Dai-kenchu-to (DKT, TJ-100), prepared from three crude herbs: Ginseng, Zanthoxylum Fruit and Dried Ginger (Table 1), is often used in Japan in the treatment of GI hypomotility such as ileus following abdominal surgery.
Among 27 manuscripts related to DKT, 18 were animal studies and nine were human studies. Only one randomized controlled study has been performed to evaluate the clinical effects of DKT.21 Among 18 animal studies, 16 articles were related to intestinal function.22–37 All nine human studies examined intestinal function (Fig. 1, Table 2).21,38–45
Effects on putative receptors or neurotransmitters A single oral administration of DKT caused significant increases in plasma levels of motilin,38 vasoactive intestinal peptide (VIP), 5-HT,39 CGRP and substance P,40 but not of gastrin and somatostatin.38 DKT induces the release of motilin and VIP into plasma mainly through the activation of M(1) muscarinic receptors.41 DKT and one of its active components, 6-shogaol, produced an increase in intestinal blood flow that was mainly mediated by CGRP,46 suggesting that DKT may be useful in the treatment of intestinal ischaemia-related organic as well as functional GI diseases. DKT also prevented bacterial translocation by reducing inflammatory reaction for maintaining intestinal integrity.47
Effects on motor patterns Gastrointestinal motility Intragastric DKT and a variety of agents including zanthoxylum fruit, ginseng root, and dried ginger rhizome stimulate upper GI motility in dogs through cholinergic and 5-HT3 receptors.22 The prokinetic effects of DKT differ with the site (stomach, duodenum, jejunum, ileum and colon) or timing (the fasting and the fed) of administration.23
Dai-kenchu-to-induced contractions accompanied by autonomous contraction at a concentration of more than 3 × 10−4 g mL−1 in a dose-related manner in the isolated guinea-pig ileum.24 DKT-induced ileal contraction was suppressed by atropine and tetrodotoxin, but not by hexamethonium, and was partially suppressed in the presence of 5-HT4 receptor antagonist. In addition, DKT was associated with an ACh-releasing action in the ileal smooth muscle, suggesting that contractile response induced by DKT is partially mediated by ACh released from the cholinergic nerve endings and that 5-HT4 receptors are involved in the effect of DKT.24 Tachykinins may be also involved in the atropine-resistant contraction by DKT.25
In an isolated rabbit jejunum, DKT acted on multiple points of the intestine to improve ileus.26 While DKT evoked both contraction and relaxation by releasing ACh, NO and other excitatory neurotransmitters in mouse small intestine, it had no effects on pacemaker mechanisms and electrical coupling between interstitial cells of Cajal in myenteric plexus (ICC-MY) and smooth muscle cells,27 suggesting that DKT may contract smooth muscles directly. Abatement of morphine-induced transit disorders by DKT in the guinea-pig ileum was reported to be caused by both moderate contraction of morphine-treated longitudinal muscle and relaxation of morphine-induced tonic contraction of circular muscle.28 In terms of colonic motility, DKT-extract powder caused a significant inhibition on carbachol-induced contraction of the rat distal colon in a concentration-dependent manner.29
Small intestinal motility Dai-kenchu-to improves accelerated small intestinal movement with mechanisms mainly through the direct inhibition of smooth muscle and partially through neural inhibition.30 The components of DKT (Table 1) that provide this effect may be dried ginger root and ginseng, which also contribute to the action of DKT on small intestinal transit.31
Dai-kenchu-to also induces phasic contractions in the duodenum and proximal jejunum, possibly mediated through cholinergic receptors.32 Such stimulatory effects on intestinal motility by DKT are selective on GI tract as DKT has no effect on the uterine motility.33
Chlorpromazine-induced hypoperistalsis Dai-kenchu-to also improves chlorpromazine-induced hypoperistalsis via cholinergic systems. One of the ingredients in DKT, zanthoxylum fruit is likely the main contributor to this action. In addition, endogenous CCK release, which has been demonstrated to occur in response to maltose syrup, may also contribute to the reversal of hypoperistalsis.34
Postoperative ileus Postoperative ileus (POI) is a transient bowel motor dysfunction that occurs after surgery. Delays in GI transit may be prolonged after laparotomy plus intestinal manipulation. DKT accelerated the delayed GI transit induced by intestinal manipulation, with or without concomitant morphine administration.35
The improvement in motor function is inhibited by pretreatment with atropine or ruthenium red. In addition, DKT-induced contractions are inhibited by tetrodotoxin, and capsazepine. As the effect of hydroxyl sanshool, one of the active compounds of DKT, is mediated by sensory nerves, the effect of DKT may be due to a combination of sensory and cholinergic nerves.36 Alternatively, the effect may be due to reversal of transient ischaemia through the improvement of the intestinal mucosal blood flow.46 In postoperative intestinal adhesion, repeated administrations of DKT significantly inhibited the formation of intestinal obstruction.37 A single administration of DKT significantly reduces intestinal transit time in POI and chemically induced ileus.37
Dai-kenchu-to-ameliorated postoperative hypoperistalsis is via cholinergic nerves and 5-HT4 receptors.48
Dai-kenchu-to treatment may be useful for the patients with POI, which is a common adverse consequence of abdominal surgical procedures. According to a double-blind, randomized study examining the effects of DKT was performed in 24 patients with POI, DKT was significantly more effective than placebo in reducing both the need for further surgery and the recurrence of POI.21 Among patients with total gastrectomy with jejunal pouch interposition, DKT increased intestinal motility and decreased postoperative symptoms.42 Furthermore, administration of DKT in conjunction with keishi-bukuryo-gan was highly effective in improving postoperative bowel motility and in reducing hospital stay.43 Also in children,44 DKT had incremental but significant effects for a variety of obstructive bowel diseases.
Constipation In a study of children with chronic constipation, DKT reduced symptoms of constipation and improved rectal reservoir function demonstrated through anorectal manometry. DKT was shown to stimulate peristalsis of the intestine, which was associated with resumption of regular bowel habits.45