULTS The incidence of acute pancreatitis was 5.4%. There was a significant difference in the incidence of PEP between the nafamostat mesylate and control groups (3.3% vs 7.4%, respectively; P = .018). Univariate analysis identified history of acute pancreatitis (P < .001), difficult cannulation (P = .023), periampullary diverticulum (P = .004), age younger than 40 years (P = .009), and >/=5 pancreatic-duct contrast injections (odds ratio [OR] 2.736, P = .012) as statistically significant risk factors. LIMITATIONS A single-center study. CONCLUSIONS Nafamostat mesylate prophylaxis is partially effective in preventing post-ERCP pancreatitis. Independent risk factors for PEP are a history of acute pancreatitis and multiple pancreatic-duct contrast injections.
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Affiliation(s)
- Cheol Woong Choi
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea
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Abstract
Reactive oxygen and reactive nitrogen species (ROS/RNS) have been implicated in the pathogenesis of acute and chronic pancreatitis. Clinical and basic science studies have indicated that ROS/RNS formation processes are intimately linked to the development of the inflammatory disorders. The detrimental effects of highly reactive ROS/RNS are mediated by their direct actions on biomolecules (lipids, proteins, and nucleic acids) and activation of proinflammatory signal cascades, which subsequently lead to activation of immune responses. The present article summarizes the possible sources of ROS/RNS formation and the detailed signaling cascades implicated in the pathogenesis of pancreatic inflammation, as observed in acute and chronic pancreatitis. A therapeutic ROS/RNS-scavenging strategy has been advocated for decades; however, clinical studies examining such approaches have been inconsistent in their results. Emerging evidence indicates that pancreatitis-inducing ROS/RNS generation may be attenuated by targeting ROS/RNS-generating enzymes and upstream mediators.
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Affiliation(s)
- Po Sing Leung
- Department of Physiology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
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Bai Y, Gao J, Zhang W, Zou D, Li Z. Meta-analysis: allopurinol in the prevention of postendoscopic retrograde cholangiopancreatography pancreatitis. Aliment Pharmacol Ther 2008; 28:557-64. [PMID: 18714440 DOI: 10.1111/j.1365-2036.2008.03756.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Several clinical trials evaluating the prophylactic effect of allopurinol on postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis have been published; however, there is no consensus on whether prophylactic allopurinol can reduce the incidence of post-ERCP pancreatitis. AIM To compare prophylactic allopurinol with placebo on post-ERCP pancreatitis reduction by performing a meta-analysis in randomized controlled trials. METHODS Databases including MEDLINE, EMBASE and the Cochrane Library, Science Citation Index were searched to find relevant trials. Two reviewers independently identified relevant randomized controlled trials assessing the effect of prophylactic allopurinol on the incidence of post-ERCP pancreatitis. Outcome measures were the incidence of post-ERCP pancreatitis. RESULTS Four trials involving 1730 patients were included. Analysis suggested that post-ERCP pancreatitis rates were not significantly different (allopurinol 8.9%, placebo 9.7%, P = 0.68), RR 0.86 (95% CI: 0.42, 1.77). Subsequent subgroup analysis confirmed that allopurinol was not statistically superior to placebo in reducing post-ERCP pancreatitis. CONCLUSION Based on current best evidence, prophylactic allopurinol may not be useful for post-ERCP pancreatitis reduction.
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Affiliation(s)
- Y Bai
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
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Andriulli A, Annese V. Risk of post-endoscopic retrograde cholangiopancreatography pancreatitis and ways to prevent it: old myths, a current need? The case of allopurinol. Clin Gastroenterol Hepatol 2008; 6:374-376. [PMID: 18387495 DOI: 10.1016/j.cgh.2008.01.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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