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Liu YQ, Li ZZ, Han YL, Wang QB. The role of efferocytosis in inflammatory bowel disease. Front Immunol 2025; 16:1524058. [PMID: 40040696 PMCID: PMC11876057 DOI: 10.3389/fimmu.2025.1524058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 01/16/2025] [Indexed: 03/06/2025] Open
Abstract
Efferocytosis is the process by which various phagocytes clear apoptotic cells. In recent years, an increasing body of evidence has emphasized the importance of efferocytosis in maintaining internal homeostasis. Intestinal macrophages play a crucial role in modulating intestinal inflammation and promoting tissue repair. Inflammatory bowel disease (IBD) is a chronic, progressive, and relapsing condition, primarily marked by the presence of ulcers in the digestive tract. The exact mechanisms underlying IBD are not yet fully understood, and current treatment approaches mainly aim at repairing the damaged intestinal mucosa and reducing inflammatory responses to ease symptoms.This article provides new perspectives on IBD treatment and clinical management by examining the expression of macrophage efferocytosis-related molecules, the effects of efferocytosis on IBD development, the various roles of macrophage efferocytosis in IBD, and treatment strategies for IBD that focus on efferocytosis.
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Affiliation(s)
- Yi-Qian Liu
- Institute of Acupuncture and Moxibustion, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Zhan-Zhan Li
- Academy of Traditional Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou, China
| | - Yong-Li Han
- Acupuncture Department, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Qing-Bo Wang
- Acupuncture Department, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
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Yoshihara T, Amano T, Shinzaki S, Tsujii Y, Asakura A, Tashiro T, Tani M, Otake-Kasamoto Y, Yamada T, Sakakibara Y, Osugi N, Ishii S, Egawa S, Araki M, Arimoto Y, Nakahara M, Murayama Y, Kobayashi I, Kinoshita K, Ogawa H, Hiyama S, Shibukawa N, Komori M, Okuda Y, Kizu T, Kitamura T, Kato M, Tsujii Y, Inoue T, Iijima H, Hayashi Y, Takehara T. Effectiveness of tacrolimus therapy in refractory ulcerative colitis compared to infliximab with propensity score matching. Sci Rep 2025; 15:68. [PMID: 39747885 PMCID: PMC11696101 DOI: 10.1038/s41598-024-77365-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 10/22/2024] [Indexed: 01/04/2025] Open
Abstract
There is insufficient evidence comparing the outcomes of tacrolimus-based remission induction therapy with infliximab in refractory ulcerative colitis (UC) and evidence regarding optimal strategies after tacrolimus-based remission induction therapy. We conducted a multi-institutional retrospective study of patients with UC treated with tacrolimus or infliximab between January 2010 and March 2019. The proportion of clinical remission at week 8 and cumulative colectomy-free rate were examined using propensity score matching analysis. The predictors for colectomy after tacrolimus induction were also investigated. Ninety patients in the tacrolimus group and 151 in the infliximab group were enrolled. The proportion of patients in clinical remission at week 8 was 65.2% in the matched tacrolimus group and 37.3% in the matched infliximab group (P = 0.0016), and the long-term colectomy-free rate was lower in the matched tacrolimus group than in the matched infliximab group (P = 0.0003). After clinical remission with tacrolimus, a serum albumin level of ≤ 3.5 g/dL at week 8 was extracted as a factor predicting colectomy (area under the curve: 0.94). Tacrolimus showed a higher remission induction effect for UC compared to infliximab. However, a high rate of colectomy after transition to maintenance treatment was found to be a concern for tacrolimus therapy.
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Affiliation(s)
- Takeo Yoshihara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 K1, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Takahiro Amano
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 K1, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Shinichiro Shinzaki
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 K1, Yamadaoka, Suita, Osaka, 565-0871, Japan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Yuri Tsujii
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 K1, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Akiko Asakura
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 K1, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Taku Tashiro
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 K1, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Mizuki Tani
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 K1, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yuriko Otake-Kasamoto
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 K1, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Takuya Yamada
- Department of Gastroenterology and Hepatology, Osaka Rosai Hospital, Sakai, Japan
| | - Yuko Sakakibara
- Department of Gastroenterology, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Naoto Osugi
- Department of Gastroenterology, Toyonaka Municipal Hospital, Toyonaka, Japan
| | - Shuji Ishii
- Department of Gastroenterology, Osaka General Medical Center, Osaka, Japan
| | - Satoshi Egawa
- Department of Gastroenterology, Osaka Police Hospital, Osaka, Japan
| | - Manabu Araki
- Department of Gastroenterology, National Hospital Organization Osaka Minami Medical Center, Kawachinagano, Japan
| | - Yuki Arimoto
- Department of Gastroenterology, Kansai Rosai Hospital, Amagasaki, Japan
| | | | - Yoko Murayama
- Department of Gastroenterology and Hepatology, Itami City Hospital, Itami, Japan
| | - Ichizo Kobayashi
- Department of Gastroenterology, Higashiosaka City Medical Center, Higashiosaka, Japan
| | - Kazuo Kinoshita
- Department of Gastroenterology, Otemae Hospital, Osaka, Japan
| | - Hiroyuki Ogawa
- Department of Gastroenterology, Nishinomiya Municipal Central Hospital, Nishinomiya, Japan
| | - Satoshi Hiyama
- Department of Gastroenterology, Japan Community Healthcare Organization Osaka Hospital, Osaka, Japan
| | - Narihiro Shibukawa
- Department of Gastroenterology, Daini Osaka Police Hospital, Osaka, Japan
| | - Masato Komori
- Department of Gastroenterology, Hyogo Prefectural Nishinomiya Hospital, Nishinomiya, Japan
| | - Yorihide Okuda
- Department of Gastroenterology, Saiseikai Senri Hospital, Suita, Japan
| | - Takashi Kizu
- Department of Gastroenterology, Yao Municipal Hospital, Yao, Japan
| | - Tetsuhisa Kitamura
- Environmental Medicine and Population Sciences, Department of Social and Environmental Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Minoru Kato
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 K1, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yoshiki Tsujii
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 K1, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Takahiro Inoue
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 K1, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hideki Iijima
- Department of Gastroenterology, Osaka Police Hospital, Osaka, Japan
| | - Yoshito Hayashi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 K1, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 K1, Yamadaoka, Suita, Osaka, 565-0871, Japan.
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Oshima N, Hiraoka S, Hayashi R, Takahashi S, Ishii M, Hashimoto S, Yashima K, Igawa S, Inokuchi T, Ueno Y, Inaba T, Matsumoto H, Kawashima K, Takami T, Isomoto H, Shiotani A, Tanaka S, Ishihara S. Predictive Factors for Efficacy of Oral Tacrolimus Induction Therapy in Moderate to Severe Ulcerative Colitis Patients: Large Multicenter Retrospective Cohort Study. Inflamm Bowel Dis 2024; 30:1087-1093. [PMID: 37598298 DOI: 10.1093/ibd/izad150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Indexed: 08/21/2023]
Abstract
BACKGROUND Tacrolimus (TAC), a calcineurin inhibitor, is used for remission induction therapy in patients with moderate to severe ulcerative colitis (UC), with short-term efficacy and related predictive factors shown in previous cohort studies. However, most studies reported data for only a limited number of patients enrolled from a single center. We performed a large multicenter retrospective cohort study to identify factors related to prediction of clinical remission in UC patients treated with oral TAC. METHODS The medical records of patients with moderate to severe UC treated with oral TAC as induction therapy at 7 institutions between April 2009 and March 2017 were retrospectively reviewed. RESULTS A total of 216 patients who received TAC for induction were analyzed, of whom 123 (56.9%) showed clinical remission at week 12. Logistic regression analysis indicated that previous or current use of antitumor necrosis factor (TNF)-α antibodies (odds ratio [OR], 0.259; P = .006), and concomitant treatment with 5-aminosalicylate (5-ASA) at the baseline (OR, 0.268; P = .005) were independent predictive factors correlated with failure of clinical remission, whereas higher levels of C-reactive protein (OR, 1.124; P = .014) predicted achievement of clinical remission. CONCLUSIONS Results of this multicenter study clearly indicate the efficacy of TAC induction therapy for patients with moderate to severe UC. Notably, previous or current use of anti-TNF-α antibodies was associated with poor achievement of clinical remission by week 12.
