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Kanika, Ahmad A, Kumar A, Rahul, Mishra RK, Ali N, Navik U, Parvez S, Khan R. Leveraging thiol-functionalized biomucoadhesive hybrid nanoliposome for local therapy of ulcerative colitis. Biomaterials 2025; 312:122747. [PMID: 39142219 DOI: 10.1016/j.biomaterials.2024.122747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 07/06/2024] [Accepted: 08/04/2024] [Indexed: 08/16/2024]
Abstract
Directly administering medication to inflamed intestinal sites for treating ulcerative colitis (UC), poses significant challenges like retention time, absorption variability, side effects, drug stability, and non-specific delivery. Recent advancements in therapy to treat colitis aim to improve local drug availability that is enema therapy at the site of inflammation, thereby reducing systemic adverse effects. Nevertheless, a key limitation lies in enemas' inability to sustain medication in the colon due to rapid peristaltic movement, diarrhea, and poor local adherence. Therefore, in this work, we have developed site-specific thiolated mucoadhesive anionic nanoliposomes to overcome the limitations of conventional enema therapy. The thiolated delivery system allows prolonged residence of the delivery system at the inflamed site in the colon, confirmed by the adhesion potential of thiolated nanoliposomes using in-vitro and in-vivo models. To further provide therapeutic efficacy thiolated nanoliposomes were loaded with gallic acid (GA), a natural compound known for its antibacterial, antioxidant, and potent anti-inflammatory properties. Consequently, Gallic Acid-loaded Thiolated 2,6 DALP DMPG (GATh@APDL) demonstrates the potential for targeted adhesion to the inflamed colon, facilitated by their small size 100 nm and anionic nature. Therapeutic studies indicate that this formulation offers protective effects by mitigating colonic inflammation, downregulating the expression of NF-κB, HIF-1α, and MMP-9, and demonstrating superior efficacy compared to the free GA enema. The encapsulated GA inhibits the NF-κB expression, leading to enhanced expression of MUC2 protein, thereby promoting mucosal healing in the colon. Furthermore, GATh@APDL effectively reduces neutrophil infiltration and regulates immune cell quantification in colonic lamina propria. Our findings suggest that GATh@APDL holds promise for alleviating UC and addressing the limitations of conventional enema therapy.
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Affiliation(s)
- Kanika
- Chemical Biology Unit, Institute of Nano Science and Technology, Sector 81, Knowledge City, Sahibzada Ajit Singh Nagar, Mohali, Punjab, 140306, India
| | - Anas Ahmad
- Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, T2N4N1, Canada
| | - Ajay Kumar
- Chemical Biology Unit, Institute of Nano Science and Technology, Sector 81, Knowledge City, Sahibzada Ajit Singh Nagar, Mohali, Punjab, 140306, India
| | - Rahul
- Department of Chemistry, Malaviya National Institute of Technology, Jaipur, Rajasthan, 302017, India
| | - Rakesh Kumar Mishra
- Department of Pharmaceutical Sciences, School of Health Sciences and Technology, UPES, Dehradun, India
| | - Nemat Ali
- Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia
| | - Umashanker Navik
- Department of Pharmacology, Central University of Punjab, Bathinda, Ghudda, Punjab, 151401, India
| | - Suhel Parvez
- Department of Toxicology, School of Chemical & Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Rehan Khan
- Chemical Biology Unit, Institute of Nano Science and Technology, Sector 81, Knowledge City, Sahibzada Ajit Singh Nagar, Mohali, Punjab, 140306, India.
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Kumar A, Kanika, Kumar V, Ahmad A, Mishra RK, Nadeem A, Siddiqui N, Ansari MM, Raza SS, Kondepudi KK, Khan R. Colon-Adhering Delivery System with Inflammation Responsiveness for Localized Therapy of Experimental Colitis. ACS Biomater Sci Eng 2023; 9:4781-4793. [PMID: 37497615 DOI: 10.1021/acsbiomaterials.3c00480] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/28/2023]
Abstract
Ulcerative colitis (UC) is a chronic inflammation-related disease that severely affects the colon and rectum regions. A variety of therapy regimens are used for the treatment of UC. Clinically, therapeutic enema is the choice of therapy for UC patients. Irrespective of on-site administration, the major limitation of therapeutic enemas is the dispossession of the medicine followed by low drug availability for the therapeutic action. In our present work, we have developed an enzyme-responsive injectable hydrogel (ER-hydrogel) to overcome the limitations of therapeutic enema. The hydrogels possess two major advantages, which are being exploited for therapeutic drug delivery in UC: prolonged retention and enzyme responsiveness. The former is one of the prominent advantages of hydrogel compared to free drug enema and the latter controls the release of the drug or provides drug release on-demand. The ER-hydrogel was formulated by the heat-cool method and for therapeutic purposes, a corticosteroid drug, budesonide (Bud), was encapsulated into the ER-hydrogel and evaluated for its various physicochemical and therapeutic potentials in dextran sodium sulfate (DSS)-induced UC. In vitro and ex vivo adhesion studies confirm the retention or mucoadhesive nature of the ER-hydrogel, and the upsurge in Bud release from the Bud-loaded ER-hydrogel upon the addition of esterase enzyme confirms the enzyme-mediated drug release from the ER-hydrogel. Moreover, Bud-loaded ER-hydrogel exhibited promising results in alleviating the disease activity index of UC, and restored the length of the colon, which is the main hallmark of UC. In terms of the health of the colon tissue, the Bud-loaded ER-hydrogel restored the colonic tissue damage, as seen in the H&E-stained, AB-NR-stained, and HID-AB-stained colon sections. Finally, the Bud-loaded ER-hydrogel also markedly subsided the IL-1β, TNF-α, MPO, and nitrite levels in serum and colon tissues. Thus, the fabricated Bud-loaded ER-hydrogel possesses appreciable translational potential due to its ability to significantly ameliorate inflammatory changes compared to naive or water-based therapeutic enema in acute experimental colitis in mice.
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Affiliation(s)
- Ajay Kumar
- Chemical Biology Unit, Institute of Nano Science and Technology, Sector-81, Knowledge City, Sahibzada Ajit Singh Nagar, Mohali, Punjab 140306, India
| | - Kanika
- Chemical Biology Unit, Institute of Nano Science and Technology, Sector-81, Knowledge City, Sahibzada Ajit Singh Nagar, Mohali, Punjab 140306, India
| | - Vibhu Kumar
- National Agri-Food Biotechnology Institute, Mohali, Punjab 140306, India
| | - Anas Ahmad
- Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada
| | - Rakesh Kumar Mishra
- Chemical Biology Unit, Institute of Nano Science and Technology, Sector-81, Knowledge City, Sahibzada Ajit Singh Nagar, Mohali, Punjab 140306, India
| | - Ahmed Nadeem
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Nahid Siddiqui
- Amity Institute of Biotechnology, Amity University, Noida 201303, India
| | - Md Meraj Ansari
- Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, S.A.S Nagar, Sector 67, Mohali, Punjab 160062, India
| | - Syed Shadab Raza
- Department of Stem Cell Biology and Regenerative Medicine, Era University, Sarfarazganj, Lucknow 226003, India
| | | | - Rehan Khan
- Chemical Biology Unit, Institute of Nano Science and Technology, Sector-81, Knowledge City, Sahibzada Ajit Singh Nagar, Mohali, Punjab 140306, India
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Raine T, Bonovas S, Burisch J, Kucharzik T, Adamina M, Annese V, Bachmann O, Bettenworth D, Chaparro M, Czuber-Dochan W, Eder P, Ellul P, Fidalgo C, Fiorino G, Gionchetti P, Gisbert JP, Gordon H, Hedin C, Holubar S, Iacucci M, Karmiris K, Katsanos K, Kopylov U, Lakatos PL, Lytras T, Lyutakov I, Noor N, Pellino G, Piovani D, Savarino E, Selvaggi F, Verstockt B, Spinelli A, Panis Y, Doherty G. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical Treatment. J Crohns Colitis 2022; 16:2-17. [PMID: 34635919 DOI: 10.1093/ecco-jcc/jjab178] [Citation(s) in RCA: 502] [Impact Index Per Article: 167.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Tim Raine
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Stefanos Bonovas
- Department of Biomedical Sciences, Humanitas University; IRCCS Humanitas Research Hospital, Milan, Italy
| | - Johan Burisch
- Gastrounit, Medical Division, Hvidovre Hospital; Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Hvidovre Hospital, University of Copenhagen, Denmark
| | - Torsten Kucharzik
- Department of Gastroenterology, Lüneburg Hospital, University of Hamburg, Lüneburg, Germany
| | - Michel Adamina
- Department of Surgery, Clinic of Visceral and Thoracic Surgery, Cantonal Hospital Winterthur, Zurich, Switzerland
- Department of Biomedical Engineering, Clinical Research and Artificial Intelligence in Surgery, Faculty of Medicine, University of Basel, Allschwil, Switzerland
| | - Vito Annese
- Department of Gastroenterology, Fakeeh University Hospital, Dubai, UAE
| | - Oliver Bachmann
- Department of Internal Medicine I, Siloah St. Trudpert Hospital, Pforzheim; Hannover Medical School, Hannover, Germany
| | - Dominik Bettenworth
- University Hospital Munster, Department of Medicine B - Gastroenterology and Hepatology, Munster, Germany
| | - Maria Chaparro
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Wladyslawa Czuber-Dochan
- King's College London, Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, London, UK
| | - Piotr Eder
- Department of Gastroenterology, Dietetics and Internal Medicine - Poznań University of Medical Sciences; Heliodor Święcicki University Hospital, Poznań, Poland
| | - Pierre Ellul
- Department of Medicine, Division of Gastroenterology, Mater Dei Hospital, Msida, Malta
| | - Catarina Fidalgo
- Gastroenterology Division, Hospital Beatriz Ângelo, Loures, Portugal
| | - Gionata Fiorino
- Department of Biomedical Sciences, Humanitas University; IBD Center, Humanitas Clinical and Research Center, Milan, Italy
| | - Paolo Gionchetti
- IBD Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna DIMEC, University of Bologna, Bologna, Italy
| | - Javier P Gisbert
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Hannah Gordon
- Department of Gastroenterology, Barts Health NHS Trust, Royal London Hospital, London, UK
| | - Charlotte Hedin
- Karolinska Institutet, Department of Medicine Solna; Karolinska University Hospital, Department of Gastroenterology, Dermatovenereology and Rheumatology, Stockholm, Sweden
| | - Stefan Holubar
- Department of Colon & Rectal Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Marietta Iacucci
- Institute of Immunology and Immunotherapy, NIHR Biomedical Research Centre, University of Birmingham; Division of Gastroenterology, University Hospitals Birmingham NHS Trust, Birmingham, UK
| | | | - Konstantinos Katsanos
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, University and Medical School of Ioannina, Ioannina, Greece
| | - Uri Kopylov
- Department of Gastroenterology, Tel-HaShomer Sheba Medical Center, Ramat Gan, and Sackler Medical School, Tel Aviv, Israel
| | - Peter L Lakatos
- Division of Gastroenterology, McGill University Health Centre, Montreal, QC, Canada
- 1st Department of Medicine, Semmelweis University, Budapest, Hungary
| | - Theodore Lytras
- School of Medicine, European University Cyprus, Nicosia, Cyprus
| | - Ivan Lyutakov
- Department of Gastroenterology, University Hospital 'Tsaritsa Yoanna - ISUL', Medical University Sofia, Sofia, Bulgaria
| | - Nurulamin Noor
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Gianluca Pellino
- Department of Advanced Medical and Surgical Sciences, Universitá degli Studi della Campania 'Luigi Vanvitelli', Naples, Italy
- Colorectal Surgery, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Daniele Piovani
- Department of Biomedical Sciences, Humanitas University; IRCCS Humanitas Research Hospital, Milan, Italy
| | - Edoardo Savarino
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Francesco Selvaggi
- Department of Advanced Medical and Surgical Sciences, Universitá degli Studi della Campania 'Luigi Vanvitelli', Naples, Italy
| | - Bram Verstockt
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven; Department of Chronic Diseases, Metabolism and Ageing, TARGID - IBD, Leuven, Belgium
| | - Antonino Spinelli
- Department of Biomedical Sciences, Humanitas University; IRCCS Humanitas Research Hospital, Milan, Italy
| | - Yves Panis
- Department of Colorectal Surgery, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, Clichy and Université of Paris, France
| | - Glen Doherty
- Department of Gastroenterology and Centre for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland
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Caprifico AE, Polycarpou E, Foot PJS, Calabrese G. Biomedical and Pharmacological Uses of Fluorescein Isothiocyanate Chitosan-Based Nanocarriers. Macromol Biosci 2020; 21:e2000312. [PMID: 33016007 DOI: 10.1002/mabi.202000312] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Indexed: 12/26/2022]
Abstract
Chitosan-based nanocarriers (ChNCs) are considered suitable drug carriers due to their ability to encapsulate a variety of drugs and cross biological barriers to deliver the cargo to their target site. Fluorescein isothiocyanate-labeled chitosan-based NCs (FITC@ChNCs) are used extensively in biomedical and pharmacological applications. The main advantage of using FITC@ChNCs consists of the ability to track their fate both intra and extracellularly. This journey is strictly dependent on the physico-chemical properties of the carrier and the cell types under investigation. Other applications make use of fluorescent ChNCs in cell labeling for the detection of disorders in vivo and controlling of living cells in situ. This review describes the use of FITC@ChNCs in the various applications with a focus on understanding their usefulness in labeled drug-delivery systems.
