Search

Natural Medicine Journal

June 7, 2023

Clinical Application of Indigo Naturalis

A review of its safety and efficacy

Mark Davis

ND

Natalie Scheeler, ND

Although ulcerative colitis affects 1 million to 3 million Americans, few reliable pharmaceutical treatments exist. Use of indigo naturalis, when monitored for safety, offers an effective option.

Abstract

Indigo naturalis (IN), also known as qing dai, has a long history of use in Chinese medicine. This article examines evidence for the safety and efficacy of IN administration for the treatment of inflammatory bowel disease (IBD). IN appears to be a very effective induction therapy for patients with IBD, particularly those with ulcerative colitis (UC), though the likelihood of adverse events is significant and seems to increase with treatment length. Additional research shows a potential benefit of IN as a maintenance therapy.

Introduction

Indigo naturalis is an ingredient in many Chinese herbal medicine formulas (notably xilei-san), and the first written record of its use comes from approximately 1,400 years ago, during the Tang Dynasty. To make IN, a rich blue pigment is extracted from dried foam from the fermented leaves and stems of several plants, including Isatis indigotica,1 Indigofera tinctoria, and Strobilanthes cusia.2 These plants have been used as blue dyes for thousands of years; and when IN has been used for UC, it has, as reported in 1 case report, induced a blue coloration of polypoid healing artifacts.3 Indigo and indirubin are the main active constituents responsible for IN’s healing properties. Considered to be energetically cooling in nature, IN has been traditionally used for “heat” conditions as an antipyretic, anti-inflammatory, and hemostatic remedy. Since the 1970s, IN has been widely used in Japan and South Korea to treat many gastrointestinal and skin conditions.4 A growing body of evidence, including human studies, supports the use of IN for the treatment of IBD, particularly ulcerative colitis. 

Ulcerative colitis is a chronic condition characterized by relapsing and remitting inflammation of the mucosal layer of the colon.2,5 The goal of treatment is to achieve remission through mucosal healing and prevent the need for surgical removal of the affected tissue.2 Currently, conventional treatments rely on pharmaceuticals, including 5-aminosalicylic acid (5-ASA) preparations, steroids, immunomodulators, and biologics.6 Although the number of pharmaceutical options has increased, UC treatment outcomes remain poor. Over half of patients using first-line 5-ASA drugs as a solo initial therapy fail to enter remission,7 requiring escalation of therapy. Biologics have decreased UC patients’ lifetime risk of colectomy from ~25% to ~15%,8 but few patients maintain long-term remission despite biologic use,9 and biologics come with their own risks. Three-quarters of IBD patients on the most common biologics experience adverse events in the first year of therapy, and 15% to 20% of those adverse events are severe.10 With judicious use, IN is a potentially safe and effective treatment for the induction of and, possibly in some circumstances, for the maintenance of remission in UC. 

Ulcerative Colitis

Since 2013, several retrospective and open-label prospective studies have demonstrated the effectiveness of IN oral administration for the treatment of ulcerative colitis,2,5,11-13 all in Japanese populations. The first and largest double-blind study evaluating the safety and efficacy of oral IN for the treatment of UC was conducted in 2016 by Naganuma et al, and it was dubbed the INDIGO study.14 Patients were divided into 3 dosage groups (0.5, 1.0, or 2.0 g/day) or a placebo group and treated for 8 weeks. This study revealed a dose-dependent effect on clinical remission and mucosal healing. Clinical remission was substantially and significantly higher in the groups receiving 1.0 g daily (55%) and 2.0 g daily (38.1%) than in the placebo group (4.5%). Mucosal healing was achieved in 56.5% of patients in the 0.5 g group, 60.0% of patients in the 1.0 g group, 47.6% of patients in the 2.0 g group, and only 13.6% in the placebo group. No serious adverse effects were observed in this trial; however, the trial was discontinued because of a report of pulmonary arterial hypertension in an outside patient treated with IN.15

The same team performed a post hoc analysis of the INDIGO study to determine the efficacy of IN in patients with treatment-refractory UC; this included patients with steroid-dependent disease, previous use of anti-TNF-α (tumor necrosis factor alpha) drugs, concomitant use of immunomodulators, or a Mayo score of 9 to 11 at baseline. The clinical response of refractory UC patients was significantly higher in the IN group than in the placebo group; 77% of patients with steroid-dependent disease, 77.5% of patients with previous use of anti-TNF-α drugs, 70.8% of patients with concomitant use of immunomodulators (thiopurine), and 76.7% of patients with a Mayo score of 9 to 11 at baseline achieved a clinical response. No patients in the placebo group showed clinical response. In the steroid-dependent group, 50% of the patients showed mucosal healing vs 0% in the placebo group.16