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Affiliation(s)
- Naoki Oshima
- Inflammatory Bowel Disease Center, Shimane University Hospital, 89-1, Enya-cho, Izumo, Shimane 693-8501, Japan
- Department of Internal Medicine II, Shimane University Faculty of Medicine, 89-1, Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Sakiko Hiraoka
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Ryohei Hayashi
- Department of Endoscopy, Hiroshima University Hospital, Hiroshima, Japan
| | - Sakuma Takahashi
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, Kagawa, Japan
| | - Manabu Ishii
- General Internal Medicine 2, General Medical Center, Kawasaki Medical School, Okayama, Japan
| | - Shinichi Hashimoto
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Kazuo Yashima
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Tottori, Japan
| | - Shoko Igawa
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Toshihiro Inokuchi
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yoshitaka Ueno
- Department of Endoscopy, Hiroshima University Hospital, Hiroshima, Japan
| | - Tomoki Inaba
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, Kagawa, Japan
| | - Hiroshi Matsumoto
- Division of Gastroenterology, Kawasaki Medical School, Okayama, Japan
| | - Kousaku Kawashima
- Inflammatory Bowel Disease Center, Shimane University Hospital, 89-1, Enya-cho, Izumo, Shimane 693-8501, Japan
- Department of Internal Medicine II, Shimane University Faculty of Medicine, 89-1, Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Taro Takami
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Hajime Isomoto
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Tottori, Japan
| | - Akiko Shiotani
- Division of Gastroenterology, Kawasaki Medical School, Okayama, Japan
| | - Shinji Tanaka
- Department of Endoscopy, Hiroshima University Hospital, Hiroshima, Japan
| | - Shunji Ishihara
- Inflammatory Bowel Disease Center, Shimane University Hospital, 89-1, Enya-cho, Izumo, Shimane 693-8501, Japan
- Department of Internal Medicine II, Shimane University Faculty of Medicine, 89-1, Enya-cho, Izumo, Shimane 693-8501, Japan
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Bhat MA, Usman I, Dhaneshwar S. Application of Drug Repurposing Approach for Therapeutic Intervention of Inflammatory Bowel Disease. Curr Rev Clin Exp Pharmacol 2024; 19:234-249. [PMID: 37859409 DOI: 10.2174/0127724328245156231008154045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 07/07/2023] [Accepted: 08/30/2023] [Indexed: 10/21/2023]
Abstract
Inflammatory bowel disease (IBD), represented by Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disorder of the gastrointestinal tract (GIT) characterized by chronic relapsing intestinal inflammation, abdominal pain, cramping, loss of appetite, fatigue, diarrhoea, and weight loss. Although the etiology of IBD remains unclear, it is believed to be an interaction between genes, and environmental factors, such as an imbalance of the intestinal microbiota, changing food habits, an ultra-hygiene environment, and an inappropriate immune system. The development of novel effective therapies is stymied by a lack of understanding of the aetiology of IBD. The current therapy involves the use of aminosalicylates, immunosuppressants, and corticosteroids that can effectively manage symptoms, induce and sustain remission, prevent complications, modify the course of the disease, provide diverse treatment options, showcase advancements in biologic therapies, and enhance the overall quality of life. However, the efficacy of current therapy is overshadowed by a plethora of adverse effects, such as loss of weight, mood swings, skin issues, loss of bone density, higher vulnerability to infections, and elevated blood pressure. Biologicals, like anti-tumour necrosis factor agents, can stimulate an autoimmune response in certain individuals that may diminish the effectiveness of the medication over time, necessitating a switch to alternative treatments. The response of IBD patients to current drug therapy is quite varied, which can lead to disease flares that underlines the urgent need to explore alternative treatment option to address the unmet need of developing new treatment strategies for IBD with high efficacy and fewer adverse effects. Drug repurposing is a novel strategy where existing drugs that have already been validated safe in patients for the management of certain diseases are redeployed to treat other, unindicated diseases. The present narrative review focuses on potential drug candidates that could be repurposed for the management of IBD using on-target and off-target strategies. It covers their preclinical, clinical assessment, mechanism of action, and safety profiles, and forecasts their appropriateness in the management of IBD. The review presents useful insights into the most promising candidates for repurposing, like anti-inflammatory and anti-apoptotic troxerutin, which has been found to improve the DSS-induced colitis in rats, an antiosteoarthritic drug diacetylrhein that has been found to have remarkable ameliorating effects on DSS-induced colitis via anti-oxidant and anti- inflammatory properties and by influencing both apoptosis and pyroptosis. Topiramate, an antiepileptic and anticonvulsant drug, has remarkably decreased overall pathophysiological and histopathological events in the experimental model of IBD in rodents by its cytokine inhibitory action.
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Affiliation(s)
- Mohammad Aadil Bhat
- Department of Pharmacology, Amity Institute of Pharmacy, Lucknow, Amity University Uttar Pradesh, UP, Noida, India
| | - Iqra Usman
- Department of Pharmacology, Amity Institute of Pharmacy, Lucknow, Amity University Uttar Pradesh, UP, Noida, India
| | - Suneela Dhaneshwar
- Department of Pharmaceutical Chemistry, Amity Institute of Pharmacy, Amity University Maharashtra, Mumbai, Maharashtra, India
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Cha N, Oshima N, Kishimoto K, Kotani S, Okimoto E, Yazaki T, Sonoyama H, Oka A, Mishima Y, Shibagaki K, Tobita H, Kawashima K, Ishimura N, Ishihara S. Long-lasting renal dysfunction following tacrolimus induction therapy in ulcerative colitis patients. J Clin Biochem Nutr 2022; 70:297-303. [PMID: 35692680 PMCID: PMC9130057 DOI: 10.3164/jcbn.21-139] [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: 10/10/2021] [Accepted: 12/27/2021] [Indexed: 12/14/2022] Open
Abstract
Although tacrolimus (TAC) has remarkable effects in ulcerative colitis (UC) patients when given as remission induction therapy, some can develop renal dysfunction during TAC administration, resulting in withdrawal, though related details remain poorly understood. This study was conducted to determine the impact of oral TAC on renal function for remission induction therapy in UC patients. Fifty-five patients (10 elderly, 45 non-elderly) with UC and treated with oral TAC at our hospital were retrospectively evaluated. Renal function was assessed using estimated glomerular filtration rate (eGFR). Although a high clinical response to TAC was seen in both elderly and non-elderly, a decline in eGFR was noted in nearly all patients regardless of age, with a maximum change of -34.4% from the baseline value at week 11. Furthermore, eGFR decline recovered quickly after TAC discontinuation, though did not return to the baseline at two years following cessation. The rate of eGFR change at week 12 was significantly associated with patient age (β = -0.3242, p = 0.0103) and peak serum trough level during TAC treatment (β = 0.3563, p = 0.0051). Furthermore, the rate of decline in eGFR was significantly greater during treatment with TAC in the elderly as compared to non-elderly, with a large difference in eGFR decline rate between those groups also noted at two years after withdrawal of treatment. Careful attention to renal function when administering oral TAC for UC is important and changes in eGFR should be monitored closely in elderly patients even after treatment cessation.
