Risk of Major Congenital Malformations Associated with the Use of Japanese Traditional (Kampo) Medicine Containing Ephedra During the First Trimester of Pregnancy.

BACKGROUND: Japanese traditional (Kampo) medicines containing ephedra may be used to treat colds during pregnancy. There are reports that ephedrine, a component of ephedra, has a risk of teratogenicity; however, the evidence remains equivocal. OBJECTIVE: This study aimed to evaluate the risk of major congenital malformations (MCMs) associated with exposure to Kampo medicines containing ephedra during the first trimester of pregnancy using the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study). METHODS: To 23,730 mother-infant pairs who participated in the TMM BirThree Cohort Study from July 2013 to March 2017, questionnaires in early and middle pregnancy were distributed approximately at weeks 12 and 26 of pregnancy, respectively. Infants' risk of MCMs in women who used Kampo medicines containing ephedra or acetaminophen during the first trimester was assessed, and the odds ratios (ORs) were estimated with unadjusted and adjusted analyses. RESULTS: Among 20,879 women, acetaminophen and Kampo medicines containing ephedra were used in 665 (3.19%) and 376 (1.80%) women, respectively, in the first trimester. Among the infants born to the mothers who used acetaminophen or Kampo medicine containing ephedra during the first trimester, 11 (1.65%) and 8 (2.13%), respectively, had overall MCMs. OR of overall MCMs was higher in women who used Kampo medicines containing ephedra than in those who used acetaminophen in the first trimester (adjusted OR, 1.45; 95% confidence interval (CIs), 0.57-3.71); however, the difference was not statistically significant. CONCLUSIONS: In this study, there was no statistically significant association between the use of Kampo medicines containing ephedra during the first trimester of pregnancy and the risk of MCMs. Although some point estimates of ORs exceeded 1.00, the absolute magnitude of any increased risks would be low.

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.

No association between major congenital malformations and exposure to Kampo medicines containing rhubarb rhizome: A Japanese database study.

Traditional Japanese (Kampo) medicines containing rhubarb rhizome are prescribed for constipation during pregnancy; however, detailed safety information of their use for pregnant women is lacking. The aim of current study was to clarify the association between prescription Kampo-containing rhubarb rhizome (KRR) in the first trimester of pregnancy and congenital malformations in newborns. Using a large Japanese health insurance claims database, we included pregnant women who enrolled the same health insurance society from 3 months before pregnancy to the delivery date, who gave birth between 2010 and 2019, and those with data related to their infants. Pregnant women who were prescribed magnesium oxide (MgO), commonly used for constipation, during the first trimester of pregnancy and their infants were extracted as controls. Associations between KRR prescribed in the first pregnancy trimester and major congenital malformations (MCM) in the infants were examined using multivariate logistic regression analysis. Of 75,398 infants, 4,607 (6.1%) were diagnosed with MCMs within the first year after birth. Furthermore, 9,852 infants were born to women prescribed MgO, among whom 680 (6.9%) had MCMs; 450 infants were born to women prescribed KRR, among whom 28 (6.2%) had MCMs. Multivariate logistic regression analysis identified no difference in MCM risk between the two types of prescriptions [crude odds ratio (OR) 0.895, 95% confidence interval (CI) 0.606-1.322, adjusted OR 0.889, 95% CI 0.599-1.320]. In conclusion, the risk of MCMs did not differ between those prescribed KRR or MgO in the first trimester of pregnancy.

The Integration of Traditional Medicine with Conventional Biomedicine: A Narrative Review of the Japanese Perspective.