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Affiliation(s)
- Anna E Caprifico
- A. E. Caprifico, Dr. E. Polycarpou, Prof. P. J. S. Foot, Dr. G. Calabrese, Pharmacy and Chemistry, Kingston University London, Penrhyn Road, Kingston upon Thames, KT1 2EE, UK
| | - Elena Polycarpou
- A. E. Caprifico, Dr. E. Polycarpou, Prof. P. J. S. Foot, Dr. G. Calabrese, Pharmacy and Chemistry, Kingston University London, Penrhyn Road, Kingston upon Thames, KT1 2EE, UK
| | - Peter J S Foot
- A. E. Caprifico, Dr. E. Polycarpou, Prof. P. J. S. Foot, Dr. G. Calabrese, Pharmacy and Chemistry, Kingston University London, Penrhyn Road, Kingston upon Thames, KT1 2EE, UK
| | - Gianpiero Calabrese
- A. E. Caprifico, Dr. E. Polycarpou, Prof. P. J. S. Foot, Dr. G. Calabrese, Pharmacy and Chemistry, Kingston University London, Penrhyn Road, Kingston upon Thames, KT1 2EE, UK
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Cha JM, Park SH, Rhee KH, Hong SN, Kim YH, Seo SI, Kim KH, Jeong SK, Lee JH, Park SY, Park H, Kim JS, Im JP, Yoon H, Kim SH, Jang J, Kim JH, Suh SO, Kim YK, Ye BD, Yang SK. Long-term prognosis of ulcerative colitis and its temporal changes between 1986 and 2015 in a population-based cohort in the Songpa-Kangdong district of Seoul, Korea. Gut 2020; 69:1432-1440. [PMID: 31822581 DOI: 10.1136/gutjnl-2019-319699] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 11/07/2019] [Accepted: 11/26/2019] [Indexed: 12/15/2022]
Abstract
OBJECTIVE No population-based study has evaluated the natural course of UC over three decades in non-Caucasians. We aimed to assess the long-term natural course of Korean patients with UC in a population-based cohort. DESIGN This Korean population-based, Songpa-Kangdong IBD cohort included all patients (n=1013) newly diagnosed with UC during 1986-2015. Disease outcomes and their predictors were evaluated. RESULTS During the median follow-up of 105 months, the overall use of systemic corticosteroids, thiopurines and antitumour necrosis factor (anti-TNF) agents was 40.8%, 13.9% and 6.5%, respectively. Over time, the cumulative risk of commencing corticosteroids decreased, whereas that of commencing thiopurines and anti-TNF agents increased. During follow-up, 28.7% of 778 patients with proctitis or left-sided colitis at diagnosis experienced proximal disease extension. A total of 28 patients (2.8%) underwent colectomy, demonstrating cumulative risks of colectomy at 1, 5, 10, 20 and 30 years after diagnosis of 1.0%, 1.9%, 2.2%, 5.1% and 6.4%, respectively. Multivariate Cox regression analysis revealed that extensive colitis at diagnosis (HR 8.249, 95% CI 2.394 to 28.430), ever use of corticosteroids (HR 6.437, 95% CI 1.440 to 28.773) and diagnosis in the anti-TNF era (HR 0.224, 95% CI 0.057 to 0.886) were independent predictors of colectomy. The standardised mortality ratio in patients with UC was 0.725 (95% CI 0.508 to 1.004). CONCLUSION Korean patients with UC may have a better clinical course than Western patients, as indicated by a lower colectomy rate. The overall colectomy rate has continued to decrease over the past three decades.
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Affiliation(s)
- Jae Myung Cha
- Department of Internal Medicine, Kyung Hee University Hospital at Gang Dong, Kyung Hee University College of Medicine, Seoul, Korea (the Republic of)
| | - Sang Hyoung Park
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (the Republic of)
| | - Kyoung Hoon Rhee
- Department of Internal Medicine, Hansol Hospital, Seoul, Korea (the Republic of)
| | - Sung Noh Hong
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of)
| | - Young-Ho Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of)
| | - Seung In Seo
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea (the Republic of)
| | - Kyung Ho Kim
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea (the Republic of)
| | - Seung Kyu Jeong
- Department of Surgery, Yang Hospital, Seoul, Korea (the Republic of)
| | - Ji Hyun Lee
- Digestive Endoscopic Center, Seoul Song Do Colorectal Hospital, Seoul, Korea (the Republic of)
| | - Sun Yong Park
- Kangdong Seoul Colon and Rectal Surgery, Seoul, Korea (the Republic of)
| | - Hyunju Park
- Department of Gastroenterology, Daehang Hospital, Seoul, Korea (the Republic of)
| | - Joo Sung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea (the Republic of)
| | - Jong Pil Im
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea (the Republic of)
| | - Hyuk Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea (the Republic of)
| | - Sung Hoon Kim
- Department of Internal Medicine, VHS Medical Center, Seoul, Korea (the Republic of)
| | - Jisun Jang
- Department of Internal Medicine, VHS Medical Center, Seoul, Korea (the Republic of)
| | - Jeong Hwan Kim
- Department of Internal Medicine, Konkuk University School of Medicine, Konkuk University Medical Center, Seoul, Korea (the Republic of)
| | - Seong O Suh
- Department of Internal Medicine, National Police Hospital, Seoul, Korea (the Republic of)
| | - Young Kyun Kim
- Jamsil Seoul Surgical Clinic, Seoul, Korea (the Republic of)
| | - Byong Duk Ye
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (the Republic of)
| | - Suk-Kyun Yang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (the Republic of)
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Nanogels of a Succinylated Glycol Chitosan-Succinyl Prednisolone Conjugate: Release Behavior, Gastrointestinal Distribution, and Systemic Absorption. Int J Mol Sci 2020; 21:ijms21072376. [PMID: 32235554 PMCID: PMC7178247 DOI: 10.3390/ijms21072376] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 03/24/2020] [Accepted: 03/26/2020] [Indexed: 12/22/2022] Open
Abstract
Recently, the potential of nanoparticles (NPs) in ulcerative colitis (UC) therapy has been increasingly demonstrated. Namely, anionic NPs have been found to be accumulated efficiently to the UC damaged area due to epithelial enhanced permeability and retention (eEPR) effect. Previously, a novel anionic nanogel system (NG(S)) was prepared, and evaluated for the efficacy and toxicity. In the present study, release behaviors and biodistribution were investigated in detail to elucidate the functional mechanisms. Rats with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced ulcerative colitis (UC) were used as biomodels. In vitro release was examined with or without the contents of the cecum or distal colon. Gastrointestinal distribution and plasma concentrations were investigated after the intragastric administration of 10 mg prednisolone (PD) eq./kg. At pH 1.2 and 6.8, release behaviors were slow, but controlled. Overall release was not markedly different irrespective of coexistence of intestinal contents. In in vivo studies, a large amount of PD was distributed in the lower parts of the gastrointestinal tract 6 and 12 h after administration with NG(S). PD accumulated well in the colonic parts, and prolonged release was noted. The systemic absorption of PD with NG(S) was hardly found. NG(S) concentrated the drug in the colon and showed controlled release. These behaviors were considered to lead to the previously reported good results, promotion of effectiveness and suppression of toxic side effects.
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Hua S. Physiological and Pharmaceutical Considerations for Rectal Drug Formulations. Front Pharmacol 2019; 10:1196. [PMID: 31680970 PMCID: PMC6805701 DOI: 10.3389/fphar.2019.01196] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 09/17/2019] [Indexed: 12/14/2022] Open
Abstract
Although the oral route is the most convenient route for drug administration, there are a number of circumstances where this is not possible from either a clinical or pharmaceutical perspective. In these cases, the rectal route may represent a practical alternative and can be used to administer drugs for both local and systemic actions. The environment in the rectum is considered relatively constant and stable and has low enzymatic activity in comparison to other sections of the gastrointestinal tract. In addition, drugs can partially bypass the liver following systemic absorption, which reduces the hepatic first-pass effect. Therefore, rectal drug delivery can provide significant local and systemic levels for various drugs, despite the relatively small surface area of the rectal mucosa. Further development and optimization of rectal drug formulations have led to improvements in drug bioavailability, formulation retention, and drug release kinetics. However, despite the pharmaceutical advances in rectal drug delivery, very few of them have translated to the clinical phase. This review will address the physiological and pharmaceutical considerations influencing rectal drug delivery as well as the conventional and novel drug delivery approaches. The translational challenges and development aspects of novel formulations will also be discussed.
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Affiliation(s)
- Susan Hua
- Therapeutic Targeting Research Group, School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia
- Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
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Zhou H, Ichikawa A, Ikeuchi-Takahashi Y, Hattori Y, Onishi H. Nanogels of Succinylated Glycol Chitosan-Succinyl Prednisolone Conjugate: Preparation, In Vitro Characteristics and Therapeutic Potential. Pharmaceutics 2019; 11:pharmaceutics11070333. [PMID: 31337090 PMCID: PMC6680395 DOI: 10.3390/pharmaceutics11070333] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 07/10/2019] [Accepted: 07/11/2019] [Indexed: 11/17/2022] Open
Abstract
A novel anionic nanogel system was prepared using succinylated glycol chitosan-succinyl prednisolone conjugate (S-GCh-SP). The nanogel, named NG(S), was evaluated in vitro and in vivo. S-GCh-SP formed a nanogel via the aggregation of hydrophobic prednisolone (PD) moieties and the introduced succinyl groups contributed to the negative surface charge of the nanogel. The resultant NG(S) had a PD content of 13.7% (w/w), was ca. 400 nm in size and had a ζ-potential of −28 mV. NG(S) released PD very slowly at gastric pH and faster but gradually at small intestinal pH. Although NG(S) was easily taken up by the macrophage-like cell line Raw 264.7, it did not decrease cell viability, suggesting that the toxicity of the nanogel was very low. The in vivo evaluation was performed using rats with trinitrobenzene sulfonic acid (TNBS)-induced colitis. NG(S) and PD alone were not very effective at 5 mg PD eq./kg. However, NG(S) at 10 mg PD eq./kg markedly suppressed colonic damage, whereas PD alone did not. Furthermore, thymus atrophy was less with NG(S) than with PD alone. These results demonstrated that NG(S) is very safe, promotes drug effectiveness and has low toxicity. NG(S) has potential as a drug delivery system for the treatment of ulcerative colitis.