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Affiliation(s)
- Na Cha
- Internal Medicine II, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Naoki Oshima
- Internal Medicine II, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
- Endoscopy Unit, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
- Inflammatory Bowel Disease Center, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Kenichi Kishimoto
- Internal Medicine II, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Satoshi Kotani
- Internal Medicine II, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Eiko Okimoto
- Internal Medicine II, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Tomotaka Yazaki
- Internal Medicine II, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Hiroki Sonoyama
- Internal Medicine II, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Akihiko Oka
- Internal Medicine II, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Yoshiyuki Mishima
- Internal Medicine II, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
- Inflammatory Bowel Disease Center, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Kotaro Shibagaki
- Internal Medicine II, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
- Endoscopy Unit, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Hiroshi Tobita
- Internal Medicine II, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Kousaku Kawashima
- Internal Medicine II, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
- Inflammatory Bowel Disease Center, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Norihisa Ishimura
- Internal Medicine II, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Shunji Ishihara
- Internal Medicine II, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
- Inflammatory Bowel Disease Center, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
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Shimizu H, Fujii T, Kinoshita K, Kawamoto A, Hibiya S, Takenaka K, Saito E, Nagahori M, Ohtsuka K, Watanabe M, Okamoto R. Intravenous tacrolimus is a superior induction therapy for acute severe ulcerative colitis compared to oral tacrolimus. BMC Gastroenterol 2021; 21:494. [PMID: 34949172 PMCID: PMC8705155 DOI: 10.1186/s12876-021-02043-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 11/22/2021] [Indexed: 11/10/2022] Open
Abstract
Background Intravenous corticosteroid is the mainstay for managing acute severe ulcerative colitis, but one-third of patients do not respond to intravenous corticosteroid. Tacrolimus, a salvage therapy before colectomy, is usually orally administered, though its bioavailability is low compared intravenous administration. The efficacy of intravenous tacrolimus has not been widely studied. Aim To determine the efficacy and safety of intravenous tacrolimus for the treatment of acute severe ulcerative colitis. Methods Eighty-seven hospitalized acute severe ulcerative colitis patients were enrolled for a prospective cohort study between 2009 and 2017. Sixty-five patients received intravenous tacrolimus and 22 received oral tacrolimus. The primary outcome was the achievement of clinical remission within 2 weeks. Relapse and colectomy incidence and adverse events were assessed at 24 weeks. Results Response rates of both treatments exceeded 50% but were not significantly different. The remission rate was higher in intravenous tacrolimus compared with oral tacrolimus. At 24 weeks, oral and intravenous tacrolimus showed similar relapse-free survival rates; however, colectomy-free survival rates were higher in intravenous tacrolimus compared with oral tacrolimus. Conclusions Patients receiving intravenous tacrolimus achieved superior remission and colectomy-free survival rates compared with patients receiving oral tacrolimus. Safety was similar between the two treatments.
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Affiliation(s)
- Hiromichi Shimizu
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Toshimitsu Fujii
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
| | - Kenji Kinoshita
- Department of Gastroenterology, Hakodate Hospital, Hakodate, Hokkaido, Japan
| | - Ami Kawamoto
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Shuji Hibiya
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Kento Takenaka
- Department of Endoscopy, Tokyo Medical and Dental University, Tokyo, Japan
| | - Eiko Saito
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Masakazu Nagahori
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Kazuo Ohtsuka
- Department of Endoscopy, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mamoru Watanabe
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Ryuichi Okamoto
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
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Cai Z, Wang S, Li J. Treatment of Inflammatory Bowel Disease: A Comprehensive Review. Front Med (Lausanne) 2021; 8:765474. [PMID: 34988090 PMCID: PMC8720971 DOI: 10.3389/fmed.2021.765474] [Citation(s) in RCA: 248] [Impact Index Per Article: 62.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 11/29/2021] [Indexed: 12/14/2022] Open
Abstract
Inflammatory bowel disease (IBD), as a global disease, has attracted much research interest. Constant research has led to a better understanding of the disease condition and further promoted its management. We here reviewed the conventional and the novel drugs and therapies, as well as the potential ones, which have shown promise in preclinical studies and are likely to be effective future therapies. The conventional treatments aim at controlling symptoms through pharmacotherapy, including aminosalicylates, corticosteroids, immunomodulators, and biologics, with other general measures and/or surgical resection if necessary. However, a considerable fraction of patients do not respond to available treatments or lose response, which calls for new therapeutic strategies. Diverse therapeutic options are emerging, involving small molecules, apheresis therapy, improved intestinal microecology, cell therapy, and exosome therapy. In addition, patient education partly upgrades the efficacy of IBD treatment. Recent advances in the management of IBD have led to a paradigm shift in the treatment goals, from targeting symptom-free daily life to shooting for mucosal healing. In this review, the latest progress in IBD treatment is summarized to understand the advantages, pitfalls, and research prospects of different drugs and therapies and to provide a basis for the clinical decision and further research of IBD.
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Affiliation(s)
- Zhaobei Cai
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
- Department of Gastroenterology and Hepatology, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Shu Wang
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, China
| | - Jiannan Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
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Gupta K, Pandey S, Bagang N, Mehra K, Singh G. Trimetazidine an emerging paradigm in renal therapeutics: Preclinical and clinical insights. Eur J Pharmacol 2021; 913:174624. [PMID: 34774496 DOI: 10.1016/j.ejphar.2021.174624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 10/30/2021] [Accepted: 11/03/2021] [Indexed: 10/19/2022]
Abstract
Trimetazidine (TMZ) is a well-known anti-ischemic agent used for the treatment of angina pectoris. In the past decades, the efficacy of this drug has been tested in a wide range of kidney injuries, including drug-induced nephrotoxicity (DIN), radio-contrast agent-induced nephropathy, and surgically induced renal ischemic injury. TMZhas renoprotective effects by attenuating oxidative stress, inflammatory cytokine release, maintaining oxygen and energy balance. Moreover, TMZ administration prevented kidney graft rejection in the porcine model by suppressing the infiltration of mononuclear cells, preserving mitochondrial functions, and maintaining Ca+ homeostasis. In DIN and diabetic kidney diseases,TMZ treatment prevents renal injury by inactivating immune cells, attenuating renal fibrosis, inflammation, apoptosis, and histological abnormalities. Interestingly, the clinical therapeutic efficacy of TMZ has also been documented in pre-existing kidney disease patients undergoing contrast exposure for diagnostic intervention. However, the mechanistic insights into the TMZ mediated renoprotective effects in other forms of renal injuries, including type-2 diabetes, drug-induced nephrotoxicity, and hypertension-induced chronic kidney diseases, remain uninvestigated and incomplete. Moreover, the clinical utility of TMZ as a renoprotective agent in radio-contrast-induced nephrotoxicity needs to be tested in a large patient population. Nevertheless, the available pieces of evidence suggest that TMZ is a promising and emerging renal therapy for the treatment and management of kidney diseases of variable etiologies. This review discusses the various pre-clinical and clinical findings and provides mechanistic insights into the TMZ mediated beneficial effects in various kidney diseases.