An open-label, dose-escalation study in 2021 found a similar efficacy of oral IN for treatment-refractory UC. The study followed 11 treatment-refractory patients, 10 of whom achieved a significant clinical response by 8 weeks, as assessed by the Mayo score, a standardized disease activity index for UC. Three patients achieved clinical remission.5

A 2020 randomized, controlled trial (RCT) evaluated the efficacy and safety of short-term oral IN administration in patients with mild-to-moderately active UC. After 2 weeks of treatment, the placebo group showed no change in score, while the intervention group improved significantly (Lichtiger Index scores decreasing from 9.04 to 4.48). Clinical response was seen in 60.9% of the intervention group, compared to 26.3% in the placebo group. Only mild headaches were reported in the intervention group with no serious adverse effects.6

Maintenance Therapy

One open-label study followed 33 patients with moderate-to-severe UC, as determined by the clinical activity index (CAI), over 52 weeks, evaluating the efficacy and safety of IN as a possible maintenance therapy. Patients received doses of 2 g/day (1 g orally twice daily). Clinical remission was observed in 67%, 75%, and 73% of the patients at weeks 4, 8, and 52, respectively; however, 17 patients (51.5%) experienced adverse events, 4 of which (12.1%) were considered severe. This rate of SAEs in maintenance therapy is comparable to the rates observed with the use of biologics.10 Although treatment for UC with IN for a year was effective, indicating its potential benefit as a maintenance therapy, side effects were seen at a significantly higher rate than shorter-term studies.2

Crohn Disease

One retrospective study has shown IN to be beneficial in the treatment of Crohn disease (CD). However, the benefit appeared to be modest in comparison to UC, and the sample size was small; only 8 patients with CD were enrolled. After 8 weeks of treatment, 37.5% of patients achieved clinical response, and 25.0% achieved clinical remission.17

Pediatric Population

No RCTs have been conducted in pediatric populations. In 2021, 29 high-volume centers treating pediatric IBD patients in Japan completed a survey and systematic review to determine IN’s efficacy and safety in the pediatric population. Of the 107 pediatric patients reported to have used IN, 80.2% achieved clinical remission within 6 months. Of these patients, 64.1% had no relapses, whereas 31.5% experienced only 1 to 2 relapses annually. The adverse event rate was comparable to that in the adult group (8%), with 1 pediatric patient developing pulmonary arterial hypertension, an SAE. However, no dosages were reported.18

Rectal Administration

One open-label trial studied the effects of 50 mg IN suppositories in 10 patients with active UC with moderate-to-severe inflammation in the rectum to the sigmoid colon. IN was found to promote mucosal healing, and 3 patients achieved clinical remission; however, the efficacy was dependent on severity. Patients with less severe proctitis and colitis were more likely to respond. Common side effects of oral administration, such as headache, epigastric/abdominal pain, and nausea, were not observed.19

Xilei-san (which is about 1/3 IN) has been studied in RCTs for patients with intractable ulcerative proctitis, both in: 1) 100-mg suppository form compared to placebo20 and 2) as a rectal suspension (1 gram of xilei-san in 60 mL fluid) compared to rectal dexamethasone.21 Xilei-san was found to be dramatically superior to placebo and noninferior to dexamethasone at inducing remission, with fewer adverse events than dexamethasone and no SAEs.

Mechanism of Action

IN contains many bioactive components including alkaloids, lignans, flavonoids, phenolic acids, and polysaccharides.1 Indole alkaloids, particularly indirubin, are the most important bioactive components.4 Indirubin and its derivatives inhibit Janus kinase(JAK); this is also the mechanism of action of a new class of IBD drugs, which, like IN, work more robustly for UC than for Crohn disease.22 In addition, indirubin has inhibitory action on transforming growth factor beta (TGF-β), TNF-α, interleukin 6 (IL-6), interferon gamma (IFN-γ), and other inflammatory cytokines, as well as on other inflammatory signaling complexes like nuclear factor kappa B (NF-κB),23 and IN increases gastrointestinal expression of thymic-derived T-regulatory cells.24 Indirubin itself has anti-inflammatory effects, but IN has a more potent effect on UC hyperinflammation than its individual constituents, while also decreasing dysbiosis.25

