研究者詳細 - 吉野　鉄大

論文 - 吉野　鉄大

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Relationship Between Conventional Medicine Chapters in ICD-10 and Kampo Pattern Diagnosis: A Cross-Sectional Study

Wu X., Le T.K., Maeda-Minami A., Yoshino T., Horiba Y., Mimura M., Watanabe K.

Frontiers in Pharmacology （Frontiers in Pharmacology） 12 2021年12月

Objectives: The newest revision to the International Classification of Diseases, the 11th edition (ICD-11) includes disease classifications from East Asian medicine, including traditional Japanese medicine (Kampo medicine). These disease classifications allow for comparisons between disease classifications from conventional medicine and Kampo medicine. Design/Location/Subjects/Interventions: This is an exploratory, cross-sectional study exploring the relationship between conventional medicine diagnoses and Kampo medicine diagnoses at a large Kampo clinic in Japan. Patients were seen from October 1st, 2014 to June 30th, 2019 and were 20 years of age or older. Outcome measures: Patients presented with one or more conventional medicine ICD-10 codes into the clinic and were given one descriptor from the ICD-11 within the heat-cold module, excess-deficiency module, and an optional body constituents module. The distribution of these Kampo medicine codes was examined in relation to conventional medicine chapters. Results: 1,209 patients were included in our final analysis. Patient number, ages, sex ratio, and BMI varied within conventional medicine ICD-10 chapters and Kampo medicine descriptor codes. Certain conventional medicine chapters are related to specific Kampo medicine descriptor codes, such as chapter IV (endocrine, nutritional, and metabolic diseases) with excess, heat, and kidney qi deficiency. Conclusion: The advent of the ICD-11 allows for systematic, standardized comparisons between Kampo medicine, and contemporary medicine. In this exploratory study, our findings support the independence of Kampo medicine pattern descriptors with ICD-10 conventional medicine chapters. Code overrepresentations in relation to conventional medicine diseases and by age and sex should be an area of future investigation to best understand how to synergize and improve patient care.

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Clinical Risk Factors of Licorice-Induced Pseudoaldosteronism Based on Glycyrrhizin-Metabolite Concentrations: A Narrative Review

Yoshino T., Shimada S., Homma M., Makino T., Mimura M., Watanabe K.

Frontiers in Nutrition （Frontiers in Nutrition） 8 2021年09月

Licorice, the dried root or stolon of Glycyrrhiza glabra or G. ularensis, is commonly used worldwide as a food sweetener or crude drug. Its major ingredient is glycyrrhizin. Hypokalemia or pseudoaldosteronism (PsA) is one of the most frequent side effects of licorice intake. Glycyrrhizin metabolites inhibit type 2 11β-hydroxysteroid dehydrogenase (11βHSD2), which decomposes cortisol into inactive cortisone in the distal nephron, thereby inducing mineralocorticoid receptor activity. Among the several reported glycyrrhizin-metabolites, 18β-glycyrrhetyl-3-O-sulfate is the major compound found in humans after licorice consumption, followed by glycyrrhetinic acid. These metabolites are highly bound to albumin in blood circulation and are predominantly excreted into bile via multidrug resistance-associated protein 2 (Mrp2). High dosage and long-term use of licorice are constitutional risk factors for PsA. Orally administered glycyrrhizin is effectively hydrolyzed to glycyrrhetinic acid by the intestinal bacteria in constipated patients, which enhances the bioavailability of glycyrrhizin metabolites. Under hypoalbuminemic conditions, the unbound metabolite fractions can reach 11βHSD2 at the distal nephron. Hyper direct-bilirubin could be a surrogate marker of Mrp2 dysfunction, which results in metabolite accumulation. Older age is associated with reduced 11βHSD2 function, and several concomitant medications, such as diuretics, have been reported to affect the phenotype. This review summarizes several factors related to licorice-induced PsA, including daily dosage, long-term use, constipation, hypoalbuminemia, hyper direct-bilirubin, older age, and concomitant medications.

