Kampo medicine, a traditional Japanese herbal medicine, is covered by the Japanese National Health Insurance and prescribed for various purposes. While relatively safe with few adverse effects, it may potentially cause severe adverse effects, such as lung injury. Herein, we describe the case of a 61-year-old Japanese woman with choreito-induced lung injury that manifested as organizing pneumonia (OP) with diffuse alveolar hemorrhage (DAH). She was referred to our department due to multiple abnormal opacities detected on annual chest radiography. Chest computed tomography (CT) revealed multiple nodules in bilateral lungs. Bloody bronchoalveolar lavage fluid was obtained from the left lingular lobe, appearing nearly normal, while a transbronchial lung biopsy from a subpleural nodule in the left lower lobe was pathologically consistent with OP. The drug lymphocyte stimulation test result was positive for choreito, which the patient had regularly consumed for 6 - 7 months to treat hematuria. Consequently, a diagnosis of choreito-induced OP and DAH was made. Owing to the discontinuation of choreito alone and without the introduction of systemic steroid therapy, the multiple nodules shrank and eventually disappeared on follow-up chest CT. Regardless of the type of crude drug used in Kampo medicine, clinicians must always be careful for potential lung injury, which may present as OP with DAH.

Kampo, a branch of traditional Japanese herbal medicine, has been the backbone of Japanese medicine for more than 1500 years. The health insurance system in Japan allows patients to access both Western and Kampo medical care at the same time in the same medical institution. Kampo has been used for the treatment of not only acute but also chronic pain in Japan. In this review, we will elaborate on the short history of Kampo, its basic concepts, and use for the treatment of pain.

Rikkunshito, a traditional Japanese herbal medicine, improves appetite via activation of gastrointestinal hormone ghrelin pathway. The function of ghrelin is mediated by growth hormone secretagogue receptor (GHSR1a), and ghrelin has been known to possess diverse physiological functions including growth suppression of some cancer cells. Considering that increased ghrelin signaling by Rikkunshito could enhance sirtuin1 (SIRT1) activity in nervous system, we aimed to investigate the effect of Rikkunshito in ovarian cancer cells. Ovarian cancer cell lines were treated with Rikkunshito, and cellular viability, gene expressions and epithelial-mesenchymal transition (EMT) status were investigated. To investigate the involvement of SIRT1 by Rikkunshito in SKOV3 cancer cells, endogenous expression of SIRT1 was depleted using small interfering RNA (siRNA). Treatment with Rikkunshito elevated ghrelin, GHSR1a and SIRT1, while cellular viability was decreased. The treatment of Rikkunshito also inhibited cellular migration and invasion status in a dose-dependent manner, and these effects were translated to the enhanced EMT status, although the role of SIRT1 was not determined. Our study revealed a novel function of Rikkunshito in enhancing EMT status of ovarian cancer cells. Therefore, we would like to propose that Rikkunshito may be used as a novel adjunctive therapy in chemotherapy of ovarian cancer because platinum-based chemotherapy frequently used for the treatment of ovarian cancer inevitably impairs appetite.

Oral ulcerative mucositis causes severe pain during eating and speaking, resulting in poor quality of life for patients with cancer undergoing chemoradiotherapy. Recently, some basic and clinical studies demonstrated that hangeshashinto, a traditional Japanese herbal medicine, alleviated oral ulcerative mucositis-induced pain. Here, we review a recently revealed pain mechanism underlying oral ulcerative mucositis in a preclinical rat model and the pharmacological analgesic effect of hangeshashinto.
In a rat model of experimentally induced oral ulcerative mucositis, the mucosal surface of the ulcerative region is damaged, which increases oral bacterial loading in the mucosa and prostanoid production. Chemotherapeutic drugs exaggerate the pathological condition and cause severe pain. The pain-related TRP channels, TRPV1, TRPA1, and/or TRPV4, mediate spontaneous and mechanical pain in oral ulcerative mucositis models. Swab application of hangeshashinto had a prolonged localized analgesic effect on oral ulcerative mucositis, even in a chemotherapy-treated oral ulcer model. Two ingredients of hangeshashinto, gingerol and shogaol, strongly inhibit voltage-activated sodium channels (though they have agonistic effects on TRPV1 and TRPA1), which confers hyposensitivity to the oral mucosa. Their analgesic effects on oral ulcerative mucositis are accompanied by accelerated delivery of drugs (other saponin-containing herbal extracts) into the ulcerative region.
Elucidation of the pain mechanism of oral ulcerative mucositis and analgesic mechanism of hangeshashinto will allow identification of novel therapeutic approaches against oral ulcerative mucositis-induced pain in patients. The traditional Japanese herbal medicine hangeshashinto is a reliable drug with supporting scientific evidence.

