First, this was a single-center, uncontrolled study, with a less number of patients. Conclusion: This is the first prospective study indicating that oral Qing-Dai is effective for inducing remission in patients with moderate UC activity and can be tolerated. These results indicate that attenuation of colitis by inducing IL10 and IL22 is AhR-dependent [22]. Zhang F, Li Y, Xu F, Chu Y, Zhao W: Comparison of Xilei-san, a Chinese herbal medicine, and dexamethasone in mild/moderate ulcerative proctitis: a double-blind randomized clinical trial. Clinical response was defined as a decrease in the Mayo score of 1 in each item. In China, IN is quality controlled as an herbal medicine containing more than 2.0% indigo and more than 0.13% indirubin. ; a multicenter RCT is needed in the near future. It is not clear whether the efficacy of IN is comparable to traditional medicine for patients with IBD and other inflammatory disorders. Received: November 09, 2015Accepted: January 25, 2016Published online: March 10, 2016 Patients with IBD are not able to obtain IN from general hospitals. In this study, the rate of clinical remission at Day 14 was significantly higher in patients receiving rectal Xilei-San than for patients receiving a placebo. Since Qing-Dai appears dark blue, it was difficult to perform a placebo-controlled trial with the powder form. This is particularly important when the recommended agent is a new and/or infrequently employed drug. It is well known that there is a particularly high rate of placebo effect in UC [38]. IN is considered an anti-inflammatory agent in Chinese textbooks from the tenth century [15]. 3b) and from 9.4 to 3.5 (p < 0.001; fig. Inflamm Bowel Dis 2012;18:803-808. However, published data on the efficacy of Qing-Dai for UC patients are mostly lacking in the English literature. Additional reports have been published on the Chinese herbal medicine Xilei-San [24,25,26], Kui Jie Qing enema [27] and Fufangkushen colon-coated capsules [28]. Gong Y, Zha Q, Li L, Liu Y, Yang B, Liu L, Lu A, Lin Y, Jiang M: Efficacy and safety of Fufangkushen colon-coated capsule in the treatment of ulcerative colitis compared with mesalazine: a double-blinded and randomized study. Recently, Qing-Dai (Indigo naturalis, IN), which is a component of crude drugs used in China, was reported to be effective for treating UC. Front Immunol 2014;5:640. The clinical disease activity was assessed by trained physicians and was scored according to the Clinical Activity Index (CAI) [7] and Mayo score [3]. a Powder form; b Capsule form. 1a) was filled into blue coated capsules (250 mg in each capsule; fig. After analyzing the data of 10 patients, we added 10 more patients predominantly for safety reasons. Thus, oral capsuled Qing-Dai is effective for inducing remission in patients with moderate UC activity and can be tolerated, although further investigation is required. Our study intended to use single herbal formulas rather than multiple herbal formulas. According to the previous study [20], we set the daily dose of 2 g, although a daily dose of 3 g is recommended in patients with psoriasis [18]. investigated the efficacy of rectal Xilei-San for active UC [26]. The other authors declare that they have no potential conflicts of interest to disclose. However, 10% of reversible liver dysfunction may be considered to be a high rate. Methods: The open-label, prospective pilot study was conducted at Keio University Hospital. Corticosteroid dependence and resistance are clinically important problems [6]. Lin etal. Mucosal healing was defined as a Mayo endoscopic score of 1. The clinical response was defined as a decrease in the Mayo score of 1 in each item. N Engl J Med 1994;330:1841-1845. Patients did not show recurrence of PAH over the subsequent 2 years without medication for PAH. Clinical remission was defined as a Mayo endoscopic score of 1 and other items of Mayo score of 0. In the recent nationwide multicenter study, no fulminant hepatitis was observed in subjects treated with IN. 3099067 Partial Mayo score and CAI also significantly improved from a mean of 5.7 to a mean of 1.4 (p < 0.001; fig. Reinisch W, Sandborn WJ, Hommes DW, D'Haens G, Hanauer S, Schreiber S, Panaccione R, Fedorak RN, Tighe MB, Huang B, Kampman W, Lazar A, Thakkar R: Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Inflammatory bowel diseases (IBD), such as ulcerative colitis (UC) and Crohns disease (CD), are chronic inflammatory conditions. The current pharmacologic management of UC has relied primarily on mesalamine [3], corticosteroids [4], and thiopurines [5]. From the results of our pilot study, we have recognized that liver dysfunction, headache and digestive symptom should be cautioned in patients with 2 g daily of Qing-Dai and the sample size can be desirable. Although 8 of 9 patients of this study previously received corticosteroid, azathioprine, or anti-TNFtreatment before initiation of IN therapy, the efficacy of IN was satisfactory for these refractory cases. Although corticosteroids, anti-TNF agents and calcineurin inhibitors are effective for inducing clinical remission, these medications have produced no response in several patients. Thiopurines were used in 10 patients (azathioprine, 50-150 mg daily in 8 patients; or 6-mercaptopurine, 5 or 35 mg daily). However, intractable cases, in which mucosal regeneration is disturbed, are not effectively treated even with recent biologics. The study protocol was reviewed and approved by the Ethics Committee of Keio University School of Medicine (No. Wang B, Ren S, Feng W, Zhong Z, Qin C: Kui jie qing in the treatment of chronic non-specific ulcerative colitis. Am J Gastroenterol 2011;106:590-599. Because topical IN is safe and effective for psoriasis, rectal IN may also be useful for UC patients. [20] have shown that Qing-Dai has significant clinical and endoscopic efficacy in treating UC patients; however, the study was retrospectively conducted, and the dose of Qing-Dai was not precisely established. The response rates were 69.6% (0.5g group), 75.0% (1.0g group), and 81.0% (2.0g group) compared with a response rate of 13.6% in the placebo group (Table 2). Recently, patients have obtained and used IN on the Internet or have received IN at private clinics. By closing this message, you are consenting to our use of cookies. Can Qing-Dai be used for maintenance of remission? Article In this article, the clinical efficacy and safety of IN are reviewed, and the current consideration of IN in the medical field is described. Nishio etal. N Engl J Med 1987;317:1625-1629. PAH is another critical adverse effect induced by IN. Existing medications mainly act on the immune system and do not target epithelial regeneration. Issue release date: June 2016, Number of Print Pages: 9 It is particularly efficacious for otherwise refractory cases [1214]. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). Another mechanism of the efficacy of Qing-Dai has been indicated through the anti-inflammatory effects because of its ability to suppress superoxide generation [36]. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 (Japan), Keywords: Inflammatory bowel diseaseUlcerative colitisUlcer healingColonChinese herbal medicineQing-DaiIndigo naturalisIndoleAryl hydrocarbon receptorInterleukin-22. The efficacy of IN for active UC was also objectively confirmed using fecal biomarkers, such as fecal calprotectin. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine. Few direct studies in human subjects have addressed IN inhibition of colitis via promoting IL-22. Additionally, we used Qing-Dai in the capsule form, rather than in the powder form, for the purpose of future randomized controlled trial using placebo capsule. For gastrointestinal diseases, Yuan et al. In the dextran sulfate sodium-induced colitis rat model, topical treatment with Xilei-San attenuates colitis by degrading proinflammatory mediators and promoting mucosal repair [29]. Cited by lists all citing articles based on Crossref citations.Articles with the Crossref icon will open in a new tab. The serum CRP level was significantly improved from a mean of 0.60 mg/dl to a mean of 0.20 mg/dl (p = 0.02) by treatment with Qing-Dai. received a research grant and lecture fees from Takeda Pharmaceutical Co., Ltd. H.O. A recent study indicates that IN significantly reduces the disease activity index and colonic myeloperoxidase activity of in a DSS colitis model [16]. J Gastroenterol Hepatol 2012;27:1808-1815. Suzuki H, Kaneko T, Mizokami Y, Narasaka T, Endo S, Matsui H, Yanaka A, Hirayama A, Hyodo I: Therapeutic efficacy of the Qing Dai in patients with intractable ulcerative colitis. Nature 2008;453:106-109. Number of Tables: 1, ISSN: 0012-2823 (Print) eISSN: 1421-9867 (Online), For additional information: https://www.karger.com/DIG. In the near future, the efficacy of IN for refractory cases should be confirmed in a large control study. Ords I, Eckmann L, Talamini M, Baumgart DC, Sandborn WJ: Ulcerative colitis. Importantly, because AhR signaling regulates microbiota and lactobacillus upregulates AhR in ILC-3 [28,29], changes in microbiota profiles before and after treatment of IN were also assessed in patients with IN and healthy controls. World J Gastroenterol 2002;8:158-161. A double-blind, dosage-controlled trial of indirubin in IN reported that Lindioil ointment with 200g/g of indirubin is most effective [42]. Two patients were treated with infliximab for over the past 1 year, but were currently at the condition of secondary failure; they discontinued its use over 4 weeks before the entry. In addition, indole-3-carboxaldehyde (IAld) is produced from tryptophan by intestinal bacteria. Treatment with indigo naturalis for infl . 2. J Ethnopharmacol 2009;125:51-58. Recently, IN was reported to be effective for treating (UC) and psoriasis. At the moment, the differential emergence of adverse effects between TCDD and natural ligands such as Qing-Dai remains unknown; there should be a high alert on these issues, although we use indole derivatives such as indigo carmine for endoscopic dye in daily practice. also demonstrated that the efficacy of Xilei-San enema is comparable to that of dexamethasone enema in mild-to moderate UC patients [27]. 3a). Another study indicated that the expressions of Ki-67 and CD3, markers of proliferation, were also decreased [38]. Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld JC, Stockinger B: The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Although the efficacy of IN in UC patients was confirmed, the trial was terminated because a case of pulmonary arterial hypertension (PAH) was reported in a patient who had used self-purchased IN outside of the study protocol. We considered that a prospective clinical trial using encapsulated IN would be beneficial [13]. These cases of IN-induced colitis developed relatively early after IN administration and mainly occurred in the right colon. Adverse effects, including PAH, are described at the next section. The clinical manifestations of TCDD exposure include progressive liver or renal failure, emphysema, and myocardial degeneration [13]. received lecture fees from Takeda Pharmaceutical Co., Ltd. More recently, Matsuno etal also reported on two cases of IN-induced colitis [33]. This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply. Liu JZ, Pezeshki M, Raffatellu M: Th17 cytokines and host-pathogen interactions at the mucosa: dichotomies of help and harm. Suzuki et al. The patients' demographic data and disease characteristics were collected. STAT3-induced mucosal healing occurred in an IL-22-dependent manner since both IL-22 and epithelial STAT3 are found to be important in wound-healing experiments [25]. In figure 4, clinical endoscopic examples of before and after treatment with Qing-Dai are shown. We use cookies to improve your website experience. World J Gastroenterol 2013;19:5738-5749. In Japan, IN is not categorized as an herbal medicine. An important group of natural AhR ligands is indole, such as indole-3-aldehyde (3-IAld), indole-3-acetaldehyde, indole-3-acetic acid and indole-3-lactic acid, which can be generated by the bacterial metabolism of tryptophan and are also derived from the metabolism of dietary intake [13,14]. A recent study also indicates that IL-22 activates STAT3 which enhances the transcription of anti-apoptotic and pro-proliferative genes [24].