Perhaps most importantly, IN and indirubin are aryl hydrocarbon receptor (AhR) ligands. AhR is an intracellular transcription factor that alters gene expression when activated, often by dietary flavonoids and probiotic metabolites, but also aberrantly by dioxin (an aryl hydrocarbon), from which AhR derives its name. AhR activation is how IN achieves many of its immunomodulatory effects above, and also, notably, AhR activation is crucial for maintaining type 3 innate lymphoid cells—the main producers of IL-22, which promotes mucosal regeneration.26 In an open-label trial in which 10 out of 11 patients with treatment-refractory UC achieved a clinical response with IN,5 AhR activity increased to more than 12,000 times its baseline concentration. In a murine model, the administration of an AhR antagonist concomitant with IN significantly reduced the anti-inflammatory benefits.

Adverse Events

It is critically important to convey that IN has the potential to induce both minor and serious adverse events. Minor adverse events include the following:

  • Headache, mild GI distress, or nausea4
  • Mild, reversible elevations in hepatic transaminases—these typically self-resolve without discontinuing IN.4
  • Acute pancreatitis has been reported in 1 pediatric patient with severe Crohn disease (twice reversed in the same patient by discontinuing IN).27
  • One report of renal dysfunction (which may or may not have been secondary to IN) was reported in a retrospective observational trial.4
  • AhR ligands, including flavonoids, polyphenols, and other anti-inflammatory agents, can be cancer-preventive in the absence of cancer, but may theoretically inhibit anti-cancer inflammation in the presence of established tumors.24 That said, IN has been associated with reduction in active tumor size and number,4 so that concern is probably only theoretical.

Serious adverse events include the following:

  • Pulmonary arterial hypertension (PAH): PAH is a dangerous vasculopathy in which excessive vascular cell growth and other factors drive an increase in pulmonary artery pressure.28 Median survival after diagnosis of nonreversible PAH is 7 years. Dyspnea is the most common initial symptom, and it is definitively diagnosed via right heart catheterization. Surveillance revealed about 1 case of PAH per 430 patients with IBD taking IN. PAH secondary to IN appears to be partially or completely reversible with discontinuation of IN.29 The patients who have experienced PAH with IN have tended to be on relatively higher doses for longer periods of time (eg, the first reported case, who had been taking 2 g/d for 6 months). AhR activation and transient hypoxia are necessary components of IN-induced PAH development.30
  • Acute colitis: It is easy to want to discount reports of acute colitis occurring in clinical trials of IN for IBD, since colitis is the condition being treated in the first place. However, 1 trial reported that 3 patients with baseline left-sided UC took 2 to 3 g IN orally per day and developed right-sided colitis with marked colon wall thickening (1 also developed submucosal phlebitis) within 3 months of initiating IN, which was withdrawn at onset of the colitis. One patient underwent right hemicolectomy, and the acute colitis spontaneously resolved in the other 2, who later elected to restart IN, and acute colitis did not recur; indeed they remained in remission at follow-up 3 years later.17,31 There are several other case reports of individuals taking doses as low as 2 grams per day for a month or 1 gram per day for 2 months who have developed acute colitis, marked by remarkable edema and sometimes intussusception.4,32 One other case report is relevant here—a patient without IBD self-administered a very large dose of IN (2 g orally 3 times daily), apparently for a very long time (15 months), and developed edematous ischemic colitis and durable colon stenosis as a result.33
  • Colonic intussusception (CI): CI is the dangerous invagination of a proximal section of colon into a distal section, which, in the context of IN, may occur in the ileocecum or ascending colon. CI may lead to tissue edema, necrosis, and perforation. It sometimes spontaneously resolves, but when it doesn’t, it needs to be surgically resected. The most common presentation is intense intermittent abdominal pain, often followed by nausea, vomiting, constipation, and abdominal distention. It is best diagnosed with a pelvic/abdominal computed tomography (CT) scan. A Japanese survey identified 877 UC patients using IN, of whom 10 experienced cecal or ascending colon intussusception, 40% of which did not resolve and required surgical intervention.34 Some case reports of acute colitis & intussusception in patients with UC using IN report that symptoms began immediately following acute vigorous exercise,32 which of course could induce the transient hypoxia necessary to produce some IN-associated, AhR-associated pathology.30

We conjecture that just as IN-triggered AhR activation sometimes leads to vasculopathy in the pulmonary arteries, causing PAH, it may similarly lead to GI vasculopathy or phlebitis. The permeability of these leaky veins would lead to interstitial fluid accumulation and cause a local (or sometimes widespread) edema, which could provide a lead point, a protrusion, that during normal peristaltic activity, can be grabbed and pulled into the distal section of bowel, causing the invagination known as intussusception. Figuratively, the cooling fluids which are poured onto the flames of inflammatory bowel disease can themselves become a larger problem than the flame itself.