Objectives: This is a narrative review of the integration of traditional medicine with conventional biomedicine in present day Japan, whose aging population is considered one of the largest globally. Design: It is focused on the aging population because this age group most avails of healthcare. We also tried to describe the unique Japanese medical situations, clinical outcome of Japanese traditional medicine (Kampo medicine) which may include acupuncture, and education of Kampo medicine workforce. Results: Conventional schools of medicine in Japan are required to teach Kampo medicine, and most Japanese physicians (>80%) prescribe traditional medicine, especially in primary care settings. The universal national healthcare system covers Kampo medicine prescribed by physicians and treatment by acupuncturists (they sometimes refer patients who may need evaluation by physicians), enhancing access to primary healthcare. Additionally, pharmacists who graduated from conventional schools of pharmacy also select and sell Kampo medicine as over-the-counter (OTC) medication. Kampo medicine available as prescription drugs and OTC is effective, and has been proven to be economically beneficial in several clinical settings. Conclusions: An aging population is a global concern for both developed and developing countries. Japan, having a significantly-large aging population, integrates conventional biomedicine and traditional medicine in its universal national healthcare coverage, through its biomedically-trained physicians and pharmacists who also learned traditional medicine, as well as the acupuncturists. By reviewing the current situation in Japan, the authors hope to introduce the future of the global contribution of traditional, complementary, and integrative medicine in primary care.

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.

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].

Refractory Chest Pain in Mild to Moderate Coronavirus Disease 2019 Successfully Treated with Saikanto, a Japanese Traditional Medicine.

Coronavirus disease 2019 (COVID-19) causes a variety of pain symptoms in the acute phase. Severe chest pain suddenly occurs even without abnormalities on examination and is sometimes refractory to analgesics. Such pain is a clinical concern in care facilities with limited resources, and this is the first report on the use of saikanto for its treatment. In Miyagi Prefecture, Japan, COVID-19 patients with mild symptoms were admitted to a hotel that operated as an isolation facility, and their symptoms were observed. In this article, we report four cases in which chest pain comorbid with mild to moderate COVID-19 was successfully treated with saikanto, a traditional Japanese (Kampo) medicine. The patients presented with chest pain and underwent medical examination at the facility. Two patients had severe chest pain refractory to acetaminophen. Critical cardiopulmonary diseases were ruled out in all the patients, and three patients had features of pneumonia on chest radiograph. Medications, including saikanto, were administered to the patients. The patients' chest pain and other symptoms improved 1-4 days after the administration of saikanto, and they left the care facility without hospitalization. The cause of the chest pain experienced by these patients is unclear, but we speculate that it could be minimal pleural inflammation or neuropathy. Previous pharmacological studies have suggested anti-inflammatory and analgesic properties of the crude drugs that constitute saikanto. This case report suggests that saikanto could be a treatment option for chest pain refractory to analgesics in patients with mild to moderate COVID-19.

Case Report: Prolonged Anorexia With Nausea Caused by Immune Checkpoint Inhibitors for Malignant Melanoma Treated Using Kampo Medicines Bukuryoingohangekobokuto and Ninjin'yoeito.

Immune checkpoint inhibitors (ICIs) are indicated for several cancers, including malignant melanoma. Anorexia and nausea resulting in malnutrition are side effects of ICIs. In such cases, conventional drugs are used for symptom relief, but the symptoms may persist. We report a case of advanced malignant melanoma with prolonged anorexia and nausea, which occurred after nivolumab administration, and was successfully treated using Kampo medicines. A 75-year-old man with nasal bleeding visited our hospital. A nasal scope revealed an obstructive tumor in the left nasal concha. Tissue biopsy showed malignant melanoma, and computed tomography showed metastasis to the liver and bone. Thus, the patient was diagnosed with stage IV malignant melanoma. He received radiotherapy (30 Gy) and nivolumab with ipilimumab four times, followed by nivolumab administration alone. During the administration of nivolumab, he complained of severe anorexia and nausea, with a numeric rating scale (no symptoms, 0; severe symptoms, 10) score of 10. He could not consume food because of these symptoms, even after nivolumab administration was discontinued. His blood pressure was 92/59 mmHg, his performance status (PS; no fatigue, 0; bedridden or disabled, 4) was 4, and his body weight gradually decreased from 60 to 39 kg in a month. The patient showed malnutrition and dehydration and experienced anxiety and depression. Nivolumab was terminated, and conventional symptomatic drugs were prescribed, but the symptoms persisted. We then prescribed 9.0 g/day of ninjin'yoeito (TJ-108, Tsumura and Co.) to allow recovery from anorexia and subsequently added bukuryoingohangekobokuto (TJ-116, Tsumura and Co.) to treat the persistent nausea. After treatment with these two Kampo medicines, the patient's appetite gradually recovered. Along with the recovery of nutritional status, his PS improved to 0, his anxiety and depressive state improved, and his body weight increased to 60 kg. The patient remained in good condition without cancer recurrence. The patient's clinical course shows the usefulness of Kampo medicine as supportive care for symptom relief and maintenance of nutritional and mental status during cancer treatment.