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Inter-Rater Reliability of Kampo Diagnosis for Chronic Diseases

Maeda-Minami A., Yoshino T., Horiba Y., Nakamura T., Watanabe K.

Journal of Alternative and Complementary Medicine （Journal of Alternative and Complementary Medicine） 27 （ 7 ） 613 - 616 2021年07月

ISSN 10755535

This single-center observational study aimed to assess the inter-rater reliability (IRR) of Kampo medicine pattern diagnosis, which is modularized into three modules for chronic diseases, using 64 participants' information documents. The linearly weighted percentage of agreement and Gwet's agreement coefficient (AC) 2 for the deficiency-excess module, among three specialists, were 85.9% and 0.708, respectively. The unweighted percentage of agreement and Gwet's AC1 were 64.6% and 0.542 for the cold-heat, and 35.9% and 0.254 for the qi-blood-fluid modules, respectively. Our findings suggest that our modularization method may improve the IRR of Kampo medicine pattern diagnosis.

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Identification of an Alternative Glycyrrhizin Metabolite Causing Liquorice-Induced Pseudohyperaldosteronism and the Development of ELISA System to Detect the Predictive Biomarker

Ishiuchi K., Morinaga O., Yoshino T., Mitamura M., Hirasawa A., Maki Y., Tashita Y., Kondo T., Ogawa K., Lian F., Ogawa-Ochiai K., Minamizawa K., Namiki T., Mimura M., Watanabe K., Makino T.

Frontiers in Pharmacology （Frontiers in Pharmacology） 12 2021年05月

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

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Bilateral pneumothorax after acupuncture treatment

Nishie M., Masaki K., Kayama Y., Yoshino T.

BMJ Case Reports （BMJ Case Reports） 14 （ 3 ） 2021年03月

A 31-year-old female physician was diagnosed with bilateral pneumothorax a day after her acupuncture treatment. Her body mass index was 16.9 and she did not have a prior history of respiratory disease or smoking. Acupuncture needles may easily reach the pleura around the end of the suprascapular angle of the levator scapulae muscle where the subcutaneous tissue is anatomically thin. In our patient, the thickness between the epidermis and the visceral pleura in this area was only 22 mm as confirmed by an ultrasound scan. Although she felt chest discomfort 30 min after the procedure, she assumed the symptom to be a reaction to the acupuncture. In light of our case, we advise practitioners to select appropriate acupuncture needles for patients based on the site of insertion and counsel them regarding the appearance of symptoms such as chest pain and dyspnoea immediately after the procedure.

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薬局薬剤師を対象とした漢方薬の書籍等情報源認知度調査

前田絢子, 湯本哲郎, 里香世子, 稲葉健二郎, 小湊英範, 木村隆夫, 中村智徳, 吉野鉄大, 堀場裕子, 渡辺賢治 and 亀井淳三

未病と抗老化 30 52 - 58 2021年

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

Takayama S., Namiki T., Ito T., Arita R., Nakae H., Kobayashi S., Yoshino T., Ishigami T., Tanaka K., Kainuma M., Nochioka K., Takagi A., Mimura M., Yamaguchi T., Ishii T.

Trials （Trials） 21 （ 1 ） 2020年10月

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.

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中村智徳, 吉野鉄大, 堀場裕子, 渡辺賢治, 三村將, 小川恵子, 南澤潔, 並木隆雄 and 牧野利明

医薬品相互作用研究 44 （ 2 ） 75 - 86 2020年09月

ISSN 0385-5015

Discrimination of prediction models between cold-heat and deficiency-excess patterns

Maeda-Minami A., Yoshino T., Katayama K., Horiba Y., Hikiami H., Shimada Y., Namiki T., Tahara E., Minamizawa K., Muramatsu S., Yamaguchi R., Imoto S., Miyano S., Mima H., Mimura M., Nakamura T., Watanabe K.

