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Vieujean S, Caron B, Jairath V, Benetos A, Danese S, Louis E, Peyrin-Biroulet L. Is it time to include older adults in inflammatory bowel disease trials? A call for action. THE LANCET. HEALTHY LONGEVITY 2022; 3:e356-e366. [PMID: 36098310 DOI: 10.1016/s2666-7568(22)00060-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 03/04/2022] [Accepted: 03/09/2022] [Indexed: 02/07/2023] Open
Abstract
The therapeutic management of older patients with inflammatory bowel disease (IBD) is challenging, particularly because of the absence of evidence-based guidelines for these patients, who seem to frequently be excluded from clinical trials. In this systematic review we investigated the exclusion of older patients with IBD from phase 3 studies registered on PubMed and ClinicalTrials.gov, by assessing the upper limit of age exclusion criteria and the percentage of patients older than 65 years included in the trials. Exclusion criteria other than age were also recorded, and comorbidities were analysed separately. Our review of 222 phase 3 studies shows that older patients are frequently excluded from IBD clinical trials because of their age, which was used as an exclusion criterion in 129 (58%) of the 222 assessed trials. Of the 32 trials that detailed the percentage of included patients who were 65 years or older, only 763 (5·4%) patients of the 14 124 patients included were older than 65 years. In addition to age, patients were also excluded because of comorbidities (mainly renal, hepatic, and cardiovascular, and used as an exclusion criterion in 76% of trials), a history of dysplasia (45% of trials), and previous treatment for IBD (19% of trials). We propose a three-step process that should enable the inclusion of all older patients in IBD clinical trials, regardless of their age, comorbidities, and frailty.
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Affiliation(s)
- Sophie Vieujean
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
| | - Bénédicte Caron
- Department of Gastroenterology and Inserm NGERE U1256, Nancy University Hospital, University of Lorraine, Vandoeuvre-lès-Nancy, France
| | - Vipul Jairath
- Department of Medicine, Western University, London, ON, Canada; Department of Epidemiology and Biostatistics, Western University, London, ON, Canada; Alimentiv, London, ON, Canada
| | - Athanase Benetos
- Inserm, DCAC, University of Lorraine, Vandoeuvre-lès-Nancy, France; CHRU-Nancy Brabois, Department of Clinical Geriatrics, University of Lorraine, Vandoeuvre-lès-Nancy, France
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milan, Italy
| | - Edouard Louis
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology and Inserm NGERE U1256, Nancy University Hospital, University of Lorraine, Vandoeuvre-lès-Nancy, France.
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Kishi M, Hirai F, Takatsu N, Hisabe T, Takada Y, Beppu T, Takeuchi K, Naganuma M, Ohtsuka K, Watanabe K, Matsumoto T, Esaki M, Koganei K, Sugita A, Hata K, Futami K, Ajioka Y, Tanabe H, Iwashita A, Shimizu H, Arai K, Suzuki Y, Hisamatsu T. A review on the current status and definitions of activity indices in inflammatory bowel disease: how to use indices for precise evaluation. J Gastroenterol 2022; 57:246-266. [PMID: 35235037 PMCID: PMC8938394 DOI: 10.1007/s00535-022-01862-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 02/06/2022] [Indexed: 02/04/2023]
Abstract
Many clinical trials have been conducted for inflammatory bowel disease (IBD), so various clinical indices (CIs) and endoscopic indices (EIs) have also been evaluated. However, recently, with the progress of IBD management, review of established indices from previous studies, and establishment of new indices, the landscape of the use of indices in clinical trials have changed. We investigated the number and frequency of the indices adapted in recent clinical trials for ulcerative colitis (CI and EI) and Crohn's disease (CI, EI, index related to magnetic resonance imaging, index for evaluating patient-reported outcomes, and health-related quality of life). Based on the results, we selected representative indices and further reviewed their content and characteristics. Moreover, various definitions, including clinical and endoscopic response or remission, have been described by means of representative indices in clinical trials.
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Affiliation(s)
- Masahiro Kishi
- Inflammatory Bowel Disease Center, Fukuoka University Chikushi Hospital, Chikushino, Japan
| | - Fumihito Hirai
- Department of Gastroenterology, Fukuoka University Faculty of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka City, Fukuoka 814-0180 Japan
| | - Noritaka Takatsu
- Inflammatory Bowel Disease Center, Fukuoka University Chikushi Hospital, Chikushino, Japan
| | - Takashi Hisabe
- Department of Gastroenterology, Fukuoka University Chikushi Hospital, Chikushino, Japan
| | - Yasumichi Takada
- Inflammatory Bowel Disease Center, Fukuoka University Chikushi Hospital, Chikushino, Japan
| | - Tsuyoshi Beppu
- Inflammatory Bowel Disease Center, Fukuoka University Chikushi Hospital, Chikushino, Japan
| | | | - Makoto Naganuma
- The Third Department of Internal Medicine, Kansai Medical University, Osaka, Japan
| | - Kazuo Ohtsuka
- Department of Endoscopy, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kenji Watanabe
- Center for Inflammatory Bowel Disease, Division of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Medicine, Iwate Medical University, Iwate, Japan
| | - Motohiro Esaki
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Kazutaka Koganei
- Department of Inflammatory Bowel Disease, Yokohama Municipal Citizen’s Hospital, Yokohama, Japan
| | - Akira Sugita
- Department of Inflammatory Bowel Disease, Yokohama Municipal Citizen’s Hospital, Yokohama, Japan
| | - Keisuke Hata
- Nihonbashi Muromachi Mitsui Tower Midtown Clinic, Tokyo, Japan
| | - Kitarou Futami
- Department of Surgery, Fukuoka University Chikushi Hospital, Chikushino, Japan
| | - Yoichi Ajioka
- Division of Molecular and Diagnostic Pathology, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan
| | - Hiroshi Tanabe
- Department of Pathology, Fukuoka University Chikushi Hospital, Fukuoka, Japan
| | - Akinori Iwashita
- AII Research Institute of Pathology and Image Diagnosis, Fukuoka, Japan
| | - Hirotaka Shimizu
- Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan
| | - Katsuhiro Arai
- Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan
| | | | - Tadakazu Hisamatsu
- Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, Tokyo, Japan
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Paridaens K, Fullarton JR, Travis SPL. Efficacy and safety of oral Pentasa (prolonged-release mesalazine) in mild-to-moderate ulcerative colitis: a systematic review and meta-analysis. Curr Med Res Opin 2021; 37:1891-1900. [PMID: 34404286 DOI: 10.1080/03007995.2021.1968813] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND Pentasa (prolonged-release mesalazine [5-ASA]) has been available for >30 years as an effective treatment for mild-to-moderate ulcerative colitis (UC). A systematic literature review and meta-analysis was undertaken to provide an up-to-date evaluation of oral Pentasa efficacy and safety for induction and maintenance of remission. METHODS Literature searches were conducted in PubMed, Embase and Cochrane databases, from inception to 02 December 2020. Unpublished studies were also sourced. Meta-analyses using a random-effects model and Bayesian inference compared Pentasa (tablets, granules, capsules) against placebo and other 5-ASAs. RESULTS Twelve studies involving 3674 patients treated with Pentasa were identified. Pentasa 2-4 g/day was superior to placebo at inducing (absolute risk difference [ARD] at 8 weeks 0.14, 95% CI 0.07‒0.21; p < .001) and maintaining (ARD 6-12 months 0.18, 95% CI 0.04‒0.33; p < .05) remission (clinical/endoscopic). Against other 5-ASAs, Pentasa had similar efficacy for induction (ARD <0.001, 95% CI -0.05‒0.05) and maintenance (ARD 0.01, 95% CI -0.07‒0.08) treatment using randomized controlled trial data. Upon inclusion of real-world study data, Pentasa was significantly better at maintaining remission compared both to Eudragit-S mesalazine and sulfasalazine (ARD 0.04, 95% CI 0.02‒0.06; p < .001). Pentasa (1-4 g/day) had similar treatment-related adverse event rates to placebo (ARD 0.02, 95% CI -0.03‒0.06) and Eudragit-L/S mesalazines (2.25-3 vs 2.4-3 g/day, respectively; ARD -0.03, 95% CI -0.12‒0.05), but was better tolerated than sulfasalazine (3 g/day) (ARD 0.07, 95% CI 0.003‒0.14; p < .05). CONCLUSION This study confirms oral Pentasa is efficacious and well-tolerated in treating active UC and maintaining remission. The availability of multiple forms of Pentasa supports physicians' ability to individualize treatment and optimize dosing to improve outcomes.