Kampo Medicine Promotes Early Recovery From Coronavirus Disease 2019-Related Olfactory Dysfunction: A Retrospective Observational Study.

Background: Olfactory dysfunction is a common symptom in patients with coronavirus disease 2019, and it significantly deteriorates patients' quality of life. Effective treatments remain unknown. Purpose: To assess the effect of Japanese traditional (Kampo) medicine on coronavirus disease 2019-related olfactory dysfunction. Study Design: Retrospective observational study. Methods: In total, 87 patients aged ≥18 years with coronavirus disease 2019 and severe dysosmia or anosmia (Numeric Rating Scale, ≥7) at isolation facilities in Miyagi Prefecture, Japan, were enrolled from October 2020 to March 2021. Patients were divided into the Kampo group (N = 52) and the control group (N = 35) based on the treatment received. Changes in Numeric Rating Scale scores were evaluated at the first visit and 2 weeks after. Results: The median reduction in the olfactory dysfunction score at both 1 and 2 weeks after the first visit was significantly greater in the Kampo group (6 and 8, respectively; p = 0.03) than in the control group (3 and 7, respectively; p = 0.04). We defined improvement in olfactory dysfunction as a median reduction in the olfactory dysfunction score of ≥5. Multiple logistic regression analysis demonstrated that only Kampo treatment was significantly associated with improvement in olfactory dysfunction. Conclusion: This study suggests that Kampo medication promotes early recovery from coronavirus disease 2019-related olfactory dysfunction.

Application of objective structured clinical examination (OSCE) for the evaluation of Kampo medicine training.

BACKGROUND: The purpose of this study was to develop an objective, content-valid, and reliable assessment method for Kampo medicine using an objective structured clinical examination (OSCE) for the assessment of clinical competence in Kampo medicine. METHODS: We developed a blueprint followed by a list of 47 assessment items and three task scenarios related to clinical competence in Kampo medicine. An eight-member test committee checked the relevance of the assessment items on a Likert scale. We calculated a content validity index and content validity ratio, and used the Angoff method to set the passing threshold. We trained a total of nine simulated patients with three assigned to each scenario. We conducted an OSCE for 11 candidates with varying medical abilities, and conducted three stations per person, which were evaluated by one evaluator in one room by direct observation. We used video recordings to test the inter-rater reliability of the three raters. We used the test results to verify the reliability of the assessment chart. RESULTS: The inter-rater reliability (intraclass correlation coefficient [2,1]) was 0.973. The reliability of the assessment chart for each scenario (Cronbach's α) was 0.86, 0.89, and 0.85 for Scenarios 1, 2, and 3, respectively. The reliability of the assessment chart for the whole OSCE (Cronbach's α) was 0.90. CONCLUSIONS: We developed a content-valid new OSCE assessment method for Kampo medicine and obtained high inter-rater and test reliabilities. Our findings suggest that this is one of the most reliable evaluation methods for assessing clinical competence in Kampo medicine.

Prescription of Kampo Formulations for Pre-natal and Post-partum Women in Japan: Data From an Administrative Health Database.