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Affiliation(s)
- Kirti Gupta
- Department of Pharmacy, Maharishi Markandeshwar Deemed to be University, Mullana, Ambala (Haryana), India
| | - Sneha Pandey
- Department of Pharmacology, Indo-Soviet Friendship College of Pharmacy, Moga, Punjab, India
| | - Newly Bagang
- Department of Pharmacology, Indo-Soviet Friendship College of Pharmacy, Moga, Punjab, India
| | - Kamalpreet Mehra
- Department of Pharmacy, Maharishi Markandeshwar Deemed to be University, Mullana, Ambala (Haryana), India
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Jacob EM, Borah A, Pillai SC, Kumar DS. Inflammatory Bowel Disease: The Emergence of New Trends in Lifestyle and Nanomedicine as the Modern Tool for Pharmacotherapy. NANOMATERIALS (BASEL, SWITZERLAND) 2020; 10:E2460. [PMID: 33316984 PMCID: PMC7764399 DOI: 10.3390/nano10122460] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 12/06/2020] [Accepted: 12/07/2020] [Indexed: 02/08/2023]
Abstract
The human intestine, which harbors trillions of symbiotic microorganisms, may enter into dysbiosis when exposed to a genetic defect or environmental stress. The naissance of chronic inflammation due to the battle of the immune system with the trespassing gut bacteria leads to the rise of inflammatory bowel disease (IBD). Though the genes behind the scenes and their link to the disease are still unclear, the onset of IBD occurs in young adults and has expanded from the Western world into the newly industrialized countries. Conventional drug deliveries depend on a daily heavy dosage of immune suppressants or anti-inflammatory drugs targeted for the treatment of two types of IBD, ulcerative colitis (UC) and Crohn's disease (CD), which are often associated with systemic side effects and adverse toxicities. Advances in oral delivery through nanotechnology seek remedies to overcome the drawbacks of these conventional drug delivery systems through improved drug encapsulation and targeted delivery. In this review, we discuss the association of genetic factors, the immune system, the gut microbiome, and environmental factors like diet in the pathogenesis of IBD. We also review the various physiological concerns required for oral delivery to the gastrointestinal tract (GIT) and new strategies in nanotechnology-derived, colon-targeting drug delivery systems.
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Affiliation(s)
| | | | | | - D. Sakthi Kumar
- Bio-Nano Electronics Research Centre, Graduate School of Interdisciplinary New Science, Toyo University, Kawagoe, Saitama 350-8585, Japan; (E.M.J.); (A.B.); (S.C.P.)
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10
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Nakase H. Optimizing the Use of Current Treatments and Emerging Therapeutic Approaches to Achieve Therapeutic Success in Patients with Inflammatory Bowel Disease. Gut Liver 2020; 14:7-19. [PMID: 30919602 PMCID: PMC6974326 DOI: 10.5009/gnl18203] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 10/06/2018] [Accepted: 10/12/2018] [Indexed: 12/18/2022] Open
Abstract
The current goal of inflammatory bowel disease (IBD) treatment is a symptom-free everyday life accompanied by mucosal healing with minimal use of corticosteroids. Recent therapeutic advances, particularly, the emergence of anti-tumor necrosis factor (anti-TNF) antibodies, have changed the natural history of IBD. Additionally, these advances also led to the emergence of the therapeutic concept of the “treat to target” strategy. With the development of new drugs and clinical trials, not only biologics but also small molecules have been applied to clinical practice to better individualize and optimize therapy. However, if newer drugs, including anti-TNF therapies, are recommended for all patients diagnosed with IBD, a significant number of patients will be overtreated. The basic goal of IBD treatment is still to make the best use of conventional treatments based on IBD pathophysiology. Thus, physicians should be familiar with the modes of action of the available drugs. In this review, the author discusses the existing data for many approved drugs and provide insights for optimizing current treatments for the management of patients with IBD in the era of biologics.
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Affiliation(s)
- Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
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11
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Nishida Y, Hosomi S, Yamagami H, Sugita N, Itani S, Yukawa T, Otani K, Nagami Y, Tanaka F, Taira K, Kamata N, Kakimoto K, Tanigawa T, Watanabe T, Fujiwara Y. Azathioprine Is Useful for Maintaining Long-term Remission Induced by Tacrolimus for the Treatment of Ulcerative Colitis: An Inverse Probability of a Treatment Weighing Analysis. Intern Med 2019; 58:2305-2313. [PMID: 31118391 PMCID: PMC6746627 DOI: 10.2169/internalmedicine.2632-19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Objective The need for and efficacy of immunomodulators for maintaining remission after tacrolimus therapy have not been sufficiently defined. This study evaluated the efficacy of immunomodulators for maintaining remission in patients with ulcerative colitis after tacrolimus therapy. Methods Patients with active ulcerative colitis who started oral tacrolimus between January 2009 and September 2017 and were responsive were retrospectively evaluated. Long-term outcomes were compared using Cox proportional hazard regression with inverse probability of treatment weighting. Results Among the 63 patients in the study, 45 received immunomodulators. During the follow-up, 30 patients (47.6%) experienced a relapse. The relapse-free survival rate was significantly worse in the group that did not receive immunomodulators than in those that did (p=0.01, log-rank test); the 2-year relapse-free rates were 22.5% and 63.6% in the non-immunomodulator and immunomodulator groups, respectively. A multivariate analysis showed immunomodulator treatment to be an independent protective factor for clinical relapse (adjusted hazard ratio: 0.35, 95% confidence interval: 0.16-0.78, p=0.01). A Cox regression analysis using inverse probability of treatment weighting also showed that immunomodulator maintenance therapy was correlated with a longer relapse-free survival (hazard ratio: 0.31, 95% confidence interval: 0.15-0.64, p<0.01), A similar response was also observed in non-steroid-dependent patients (hazard ratio: 0.36, 95% confidence interval: 0.14-0.99, p=0.047). No serious adverse events occurred due to tacrolimus or immunomodulator, and immunomodulator use did not increase the incidence of adverse events caused by tacrolimus. Conclusion Our data suggest that the use of immunomodulators to maintain remission after tacrolimus therapy is beneficial for patients with ulcerative colitis.
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Affiliation(s)
- Yu Nishida
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Japan
| | - Shuhei Hosomi
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Japan
| | - Hirokazu Yamagami
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Japan
| | - Naoko Sugita
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Japan
| | - Shigehiro Itani
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Japan
| | - Tomomi Yukawa
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Japan
| | - Koji Otani
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Japan
| | - Yasuaki Nagami
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Japan
| | - Fumio Tanaka
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Japan
| | - Koichi Taira
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Japan
| | - Noriko Kamata
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Japan
| | - Kazuki Kakimoto
- Second Department of Internal Medicine, Osaka Medical College, Japan
| | - Tetsuya Tanigawa
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Japan
| | - Toshio Watanabe
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Japan
| | - Yasuhiro Fujiwara
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Japan
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12
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Sen A, Stark H. Role of cytochrome P450 polymorphisms and functions in development of ulcerative colitis. World J Gastroenterol 2019; 25:2846-2862. [PMID: 31249444 PMCID: PMC6589734 DOI: 10.3748/wjg.v25.i23.2846] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 04/26/2019] [Accepted: 05/08/2019] [Indexed: 02/06/2023] Open
Abstract
Cytochromes P450s (CYPs) are terminal enzymes in CYP dependent monooxygenases, which constitute a superfamily of enzymes catalysing the metabolism of both endogenous and exogenous substances. One of their main tasks is to facilitate the excretion of these substances and eliminate their toxicities in most phase 1 reactions. Endogenous substrates of CYPs include steroids, bile acids, eicosanoids, cholesterol, vitamin D and neurotransmitters. About 80% of currently used drugs and environmental chemicals comprise exogenous substrates for CYPs. Genetic polymorphisms of CYPs may affect the enzyme functions and have been reported to be associated with various diseases and adverse drug reactions among different populations. In this review, we discuss the role of some critical CYP isoforms (CYP1A1, CYP2D6, CYP2J2, CYP2R1, CYP3A5, CYP3A7, CYP4F3, CYP24A1, CYP26B1 and CYP27B1) in the pathogenesis or aetiology of ulcerative colitis concerning gene polymorphisms. In addition, their significance in metabolism concerning ulcerative colitis in patients is also discussed showing a clear underestimation in genetic studies performed so far.
