Analysis of clinical factors associated with Kampo formula-induced pseudoaldosteronism based on self-reported information from the Japanese Adverse Drug Event Report database.

Drug-induced pseudoaldosteronism is a typical adverse effect of Kampo formulas. Previous research described the potential risks of Kampo formula-linked pseudoaldosteronism. However, few studies assessed the risk factors using a real-world database and a data-mining approach. Using the Japanese Adverse Drug Event Report database, we extracted pseudoaldosteronism reports for 148 Kampo formulas covered by Japanese national health insurance. Adverse events were decided according to the preferred terminology of the Medical Dictionary for Regulatory Activities/Japanese version 25.1. We calculated reporting odds ratio (RORs) and identified Kampo formulas as suspected causes of pseudoaldosteronism. Moreover, we evaluated clinical factors associated with Kampo formula-induced pseudoaldosteronism via logistic regression. From April 2004 to November 2022, 6334 adverse events related to the Kampo formulas were reported. We selected 2471 reports containing complete clinical data, including 210 reports on pseudoaldosteronism. In the pseudoaldosteronism group, 69.0% of patients were female, and 85.2% were ≥70 years old. The formulas most commonly associated with pseudoaldosteronism were Shakuyakukanzoto, Yokukansan, and Ryokeijutsukanto (ROR [95% confidence interval {CI}] = 18.3 [13.0-25.9], 8.1 [5.4-12.0], and 5.5 [1.4-21.9], respectively). Logistic analysis identified female sex (odds ratio [OR] [95% CI] = 1.7 [1.2-2.6]; P = 0.006), older age (≥70, 5.0 [3.2-7.8]; P < 0.001), low body weight (<50 kg, 2.2 [1.5-3.2]; P < 0.001), diuretics usage (2.1 [1.3-4.8]; P = 0.004), hypertension (1.6 [1.1-2.4]; P = 0.014), and dementia (7.0 [4.2-11.6]; P < 0.001) as pseudoaldosteronism-related factors. Additionally, the daily Glycyrrhiza dose (OR = 2.1 [1.9-2.3]; P < 0.001) and duration of administration (>14 days, OR = 2.8 [1.7-4.5]; P < 0.001) were associated with adverse events. We did not observe an interaction between aging and hypertension. Careful follow-up is warranted during long-term Glycyrrhiza-containing Kampo formula use in patients with multiple clinical factors for pseudoaldosteronism.

A Case Report of Burning Mouth Syndrome with Dry Mouth Managed by Kampo Medicine.

The patient was a 56-year-old woman who complained of chronic pain involving her tongue. We diagnosed her with burning mouth syndrome (BMS) based on exclusion of any local factors or systemic conditions. The patient not only had tongue pain but also had other signs and symptoms like scalloped tongue, dry mouth, and headache. To manage these additional issues, we used Goreisan, an herbal Kampo medicine, as a complementary alternative medicine (CAM) approach along with cognitive behavioral therapy (CBT). The patient's BMS was successfully managed with the combination of CAM and CBT, which may suggest that the pathophysiology for BMS might be nociplastic pain rather than purely nociceptive or neuropathic.

Exploration for the real causative agents of licorice-induced pseudoaldosteronism.

