Published papers

OBJECTIVE: The purpose of this study was to predict the four cold-heat patterns in patients who have the subjective symptoms of the cold-heat pattern described in the International Classification of Diseases Traditional Medicine Conditions - Module 1 by applying a machine learning algorithm. METHODS: Subjects were first-visit Kampo outpatients at six institutions who agreed to participate in this multicenter prospective observational study. The cold pattern model and the heat pattern model were created separately with 148 symptoms, body mass index, blood pressure (systolic and diastolic), age, and sex. Along with a single cold or heat pattern, the tangled heat/cold pattern is defined as being predicted by both cold and heat patterns, while the moderate (heat/cold) pattern is defined as being predicted by neither the cold pattern nor the heat pattern. RESULTS: We included 622 participants (mean age ±standard deviation, 54.4 ± 16.9; with female 501). The accuracy, macro-recall, precision, and F1-score of a combination of the two prediction models were 96.7%, 93.2%, 85.6%, and 88.5% respectively. The important items were compatible with the definitions of the cold-heat pattern. CONCLUSION: We developed a prediction model on cold-heat patterns with data from patients whose subjective cold/heat-related symptoms matched the cold-heat pattern diagnosis by the physician.

The traditional Japanese (Kampo) medicine, kakkonto with shosaikotokakikyosekko, has antiviral and anti-inflammatory effects. In this randomized trial, patients with mild and moderate coronavirus disease (COVID-19) were randomly allocated to the control group receiving conventional treatment for symptom relief such as antipyretics and antitussives or the Kampo group receiving mixed extract granules of kakkonto (2.5 g) and shosaikotokakikyosekko (2.5 g) three times a day for 14 days in addition to conventional treatment. The main outcome was the number of days until total symptom relief. The secondary outcome was the number of days until each symptom’s relief and whether the disease progressed to respiratory failure. We enrolled a total of 161 patients (Kampo group, n = 81; control group, n = 80). The results from Kaplan–Meier estimates of symptom relief showed that there are no significant differences between the groups. However, covariate-adjusted cumulative incidence of fever relief considering competitive risk showed that the recovery was significantly faster in the Kampo group than in the control group (HR 1.76, 95% CI 1.03–3.01). Additionally, the risk of disease progression to moderate COVID-19 requiring oxygen inhalation was lower in the Kampo group than in the control group (Risk Difference −0.13, 95% CI −0.27–0.01). No significant drug-related side effects were observed. Kakkonto with shosaikotokakikyosekko is effective for fever relief with suppression of disease progression in COVID-19 patients. Clinical Trial Registration: https://jrct.niph.go.jp/en-latest-detail/jRCTs021200020, identifier [jRCTs021200020]

In this self-controlled case series, we aimed to investigate the variation in estimated glomerular filtration rate (eGFR) after taking astragalus-containing preparations in patients with mild to moderate chronic kidney disease (CKD) by retrospectively reviewing their charts in our clinic. We set the inclusion criteria as first-visit patients aged 20 years or older presenting to our clinic between 1 October 2014, and 31 June 2019, and who were prescribed astragalus-containing herbal preparations for any reason. We calculated the mean eGFR from the readings taken 6 months before (pre) and after (post) the intake of astragalus-containing preparations for each participant. Among the 37 patients included in our final analysis, we found a statistically significant improvement in the eGFR after prescribing astragalus-containing preparations (pre, 66 ± 12 ml/min/1.73 m2 vs. post, 70 ± 14 ml/min/1.73 m2; p < 0.001 by paired t-test). Our results were consistent regardless of age, sex, CKD stage of the participants (G2 or G3), daily dosage of astragalus root, or duration of astragalus-containing preparations. No severe adverse reactions were recorded in the charts of the study participants. Our results suggest that there is eGFR improvement after taking astragalus-containing preparations in mild to moderate CKD cases as reported previously. The findings should be considered with caution due to major limitations such as small sample size without optimum control, short follow-up period, and incomplete data. Further adequately powered and designed studies are needed to confirm the efficacy and safety of the long-term use of astragalus root in patients with mild to moderate CKD.