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Affiliation(s)
- Haiyan Zhou
- Department of Drug Delivery Research, Hoshi University, 2-4-41, Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
| | - Atsuko Ichikawa
- CMIC Pharma Science Co., Ltd., 10221, Kobuchisawacho, Hokuto 408-0044, Yamanashi, Japan
| | - Yuri Ikeuchi-Takahashi
- Department of Drug Delivery Research, Hoshi University, 2-4-41, Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
| | - Yoshiyuki Hattori
- Department of Drug Delivery Research, Hoshi University, 2-4-41, Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
| | - Hiraku Onishi
- Department of Drug Delivery Research, Hoshi University, 2-4-41, Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
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Battat R, Duijvestein M, Guizzetti L, Choudhary D, Boland BS, Dulai PS, Parker CE, Nguyen TM, Singh S, Vande Casteele N, Pai RK, Feagan BG, Sandborn WJ, Jairath V. Histologic Healing Rates of Medical Therapies for Ulcerative Colitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Am J Gastroenterol 2019; 114:733-745. [PMID: 30694863 DOI: 10.14309/ajg.0000000000000111] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Histologic remission is a potentially valuable means of assessing disease activity and treatment response in ulcerative colitis (UC). However, the efficacy of existing therapies to achieve this outcome is unclear. We performed a systematic review and meta-analysis of histologic outcomes in UC randomized controlled trials and examined the relationship between histologic and endoscopic outcomes. METHODS MEDLINE, EMBASE, CENTRAL, and the Cochrane IBD Register were searched for randomized controlled trials of aminosalicylates, corticosteroids, immunosuppressives, biologics, and small molecules. Histologic and endoscopic remission and response data were independently extracted and pooled using binomial-normal random-effect or fixed-effect models. Pooled efficacy estimates were calculated as risk ratios (RRs) using the Mantel-Haenszel method. Univariable and multivariable random-effect meta-regression models examined factors associated with histologic remission. RESULTS Seventy-four studies (68 induction and 7 maintenance) were identified. Topical aminosalicylate enemas [37.2%, 95% confidence interval (CI), 29.0-46.3] and suppositories (44.9%, 95% CI, 28.9-62.3) had the highest induction of histologic remission rates. Aminosalicylate enemas (RR = 4.14, 95% CI, 2.35-7.31), aminosalicylate suppositories (RR = 3.94, 95% CI, 1.26-12.32), and budesonide multimatrix (RR = 1.47, 95% CI 1.08-1.99) had higher histologic remission rates than placebo. Data were lacking for biologics and immunosuppressives. The pooled histologic remission rate for placebo in induction studies was 10.4% (95% CI, 7.1-15.2). Histologic and endoscopic remission correlated strongly (r = 0.66; 95% CI, 0.50-0.78). In multivariate analysis of placebo-arm data, less severe clinical disease activity and corticosteroid use were associated with higher histologic remission rates. Similarly, mild clinical disease activity was associated with higher histologic remission rates when active-arm data were analyzed. CONCLUSIONS Histologic remission rates for current UC treatments ranged from 15.0% to 44.9% according to drug class and patient population with the highest rates observed for topical aminosalicylates. Placebo remission rates were low with relatively narrow CIs. These data provide benchmarks to inform future trial design. Histologic remission is a potential treatment target in clinical practice.
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Affiliation(s)
- Robert Battat
- Division of Gastroenterology, University of California, San Diego, La Jolla, California, USA
- Robarts Clinical Trials Inc., London, Ontario, Canada
| | - Marjolijn Duijvestein
- Robarts Clinical Trials Inc., London, Ontario, Canada
- Academic Medical Center, Amsterdam, Netherlands
| | | | - Daksh Choudhary
- Department of Medicine, University of Western Ontario, London, Ontario, Canada
| | - Brigid S Boland
- Division of Gastroenterology, University of California, San Diego, La Jolla, California, USA
| | - Parambir S Dulai
- Division of Gastroenterology, University of California, San Diego, La Jolla, California, USA
| | | | - Tran M Nguyen
- Robarts Clinical Trials Inc., London, Ontario, Canada
| | - Siddharth Singh
- Division of Gastroenterology, University of California, San Diego, La Jolla, California, USA
| | - Niels Vande Casteele
- Division of Gastroenterology, University of California, San Diego, La Jolla, California, USA
- Robarts Clinical Trials Inc., London, Ontario, Canada
| | - Rish K Pai
- Department of Pathology, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - Brian G Feagan
- Robarts Clinical Trials Inc., London, Ontario, Canada
- Department of Medicine, University of Western Ontario, London, Ontario, Canada
- Department of Epidemiology and Biostatistics, University of Western Ontario, London Ontario, Canada
| | - William J Sandborn
- Division of Gastroenterology, University of California, San Diego, La Jolla, California, USA
| | - Vipul Jairath
- Robarts Clinical Trials Inc., London, Ontario, Canada
- Department of Medicine, University of Western Ontario, London, Ontario, Canada
- Department of Epidemiology and Biostatistics, University of Western Ontario, London Ontario, Canada
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10
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Ko CW, Singh S, Feuerstein JD, Falck-Ytter C, Falck-Ytter Y, Cross RK. AGA Clinical Practice Guidelines on the Management of Mild-to-Moderate Ulcerative Colitis. Gastroenterology 2019; 156:748-764. [PMID: 30576644 PMCID: PMC6858922 DOI: 10.1053/j.gastro.2018.12.009] [Citation(s) in RCA: 200] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Cynthia W Ko
- Division of Gastroenterology, University of Washington, Seattle, Washington
| | - Siddharth Singh
- Division of Gastroenterology, University of California, San Diego, La Jolla, California
| | - Joseph D Feuerstein
- Division of Gastroenterology and Center for Inflammatory Bowel Diseases, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Corinna Falck-Ytter
- Division of Internal Medicine, Louis Stokes Veterans Affairs Medical Center, Case Western Reserve University, Cleveland, Ohio
| | - Yngve Falck-Ytter
- Division of Gastroenterology, Case Western Reserve University, and Louis Stokes Veterans Affairs Medical Center, Cleveland, Ohio
| | - Raymond K Cross
- Division of Gastroenterology and Hepatology, University of Maryland, Baltimore, Maryland
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11
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Singh S, Feuerstein JD, Binion DG, Tremaine WJ. AGA Technical Review on the Management of Mild-to-Moderate Ulcerative Colitis. Gastroenterology 2019; 156:769-808.e29. [PMID: 30576642 PMCID: PMC6858923 DOI: 10.1053/j.gastro.2018.12.008] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Most patients with ulcerative colitis (UC) have mild-to-moderate disease activity, with low risk of colectomy, and are managed by primary care physicians or gastroenterologists. Optimal management of these patients decreases the risk of relapse and proximal disease extension, and may prevent disease progression, complications, and need for immunosuppressive therapy. With several medications (eg, sulfasalazine, diazo-bonded 5-aminosalicylates [ASA], mesalamines, and corticosteroids, including budesonide) and complex dosing formulations, regimens, and routes, to treat a disease with variable anatomic extent, there is considerable practice variability in the management of patients with mild-moderate UC. Hence, the American Gastroenterological Association prioritized clinical guidelines on this topic. To inform clinical guidelines, this technical review was developed in accordance with the Grading of Recommendations Assessment, Development and Evaluation framework for interventional studies. Focused questions included the following: (1) comparative effectiveness and tolerability of different oral 5-ASA therapies (sulfalsalazine vs diazo-bonded 5-ASAs vs mesalamine; low- (<2 g) vs standard (2-3 g/d) vs high-dose (>3 g/d) mesalamine); (2) comparison of different dosing regimens (once-daily vs multiple times per day dosing) and routes (oral vs rectal vs both oral and rectal); (3) role of oral budesonide in patients mild-moderate UC; (4) comparative effectiveness and tolerability of rectal 5-ASA and corticosteroid formulations in patients with distal colitis; and (5) role of alternative therapies like probiotics, curcumin, and fecal microbiota transplantation in the management of mild-moderate UC.
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Affiliation(s)
- Siddharth Singh
- Division of Gastroenterology, University of California, San Diego, La Jolla, California
| | - Joseph D Feuerstein
- Division of Gastroenterology and Center for Inflammatory Bowel Diseases, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - David G Binion
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - William J Tremaine
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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12
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Ayiku L, Levay P, Hudson T, Craven J, Barrett E, Finnegan A, Adams R. The medline UK filter: development and validation of a geographic search filter to retrieve research about the UK from OVID medline. Health Info Libr J 2017; 34:200-216. [PMID: 28703418 DOI: 10.1111/hir.12187] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Accepted: 05/28/2017] [Indexed: 11/27/2022]
Abstract
BACKGROUND A validated geographic search filter for the retrieval of research about the United Kingdom (UK) from bibliographic databases had not previously been published. OBJECTIVES To develop and validate a geographic search filter to retrieve research about the UK from OVID medline with high recall and precision. METHODS Three gold standard sets of references were generated using the relative recall method. The sets contained references to studies about the UK which had informed National Institute for Health and Care Excellence (NICE) guidance. The first and second sets were used to develop and refine the medline UK filter. The third set was used to validate the filter. Recall, precision and number-needed-to-read (NNR) were calculated using a case study. RESULTS The validated medline UK filter demonstrated 87.6% relative recall against the third gold standard set. In the case study, the medline UK filter demonstrated 100% recall, 11.4% precision and a NNR of nine. CONCLUSION A validated geographic search filter to retrieve research about the UK with high recall and precision has been developed. The medline UK filter can be applied to systematic literature searches in OVID medline for topics with a UK focus.
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Affiliation(s)
- Lynda Ayiku
- National Institute for Health and Care Excellence (NICE), Manchester, UK
| | - Paul Levay
- National Institute for Health and Care Excellence (NICE), Manchester, UK
| | - Tom Hudson
- National Institute for Health and Care Excellence (NICE), Manchester, UK
| | - Jenny Craven
- National Institute for Health and Care Excellence (NICE), Manchester, UK
| | - Elizabeth Barrett
- National Institute for Health and Care Excellence (NICE), Manchester, UK
| | - Amy Finnegan
- National Institute for Health and Care Excellence (NICE), Manchester, UK
| | - Rachel Adams
- National Institute for Health and Care Excellence (NICE), Manchester, UK
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13
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Zhao X, Zhou C, Ma J, Zhu Y, Sun M, Wang P, Zhang Y, Ma H, Zhang H. Efficacy and safety of rectal 5-aminosalicylic acid versus corticosteroids in active distal ulcerative colitis: a systematic review and network meta-analysis. Sci Rep 2017; 7:46693. [PMID: 28440311 PMCID: PMC5404224 DOI: 10.1038/srep46693] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 03/24/2017] [Indexed: 12/14/2022] Open
Abstract
Topical 5-aminosalicylic acid (5-ASA) and corticosteroids are used frequently in the treatment of active distal ulcerative colitis (UC). Our study aimed to determine the efficacy and safety of different topical drugs used to treat active distal UC. A random-effects model within a Bayesian framework was utilized to compare treatment effects and safety as odds ratios (ORs) with corresponding 95% credible intervals (CrI). The surface under the cumulative ranking area (SUCRA) and median rank (MR) with corresponding 95% CrI were calculated to rank the treatment outcomes. In the induction of clinical and endoscopic remission, most regimens showed significant advantages over placebo except topical budesonide 0.5 mg/d and hydrocortisone 100 mg/d. According to SUCRA and MR values, rectal 5-ASA 1.5 to 2.0 g/d + Beclomethasone dipropionate (BDP) 3 mg/d rendered the highest probability of being the best regimen to achieve clinical and endoscopic remission, followed by the separate use of 5-ASA 4 g/d and BDP 3 mg/d. The occurrence of adverse events was not significantly different between each treatments and placebo. In conclusion, the combined use of topical 5-ASA and BDP proved to be the best choice for active distal UC and further well-designed researches are warranted to assess its efficacy and safety.