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Affiliation(s)
| | | | - Simon P L Travis
- NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK
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Deissler H, Krammer H, Gillessen A. pH-dependent vs. constant release of mesalazine in the treatment of ulcerative colitis: Do drug delivery concepts determine therapeutic efficacy? (Review). Biomed Rep 2021; 15:96. [PMID: 34631051 PMCID: PMC8493545 DOI: 10.3892/br.2021.1472] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 09/02/2021] [Indexed: 12/11/2022] Open
Abstract
Inflammatory bowel diseases (IBD) have developed to become a major global health problem. Ulcerative colitis (UC) is one of two main types of IBD, and >90% of patients suffering from mild or moderate forms of UC are treated with mesalazine, a well-tolerated and cost-effective drug. To allow oral administration, the drug has to be protected from resorption before it can reach the affected sites in the colon. The drug is therefore released from most currently used medications either constantly slow (time-dependent) or triggered by an increased pH during gastrointestinal transition. Both variants are widely used in clinical practice and it is surprising that they have not yet been compared directly in a large clinical study. In this overview, the evidence that may suggest preferential use of one type of mesalazine formulation over the other in general or for defined subgroups of patients is summarized and evaluated. Data from in vitro modelling of drug release and measurements of drug concentrations in colonic mucosa suggest that in many cases, constant release and pH-dependent formulations are of similar therapeutic efficiency; however, pH-triggered release may be superior in patients with proctitis-type UC or sites of inflammation in the proximal colon. Additionally, patients with a long gastric residence time, slow small intestinal transition, disease-related diarrhea or sensitivity to systemic adverse effects may benefit more from pH-dependent release formulations. In general, medications based on both concepts show similar efficacies, but the pH-dependent release formulations seem to be more robust in the treatment of a not further classified group of patients with UC. Future comparative clinical studies are required to clearly define the subgroups of patients that should be treated preferably with constant or pH-dependent release formulations of mesalazine.
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Affiliation(s)
| | - Heinrich Krammer
- Gastroenterological Practice, Center for Colon and Rectal Diseases, D-68165 Mannheim, Germany
| | - Anton Gillessen
- Department of Internal Medicine (Gastroenterology), Herz-Jesu Hospital, D-48165 Muenster, Germany
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Anothra P, Pradhan D, Naik PK, Ghosh G, Rath G. Development and characterization of 5-fluorouracil nanofibrous film for the treatment of stomach cancer. J Drug Deliv Sci Technol 2021. [DOI: 10.1016/j.jddst.2020.102219] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
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Murray A, Nguyen TM, Parker CE, Feagan BG, MacDonald JK. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2020; 8:CD000543. [PMID: 32786164 PMCID: PMC8189994 DOI: 10.1002/14651858.cd000543.pub5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Oral 5-aminosalicylic acid (5-ASA) preparations were intended to avoid the adverse effects of sulfasalazine (SASP) while maintaining its therapeutic benefits. It was previously found that 5-ASA drugs in doses of at least 2 g/day were more effective than placebo but no more effective than SASP for inducing remission in ulcerative colitis (UC). This review is an update of a previously published Cochrane Review. OBJECTIVES To assess the efficacy, dose-responsiveness and safety of oral 5-ASA compared to placebo, SASP, or 5-ASA comparators (i.e. other formulations of 5-ASA) for induction of remission in active UC. A secondary objective was to compare the efficacy and safety of once-daily dosing of oral 5-ASA versus conventional dosing regimens (two or three times daily). SEARCH METHODS We searched MEDLINE, Embase and the Cochrane Library on 11 June 2019. We also searched references, conference proceedings and study registers to identify additional studies. SELECTION CRITERIA We considered randomized controlled trials (RCTs) including adults (aged 18 years or more) with active UC for inclusion. We included studies that compared oral 5-ASA therapy with placebo, SASP, or other 5-ASA formulations. We also included studies that compared once-daily to conventional dosing as well as dose-ranging studies. DATA COLLECTION AND ANALYSIS Outcomes include failure to induce global/clinical remission, global/clinical improvement, endoscopic remission, endoscopic improvement, adherence, adverse events (AEs), serious adverse events (SAEs), withdrawals due to AEs, and withdrawals or exclusions after entry. We analyzed five comparisons: 5-ASA versus placebo, 5-ASA versus sulfasalazine, once-daily dosing versus conventional dosing, 5-ASA (e.g. MMX mesalamine, Ipocol, Balsalazide, Pentasa, Olsalazine and 5-ASA micropellets) versus comparator 5-ASA (e.g. Asacol, Claversal, Salofalk), and 5-ASA dose-ranging. We calculated the risk ratio (RR) and 95% confidence interval (95% CI) for each outcome. We analyzed data on an intention-to-treat basis, and used GRADE to assess the overall certainty of the evidence. MAIN RESULTS We include 54 studies (9612 participants). We rated most studies at low risk of bias. Seventy-one per cent (1107/1550) of 5-ASA participants failed to enter clinical remission compared to 83% (695/837) of placebo participants (RR 0.86, 95% CI 0.82 to 0.89; 2387 participants, 11 studies; high-certainty evidence). We also observed a dose-response trend for 5-ASA. There was no difference in clinical remission rates between 5-ASA and SASP. Fifty-four per cent (150/279) of 5-ASA participants failed to enter remission compared to 58% (144/247) of SASP participants (RR 0.90, 95% CI 0.77 to 1.04; 526 participants, 8 studies; moderate-certainty evidence). There was no difference in remission rates between once-daily dosing and conventional dosing. Sixty per cent (533/881) of once-daily participants failed to enter clinical remission compared to 61% (538/880) of conventionally-dosed participants (RR 0.99, 95% CI 0.93 to 1.06; 1761 participants, 5 studies; high-certainty evidence). Eight per cent (15/179) of participants dosed once daily failed to adhere to their medication regimen compared to 6% (11/179) of conventionally-dosed participants (RR 1.36, 95% CI 0.64 to 2.86; 358 participants, 2 studies; low-certainty evidence). There does not appear to be any difference in efficacy among the various 5-ASA formulations. Fifty per cent (507/1022) of participants in the 5-ASA group failed to enter remission compared to 52% (491/946) of participants in the 5-ASA comparator group (RR 0.94, 95% CI 0.86 to 1.02; 1968 participants, 11 studies; moderate-certainty evidence). There was no evidence of a difference in the incidence of adverse events and serious adverse events between 5-ASA and placebo, once-daily and conventionally-dosed 5-ASA, and 5-ASA and comparator 5-ASA formulation studies. Common adverse events included flatulence, abdominal pain, nausea, diarrhea, headache and worsening UC. SASP was not as well tolerated as 5-ASA. Twenty-nine per cent (118/411) of SASP participants experienced an AE compared to 15% (72/498) of 5-ASA participants (RR 0.48, 95% CI 0.36 to 0.63; 909 participants, 12 studies; moderate-certainty evidence). AUTHORS' CONCLUSIONS There is high-certainty evidence that 5-ASA is superior to placebo, and moderate-certainty evidence that 5-ASA is not more effective than SASP. Considering relative costs, a clinical advantage to using oral 5-ASA in place of SASP appears unlikely. High-certainty evidence suggests 5-ASA dosed once daily appears to be as efficacious as conventionally-dosed 5-ASA. There may be little or no difference in efficacy or safety among the various 5-ASA formulations.
