Journal of Pediatric Gastroenterology & Nutrition:
Original Articles: Gastroenterology
Tolerability of Curcumin in Pediatric Inflammatory Bowel Disease: A Forced-Dose Titration Study
Suskind, David L.*; Wahbeh, Ghassan*; Burpee, Tyler*; Cohen, Morty‡; Christie, Dennis*; Weber, Wendy†
*Department of Pediatrics, Seattle Children's Hospital and University of Washington, Seattle
†National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland
‡Pharmacy Department, Seattle Children's, Seattle, Washington.
Address correspondence and reprint requests to David L. Suskind, MD, Seattle Children's Hospital, 4800 Sandpoint Way NE, Seattle, WA 98105 (e-mail: David.Suskind@seattlechildrens.org).
Received 22 February, 2012
Accepted 27 September, 2012
www.clinicaltrials.gov registration number NCT00889161 and IND 103,826.
This work was supported by grants from the Institute of Translational Health Sciences (ITHS) at the University of Washington. The institute is supported by grants UL1 RR025014, KL2 RR025015, and TL1 RR025016 from the NIH National Center for Research Resources.
The authors report no conflicts of interest.
Background: Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation in the absence of a recognized etiology. The primary therapies are medications that possess anti-inflammatory or immunosuppressive effects. Given the high use of complementary alternative medicines in pediatric IBD, a prospective tolerability study of curcumin, an herbal therapy with known anti-inflammatory effects, was conducted to assess possible dosage in children with IBD.
Methods: Prospectively, patients with Crohn disease or ulcerative colitis in remission or with mild disease (Pediatric Crohn's Disease Activity Index [PCDAI] <30 or Pediatric Ulcerative Colitis Activity Index [PUCAI] score <34) were enrolled in a tolerability study. All patients received curcumin in addition to their standard therapy. Patients initially received 500 mg twice per day for 3 weeks. Using the forced-dose titration design, doses were increased up to 1 g twice per day at week 3 for a total of 3 weeks and then titrated again to 2 g twice per day at week 6 for 3 weeks. Validated measures of disease activity, using the PUCAI and PCDAI, and the Monitoring of Side Effect System score were obtained at weeks 3, 6, and 9.
Results: All patients tolerated curcumin well, with the only symptom that was consistently reported during all 3 visits being an increase in gassiness, which occurred in only 2 patients. Three patients saw improvement in PUCAI/PCDAI score.
Conclusions: This pilot study suggests that curcumin may be used as an adjunctive therapy for individuals seeking a combination of conventional medicine and alternative medicine.
Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation in the absence of a recognized etiology. Human and animal studies support the theory that patients with IBD have dysfunction of reactive and innate immune systems in response to an unknown trigger. Therapy of IBD with anti-inflammatory or immunosuppressive agents is effective, but carries many well-known adverse effects and intolerabilities (1).
Curcumin is the principal natural curcuminoid (a class of phenols) found in the plant Curcuma longa, which is used as a food additive known as turmeric. In India, it has been used as a spice and food preservative as well as for treatment in Ayurveda (traditional Indian medicine). In the United States, it is also commonly used as a coloring agent in foods. Curcumin has a broad spectrum of pharmacologic actions, including anti-inflammatory, antioxidant, and antitumor effects (2). Many in vitro and animal studies have been conducted to evaluate curcumin's effect on inflammation. The pleiotropic effects of curcumin are attributable in part to the inhibition of the transcriptional nuclear factor-κB with subsequent inhibition of tumor necrosis factor, interleukin-12, and interleukin-2; all important cytokines in the inflammatory cascade (2–5). Recent animal and adult human studies have shown beneficial effects in intestinal inflammation. Given its anti-inflammatory effects and its prior usage in ayurvedic medicine, we conducted a tolerability study to assess increasing dosages of curcumin in children with IBD.