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Affiliation(s)
- Xiaojing Zhao
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Changcheng Zhou
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, Jiangsu 210006, China
| | - Jingjing Ma
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Yunjuan Zhu
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Min Sun
- Department of Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China
| | - Peixue Wang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Yi Zhang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Haiqin Ma
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Hongjie Zhang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
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14
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Vuitton L, Peyrin-Biroulet L, Colombel JF, Pariente B, Pineton de Chambrun G, Walsh AJ, Panes J, Travis SPL, Mary JY, Marteau P. Defining endoscopic response and remission in ulcerative colitis clinical trials: an international consensus. Aliment Pharmacol Ther 2017; 45:801-813. [PMID: 28112419 DOI: 10.1111/apt.13948] [Citation(s) in RCA: 103] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Revised: 09/07/2016] [Accepted: 12/27/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Recently, endpoints for clinical trials have been changing from measuring clinical response to mucosal healing in ulcerative colitis. Endoscopic evaluation is the current gold standard to assess mucosal lesions and has become a major measure of therapeutic efficacy in addition to patients reported outcomes. AIM To achieve consensus on endoscopic definitions of remission and response for clinical trials in patients with ulcerative colitis. METHODS In reaching the current international recommendations on an International Organization For the Study of Inflammatory Bowel Disease (IOIBD) initiative, we first performed a systematic review of technical aspects of endoscopic scoring systems. Then, to achieve consensus on endoscopic definitions of remission and response for clinical trials, we conducted a two-round vote using a Delphi-style process among fifteen specialists in the field of inflammatory bowel diseases. RESULTS The literature review showed that many endoscopic indices have been proposed to evaluate disease activity in ulcerative colitis; most are unvalidated and arbitrary definitions have been used in clinical trials for defining endoscopic response or remission. At the end of the voting process, the investigators ranked initially the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) 0 for the definition of endoscopic remission, and a decrease in Mayo endoscopic score ≥1 grade or a decrease in UCEIS ≥2 points for the definition of endoscopic response in ulcerative colitis. CONCLUSIONS These international recommendations represent the first consensus on measurement indices for endoscopic outcomes in ulcerative colitis. They should be subject to prospective testing in clinical trials of ulcerative colitis.
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15
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Mucoadhesive chitosan hydrogels as rectal drug delivery vessels to treat ulcerative colitis. Acta Biomater 2017; 48:247-257. [PMID: 27769943 DOI: 10.1016/j.actbio.2016.10.026] [Citation(s) in RCA: 107] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Revised: 10/11/2016] [Accepted: 10/17/2016] [Indexed: 01/17/2023]
Abstract
Mucoadhesive drug delivery systems stick to mucosal tissues and prolong the local retention time of drugs. Since the colon is covered by a mucosal layer, mucoadhesive rectal formulations may improve treatment of such diseases as hypertension or colon cancer. Ulcerative colitis (UC) is an inflammatory bowel disease characterized by chronic inflammation of the colonic mucosa. It is commonly treated with sulfasalazine (SSZ), which is metabolized by the intestinal flora into the therapeutic 5-aminosalicylic acid (5-ASA) and a toxic by-product sulfapyridine (SP). SSZ can be administered orally or rectally. The latter route avoids unintended absorption of the drug or its degradation products in the upper gastrointestinal tract, but often fails due to limited retention time. Here, we propose a mucoadhesive hydrogel to improve the efficacy of rectal SSZ administration. The gel is made of catechol modified-chitosan (Cat-CS) crosslinked by genipin. After loading the gel with SSZ, we evaluated its efficacy in a mouse model of UC. Compared to oral SSZ treatment, rectal SSZ/Cat-CS delivery was more therapeutic, showed equivalent histological scores, and induced a lower plasma concentration of the potentially toxic SP by-product. These results show SSZ/Cat-CS rectal hydrogels are more effective and safer formulations for UC treatment than oral SSZ. STATEMENT OF SIGNIFICANCE Ulcerative colitis affects the colon by causing chronic inflammation on the mucosa. One of the most common drugs to treat mild to moderate UC is sulfasalazine, which can be administrated both orally and rectally. Rectal formulations are preferable, since their therapeutic effect happens topically, and they prevent side effects related to absorption of the drug in the small intestine. However, the efficacy of rectal sulfasalazine formulations is decreased by their limited colon residence time. Here we propose a chitosan-catechol mucoadhesive gel that allows delivering sulfasalazine more effectively and safely than oral administration. Our results bring new insights into the field of mussel-inspired catechol hydrogels, showing their potential as drug delivery systems to treat a widespread disease such as ulcerative colitis.
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16
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Patil DT, Moss AC, Odze RD. Role of Histologic Inflammation in the Natural History of Ulcerative Colitis. Gastrointest Endosc Clin N Am 2016; 26:629-40. [PMID: 27633592 DOI: 10.1016/j.giec.2016.06.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The goals of therapy for ulcerative colitis have moved from symptom improvement to mucosal healing, and finally histologic resolution. The natural history of histologic inflammation in ulcerative colitis progresses from initial cellular infiltration to architectural disruption and recovery on medical therapy. Many studies have linked histologic changes to clinical outcomes, providing prognostic value to histologic abnormalities. This review covers all these components.
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Affiliation(s)
- Deepa T Patil
- Cleveland Clinic, 9500 Euclid Av, L-25, Cleveland, OH 44195, USA.
| | - Alan C Moss
- Harvard Medical School, 330 Brookline Ave., Boston, MA 02215, USA
| | - Robert D Odze
- Gastrointestinal Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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17
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Bressler B, Marshall JK, Bernstein CN, Bitton A, Jones J, Leontiadis GI, Panaccione R, Steinhart AH, Tse F, Feagan B. Clinical practice guidelines for the medical management of nonhospitalized ulcerative colitis: the Toronto consensus. Gastroenterology 2015; 148:1035-1058.e3. [PMID: 25747596 DOI: 10.1053/j.gastro.2015.03.001] [Citation(s) in RCA: 294] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2014] [Accepted: 02/09/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS The medical management of ulcerative colitis (UC) has improved through the development of new therapies and novel approaches that optimize existing drugs. Previous Canadian consensus guidelines addressed the management of severe UC in the hospitalized patient. We now present consensus guidelines for the treatment of ambulatory patients with mild to severe active UC. METHODS A systematic literature search identified studies on the management of UC. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a working group of specialists. RESULTS The participants concluded that the goal of therapy is complete remission, defined as both symptomatic and endoscopic remission without corticosteroid therapy. The consensus includes 34 statements focused on 5 main drug classes: 5-aminosalicylate (5-ASA), corticosteroids, immunosuppressants, anti-tumor necrosis factor (TNF) therapies, and other therapies. Oral and rectal 5-ASA are recommended first-line therapy for mild to moderate UC, with corticosteroid therapy for those who fail to achieve remission. Patients with moderate to severe UC should undergo a course of oral corticosteroid therapy, with transition to 5-ASA, thiopurine, anti-TNF (with or without thiopurine or methotrexate), or vedolizumab maintenance therapy in those who successfully achieve symptomatic remission. For patients with corticosteroid-resistant/dependent UC, anti-TNF or vedolizumab therapy is recommended. Timely assessments of response and remission are critical to ensuring optimal outcomes. CONCLUSIONS Optimal management of UC requires careful patient assessment, evidence-based use of existing therapies, and thorough assessment to define treatment success.
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Affiliation(s)
- Brian Bressler
- Division of Gastroenterology, Department of Medicine, St Paul's Hospital, Vancouver, British Columbia.
| | - John K Marshall
- Department of Medicine, McMaster University, Hamilton, Ontario
| | - Charles N Bernstein
- IBD Clinical and Research Centre, University of Manitoba, Winnipeg, Manitoba
| | - Alain Bitton
- Department of Medicine, McGill University Health Centre, Montreal, Quebec
| | - Jennifer Jones
- Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan
| | | | - Remo Panaccione
- Department of Medicine, University of Calgary, Calgary, Alberta
| | | | - Francis Tse
- Department of Medicine, McMaster University, Hamilton, Ontario
| | - Brian Feagan
- Robarts Research Institute, Western University, London, Ontario, Canada
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18
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Bryant RV, Winer S, Travis SPL, Riddell RH. Systematic review: histological remission in inflammatory bowel disease. Is 'complete' remission the new treatment paradigm? An IOIBD initiative. J Crohns Colitis 2014; 8:1582-97. [PMID: 25267173 DOI: 10.1016/j.crohns.2014.08.011] [Citation(s) in RCA: 233] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Revised: 08/06/2014] [Accepted: 08/12/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Advances in the medical management of inflammatory bowel disease (IBD) have altered treatment targets. Endoscopic mucosal healing is associated with better outcomes in IBD, though less is known about the significance of achieving histological remission. Our aim was to perform a systematic review to investigate whether histological or 'complete' remission constitutes a further therapeutic target in IBD. METHODS A bibliographic search was performed on the 1st of October 2013 and subsequently on the 1st of March 2014 of online databases (OVID SP MEDLINE, OVID EMBASE, National Pubmed Central Medline, Cochrane Library, ISI, conference abstracts), using MeSH terms and key words: ("inflammatory bowel diseases" OR "crohn disease" OR "ulcerative colitis" OR "colitis") AND ("mucosal healing" OR "histological healing" OR "pathological healing" OR "histological scoring" OR "pathological scoring"). RESULTS The search returned 2951 articles. 120 articles were cited in the final analysis. There is no validated definition of histological remission in IBD. There are 22 different histological scoring systems for IBD, none of which are fully validated. Microscopic inflammation persists in 16-100% of cases of endoscopically quiescent disease. There is evidence that histological remission may predict risk of complications in ulcerative colitis beyond endoscopic mucosal healing, though data are scarce in Crohn's disease. CONCLUSIONS Histological remission in IBD represents a target distinct from endoscopic mucosal healing, not yet routinely sought in clinical trials or practice. There remains a need for a standardized and validated histological scoring system and to confirm the prognostic value of histological remission as a treatment target in IBD.
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Affiliation(s)
- R V Bryant
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford University Hospitals, United Kingdom
| | - S Winer
- Department of Pathology and Laboratory Medicine, Mt Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada
| | - S P L Travis
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford University Hospitals, United Kingdom
| | - R H Riddell
- Department of Pathology and Laboratory Medicine, Mt Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
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Pagnini C, Menasci F, Festa S, Rizzatti G, Fave GD. “Mucosal healing” in ulcerative colitis: Between clinical evidence and market suggestion. World J Gastrointest Pathophysiol 2014; 5:54-62. [PMID: 24891976 PMCID: PMC4025073 DOI: 10.4291/wjgp.v5.i2.54] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Revised: 04/04/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
In recent decades, the prominent role of endoscopy in the management of ulcerative colitis (UC) has been translated into the concept of mucosal healing (MH) as a fundamental therapeutic end-point. This is partially the consequence of growing evidence of a positive prognostic role of MH on the disease course and partially due to market cues indicating a higher rate of MH in patients treated by novel potent biologic agents. The aim of the present review is to clarify the current knowledge of MH in UC, analyzing the definition, the putative prognostic role and the association of MH with the current drugs used to treat UC patients. Because solid data about the management of UC patients based solely on the healing of the mucosa are not yet available, a tailored approach for individual patients thatconsiders the natural history of UC and the presence of prognostic indicators of aggressive disease is desirable. Consequently, unnecessary examinations and treatment would be avoided and restricted to UC patients who require the maximum amount of effort to affect the disease course in the short and long term.
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Mazzuoli S, Guglielmi FW, Antonelli E, Salemme M, Bassotti G, Villanacci V. Definition and evaluation of mucosal healing in clinical practice. Dig Liver Dis 2013; 45:969-977. [PMID: 23932331 DOI: 10.1016/j.dld.2013.06.010] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2013] [Revised: 05/21/2013] [Accepted: 06/26/2013] [Indexed: 12/11/2022]
Abstract
Since the introduction of biological therapy, endoscopic and histological remission, i.e. mucosal healing, has become an important therapeutic goal in Crohn's Disease and Ulcerative Colitis. Mucosal healing is associated with lower rates of hospitalization and surgery, although its role in preventing progression and changing the natural history of the disease has not been clearly demonstrated. A precise definition of mucosal healing has not yet been established, although the concept used in clinical trials is the "complete absence of all inflammatory and ulcerative lesions in all segments of gut" at endoscopy. This definition does not include mucosal improvement and does not distinguish among grades of mucosal healing. In both Crohn's Disease and Ulcerative Colitis trials, several qualitative and quantitative numeric endoscopic indices have been proposed to measure and distinguish endoscopic changes. In addition, the microscopic features associated with inflammatory bowel diseases are considerably modified by the course of the disease and the treatments adopted. However, it is not yet clear whether microscopic healing should be a primary endpoint in clinical trials. In this paper we discuss endoscopic and histological findings and the limitations of the endoscopic and histological indices as a basis for a standardised diagnosis of mucosal healing.