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Affiliation(s)
- Alistair Murray
- Schulich School of Medicine & Dentistry, University of Western Ontario, London, Canada
| | | | | | - Brian G Feagan
- Robarts Clinical Trials, London, Canada
- Department of Medicine, University of Western Ontario, London, Canada
- Department of Epidemiology and Biostatistics, University of Western Ontario, London, Canada
| | - John K MacDonald
- Department of Medicine, University of Western Ontario, London, Canada
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Pourjafar H, Noori N, Gandomi H, Basti AA, Ansari F. Viability of microencapsulated and non-microencapsulated Lactobacilli in a commercial beverage. ACTA ACUST UNITED AC 2020; 25:e00432. [PMID: 32099822 PMCID: PMC7030990 DOI: 10.1016/j.btre.2020.e00432] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 01/19/2020] [Accepted: 02/05/2020] [Indexed: 12/29/2022]
Abstract
Ca-alginate-chitosan and eudragit S100 nanoparticles were used for encapsulation. The encapsulation increased the viability of probiotics into Iranian Doogh beverage. The encapsulation increased the viability of probiotics under GI conditions. The survival rate of free and encapsulated L. acidophilus and L. rhamnosus into Doogh beverage and simulated gastrointestinal conditions during 42-day were studied. Microencapsulation considerably protected both L. acidophilus and L. rhamnosus in Doogh beverage storage and in gastrointestinal conditions. Microencapsulation provided better protection to L. acidophilus than to L. rhamnosus during Doogh storage. In beverages containing the free form of bacteria, pH and acidity changes were greater than those of microencapsulated and control groups. More activity of the free probiotic bacteria (during a 42-day period especially after 21-day) produced more acid and metabolites inside the product, thereby reducing the organoleptic properties scores, However, acidity, pH and organoleptic characteristics of Doogh containing microencapsulated bacteria did not change considerably. In conclusion, this study suggests that the encapsulation and double coating of L. acidophilus and L. rhamnosus can increase the viability of them in Doogh beverage and in simulated GI conditions.
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Affiliation(s)
- Hadi Pourjafar
- Department of Food Sciences, Maragheh University of Medical Sciences, Maragheh, Iran
| | - Negin Noori
- Department of Food Hygiene, Faculty of Veterinary Medicine, University of Tehran, Iran
| | - Hasan Gandomi
- Department of Food Hygiene, Faculty of Veterinary Medicine, University of Tehran, Iran
| | | | - Fereshteh Ansari
- Research Center for Evidence-Based Medicine, Health Management and Safety Promotion Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran.,Iranian EBM Centre: A Joanna Briggs Institute Affiliated Group, Iran.,Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Tehran. Iran
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Yasutomi E, Hiraoka S, Yamamoto S, Oka S, Hirai M, Yamasaki Y, Inokuchi T, Kinugasa H, Takahara M, Harada K, Kato J, Okada H. Switching between Three Types of Mesalazine Formulation and Sulfasalazine in Patients with Active Ulcerative Colitis Who Have Already Received High-Dose Treatment with These Agents. J Clin Med 2019; 8:E2109. [PMID: 31810227 PMCID: PMC6970226 DOI: 10.3390/jcm8122109] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 11/27/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND AND AIM Oral mesalazine and sulfasalazine (SASP) are key drugs for treating ulcerative colitis (UC). The efficacy of switching from one of the several mesalazine formulations to another is largely unknown. This study assessed the efficacy of switching among three types of mesalazine formulation and SASP for UC therapy. METHODS UC patients receiving high-dose mesalazine/SASP who switched to other formulations due to disease activity were considered eligible. Efficacy was evaluated 2, 6, and 12 months after switching. RESULTS A total of 106 switches in 88 UC patients were analyzed. The efficacy at 2 months after switching was observed in 23/39 (59%) cases from any mesalazine formulation to SASP, in 18/55 (33%) cases from one mesalazine to another, and in 2/12 (17%) cases from SASP to any mesalazine formulation. Nine of 43 effective cases showed inefficacy or became intolerant post-switching. Delayed efficacy more than two months after switching was observed in four cases. Steroid-free remission was achieved in 42/106 (39%) cases-within 100 days in 35 of these cases (83%). CONCLUSIONS Switching from mesalazine to SASP was effective in more than half of cases. The efficacy of switching between mesalazine formulations was lower but may be worth attempting in clinical practice from a safety perspective.
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Affiliation(s)
- Eriko Yasutomi
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; (E.Y.); (S.Y.); (S.O.); (M.H.); (Y.Y.); (T.I.); (H.K.); (M.T.); (K.H.); (H.O.)
| | - Sakiko Hiraoka
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; (E.Y.); (S.Y.); (S.O.); (M.H.); (Y.Y.); (T.I.); (H.K.); (M.T.); (K.H.); (H.O.)
| | - Shumpei Yamamoto
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; (E.Y.); (S.Y.); (S.O.); (M.H.); (Y.Y.); (T.I.); (H.K.); (M.T.); (K.H.); (H.O.)
| | - Shohei Oka
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; (E.Y.); (S.Y.); (S.O.); (M.H.); (Y.Y.); (T.I.); (H.K.); (M.T.); (K.H.); (H.O.)
| | - Mami Hirai
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; (E.Y.); (S.Y.); (S.O.); (M.H.); (Y.Y.); (T.I.); (H.K.); (M.T.); (K.H.); (H.O.)
| | - Yasushi Yamasaki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; (E.Y.); (S.Y.); (S.O.); (M.H.); (Y.Y.); (T.I.); (H.K.); (M.T.); (K.H.); (H.O.)
| | - Toshihiro Inokuchi
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; (E.Y.); (S.Y.); (S.O.); (M.H.); (Y.Y.); (T.I.); (H.K.); (M.T.); (K.H.); (H.O.)
| | - Hideaki Kinugasa
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; (E.Y.); (S.Y.); (S.O.); (M.H.); (Y.Y.); (T.I.); (H.K.); (M.T.); (K.H.); (H.O.)
| | - Masahiro Takahara
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; (E.Y.); (S.Y.); (S.O.); (M.H.); (Y.Y.); (T.I.); (H.K.); (M.T.); (K.H.); (H.O.)
| | - Keita Harada
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; (E.Y.); (S.Y.); (S.O.); (M.H.); (Y.Y.); (T.I.); (H.K.); (M.T.); (K.H.); (H.O.)
| | - Jun Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba 260-0856, Japan;
| | - Hiroyuki Okada
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; (E.Y.); (S.Y.); (S.O.); (M.H.); (Y.Y.); (T.I.); (H.K.); (M.T.); (K.H.); (H.O.)
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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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Efficacy of co-administration of modified apple polysaccharide and probiotics in guar gum-Eudragit S100 based mesalamine mini tablets: A novel approach in treating ulcerative colitis. Int J Biol Macromol 2019; 126:427-435. [DOI: 10.1016/j.ijbiomac.2018.12.154] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 11/28/2018] [Accepted: 12/16/2018] [Indexed: 02/07/2023]
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11
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Wang J, Ghali S, Xu C, Mussatto CC, Ortiz C, Lee EC, Tran DH, Jacobs JP, Lagishetty V, Faull KF, Moller T, Rossetti M, Chen X, Koon HW. Ceragenin CSA13 Reduces Clostridium difficile Infection in Mice by Modulating the Intestinal Microbiome and Metabolites. Gastroenterology 2018; 154:1737-1750. [PMID: 29360463 PMCID: PMC5927842 DOI: 10.1053/j.gastro.2018.01.026] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 12/21/2017] [Accepted: 01/15/2018] [Indexed: 01/01/2023]
Abstract
BACKGROUND & AIMS Clostridium difficile induces intestinal inflammation by releasing toxins A and B. The antimicrobial compound cationic steroid antimicrobial 13 (CSA13) has been developed for treating gastrointestinal infections. The CSA13-Eudragit formulation can be given orally and releases CSA13 in the terminal ileum and colon. We investigated whether this form of CSA13 reduces C difficile infection (CDI) in mice. METHODS C57BL/6J mice were infected with C difficile on day 0, followed by subcutaneous administration of pure CSA13 or oral administration of CSA13-Eudragit (10 mg/kg/d for 10 days). Some mice were given intraperitoneal vancomycin (50 mg/kg daily) on days 0-4 and relapse was measured after antibiotic withdrawal. The mice were monitored until day 20; colon and fecal samples were collected on day 3 for analysis. Blood samples were collected for flow cytometry analyses. Fecal pellets were collected each day from mice injected with CSA13 and analyzed by high-performance liquid chromatography or 16S sequencing; feces were also homogenized in phosphate-buffered saline and fed to mice with CDI via gavage. RESULTS CDI of mice caused 60% mortality, significant bodyweight loss, and colonic damage 3 days after infection; these events were prevented by subcutaneous injection of CSA13 or oral administration CSA13-Eudragit. There was reduced relapse of CDI after administration of CSA13 was stopped. Levels of CSA13 in feces from mice given CSA13-Eudragit were significantly higher than those of mice given subcutaneous CSA13. Subcutaneous and oral CSA13 each significantly increased the abundance of Peptostreptococcaceae bacteria and reduced the abundance of C difficile in fecal samples of mice. When feces from mice with CDI and given CSA13 were fed to mice with CDI that had not received CSA13, the recipient mice had significantly increased rates of survival. CSA13 reduced fecal levels of inflammatory metabolites (endocannabinoids) and increased fecal levels of 4 protective metabolites (ie, citrulline, 3-aminoisobutyric acid, retinol, and ursodeoxycholic acid) in mice with CDI. Oral administration of these CSA13-dependent protective metabolites reduced the severity of CDI. CONCLUSIONS In studies of mice, we found the CSA13-Eudragit formulation to be effective in eradicating CDI by modulating the intestinal microbiota and metabolites.