Two representative Kampo formulas, keishibukuryogan and tokishakuyakusan, are frequently prescribed for patients with dysmenorrhea. We previously constructed a model that could predict which of these 2 formulas was most suitable, which is based on 4 subjective symptoms and 3 objective signs. To evaluate the prognosis of patients with dysmenorrhea using the established prediction model and assess the treatment outcomes between those treated in accordance with the prediction model and those who received various other treatments. In this retrospective, observational study, we included patients with menstrual pain who visited the Kampo Clinic at the Keio University Hospital for the first time between October 2014 and December 2020. These patients were monitored over a 90-day follow-up period. Participants were categorized into 2 groups: model-accordance and various-options. The progression of visual analogue scale (VAS) values was evaluated by determining the slopes from regression analysis between these 2 groups, with changes corroborated by the medical records. The study comprised 57 patients: 37 in the model-accordance group and 20 in the various-options group. Notably, the various-options group reported a significantly higher number of subjective symptoms (P = .03). The VAS value showed a decline, as indicated by the negative slope value of the regression line, across both groups - irrespective of their classification. There were no significant differences in the occurrence of adverse events between the 2 groups. The prognosis of patients with dysmenorrhea and the incidence of adverse events remained consistent, regardless of whether the treatment approach was in accordance with the prediction model or varied. Further studies are warranted to assess the prognosis when Kampo formulas are chosen based on the prediction model in the various-options population.

Menstrual pain is one of the common symptoms among women. It is estimated that 5-14% of women are sometimes absent from school or work because of pain. Usually gynecologists prescribe analgesics and/or low-dose oral contraceptives. However, such treatment is not always effective and sometimes causes an adverse effect, such as stomach pain or low body temperature. Kampo medicine is one of the choices for the menstrual pain in Japan. Tokishakuyakusan, kamishoyosan, or keishibukuryogan is commonly used for the treatment of menstrual pain. Here we report a case of menstrual pain successfully treated with daisaikoto which is not commonly used for such a case. Twenty-five-year-old woman suffered from severe menstrual pain and stress at company. She also had constipation and abdominal distension. We prescribed daisaikoto extract 7.5 g per day. Not only menstrual pain but also constipation and abdominal distension improved within 6 months. Here we propose that daisaikoto is one of the choices for the treatment of menstrual pain with mental stress.

© 2019 Elsevier Ltd Objectives: In Kampo medicine, a traditional medicine pattern(TM1) refers to the complete clinical presentation of the patient at a given moment in time. Candidate herbal formulas are chosen for a chief complaint, and an appropriate formula is determined on the basis of the pattern(TM1) diagnosis. In this study, we demonstrated the importance of accompanying symptoms in diagnosing traditional medicine patterns(TM1). Design: Single centre observational study. Setting: We analysed data from 524 new patients with a hypersensitivity to cold sensation as their primary diagnosis (mean age 51.6 ± 17.8 years; female ratio 82.1%) who visited the Keio University Hospital Kampo Clinic between 2008 and 2013. Main outcome measures: Accompanying symptoms were recorded on the browser-based e-questionnaire system, which contained 128 items. The Japan Society for Oriental Medicine's board certified Kampo specialists diagnosed the traditional medicine patterns(TM1). Results: When participants were classified according to the origin of their cold sensation, there were no differences in their traditional medicine patterns. In contrast, when patients were classified based on the number of accompanying symptoms, a significant difference in the patterns was identified. An increasing number of accompanying symptoms was associated with more frequent qi stagnation and blood stasis pattern(TM1). Patients with a qi stagnation pattern had higher rates of depression and insomnia. In contrast, patients with a blood stasis pattern(TM1), had higher rates of acne, body stiffness, and menstrual abnormality. Conclusions: Qi stagnation and blood stasis patterns(TM1) are related to a number of different accompanying symptoms in the patients with hypersensitivity to cold sensation.