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Affiliation(s)
- Silvia Mazzuoli
- Gastroenterology and Artificial Nutrition Department, "San Nicola Pellegrino" Hospital Trani, BT, Italy
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21
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Villanacci V, Antonelli E, Geboes K, Casella G, Bassotti G. Histological healing in inflammatory bowel disease: a still unfulfilled promise. World J Gastroenterol 2013; 19:968-978. [PMID: 23467585 PMCID: PMC3582008 DOI: 10.3748/wjg.v19.i7.968] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2012] [Revised: 09/11/2012] [Accepted: 09/19/2012] [Indexed: 02/06/2023] Open
Abstract
Treatment of inflammatory bowel disease (IBD) is traditionally based on several drugs, including salicylates, corticosteroids, and antibiotics; in addition, the therapeutic armamentarium has considerably evolved with the advent of newer, effective therapeutic measures (such as the biological agents) that are able to improve in a considerable manner both the clinical and endoscopic variables. Thus, mucosal healing, at least considered from an endoscopic point of view, is today regarded as the ultimate endpoint for treatment of these conditions. However, it is also increasingly clear that endoscopic healing is not necessarily paralleled by histological healing; There are few doubts that the latter should be considered as a true, objective healing and the ultimate goal to reach when treating patients with IBD. Unfortunately, and surprisingly, only a few, incomplete, and somewhat conflicting data exist on this topic, especially because there is still the need to standardize both histological assessment and the severity grading of these disorders; Issues that have not been yet been resolved for clinical practice and therapeutic trials. Hopefully, with the help of an increased awareness on the clinical researchers' side, and the availability of dedicated pathologists on the other side, this matter will be effectively faced and resolved in the near future.
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Outcome following aminosalicylate therapy in children newly diagnosed as having ulcerative colitis. J Pediatr Gastroenterol Nutr 2013; 56:12-8. [PMID: 22847466 DOI: 10.1097/mpg.0b013e31826ac41a] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Despite a paucity of published supporting data, 5-aminosalicylate (5-ASA) use in pediatric ulcerative colitis (UC) is common. The present study describes the use and outcome of a large multicenter inception cohort of children with UC treated with 5-ASA. METHODS Data were obtained from the Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry, a prospective North American observational study of children newly diagnosed as having inflammatory bowel disease ages 16 years or younger. Patient data are recorded at diagnosis, 30 days, and then quarterly. Patients are managed by physician dictate, not protocol. Disease activity is classified by physician global assessment. The primary outcome examined was corticosteroid (CS) free, inactive UC at 1 year following initiation of 5-ASA within 30 days of diagnosis (with or without concomitant CS use) without the need for rescue therapy (immunomodulators, biologics, or colectomy). RESULTS Study subjects included 213 patients newly diagnosed as having UC who received oral 5-ASA compounds (115 of whom also received CS) during the first 30 days after diagnosis, and no other oral therapies for the treatment of UC. Of these 213 patients, 86 (40%) were CS free and physician global assessment inactive at 1 year without rescue. Outcome was not associated with disease severity at diagnosis, demographic or laboratory factors examined, or initial dose of 5-ASA used. CONCLUSIONS Forty percent of children taking 5-ASA as primary maintenance therapy at diagnosis are in CS-free remission after 1 year of treatment. Further pediatric studies will be needed to address whether increased adherence and/or higher dosing schedules will improve outcomes.
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Römkens TEH, Kampschreur MT, Drenth JPH, van Oijen MGH, de Jong DJ. High mucosal healing rates in 5-ASA-treated ulcerative colitis patients: results of a meta-analysis of clinical trials. Inflamm Bowel Dis 2012; 18:2190-8. [PMID: 22419617 DOI: 10.1002/ibd.22939] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2012] [Accepted: 02/14/2012] [Indexed: 12/16/2022]
Abstract
BACKGROUND Recently, mucosal healing (MH) is regarded as an important treatment goal in ulcerative colitis (UC). 5-Aminosalicylates (5-ASA) are the standard treatment in mild-to-moderate UC, but the effect on MH is less known. The aim of this study was to systematically review the medical literature in order to compare different preparations of 5-ASA for the effect on MH. METHODS We conducted a structured search of PubMed and the Cochrane Central Register of Controlled Trials to identify randomized controlled clinical trials with 5-ASA in UC providing data about MH. We calculated the sample size-weighted pooled proportion of patients with MH, and performed meta-analysis of head-to-head comparisons. RESULTS Out of 645 hits, we included 90 treatment arms, involving 3977 patients using oral 5-ASA (granulate and tablets) and 2513 patients using rectal 5-ASA (suppositories, enema, and foam). Overall, 43,7% of 5-ASA treated patients achieved MH (oral 36,9%; rectal 50,3%). In oral studies, 49% of patients using granulate (7 treatment-arms) achieved MH compared to 34,9% using tablets (43 treatment-arms). In rectal studies the proportion of MH was 62% for suppositories (eight treatment arms), 51% for foam (nine treatment arms), and 46% for enema (23 treatment arms), respectively. CONCLUSIONS 5-ASA preparations achieved MH in nearly 50% of UC patients. There were no significant differences in MH between the various 5-ASA agents, either in the oral or the rectal treatment groups.
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Affiliation(s)
- Tessa E H Römkens
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
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Navaneethan U, Shen B. Pros and cons of medical management of ulcerative colitis. Clin Colon Rectal Surg 2012; 23:227-38. [PMID: 22131893 DOI: 10.1055/s-0030-1268249] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Ulcerative colitis (UC) is a chronic inflammatory disease characterized by diffuse mucosal inflammation limited to the colon and rectum. Although a complete medical cure may not be possible, UC can be treated with medications that induce and maintain remission. The medical management of this disease continues to evolve with a goal to avoid colectomy and ultimately alter the natural history of UC. Emergence of antitumor necrosis factor-α (TNF-α) agents has expanded the medical armamentarium. 5-Aminosalicylates continue to be used in mild to moderate UC and corticosteroids are mainly used for induction of remission with immunomodulators (6-mercaptopurine/azathiopurine/methotrexate) being applied as steroid-sparing agents for maintenance therapy. Infliximab has been approved by the U.S. Food and Drug Administration and used in the treatment of moderate to severe UC; nevertheless, its use may be associated with significant adverse effects and have a negative impact on the postoperative course should the patients undergo restorative proctocolectomy. In addition, there is always a concern about patients' compliance to medical therapy, cost of medications, and risk for UC-associated dysplasia. The authors discuss the pros and cons of medications used in the treatment of UC.
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Affiliation(s)
- Udayakumar Navaneethan
- Center for Inflammatory Bowel Disease, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio. USA
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Best practice in the management of mild-to-moderately active ulcerative colitis and achieving maintenance of remission using mesalazine. Eur J Gastroenterol Hepatol 2010; 22:912-6. [PMID: 20665988 DOI: 10.1097/meg.0b013e32833944bf] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Optimizing treatment goals in ulcerative colitis requires recognizing the needs of patients. It is increasingly recognized that adapting treatment strategies aligned with patient needs can improve patient compliance and consequently minimize relapse rates. Tailoring of treatment strategies can improve not only patient quality of life, and decrease the number harmed by adverse events from more potent drugs, but can also save valuable healthcare costs by avoiding high-cost treatment interventions associated with acute ulcerative colitis. This review will consider several elements of mesalazine management from the patient perspective based on a range of clinical and patient-focused evidence. By highlighting patient preferences in disease management it is envisaged that this review will aid physicians to optimize treatment decisions with the different mesalazine preparations available.
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Foams for pharmaceutical and cosmetic application. Int J Pharm 2010; 394:1-17. [DOI: 10.1016/j.ijpharm.2010.04.028] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2009] [Revised: 04/21/2010] [Accepted: 04/21/2010] [Indexed: 01/11/2023]
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Koutroubakis IE. Recent advances in the management of distal ulcerative colitis. World J Gastrointest Pharmacol Ther 2010; 1:43-50. [PMID: 21577295 PMCID: PMC3091147 DOI: 10.4292/wjgpt.v1.i2.43] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2010] [Revised: 01/29/2010] [Accepted: 02/05/2010] [Indexed: 02/06/2023] Open
Abstract
The most frequent localization of ulcerative colitis (UC) is the distal colon. In treating patients with active distal UC, efficacy and targeting of the drug to the distal colon are key priorities. Oral and rectal 5-aminosalicylic acid (5-ASA) preparations represent the first line therapy of mild-to-moderate distal UC for both induction and maintenance treatment. It has been reported that many UC patients are not adherent to therapy and that non-compliant patients had a 5-fold risk of experiencing a relapse. These findings led to the introduction of once-daily oral regimens of 5-ASA as better therapeutic options in clinical practice due to improved adherence. New formulations of mesalazine, including the multi-matrix delivery system, and mesalazine granules, which allow once-daily administration, have been developed. They have been demonstrated to be efficacious in inducing and maintaining remission in mild-to-moderate distal UC in large clinical trials. However, existing data for distal UC are rather insufficient to make a comparison between new and classical 5-ASA formulations. It seems that the new formulations are at least as effective as classical oral 5-ASA formulations. Other treatment options, in the case that 5-ASA therapy is not effective, include systemic corticosteroids, thiopurines (azathioprine or 6-mercaptopurine), cyclosporine, infliximab and surgery. The combination of a prompt diagnostic work-up, a correct therapeutic approach and an appropriate follow-up schedule is important in the management of patients with distal UC. This approach can shorten the duration of symptoms, induce a prolonged remission, improve patient’s quality of life, and optimize the use of health resources.
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Affiliation(s)
- Ioannis E Koutroubakis
- Ioannis E Koutroubakis, Department of Gastroenterology, University Hospital Heraklion, PO BOX 1352, 71110 Heraklion, Crete, Greece
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Marshall JK, Thabane M, Steinhart AH, Newman JR, Anand A, Irvine EJ. Rectal 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2010:CD004115. [PMID: 20091560 DOI: 10.1002/14651858.cd004115.pub2] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND 5-Aminosalicylates (5-ASA) are considered a first-line therapy for inducing and maintaining remission of mild to moderately active ulcerative colitis (UC). When inflammation in UC is limited to the distal colon, 5-ASA can also be administered rectally as a suppository, enema or foam. OBJECTIVES A systematic review was undertaken to evaluate the efficacy of rectal 5-ASA for treating active distal UC. SEARCH STRATEGY Electronic searches of the MEDLINE database (1966-2008), the Cochrane Central Register of Controlled Trials and the Cochrane IBD/FBD Group Specialized Trials Register were supplemented by manual reviews of reference listings and conference proceedings. SELECTION CRITERIA Randomized trials comparing rectal 5-ASA to placebo or another active therapy were eligible for inclusion. Eligible trials enrolled patients with a distal disease margin less than 60 cm from the anal verge or distal to the splenic flexure. Trials that enrolled subjects less than 12 years of age were excluded. DATA COLLECTION AND ANALYSIS Eligibility was assessed by three authors. Data were extracted by two authors using standardized forms. Pooled odds ratios (POR) for inducing improvement and remission by symptomatic, endoscopic and histologic criteria were calculated using an intention to treat principle. Fixed effects models were used unless heterogeneity was encountered within groups (P < 0.10), where random effects models were used. All statistical analyses were performed using RevMan 5. Where sufficient data were available, subgroup analyses were performed for disease extent, total daily 5-ASA dose, 5-ASA formulation (enema,suppository, foam) and the type of control intervention (placebo or another active therapy). MAIN RESULTS Thirty-eight studies fulfilled the inclusion criteria. Rectal 5-ASA was superior to placebo for inducing symptomatic, endoscopic and histological improvement and remission, with POR for symptomatic improvement 8.87 (8 trials, 95% CI: 5.30 to 14.83; P < 0.00001), endoscopic improvement 11.18 (5 trials, 95% CI 5.99 to 20.88; P < 0.00001), histologic improvement 7.69 (6 trials, 95% CI 3.26 to 18.12; P < 0.00001), symptomatic remission 8.30 (8 trials, 95% CI 4.28 to 16.12; P < 0.00001), endoscopic remission 5.31 (7 trials, 95% CI 3.15 to 8.92; P < 0.00001), and histologic remission 6.28 (5 trials, 95% CI 2.74 to 14.40; P < 0.0001). Rectal 5-ASA was superior to rectal corticosteroids for inducing symptomatic improvement and remission with POR 1.56 (6 trials, 95% CI 1.15 to 2.11; P = 0.004) and 1.65 (6 trials, 95% CI 1.11 to 2.45; P = 0.01), respectively. Rectal 5-ASA was not superior to oral 5-ASA for symptomatic improvement (POR 2.25; 95% CI 0.53 to 19.54; P = 0.27). Neither total daily dose nor 5-ASA formulation affected treatment response. AUTHORS' CONCLUSIONS Rectal 5-ASA should be considered a first-line therapy for patients with mild to moderately active distal UC. The optimal total daily dose and dose frequency of 5-ASA remain to be determined. Future research should define differences in efficacy among patient subgroups defined by proximal disease margin and disease activity. There is a strong need for consensus standardization of outcome measurements for clinical trials in ulcerative colitis.