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Affiliation(s)
- Jiani Wang
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095,Department of Gastroenterology, First Affiliated Hospital, China Medical University, Shenyang City, Liaoning Province, China
| | - Sally Ghali
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095
| | - Chunlan Xu
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095,The Key Laboratory for Space Bioscience and Biotechnology, School of Life Science, Northwestern Polytechnical University, Xian, Shaanxi Province, China
| | - Caroline C. Mussatto
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095
| | - Christina Ortiz
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095
| | - Elaine C. Lee
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095
| | - Diana H. Tran
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095
| | - Jonathan P. Jacobs
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095
| | - Venu Lagishetty
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095
| | - Kym F. Faull
- Pasarow Mass Spectrometry Laboratory, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095
| | - Travis Moller
- Pasarow Mass Spectrometry Laboratory, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095
| | - Maura Rossetti
- Immunogenetics Center, Department of Pathology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095
| | - Xinhua Chen
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
| | - Hon Wai Koon
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California.
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Ansari F, Pourjafar H, Jodat V, Sahebi J, Ataei A. Effect of Eudragit S100 nanoparticles and alginate chitosan encapsulation on the viability of Lactobacillus acidophilus and Lactobacillus rhamnosus. AMB Express 2017; 7:144. [PMID: 28687035 PMCID: PMC5500604 DOI: 10.1186/s13568-017-0442-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 06/22/2017] [Indexed: 01/03/2023] Open
Abstract
In this study, we examined a novel method of microencapsulation with calcium alginate-chitosan and Eudragit S100 nanoparticles for the improving viability of probiotic bacteria, Lactobacillus acidophilus and Lactobacillus rhamnosus. Extrusion technique was carried out in microencapsulation process. The viability of two probiotics in single coated beads (with only chitosan), double coated beads (with chitosan and Eudragit nanoparticles), and as free cells (unencapsulated) were conducted in simulated gastric juice (pH 1.55, without pepsin) followed by incubation in simulated intestinal juice (pH 7.5, with 1% bile salt). In case of single coated beads, presumably, lack of sufficient strength of chitosan under simulated gastric condition was the main reason of 4-log and 5-log reduction of the counts of the L. acidophilus and L. rhamnosus respectively. The results showed that with the second coat forming (Eudragit nanoparticles) over the first coat (chitosan), the strength of the beads and then viability rate of the bacteria were increased in comparison with the single coated beads.
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Vinner GK, Vladisavljević GT, Clokie MRJ, Malik DJ. Microencapsulation of Clostridium difficile specific bacteriophages using microfluidic glass capillary devices for colon delivery using pH triggered release. PLoS One 2017; 12:e0186239. [PMID: 29023522 PMCID: PMC5638336 DOI: 10.1371/journal.pone.0186239] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 09/27/2017] [Indexed: 12/14/2022] Open
Abstract
The prevalence of pathogenic bacteria acquiring multidrug antibiotic resistance is a global health threat to mankind. This has motivated a renewed interest in developing alternatives to conventional antibiotics including bacteriophages (viruses) as therapeutic agents. The bacterium Clostridium difficile causes colon infection and is particularly difficult to treat with existing antibiotics; phage therapy may offer a viable alternative. The punitive environment within the gastrointestinal tract can inactivate orally delivered phages. C. difficile specific bacteriophage, myovirus CDKM9 was encapsulated in a pH responsive polymer (Eudragit® S100 with and without alginate) using a flow focussing glass microcapillary device. Highly monodispersed core-shell microparticles containing phages trapped within the particle core were produced by in situ polymer curing using 4-aminobenzoic acid dissolved in the oil phase. The size of the generated microparticles could be precisely controlled in the range 80 μm to 160 μm through design of the microfluidic device geometry and by varying flow rates of the dispersed and continuous phase. In contrast to free 'naked' phages, those encapsulated within the microparticles could withstand a 3 h exposure to simulated gastric fluid at pH 2 and then underwent a subsequent pH triggered burst release at pH 7. The significance of our research is in demonstrating that C. difficile specific phage can be formulated and encapsulated in highly uniform pH responsive microparticles using a microfluidic system. The microparticles were shown to afford significant protection to the encapsulated phage upon prolonged exposure to an acid solution mimicking the human stomach environment. Phage encapsulation and subsequent release kinetics revealed that the microparticles prepared using Eudragit® S100 formulations possess pH responsive characteristics with phage release triggered in an intestinal pH range suitable for therapeutic purposes. The results reported here provide proof-of-concept data supporting the suitability of our approach for colon targeted delivery of phages for therapeutic purposes.
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Affiliation(s)
- Gurinder K. Vinner
- Chemical Engineering Department, Loughborough University, Loughborough, United Kingdom
| | | | - Martha R. J. Clokie
- Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom
| | - Danish J. Malik
- Chemical Engineering Department, Loughborough University, Loughborough, United Kingdom
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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] [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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Role of synbiotics in polysaccharide assisted colon targeted microspheres of mesalamine for the treatment of ulcerative colitis. Int J Biol Macromol 2017; 95:438-450. [DOI: 10.1016/j.ijbiomac.2016.11.066] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 11/03/2016] [Accepted: 11/18/2016] [Indexed: 12/22/2022]
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Wang Y, Parker CE, Bhanji T, Feagan BG, MacDonald JK. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2016; 4:CD000543. [PMID: 27101467 PMCID: PMC7045743 DOI: 10.1002/14651858.cd000543.pub4] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Oral 5-aminosalicylic acid (5-ASA) preparations were intended to avoid the adverse effects of sulfasalazine (SASP) while maintaining its therapeutic benefits. Previously, it was found that 5-ASA drugs in doses of at least 2 g/day, were more effective than placebo but no more effective than SASP for inducing remission in ulcerative colitis. This updated review includes more recent studies and evaluates the efficacy and safety of 5-ASA preparations used for the treatment of mild to moderately active ulcerative colitis. OBJECTIVES The primary objectives were to assess the efficacy, dose-responsiveness and safety of oral 5-ASA compared to placebo, SASP, or 5-ASA comparators for induction of remission in active ulcerative colitis. A secondary objective of this systematic review was to compare the efficacy and safety of once daily dosing of oral 5-ASA with conventional (two or three times daily) dosing regimens. SEARCH METHODS A computer-assisted literature search for relevant studies (inception to July 9, 2015) was performed using MEDLINE, EMBASE and the Cochrane Library. Review articles and conference proceedings were also searched to identify additional studies. SELECTION CRITERIA Studies were accepted for analysis if they were randomized controlled clinical trials of parallel design, with a minimum treatment duration of four weeks. Studies of oral 5-ASA therapy for treatment of patients with active ulcerative colitis compared with placebo, SASP or other formulations of 5-ASA were considered for inclusion. Studies that compared once daily 5-ASA treatment with conventional dosing of 5-ASA (two or three times daily) and 5-ASA dose ranging studies were also considered for inclusion. DATA COLLECTION AND ANALYSIS The outcomes of interest were the failure to induce global/clinical remission, global/clinical improvement, endoscopic remission, endoscopic improvement, adherence, adverse events, withdrawals due to adverse events, and withdrawals or exclusions after entry. Trials were separated into five comparison groups: 5-ASA versus placebo, 5-ASA versus sulfasalazine, once daily dosing versus conventional dosing, 5-ASA versus comparator 5-ASA, and 5-ASA dose-ranging. Placebo-controlled trials were subgrouped by dosage. SASP-controlled trials were subgrouped by 5-ASA/SASP mass ratios. Once daily versus conventional dosing studies were subgrouped by formulation. 