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- Materials And Methods
- Supporting Information
Complementary and alternative medicine (CAM) is a combination of healing philosophies and therapies that is not commonly used in conventional medicine. Over the last decade, the US population has shown a substantial and steady use of CAM. It is estimated that 38.3% of adults in the United States use some form of CAM; among these CAM therapies, natural products (17.7%) are the second most commonly used, after prayer. In 2007, there was expenditure of $14.8 billion to purchase natural products such as herbal medicines. Although herbal medicines have been widely use to treat gastrointestinal (GI) symptoms, there are few studies documenting the pharmacological effects of these agents.
Daikenchuto, a Japanese herbal medicine, which consists of an extract powder from dried Sichuan pepper, processed ginger, ginseng and maltose powder, has been used for the treatment of paralytic ileus and radiation-induced enteritis due to its possible prokinetic effect.[5-7]
In animal studies, intraduodenal and intrajejunal administration of TU-100 (a modern herbal product of daikenchuto manufactured in the granule form) dose dependently increased motility of the duodenum, proximal jejunum and distal jejunum in conscious dogs. In vivo and in vitro experiments have shown that the prokinetic effect of daikenchuto after intestinal dysmotility, induced laparoscopically or chemically, was inhibited by atropine or a 5-HT4 antagonist, suggesting that daikenchuto modulates cholinergic and serotonergic mechanisms.[9-11] Daikenchuto also stimulated acetylcholine release in pig ileal smooth muscle.
In a study in healthy adult humans, TU-100 appeared to be safe and well tolerated and demonstrated prokinetic effects on ascending colon transit emptying. In another study, daikenchuto decreased the sensation thresholds (implying enhanced sensation) and rectal compliance in children with severe constipation; the authors attributed the potential beneficial clinical effect on constipation to decrease in rectal reservoir volume and increased intestinal peristalsis.
Given the known delay in colonic transit in patients with constipation, the promising prokinetic effects seen with TU-100 in healthy adults and the lack of data from TU-100 on rectal sensation and compliance in adults, we aimed to evaluate the effects of TU-100 on gastrointestinal and colonic transit, rectal sensation and compliance, bowel function and quality of life in female adults with functional constipation.
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- Materials And Methods
- Supporting Information
In this randomised, double-blind, placebo-controlled study, we sought to address the effects of TU-100 on gastrointestinal motor function in female patients with constipation. The study met target for accrual and had adequate power to detect clinically relevant differences between treatment groups; no significant treatment effects were observed for TU-100 on any of the outcomes under study.
Previous literature suggested TU-100 as a potential intestinal prokinetic. Our group observed a promotility effect in small intestine and ascending colon transit in healthy adults treated for 5 days with TU-100 (13). Such a promotility effect was also reproduced in dogs, distal to and at the sites of intraluminal administration, and in guinea pigs.[12, 27, 28] However, in prior human studies, no effects were demonstrated on gastric emptying in healthy adults or on stool frequency or consistency in patients with severe constipation.
Based on the apparent pharmacological action of daikenchuto on serotonergic and cholinergic mechanisms, its extensive use in Japan for relief of abdominal bloating, constipation and intestinal pseudo-obstruction, as well as its favourable safety profile, we sought to further investigate the effects of TU-100 in patients with functional constipation by measuring geometric centre of colonic transit at 24 h and ascending colon emptying half-time. We took the additional precaution of excluding patients with clinical evidence of a rectal evacuation disorder. Delayed emptying of ascending colon transit is observed in patients with severe constipation and in patients with constipation-predominant irritable bowel syndrome (IBS-C). Our current findings do not confirm our prior observation in a study of TU-100 in healthy adults, in which the same medication at a dose of 2.5 g t.d.s decreased ascending colon half-time. It is conceivable that the lack of response in patients with chronic constipation is due to known deficits in colonic innervation or interstitial cells of Cajal (ICCs) in patients with slow transit constipation.[32, 33] Animal models lacking ICCs have reduced gastrointestinal smooth muscle responses to acetylcholine released by excitatory motor neurons. Daikenchuto's actions are mediated through cholinergic pathways, which may be less responsive in patients with slow transit constipation compared with healthy individuals. We considered that the lack of significant effects in our study could be explained by one of five main reasons: lack of power (type II error), placebo effect, low sensitivity of our data collection methods, tachyphylaxis or a true effect.