Introduction: Traditional Japanese (Kampo) medicines are often prescribed for women in Japan before, during, and after pregnancy. However, detailed information on the actual frequency of use and safety of Kampo preparations during pregnancy is lacking. Aim: To investigate the frequency of prescription of Kampo medicines for pregnant women in Japan. Methods: Information on Kampo medicines prescribed during outpatient care and hospitalization of selected mothers from January 2005 to August 2016 were extracted from the Japan Medical Data Center (Tokyo, Japan), which is a large claims database. Results: Of the 33,941 subscribers identified from the database, 16,294 (48%) received at least one prescription of a Kampo medicine. Kakkonto was the formula most prescribed during the study period, followed by shoseiryuto and tokishakuyakusan. In the 180 days before pregnancy, the most prescribed medicine was tokishakuyakusan, followed by kakkonto and shoseiryuto. Shoseiryuto, tokishakuyakusan, and kakkonnto were the formulae most prescribed during pregnancy. The most prescribed medicines during the 180 days postpartum were kakkonto, shoseiryuto, and saireito. Conclusions: Information in the Japanese insurance system shows that Kampo medicines are often prescribed during pregnancy. Most of these prescriptions are generally used for the treatment of common cold. Tokishakuyakusan in particular is usually used in the treatment of various symptoms of pregnancy. Further research is needed to clarify the relationship between the use of Kampo medicines during pregnancy and adverse events in infants in Japan.

Kampo Medicine Treatment for Advanced Pancreatic Cancer: A Case Series.

Aims: The present report aims to investigate the use of Kampo medicine for advanced pancreatic cancer patients in order to prolong survival. Methods: We retrospectively reviewed medical records of patients with pancreatic cancer who presented to our Shimizu Clinic from 2000 to 2020. Patients who survived at least twice as long as the initial prognostic estimate were selected and their treatment was reviewed. The Kampo formula and crude drugs were selected according to the Kampo diagnosis and treatment strategy, which included qi and blood supplementation; qi, blood and water smoothing; and inflammation (termed "heat") and cancer suppression. Results: Ten patients aged 45-80 years (six males and four females) with stage IV advanced cancer were selected. All patients received hozai, which is a tonic formula, of juzentaihoto (JTT) or hochuekkito (HET) decoction. Anti-cancer crude drugs were included in the decoctions of nine patients. At the first visit, the estimated life expectancy for all patients was no more than 1 year; however, treatment with Western and Kampo medicine led to a relatively long survival period of over 2 years. Three patients were still living at the time of this writing, more than 2, 6, and 14 years after treatment initiation. Conclusion: Our results suggest that Kampo medicine may be useful for disease control and supportive care for patients with advanced pancreatic cancer.

Prevention and Recovery of COVID-19 Patients With Kampo Medicine: Review of Case Reports and Ongoing Clinical Trials.

Coronavirus disease 2019 (COVID-19) spread to Japan in 2020, where the number of infected patients exceeded 250,000 and COVID-related deaths exceeded 3,500 in one year. Basic guidelines for infection control were implemented in Japan, and research and development of effective drugs and vaccines were promoted. This included considering Kampo medicine, which has a long history of treating recurring emerging viral infections. Considering the characteristics of the disease (inflammation of the upper and lower respiratory tract as well as potential neural damage and vasculitis), Kampo medicine could be considered as a treatment strategy due to its antiviral and anti-inflammatory effects induced by multiple active substances that could aid in disease prevention and recovery. In this study, case reports on the management of COVID-19 with Kampo medicine, which were published until March 31, 2021, were reviewed. The search strategy involved the use of Medline and hand-searching. Twenty two patients were treated using Kampo medicines with or without Western medicine, based on individual conditions. On the other hand, the effects of Kampo medicines as a potential preventive treatment (pre-infection), active treatment (especially in the acute and subacute stage), or treatment of sequelae to aid recovery (after infection) in the different stages of COVID-19 are being studied as research projects in the Japan Society for Oriental Medicine (JSOM). JSOM has also organized a pioneering project of clinical trials for COVID-19, some of which are now in progress.

Treatment of COVID-19-Related Olfactory Disorder Promoted by Kakkontokasenkyushin'i: A Case Series.