5-ASA-controlled trials were subgrouped by common 5-ASA comparators (e.g. Asacol, Claversal, Salofalk and Pentasa). Dose-ranging studies were subgrouped by 5-ASA formulation. We calculated the relative risk (RR) and 95% confidence intervals (95% CI) for each outcome. Data were analyzed on an intention-to-treat basis. MAIN RESULTS Fifty-three studies (8548 patients) were included. The majority of included studies were rated as low risk of bias. 5-ASA was significantly superior to placebo with regard to all measured outcome variables. Seventy-one per cent of 5-ASA patients failed to enter clinical remission compared to 83% of placebo patients (RR 0.86, 95% CI 0.82 to 0.89). A dose-response trend for 5-ASA was also observed. No statistically significant differences in efficacy were found between 5-ASA and SASP. Fifty-four per cent of 5-ASA patients failed to enter remission compared to 58% of SASP patients (RR 0.90, 95% CI 0.77 to 1.04). No statistically significant differences in efficacy or adherence were found between once daily and conventionally dosed 5-ASA. Forty-five per cent of once daily patients failed to enter clinical remission compared to 48% of conventionally dosed patients (RR 0.94, 95% CI 0.83 to 1.07). Eight per cent of patients dosed once daily failed to adhere to their medication regimen compared to 6% of conventionally dosed patients (RR 1.36, 95% CI 0.64 to 2.86). There does not appear to be any difference in efficacy among the various 5-ASA formulations. Fifty per cent of patients in the 5-ASA group failed to enter remission compared to 52% of patients in the 5-ASA comparator group (RR 0.94, 95% CI 0.86 to 1.02). A pooled analysis of 3 studies (n = 1459 patients) studies found no statistically significant difference in clinical improvement between Asacol 4.8 g/day and 2.4 g/day used for the treatment of moderately active ulcerative colitis. Thirty-seven per cent of patients in the 4.8 g/day group failed to improve clinically compared to 41% of patients in the 2.4 g/day group (RR 0.89; 95% CI 0.78 to 1.01). Subgroup analysis indicated that patients with moderate disease may benefit from the higher dose of 4.8 g/day. One study compared (n = 123 patients) Pentasa 4 g/day to 2.25 g/day in patients with moderate disease. Twenty-five per cent of patients in the 4 g/day group failed to improve clinically compared to 57% of patients in the 2.25 g/day group (RR 0.44; 95% CI 0.27 to 0.71). A pooled analysis of two studies comparing MMX mesalamine 4.8 g/day to 2.4 g/day found no statistically significant difference in efficacy (RR 1.03, 95% CI 0.82 to 1.29). There were no statistically significant differences in the incidence of adverse events between 5-ASA and placebo, once daily and conventionally dosed 5-ASA, 5-ASA and comparator 5-ASA formulation and 5-ASA dose ranging (high dose versus low dose) studies. Common adverse events included flatulence, abdominal pain, nausea, diarrhea, headache and worsening ulcerative colitis. SASP was not as well tolerated as 5-ASA. Twenty-nine percent of SASP patients experienced an adverse event compared to 15% of 5-ASA patients (RR 0.48, 95% CI 0.37 to 0.63). AUTHORS' CONCLUSIONS 5-ASA was superior to placebo and no more effective than SASP. Considering their relative costs, a clinical advantage to using oral 5-ASA in place of SASP appears unlikely. 5-ASA dosed once daily appears to be as efficacious and safe as conventionally dosed 5-ASA. Adherence does not appear to be enhanced by once daily dosing in the clinical trial setting. It is unknown if once daily dosing of 5-ASA improves adherence in a community-based setting. There do not appear to be any differences in efficacy or safety among the various 5-ASA formulations. A daily dosage of 2.4 g appears to be a safe and effective induction therapy for patients with mild to moderately active ulcerative colitis. Patients with moderate disease may benefit from an initial dose of 4.8 g/day.
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Affiliation(s)
- Yongjun Wang
- University of Western OntarioSchulich School of Medicine & DentistryLondonONCanada
| | - Claire E Parker
- Robarts Clinical TrialsCochrane IBD Group100 Dundas Street, Suite 200LondonONCanadaN6A 5B6
| | - Tania Bhanji
- University of Western OntarioInternal MedicineLondonONCanada
| | - Brian G Feagan
- Robarts Clinical TrialsCochrane IBD Group100 Dundas Street, Suite 200LondonONCanadaN6A 5B6
- University of Western OntarioDepartment of MedicineLondonONCanada
- University of Western OntarioDepartment of Epidemiology and BiostatisticsLondonONCanada
| | - John K MacDonald
- Robarts Clinical TrialsCochrane IBD Group100 Dundas Street, Suite 200LondonONCanadaN6A 5B6
- University of Western OntarioDepartment of MedicineLondonONCanada
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Ye B, van Langenberg DR. Mesalazine preparations for the treatment of ulcerative colitis: Are all created equal? World J Gastrointest Pharmacol Ther 2015; 6:137-144. [PMID: 26558148 PMCID: PMC4635154 DOI: 10.4292/wjgpt.v6.i4.137] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Revised: 08/24/2015] [Accepted: 10/13/2015] [Indexed: 02/06/2023] Open
Abstract
Oral mesalazine (also known as mesalamine) is a 5-aminosalicylic acid compound used in the treatment of mild to moderate ulcerative colitis, with high rates of efficacy in induction and maintenance of remission. The therapeutic effect of mesalazine occurs topically at the site of diseased colonic mucosa. A myriad of oral mesalazine preparations have been formulated with various drug delivery methods to minimize systemic absorption and maximise drug availability at the inflamed colonic epithelium. It remains unclear whether different oral mesalazine formulations are bioequivalent. This review aims to evaluate the differences between mesalazine formulations based on the currently available literature and explore factors which may influence the selection of one agent above another.
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Bressenot A, Salleron J, Bastien C, Danese S, Boulagnon-Rombi C, Peyrin-Biroulet L. Comparing histological activity indexes in UC. Gut 2015; 64:1412-8. [PMID: 25246423 DOI: 10.1136/gutjnl-2014-307477] [Citation(s) in RCA: 102] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Accepted: 09/02/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND Assessment of disease activity in UC is important for designing an optimal therapeutic strategy. No single histology score is considered optimum. The aim of this study was to compare intraobserver reproducibility and the interobserver agreement of available histological UC activity indexes. METHODS One hundred and two biopsy specimens (collected between 2003 and 2014) were scored blindly by three pathologists by determining Geboes, Riley, Gramlich and Gupta indexes and global visual evaluation (GVE). Intraobserver reproducibility and interobserver agreements for index and items of index were studied by intraclass correlation coefficient for quantitative parameter and by κ values and Krippendorff index for qualitative parameters. Relationship between indexes was studied by computation of Pearson's and Spearman's correlation coefficients. RESULTS Geboes, Riley, Gramlich and Gupta indexes and GVE showed good intraobserver reproducibility and a good interobserver agreement. Histological items that showed the best interobserver agreement were 'erosion/ulceration or surface epithelial integrity' and 'acute inflammatory cells infiltrate/neutrophils in lamina propria'. The five scores were strongly correlated. CONCLUSIONS Correlation between indexes is strong. Intraobserver reproducibility and interobserver agreement for all indexes is very good. Histological items that showed the best interobserver agreement are 'erosion/ulceration' and 'acute inflammatory cells infiltrate/neutrophils in lamina propria'.