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Affiliation(s)
- John K Marshall
- Division of Gastroenterology, McMaster University, 1200 Main Street 2F59, Hamilton, Ontario, Canada, L8N 3Z5
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Pineton de Chambrun G, Peyrin-Biroulet L, Lémann M, Colombel JF. Clinical implications of mucosal healing for the management of IBD. Nat Rev Gastroenterol Hepatol 2010; 7:15-29. [PMID: 19949430 DOI: 10.1038/nrgastro.2009.203] [Citation(s) in RCA: 341] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Mucosal healing (MH) has emerged as an important treatment goal for patients with IBD. Historically, the therapeutic goals of induction and maintenance of clinical remission seemed insufficient to change the natural history of IBD. Evidence has now accumulated to show that MH can alter the course of IBD, as it is associated with sustained clinical remission, and reduced rates of hospitalization and surgical resection. In patients with ulcerative colitis, MH may represent the ultimate therapeutic goal because inflammation is limited to the mucosa. In patients with Crohn's disease, which is a transmural disease, MH could be considered as a minimum therapeutic goal. This Review focuses on the definition of MH and discusses the ability of each available IBD medication to induce and maintain MH. The importance of achieving MH is also discussed and literature that demonstrates improvement of disease course with MH is reviewed. Finally, we discuss how best to integrate the treatment end point of MH into clinical practice for the management of patients with IBD.
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Affiliation(s)
- Guillaume Pineton de Chambrun
- Clinique des maladies de l'appareil digestif et de la nutrition, Hôpital Claude Huriez, Rue Michel Polonovski, 59037 Lille Cedex, France
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Abstract
Induction and maintenance of remission, mucosal healing, the avoidance of surgical intervention, and decreasing the likelihood of cancer developing are the primary therapeutic goals in ulcerative colitis (UC). For the traditional therapies, 5-aminosalicylic acid (including mesalamine), corticosteroids, and thiopurines (azathioprine and mercaptopurine), there are major changes evolving in terms of formulation, patterns of use, and appreciation of long-term benefits and toxicities. The calcineurin inhibitors cyclosporin and tacrolimus, and infliximab, have recently defined, well-established roles. Preliminary supportive evidence is emerging in relation to novel antiinflammatory molecules such as curcumin, manipulation of the bacterial flora, enhancement of the mucosal barrier, and direct epithelial restoration. For patients in whom the disease is resistant to standard simple therapies, strategies are required to integrate these developing and new therapies into clinical practice. This review aims to highlight the evidence supporting new patterns of use of existing therapies and new therapies, and to devise therapeutic pathways that incorporate these new treatments. We propose how treatment might be optimized to improve the outcome in patients with mild-to-moderately active UC, chronic active UC, resistant proctitis, and fulminant UC.
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Cortot A, Maetz D, Degoutte E, Delette O, Meunier P, Tan G, Cazals JB, Dewit O, Hebuterne X, Beorchia S, Grunberg B, Leprince E, D'Haens G, Forestier S, Idier I, Lémann M. Mesalamine foam enema versus mesalamine liquid enema in active left-sided ulcerative colitis. Am J Gastroenterol 2008; 103:3106-14. [PMID: 19086960 DOI: 10.1111/j.1572-0241.2008.02152.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
AIM To determine in a noninferiority study whether mesalamine foam is as effective as mesalamine liquid enema for inducing clinical remission in patients with active left-sided ulcerative colitis (UC). METHODS In a multicenter investigator-blind trial, 375 patients with mild-to-moderate UC were randomized to receive mesalamine foam 1 g/80 mL/day or mesalamine liquid enema 1 g/100 mL/day for 4 wk (W). Inclusion criteria were: disease extension at least 5 cm from anorectal junction and not above splenic flexure and Clinical Activity Index (CAI) 1-4 > or = 4. Primary end point was clinical remission at W4 defined as a CAI 1-4 < or = 2. Noninferiority of the foam to liquid enema was declared if the lower limit of the 97.5% unilateral confidence interval (97.5% CI) of the difference in remission rates between foam and liquid enema groups was greater than -15% . RESULTS Remission rates at W4 in foam versus liquid were 68.3%versus 73.6% in per protocol (PP) population (lower limit of 97.5% CI -15.1%) and 66.7%versus 70.5% in intention-to-treat (ITT) population (97.5% CI -13.4%). Remission rates at W2 were 48.1 %versus 50.6% in ITT (97.5% CI -12.8%) and 49.1%versus 52.1% in PP (97.5% CI -13.8%) in foam versus liquid, respectively. Both treatments were well tolerated. CONCLUSIONS A 4-wk treatment of 1 g mesalamine foam induced a clinical remission in 68% patients versus 73% with 1 g mesalamine liquid enema. Although the noninferiority of mesalamine foam could not be strictly demonstrated at W4 in the PP analysis, it was achieved in the ITT population and at W2 in both populations. Mesalamine foam represents a therapeutic alternative to mesalamine liquid enema in patients with mild-to-moderate active proctitis and proctosigmoiditis.
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Park SH, Kim YM, Yang SK, Kim SH, Byeon JS, Myung SJ, Cho YK, Yu CS, Choi KS, Chung JW, Kim B, Choi KD, Kim JH. Clinical features and natural history of ulcerative colitis in Korea. Inflamm Bowel Dis 2007; 13:278-83. [PMID: 17206722 DOI: 10.1002/ibd.20015] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The clinical characteristics of ulcerative colitis (UC) in Asian populations have not been well characterized. We therefore investigated the clinical features and natural history of UC in Korea. METHODS We retrospectively analyzed 304 Korean patients with UC first diagnosed at the Asan Medical Center between June 1989 and August 2005. RESULTS The male-to-female ratio of the patients was 0.94:1, and their median age at diagnosis was 40.0 years (range, 12-72 years). At diagnosis, proctitis was noted in 134 patients (44.1%), left-sided colitis in 69 patients (22.7%), and extensive colitis in 101 patients (33.2%). Disease activity at diagnosis was mild in 149 patients (49.0%), moderate in 125 patients (41.1%), and severe in 26 patients (8.6%). In addition, 4 asymptomatic patients (1.3%) were detected as a result of a screening colonoscopy. Clinical remission after the first attack was documented in 97.4% of patients. The cumulative relapse rate after 1, 5, and 10 years was 30.2%, 72.0%, and 88.4%, respectively. The cumulative risk of proximal extension in patients with proctitis or left-sided colitis was 33.0% after 5 years and 44.5% after 10 years. The cumulative probability of colectomy was 2.0% after 1 year, 2.8% after 3 years, and 3.3% after 5 to 15 years. The cumulative survival rate after 1, 5, and 10 years was 100%, 99.4%, and 97.4%, respectively. CONCLUSIONS The clinical features of Korean UC patients at diagnosis are similar to those of Westerners. However, UC in Koreans may have a milder course than in Westerners, as indicated by the lower rate of colectomy among Koreans.
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Affiliation(s)
- Sang Hyoung Park
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
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Abstract
Ulcerative colitis (UC) and Crohn disease (CD) are chronic intestinal inflammatory diseases that can present as bloody diarrhea, abdominal pain, and malnutrition. Collectively, these disorders are referred to as inflammatory bowel disease (IBD). All patients with IBD share a common pathophysiology. However, there are a number of developmental, psychosocial, and physiologic issues that are unique to the approximate, equals 20% of patients that present during childhood or adolescence. These include the possibility of disease-induced delays in linear growth or physical development, differences in drug dosing, and the changes in social and cognitive development that occur as children move from school-age years into adolescence and early adulthood. Gastroenterologists caring for these children must therefore develop an optimal regimen of pharmacologic therapies, nutritional management, psychologic support, and properly timed surgery (when necessary) that will maintain disease remission, minimize disease and drug-induced adverse effects, and optimize growth and development. This article reviews current approaches to the management of patients with UC and CD and highlights issues specific to the treatment of children with IBD. The principal medical therapies used to induce disease remission in patients with UC are aminosalicylates (for mild disease), corticosteroids (for moderate disease), and cyclosporine (ciclosporin) (for severe disease). If a patient responds to the induction regimen, maintenance therapies that are used to prevent disease relapse include aminosalicylates, mercaptopurine, and azathioprine. Colectomy with creation of an ileal pouch anal anastomosis (J pouch) has become the standard of care for patients with severe or refractory colitis and results in an improved quality of life in most patients. Therefore, the risks associated with using increasingly potent immunosuppressant agents must be balanced in each case against a patient's desire to retain their colon and avoid a temporary or potentially permanent ileostomy. Decisions about drug therapy in the management of patients with CD are more complex and depend on both the location (e.g. gastroduodenal vs small intestinal vs colonic), as well as the behavior of the disease (inflammatory/mucosal vs stricturing vs perforating) in a given patient. Induction therapies for CD typically include aminosalicylates and antibiotics (for mild mucosal disease), nutritional therapy (including elemental or polymeric formulas), corticosteroids (for moderate disease), and infliximab (for corticosteroid-resistant or fistulizing disease). Aminosalicylates, mercaptopurine, azathioprine, methotrexate, and infliximab can be used as maintenance therapies. Because surgical treatment of CD is not curative, it is typically reserved for those patients either with persistent symptoms and disease limited to a small section of the intestine (e.g. the terminal ileum and cecum) or for the management of complications of the disease including stricture or abdominal abscess. When surgery is necessary, maintenance medications administered postoperatively will postpone recurrence. Patients with UC and CD are at risk for the development of micronutrient deficiencies (including folate, iron, and vitamin D deficiencies) and require close nutritional monitoring. In addition, patients with UC and CD involving the colon are at increased risk of developing colon cancer, and should be enrolled into a colonoscopy surveillance program after 8-10 years of disease duration.
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Affiliation(s)
- Paul A Rufo
- Center for Inflammatory Bowel Diseases, Combined Program in Gastroenterology and Nutrition, Children's Hospital, Boston, Massachusetts 02115, USA.
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Travis SPL. New thinking: theory vs practice. A case study illustrating evidence-based therapeutic decision making. Colorectal Dis 2006; 8 Suppl 1:25-9. [PMID: 16594961 DOI: 10.1111/j.1463-1318.2006.00989.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Evidence-based medicine (EBM) plays a key role for decision making in clinical practice. Clinicians are encouraged to adhere to treatment guidelines based on high quality clinical trials, systematic reviews and meta-analyses, that are the focus of the Cochrane Collaboration. EBM is not, however, a panacea for medical decision making. The results of randomized clinical trials apply to populations of patients, and the challenge is to translate the results to individuals. Individual patients require different thought processes because presentation and response vary, and external factors (e.g. patient preference) influence the choice of treatment. The application of EBM demands clinical judgement. The case of a 28 year old scientist who presented with typical features of moderate ulcerative colitis, illustrates the dilemma. At each stage of his illness the treatment options based on EBM were discussed, including high dose 5-aminosalicyclic acid with or without topical therapy, corticosteroids, infliximab, immunomodulation, complementary therapy and surgery. Ultimately, therapeutic decisions depended on the patient's circumstances, preferences and response. Decisions should avoid circular motion caused by the illusion of progress and always consider the direction of travel.
