Inhibition of compound action potentials in the frog sciatic nerve by inchinkoto, a traditional Japanese medicine used for oral mucositis.

OBJECTIVE: This study aimed to determine the effects of traditional Japanese (Kampo) medicines used to treat oral mucositis on nerve conduction. METHODS: The effects of Kampo medicines, crude drugs, and chemical compounds on compound action potentials (CAPs) were analyzed using extracellular recordings in frog sciatic nerves. RESULTS: Among the Kampo medicines, inchinkoto demonstrated the most significant reduction in CAP amplitude, with a half-maximal inhibitory concentration (IC50) of 5.4 mg/mL. Hangeshashinto, shosaikoto, hochuekkito, and juzentaihoto also showed a significant reduction. Regarding inchinkoto, Artemisiae Capillari Spica (artemisia) was the most effective crude drug, with an IC50 of 4.2 mg/mL for CAP amplitude reduction, whereas Gardeniae Fructus (gardenia) exerted no significant effect. However, the combined use of artemisia and gardenia reduced the CAP amplitude more effectively than artemisia alone, indicating a synergistic interaction. The chemical ingredient eugenol from artemisia administered at 1 and 3 mmol/L reduced CAP amplitude, whereas other chemical ingredients administered at 0.1 and 1 mmol/L had no significant effects. CONCLUSIONS: Inchinkoto exhibited the most effective reduction in CAP amplitude in the sciatic nerve of frogs, primarily through the action of artemisia, with potential synergistic interaction between artemisia and gardenia.

Potential of the Novel Slot Blot Method with a PVDF Membrane for Protein Identification and Quantification in Kampo Medicines.

Kampo is a Japanese traditional medicine modified from traditional Chinese medicine. Kampo medicines contain various traditional crude drugs with unknown compositions due to the presence of low-molecular-weight compounds and proteins. However, the proteins are generally rare and extracted with high-polarity solvents such as water, making their identification and quantification difficult. To develop methods for identifying and quantifying the proteins in Kampo medicines, in the current study we employ previous technology (e.g., column chromatography, electrophoresis, and membrane chromatography), focusing on membrane chromatography with a polyvinylidene difluoride (PVDF) membrane. Moreover, we consider slot blot analysis based on the principle of membrane chromatography, which is beneficial for analyzing the proteins in Kampo medicines as the volume of the samples is not limited. In this article, we assess a novel slot blot method developed in 2017 and using a PVDF membrane and special lysis buffer to quantify advanced glycation end products-modified proteins against other slot blots. We consider our slot blot analysis superior for identifying and quantifying proteins in Kampo medicines compared with other methods as the data obtained with our novel slot blot can be shown with both error bars and the statistically significant difference, and our operation step is simpler than those of other methods.

A Narrative Review of the Herbal Preparation of Ayurvedic, Traditional Chinese, and Kampo Medicines Applied as Radioprotectors.

In recent years, there has been growing scientific interest in the search for natural radioprotectors that can be used to mitigate the effects of radiation on patients, healthcare personnel, and even for space travel. This narrative review covers the past fifty years and focuses on herbal preparations of Ayurvedic, Traditional Chinese, and Kampo Medicines that have the potential to reduce or eliminate the harmful effects of radiation. Our findings highlight ten herbal preparations, namely Abana, Amalakyadi Churna, Amritaprasham, Brahma, Bu-zhong-yi-qi-tang (BZYQT), Chyavanaprasha, Cystone, Geriforte, Mentat, and Triphala, which have demonstrated potential radioprotective effects. This review examines their composition, properties, and possible mechanisms of action in relation to their radioprotective properties. Exploring the ethnobotany of traditional Asian medicine is particularly interesting as it may lead to the discovery of new active compounds with radioprotective properties.

Novel In Vitro Assay of the Effects of Kampo Medicines against Intra/Extracellular Advanced Glycation End-Products in Oral, Esophageal, and Gastric Epithelial Cells.