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Affiliation(s)
- Alaattin Sen
- Department of Molecular Biology and Genetics, Faculty of Life and Natural Sciences, Abdullah Gul University, Kayseri 38080, Turkey
- Biology Department, Faculty of Arts and Sciences, Pamukkale University, Denizli 20070, Turkey
| | - Holger Stark
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Duesseldorf 40225, Germany
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13
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Suzuki T, Mizoshita T, Tanida S, Sugimura N, Katano T, Nishie H, Kataoka H. The efficacy of maintenance therapy after remission induction with tacrolimus in ulcerative colitis with and without previous tumor necrosis factor-α inhibitor. JGH OPEN 2019; 3:217-223. [PMID: 31276039 PMCID: PMC6586576 DOI: 10.1002/jgh3.12140] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 12/16/2018] [Indexed: 01/08/2023]
Abstract
Background and Aim Tacrolimus (TAC) is an important therapeutic option for remission induction in patients with refractory ulcerative colitis (UC). However, there is little evidence available on long‐term outcomes and maintenance treatments after TAC therapy, especially in cases with previous tumor necrosis factor‐α (TNF‐α) inhibitor therapy. Methods Long‐term outcomes and remission induction after TAC treatment were retrospectively examined in refractory UC patients with and without previous TNF‐α inhibitor therapy. Results The mean disease activity index and the endoscopic activity index scores decreased significantly during the 12‐week treatment after TAC therapy in both groups, showing a significantly greater decrease in the group without TNF‐α inhibitor therapy than in the group with previous TNF‐α inhibitor therapy. One year or more after TAC therapy, TNF‐α inhibitor and/or azathioprine was used as maintenance therapy in most cases in the group without previous TNF‐α inhibitor treatment, while azathioprine was primarily used in the group with previous TNF‐α inhibitor treatment. Colectomy was performed in 45.5% (5/11) and 15.6% (7/45) of the groups with and without previous TNF‐α inhibitor therapy, respectively, and the group without previous TNF‐α inhibitor treatment had a better colectomy‐free rate than the group with previous TNF‐α inhibitor treatment after TAC therapy on Kaplan–Meier analysis. Conclusions TAC is effective for remission induction in refractory UC patients with and without previous TNF‐α inhibitor treatment. Maintenance medication after TAC therapy is an issue for the future, especially in UC cases with previous TNF‐α inhibitor treatment failure.
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Affiliation(s)
- Taketo Suzuki
- Department of Gastroenterology and Metabolism Nagoya City University Graduate School of Medical Sciences Nagoya Japan
| | - Tsutomu Mizoshita
- Department of Gastroenterology and Metabolism Nagoya City University Graduate School of Medical Sciences Nagoya Japan
| | - Satoshi Tanida
- Department of Gastroenterology and Metabolism Nagoya City University Graduate School of Medical Sciences Nagoya Japan
| | - Naomi Sugimura
- Department of Gastroenterology and Metabolism Nagoya City University Graduate School of Medical Sciences Nagoya Japan
| | - Takahito Katano
- Department of Gastroenterology and Metabolism Nagoya City University Graduate School of Medical Sciences Nagoya Japan
| | - Hirotada Nishie
- Department of Gastroenterology and Metabolism Nagoya City University Graduate School of Medical Sciences Nagoya Japan
| | - Hiromi Kataoka
- Department of Gastroenterology and Metabolism Nagoya City University Graduate School of Medical Sciences Nagoya Japan
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14
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Zhang X, Lin G, Tan L, Li J. Current progress of tacrolimus dosing in solid organ transplant recipients: Pharmacogenetic considerations. Biomed Pharmacother 2018; 102:107-114. [DOI: 10.1016/j.biopha.2018.03.054] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 02/27/2018] [Accepted: 03/09/2018] [Indexed: 12/11/2022] Open
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Abstract
INTRODUCTION Ulcerative colitis (UC) is a chronic inflammatory bowel disease with a relapsing-remitting course that determines significant morbidity and can associate with local complications and/or extra-intestinal manifestations. Pharmacological therapies are often required for a lifetime with possible risks of toxicity and side effects. Areas covered: Non-biological therapies (i.e. aminosalicylates, corticosteroids and immunosuppressive drugs) are widely used in UC patients for controlling the active phases of the disease and maintaining remission. Expert Opinion: Aminosalycilates have a good safety profile with a low risk of idiosyncrasic reactions. In contrast, the use of corticosteroids and immunosuppressive drugs can associate with unacceptable side effects, some of which are potentially life threatening. Mechanisms underlying the development of these side effects are not fully understood and strategies aimed to prevent them have not yet been standardized. However, clinicians should monitor the patients during therapy to recognize the adverse events at an early stage of the occurrence. New drugs that selectively target molecules involved in the amplification of the ongoing mucosal inflammation are currently under investigation. Preliminary data indicate that such compounds have better overall safety and tolerability than corticosteroids and immunosuppressive drugs.
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Affiliation(s)
- Edoardo Troncone
- a Department of Systems Medicine , University of Rome "Tor Vergata" , Rome , Italy
| | - Giovanni Monteleone
- a Department of Systems Medicine , University of Rome "Tor Vergata" , Rome , Italy
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16
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Komaki Y, Komaki F, Micic D, Yamada A, Suzuki Y, Sakuraba A. Pharmacologic therapies for severe steroid refractory hospitalized ulcerative colitis: A network meta-analysis. J Gastroenterol Hepatol 2017; 32:1143-1151. [PMID: 27957761 DOI: 10.1111/jgh.13674] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Revised: 11/20/2016] [Accepted: 12/05/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM A limited option of therapies is available for hospitalized patients with severe steroid refractory ulcerative colitis (UC). Furthermore, there exists a paucity of direct comparisons between them. To provide a comparative evaluation of the efficacy and safety of pharmacologic therapies, we conducted a network meta-analysis combined with a benefit-risk analysis of randomized controlled trials (RCTs) performed in hospitalized patients with severe steroid refractory UC. METHODS Electronic databases were searched through November 2015 for RCTs evaluating the efficacy of therapies for severe steroid refractory hospitalized UC. The outcomes were clinical response, colectomy free rate, and severe adverse events leading to discontinuation of therapy. The primary endpoints were the rank of therapies based on network meta-analysis combined with benefit-risk analysis between clinical response and severe adverse events as well as colectomy free rate and severe adverse events. RESULTS Eight RCTs of 421 patients were identified. Cyclosporine, infliximab, and tacrolimus as well as placebo were included in our analysis. Network meta-analysis with benefit-risk analysis simultaneously assessing clinical response and severe adverse events demonstrated the rank order of efficacy as infliximab, cyclosporine, tacrolimus, and placebo. Similar analysis for colectomy-free rate and severe adverse events demonstrated the same rank order of efficacy. The differences among infliximab, cyclosporine, and tacrolimus were small in all analyses. CONCLUSION The results of the present comprehensive benefit-risk assessment using network meta-analysis provide RCT-based evidence on efficacy and safety of infliximab, cyclosporine, and tacrolimus for hospitalized patients with severe steroid refractory UC.