Complementary Therapies in Medicine （Complementary Therapies in Medicine） 49 2020年03月

ISSN 09652299

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

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Prediction of Deficiency, Medium, and Excess Patterns in Japanese Kampo Medicine: A Multicenter Prospective Observational Study

Ayako Maeda-Minami, Tetsuhiro Yoshino, Yuko Horiba, Hiroaki Hikiami, Yutaka Shimada, Takao Namiki, Eiichi Tahara, Kiyoshi Minamizawa, Shinichi Muramatsu, Masaru Mimura, Tomonori Nakamura, and Kenji Watanabe

2020年

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Identification of glycyrrhizin metabolites in humans and of a potential biomarker of liquorice-induced pseudoaldosteronism: a multi-centre cross-sectional study

Takahashi K., Yoshino T., Maki Y., Ishiuchi K., Namiki T., Ogawa-Ochiai K., Minamizawa K., Makino T., Nakamura T., Mimura M., Watanabe K.

Archives of Toxicology （Archives of Toxicology） 93 （ 11 ） 3111 - 3119 2019年11月

ISSN 03405761

Liquorice [main ingredient, glycyrrhizin (GL)] is widely used as a food sweetener and herbal medicine. Occasionally, liquorice consumption causes pseudoaldosteronism as a side effect which causes oedema, hypokalaemia, and hypertension due to hyperactivity of mineral corticoid receptor. We aimed to detect GL metabolites in human blood and urine samples and to determine the pathological relationship between GL metabolites and pseudoaldosteronism. For this multi-centre, retrospective, cross-sectional study, we recruited patients who had visited Center for Kampo Medicine in Keio University Hospital, Department of Japanese Oriental (Kampo) Medicine in Chiba University Hospital, Clinic of Japanese Oriental (Kampo) Medicine in Kanazawa University Hospital, and Department of Oriental Medicine in Kameda Medical Center from November 2011 to July 2018. We collected laboratory data including concentration of serum potassium, plasma activity of renin and aldosterone, and residual blood and/or urine samples of participants who had experienced symptoms/signs of pseudoaldosteronism in the form of increase in blood pressure and occurrence or aggregation of oedema while taking liquorice-containing herbal preparations, and measured GL metabolites using a highly selective liquid chromatography tandem mass spectrometer system. We registered 97 participants (mean age 60 ± 15 years; male:female 14:83). 18β-glycyrrhetinic acid (GA) was detected in 67 serum samples (median 122 nM, range 5 nM–1.8 µM) and 18β-glycyrrhetyl-3-O-sulfate (compound 3) in 68 samples (median 239 nM, range 2 nM–4.2 µM). 3-Monoglucuronyl 18β-glycyrrhetinic acid, 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate-30-glucuronide, 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate, and GL itself were not or rarely detected. We could not find any correlation between blood pressure or peripheral oedema and serum concentration of GL metabolites. Sulfotransferase 2A1 catalysed the metabolic reaction of GA to compound 3, a major GL metabolite in human blood. High serum concentration of compound 3 was related to lower renin, aldosterone, and potassium levels, suggesting a pathological relationship between compound 3 and liquorice-induced pseudoaldosteronism. This is the first study to identify the association between a novel metabolite, compound 3, and the incidence of pseudoaldosteronism, highlighting it as a promising biomarker.

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Differences in demographics and complementary and alternative medicine use between patients attending integrative kampo versus biomedical clinics in Japan

Melby M., Yoshino T., Tonob D., Horiba Y., Watanabe K.

Complementary Therapies in Medicine （Complementary Therapies in Medicine） 46 202 - 209 2019年10月

ISSN 09652299

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

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Prediction of deficiency-excess pattern in Japanese Kampo medicine: Multi-centre data collection

Complementary Therapies in Medicine （Complementary Therapies in Medicine） 45 228 - 233 2019年08月