Kampo medicines are Japanese traditional medicines developed from Chinese traditional medicines. The action mechanisms of the numerous known compounds have been studied for approximately 100 years; however, many remain unclear. While components are normally affected through digestion, absorption, and metabolism, in vitro oral, esophageal, and gastric epithelial cell models avoid these influences and, thus, represent superior assay systems for Kampo medicines. We focused on two areas of the strong performance of this assay system: intracellular and extracellular advanced glycation end-products (AGEs). AGEs are generated from glucose, fructose, and their metabolites, and promote lifestyle-related diseases such as diabetes and cancer. While current technology cannot analyze whole intracellular AGEs in cells in some organs, some AGEs can be generated for 1-2 days, and the turnover time of oral and gastric epithelial cells is 7-14 days. Therefore, we hypothesized that we could detect these rapidly generated intracellular AGEs in such cells. Extracellular AEGs (e.g., dietary or in the saliva) bind to the receptor for AGEs (RAGE) and the toll-like receptor 4 (TLR4) on the surface of the epithelial cells and can induce cytotoxicity such as inflammation. The analysis of Kampo medicine effects against intra/extracellular AGEs in vitro is a novel model.

Contribution of traditional Japanese Kampo medicines, kakkonto with shosaikotokakikyosekko, in treating patients with mild-to-moderate coronavirus disease 2019: Further analysis of a multicenter, randomized controlled trial.

We previously reported the finding of symptom relief in a randomized controlled trial with the combined use of kakkonto and shosaikotokakikyosekko added to conventional treatment in patients with coronavirus disease 2019 (COVID-19). For further evaluation, we performed post hoc analysis focused on symptom disappearance without recurrence, to determine a clearer effect of Kampo medicine. Patients with mild and moderate COVID-19 were randomly allocated to a control group receiving symptomatic therapy or a Kampo group receiving kakkonto (2.5 g) with shosaikotokakikyosekko (2.5 g) three times daily in addition to symptomatic therapy. The data of 161 patients (Kampo group, n = 81; control group, n = 80) were analyzed post hoc for the time to symptom disappearance. Kaplan-Meier and Cox proportional hazard estimates of disappearance of symptoms showed that all and each symptom targeted in this study disappeared faster in the Kampo group than in the control group, although not statistically significant (all symptomatic cases; hazard ratio [HR] 3.73, 95% confidence interval [CI] 0.46-29.98, log-rank p = 0.1763). In a supplemental assessment using covariate adjustment and competing risk analysis, fever disappeared faster in the Kampo group than in the control group (all symptomatic cases, HR 1.62, 95% CI 0.99-2.64, p = 0.0557; unvaccinated cases, HR 1.68, 95% CI 1.00-2.83, p = 0.0498) and shortness of breath disappeared significantly faster in Kampo group than in control group (all symptomatic cases, HR 1.92, 95% CI 1.07-3.42, p = 0.0278; unvaccinated cases, HR 2.15, 95% CI 1.17-3.96, p = 0.0141). These results demonstrate the advantages of Kampo treatment for acute COVID-19.

A Case of Pseudohyperaldosteronism Induced by Yokukansan and Shakuyakukanzoto That Resulted in Severe Hypokalemia.

Pseudohyperaldosteronism can be induced by the excessive use of Chinese herbal medicines (Kampo medicines), resulting in serious disorders. We report a case of pseudohyperaldosteronism induced by two Kampo medicines which resulted in severe hypokalemia. A 70-year-old woman was hospitalized for a left calcaneal fracture. She had no subjective symptoms other than trauma. On her admission, blood test results revealed a low serum potassium level of 2.4 mmol/L by chance, as well as low levels of both renin and aldosterone. The patient had been taking 5 g of Yokukansan per day for the past three months. In addition, she was on 5 g Shakuyakukanzoto per day for three months until a month prior to hospitalization. The daily licorice content from the aforementioned herbs was 1.0 g and 4.0 g, respectively. After hospitalization, the administration of the Kampo medicines was discontinued, and 610 mmol of potassium was administered over a period of 13 days, which resulted in the normalization of serum potassium levels. Pre-existing hypertension slowly improved as well. Patients consuming licorice at doses of 2.5 g per day or more, as in our case, are at a high risk of developing pseudohyperaldosteronism. Furthermore, the risk is particularly high with long-term licorice consumption as well as for women and elderly patients. To this end, high-dose potassium supplementation may be necessary for normalizing serum potassium levels. Therefore, awareness regarding the adverse effects of licorice is crucial, even in cases of low dosages of licorice.

Significant association between HLA-B*35:01 and onset of drug-induced liver injury caused by Kampo medicines in Japanese patients.