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Affiliation(s)
- Yuga Komaki
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
| | - Fukiko Komaki
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
| | - Dejan Micic
- Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Akihiro Yamada
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA.,Department of Internal Medicine, Toho University Sakura Medical Center, Chiba, Japan
| | - Yasuo Suzuki
- Department of Internal Medicine, Toho University Sakura Medical Center, Chiba, Japan
| | - Atsushi Sakuraba
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
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Asada A, Bamba S, Morita Y, Takahashi K, Imaeda H, Nishida A, Inatomi O, Sugimoto M, Sasaki M, Andoh A. The effect of CYP3A5 genetic polymorphisms on adverse events in patients with ulcerative colitis treated with tacrolimus. Dig Liver Dis 2017; 49:24-28. [PMID: 27717793 DOI: 10.1016/j.dld.2016.09.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2016] [Revised: 07/30/2016] [Accepted: 09/11/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND Tacrolimus is an immunosuppressive agent, used in the remission induction therapy of ulcerative colitis (UC). AIMS We investigated the correlation between CYP3A5 genetic polymorphisms and the adverse events in patients with UC. The pharmacokinetics of tacrolimus after oral administration were also analyzed. METHODS We enrolled 29 hospitalized patients with UC received oral tacrolimus. Genotyping for CYP3A5 A6986G (rs776746) was performed using Custom TaqMan® SNP genotyping assays. Adverse events, concentration and dose (C/D) ratios and clinical outcomes were investigated. RESULTS CYP3A5 expressers and non-expressers were 16 and 13, respectively. C/D ratios of CYP3A5 expressers were significantly lower compared to non-expressers. The response rate in CYP3A5 non-expressers was relatively higher in the early phase of treatment compared to expressers, but not statistically significant. The incidence of overall adverse events was significantly higher in CYP3A5 expressers than in non-expressers (P=0.034, chi-squared test). In particular, the incidence of nephrotoxicity was significantly higher in CYP3A5 expressers compared to non-expressers (P=0.027, chi-squared test). All of the nephrotoxicity were reversible and resolved by discontinuation or dose reduction of tacrolimus. CONCLUSION The adverse events especially nephrotoxicity were frequently observed in CYP3A5 expressers. CYP3A5 expressers should be paid attention to the onset of nephrotoxicity.
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Affiliation(s)
- Ayumi Asada
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
| | - Shigeki Bamba
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan.
| | - Yukihiro Morita
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
| | | | - Hirotsugu Imaeda
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
| | - Atsushi Nishida
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
| | - Osamu Inatomi
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
| | | | - Masaya Sasaki
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
| | - Akira Andoh
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
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Naganuma M, Mizuno S, Nanki K, Sugimoto S, Kanai T. Recent trends and future directions for the medical treatment of ulcerative colitis. Clin J Gastroenterol 2016; 9:329-336. [DOI: 10.1007/s12328-016-0686-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 09/22/2016] [Indexed: 02/07/2023]
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Komaki Y, Komaki F, Ido A, Sakuraba A. Efficacy and Safety of Tacrolimus Therapy for Active Ulcerative Colitis; A Systematic Review and Meta-analysis. J Crohns Colitis 2016; 10:484-94. [PMID: 26645641 PMCID: PMC4946757 DOI: 10.1093/ecco-jcc/jjv221] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2015] [Accepted: 11/12/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND Approximately 25% of patients with ulcerative colitis [UC] experience a severe flare requiring steroid therapy to avoid colectomy. We performed a systematic review and meta-analysis to assess the efficacy of tacrolimus as a rescue therapy for active UC. METHODS Electronic databases were searched for relevant studies assessing the efficacy of tacrolimus for active UC. Outcomes included short- and long-term clinical response, colectomy free rates, and rate of adverse events in randomised controlled trials [RCTs] and observational studies. RESULTS Two RCTs comparing high trough concentration [10-15ng/ml] versus placebo [n = 103] and 23 observational studies [n = 831] were identified. Clinical response at 2 weeks was significantly higher with tacrolimus compared with placebo (risk ratio [RR] = 4.61, 95% confidence interval [CI] = 2.09-10.17, p = 0.15 x 10(-3)] among RCTs. Rates of clinical response at 1 and 3 months were 0.73 [95% CI = 0.64-0.81] and 0.76 [95% CI = 0.59-0.87], and colectomy-free rates remained high at 1, 3, 6, and 12 months [0.86, 0.84, 0.78, and 0.69, respectively] among observational studies. Among RCTs, adverse events were more frequent compared with placebo [RR = 2.01, 95% CI = 1.20-3.37, p = 0.83 x 10(-2)], but there was no difference in severe adverse events [RR = 3.15, 95% CI = 0.14-72.9, p = 0.47]. Severe adverse events were rare among observational studies [0.11, 95% CI = 0.06-0.20]. CONCLUSIONS In the present meta-analysis, tacrolimus was associated with high clinical response and colectomy-free rates without increased risk of severe adverse events for active UC.
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Affiliation(s)
- Yuga Komaki
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, IL, USA,
| | - Fukiko Komaki
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, IL, USA,
| | - Akio Ido
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Atsushi Sakuraba
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, IL, USA,
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A Comparison of Short- and Long-Term Therapeutic Outcomes of Infliximab- versus Tacrolimus-Based Strategies for Steroid-Refractory Ulcerative Colitis. Gastroenterol Res Pract 2016; 2016:3162595. [PMID: 26904108 PMCID: PMC4745932 DOI: 10.1155/2016/3162595] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Revised: 12/24/2015] [Accepted: 01/03/2016] [Indexed: 12/16/2022] Open
Abstract
Background/Aims. Antitumor necrosis factor antibodies and calcineurin inhibitors have shown good therapeutic efficacy for steroid-refractory ulcerative colitis (UC). Although some studies have compared the efficacy of infliximab (IFX) and cyclosporin A, there are no published studies comparing IFX and tacrolimus (Tac). This study aimed to compare therapeutic efficacies between IFX- and Tac-based strategies for steroid-refractory UC. Methods. Between July 2009 and August 2013, 95 patients with steroid-refractory UC received either IFX (n = 48) or Tac (n = 47) in our hospital. In the IFX group, the patients continued to receive maintenance treatment with IFX. In the Tac group, patients discontinued Tac treatment up to 3 months and subsequently received thiopurine. We retrospectively compared the therapeutic outcomes between the groups. Results. There was no significant difference in the colectomy-free rate, clinical remission rate, and clinical response rate at 2 months between the groups. However, relapse-free survival was significantly higher in the IFX group than in the Tac group (p < 0.001; log-rank test). The proportions of serious adverse events did not differ between the groups. Conclusion. The findings of our study showed that IFX and Tac have similar short-term therapeutic efficacy for steroid-refractory UC. Maintenance treatment with IFX, however, yields better long-term outcomes than Tac-thiopurine bridging treatment.
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21
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Grevenitis P, Thomas A, Lodhia N. Medical Therapy for Inflammatory Bowel Disease. Surg Clin North Am 2015; 95:1159-82, vi. [DOI: 10.1016/j.suc.2015.08.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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22
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Role in calcineurin inhibitors for inflammatory bowel disease in the biologics era: when and how to use. Inflamm Bowel Dis 2014; 20:2151-6. [PMID: 25029618 DOI: 10.1097/mib.0000000000000130] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Ulcerative colitis and Crohn's disease, which is the 2 major forms of inflammatory bowel disease, are chronic relapsing and remitting inflammatory disorder of the gastrointestinal tract. During the last 30 years, the therapy for patients with refractory inflammatory bowel diseases is still challenging despite the fact that morbidity and mortality rates have been obviously reduced. The conventional management with corticosteroids has been modified by the introduction of calcineurin inhibitors and biologics. In this review, we focus on role in calcineurin inhibitors for patients with inflammatory bowel disease in the currently clinical practice.