The protocol was approved by the Seattle Children's Hospital institutional review board. Patients were recruited from the outpatient service of the Division of Pediatric Gastroenterology at University of Washington, Seattle Children's Hospital. Informed consent was obtained from all parents, and assent was obtained from all participants. Prospectively, patients with Crohn disease or ulcerative colitis (UC) in remission or with mild disease (pediatric Crohn disease activity index (PCDAI) <30 or pediatric ulcerative colitis activity index (PUCAI) score <34) were enrolled in a tolerability study (6,7). Curcumin was supplied as 500-mg capsules (Vital Nutrients Inc, Middletown, CT). The curcumin extract underwent both drug quality testing for curcuminoid content and food testing at an independent laboratory before dispensing (Integrated Biomolecule Corporation, Tucson, AZ). All patients received curcumin in addition to their standard therapy. No placebos were used in the present study. The patients initially received 500 mg twice per day for 3 weeks. Using the forced dose titration design, doses were increased to 1 g twice per day at week 3 for a total of 3 weeks and then titrated again to 2 g twice per day at week 6 for 3 weeks. The patients were seen at baseline, and at 3, 6, and 9 weeks. Validated measures of disease activity, using the PUCAI or PCDAI scores, were completed during each study visit. The Monitoring of Side Effect System scale was obtained at weeks 3, 6, and 9. The patients were given the option of discontinuation or de-escalation of curcumin dose to the previously tolerated dose if toxicity was detected. Laboratory measures were obtained at each visit including complete blood count, sedimentation rate, C-reactive protein, creatinine, amylase, and alanine transaminase.
A total of 11 patients (7 boys/4 girls; 14.6 ± 2.3 years, range 11–18 years) were enrolled in the study (Table 1). Six had Crohn disease and 5 had UC. Six patients were receiving mesalamine and 5 patients were receiving antitumor necrosis factor biological therapy. Before beginning the study, all of the patients were receiving maintenance medication for >6 months except 2 patients with UC and mild active disease who had been receiving maintenance medication for 2 months. Nine patients completed the study. Two patients dropped from the study for reasons unrelated to the study drug, that is, unable to make clinic follow-up. All of the other patients tolerated curcumin well at all study doses. Two patients reported increase gassiness during 3 visits. Inconsistent reports of symptoms (symptoms occurring only once or resolving on their own) occurred in the majority of patients but were not believed to be related to the curcumin by patient, parent, or physician. All symptoms reported were mild, not clearly related to curcumin, and did not require de-escalation of the curcumin. Laboratory studies remained within normal range during the study. Three patients had lowering of PUCAI or PCDAI scores. Two patients with UC had PUCAI scores decreased by 20 points, indicating remission (scores dropped from 30 to 10 and 25 to 5, respectively). The Crohn patients’ score dropped from 5 to 0, suggesting improvement. No participants experienced a relapse or worsening of symptoms while receiving the study medication.
Curcumin is a natural compound found in the plant Curcuma longa, which is used as a food additive known as turmeric (8). Humans appear to tolerate curcumin well. In India, the average intake of turmeric in the diet is approximately 2 to 2.5 g/day in a 60-kg individual. This corresponds to an intake of 60 to 100 mg of curcumin daily (9). Humans appear to be able to tolerate high doses of curcumin without significant adverse effect. In a prospective phase-I study in adults using up to 8 g/day of curcumin, no toxic effect of curcumin was found (10). Studies evaluating curcumin in patients with rheumatoid arthritis, postsurgical inflammation, and uveitis have shown beneficial effects without adverse effect (11,12).
A pilot study in adults with ulcerative proctitis or Crohn disease showed a reduction in symptoms with administration of 550-mg curcumin 3 times per day (13). Curcumin has also been used in adults with UC in a randomized double-blind trial in the prevention of relapse (14). In the present study, patients received standard treatment (sulfasalazine/mesalamine) with either placebo or curcumin. Using doses of 1 g twice per day for a 6-month period, patients receiving curcumin showed a significant decrease in relapse (4.6% vs 20.5% P = 0.04). The recurrence rates evaluated on the basis of intention to treat showed significant difference between curcumin and placebo (P = 0.049). Furthermore, curcumin improved both clinical activity index (P = 0.038) and endoscopic index (P = 0.0001), thus suppressing the morbidity associated with UC.
Presently, 36% to 50% of pediatric patients treated for IBD in gastroenterology clinics have used complementary and alternative therapies (15,16). In most instances, there are limited data on efficacy, tolerability, and adverse effects of these interventions. This is the first study to prospectively assess the tolerability of curcumin in pediatric IBD. Our results show that in this small sample of pediatric patients, curcumin is tolerated at doses up to 2 g twice per day. This pilot study suggests that curcumin may be used as an adjunctive therapy for individuals seeking a combination of conventional and alternative medicine without clinically significant adverse events. Further studies are required to fully assess the safety and efficacy of curcumin in larger studies of patients with pediatric IBD.
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complementary alternative medicine; Crohn disease; curcumin; inflammatory bowel disease; pediatrics; turmeric; ulcerative colitis
Copyright 2013 by ESPGHAN and NASPGHAN
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