Olfactory disorders are one of the characteristic symptoms of the coronavirus disease of 2019 (COVID-19), which causes infection and inflammation of the upper and lower respiratory tract. To our knowledge, there are no treatments for COVID-19-related olfactory disorder. Here, we report five olfactory disorder cases in COVID-19, treated using the Japanese traditional (Kampo) medicine, kakkontokasenkyushin'i. We treated five patients with mild COVID-19 at an isolation facility using Kampo medicine, depending on their symptoms. Patients with the olfactory disorder presented with a blocked nose, nasal discharge or taste impairment. Physical examination using Kampo medicine showed similar findings, such as a red tongue with red spots and sublingual vein congestion, which presented as blood stasis and inflammation; thus, we prescribed the Kampo medicine, kakkontokasenkyushin'i. After administration, the numeric rating scale scores of the smell impairment improved within 3 days from 9 to 3 in case 1, from 10 to 0 in case 2, from 9 to 0 in case 3, from 5 to 0 in case 4, and from 9 to 0 within 5 days in case 5. Following the treatment, other common cold symptoms were also alleviated. Kakkontokasenkyushin'i can be used for treating nasal congestion, rhinitis, and inflammation in the nasal mucosa. The olfactory disorder in COVID-19 has been reportedly associated with inflammation and congestion, especially in the olfactory bulb and olfactory cleft. Kakkontokasenkyushin'i may be one of the treatment alternatives for the olfactory disorder with rhinitis in patients with COVID-19.

Bukuryoingohangekobokuto may improve recurrent aspiration pneumonia in patients with brain damage and reduce the caregiver burden.

A 17-year-old girl with hypoxic encephalopathy was hospitalized over four times in a year because of recurrent aspiration pneumonia (AP). She had dysphagia and reduced cough reflex as sequelae of brain damage. To prevent aspiration, a gastric tube was placed for feeding, but it did not reduce the frequency of AP because the gastroesophageal reflux caused backflow. However, after the Kampo medicine bukuryoingohangekobokuto (BRIHK) was added to the prescriptions, her sputum and gastroesophageal reflux was remarkably reduced. BRIHK is a Kampo medicine that confers multiple benefits such as improving swallowing and cough reflexes, reducing sputum, and improving gastric emptying. Subsequently, the frequency of sputum suction reduced from every 15 min to 30 min, thus reducing the burden on her mother. As a result, she has never been hospitalized for AP in the 7 years after treatment. Overall, BRIHK may be a treatment of choice for similar patients.

Retrospective study revealed that Zn relate to improvement of swallowing function in the older adults.

BACKGROUND: Zinc is an essential micronutrient for maintaining biological activity. The level of zinc in the blood is known to decrease with age, especially in those over 75 years of age. In older adults patients with impaired functional status, aspiration pneumonia based on dysphagia often becomes problematic. However, the relationship between zinc deficiency and swallowing function has not been studied before. METHODS: A total of 52 older adults subjects (15 males and 37 females) living in a nursing home were enrolled for this study. At the time of enrollment, data of gender, age, body weight, serum zinc levels, serum albumin levels, and the time in a simple 2-step swallowing provocation test (S-SPT) were collected. In patients with serum zinc levels < 60 µg/dL, we initiated 2 months of oral zinc supplementation therapy with a 34 mg/day zinc load. Those who underwent zinc supplementation were re-evaluated after the treatment period and serum zinc levels and S-SPT time were measured. RESULTS: At the time of enrollment, serum zinc level was significantly correlated with serum albumin levels (Pearson's R = 0.58, p < 0.0001) and time in the S-SPT (Spearman's rho = - 0.32, p = 0.0219). Twenty-five of the 52 patients had zinc deficiency with a serum zinc level < 60 µg/dL. After 2 months of oral zinc supplementation, both serum zinc levels (p < 0.0001) and time in the S-SPT (p = 0.04) significantly improved. Meanwhile, serum albumin level (p = 0.48) or body weight (p = 0.07) did not significantly change following zinc supplementation. Zinc supplementation significantly improved swallowing function, especially in the older adults who had comorbid dysphagia and zinc deficiency. CONCLUSIONS: Zinc deficiency is associated with compromised swallowing function in older adults patients with impaired general functions. Oral zinc supplementation can alleviate dysphagia in older adults patients with zinc deficiency even though this is a retrospective study. Further study will be needed to confirm this positive effect.