Non-IBD Uses

In addition to inflammatory bowel disease, IN has been investigated for its use in the treatment of psoriasis, atopic dermatitis, chemotherapy-induced oral mucositis, and acute promyelocytic leukemia. Topical IN is a safe and effective treatment for psoriasis, likely due to the modulation of the proliferation and differentiation of keratocytes and inhibition of T-cell infiltration into the epidermis, thus decreasing inflammation.35 One RCT suggested that topical IN may be a safe and effective treatment for atopic dermatitis as well.36 Based on the anti-inflammatory properties and induction of IL-22 expression observed in UC studies, researchers conducted a feasibility study to analyze the topical use of an IN ointment on chemotherapy-induced oral mucositis. The IN ointment was found to be a feasible, potentially safe, and effective treatment for chemotherapy-induced oral mucositis.37 Finally, oral IN administered with all-trans retinoic acid has been shown to be an effective treatment for acute promyelocytic leukemia and may be associated with less toxicity and fewer side effects than current conventional options.38

Conclusions

UC affects between 1 million and 3 million people in the United States,39 and its global incidence is increasing. Although pharmaceutical options for UC have increased substantially in recent years, outcomes remain poor. IN is a highly efficacious and conditionally safe therapy for the induction of remission for patients with UC (and to a lesser degree, CD); this is likely primarily due to the activation of aryl hydrocarbon receptors, leading to dramatic decreases in inflammation and upregulation of IL-22 expression, which promotes mucosal healing. This benefit has been observed in both nontreatment-refractory and treatment-refractory patients. Due to the potential for severe adverse events in patients taking IN orally, safety is a major consideration. We recommend monitoring liver transaminases and observing for new-onset abdominal pain that could be intussusception or acute colitis, as well as observing for new-onset dyspnea that could be PAH. Risks of developing both PAH and the edematous colitis associated with intussusception may be reduced by limiting the use of IN to IBD patients presenting in an energetically hot way—eg, frequent, urgent, loose, bloody stool—and not continuing the use of IN for too long after the symptomology is no longer considered “hot” in the Chinese medicine paradigm. In addition, a lower dose and/or duration of treatment may reduce the risk of adverse events. IN may also be effective in patients with pediatric UC, but more research is needed to examine its safety and appropriate dosing in this population.18

In our clinical experience, patients with actively inflamed UC (and sometimes CD) using IN tend to experience clinical response in days to weeks, often achieving clinical remission in 2 to 3 weeks. We’ve used IN in dozens of patients with inflammatory bowel disease, almost exclusively in patients with energetically “hot” presentations including frequent, loose, bloody bowel movements. The infrequent cases of intussusception that have been associated with IN use have most often occurred with patients on higher doses, for longer periods of time, and several cases occurred after vigorous physical activity; therefore, we tend to initiate therapy at a relatively conservative dose of 500-mg powdered herb capsule (compounded by traditional Chinese medicine herbal medicinaries) orally twice daily for 50 days to induce remission (quickly tapering once “hot” symptoms disappear and clinical remission is achieved), and we counsel patients to avoid the types of exercise that would leave them sweaty and/or out of breath during that 50 day period. This might be overly conservative—we have colleagues who use higher doses and allow their UC patients to exercise vigorously during IN therapy. Just as none of our patients have experienced serious adverse events following IN use that we’ve prescribed, neither have any of theirs.

IN offers the possibility of rapid onset reduction in GI inflammation, which can help IBD patients control their symptoms and disease activity, giving time for other medium- and long-term therapies, including dietary and lifestyle interventions, as well as botanical and supplement interventions with superior safety profiles, to begin working.

Categorized Under

Mark Davis

Mark Davis

ND
Mark Davis, ND, FABNG, is a 2011 graduate of National University of Natural Medicine. He’s licensed in Maryland, the District of Columbia, Oregon, and California, but he’s currently on sabbatical from clinical care. He’s on the board of directors of the Gastroenterology Association of Naturopathic Physicians and the editorial board of the Natural Medicine Journal. He teaches the gastroenterology course at Southwest College of Naturopathic Medicine and has focused on patients with inflammatory bowel disease since 2016.