ISSN 09652299

© 2019 Elsevier Ltd Objective: The purpose of the present study was to compare important patient questionnaire items by creating a random forest model for predicting deficiency-excess pattern diagnosis in six Kampo specialty clinics. Design: A multi-centre prospective observational study. Setting: Participants who visited six Kampo specialty clinics in Japan from 2012 to 2015. Main outcome measure: Deficiency-excess pattern diagnosis made by board-certified Kampo experts. Methods: To predict the deficiency-excess pattern diagnosis by Kampo experts, we used 153 items as independent variables, namely, age, sex, body mass index, systolic and diastolic blood pressures, and 148 subjective symptoms recorded through a questionnaire. We extracted the 30 most important items in each clinic's random forest model and selected items that were common among the clinics. We integrated participating clinics’ data to construct a prediction model in the same manner. We calculated the discriminant ratio using this prediction model for the total six clinics’ data and each clinic's independent data. Results: Fifteen items were commonly listed in top 30 items in each random forest model. The discriminant ratio of the total six clinics’ data was 82.3%; moreover, with the exception of one clinic, the independent discriminant ratio of each clinic was approximately 80% each. Conclusions: We identified common important items in diagnosing a deficiency-excess pattern among six Japanese Kampo clinics. We constructed the integrated prediction model of deficiency-excess pattern.

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Classification of patients with cold sensation by a review of systems database: A single-centre observational study

Yoshino T., Katayama K., Yamaguchi R., Imoto S., Miyano S., Mima H., Watanabe K.

Complementary Therapies in Medicine （Complementary Therapies in Medicine） 45 7 - 13 2019年08月

ISSN 09652299

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

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Risk factors associated with pseudoaldosteronism in patients with chronic hepatitis: A retrospective cohort study

Komatsu A., Yoshino T., Suzuki T., Nakamura T., Kanai T., Watanabe K.

Basic and Clinical Pharmacology and Toxicology （Basic and Clinical Pharmacology and Toxicology） 124 （ 5 ） 607 - 614 2019年05月

ISSN 17427835

© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society) Glycyrrhizin is used to treat chronic hepatitis, but it also plays an important role in pseudoaldosteronism. Multidrug resistance-associated protein 2 is important for glycyrrhizin excretion. Dysfunction of this transporter increases the serum levels of direct bilirubin, glycyrrhizin and its metabolites. Hence, elevated direct-bilirubin levels could predict the risk of pseudoaldosteronism. This study aimed to evaluate the relationship between elevated direct-bilirubin levels and hypokalaemia, which is the most sensitive marker of pseudoaldosteronism. This retrospective cohort study was conducted in a Japanese university hospital. The occurrence of hypokalaemia is defined as a serum potassium level of ≤3.5 mEq/L after the administration of a glycyrrhizin-containing medication, and a further decline of ≥0.5 mEq/L or an increase of ≥0.5 mEq/L after discontinuing the glycyrrhizin-containing medication was examined in patients with chronic hepatitis between January 2009 and December 2015. This analysis involved 1392 patients, including 596 women. Hepatitis C virus infections were the most common cause of chronic hepatitis in this study. Seventy-nine patients received glycyrrhizin (exposed group; mean age: 60.5 ± 14.2) and 1313 did not receive glycyrrhizin (control group; mean age: 58.3 ± 15.8 years). Synergistic effects of glycyrrhizin-containing medications and elevated direct-bilirubin levels were associated with hypokalaemia. Elevated direct-bilirubin levels and hypoalbuminaemia were associated with hypokalaemia in the exposed group. Older age, female sex, high daily glycyrrhizin dosage, longer duration of glycyrrhizin intake, and potassium-lowering medications were not associated with hypokalaemia after the model adjustment. Elevated direct-bilirubin levels and hypoalbuminaemia may predict pseudoaldosteronism caused by glycyrrhizin.

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The use of maoto (Ma-Huang-Tang), a traditional Japanese Kampo medicine, to alleviate flu symptoms: A systematic review and meta-analysis

Yoshino T., Arita R., Horiba Y., Watanabe K.