AIM: Drug-induced liver injury (DILI) is a severe and life-threatening immune-mediated adverse effect, occurring rarely among treated patients. We examined genomic biomarkers in the Japanese population that predict the onset of DILI after using a certain class of drugs, such as Kampo products (Japanese traditional medicines). METHODS: A total of 287 patients diagnosed as DILI by hepatology specialists were recruited after written informed consent was obtained. A genome-wide association analysis and human leukocyte antigen (HLA) typing in four digits were performed. RESULTS: We found a significant association (p = 9.41 × 10-10 ) of rs146644517 (G > A) with Kampo product-related DILI. As this polymorphism is located in the HLA region, we evaluated the association of HLA types and found that 12 (63.2%) of 19 Kampo-DILI patients contained HLA-B*35:01, whereas only 15.2% were positive for this HLA among healthy volunteers. The odds ratio was 9.56 (95% confidence interval 3.75-24.46; p = 2.98 × 10-6 , corrected p = 4.17 × 10-5 ), and it increased to 13.55 compared with the DILI patients not exposed to Kampo products. The individual crude drug components in the Kampo products, including Scutellaria root (ougon in Japanese), rhubarb (daiou), Gardenia fruit (sanshishi), and Glycyrrhiza (kanzou), were significantly associated with HLA-B*35:01. CONCLUSIONS: HLA-B*35:01 is a genetic risk factor and a potential predictive biomarker for Kampo-induced DILI in the Japanese population.

Conventional and Kampo Medicine Treatment for Mild-to-moderate COVID-19: A Multicenter, Retrospective, Observational Study by the Integrative Management in Japan for Epidemic Disease (IMJEDI Study-observation).

Objective Patients in whom coronavirus disease 2019 (COVID-19) was suspected or confirmed between January 1, 2020, and October 31, 2021, were enrolled from Japanese hospitals in this multicenter, retrospective, observational study. Methods Data on the treatment administered (including conventional and Kampo medicine) and changes in common cold-like symptoms (such as fever, cough, sputum, dyspnea, fatigue, and diarrhea) were collected from their medical records. The primary outcome was the number of days without a fever (with a body temperature <37°C). The secondary outcomes were symptomatic relief and the worsening of illness, defined as the presence of a condition requiring oxygen inhalation. The outcomes of patients treated with and without Kampo medicine were compared. Patients We enrolled 962 patients, among whom 528 received conventional and Kampo treatment (Kampo group) and 434 received conventional treatment (non-Kampo group). Results Overall, after adjusting for the staging of COVID-19 and risk factors, there were no significant between-group differences in the symptoms or number of days being afebrile. After performing propensity score matching and restricting the included cases to those with confirmed COVID-19 who did not receive steroid administration and initiated treatment within 4 days from the onset, the risk of illness worsening was significantly lower in the Kampo group than in the non-Kampo group (odds ratio=0.113, 95% confidence interval: 0.014-0.928, p=0.0424). Conclusion Early Kampo treatment may suppress illness worsening risk in COVID-19 cases without steroid use. Further randomized controlled studies are needed to confirm the clinical benefit of Kampo medicine for COVID-19.

Analysis of Crude, Diverse, and Multiple Advanced Glycation End-Product Patterns May Be Important and Beneficial.

Lifestyle-related diseases (LSRDs), such as diabetes mellitus, cardiovascular disease, and nonalcoholic steatohepatitis, are a global crisis. Advanced glycation end-products (AGEs) have been extensively researched because they trigger or promote LSRDs. Recently, techniques such as fluorimetry, immunostaining, Western blotting, slot blotting, enzyme-linked immunosorbent assay, gas chromatography-mass spectrometry, matrix-assisted laser desorption-mass spectrometry (MALDI-MS), and electrospray ionization-mass spectrometry (ESI-MS) have helped prove the existence of intra/extracellular AGEs and revealed novel AGE structures and their modifications against peptide sequences. Therefore, we propose modifications to the existing categorization of AGEs, which was based on the original compounds identified by researchers in the 20th century. In this investigation, we introduce the (i) crude, (ii) diverse, and (iii) multiple AGE patterns. The crude AGE pattern is based on the fact that one type of saccharide or its metabolites or derivatives can generate various AGEs. Diverse and multiple AGE patterns were introduced based on the possibility of combining various AGE structures and proteins and were proven through mass analysis technologies such as MALDI-MS and ESI-MS. Kampo medicines are typically used to treat LSRDs. Because various compounds are contained in Kampo medicines and metabolized to exert effects on various organs or tissues, they may be suitable against various AGEs.