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Affiliation(s)
- S P L Travis
- John Radcliffe Hospital and Linacre College, Oxford, UK.
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Abstract
Pharmacotherapy is the cornerstone of management in ulcerative colitis. However, controversy remains over optimal medical strategies. Specifically, differences in the onset of action of various drug therapies are thought to influence the achievement and maintenance of remission of disease, yet this is poorly characterised. There is a wide range of recent data concerning aminosalicylates, with much debate as to the relative merits of the various formulations and delivery systems. Meta-analyses confirm the efficacy of aminosalicylates for the induction and maintenance of remission and suggest that the newer agents are comparable in efficacy to sulfasalazine. Among aminosalicylates, data from clinical trials reveal that the onset of action is earlier with balsalazide than mesalazine. Although the efficacy of the newer 5-aminosalicylate agents is no greater than that of sulfasalazine, they have better adverse effect profiles. Factors such as tolerability and adherence appear more important than onset of action in long-term maintenance. Corticosteroids have long been used in the treatment of ulcerative colitis, yet there is a paucity of data regarding this. They have a rapid onset of action but considerable systemic adverse effects. Therefore, corticosteroids are reserved for disease that fails to respond to other agents or for primary therapy in patients with severe disease, although there is no universal acceptance of a threshold at which to initiate corticosteroid treatment.Rectal preparations of both aminosalicylates and corticosteroids have been developed in an attempt to exert a more rapid and direct onset of action while minimising adverse systemic effects. In clinical trials, topical preparations of both aminosalicylates and corticosteroids are effective in inducing remission. However, patient acceptability and proximal extent of disease dictate selection of a topical agent more than concern with rate of onset.A wide range of immunomodulators have been investigated in patients with steroid-refractory ulcerative colitis. The thioguanine derivatives are the most widely used but have a limited evidence base to support this use with controlled trials providing equivocal results regarding efficacy in severe ulcerative colitis. In addition, the thioguanine derivatives have a protracted onset of action and a considerable serious adverse effect profile. Calcineurin inhibitors and methotrexate have a more rapid onset of action than the thiopurines but have even less data to support their widespread use. They are widely regarded as salvage therapy and further data are required. Regarding biological agents, infliximab revolutionised the treatment of Crohn's disease, yet results in ulcerative colitis have been disappointing. Further trials are ongoing with great anticipation for more favourable data. The practical clinical implications of any differences between the agents depend on patient satisfaction with various therapies. Noncompliance is a major concern in maintenance therapy and is probably associated with relapse. Dose administration schedules and acceptability of therapy appear to be important factors in adherence. Overall, it is not clear that onset of action has a major influence on patient adherence and addressing issues of compliance may have more direct clinical impact.
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Affiliation(s)
- Steven Masson
- Department of Gastroenterology, Royal Victoria Infirmary, Newcastle, UK
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Ingram JR, Rhodes J, Evans BK, Newcombe RG, Thomas GAO. Comparative study of enema retention and preference in ulcerative colitis. Postgrad Med J 2006; 81:594-8. [PMID: 16143691 PMCID: PMC1743341 DOI: 10.1136/pgmj.2004.031690] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
BACKGROUND Therapeutic enemas are often used to treat active colitis but their retention may be limited because of urgency to defecate. Some preparations may be better retained and tolerated than others because of their physical properties. AIM To compare patient preference and retention of four therapeutic enemas, including a nicotine enema, in patients with ulcerative colitis (UC). METHODS Twenty four patients with active UC received the four trial enemas-corticosteroid, 5-amino salicylate (5-ASA), and nicotine liquid enemas and a corticosteroid foam, in a randomised order, taking one enema on each of four successive nights. Patients scored them 1 to 4 for ease of administration and retention, degree of abdominal bloating, and for their overall preference. RESULTS Fifteen patients rated nicotine their overall favourite or second favourite, compared with 14 for corticosteroid foam and 11 for 5-ASA and corticosteroid liquids, but this was not significant (p = 0.302). Overall, there was no significant difference in overnight retention. However, the nicotine enema tended to be less well retained in patients with milder urgency but a higher proportion retained it overnight with more severe urgency (p = 0.031 compared with 5-ASA enema). CONCLUSION There was no significant difference in patient preference or overall duration of retention for the four enemas.
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Affiliation(s)
- J R Ingram
- Department of Gastroenterology, Cardiff and Vale NHS Trust, Cardiff, UK
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Byeon JS, Yang SK, Myung SJ, Pyo SI, Park HJ, Kim YM, Lee YJ, Hong SS, Kim KJ, Lee GH, Jung HY, Hong WS, Kim JH, Min YI. Clinical course of distal ulcerative colitis in relation to appendiceal orifice inflammation status. Inflamm Bowel Dis 2005; 11:366-71. [PMID: 15803026 DOI: 10.1097/01.mib.0000164018.06538.6e] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Although appendiceal orifice inflammation (AOI) is frequently observed as a skip lesion of ulcerative colitis (UC), its clinical significance is not clearly understood. We aimed to evaluate whether AOI is associated with the clinical course of UC. METHODS Ninety-four patients with newly diagnosed distal UC were prospectively enrolled at the Asan Medical Center between March 1996 and October 2002. Clinical features and colonoscopic findings during the follow-up period were analyzed in relation to initial AOI status. RESULTS Forty-eight patients were found to be initially AOI-positive and 46 to be initially AOI-negative. We found no difference in the baseline demographics and clinical characteristics between these two groups. The median follow-up periods for AOI-positive and AOI-negative groups were 45 and 41 months, respectively. Clinical remission was achieved in all patients of each group. The cumulative risk of relapse at 1, 3, and 5 years after remission was 31.2%, 59.8%, and 69.2%, respectively, in the AOI-positive group and 17.4%, 46.5%, and 67.2%, respectively, in the AOI-negative group (P = 0.124). The cumulative risk of proximal disease extension at 1, 3, and 5 years after diagnosis was 17.9%, 24.9%, and 44.5%, respectively, in the AOI-positive group and 9.8%, 21.5%, and 43.9%, respectively, in the AOI-negative group (P = 0.522). Proctocolectomy was performed in no patients in the AOI-positive group and in 1 patient in the AOI-negative group. No mortalities were observed in either group. CONCLUSIONS In patients with distal UC, AOI may have no prognostic implications in terms of remission, relapse, or proximal disease extension.
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Affiliation(s)
- Jeong-Sik Byeon
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
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Banerjee S, Peppercorn MA. Inflammatory bowel disease. Medical therapy of specific clinical presentations. Gastroenterol Clin North Am 2002; 31:185-202, x. [PMID: 12122731 DOI: 10.1016/s0889-8553(01)00012-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ulcerative colitis and Crohn's disease are chronic relapsing inflammatory disorders of the gastrointestinal tracts. The inflammatory process is restricted to the mucosa and submucosa of the colon in ulcerative colitis and is transmural and may occur anywhere in the gastrointestinal tract in Crohn's disease. Clinical presentation of these inflammatory disorders depends on the segments of digestive tract affected and on the extent and aggressiveness of the disease process. The treatment of specific clinical presentations of these disorders is discussed in this article.
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Affiliation(s)
- Subhas Banerjee
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
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Gisbert JP, Gomollón F, Maté J, Pajares JM. Role of 5-aminosalicylic acid (5-ASA) in treatment of inflammatory bowel disease: a systematic review. Dig Dis Sci 2002; 47:471-88. [PMID: 11911332 DOI: 10.1023/a:1017987229718] [Citation(s) in RCA: 80] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Javier P Gisbert
- Department of Gastroenterology, University Hospital of La Princesa, Madrid, Spain
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Malchow H, Gertz B. A new mesalazine foam enema (Claversal Foam) compared with a standard liquid enema in patients with active distal ulcerative colitis. Aliment Pharmacol Ther 2002; 16:415-23. [PMID: 11876694 DOI: 10.1046/j.1365-2036.2002.01199.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND Rectally administered mesalazine (5-aminosalicylic acid) is a recognized therapy for distal ulcerative colitis. It is frequently applied as a liquid enema. However, there are reasons (acceptability to the patient, more uniform topical dispersion and effective adhesion) to prefer a foam-based enema. AIM This study compared a foam enema (2 g mesalazine per day, Claversal Foam) with a standard liquid enema (4 g mesalazine per day, Salofalk enema). METHODS Patients with active distal ulcerative colitis, diagnosed according to standardized criteria, were treated for 4 weeks. The primary goal was clinical remission; endoscopic remission, histological changes, global assessment and standard safety measures were also analysed. A major subset of the patients also provided quality-of-life data. RESULTS Both foam and liquid enema gave good rates of clinical and endoscopic remission. The foam enema was shown to be as efficacious as the reference, even though the daily dose in the foam treatment contained only half as much active drug as in the reference treatment. Minor regional differences in efficacy were seen. The tolerabilities of the two formulations were comparable. CONCLUSIONS The foam enema offers a safe, efficacious and acceptable treatment for distal ulcerative colitis.
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Abstract
Since its synthesis in the 1930s and subsequent introduction, sulfasalazine has been an effective treatment for inflammatory bowel disease. However, up to one-third of patients are unable to take the drug because of severe intolerance. The finding in 1977 that the anticolitic effect of sulfasalazine lay in its 5-aminosalicylic [(5-ASA); mesalazine] moiety led to the development of new generations of 5-ASA agents. These new agents include a slow continuous release formulation, pH-dependent release formulations, formulations using alternative carrier molecules and rectally administered formulations. Newer 5-ASA formulations are more effective than placebo in maintaining remission of ulcerative colitis. They have also been used for the treatment of active Crohn's disease as well as maintenance treatment of ileocolonic Crohn's disease, although their role in isolated small bowel disease is controversial. In general terms, all of the newer 5-ASA preparations are much better tolerated than sulfasalazine. The use of standard dosages of mesalazine in pregnancy appears to be tolerated; however, continuing surveillance of pregnancy outcome is recommended. While there is evidence that mesalazine can cause nephrotoxic reactions, these reactions can occur with all 5-ASA-containing preparations, particularly in individuals with existing renal disease. Blood dyscrasias can also occur with all aminosalicylates.
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Affiliation(s)
- S Ishaq
- Queen Elizabeth Hospital, Birmingham, England.
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Pokrotnieks J, Marlicz K, Paradowski L, Margus B, Zaborowski P, Greinwald R. Efficacy and tolerability of mesalazine foam enema (Salofalk foam) for distal ulcerative colitis: a double-blind, randomized, placebo-controlled study. Aliment Pharmacol Ther 2000; 14:1191-8. [PMID: 10971236 DOI: 10.1046/j.1365-2036.2000.00784.x] [Citation(s) in RCA: 48] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
BACKGROUND Rectal formulations of mesalazine are the treatment of choice in mildly to moderately active ulcerative colitis. A new foam formulation of mesalazine was developed to improve both drug delivery and patient acceptance. METHODS In this multicentre, randomized, double-blind, parallel-group study, 111 patients with mildly to moderately active proctitis, proctosigmoiditis, or left-sided ulcerative colitis received mesalazine foam enema or placebo enema (2 g mesalazine per day) for 6 weeks. Disease activity was monitored on the basis of the Clinical Activity Index, Endoscopic Index, Histological Index, and global efficacy assessment by the investigators. Safety assessments included the recording of adverse events, laboratory variables and vital signs. RESULTS Clinical remission was more frequent in the mesalazine group than the placebo group (65% vs. 40%; P=0.0082), particularly in patients with mild disease and patients with proctosigmoiditis. The frequency of patients with an endoscopic remission was higher in the mesalazine group (57%) than in the placebo group (37%). Similarly, 59% of patients receiving mesalazine but only 41% of those receiving placebo showed an improved Histological Index. The foam enemas were generally well-tolerated, and no treatment-related changes on laboratory variables and vital signs were noted. CONCLUSIONS Mesalazine foam enema was well-tolerated and was more effective than placebo in the treatment of patients with distal ulcerative colitis.