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Saito E, Nagahori M, Fujii T, Ohtsuka K, Watanabe M. Efficacy of salvage therapy and its effect on operative outcomes in patients with ulcerative colitis. Digestion 2014; 89:55-60. [PMID: 24458114 DOI: 10.1159/000356221] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
AIMS To evaluate the efficacy and safety of salvage therapy, and to identify risk factors of operative complications among hospitalized ulcerative colitis (UC) patients. PATIENTS AND METHODS We evaluated 88 UC patients hospitalized at our center between April 2010 and November 2012. We compared characteristics of corticosteroid-refractory patients treated with calcineurin inhibitor and those with infliximab as second-line therapy. Furthermore, we compared the characteristics of operative and nonoperative patients. The association between perioperative treatments and complications was also investigated. RESULTS Calcineurin inhibitor and infliximab were used in 42 and 22 patients, respectively. We found no difference in the clinical background between them. Efficacy rates were 67 and 50%, respectively. Eight out of 10 nonresponders of each treatment were treated with the other drug as third-line therapy. The efficacy rates of calcineurin inhibitor and infliximab as the third-line therapy were 75 and 50%, respectively. Operative patients had more severe disease (87.5 vs. 31%, p < 0.01), higher Lichtiger score (14.1 vs. 11.5, p < 0.01), higher Rachmilewitz endoscopic index (10.5 vs. 8.4, p < 0.01), higher C-reactive protein (7.6 vs. 4.0, p = 0.015) and lower serum albumin (3.1 vs. 3.6, p = 0.014) than nonoperative patients. Complications were observed in 7 out of 16 (44 %) operative patients. Postoperative complications were not increased even when patients were treated with second- or third-line therapy. However, the complication rate in corticosteroid users was 54.5 (6/11) and 20% (1/5) in nonusers. CONCLUSIONS Third-line salvage therapy is effective and tolerable in carefully selected UC patients. Perioperative use of corticosteroids may lead to more adverse outcomes.
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Affiliation(s)
- Eiko Saito
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
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Tacrolimus induction followed by maintenance monotherapy is useful in selected patients with moderate-to-severe ulcerative colitis refractory to prior treatment. Dig Liver Dis 2014; 46:875-80. [PMID: 25023007 DOI: 10.1016/j.dld.2014.06.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Revised: 05/02/2014] [Accepted: 06/13/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Tacrolimus in refractory ulcerative colitis often serves as a bridge to long-term maintenance therapy with thiopurines. Our aim was to review efficacy and safety of tacrolimus in active ulcerative colitis resistant to conventional therapies, including anti-tumour necrosis factor. METHODS Charts of consecutive outpatients with refractory ulcerative colitis, in whom tacrolimus was orally administered as a 12 week-induction (target trough levels 10-15ng/mL) followed by a maintenance therapy (target trough levels 5-10ng/mL), were retrospectively reviewed. Clinical remission and response at weeks 4, 12 and 52 as well as adverse events within 1-year therapy were reported. RESULTS Twelve (40%) and six (20%) of the 30 patients included (14 males, mean age 37.1±1.4 years) achieved a clinical remission and response, respectively, at week 12. Three responders to tacrolimus initiation experienced drug-related adverse events requiring discontinuation. Among the 18 remaining initial responders who tolerated tacrolimus, 8 (27%) were in clinical remission at week 52, whereas the remainder either experienced adverse events requiring drug withdrawal (n=4) or relapsed (n=6). Overall adverse events were recorded in 14 patients (46%), mainly finger tremor and urinary infections. CONCLUSION Oral monotherapy with tacrolimus may be a valuable long-term therapeutic option in selected patients with moderate-to-severe active refractory ulcerative colitis.
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Narabayashi K, Inoue T, Sakanaka T, Iguchi M, Fujiwara K, Yorifuji N, Kakimoto K, Nouda S, Okada T, Ishida K, Abe Y, Masuda D, Takeuchi T, Fukunishi S, Umegaki E, Higuchi K. Oral tacrolimus for megacolon in patients with severe ulcerative colitis. Intern Med 2014; 53:1755-8. [PMID: 25130105 DOI: 10.2169/internalmedicine.53.2624] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Toxic megacolon is an infrequent but life-threatening complication that occurs most commonly in patients with severe ulcerative colitis. Intravenous steroids are often recommended for patients with toxic megacolon secondary to ulcerative colitis. However, steroid dependency may mask the presence of intra-abdominal sepsis and is associated with refractoriness, during which cytomegalovirus reactivation may occur. In this report, we present two rare cases of megacolon accompanying pancolonic severe ulcerative colitis that were successfully treated with oral tacrolimus, including one steroid-naïve patient. In cases of ulcerative colitis with megacolon, treatment with oral tacrolimus is recommended, thereby avoiding steroid dependency and improving the long-term prognosis.
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Affiliation(s)
- Ken Narabayashi
- The Second Department of Internal Medicine, Osaka Medical College, Japan
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Abstract
The clinical management of ulcerative colitis (UC) involves first treating the acute symptoms to induce remission, and then successfully maintaining it. Oral 5-aminosalicylic acids are safe and useful for maintaining remission in patients with UC. In terms of adherence, a once-daily form of 5-aminosalicylic acid is superior in maintaining remission as compared with split dosing. Patients at high risk of relapse may be candidates for treatment with thiopurines and/or biologics in the early stages of UC. Calcineurin inhibitors, such as cyclosporine and tacrolimus, are effective for severe, steroid-refractory UC patients. It is suggested that these patients use thiopurines as their maintenance therapy once they achieve remission with calcineurin inhibitors. Recent studies have confirmed that biologics are effective for inducing clinical and endoscopic remission of UC, and thus they may improve long-term prognosis of UC.
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Affiliation(s)
- Makoto Naganuma
- Center for Diagnostic and Therapeutic Endoscopy, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan
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Colon Mucosa Exhibits Loss of Ectopic MUC5AC Expression in Patients with Ulcerative Colitis Treated with Oral Tacrolimus. ISRN GASTROENTEROLOGY 2013; 2013:304894. [PMID: 23691335 PMCID: PMC3649514 DOI: 10.1155/2013/304894] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/04/2013] [Accepted: 03/21/2013] [Indexed: 02/07/2023]
Abstract
Background. Tacrolimus (FK506) is effective for patients with ulcerative colitis (UC). However, there are few reports on tacrolimus therapy (TT) with respect to the relationship with endoscopic and clinicopathologic findings. Methods. Thirty patients with moderate/severe active UC refractory to or dependent on corticosteroid were treated with oral tacrolimus. The expression of ectopic MUC5AC in the colon was pathologically analyzed before and at 12 weeks after TT, evaluating the Mayo score and steroid-sparing effects. Results. Both mean disease and endoscopic activity index scores were reduced at levels of statistical significance in 26 UC patients receiving more than one month of TT (P < 0.0001). The dose of prednisolone was reduced by a statistically significant amount (P = 0.00022), and 14 of the 26 patients (53.8%) had steroid-free status 12 weeks after TT. The decrease in ectopic MUC5AC expression in the mucous cells of the colon was significantly associated with endoscopic improvement of inflammation in the UC patients with TT (P = 0.043). Loss of ectopic MUC5AC expression was detected in all patients who had complete response. Conclusions. Tacrolimus appears to be effective for the treatment of moderate/severe UC patients. Loss of ectopic MUC5AC expression may be important for pathologic remission in the colon of UC patients.