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Affiliation(s)
- Aude Bressenot
- Inserm U954, Genetic nutrition and exposure to environmental risks (NGERE), University of Lorraine, Vandoeuvre-lès-Nancy, France Department of Pathology, University Hospital of Lorraine, Vandoeuvre-lès-Nancy, France
| | - Julia Salleron
- Department of biostatistics, Institute de Cancérologie de Lorraine, Vandoeuvre-lès-Nancy, France
| | - Claire Bastien
- Department of Pathology, University Hospital of Lorraine, Vandoeuvre-lès-Nancy, France
| | - Silvio Danese
- IBD center, Division of Gastroenterology, Humanitas Clinical and Research hospital, Rozzano, Milano, Italy
| | | | - Laurent Peyrin-Biroulet
- Inserm U954, Genetic nutrition and exposure to environmental risks (NGERE), University of Lorraine, Vandoeuvre-lès-Nancy, France Department of Hepato-Gastroenterology, University Hospital of Lorraine, Vandoeuvre-lès-Nancy, France
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Dignass A, Lindsay JO, Sturm A, Windsor A, Colombel JF, Allez M, d'Haens G, d'Hoore A, Mantzanaris G, Novacek G, Öresland T, Reinisch W, Sans M, Stange E, Vermeire S, Travis S, van Assche G. [Second European evidence-based consensus on the diagnosis and management of ulcerative colitis Part 2: Current management (Spanish version)]. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2015; 80:32-73. [PMID: 25769217 DOI: 10.1016/j.rgmx.2014.10.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 10/23/2014] [Indexed: 02/06/2023]
Affiliation(s)
- A Dignass
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso.
| | | | - A Sturm
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - A Windsor
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - J-F Colombel
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - M Allez
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - G d'Haens
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - A d'Hoore
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - G Mantzanaris
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - G Novacek
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - T Öresland
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - W Reinisch
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - M Sans
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - E Stange
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - S Vermeire
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - S Travis
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
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Lautenschläger C, Schmidt C, Fischer D, Stallmach A. Drug delivery strategies in the therapy of inflammatory bowel disease. Adv Drug Deliv Rev 2014; 71:58-76. [PMID: 24157534 DOI: 10.1016/j.addr.2013.10.001] [Citation(s) in RCA: 189] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Revised: 10/08/2013] [Accepted: 10/10/2013] [Indexed: 12/17/2022]
Abstract
Inflammatory bowel disease (IBD) is a frequently occurring disease in young people, which is characterized by a chronic inflammation of the gastrointestinal tract. The therapy of IBD is dominated by the administration of anti-inflammatory and immunosuppressive drugs, which suppress the intestinal inflammatory burden and improve the disease-related symptoms. Established treatment strategies are characterized by a limited therapeutical efficacy and the occurrence of adverse drug reactions. Thus, the development of novel disease-targeted drug delivery strategies is intended for a more effective therapy and demonstrates the potential to address unmet medical needs. This review gives an overview about the established as well as future-oriented drug targeting strategies, including intestine targeting by conventional drug delivery systems (DDS), disease targeted drug delivery by synthetic DDS and disease targeted drug delivery by biological DDS. Furthermore, this review analyses the targeting mechanisms of the respective DDS and discusses the possible field of utilization in IBD.
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Affiliation(s)
- Christian Lautenschläger
- Clinic of Internal Medicine IV, University Hospital Jena, Erlanger Allee 101, 07740 Jena, Germany.
| | - Carsten Schmidt
- Clinic of Internal Medicine IV, University Hospital Jena, Erlanger Allee 101, 07740 Jena, Germany.
| | - Dagmar Fischer
- Institute of Pharmacy, Department of Pharmaceutical Technology, Friedrich-Schiller University Jena, Otto-Schott-Strasse 41, 07745 Jena, Germany.
| | - Andreas Stallmach
- Clinic of Internal Medicine IV, University Hospital Jena, Erlanger Allee 101, 07740 Jena, Germany.
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21
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Abstract
BACKGROUND The consistency of endoscopic and histologic findings in patients with ulcerative colitis (UC) has not been elucidated. Choice of assessment may affect study outcomes. METHODS Post hoc analyses were performed using data from 2 randomized, controlled multicenter trials: (1) SAG-26, mesalazine granules for induction of remission in UC (n = 380), and (2) SAG-27, mesalazine granules for maintenance of UC remission (n = 647). Assessments included Clinical Activity Index, Endoscopic Index, modified Disease Activity Index, and Histology Index. RESULTS In SAG-26, 52 of 380 patients (13.7%) with clinically (Clinical Activity Index >4) and endoscopically (Endoscopic Index ≥4) active UC showed no histological signs of active inflammation (Histology Index ≤1) at baseline. Among endoscopically and histologically active patients, 246 of 327 (75.2%) reached clinical remission versus 48 of 52 patients (92.3%) with active endoscopy but no inflammation on histology (difference, 17.1%; P = 0.006). The difference in the proportion of patients achieving clinical remission according to endoscopy and histology in clinically inactive (Clinical Activity Index ≤4) patients was 30.8% in SAG-26 (at the study end) and 28.1% in SAG-27 (at baseline). In SAG-27, clinical relapse occurred in 21.2% of patients with endoscopic and histologic remission at baseline and 27.1% of patients with some histological inflammation at baseline (P = 0.111). Using the modified Disease Activity Index ≤1 (mucosal healing) instead of the Endoscopic Index score, the difference was similar (21.2% versus 28.0%, P = 0.073). CONCLUSIONS Endoscopic and histologic assessments differ in both active and inactive UC. Overdiagnosis of inflammation using endoscopy versus histology can significantly affect outcomes, at least in studies using induction of clinical remission as an endpoint. The assessment criteria for trials in UC should be reconsidered.
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22
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Are there any differences in the efficacy and safety of different formulations of Oral 5-ASA used for induction and maintenance of remission in ulcerative colitis? evidence from cochrane reviews. Inflamm Bowel Dis 2013; 19:2031-40. [PMID: 23811638 DOI: 10.1097/mib.0b013e3182920108] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND We systematically reviewed and compared the efficacy and safety of oral mesalamine formulations (sustained release, delayed release, and prodrugs) used for induction and maintenance of remission in ulcerative colitis. The main objective of this review was to determine if there are any differences in efficacy or safety among the oral 5-ASA drugs. METHODS A literature search in February 2013 identified all applicable randomized trials. Study quality was evaluated using the Cochrane risk of bias tool. The Grading of Recommendations Assessment, Development and Evaluation criteria were used to assess the overall quality of the evidence. Studies were subgrouped by common mesalamine comparators for meta-analysis. Studies were pooled for analysis if they compared equimolar doses of oral 5-ASA. RESULTS Seventeen studies that evaluated 2925 patients were identified. The risk of bias was low for most factors, although 1 study was single blind and 3 were open label. No difference was observed between oral 5-ASA and comparator 5-ASA formulations in the proportion of patients with clinical remission (relative risk, 0.94; 95% confidence interval, 0.86-1.02), clinical improvement (relative risk, 0.89; 95% confidence interval, 0.77-1.01), or relapse at 12 months (relative risk, 1.01; 95% confidence interval, 0.80-1.28). Subgroup analyses showed no important differences in efficacy. No significant difference was demonstrated in rates of adverse events or withdrawal due to adverse events. CONCLUSIONS There does not seem to be any difference in efficacy or safety among the various formulations of oral 5-ASA. Oral mesalamine is an effective and safe treatment of mild-to-moderate or quiescent ulcerative colitis regardless of the chosen formulation.
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23
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Dignass A, Lindsay JO, Sturm A, Windsor A, Colombel JF, Allez M, D'Haens G, D'Hoore A, Mantzaris G, Novacek G, Oresland T, Reinisch W, Sans M, Stange E, Vermeire S, Travis S, Van Assche G. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management. J Crohns Colitis 2012; 6:991-1030. [PMID: 23040451 DOI: 10.1016/j.crohns.2012.09.002] [Citation(s) in RCA: 692] [Impact Index Per Article: 53.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2012] [Accepted: 09/03/2012] [Indexed: 02/07/2023]
Affiliation(s)
- Axel Dignass
- Department of Medicine 1, Agaplesion Markus Hospital, Wilhelm-Epstein-Str. 4, D-60431 Frankfurt/Main, Germany.