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Affiliation(s)
- J Pokrotnieks
- Medical Academy of Latvia, I Clinic of Internal Diseases, Centre of Gastroenterology, Pilsonu 13, Riga LV-1002, Latvia.
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Abstract
Oral aminosalicylates such as sulfasalazine and mesalamine are widely prescribed for the treatment of mild or moderately active distal ulcerative colitis. However, a critical review of the literature demonstrates that rectal 5-aminosalicylic acid (5-ASA) is the optimal therapy for this disease. Meta-analyses of published trials show that rectally delivered 5-ASA is superior to placebo and to conventional rectal corticosteroids in inducing remission of distal ulcerative colitis, whereas the combination of rectal 5-ASA with a rectal corticosteroid or oral aminosalicylate is superior to rectal 5-ASA alone. For maintaining remission of distal ulcerative colitis, rectal 5-ASA is significantly better than placebo and at least as effective as oral 5-ASA. The dosage forms available for rectal delivery include suppositories, foams, and liquid enemas, and selection among these preparations should be guided by the proximal extent of disease and patient preference. The efficacy of rectal 5-ASA is complemented by its low rate of reported adverse effects, which may reflect its reduced potential for systemic absorption. This review summarizes the evidence supporting the role of rectal 5-ASA as a first-line therapy for mild or moderately active distal ulcerative colitis, and offers guidelines for its use.
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Affiliation(s)
- J K Marshall
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
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Cohen RD, Woseth DM, Thisted RA, Hanauer SB. A meta-analysis and overview of the literature on treatment options for left-sided ulcerative colitis and ulcerative proctitis. Am J Gastroenterol 2000; 95:1263-76. [PMID: 10811338 DOI: 10.1111/j.1572-0241.2000.01940.x] [Citation(s) in RCA: 166] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Therapeutic trials in left-sided ulcerative colitis (L-UC) and ulcerative proctitis (UP) have lacked control for medication type, dose, delivery, and duration of therapy. METHODS All published therapeutic articles and abstracts in L-UC or UP from 1958-1997 were reviewed. Improvement, remission rates, and adverse events were recorded for all (ALL), placebo-controlled (PC) studies, and for PC studies passing quality assessment (QA) scoring. Meta-analysis was used where appropriate. RESULTS Left-sided UC: For active disease, 67 studies (17 PC; 10 QA) were identified. Mesalamine enemas achieved remission in a duration but not a dose response (QA), with higher remission rates than steroid enemas (ALL) and clinical improvement rates superior to oral therapies (QA, ALL). Remission maintenance: 17 (six PC, six QA) studies were identified. Mesalamine therapies had comparable remission rates at 6 months, with a possible dose but not delivery effect. Mesalamine enema dosing intervals between QHS to Q3 days maintained efficacy. Reported adverse events were most common with oral sulfasalazine and dose-independent for mesalamine. Withdrawals from therapy were less than placebo, or < or =3%. Ulcerative proctitis: For active disease, 18 (nine PC, three QA) studies were identified. Mesalamine suppositories achieved clinical improvement and remission in a duration but not dose response, with higher rates of remission than topical steroids (ALL). Remission maintenance: three (three PC, two QA) studies were identified. Remission ranged from 75% to 90% (6 months) and 61-90% (12 months) for mesalamine agents. Reported adverse events were most common for mesalamine foam (8%). Withdrawals from therapy were <2%. CONCLUSIONS In L-UC and UP, the efficacy and side-effect profile of topical mesalamine are dose independent and superior to oral therapies and topical steroids. Economic analysis suggests that use of these agents will also result in an overall decrease in patient costs.
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Affiliation(s)
- R D Cohen
- Department of Medicine, University of Chicago Medical Center, Pritzker School of Medicine, University of Chicago, Illinois 60637, USA
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Frieri G, Pimpo MT, Palumbo GC, Onori L, Viscido A, Latella G, Galletti B, Pantaleoni GC, Caprilli R. Rectal and colonic mesalazine concentration in ulcerative colitis: oral vs. oral plus topical treatment. Aliment Pharmacol Ther 1999; 13:1413-7. [PMID: 10571596 DOI: 10.1046/j.1365-2036.1999.00642.x] [Citation(s) in RCA: 71] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
AIM To measure mucosal concentrations of mesalazine in ulcerative colitis patients treated with oral mesalazine alone, compared to patients treated with both topical and oral mesalazine. METHODS Twenty-two patients with mild to moderate ulcerative colitis were randomized to receive 2.4 g/day of oral mesalazine (11 patients) or 2.4 g/day oral plus 4 g/day of topical mesalazine (11 patients). After 2 weeks of treatment, endoscopic biopsies specimens were taken from the rectum and in descending colon just distal of the splenic flexure and stored to -80 degrees C for later assay (HPLC). Wilcoxon's rank sum test for unpaired data was used for the statistical analysis. RESULTS Mucosal levels of mesalazine in the rectum were significantly higher in patients who received oral plus topical treatment than in those who had oral treatment alone (52.1 ng/mg, range: 13.6-122.1 vs. 0.2 ng/mg, range: 0.2-9.7, respectively; P < 0.0001). Similarly, in the descending colon, the mucosal concentrations of mesalazine were significantly higher in patients who had oral plus topical treatment than in those receiving oral treatment alone (46.6 ng/mg, range: 6-112.6 vs. 15.9 ng/mg, range: 2.3-42.4, respectively; P=0.01). CONCLUSIONS Topical treatment of mesalazine significantly increases mucosal concentrations of mesalazine up to the splenic flexure, supporting the rationale to treat left-sided ulcerative colitis with topical formulations of mesalazine.
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Affiliation(s)
- G Frieri
- Gastroenterology Unit, University of l'Aquila, Italy.
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Gionchetti P, Ardizzone S, Benvenuti ME, Bianchi Porro G, Biasco G, Cesari P, D'albasio G, De Franchis R, Monteleone G, Pallone F, Ranzi T, Trallori G, Valpiani D, Vecchi M, Campieri M. A new mesalazine gel enema in the treatment of left-sided ulcerative colitis: a randomized controlled multicentre trial. Aliment Pharmacol Ther 1999; 13:381-8. [PMID: 10102972 DOI: 10.1046/j.1365-2036.1999.00482.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND A new mesalazine rectal gel preparation (without propellant gas) has been recently developed to improve topical treatment in distal ulcerative colitis. AIM To evaluate the efficacy, safety and patient tolerability of mesalazine gel enema compared with mesalazine foam enema in the treatment of patients with acute left-sided ulcerative colitis. METHODS In a randomized multicentre investigator-blind parallel group trial, 103 patients with mild to moderate left-sided colitis or proctosigmoiditis were randomly allocated to mesalazine 2 g gel enema (n = 50 evaluable patients) and mesalazine 2 g foam enema (n = 53 evaluable patients) for 4 weeks. Clinical symptoms, endoscopic and histological findings were assessed at entry, 2 and 4 weeks. Patients' evaluation of treatment tolerability and acceptability was assessed at 2 and 4 weeks. RESULTS After 4 weeks of treatment, clinical remission was achieved by 76% of mesalazine gel enema-treated patients and 69% of patients treated with mesalazine foam enema (P = 0.608). Endoscopic remission rates at week 4 were 51 and 52% for the mesalazine gel and foam enemas, respectively (P = 0.925). Histological remission was achieved by 30% of patients in both groups. Patients reported that the new mesalazine gel preparation was significantly better tolerated than the foam enema. Patients in the foam group had significantly more difficulty in retention (25% vs. 6%, P < 0.05), abdominal bloating (50% vs. 26%, P < 0.005) and discomfort during administration (48% vs. 26%, P < 0.05). CONCLUSION The new mesalazine gel enema is efficacious and significantly better tolerated than the mesalazine foam enema.
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Sardella A, Demarosi F, Oltolina A, Rimondini L, Carrassi A. Efficacy of topical mesalazine compared with clobetasol propionate in treatment of symptomatic oral lichen planus. Oral Dis 1998; 4:255-9. [PMID: 10200704 DOI: 10.1111/j.1601-0825.1998.tb00289.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To compare topically applied mesalazine (5-aminosalicylic acid) to topically applied clobetasol propionate in the treatment of patients suffering from symptomatic oral lichen planus. DESIGN Randomized controlled longitudinal investigation. PATIENTS AND METHODS Twenty-five out-patients suffering from oral lichen planus and referred to the Department of Oral Pathology and Oral Medicine of the University of Milan, Italy, during the period January to August 1997. Patients were randomly allocated (Group A and Group B) to treatment with mesalazine 5% or clobetasol propionate 0.05%. The drugs were topically applied twice daily for 4 weeks. Discomfort and pain were evaluated by the patient before and after treatment using a Visual Analogue Scale from zero (no pain) to 10 (extreme pain). Results were statistically evaluated by a Mann-Whitney U test. RESULTS The two pharmacological regimens obtained partial and complete absence of symptoms. In particular, the mesalazine tested group disclosed 57% complete absence of symptoms, 21.3% partial response and 9% no response. No statistically relevant difference has been detected between the two regimens. CONCLUSIONS The results of this preliminary study, if confirmed by further investigations, suggest that mesalazine might be considered an alternative to clobetasol propionate for treatment of symptomatic oral lichen planus.
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Affiliation(s)
- A Sardella
- Department of Oral Pathology and Oral Medicine, School of Dentistry, University of Milan, Italy
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Abstract
Severe ulcerative colitis is a potentially life-threatening condition but the mortality has fallen dramatically over the past 30-40 years. It is now less than 2%, including surgical mortality, and should only be seen in patients with significant co-existing disease. Early recognition of the severity of the colitis, intensive medical therapy, close liaison between physician and surgeon, and prompt surgery when necessary have all contributed to this improved outcome. Despite the use of high-dose intravenous corticosteroids, 20-30% of patients will make a poor response and will require urgent surgery. The use of intravenous cyclosporin has proved effective at reducing the immediate surgical rate in this group of unresponsive patients and appears safe. Whether cyclosporin reduces the need for surgery in the longer term is much less certain. Clinical, radiological, endoscopic and laboratory parameters can now be used to predict the course of a severe attack. These help in the timing of urgent surgery and are potentially helpful in determining when to begin other therapies such as cyclosporin.
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Abstract
BACKGROUND Clear strategies to optimise the use of corticosteroids in ulcerative colitis are lacking. AIM A meta-analysis was undertaken to examine critically the role of rectal corticosteroids in the management of active distal ulcerative colitis. METHODS All reported randomised controlled trials were retrieved by searching the Medline and EMBASE databases and the bibliographies of relevant studies. Trials which met inclusion criteria were assessed for scientific rigour. Data were extracted by two independent observers according to predetermined criteria. RESULTS Of 83 trials retrieved, 33 met inclusion criteria. Pooled odds ratios (POR) showed conventional rectal corticosteroids and rectal budesonide to be clearly superior to placebo. In seven trials, rectal 5-aminosalicylic acid (5-ASA) was significantly better than conventional rectal corticosteroids for inducing remission of symptoms, endoscopy, and histology with POR of 2.42 (95% confidence interval (CI) 1.72-3.41), 1.89 (95% CI 1.29-2.76), and 2.03 (95% CI 1.28-3.20), respectively. Rectal budesonide was of comparable efficacy to conventional corticosteroids but produced less endogenous cortisol suppression. Side effects, although inconsistently reported, were generally minor. A cost comparison of rectal preparations showed 5-ASA to be less expensive than corticosteroids. CONCLUSIONS Rectal 5-ASA is superior to rectal corticosteroids in the management of distal ulcerative colitis.
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Affiliation(s)
- J K Marshall
- Division of Gastroenterology and Intestinal Disease Research Programme, McMaster University, Hamilton, Ontario, Canada
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