BMC Complementary and Alternative Medicine （BMC Complementary and Alternative Medicine） 19 （ 1 ） 2019年03月

© 2019 The Author(s). Background: Influenza is a common viral infection worldwide. Maoto (ma-huang-tang) was developed in ancient China and is used to alleviate flu symptoms. Currently, no meta-analyses have evaluated the efficacy and safety of maoto for alleviating flu symptoms. Methods: In the present study, we searched MEDLINE/PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, a Japanese database (Ichushi), two Chinese databases (China National Knowledge Infrastructure and VIP), and two Korean databases (Korean Medical database and Korean Association of Medical Journal Editors) for studies published in or before October 2017. Clinical studies that compared maoto plus neuraminidase inhibitors (NAIs) vs. NAIs alone, or maoto alone vs. NAIs alone, were included in the present analysis. The primary outcome measure (efficacy) was the length of time from the start of medication to resolution of influenza symptoms (fever, headache, malaise, myalgia, and chills) and virus isolation. The secondary outcome measures (safety) were as follows: (1) side effects and adverse reactions, such as nausea, abnormal behaviour, or discontinuation of symptomatic treatment; (2) morbidity (complications caused by influenza infection) or mortality; and (3) hospitalisation for any reason. Results: Twelve relevant studies were identified, including two randomised controlled trials (RCTs, N = 60) and ten non-randomised studies (NRSs, N = 1110). We found that maoto plus NAIs was superior to NAIs alone in terms of the duration of fever in one RCT (P < 0.05, median difference = - 6 h) and four NRSs (P = 0.003, weighted mean difference = - 5.34 h). The duration of symptoms or virus isolation did not differ between maoto and NAIs. No severe side effects or adverse reactions were reported related to maoto or NAIs. Conclusions: Although we could not reach a definitive conclusion because of the small sample sizes and high risk of bias in the analysed studies, maoto may lower the duration of fever when it is used alone or in combination with NAIs and may be a well-tolerated treatment. More RCTs are needed to determine the efficacy and safety of maoto.

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Pseudoaldosteronism as an adverse effect of Glycyrrhiza intake: pathophysiology and detection of the causative metabolite

Yoshino, Tetsuhiro

2019年

Use of maoto (Ephedra Decoction) to Alleviate Flu Symptoms

Tetsuhiro Yoshino, Ryutaro Arita, Yuko Horiba and Watanabe, Kenji

2019年

Relationship Between the Frequency of Accompanying Symptoms and Traditional Medicine Pattern Diagnosis

Yoshino, Tetsuhiro

2019年

漢方処方の使い分けは弁証なしで統計学的に再現できるのか

吉野鉄大

日本中医学会雑誌 8 （ 1 ） 27 - 34 2018年

ISSN 2185-8713

Maoto, Traditional Kampo Formula, for Influenza: A Systematic Review and Meta-analysis

Yoshino, Tetsuhiro

2018年

胃切除術後難治性嘔吐を大逆上気ととらえて麦門冬湯を投与した1例

吉野鉄大, 清水芳政, 秋葉哲生, 渡辺賢治

日本東洋医学雑誌 65 （ 1 ） 45 - 48 2015年

Daisaikoto for menstrual pain: a lesson from a case with menstrual pain successfully treated with daisaikoto

Horiba, Y., Yoshino, T. and Watanabe, K.

Case Rep Med 2015 929514 2015年

ISSN 1687-9627

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

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月経困難症に対して頻用される当帰芍薬散と桂枝茯苓丸の使い分けを支援する統計的モデルの検証

吉野鉄大, 堀場裕子, 牧田和也, 片山琴絵, 宗形佳織, 山口類, 井元清哉, 宮野悟 and 渡辺賢治

産婦人科漢方研究のあゆみ 04 （ 32 ） 96 - 99 2015年

研究論文（研究会，シンポジウム資料等）, 査読有り

Risk Factors for Pseudoaldosteronism with Rhabdomyolysis Caused by Consumption of Drugs Containing Licorice and Differences Between Incidence of These Conditions in Japan and Other Countries: Case Report and Literature Review

Yoshino, T., Yanagawa, T. and Watanabe, K.