Multicenter, randomized controlled trial of traditional Japanese medicine, kakkonto with shosaikotokakikyosekko, for mild and moderate coronavirus disease patients.

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].

Oral Astragalus Root Supplementation for Mild to Moderate Chronic Kidney Disease: A Self-Controlled Case-Series.

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.

Adverse Effects of Kampo Medicines.

This review summarizes the adverse effects of Kampo medicines. These adverse effects in terms of immunoallergic reactions include interstitial pneumonia, liver injury, allergic cystitis, and drug eruption. Many cases of interstitial pneumonia, liver injury, and allergic cystitis associated with Kampo formulas have been reported to be caused by formulas containing Scutellariae Radix (Scutellaria root, ogon). The known adverse effects linked to overdose of Kampo formulas include pseudoaldosteronism [caused by Glycyrrhizae Radix (licorice, kanzo)], sympathomimetic symptoms [caused by Ephedrae Herba (ephedra, mao)], aconite poisoning [caused by Aconiti Tuber (processed aconite root, bushi and uzu)], and diarrhea [caused by Rhei Rhizoma (rhubarb, daio)]. In recent years, mesenteric phlebosclerosis caused by the long-term administration of Gardeniae Fructus (gardenia fruit, sanshishi) has also been reported. It is necessary to consider these potential adverse effects when prescribing Kampo medicines in clinical practice.

Juzentaihoto Exerts Anti-Allergic Effects by Inhibiting Effector T-Cell Activation and Inducing and/or Activating Regulatory T Cells in a Murine Model of Contact Hypersensitivity.

BACKGROUND: Juzentaihoto (JTT) is a Kampo prescription that has been used clinically for treating skin diseases such as atopic dermatitis in Japan. We have previously studied the anti-allergic effects of JTT on 2,4,6-trinitrochlorobenzene (TNCB)-induced contact hypersensitivity (CHS) in mice and demonstrated that it significantly suppresses ear swelling in a dose-dependent manner. However, the mechanism underlying the anti-allergic actions of JTT is obscure. METHODS: We investigated the mechanism underlying the anti-allergic effects of JTT using a TNCB-induced murine CHS model and adoptive cell transfer experiments. RESULTS: We showed that the anti-allergic effects of JTT are due to inhibition of effector T-cell activation and induction and/or activation of regulatory T cells. Furthermore, ex vivo experiments confirmed the effect of JTT on the activation of effector T cells and regulatory T cells, as interferon-γ production decreased, whereas interleukin (IL)-10 production increased, in the cultured lymphocytes obtained from 5% TNCB-sensitized mice treated with anti-CD3ε and anti-CD28 monoclonal antibodies. Flow cytometry showed that the CD4+CD25+Foxp3+, CD4+CD25+Foxp3-, and CD8+CD122+ cell population increased after oral administration of JTT. Finally, the anti-allergic effect of JTT by inducing and/or activating regulatory T cells (Tregs) was confirmed to be mediated by IL-10 through in vivo neutralization experiments with anti-IL-10 monoclonal antibodies. CONCLUSION: We suggested that JTT exerts anti-allergic effects by regulating the activation of effector T cells and Tregs involved in murine CHS model.

Steroidal Saponins Isolated from the Rhizome of Dioscorea tokoro Inhibit Cell Growth and Autophagy in Hepatocellular Carcinoma Cells.

Our preliminary screening identified an extract from the rhizome of Dioscorea tokoro, which strongly suppressed the proliferation of HepG2 hepatocellular carcinoma cells and inhibited autophagy. This study aimed to isolate active compounds from the rhizome of D. tokoro that exert antiproliferative effects and inhibit autophagy. The bioassay-guided fractionation of the active fraction led to the isolation of two spirostan-type steroidal saponins, dioscin (1) and yamogenin 3-O-α-l-rhamnopyranosyl (1→4)-O-α-l-rhamnopyranosyl(1→2)-ß-d-glucopyranoside (2), and the frostane-type steroidal saponin protodioscin (3) from the n-BuOH fraction. Furthermore, acid hydrolysis of 1 and 2 produced the aglycones diosgenin (4) and yamogenin (5), respectively. Compounds 1-5 suppressed proliferation of HepG2 cells. The analysis of structure-activity relationships indicated that the 25(R)-conformation, structures with a sugar moiety, and the spirostan-type aglycone moiety contributed to antiproliferative activity. Analysis of autophagy-related proteins demonstrated that 1-3 clearly increased the levels of both LC3-II and p62, implying that 1-3 deregulate the autophagic pathway by blocking autophagic flux, which results in p62 and LC3-II accumulation. In contrast, 1-3 did not significantly affect caspase-3 activation and PARP cleavage, suggesting that the antiproliferative activity of 1-3 occurred independently of caspase-3-mediated apoptosis. In summary, our study showed that 1-3, active compounds in the rhizome of D. tokoro, suppressed cell proliferation and autophagy, and might be potential agents for autophagy research and cancer chemoprevention.