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.

Integrative therapy for advanced pancreatic cancer using Kampo and western medicine: A case report.

A 45-year-old male patient diagnosed as stage IVa pancreatic cancer received anti-cancer treatment with chemotherapy and radiotherapy. During the treatment, he complained of nausea, appetite loss, and fatigue. He received a Kampo diagnosis of qi deficiency, blood stasis, and heat with phlegm; consequently, qi supplementation, smoothing blood, and relieving fever were initiated using Juzentaihoto and Keppuchikuoto. After this treatment, the symptoms showed remarkable improvement. However, computed tomography revealed multiple lung nodules. We prescribed crude drugs with anti-cancer effects, including Scutellaria barbata and Oldenlandia diffusa. These drugs led to slowed development of lung metastases that could be surgically resected. He survived for 7 years after the advanced diagnosis without loss of quality of life. Kampo medicine may be useful for disease control and supportive care in advanced pancreatic cancer patients.

Two Cases of Multiple Chemical Sensitivity Successfully Treated With Kampo Medicine.

CONTEXT: Multiple chemical sensitivity (MCS) is a chronic disorder in which minimal but sustained exposure to particular chemicals causes headaches, vertigo, and multiple other symptoms. Up to 10% of cases are clinically unresponsive to treatment. Kampo medicines include multiple crude components with many applications for organ disorders. OBJECTIVE: The research team aimed to assess the efficacy of goreisan, a Japanese Kampo medicine, for 2 patients diagnosed with intractable cases of MCS. DESIGN: The research team conducted case studies with 2 female patients. SETTING: The study took place at the Kampo clinic in the Department of Gynecology and Obstetrics at the Japanese Red Cross Maebashi Hospital in Maebashi, Gunma, Japan. PARTICIPANTS: The participants were patients at the clinic. INTERVENTION: The first participant received the Kampo formula goreisan for her headaches and keigairengyoto for her mucosal discomfort; the second received goreisan for her headaches and kakkonto to reduce her shoulder-muscle stiffness. The participants received Kampo treatments for one month. OUTCOME MEASURES: The first participant's MCS symptoms were evaluated with the Quick Environment Exposure Sensitivity Inventory questionnaire (QEESI); the second using a numeric rating scale (NRS). RESULTS: After the Kampo treatments, the first participant's QEESI scores for chemical intolerance, symptom severity, and life impact were reduced from 47, 92, and 76 to 37, 39, and 55 points, respectively. The second participant's NRS scores were likewise reduced from 6, 8, and 8 out of 10 to 1, 2, and 1 out of 10. Symptoms were relieved in both patients, and didn't recur. CONCLUSIONS: These results highlight the potential benefits of Kampo medicine for the treatment of intractable MCS. Further investigations will be needed to confirm the mechanism of action, thereby improving the understanding of the effectiveness of Kampo medicine for MCS therapy.

Orengedokuto and shosaikoto for intractable intracranial carmustine implant-induced fever in a patient with brain tumor: A case report.

INTRODUCTION: Anaplastic astrocytoma has a dismal prognosis with conventional treatment. Multidisciplinary treatment is needed to control the disease; however, side effects of the treatment reduce a patient's quality of life (QOL). Carmustine-impregnated wafers (Gliadel®, Eisai Co., Ltd., Tokyo, Japan), one of the treatment modalities for anaplastic astrocytoma, has been reported to have drug-induced fever as a side effect. CASE REPORT: A 36-year-old man underwent excision for a recurrent brain tumor. Histopathological examination established a diagnosis of anaplastic astrocytoma and an intracranial carmustine implant was placed for local chemotherapy. Postoperatively, the patient developed high fever, which could not be controlled using antipyretics. The high fever ameliorated dramatically after the administration of Kampo medicines, specifically orengedokuto and shosaikoto, and the patient could continue chemotherapy. CONCLUSION: To the best of our knowledge, this is the first report of successful treatment of intractable carmustine implant-induced fever using Kampo medicine. In this case, Kampo medicine led to an improvement of QOL.