© 2019 Elsevier Ltd Objectives: Growing interest in integrative medicine motivates examination of who seeks integrative care, and why. By examining differences in demographics and complementary and alternative medicine (CAM) use between patients recruited from Japanese Kampo (traditional herbal medicine) versus biomedical clinics, this study aimed to identify whether integrative medicine options might attract different patients. Design and setting: In this cross-sectional, observational study we administered the International Complementary and Alternative Medicine-Questionnaire (I-CAM-Q) to 209 patients recruited from four hospital clinics. Demographics, use of different types of CAM (self-help CAM, CAM practitioners, CAM products), and motivations were compared between Kampo and Non-Kampo patients and by gender. Factors influencing attendance at the Kampo clinic and CAM use were identified using logistic regression. Results: While some demographic characteristics, CAM provider and total CAM use differed between Kampo and non-Kampo patients, self-help CAM use did not. Motivations (for acute, long-term, health maintenance, or other reasons) differed between Kampo and non-Kampo clinic patients for going to non-Kampo physicians (P = 0.02) and Kampo physicians (P = 0.1). Logistic regression results for ‘any CAM’ use showed odds ratio of 0.32 (95%CI 0.15-0.67) for self-rated health, and 1.60 (95%CI 1.10–2.32) for Macarthur subjective social status scale. Attendance at the Kampo clinic showed odds ratios of 1.50 (95%CI 1.11–2.02) for education and 0.56 (95%CI 0.39-0.80) for employment status. Conclusions: Better understanding of factors such as motivation, self-rated health, and socioeconomic conditions that influence patients’ CAM use and integrative clinic attendance may enable more effective targeting of populations and integration of CAM into biomedical settings.

Objective: The purpose of this study was to extract important patient questionnaire items by creating random forest models for predicting pattern diagnosis considering an interaction between deficiency-excess and cold-heat patterns. Design: A multi-centre prospective observational study. Setting: Participants visiting six Kampo speciality clinics in Japan from 2012 to 2015. Main outcome measure: Deficiency–excess pattern diagnosis made by board-certified Kampo experts. Methods: We used 153 items as independent variables including, age, sex, body mass index, systolic and diastolic blood pressures, and 148 subjective symptoms recorded through a questionnaire. We sampled training data with an equal number of the different patterns from a 2 × 2 factorial combination of deficiency–excess and cold–heat patterns. We constructed the prediction models of deficiency–excess and cold–heat patterns using the random forest algorithm, extracted the top 10 essential items, and calculated the discriminant ratio using this prediction model. Results: BMI and blood pressure, and subjective symptoms of cold or heat sensations were the most important items in the prediction models of deficiency–excess pattern and of cold–heat patterns, respectively. The discriminant ratio was not inferior compared with the result ignoring the interaction between the diagnoses. Conclusions: We revised deficiency–excess and cold–heat pattern prediction models, based on balanced training sample data obtained from six Kampo speciality clinics in Japan. The revised important items for diagnosing a deficiency–excess pattern and cold–heat pattern were compatible with the definition in the 11th version of international classification of diseases.