I investigated the causative agents of licorice-induced pseudoaldosteronism, which is a frequent side effect of Japanese traditional Kampo medicines. Glycyrrhizin (GL), the main ingredient of licorice, is absorbed after being metabolized to glycyrrhetinic acid (GA) by intestinal bacteria, and then metabolized in liver to 3-monoglucuronyl-glycyrrhetinic acid (3MGA). In normal condition, 3MGA is excreted into bile via a multidrug resistance-related protein (Mrp) 2, therefore, 3MGA does not appear in blood circulation. However, under the dysfunction of Mrp2, 3MGA appears in the blood circulation and is excreted into the urine by not glomerular filtration but tubular secretion via organic anion transporter (OAT) 1 and 3. At this time, 3MGA inhibits type 2 11ß-hydroxysteroid dehydrogenase (11ßHSD2) in tubular cells to cause pseudoaldosteronism. Since GA is not the substrates of these transporters, GA cannot inhibit 11ßHSD2 in tubular cells. Therefore, it was considered that 3MGA was the causative agents of licorice-induced pseudoaldosteronism. After that, I isolated and identified three other GL metabolites, 22α-hydroxy-18ß-glycyrrhetyl-3-O-sulfate-30-glucuronide (1), 22α-hydroxy-18ß-glycyrrhetyl-3-O-sulfate (2), and 18ß-glycyrrhetyl-3-O-sulfate (3) from the urine of Mrp2-deficient rats orally treated with GA, and found that their blood and urinary concentrations were much higher than 3MGA and that their pharmacokinetic behaviors were similar to 3MGA. 3MGA was not detected in the blood of patients with pseudoaldosteronism who developed rhabdomyolysis due to licorice, and compound 3 was detected at a high concentration. In addition, a multicenter retrospective study was conducted using the serum and urine of 97 patients who took Kampo medicines containing licorice. Of a total of 97 patients, 67 detected GA in the serum (median 122 nM, 5 nM-1.8 µM) and 68 detected compound 3 (median 239 nM, 2 nM-4.2 µM), and there were no cases of detection of GL, 3MGA, compounds 1, and 2. High blood concentrations of compound 3 were associated with low plasma renin activity, plasma aldosterone levels, and serum potassium levels. It is highly probable that compound 3 is the true causative agent of pseudoaldosteronism.

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.

Successful treatment of orthostatic dysregulation with Japanese (Kampo) herbal medicine ryokeijutsukanto.

CONTEXT: Pharmacologic treatment of dizziness is still not well-established. Consequently, traditional Japanese (Kampo) herbal medicine is commonly used. Ryokeijutsukanto is used to treat dizziness caused by orthostatic dysregulation (OD). OBJECTIVE: We aimed to evaluate the effectiveness of ryokeijutsukanto, a traditional Japanese (Kampo) herbal medicine, in treating dizziness, including light-headedness and/or palpitations. We focused on dizziness caused by OD, a condition commonly treated with ryokeijutsukanto. DESIGN: We used a case series design. SETTING: The study was centered in the department of internal medicine and department of otolaryngology at a general hospital. PATIENTS: We tested ryokeijutsukanto in four female patients who were experiencing dizziness and who were diagnosed with OD. INTERVENTION(S): The patients received ryokeijutsukanto (1.5 g to 4.2 g of dried extract daily). MAIN OUTCOME MEASURE(S): Ryokeijutsukanto was prescribed to the four patients; clinical efficacy and improvement in dizziness were assessed using the Clinical Global Impression-Improvement scale and Vertigo Symptom Scale-Short Form. RESULTS: All patients intended to continue Kampo treatment since high curative effects and no adverse effects were observed. CONCLUSIONS: To the best of our knowledge, this is the first report elucidating the effectiveness of ryokeijutsukanto in treating dizziness as a result of OD. Ryokeijutsukanto may be an appropriate complementary therapy for OD.

A Study of Factors Associated with the Development of Pseudoaldosteronism in Outpatients.

Objective: The development of pseudoaldosteronism is shown to be mainly associated with four factors: daily dose of glycyrrhiza (licorice), duration of glycyrrhiza use, body size, and age. Recently, direct bilirubinemia and hypoalbuminemia are newly reported as possible factors that trigger pseudoaldosteronism due to glycyrrhiza ingestion. Pseudoaldosteronism occurs in the presence of combinations of these factors; therefore, the importance of each factor on the tolerance to glycyrrhiza loading is still unclear. Methods: In seven patients (63-78 years old, six women) who developed pseudoaldosteronism due to ingestion of glycyrrhiza-containing Kampo extract in their clinic, serum albumin and direct bilirubin (D-bil) levels were investigated. In six women, the authors evaluated the correlations between daily dose of glycyrrhiza ingested and each factor: age, height, weight, body mass index, body surface area (BSA), and duration of ingestion (Pearson's correlation coefficient). Results: No patients had abnormal levels of serum albumin or D-bil around the time of the onset. In six women, the highest correlation coefficient was observed between BSA and the glycyrrhiza dose in Kampo extract at the onset of pseudoaldosteronism. Conclusions: The findings suggested that in elderly women, BSA should be considered first as a factor for predicting the development of pseudoaldosteronism.