Natalie Scheeler, ND

Natalie Scheeler, ND, received her doctorate of naturopathic medicine from Southwest College of Naturopathic Medicine in 2020, graduating with academic honors and specialized community health honors. She completed a 2-year general medicine residency through SCNM and Capital Integrative Health/Bastyr University, which included training in fecal microbiota transplantation (FMT) with Mark Davis, ND. She currently practices at Capital Integrative Health in Bethesda, MD, and is in the process of obtaining a master’s in public health at Johns Hopkins Bloomberg School of Public Health. 

References

  1. Feng J, Huang D, Yang Y, et al. Isatis indigotica: from (ethno) botany, biochemistry to synthetic biology. Mol Horticulture. 2021;1(1):17.
  2. Matsuno Y, Torisu T, Umeno J, et al. One-year clinical efficacy and safety of indigo naturalis for active ulcerative colitis: a real-world prospective study. Intest Res. 2022;20(2):260-268.
  3. Kato J, Yoshida T, Niwa T. Blue polypoid colorectal lesions in a woman with ulcerative colitis taking qing-dai. Clin Gastroenterol Hepatol. 2016;14(8):A32.
  4. Sun Q, Leng J, Tang L, Wang L, Fu C. A comprehensive review of the chemistry, pharmacokinetics, pharmacology, clinical applications, adverse events, and quality control of indigo naturalis. Front Pharmacol. 2021;12:664022.
  5. Saiki JP, Andreasson JO, Grimes KV, et al. Treatment-refractory ulcerative colitis responsive to indigo naturalis. BMJ Open Gastroenterol. 2021;8(1):e000813.
  6. Uchiyama K, Takami S, Suzuki H, et al. Efficacy and safety of short-term therapy with indigo naturalis for ulcerative colitis: an investigator-initiated multicenter double-blind clinical trial. PLoS One. 2020;15(11):e0241337.
  7. Murray A, Nguyen TM, Parker CE, Feagan BG, MacDonald JK. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2020;8(8):CD000543.
  8. Barnes EL, Jiang Y, Kappelman MD, et al. Decreasing colectomy rate for ulcerative colitis in the United States between 2007 and 2016: a time trend analysis. Inflamm Bowel Dis. 2020;26(8):1225-1231.
  9. Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017;376(18):1723-1736.
  10. Peyrin-Biroulet L, Arkkila P, Armuzzi A, et al. Comparative efficacy and safety of infliximab and vedolizumab therapy in patients with inflammatory bowel disease: a systematic review and meta-analysis. BMC Gastroenterol. 2022;22(1):291.
  11. Urushikubo J, Yanai S, Nakamura S, et al. Efficacy of indigo naturalis therapy for ulcerative colitis: a case series. Intern Med. 2019;58(16):2299-2304.
  12. Suzuki H, Kaneko T, Mizokami Y, et al. Therapeutic efficacy of the Qing Dai in patients with intractable ulcerative colitis. World J Gastroenterol. 2013;19(17):2718-2722.
  13. Sugimoto S, Naganuma M, Kiyohara H, et al. Clinical efficacy and safety of oral qing-dai in patients with ulcerative colitis: a single-center open-label prospective study. Digestion. 2016;93(3):193-201.
  14. Naganuma M, Sugimoto S, Mitsuyama K, et al. Efficacy of indigo naturalis in a multicenter randomized controlled trial of patients with ulcerative colitis. Gastroenterol. 2018;154(4):935-947.  
  15. Nishio M, Hirooka K, Doi Y. Chinese herbal drug natural indigo may cause pulmonary artery hypertension. Eur Heart J. 2016;37(25):1992.
  16. Naganuma M, Sugimoto S, Fukuda T, et al. Indigo naturalis is effective even in treatment-refractory patients with ulcerative colitis: a post hoc analysis from the INDIGO study. J Gastroenterol. 2020;55(2):169-180.
  17. Matsuno Y, Hirano A, Torisu T, et al. Short-term and long-term outcomes of indigo naturalis treatment for inflammatory bowel disease. J Gastroenterol Hepatol. 2020;35(3):412-417.
  18. Kudo T, Jimbo K, Shimizu H, et al. Qing-Dai for pediatric ulcerative colitis multicenter survey and systematic review. Pediatr Int. 2022;64(1):e15113.