Evaluation of the Amounts of Sennosides A and B in Rhubarb-containing Kampo Medicines to Create a Ranking of Kampo Medicines for Appropriate Selection of Laxatives.

OBJECTIVES: To evaluate 20 Kampo medicines, which comprised 6 formulas, Otsujito, Junchoto, Tokakujokito, Bofutsushosan, Mashiningan, and Keishikashakuyakudaioto, from 7 brands, to create a ranking of Kampo medicines for appropriate selection of laxatives. METHODS: The amounts of sennosides A and B, the important components showing laxative effects contained in Kampo medicines, were analysed using High Performance Liquid Chromatography. RESULTS: We found that the amounts of sennosides A and B were different among brands, even when they had the same formula. Furthermore, the amounts of sennosides differed when the same amounts of rhubarb were used. CONCLUSIONS: These results suggest that the differences in amounts of sennosides are caused by the quality of the rhubarb used. Kampo medicines containing laxatives other than rhubarb, including disodium sulphate and hemp seed, had synergistic laxative effects. Thus, in the future, it may be possible to adjust laxative potency of Kampo medicines through further clinical tests.

Pharmacokinetic study of Ninjin'yoeito: Absorption and brain distribution of Ninjin'yoeito ingredients in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Ninjin'yoeito (NYT), a Japanese traditional Kampo medicine, has been reported to exert various clinical benefits such as relief from fatigue, malaise, anorexia, frailty, sarcopenia, and cognitive dysfunction. Recently, some review articles described the pharmacological effects of NYT and additionally indicated the possibility that multiple ingredients in NYT contribute to these effects. However, pharmacokinetic data on the ingredients are essential in addition to data on their pharmacological activities to accurately determine the active ingredients in NYT. AIM OF THE STUDY: This study assessed the in vivo pharmacokinetics of NYT using mice. MATERIALS AND METHODS: Target liquid chromatography-mass spectrometry (LC-MS) and wide target LC-MS or LC-tandem MS of NYT ingredients in plasma and the brain after oral administration of NYT were performed. Imaging MS was performed to investigate the detailed brain distributions of NYT ingredients. RESULTS: The concentrations of 13 ingredients in plasma and schizandrin in the brain were quantified via target LC-MS, and the wide target analysis illustrated that several ingredients are absorbed into blood and transported into the brain. Imaging MS revealed that schizandrin was homogenously dispersed in the NYT-treated mouse brain. CONCLUSION: These results should be useful for clarifying the active ingredients of NYT and their mechanisms of actions.

A structured summary of a study protocol for a multi-center, randomized controlled trial (RCT) of COVID-19 prevention with Kampo medicines (Integrative Management in Japan for Epidemic Disease by prophylactic study: IMJEDI P1 study).