Recurrent Drug-induced Liver Injury Caused by the Incidental Readministration of a Kampo Formula Containing Scutellariae Radix.

A 67-year-old woman experiencing coughing visited a clinic and was prescribed drugs, including shosaikoto extract, for 4 days. She subsequently suffered from liver injury, but her condition improved after the discontinuation of all medications. Approximately 1 year later, she experienced fatigue, consulted another clinic, and received saikokeishikankyoto extract for 21 days. She subsequently suffered liver injury again. Both shosaikoto and saikokeishikankyoto contain Scutellariae Radix. This case is thought to be one of recurrent drug-induced liver injury caused by the incidental readministration of a Kampo formula containing Scutellariae Radix. An awareness of adverse drug events caused by Kampo formulas, especially those containing Scutellariae Radix, is essential.

Patient safety incident reports related to traditional Japanese Kampo medicines: medication errors and adverse drug events in a university hospital for a ten-year period.

BACKGROUND: Kampo medicine is traditional Japanese medicine, which originated in ancient traditional Chinese medicine, but was introduced and developed uniquely in Japan. Today, Kampo medicines are integrated into the Japanese national health care system. Incident reporting systems are currently being widely used to collect information about patient safety incidents that occur in hospitals. However, no investigations have been conducted regarding patient safety incident reports related to Kampo medicines. The aim of this study was to survey and analyse incident reports related to Kampo medicines in a Japanese university hospital to improve future patient safety. METHODS: We selected incident reports related to Kampo medicines filed in Toyama University Hospital from May 2007 to April 2017, and investigated them in terms of medication errors and adverse drug events. RESULTS: Out of 21,324 total incident reports filed in the 10-year survey period, we discovered 108 Kampo medicine-related incident reports. However, five cases were redundantly reported; thus, the number of actual incidents was 103. Of those, 99 incidents were classified as medication errors (77 administration errors, 15 dispensing errors, and 7 prescribing errors), and four were adverse drug events, namely Kampo medicine-induced interstitial pneumonia. The Kampo medicine (crude drug) that was thought to induce interstitial pneumonia in all four cases was Scutellariae Radix, which is consistent with past reports. According to the incident severity classification system recommended by the National University Hospital Council of Japan, of the 99 medication errors, 10 incidents were classified as level 0 (an error occurred, but the patient was not affected) and 89 incidents were level 1 (an error occurred that affected the patient, but did not cause harm). Of the four adverse drug events, two incidents were classified as level 2 (patient was transiently harmed, but required no treatment), and two incidents were level 3b (patient was transiently harmed and required substantial treatment). CONCLUSIONS: There are many patient safety issues related to Kampo medicines. Patient safety awareness should be raised to prevent medication errors, especially administration errors, and adverse drug events in Kampo medicine.

Involvement of herbal medicine as a cause of mesenteric phlebosclerosis: results from a large-scale nationwide survey.

BACKGROUND: Mesenteric phlebosclerosis (MP) is a rare disease characterized by venous calcification extending from the colonic wall to the mesentery, with chronic ischemic changes from venous return impairment in the intestine. It is an idiopathic disease, but increasing attention has been paid to the potential involvement of herbal medicine, or Kampo, in its etiology. Until now, there were scattered case reports, but no large-scale studies have been conducted to unravel the clinical characteristics and etiology of the disease. METHODS: A nationwide survey was conducted using questionnaires to assess possible etiology (particularly the involvement of herbal medicine), clinical manifestations, disease course, and treatment of MP. RESULTS: Data from 222 patients were collected. Among the 169 patients (76.1 %), whose history of herbal medicine was obtained, 147 (87.0 %) used herbal medicines. The use of herbal medicines containing sanshishi (gardenia fruit, Gardenia jasminoides Ellis) was reported in 119 out of 147 patients (81.0 %). Therefore, the use of herbal medicine containing sanshishi was confirmed in 70.4 % of 169 patients whose history of herbal medicine was obtained. The duration of sanshishi use ranged from 3 to 51 years (mean 13.6 years). Patients who discontinued sanshishi showed a better outcome compared with those who continued it. CONCLUSIONS: The use of herbal medicine containing sanshishi is associated with the etiology of MP. Although it may not be the causative factor, it is necessary for gastroenterologists to be aware of the potential risk of herbal medicine containing sanshishi for the development of MP.