Liquorice is usually used as crude drug in traditional Japanese Kampo medicine and traditional Chinese medicine. Liquorice-containing glycyrrhizin (GL) can cause pseudohyperaldosteronism as a side effect. Previously, we identified 18β-glycyrrhetyl-3-O-sulfate (3) as a GL metabolite in Eisai hyperbilirubinuria rats (EHBRs) with the dysfunction of multidrug resistance-related protein (Mrp2). We speculated that 3 was associated with the onset of liquorice-induced pseudohyperaldosteronism, because it was mainly detected in serum of patients with suspected to have this condition. However, it is predicted that other metabolites might exist in the urine of EHBRs orally treated with glycyrrhetinic acid (GA). We explored other metabolites in the urine of EHBRs, and investigated the pharmacokinetic profiles of the new metabolite in EHBRs and normal Sprague-Dawley rats. We further analyzed the serum concentrations of the new metabolite in the patients of pseudohyperaldosteronism. Finally, we developed the analyzing method of these metabolites as a preventive biomarker for the onset of pseudohyperaldosteronism using an enzyme-linked immunosorbent assay (ELISA). We isolated a new GL metabolite, 18β-glycyrrhetyl-3-O-sulfate-30-O-glucuronide (4). Compound 4 significantly inhibited rat type-2 11β-hydroxysteroid dehydrogenase (11β-HSD2) and was a substrate of both organic anion transporter (OAT) 1 and OAT3. Compound 4 was also detected in the serum of patients with suspected pseudohyperaldosteronism at an approximately 10-fold lower concentrations than 3, and these concentrations were positively correlated. Compound 4 showed a lower serum concentration and weaker inhibitory titer on 11β-HSD2 than 3. We developed an enzyme-linked immunosorbent assay system using an anti-18β-glycyrrhetyl-3-O-glucuronide (3MGA) monoclonal antibody to measure the serum concentration of 3 to facilitate the measurement of biomarkers to predict the onset of pseudohyperaldosteronism. Although we found 4 as the secondary candidate causative agent, 3 could be the main potent preventive biomarker of liquorice-induced pseudohyperaldosteronism. Compound 3 was detected in serum at a higher concentration than GA and 4, implying that 3 may be a pharmacologically active ingredient mediating not only the development of pseudohyperaldosteronism but anti-inflammatory effects in humans administered GL or other liquorice-containing preparations.

Purpose: To date, no studies have assessed climacteric symptoms after hystero-adnexectomy for endometrial, cervical, or ovarian cancer. Thus, this study aimed to compare climacteric symptoms among patients who underwent surgery for these three cancer types. Methods: In this cross-sectional study, we interviewed patients who were registered at a menopausal outpatient clinic between January 1999 and July 2016 after undergoing total hysterectomy, intrapelvic only or intrapelvic plus para-aortic lymph node dissection, and bilateral adnexectomy performed via laparotomy as a cancer treatment. Climacteric symptoms were assessed using a patient-reported questionnaire covering core domains with five symptoms only at the initial consultation. Each symptom was graded from 0 (no symptoms) to 3 (severe symptoms). We evaluated the frequency of symptom severity according to the time elapsed since surgery and the cancer type. Results: The numbers of patients with endometrial, ovarian, and cervical cancer were 328, 90, and 107, respectively. Overall, climacteric symptoms were more severe in patients with cervical cancer than in those with endometrial or ovarian cancer; symptom severity decreased with increasing time since surgery. However, symptom severity did not decrease significantly over time in patients with cervical cancer even after > 5 years had elapsed since surgery. Conclusion: The climacteric symptoms were less severe in patients with endometrial or ovarian cancer with longer time elapsed since surgery but not in those with cervical cancer. Patients with cervical cancer may require more prompt interventions, including symptomatic treatment and longer follow-up period, than those with endometrial or ovarian cancer.

Seven young researchers presented their studies in the field of traditional Japanese herbal medicine (Wakan-yaku) at the Fifth Annual Young Researcher Forum held the day before the 2024 annual meeting of the Japan Society of Medical and Pharmaceutical Sciences for Traditional Medicine. Ms Tanide presented on the changes in flavonoid and synephrine content in chimpi based on the storage period. Ms Hamai discussed natural compounds that contribute to improving bortezomib resistance in myeloma cells and their mechanisms of action. Ms Nishiura presented the production of a monoclonal antibody against geniposide and its application in indirect competitive enzyme-linked immunosorbent assay. Mr Hatae presented about the effects of ninjin'yoeito on cisplatin-induced anorexia and the variations in intestinal clock genes. Ms Nose explored the analgesic effects of bushi-containing Kampo formulas, with a focus on goshajinkigan's improvement of cold allodynia. Dr Oda discussed the antifungal activity of henna leaves against Malassezia. Lastly, Mr Fukuda presented how cultivation environments affect the quality of Schizonepeta spikes, including their morphology and component content. The event, conducted both in person and online, attracted a total of 54 participants. Looking ahead, we aim to further develop and continue hosting this forum in 2025 and beyond, fostering the advancement of research in this field.