OBJECTIVE: We aimed to test our hypothesis that traditional Japanese (Kampo) medicine, hochuekkito (Hochu-ekki-to: HET) has a preventive effect for the symptoms on COVID-19. TRIAL DESIGN: The study is designed as a multi-center, interventional, parallel-group, randomized (1:1 ratio), investigator sponsored, two-arm study. PARTICIPANTS: Six thousand participants will be recruited from healthy hospital workers in 7 Japanese University Hospitals. INCLUSION CRITERIA: 1. Age from 20 to 75 years old at the time of registration 2. Asymptomatic and body temperature below 37°C at the time of registration 3. Capable of eating orally Exclusion criteria: 1. Previous upper respiratory inflammation due to viral infection (including suspected COVID-19) 2. Taking immunosuppressants 3. Allergic to the Kampo medicines used in this study 4. History of hypokalaemia, severe hypertension, severe liver dysfunction, and interstitial pneumonia 5. Regularly taking other Kampo medicines 6. Pregnant or possibly pregnant 7. Participating in other research 8. Judged to be unsuitable for this study by the doctor in charge INTERVENTION AND COMPARATOR: Kampo group: participants receive HET in 9 tablets 2 times per day for 8 weeks. CONTROL GROUP: participants receive placebo in the same dosage as the Intervention group - 9 tablets 2 times per day for 8 weeks. Placebo tablets are identical in appearance and package to HET. Taste of placebo is different from that of HET. The Ohsugi Pharmaceutical Co. Ltd, Osaka, Japan manufactured the placebo and HET. MAIN OUTCOMES: Primary outcome: Number of patients with a SARS-CoV-2 RNA by ploymerase chain reaction (PCR) positive result with at least one symptom (fever, cough, sputum, malaise, shortness of breath) during the 12-week study period (including the 4-week observation period after oral administration). SECONDARY OUTCOMES: 1. Period from infection to onset 2. Period from the appearance of symptoms to the disappearance of PCR positive 3. Number of days until the appearance or improvement of symptoms 4. Severe stage: presence of hospitalization 5. Shock stage: ICU management required for mechanical ventilation, shock vitals or failure of organ(s) other than lungs Safety endpoints include numbness in the hands and/or feet, edema, skin rash or other allergic symptoms, and gastric discomfort. RANDOMISATION: Patients are randomized (1:1 ratio) to each group using minimization implemented with the Electric data capture system (DATATRAK Enterprise Cloud), with balancing of the arms with age range (under 50 years of age or not) and having a history of risk factors for COVID-19 (cardiovascular disease, hypertension, diabetes, respiratory diseases). BLINDING (MASKING): Only participants will be randomized. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The main research hypothesis of this study is that Kampo medicines significantly prevent the onset of COVID-19. It is assumed that the infection rate before the administration of the drug under consideration will be 0% and that the incidence of COVID-19 thereafter will be 2- 3%, of which 70%-80% will show symptoms of COVID-19. Assuming that the pharmaceutical effect of the drug will be effective in 50% of patients and that the incidence rates in the placebo and drug groups will be 1.4%-2.4% and 0.7%-1.2%, respectively, the placebo is calculated at 2%, and the study drug at 1%. Since the frequency of verification is low and the number of cases will be large, we set a total of 10 analyses (9 interim analyses and a final analysis). Since the number of cases at the time of the final analysis will be 4,986 under the conditions of α = 0.05 and a power of 80% by the Peto method. We set at 600 cases in each interim analysis with an estimated dropout rate of 16.9%. Finally, the total number of cases is set to 6,000 with 3,000 in the placebo group and 3,000 in the HET group. TRIAL STATUS: Protocol version 1.3 of October 23rd , 2020. Recruitment start (expected): December 1st, 2020. Recruitment finish (expected): December 31st, 2022. TRIAL REGISTRATION: This trial is registered in the Japan Registry of Clinical Trials (jRCT) ( jRCTs031200150 ) on 14 October 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Medical Safety Committee Report :Medical Accident Information and Minor Incidents from Medical Institutions Related to Kampo Products / 日本東洋医学雑誌

The Medical Safety Committee analyzed the case reports of minor incidents from the pharmacies last time as part of an activity to promote patient safety in Japanese traditional Kampo medicine. This time, we analyzed the case reports of medical accidents and minor incidents from the medical institutions. We extracted 626 reports related to Kampo products from the public database, which the Japan Council for Quality Health Care has established based on the collected information related to the medical accidents and minor incidents. The medical accident information includes case reports related to drug-induced liver injury. The minor incident reports include prescribing error due to misinterpretation related to the quantity of one sachet of Kampo extract product, dispensing error due to similarity of product appearance, number or name, and administration error due to judging the medicine only by Kanji characters or product company names without checking the Kampo formula name. Additionally, the minor incidents were often discovered by people belonging to different professions or patients themselves. In order to promote patient safety, knowledge about these incidents should be shared among the people involved in the same or different professions.

A Case of Pleural Effusion Due to Bacterial Pleurisy Markedly Reduced by Treatment with Saikanto / 日本東洋医学雑誌

Although saikanto has often been used for infectious pleuritis, there are few reports on the usefulness of it in recent years. We experienced a patient successfully treated with saikanto, who was suffering from bacterial pleuritis with residual pleural effusion, which was difficult to drain and treat with antibacterial drugs. Kampo treatment including saikanto should be used for pleuritis that is not sufficiently improved by Western medical treatment alone.