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24
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Dhanda AD, Creed TJ, Greenwood R, Sands BE, Probert CS. Can endoscopy be avoided in the assessment of ulcerative colitis in clinical trials? Inflamm Bowel Dis 2012; 18:2056-62. [PMID: 22271464 DOI: 10.1002/ibd.22879] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Accepted: 12/19/2011] [Indexed: 01/18/2023]
Abstract
BACKGROUND There is no gold standard index in the measurement of ulcerative colitis (UC) disease activity in clinical trials. Mucosal healing has been described as an important clinical endpoint requiring endoscopic assessment, which is unpleasant for the patient and may hamper recruitment to trials. The aim of this study was to determine whether endoscopy is necessary in the assessment of UC disease activity and whether a noninvasive disease activity index (partial Mayo score) could be used to predict the Mayo score. METHODS In all, 149 subjects with moderate to severe UC enrolled in a clinical trial were assessed using total and partial Mayo scores. Histologic assessment of biopsies was performed. A regression model was constructed to predict total Mayo score from the partial Mayo score and histology score from the Mayo score. A Bland-Altman test of agreement was performed. RESULTS The partial Mayo score correlated closely with the total Mayo score at week 4 (rho = 0.97) and week 8 (rho = 0.98). The model to predict total from partial Mayo score showed excellent correlation (rho = 0.97) and good agreement with the total Mayo score at week 4 and the week 8 validation set (rho = 0.97) and accurately classified disease severity (kappa = 0.82). The model to predict histology score from the Mayo score correlated only moderately with the actual histology score at week 4 (rho = 0.59) and week 8 (rho = 0.36). CONCLUSIONS The Mayo score can be accurately predicted from the partial Mayo score. A noninvasive index can replace the Mayo score in future clinical trials.
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Affiliation(s)
- Ashwin D Dhanda
- School of Clinical Sciences, University of Bristol, Bristol, UK.
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25
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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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26
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Abstract
BACKGROUND Oral 5-aminosalicylic acid (5-ASA) preparations were intended to avoid the adverse effects of sulfasalazine (SASP) while maintaining its therapeutic benefits. Previously, it was found that 5-ASA drugs in doses of at least 2 g/day, were more effective than placebo but no more effective than SASP for inducing remission in ulcerative colitis. This updated review includes more recent studies and evaluates the efficacy and safety of 5-ASA preparations used for the treatment of mild to moderately active ulcerative colitis. OBJECTIVES The primary objectives were to assess the efficacy, dose-responsiveness and safety of oral 5-ASA compared to placebo, SASP, or 5-ASA comparators for induction of remission in active ulcerative colitis. A secondary objective of this systematic review was to compare the efficacy and safety of once daily dosing of oral 5-ASA with conventional (two or three times daily) dosing regimens. SEARCH METHODS A computer-assisted literature search for relevant studies (inception to January 20, 2012) was performed using MEDLINE, EMBASE and the Cochrane Library. Review articles and conference proceedings were also searched to identify additional studies. SELECTION CRITERIA Studies were accepted for analysis if they were randomized controlled clinical trials of parallel design, with a minimum treatment duration of four weeks. Studies of oral 5-ASA therapy for treatment of patients with active ulcerative colitis compared with placebo, SASP or other formulations of 5-ASA were considered for inclusion. Studies that compared once daily 5-ASA treatment with conventional dosing of 5-ASA (two or three times daily) and 5-ASA dose ranging studies were also considered for inclusion. DATA COLLECTION AND ANALYSIS The outcomes of interest were the failure to induce global/clinical remission, global/clinical improvement, endoscopic remission, endoscopic improvement, adherence, adverse events, withdrawals due to adverse events, and withdrawals or exclusions after entry. Trials were separated into five comparison groups: 5-ASA versus placebo, 5-ASA versus sulfasalazine, once daily dosing versus conventional dosing, 5-ASA versus comparator 5-ASA, and 5-ASA dose-ranging. Placebo-controlled trials were subgrouped by dosage. SASP-controlled trials were subgrouped by 5-ASA/SASP mass ratios. Once daily versus conventional dosing studies were subgrouped by formulation. 5-ASA-controlled trials were subgrouped by common 5-ASA comparators (e.g. Asacol, Claversal, Salofalk and Pentasa). Dose-ranging studies were subgrouped by 5-ASA formulation. We calculated the relative risk (RR) and 95% confidence intervals (95% CI) for each outcome. Data were analyzed on an intention to treat basis. MAIN RESULTS Forty-eight studies (7776 patients) were included. The majority of included studies were rated as low risk of bias. 5-ASA was significantly superior to placebo with regard to all measured outcome variables. Seventy-two per cent of 5-ASA patients failed to enter clinical remission compared to 85% of placebo patients (RR 0.86, 95% CI 0.81 to 0.91). A dose-response trend for 5-ASA was also observed. No statistically significant differences in efficacy were found between 5-ASA and SASP. Fifty-four per cent of 5-ASA patients failed to enter remission compared to 58% of SASP patients (RR 0.90, 95% CI 0.77 to 1.04). No statistically significant differences in efficacy or adherence were found between once daily and conventionally dosed 5-ASA. Forty-two per cent of once daily patients failed to enter clinical remission compared to 44% of conventionally dosed patients (RR 0.95, 95% CI 0.82 to 1.10). Eight per cent of patients dosed once daily failed to adhere to their medication regimen compared to 6% of conventionally dosed patients (RR 1.36, 95% CI 0.64 to 2.86). There does not appear to be any difference in efficacy among the various 5-ASA formulations. Forty-eight per cent of patients in the 5-ASA group failed to enter remission compared to 50% of patients in the 5-ASA comparator group (RR 0.94, 95% CI 0.86 to 1.03). A pooled analysis of the ASCEND (I, II and III, n = 1459 patients) studies found no statistically significant difference in clinical improvement between Asacol 4.8 g/day and 2.4 g/day used for the treatment of moderately active ulcerative colitis. Thirty-seven per cent of patients in the 4.8 g/day group failed to improve clinically compared to 41% of patients in the 2.4 g/day group (RR 0.89; 95% CI 0.78 to 1.01). Subgroup analysis indicated that patients with moderate disease may benefit from the higher dose of 4.8 g/day. One study compared (n = 123 patients) Pentasa 4 g/day to 2.25 g/day in patients with moderate disease. Twenty-five per cent of patients in the 4 g/day group failed to improve clinically compared to 57% of patients in the 2.25 g/day group (RR 0.44; 95% CI 0.27 to 0.71). A pooled analysis of two studies comparing MMX mesalamine 4.8 g/day to 2.4 g/day found no statistically significant difference in efficacy (RR 1.03, 95% CI 0.82 to 1.29). 5-ASA was generally safe and common adverse events included flatulence, abdominal pain, nausea, diarrhea, headache and worsening ulcerative colitis. There were no statistically significant differences in the incidence of adverse events between 5-ASA and placebo, once daily and conventionally dosed 5-ASA, 5-ASA and comparator 5-ASA formulation and 5-ASA dose ranging (high dose versus low dose) studies. SASP was not as well tolerated as 5-ASA. Twenty-nine percent of SASP patients experienced an adverse event compared to 15% of 5-ASA patients (RR 0.48, 95% CI 0.37 to 0.63). AUTHORS' CONCLUSIONS 5-ASA was superior to placebo and no more effective than SASP. Considering their relative costs, a clinical advantage to using oral 5-ASA in place of SASP appears unlikely. 5-ASA dosed once daily appears to be as efficacious and safe as conventionally dosed 5-ASA. Adherence does not appear to be enhanced by once daily dosing in the clinical trial setting. It is unknown if once daily dosing of 5-ASA improves adherence in a community-based setting. There do not appear to be any differences in efficacy or safety among the various 5-ASA formulations. A daily dosage of 2.4 g appears to be a safe and effective induction therapy for patients with mild to moderately active ulcerative colitis. Patients with moderate disease may benefit from an initial dose of 4.8 g/day.
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Affiliation(s)
- Brian G Feagan
- Robarts Clinical Trials, Robarts Research Institute, London, Ontario, Canada.