Four young researchers presented their studies in the field of traditional Japanese herbal medicine (Wakan-yaku) at the Fourth Annual Young Researcher Forum held the day before the 2023 annual meeting of the Japan Society of Medical and Pharmaceutical Sciences for Traditional Medicine. Mr Sakoda outlined his research plan, emphasizing the potential of yokukansan to enhance palliative care for cancer patients. Meanwhile, Ms Tanide and Mr Nishihara explored the correlation among component contents in Coptis japonica on Sado Island. Additionally, Mr Okayama presented his study, focusing on the use of Sinomenium acutum-derived compounds to inhibit the Wnt/β-catenin pathway and eradicate cancer stem cells. Finally, Mr Muraoka shared insights from his research on the inhibitory properties of Cassia obtusifolia sprout components. The event, conducted both in person and online, attracted a total of 58 participants. Looking ahead, we aim to further develop and continue hosting this forum in 2024 and beyond, fostering the advancement of research in this field.

Five young researchers presented their studies in the field of traditional Japanese herbal medicine (Wakan-yaku) at the second annual young researcher forum entitled “Growing Research Buds by Young Investigators,” held during the annual meeting of the Japan Society of Medical and Pharmaceutical Sciences for Traditional Medicine 2021. Mr. Yoneda presented exploratory research on new pharmaceutical seed compounds from garlic (Allium sativum). Dr. Yang investigated whether diosgenin promoted proper axonal regeneration in the brain using a mouse model of Alzheimer's disease. Her study clarified the molecular mechanisms of the diosgenin-driven accurate pathfinding of injured axons. Mr. Nishihara presented his research on promoting the effective utilization of Phellodendron trees in Nara Prefecture. His research team evaluated the possibility of short-term cultivation, screened for useful components in the leaves. Dr. Ogawa used the Japanese Adverse Drug Event Report (JADER) database, which contains reports of side effects associated with drug treatment, to demonstrate the effectiveness of hokizai in reducing side effects, particularly those of anticancer drugs. Dr. Kitamura reported that Cnidium monnieri (L.) Cusson fruit extract and the isolated active ingredients, osthol and imperatorin, strongly inhibited the activity of furin-like enzymes. Further screening indicated that root extracts of Paeonia lactiflora Pall. and Scutellaria baicalensis Georgi suppressed cell syncytial formation by the S protein. The event was held online, and we had 86 participants. We can improve this forum in terms of format, frequency, and publicity activities; however, we hope to hold this forum in 2022 and in the future.

Four young researchers presented their studies in the field of traditional Japanese herbal medicine (Wakan-yaku) at the third annual young researcher forum entitled “Respecting and Breaking Traditions,” held 1 week before the 2022 annual meeting of the Japan Society of Medical and Pharmaceutical Sciences for Traditional Medicine. Dr. Yokogawa presented her research focusing on the mechanism of the Ayurveda drug-eluting string, Kshara Sutra, in treating anal fistulas, reporting on its effects on the anal tissue in an anal fistula rat model and its antibacterial activity against Escherichia coli and Staphylococcus aureus, the causative organisms of anal fistulas. Mr. Nakamichi presented his research focusing on the relationship between the efficacy of Kampo medicines with anti-obesity effects and intestinal microbiota composition. His results partially revealed that bofutsushosan and boiogito affect lipid metabolism in mice and correlate with the intestinal microbiota composition. Dr. Manse reported the anti-inflammatory activity of diterpenoid components in Enmei-so (Isodonis Herba), revealing its novel inhibitory activity on nitric oxide released from activated macrophages and on inflammatory cytokines, and identified active components contributing to the inhibition and the mechanism of action. Mr. Yoshikawa reported the anticancer activity of small molecular compounds isolated from the medicinal plants, Valeriana fauriei and Hypericum erectum. His results suggest that five compounds may increase the sensitivity of human cervical carcinoma cells to adriamycin via HSP105 expression suppression. The event was conducted online, and included 78 participants. We intend to hold and improve this forum in 2023 and the future.