A multi-center, randomized controlled trial by the Integrative Management in Japan for Epidemic Disease (IMJEDI study-RCT) on the use of Kampo medicine, kakkonto with shosaikotokakikyosekko, in mild-to-moderate COVID-19 patients for symptomatic relief and prevention of severe stage: a structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: We aimed to test our hypothesis that additional administration of traditional Japanese (Kampo) medicine, kakkonto (kakkon-to: KT) and shosaikotokakikyosekko (sho-saiko-to-ka-kikyo-sekko: SSKKS), is more effective in relieving symptoms and preventing the onset of severe infection in mild-to-moderate COVID-19 patients compared to those treated only with conventional treatment. TRIAL DESIGN: The study is designed as a multi-center, interventional, parallel-group, randomized (1:1 ratio), investigator-sponsored, two-arm study. PARTICIPANTS: Patients and inpatients will be recruited from 8 Japanese academic and non-academic hospitals. The inclusion and exclusion criteria are as follows: Inclusion criteria: 1. Diagnosed as positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 2. Clinical stages of mild-to-moderate COVID-19 3. Symptomatic 4. ≥ 20 years of age 5. Male or female 6. Ability to communicate in Japanese 7. Outpatients and inpatients 8. Provided informed consent Exclusion criteria: 1. Difficulty in providing informed consent due to dementia, psychosis, or psychiatric symptoms 2. Allergic to Kampo or Western medicines used in this study 3. Pregnant and lactating 4. Unable to follow up 5. Participating in another clinical trial or interventional study 6. Hypokalemic or taking oral furosemide or steroids 7. Determined unsuitable for this study by the physician INTERVENTION AND COMPARATOR: Patients in the control group will receive conventional treatment with antipyretics, painkillers, or antitussives for symptoms that occurred after they contracted the SARS-CoV-2 infection. Patients in the Kampo group will receive 2.5 g of KT (TJ-1@TSUMURA and Co.) and 2.5 g of SSKKS (TJ-109@TSUMURA and Co.) 3 times a day, orally, for 14 days in addition to the conventional treatment as mentioned above. MAIN OUTCOMES: The number of days till at least one of the symptoms (fever, cough, sputum, malaise, shortness of breath) improves in the first 14 days of treatment. To assess the cough, sputum, malaise, and shortness of breath, a numeric rating scale will be used to define improvement in terms of a 2-point decrease in the number of days from the start of treatment for at least 2 days. Fever will be defined as an improvement when the temperature is less than 37 °C. RANDOMIZATION: Patients are randomized (1:1 ratio) to each group using the minimization method, with balancing of the arms with severity of disease stage and patient age (< 65, 65 to < 75, or ≥ 75 years). Computer-generated random numbers will be used for the minimization method. BLINDING (MASKING): Open-label with no blinding NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): The main research hypothesis of this study is that the combination of Kampo medicine and conventional treatment will significantly improve the patients' symptoms (fever, fatigue, cough, sputum, and shortness of breath) during the first 14 days of treatment as compared with conventional treatment alone. Concerning the analysis of the primary endpoint, the duration of time before improvement of at least one of the common cold-like symptoms (fever, malaise, cough, sputum, and shortness of breath) will be estimated using the Kaplan-Meier method, and the survival curves will be compared between groups using the log-rank test. Assuming this method of analysis and based on previous studies reporting the efficacy of Kampo medicine for COVID-19 and H1N1 influenza patients, the median survival time in the Kampo medicine group is estimated as 3 days; this time will be 1.5 times longer in the control group. Assuming a one-sided significance level of 5%, a power of 70%, and an allocation ratio of 1:1, the required sample size is calculated as 126 cases. To compensate for a loss in follow-up, we plan to include 150 cases in both groups (Kampo group = 75, control group = 75). TRIAL STATUS: Protocol version 1.2 as of August 20, 2020 Recruitment start (expected): October 1, 2020 Recruitment finish (expected): October 31, 2023 TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) jRCTs021200020 . Registered on August 25, 2020 FULL PROTOCOL: The full protocol is attached as an additional file and is accessible from the Trials website (Additional file 1). In the interest of expediting the dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.