  19. Yoshimatsu Y, Naganuma M, Sugimoto S, et al. Development of an indigo naturalis suppository for topical induction therapy in patients with ulcerative colitis. Digestion. 2020;101(4):492-498.
  20. Fukunaga K, Ohda Y, Hida N, et al. Placebo controlled evaluation of Xilei San, a herbal preparation in patients with intractable ulcerative proctitis. J Gastroenterol Hepatol. 2012;27(12):1808-1815.
  21. 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. J Altern Complement Med. 2013;19(10):838-842.
  22. Kim JW, Kim SY. The era of janus kinase inhibitors for inflammatory bowel disease treatment. Int J Mol Sci. 2021;22(21):11322.
  23. Yang L, Li X, Huang W, Rao X, Lai Y. Pharmacological properties of indirubin and its derivatives. Biomed Pharmacother. 2022;151:113112.
  24. Yoshimatsu Y, Sujino T, Miyamoto K, et al. Aryl hydrocarbon receptor signals in epithelial cells govern the recruitment and location of Helios+ Tregs in the gut. Cell Rep. 2022;39(6):110773.
  25. Yang QY, Ma LL, Zhang C, et al. Exploring the mechanism of indigo naturalis in the treatment of ulcerative colitis based on TLR4/MyD88/NF-κB signaling pathway and gut microbiota. Front Pharmacol. 2021;12:674416.
  26. De Juan A, Segura E. Modulation of immune responses by nutritional ligands of aryl hydrocarbon receptor. Front Immunol. 2021;12:645168.
  27. Kim HA, Suh HR, Kang B, Choe BH; Crohn’s and colitis association in DaeguGyeongbuk (CCAiD). Acute pancreatitis associated with indigo naturalis in pediatric severe Crohn’s disease. Intest Res. 2019;17(1):144-148.
  28. Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F. Mechanisms of disease: pulmonary arterial hypertension. Nat Rev Cardiol. 2011;8(8):443-455.
  29. Nishio M, Hirooka K, Doi Y. Pulmonary arterial hypertension associated with the Chinese herb indigo naturalis for ulcerative colitis: it may be reversible. Gastroenterol. 2018;155(2):577-578.
  30. Masaki T, Okazawa M, Asano R, et al. Aryl hydrocarbon receptor is essential for the pathogenesis of pulmonary arterial hypertension. Proc Natl Acad Sci U S A. 2021;118(11):e2023899118.
  31. Matsuno Y, Hirano A, Esaki M. Possible association of phlebitis-induced colitis with indigo naturalis. Gastroenterol. 2018;155(2):576–577.
  32. Kondo S, Araki T, Okita Y, et al. Colitis with wall thickening and edematous changes during oral administration of the powdered form of Qing-dai in patients with ulcerative colitis: a report of two cases. Clin J Gastroenterol. 2018;11(4):268-272.
  33. Zhang ZM, Lin XC, Ma L, et al. Ischemic or toxic injury: a challenging diagnosis and treatment of drug-induced stenosis of the sigmoid colon. World J Gastroenterol. 2017;23(21):3934-3944.
  34. Naganuma M, Sugimoto S, Suzuki H, et al. Adverse events in patients with ulcerative colitis treated with indigo naturalis: a Japanese nationwide survey. J Gastroenterol. 2019;54(10):891-896.
  35. Lin YK, Wong WR, Chang YC, et al. The efficacy and safety of topically applied indigo naturalis ointment in patients with plaque-type psoriasis. Dermatology. 2007;214(2):155-161.
  36. Lin YK, Chang SH, Yang CY, See LC, Lee BH, Shih IH. Efficacy and safety of indigo naturalis ointment in treating atopic dermatitis: a randomized clinical trial. J Ethnopharmacol. 2020;250:112477.
  37. Hirata K, Yamada Y, Hamamoto Y, et al. Prospective feasibility study of indigo naturalis ointment for chemotherapy-induced oral mucositis. BMJ Support Palliat Care. 2021;bmjspcare-2021-003199. Published online ahead of print.
  38. Luo S, Tian J, Sun X, et al. Oral realgar-indigo naturalis formula treatment for acute promyelocytic leukemia in children: a randomized, control clinical trial. Evid Based Complement Alternat Med. 2022;2022:8314176.
  39. Xu F, Carlson SA, Liu Y, Greenlund KJ. Prevalence of inflammatory bowel disease among Medicare fee-for-service beneficiaries — United States, 2001−2018. MMWR Morb Mortal Wkly Rep. 2021;70:698-701.

Diversified Communications
© 2024 Diversified Communications. All rights reserved.