Complementary and synergistic therapeutic effects of compounds found in Kampo medicine: analysis of daikenchuto

Abstract

Herbal medicines have been used in Japan for more than 1500 years and traditional Japanese medicines (Kampo medicines) are now fully integrated into the modern healthcare system. In total, 148 Kampo formulae are officially approved as prescription drugs and covered by the national health insurance system in Japan. However, despite their long track record of clinical use, the multi-targeted, multi-component properties of Kampo medicines, which are fundamentally different from Western medicines, have made it difficult to create a suitable framework for conducting well-designed, large-scale clinical trials. In turn, this has led to misconceptions among western trained physicians concerning the paucity of scientific evidence for the beneficial effects of Kampo medicines. Fortunately, there has been a recent surge in scientifically robust data from basic and clinical studies for some of the Kampo medicines, e.g., daikenchuto (TU-100). Numerous basic and clinical studies on TU-100, including placebo-controlled double-blind studies for various gastrointestinal disorders, and absorption, distribution, metabolism and excretion (ADME) studies, have been conducted or are in the process of being conducted in both Japan and the USA. Clinical studies suggest that TU-100 is beneficial for postoperative complications, especially ileus and abdominal bloating. ADME and basic studies indicate that the effect of TU-100 is a composite of numerous actions mediated by multiple compounds supplied via multiple routes. In addition to known mechanisms of action via enteric/sensory nerve stimulation, novel mechanisms via the TRPA1 channel and two pore domain potassium channels have recently been elucidated. TU-100 compounds target these channels with and without absorption, both before and after metabolic activation by enteric flora, with different timings and possibly with synergism.

Keywords: Kampo; adrenomedullin; daikenchuto; hydroxy-α-sanshool; potassium leak channels; traditional Japanese herbal medicine; transient receptor potential ankyrin 1.

Figure 1

Daikenchuto components and its manufacturing process. Daikenchuto is a herbal formulation consisting of processed ginger, Japanese pepper, and ginseng radix. The normal adult dosage is between 7.5 and 15 g given as two or three doses.

Figure 2

Diagrammatic representation of the hypothesized journey of TU-100 compounds after ingestion. The concentrations of TU-100 compounds and their conjugates after oral administration of TU-100 in rat intestinal, portal blood and peripheral blood and in human ileal effluent and peripheral blood were measured in several PK studies (Munekage et al., , ; Watanabe et al., in press). The results are summarized as indicated in the figure. The diagram of digestive sysytem (A), and the fate of Japanese pepper (B), Ginger (C) and ginseng (D) ingredients are shown. The effect of TU-100 on the intestines should be a composite of multiple actions by multiple compounds supplied via multiple routes. Quoted from Watanabe et al. (in press).

Figure 3

Multi-target actions of intraluminal TRPA1 agonists. Gut TRPA1 elicits physiological and pathophysiological responses by three distinct mechanisms. TRPA1 activators, in this case shogaols, gingerols and hydroxysanhools, have three potential target cells: intestinal epithelial (IE) cells, enterochromaffin (EC) cells, and TRPA1-positive sensory neurons. As a result of TRPA1 stimulation, TRPA1 agonists stimulate IE cells to release ADM, EC cells to release 5-HT, and sensory neurons to release CGRP/substance P, respectively, resulting in physiological and biodefensive responses in vasodilatation, motility, secretion, and pain signaling. Quoted from Kono et al. (2013).

Figure 4

Hypotheses on synergism of TU-100 compounds on colonic motility. (A) Two-pore-domain potassium channels (i.e., KCNKs family channels) are expressed in many types of excitable cells throughout the body and have been implicated in various cellular functions, including the maintenance of the resting potential and regulation of excitability. Low doses of ginger compounds cannot evoke action potentials. (B) One of compounds of daikenchuto, hydroxy-α-sanshool, acts as a blocker of two-pore-domain potassium leak channels (KCNK3 and KCNK9) and alters the excitability of a cell via voltage-activated cation channels. Low doses of ginger compounds can evoke action potentials.