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Brooks AJ, Lobo AJ. Are mesalazine granules superior to Eudragit-L-coated mesalazine tablets for induction of remission in distal ulcerative colitis? Aliment Pharmacol Ther 2012; 35:193-4. [PMID: 22150535 DOI: 10.1111/j.1365-2036.2011.04891.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- A J Brooks
- Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK
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28
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Leifeld L, Pfützer R, Morgenstern J, Gibson PR, Marakhouski Y, Greinwald R, Mueller R, Kruis W. Mesalazine granules are superior to Eudragit-L-coated mesalazine tablets for induction of remission in distal ulcerative colitis - a pooled analysis. Aliment Pharmacol Ther 2011; 34:1115-22. [PMID: 21923715 DOI: 10.1111/j.1365-2036.2011.04840.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Different oral formulations of 'mesalazine (mesalamine)' may have different efficacy in distal ulcerative colitis. AIM To evaluate the efficacy of mesalazine granules (Salofalk granules) vs. mesalazine tablets (Salofalk tablets) as induction therapy in patients with distinct extensions of ulcerative colitis. METHODS A pooled analysis of 705 patients from four prospective, randomised, double-blind phase III trials was performed. The efficacy of 8 weeks' induction with 3 g/day mesalazine granules [3 g once daily (o.d.) or 1 g three times daily (t.d.s)] vs. 3 g/day mesalazine tablets (1 g t.d.s.) was compared in terms of clinical remission (CR: CAI ≤ 4) and endoscopic remission (ER: EI ≤ 3) (both according to Rachmilewitz) in subgroups with pancolitis, left-sided colitis, or proctosigmoiditis. RESULTS Mesalazine granules were equipotent to mesalazine tablets in pancolitis regarding CR (72% vs. 71%, P = 0.909) and ER (58% vs. 49%, P = 0.338). In left-sided colitis, both mesalazine formulations were equipotent regarding CR (66% vs. 67%; P = 0.843) but mesalazine granules were superior regarding ER (56% vs. 37%; P = 0.025). In proctosigmoiditis, mesalazine granules were significantly more effective than mesalazine tablets regarding CR (78% vs. 55% P < 0.001) and ER (67% vs. 43% P < 0.001). Furthermore, o.d. application of mesalazine granules was more effective than t.d.s. dosing in left-sided colitis (CR 73% vs. 62%, P = 0.181; ER 71% vs. 48% P = 0.005) and proctosigmoiditis (CR 86% vs. 73%, P = 0.020; ER 75% vs. 61%, P = 0.021), but not in pancolitis. CONCLUSION This pooled analysis supports the hypothesis that mesalazine granules are superior to mesalazine tablets in induction of remission in distal colitis and should be taken once daily.
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Affiliation(s)
- L Leifeld
- Evangelisches Krankenhaus Kalk, Cologne, Germany.
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Abstract
Mesalamine has been the first-line of therapy in patients with inflammatory bowel disease (IBD) since the 1960s. This article serves as a review of the different 5-aminosalicylic acid compounds, release formulations, use and dosing in the treatment of IBD, in particular ulcerative colitis.
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Haddish-Berhane N, Farhadi A, Nyquist C, Haghighi K, Keshavarzian A. SIMDOT-AbMe: microphysiologically based simulation tool for quantitative prediction of systemic and local bioavailability of targeted oral delivery formulations. Drug Metab Dispos 2009; 37:608-18. [PMID: 19047471 DOI: 10.1124/dmd.108.021949] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The purpose of this study was to develop a physiologically based simulation tool that is able to predict local as well as systemic bioavailability of 5-aminosalicylic acid (5-ASA)-targeted delivery formulations using the existing understanding of the transport and metabolism mechanisms of 5-ASA. The model accounts for active and passive transcellular transport (absorptive and efflux), passive paracellular transport, intestinal biotransformation, and systemic metabolism and clearance. The intestinal physiology was represented by transverse segments for ileum and proximal colon and longitudinal compartments for the microphysiology of the intestinal tissue. The tool, equipped with an optimization routine that enables tuning model parameters, was developed in Matlab and uses a user-friendly graphical interface for data input and output. Physiologic and kinetic model parameters were estimated either from literature monolayer transport studies using nonlinear curve fitting or obtained directly from the literature. 5-ASA clinical pharmacokinetic profiles of a once-daily (one 4-g/day dose) and twice-daily (two 2-g/day doses) dosing regimen were used to partially calibrate and validate the model, respectively. Simulation results showed that drug C(max) in the gut mucosal layers reached a higher level and was achieved sooner than in the systemic blood level. The computed relative local bioavailability with respect to the systemic bioavailability was 0.063. With use of the model, the relative local bioavailability of different formulations can be established for fast performance verification of new preparations based on measured systemic bioavailability. These types of models play a critical role in designing such preparations and rapidly assessing their effectiveness and will foster efficient experimental designs, saving time and resources.
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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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Cortesi R, Ajanji SCL, Sivieri E, Manservigi M, Fundueanu G, Menegatti E, Esposito E. Eudragit® microparticles as a possible tool for ophthalmic administration of acyclovir. J Microencapsul 2008; 24:445-56. [PMID: 17578734 DOI: 10.1080/02652040701374889] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
This paper describes the production and characterization of polyacrylic polymer (Eudragit RL, RS and NE) microparticles by spray drying method. Microparticles were designed for ophthalmic administration of acyclovir. Microparticle morphology was characterized by optical and electron microscopy. The release kinetics of the drug from microspheres were determined by a dialysis method. The spray drying method described allows the production of microparticles with acceptable encapsulation efficiency and appropriate dimensional characteristics for ophthalmic administration. Release profile data indicate that acyclovir is released from microparticles in a controlled manner. In addition the release pattern of the drug is influenced by the type of Eudragit used for microparticle production. Moreover the plaque reduction efficiency of acyclovir containing microparticles (except for RS/NE microspheres) is comparable to that displayed by the free drug. Finally our results suggest that acyclovir containing microparticles could represent an interesting system for the release of this antiviral drug at the eye site.
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Affiliation(s)
- Rita Cortesi
- Department of Pharmaceutical Sciences, University of Ferrara.
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Abstract
5-aminosalicylic acid (5-ASA) is the standard first-line treatment for mild-to-moderate ulcerative colitis. A variety of 5-ASA delivery systems are available and in development, including both oral and rectal formulations; all of which aim to deliver the active drug to the colon while minimizing systemic absorption. Because the efficacy of most oral 5-ASA therapies is broadly similar, the appropriate selection of a given formulation often relies on other factors. This article explores the differences between oral 5-ASA formulations in terms of their delivery system, reviews the available data on oral 5-ASA treatment efficacy and tolerability, and examines the rationale for changing from one 5-ASA formulation to another if a patient does not respond to, or worsens on, their existing agent.
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Eliakim R, Tulassay Z, Kupcinskas L, Adamonis K, Pokrotnieks J, Bar-Meir S, Lavy A, Mueller R, Greinwald R, Chermesh I, Gross V. Clinical trial: randomized-controlled clinical study comparing the efficacy and safety of a low-volume vs. a high-volume mesalazine foam in active distal ulcerative colitis. Aliment Pharmacol Ther 2007; 26:1237-49. [PMID: 17944738 DOI: 10.1111/j.1365-2036.2007.03468.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Rectally administered mesalazine (mesalamine; 5-aminosalicylic acid) is the first-line therapy for treatment of distal ulcerative colitis. Recently, a high-volume 5-aminosalicylic acid foam has been shown to be as effective and safe as standard 5-aminosalicylic acid enema. AIM To study the efficacy and safety of a low-volume vs. a high-volume 5-aminosalicylic acid foam. METHODS In this investigator-blinded study, patients with active distal ulcerative colitis [Clinical Activity Index (CAI) > 4, Endoscopic Index > or = 4] were randomized to receive 2 x 1 g/30 mL low-volume (n = 163) or 2 x 1 g/60 mL high-volume 5-aminosalicylic acid foam (n = 167) for 42 days. Primary end point was clinical remission (CAI < or = 4) at the final/withdrawal visit (per-protocol). RESULTS 330 patients were evaluable for efficacy and safety by intention-to-treat, 290 for per-protocol analysis. Clinical remission rates at week 6 (per-protocol) were 77% on low-volume foam vs. 77% on high-volume foam (P = 0.00002 for non-inferiority). The low-volume foam was associated with a lower frequency of severe discomfort, pain and retention problems. CONCLUSIONS Low-volume 5-aminosalicylic acid foam is as effective and safe as a high-volume 5-aminosalicylic acid foam in the treatment of active distal ulcerative colitis, but offers compliance advantages compared to the high-volume preparation.
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Affiliation(s)
- R Eliakim
- Gastroenterology Department, Rambam Medical Center, Haifa, Israel.
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D'Haens G, Sandborn WJ, Feagan BG, Geboes K, Hanauer SB, Irvine EJ, Lémann M, Marteau P, Rutgeerts P, Schölmerich J, Sutherland LR. A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis. Gastroenterology 2007; 132:763-86. [PMID: 17258735 DOI: 10.1053/j.gastro.2006.12.038] [Citation(s) in RCA: 771] [Impact Index Per Article: 42.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2006] [Accepted: 10/12/2006] [Indexed: 02/06/2023]
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Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiol Drug Saf 2006. [DOI: 10.1002/pds.1182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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