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Ehinger KHJ, Hansson MJ, Sjövall F, Elmér E. Bioequivalence and tolerability assessment of a novel intravenous ciclosporin lipid emulsion compared to branded ciclosporin in Cremophor ® EL. Clin Drug Investig 2013; 33:25-34. [PMID: 23179472 PMCID: PMC3586182 DOI: 10.1007/s40261-012-0029-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Ciclosporin is used as an immunosuppressant in current clinical practice but recent research implies novel indications for the drug, such as neuro- and cardioprotection. The intravenous formulation currently on the market, Sandimmune(®) Injection (Sandimmune(®)), uses Cremophor(®) EL as emulsifying excipient. Cremophor(®) EL is known to cause hypersensitivity reactions in some patients, ranging from skin reactions to potentially fatal anaphylactic shock. OBJECTIVES The primary objective was to assess if CicloMulsion(®), a Cremophor(®) EL-free lipid emulsion of ciclosporin for intravenous administration, is bioequivalent to Sandimmune(®), and the secondary objective was to compare the tolerability profiles of the two preparations. METHODS This was a single-centre, open-label, subject-blind, laboratory-blind, single-dose, randomized, two-treatment, two-period, two-sequence crossover study of the pharmacokinetics of two formulations of intravenous ciclosporin. Fifty-two healthy volunteer subjects were administered 5 mg/kg of each of the two formulations of ciclosporin as a 4-h intravenous infusion. The last blood sample was acquired 48 h after the end of the infusion. Bioequivalence assessments according to current guidelines were performed. RESULTS The geometric mean ratios for CicloMulsion(®)/Sandimmune(®) (90 % confidence interval [CI]) were 0.90 (0.88, 0.92) for AUC(0-last) (area under the blood concentration-time curve from time zero to time of last measurable concentration) and 0.95 (0.92, 0.97) for C(max) (maximum blood concentration). For all additional variables analysed, the 90 % CIs were also within the accepted bioequivalence range of 0.80-1.25. One anaphylactoid and one anaphylactic reaction, both classified as serious adverse events, were reported after treatment with Sandimmune(®). No serious adverse events were recorded after treatment with CicloMulsion(®). CONCLUSION We have assessed the pharmacokinetics and tolerability of a new Cremophor(®) EL-free lipid emulsion of ciclosporin, CicloMulsion(®), compared to Sandimmune(®). The proportion of adverse events was significantly higher for the Cremophor(®) EL-based product Sandimmune(®). We conclude that CicloMulsion(®) is bioequivalent to Sandimmune(®) and exhibits fewer adverse reactions.
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Aomatsu T, Imaeda H, Takahashi K, Fujimoto T, Kasumi E, Yoden A, Tamai H, Fujiyama Y, Andoh A. Tacrolimus (FK506) suppresses TNF-α-induced CCL2 (MCP-1) and CXCL10 (IP-10) expression via the inhibition of p38 MAP kinase activation in human colonic myofibroblasts. Int J Mol Med 2012; 30:1152-8. [PMID: 22895606 DOI: 10.3892/ijmm.2012.1094] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2012] [Accepted: 07/09/2012] [Indexed: 11/06/2022] Open
Abstract
In order to investigate the molecular mechanisms underlying the immunosuppressive effects of tacrolimus (FK506) on intestinal inflammation, we examined whether FK506 effects cytokine/chemokine secretion in human colonic myofibroblasts. Human colonic myofibroblasts were isolated from normal human colonic tissue. The mRNA and protein expression for human CCL2 and CXCL10 were analyzed by real-time PCR and ELISA, respectively. p38 MAP kinase activation was evaluated by western blotting. Tacrolimus (1 µM) suppressed tumor necrosis factor (TNF)-α-induced CCL2 and CXCL10 mRNA expression, but did not modulate TNF-α-induced interleukin (IL)-6 or CXCL8 mRNA expression. Dose-dependent, inhibitory effects of tacrolimus on CCL2 and CXCL10 expression were observed at the mRNA and protein levels. Significant inhibitory effects of tacrolimus were observed at concentrations as low as 0.5 µM for CCL2 and 0.1 µM for CXCL10, respectively. TNF-α-induced CCL2 and CXCL10 expression depended on p38 MAP kinase activation, and tacrolimus strongly inhibited the TNF-α-induced phosphorylation of p38 MAP kinase. Tacrolimus did not affect interferon (IFN)-γ-induced signaling transducer and activator of transcription (STAT)-1 phosphorylation, nor did it modulate CXCL10 mRNA and protein expression. In conclusion, tacrolimus suppressed CCL2 and CXCL10 expression in human colonic myofibroblasts. These inhibitory effects of tacrolimus may play key roles in the therapeutic effects of colonic inflammation in inflammatory bowel disease (IBD) patients.
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Affiliation(s)
- Tomoki Aomatsu
- Department of Medicine, Shiga University of Medical Science, Seta Tsukinowa, Otsu 520-2192, Japan
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Ogata H, Kato J, Hirai F, Hida N, Matsui T, Matsumoto T, Koyanagi K, Hibi T. Double-blind, placebo-controlled trial of oral tacrolimus (FK506) in the management of hospitalized patients with steroid-refractory ulcerative colitis. Inflamm Bowel Dis 2012; 18:803-8. [PMID: 21887732 DOI: 10.1002/ibd.21853] [Citation(s) in RCA: 151] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2011] [Accepted: 07/13/2011] [Indexed: 12/17/2022]
Abstract
BACKGROUND We report a multicenter study of oral tacrolimus (FK506) therapy in steroid-refractory ulcerative colitis (UC). METHODS In a placebo-controlled, double-blind study, 62 patients with steroid-refractory, moderate-to-severe UC were randomized into either a tacrolimus group or a placebo for 2 weeks. Patients were evaluated using the Disease Activity Index (DAI). As an entry criterion, patients had to have a total DAI score of 6 or more as well as a mucosal appearance subscore of 2 or 3. Clinical response was defined as improvement in all DAI subscores. Mucosal healing was defined as mucosal appearance subscore of 0 or 1. Clinical remission was defined as a total DAI score ≤ 2 with an individual subscore of 0 or 1. RESULTS The mean total DAI score at study entry was 9.8 ± 1.61 in the tacrolimus group and 9.1 ± 1.05 in the placebo group. At week 2 the clinical response rate was 50.0% (16/32) in the tacrolimus group and 13.3% (4/30) in the placebo group (P = 0.003). The rate of mucosal healing observed was 43.8% (14/32) in the tacrolimus group and 13.3% (4/30) in the placebo group (P = 0.012) and the rate of clinical remission observed was 9.4% (3/32) in the tacrolimus group and 0.0% (0/30) in the placebo group (P = 0.238). The therapies in this study were well tolerated, with only minor side effects. CONCLUSIONS Oral tacrolimus therapy in patients with steroid-refractory UC shortened the acute phase and induced rapid mucosal healing. These results suggest that tacrolimus therapy is useful as an alternative therapy for steroid-refractory UC.
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Affiliation(s)
- Haruhiko Ogata
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
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Collnot EM, Ali H, Lehr CM. Nano- and microparticulate drug carriers for targeting of the inflamed intestinal mucosa. J Control Release 2012; 161:235-46. [PMID: 22306429 DOI: 10.1016/j.jconrel.2012.01.028] [Citation(s) in RCA: 179] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2011] [Revised: 01/18/2012] [Accepted: 01/19/2012] [Indexed: 12/14/2022]
Abstract
Conventional treatment of inflammatory bowel disease (IBD) is based on the daily administration of high doses of immune-suppressant or anti-inflammatory drugs, often complicated by serious adverse effects. Thus, a carrier system that delivers the drug specifically to the inflamed intestinal regions and shows prolonged drug release would be desirable. The advent of TNF-α antibodies and other biopharmaceuticals as potent and specific immune modulators in recent years has broadened the treatment options in IBD, but further increases the necessity for adequate drug delivery, as integrity and bioactivity of the biological active have to be ensured. Exploiting the pathophysiological idiosyncrasies of IBD such as increased mucus production, changes in the structure of the intestinal epithelium and invasion of activated macrophages, different colloidal drug carrier systems have been designed to passively or actively target the site of inflammation. This review introduces different micro- or nanoparticulate drug delivery systems for oral application in IBD therapy for the delivery of small molecular compounds and next generation therapeutics from the group of biological (i.e. peptide and nucleotide based) drugs.
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Affiliation(s)
- Eva-Maria Collnot
- Helmholtz-Institute for Pharmaceutical Research Saarland, Dept. of Drug Delivery Saarland University, Campus A 4 1, 66123 Saarbrücken, Germany.
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