Past Project - ICRC
International Center for Research on Complementary (ICRC) Medicine
PI: Brian Berman, MD; Co-PI: Joseph Sung, MD
This ICRC center grant was an international, multi-institution project originally funded by National Institutes of Health/National Center for Complementary and Alternative Medicine (NCCAM) in 2005 for $4 million that investigated the use of TCM (acupuncture and a 20-herb compound) in treating functional bowel disorder. This grant built upon a two-year planning grant awarded to us in 2003 by NCCAM and cemented our collaborations with the Chinese University of Hong Kong (CUHK), the University of Illinois, Chicago, and the University of Western Sydney. The overall aim of the international center grants was to “establish partnerships and cross-cultural exchange through which foreign and US institutions and investigators collaborate to design and implement research on CAM/traditional indigenous medical systems or components thereof in the cultures and/or environments in which they originated.” The studies of our center grant were supported by 3 cores: 1) administrative; 2) botanical; and 3) data management and statistical analysis. In addition to oversight of the following 3 studies, the administrative core was involved in the planning and implementation of an international conference on TCM for Functional Bowel Disorder, and conducted a fellows training program for Chinese scholars to study at the University of Maryland.
Project 1: Effect of Electroacupuncture on Behavioral Response and Colonic, Spinal, and Central Serotonergic Neurotransmitter Systems in an Animal Model of IBS
PI: Justin Wu, PhD, Co-PI Lixing Lao, PhD
The objective was to evaluate the effect and mechanism of extended 5-day electroacupuncture (EA) on treatment of irritable bowel syndrome in a rat model of visceral hyperalgesia. The aims were to determine the effect of EA on behavioral and visceromotor response to visceral pain in rat model of visceral hyperalgesia; to determine the effect of EA on colonic mucosal serotoninergic signaling in rats with visceral hyperalgesia; to determine the effect of EA on neurochemical changes in spinal cord in rats with visceral hyperalgesia; and to determine the effect of EA on neurochemical changes in brainstem in rats with visceral hyperalgesia.
The methodology was: Sprague-Dawley rats with prior neonatal maternal separation stress were randomly allocated to receive 5-day 20-minute treatment of either electro-acupuncture (EA) at frequency of 10Hz or sham acupuncture at acupoint ST-36. Stepwise colorectal distension (CRD) with distension pressures at 10, 20 and 40 mmHg was performed on the day after acupuncture treatment. The two groups were compared for pain threshold as determined by abdominal withdrawal reflex and visceromotor response as measured by electromyogram (EMG). Colon, spinal cord, and brainstem were sampled for topographic distribution and quantitative assessment of serotonin (5-HT) and serotonin reuptake transporter protein (SERT) expression.
Final Results: There was significant difference in pain thresholds and visceromotor response to graded colorectal distensions between EA and sham treatment. There was also no significant difference in SERT expression in the brain gut axis.
Project 2: Chinese Herbal Formula for the Treatment of Functional Bowel Disorders: In vitro and in vivo Evaluation of Safety and biological Potentials
PI: Chun-Tao Che, Co-I: Lixing Lao, PhD
The major objectives of Project 2 are to conduct non-clinical safety evaluation of a 20-herb Chinese medicinal preparation for the treatment of irritable bowel syndrome (IBS), to establish the biological potential of the herbal preparation, and to provide bioassay support for the discovery of active components in Botanical Core.
To achieve these objectives, the following tasks were proposed: (1) Safety evaluation of the herbal preparation based on acute toxicity (single treatment), sub-chronic toxicity (7-day treatment), chronic toxicity (2-month treatment), and mutagenicity test results; (2) In vitro sensorimotor-modulatory and receptor binding effects of the herbal preparations; and (3) In vivo effect on stress-induced visceral hyperalgesia.
Final Results: The aims and objectives of Project 2 have been fulfilled. All 20 herbs as well as the composite formula (the 20-herb mixture) were evaluated for relaxation effect in acetylcholine- and serotonin-induced intestinal contractions. For the 20-herb mixture, the water extract at 0.34 and 1.7 g/kg significantly reduced abdominal pain induced by increasing colorectal distension pressure as indicated by both abdominal withdrawal reflex and electromyographic measurements.
As far as the toxicity tests are concerned, the water extract of the 20-herb mixture was shown to be non-toxic up to a human equivalent dose of 170 g extract/day. In addition, the herbal preparation did not show mutagenic effects as evidenced by the results of Ames test, chromosome aberration test, and bone marrow micronucleus test.
The effect of the herbal extracts on opioid receptor was tested and seven plant extracts displayed activity against electric field-induced intestinal contraction. However, the responses were not abolished by naloxone, indicating a non-specific effect rather than an interaction at the opioid receptor.
In an attempt to reveal possible mechanisms of the herbal preparation, the 5HT contents in distal colon were found to be increased in hyperalgesic rats (compared with normal rats), while treatment with the 20-herb preparation significantly suppressed the elevated serotonin. However, no change in 5-HT3 receptor and serotonin transporter levels was detected in this animal model.
We have also measured EMG signals of the treated animals at different time points. A sustained effect was detected up to the 8th day after the last dose of herbal treatment.
As proposed in a previous interim report, an alternative animal model of IBS (by injection of diluted acetic acid) has been preliminarily evaluated. The decrease in pain threshold was found to be smaller than that of the NMSS model.
Project 3: A Randomized, Placebo-Controlled, Dose-Finding Clinical Trial Evaluating the Safety and Dose-Response of the Herbal Formulation in Patients with IBS
PI: Francis Chan, MD
This was a dose-finding, randomized, placebo-controlled, double-blind, phase II clinical trial of N=104 participants to look at the effect of the 20-herb formulation on reducing symptoms of irritable bowel syndrome (IBS) in patients attending the Prince of Wales Hospital in Hong Kong. The study is called “Traditional Chinese Medicine for Irritable Bowel Syndrome (TCM-IBS)”.
Enrolled participants were assessed at baseline and randomized to receive the 20-herb formula, or to receive an identical placebo. They took their assigned study drug for 8 weeks and were assessed at 2, 4 and 8 weeks for IBS symptoms, adverse events and blood immune and endocrine markers to assess safety. The final follow-up was at 10 weeks, for safety assessment.
The TCM-IBS study uses a 20-herb formulation that has been prepared and thoroughly tested for safety and bioactivity by the Botanical Core of this U19 center grant. The liquid herbal extract has been spray-dried into granules which are put into small packets, in a method similar to making instant coffee. Participants mixed the contents of the packet with boiling water to make an herbal tea, which they drank once or twice a day, depending on the dose. There are two dosing levels in this study, so that the lowest effective dose of the herbal formula may be identified. The lower dose was 17 gm per day, and the higher dose was 35 gm per day. 52 participants were enrolled at the lower dose, and n=52 participants enrolled at the higher dose. After the participants in the lower dose completed their study activities, a Data and Safety Monitoring Board (DSMB) evaluated safety and effect of the lower dose, before proceeding to the higher dose. The DSMB continued to monitor safety throughout the higher dose activities.
Final Results: For the primary outcome measure, the rate of adequate global symptom relief were 28% in High dose HLXL, 27% in Low dose HLXL and 30% in Placebo group, respectively. There was no significant difference in adequate relief of global symptom (Table 2, p=0.95). Multivariate analysis of potential confounding factors (age, treatment group, use of anti-diarrheal drug) did not identify any predictor of clinical response. For the secondary outcome measures, there was no significant difference in the bowel symptom score using 0-100 visual analogue scale among the three treatment groups at week 4, 8 and 12 weeks.