Stomatitis is occasionally multiple, recurrent, and refractory. Currently, mucositis induced by chemotherapy and radiation therapy in patients with cancer has become a significant clinical problem. Effective treatments have not been established and the treatment of numerous cases remains a challenge for physicians. Traditional Japanese herbal medicines termed Kampo formulae (i.e., Hangeshashinto, Orengedokuto, Inchinkoto, Orento, Byakkokaninjinto, Juzentaihoto, Hochuekkito, and Shosaikoto) are used for treating various types of stomatitis and mucositis. Its use has been based on the Kampo medical theories-empirical rules established over thousands of years. However, recently, clinical and basic research studies investigating these formulae have been conducted to obtain scientific evidence. Clinical studies investigating efficacies of Shosaikoto and Orento for the treatment of cryptogenic stomatitis and acute aphthous stomatitis and those investigating the effects of Hangeshashinto, Orengedokuto, and Juzentaihoto on chemotherapy- or radiotherapy-induced mucositis have been conducted. The Kampo formulae comprise several crude drugs, whose mechanisms of action are gradually being clarified. Most of these drugs that are used for the treatment of stomatitis possess anti-inflammatory, analgesic, and antioxidative properties. In this review, we introduce the clinical applications and summarize the available evidence on the Kampo formulae for the treatment of stomatitis and oral mucositis.

A 74-year-old man developed tetanus 3 days after working with cow and poultry manure. Kakkonto and shakuyakukanzoto, traditional Japanese herbal medicines that are effective for the relief of pain primarily related to muscle contraction, were given to control the trismus and painful contracture of the neck. Generalized convulsions were controlled without the use of muscle relaxants.
After 30 days, the patient was discharged from the hospital without any sequelae.
Kakkonto and shakuyakukanzoto may be useful for the control of muscle spasms resulting from generalized tetanus.

A 65-year-old woman ingested glyphosate-surfactant herbicide in an attempt to commit suicide. She experienced glyphosate intoxication associated with multiple organ failure and developed a paralytic ileus. Daijokito, a traditional Japanese Kampo medicine was given to the patient to improve constipation and psychological symptoms. Next, rikkunshito was given to increase her gastric motility. Finally, daikenchuto was given to improve overall digestive peristalsis.
All abdominal symptoms ultimately improved after treatment with daikenchuto.
Kampo medicines may help improve abdominal symptoms associated with glyphosate intoxication in cases where modern medical treatment alone proves inadequate.

Although it has been widely demonstrated that administration of Daikenchuto (DKT), a traditional Japanese herbal medicine, improves gastrointestinal (GI) motility in patients undergoing abdominal surgery, few studies have investigated the efficacy of perioperative DKT administration for relief of postoperative ileus (PI) in patients undergoing surgery for GI cancer. Therefore, the aim of this study was to investigate whether perioperative administration of DKT relieves PI in patients with GI cancer.
We performed a comprehensive electronic search of the literature (Cochrane Library, PubMed, the Web of Science and ICHUSHI) up to December 2016 to identify studies that had shown the efficacy of perioperative DKT administration for relief of PI in patients with GI cancer. To integrate the individual effect of DKT, a meta-analysis was performed using random-effects models to calculate the risk ratio (RR) and 95% confidence interval (CI), and heterogeneity was analyzed using I2 statistics.
Seven studies involving a total of 1,134 patients who had undergone GI cancer surgery were included in this meta-analysis. Among 588 patients who received DKT perioperatively, 67 (11.4%) had PI, whereas among 546 patients who did not receive DKT perioperatively, 87 (15.9%) had PI. Perioperative administration of DKT significantly reduced the occurrence of PI (RR=0.58, 95% CI=0.35-0.97, p=0.04, I2=48%) in comparison to patients who did not receive DKT or received placebo.
The result of this meta-analysis suggests that perioperative administration of DKT relieves PI in patients undergoing surgery for GI cancer.

Cinnamon bark is commonly used in traditional Japanese herbal medicines (Kampo medicines). The coumarin contained in cinnamon is known to be hepatotoxic, and a tolerable daily intake (TDI) of 0.1 mg/kg/day, has been quantified and used in Europe to insure safety. Risk assessments for hepatotoxicity by the cinnamon contained in foods have been reported. However, no such assessment of cinnamon bark has been reported and the coumarin content of Kampo medicines derived from cinnamon bark is not yet known. To assess the risk for hepatotoxicity by Kampo medicines, we evaluated the daily coumarin intake of patients who were prescribed Kampo medicines and investigated the relation between hepatotoxicity and the coumarin intake. The clinical data of 129 outpatients (18 male and 111 female, median age 58 years) who had been prescribed keishibukuryogankayokuinin (TJ-125) between April 2008 and March 2013 was retrospectively investigated. Concurrent Kampo medicines and liver function were also surveyed. In addition to TJ-125, the patients took some of the other 32 Kampo preparations and 22 decoctions that include cinnamon bark. The coumarin content of these Kampo medicines was determined by high performance liquid chromatography (HPLC). TJ-125 had the highest daily content of coumarin (5.63 mg/day), calculated from the daily cinnamon bark dosage reported in the information leaflet inserted in each package of Kampo medicine. The coumarin content in 1g cinnamon bark decoction was 3.0 mg. The daily coumarin intake of the patients was 0.113 (0.049-0.541) mg/kg/day, with 98 patients (76.0%) exceeding the TDI. Twenty-three patients had an abnormal change in liver function test value, but no significant difference was found in the incidence of abnormal change between the group consuming less than the TDI value (6/31, 19.4%) and the group consuming equal to or greater than the TDI value (17/98, 17.3%). In addition, no abnormal change related to cinnamon bark was found for individual patients. This paper was done to assess the risk of hepatotoxicity by the coumarin contained in Kampo medicines and to clarify whether or not the Kampo preparations in general use that contain cinnamon bark may be safely used in clinical practice.

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.