Herbal medicines: challenges in the modern world. Part 3. China and Japan.

INTRODUCTION: Medicinal plants, and formulations prepared from them, have been used in China and Japan for thousands of years. Nowadays, ancient formulations of Traditional Chinese and Kampo (Japanese) Medicines coexist with Western herbal medicines (HMs) and complement each other. HMs are used for the treatment of mild and chronic diseases, as an adjunct therapy, to improve wellbeing and delay aging, or as healthy (functional) foods. AREAS COVERED: This article, a third part in a series of reviews, is focusing on history, use and regulation of the traditional and modern HMs in Japan and China. Materials available from legislative and governmental websites, PubMed and news media were used. Expert commentary: HMs are heavily regulated in both countries, often in a similar manner as conventional pharmaceutical drugs. The majority of herbal formulations are sold as over-the-counter medications supplied with leaflets describing indications and appropriate dosages for patients of different ages. Medical practitioners prescribe herbal formulations that are tailored to the needs of particular patients. Both countries had problems with adverse drug reactions and toxicity of single herbs and herbal formulations that have been investigated by authorities, and some drugs have been removed from the market.

Clinical Search for Undiagnosed Mesenteric Phlebosclerosis at Outpatient Departments Specializing in Herbal (Kampo) Medicine.

OBJECTIVE: Mesenteric phlebosclerosis (MP) is a disease characterized by calcification of the mesenteric vein, which causes chronic mesenteric ischemia. Recently, the long-term intake of gardenia fruit ('Sanshishi' in Japanese) has been attracting attention as a possible cause. Usually, only advanced, severe MP cases get reported. However, we suspected that some latent cases of this disease may exist. We performed this study in order to determine the prediagnostic cases at our outpatient departments of herbal (Kampo) medicine, with particular attention paid to the initial changes, such as any slight color change of the colon, as shown in colonoscopy. METHODS: We recommend colonoscopy and computed tomography (CT) scans for patients with a long-term history of taking herbal medicines containing gardenia fruit. Clinical examinations were performed upon receiving patients' consent from December 2013 to November 2014. RESULTS: Of the 103 patients who took gardenia fruit long-term, 29 agreed to be checked for MP. 14 patients underwent colonoscopy. Four patients were confirmed to have MP due to the presence of fibrotic deposition of the colonic membrane on histological inspection. Twenty-one patients underwent abdominal CT screening. Characteristic calcification of the mesenteric vein was observed on CT scans in 2 patients. All 4 MP patients took Kampo formulas containing gardenia fruit for more than 6.8 years. The other patients did not develop MP, despite long-term gardenia fruit intake. CONCLUSION: We detected the latent and undiagnosed MP cases. All diagnoses were made while paying careful attention to any slight changes in colonoscopy and CT scans.

[Pure red cell aplasia and hypogammaglobulinemia after administration of Dioscorea rhizome and Poria cocos].

A 56-year-old woman was referred to our department for detailed examination of anemia. She was diagnosed with pure red cell aplasia (PRCA) associated with severe reticulocytopenia based on blood testing and severe erythroblastopenia based on bone marrow aspiration. Blood tests revealed severe hypogammaglobulinemia, but monoclonal protein was not detected in either serum or urine by immunoelectrophoresis. Plasma cells were not increased in bone marrow aspirates or the biopsy specimen. Neither osteolytic lesions nor plasmacytoma was detected by computed tomography. We thus ruled out multiple myeloma. She had been treated with various Chinese herbal medicines prescribed at the referring hospital. We suspected PRCA induced by one of the Chinese herbal medicines and completely discontinued all of these herbal preparations. Hematologic testing revealed that the reticulocyte count and hemoglobin concentration began to recover on day 7 and the hemoglobin concentration and IgG levels had reached reference ranges on day 73 after discontinuation of the Chinese herbal medicines. We suspected Sanyaku (Dioscorea rhizome) or Bukuryou (Poria cocos) to have induced PRCA and hypogammaglobulinemia in this patient. To the best of our knowledge, this is the first report of PRCA and hypogammaglobulinemia induced by a Chinese herbal medicine. Clinicians must consider the possibility of drug-induced PRCA and hypogammaglobulinemia in patients taking Chinese herbal preparations.