First, a post hoc power analysis showed that the coefficient of variation (COV) between groups was nearly the same as our predicted COV that led to the proposed sample size of 15 individuals per group; this suggests that lack of power is an unlikely explanation of the lack of response.
Second, we did not observe an important effect of placebo. Thus, the mean values of colonic GC24 at pre-treatment were 1.76, 1.77, 1.84 for the placebo, 2.5 g t.d.s. and 5 g t.d.s. groups respectively. The corresponding (mean) deltas, posttreatment minus pre-treatment for GC24 were, respectively, 0.17, 0.00 and 0.18. The delta of 0.17 GC units at 24 h observed in the placebo group is consistent with the intra-individual variation in colonic transit in patients with irritable bowel syndrome. Thus, Deiteren et al. showed that the mean difference between replicate transit assessments, performed within a 3-week period, was 0.08 ± 0.11 for GC24.
Third, our data collection methods have been extensively studied, standardised and validated for studies evaluating gastrointestinal transit physiology and collection of bowel diaries, as summarised elsewhere; hence, we believe that a low sensitivity of our assessments does not play a role in the observed findings of this study.
Fourth, tachyphylaxis may be a reason to explain the lack of drug effect in our study. Other studies have shown the acute beneficial effect of daikenchuto in patients with post-operative ileus, or the prokinetic effects on ascending colon transit emptying in healthy adults after a shorter period of only 5 days of treatment, during which time tachyphylaxis may not have occurred.
Finally, poor medication compliance was unlikely, as all patients recorded the time of the administration of the study drug daily in a diary, and during each follow-up visit, the participants were specifically asked about compliance with medications and were required to provide the empty packets to maintain a count, which resulted in nearly complete compliance.
Consistent with our previous findings in healthy adults, this study did not show statistically significant changes in stool frequency or consistency, or quality of life in patients with chronic constipation. However, this study was not powered to detect a change in stool frequency or consistency, or quality of life. Other IBS symptoms such as pain and bloating were not addressed in our study. There is an ongoing clinical trial to address the effect of TU-100 in functional constipation using the Constipation Severity Instrument (CSI, NCT01348152).
In addition, our study appraised rectal sensation thresholds, but not sensory ratings in response to barostat-controlled rectal distensions. The association of effects on rectal sensation thresholds with prediction of effects on visceral hypersensitivity is imperfect, with higher coefficients of variation with estimates by the ascending limits of threshold for sensation method compared with sensory ratings in response to standardised distension pressures. It is possible that the ascending limits of threshold for sensation method may be associated with response bias, where participants report their sensation at each of the escalating pressure levels. Thus, the current observations do not support a potential benefit of the drug on sensory mechanisms. In fact, the 5 g t.d.s. dose was associated with lower sensation thresholds for first sensation and gas (unadjusted P-values: 0.045 and 0.024, respectively), which suggests an increase in rectal sensation.
Our findings are limited to female patients with functional constipation, and future studies of TU-100 should include sensation ratings in response to distension and address whether it is beneficial for patients with IBS symptoms of pain and/or abdominal bloating or for patients with documented visceral hypersensitivity.
In summary, in this pharmacodynamic study, there were no significant treatment effects of TU-100 at 2.5 g t.d.s. or 5 g t.d.s dosages on gastrointestinal or colonic transit, rectal compliance, thresholds for sensation and anal sphincter pressures. The mechanisms underlying the clinically observed benefit of this Japanese traditional medication remain unclear.