The Kampo Medicine Yokukansan Decreases MicroRNA-18 Expression and Recovers Glucocorticoid Receptors Protein Expression in the Hypothalamus of Stressed Mice.

It is well known that glucocorticoid receptor (GR) signaling regulates the hypothalamic-pituitary-adrenal (HPA) axis, and GR expression level is associated with HPA axis activity. Recent studies revealed that microRNA- (miR-) 18 and/or 124a are candidate negative regulators of GR in the brain. The Kampo medicine Yokukansan (YKS) can affect psychological symptoms such as depression and anxiety that are associated with stress responses. In this study, we evaluated the effect of YKS on miR-18 and 124a and GR levels in mice exposed to stress. We found that YKS pretreatment normalized elevated plasma corticosterone levels in stress-exposed mice. In addition, GR mRNA levels were downregulated in the brain following stress exposure. While miR-124a expression levels were not altered in the hypothalamus of stress-exposed mice, miR-18 levels decreased in the hypothalamus of YKS-pretreated mice after stress exposure. Finally, GR protein levels in the paraventricular nucleus (PVN) of the hypothalamus after stress exposure recovered in YKS-pretreated mice. Collectively, these data suggest that YKS normalizes GR protein levels by regulating miR-18 expression in the hypothalamus, thus normalizing HPA axis activity following stress exposure.

[Kampo Therapy for Patients with Cancer--The Role of Kampo Medicine in Team Therapy].

This study details the role of Kampo medicine in cancer therapy. Cancer normally cannot be cured only with Kampo medicine. Therefore, Kampo should be administered in combination with surgery, chemotherapy, or radiotherapy. In that context, Kampo is useful in team therapy for patients with cancer. One of the characteristics of Kampo medicine is that Kampo diagnosis does not target the disease, but the patient with the disease. Kampo diagnosis is called"pattern diagnosis". Many patients with cancer are diagnosed with a"deficiency pattern","cold pattern","qi deficiency pattern", or"blood deficiency pattern". Based on these diagnoses, hochuekkito or juzentaihoto are often used for patients with cancer. Many other Kampo formulae can be used for patients with cancer diagnosed with the"qi deficiency pattern"and/or"blood deficiency pattern". Kampo is not only considered an herbal therapy, but also acupuncture/moxibustion and Yojo (nourishing life). To implement these Kampo modalities comprehensively, team therapy is essential. In order to treat a patient with cancer, rather than the cancer itself, Kampo can be used effectively.

Evidence-based research on traditional Japanese medicine, Kampo, in treatment of gastrointestinal cancer in Japan.

Gastrointestinal cancer is a great threat to human health in Japan. Conventional anticancer therapies including surgery, radiation, and chemotherapy are the main strategies and play important roles in curing this disease or extending the life of patients with these cancers. On the other hand, patients undergo great suffering induced by these treatments. Kampo, the Japanese traditional medicine, has been used in clinics to reduce side effects and to improve the quality of life of gastrointestinal cancer patients in Japan. In order to testify to the efficacy and safety of these Kampo medicines and to clarify the underlying mechanisms, a number of clinical and basic studies were implemented in the past several decades. These studies suggested the benefits of Kampo medicine as an adjuvant to conventional anti-cancer therapies in treating gastrointestinal cancer. Since the safety and efficacy as well as quality control of traditional medicine have long been focused worldwide, the development course of Kampo medicine may provide reference to other countries in the world.

Letter: Fixed drug eruption caused by the Japanese herbal drug kakkonto.

Herbal drugs are now widely used throughout the world. The general public tends to believe these agents to be safe because of their natural origin; thus, they are used frequently. However, the side effects of many of these potent chemicals may be significant. Several cases of fixed drug eruption (FDE) caused by herbal drugs have been reported. We herein report a case of FDE caused by kakkonto.