Journal of Alternaative and Complementaly Medicine 20 （ 6 ） 516 - 20 2014年03月

ISSN 1557-7708

Abstract Background: The pathogenesis of licorice-induced pseudoaldosteronism is thought to involve the inhibition of 11beta-hydroxysteroid dehydrogenase type 2 by glycyrrhetinic acid. Some risk factors have been reported, but differences between Japan and other countries have not been reported. Case Presentation: A 79-year-old woman was hospitalized because of pseudoaldosteronism with rhabdomyolysis caused by ingestion of herbal medicines containing licorice. She had been prescribed shakuyakukanzobushito (decocted, 3 g of licorice) and keishikajutsubuto (decocted, 2 g of licorice) for the treatment of lower back pain and had been taking antihypertensive agents for the treatment of essential hypertension. After taking the herbal medicines for 2 weeks, the patient developed weakness of the extremities and pain in both thighs. On admission, she had hypertension, oliguria, an elevated serum creatine kinase level, hypokalemia, alkalemia associated with metabolic alkalosis, low plasma renin activity, and low plasma aldosterone levels. Intravenous and oral potassium supplementation and the administration of spironolactone resulted in the normalization of her condition within approximately 2 weeks. Discussion: An analysis of case reports of pseudoaldosteronism with rhabdomyolysis revealed that in Japan, most cases occurred in elderly women with essential hypertension and were caused by drugs such as herbal medicines. In contrast, in other countries, many cases involved younger men, and the dominant causes were foods containing licorice. The use of herbal medicines is increasing all over the world, and when a patient with risk factors is prescribed an herbal medicine containing licorice, careful follow-up is required.

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当院漢方医学センター外来の月経困難症患者の特徴と頻用処方予測モデルの提案

吉野鉄大, 堀場裕子, 牧田和也, 片山琴絵, 宗形佳織, 山口, 類, 井元, 清哉, 宮野, 悟 and 渡辺, 賢治

産婦人科漢方研究のあゆみ 04 （ 31 ） 80 - 84 2014年

研究論文（研究会，シンポジウム資料等）

当院健康維持外来における慢性頭痛に対する呉茱萸湯の検討

堀場裕子, 吉野鉄大, 牧田和也, 横田, めぐみ, 岩田, 卓, 青木, 大輔 and 吉村, 泰典

産婦人科漢方研究のあゆみ 04 （ 31 ） 89 - 93 2014年

研究論文（研究会，シンポジウム資料等）

月経困難症に大柴胡湯単独で奏効した2例

堀場, 裕子, 吉野, 鉄大 and 渡辺, 賢治

日本東洋医学雑誌 65 （ 4 ） 298 - 301 2014年

ISSN 0287-4857

月経困難症の漢方治療では、駆お血剤が処方されることが多く、大柴胡湯が第一選択になることは少ない。今回、月経困難症に大柴胡湯単独で奏効した2例を報告する。症例1は19歳、大学入学後から月経痛が悪化し、市販の鎮痛剤が無効であり、頭痛や嘔吐のため講義に出席できないこともあった。腹力充実、腹部膨満、胸脇苦満、左右臍傍の圧痛を認め、実証、熱証、気うつ証・お血証とした。大柴胡湯エキス内服4週後には月経前の頭痛や嘔気が軽減し、20週後には月経痛に対する鎮痛剤が不要となった。症例2は35歳、息子の進学問題と転居を契機に月経痛や頭痛、いらいらが出現した。腹力やや充実、腹部膨満、胸脇苦満、心下痞硬、左右臍傍の圧痛を認め、実証、熱証、気うつ証・お血証とした。大柴胡湯エキス内服8週後には頭痛やイライラが消失し、20週後には月経痛は気にならなくなった。2例とも大柴胡湯にて「気うつ」が消失し、月経痛が改善した。(著者抄録)

Kampo Traditional Pattern Diagnosis and the Clustering Analysis of Patients with Cold Sensation

Yoshino, Tetsuhiro, Katayama, Kotoe, Munakata, Kaori, Horiba, Yuko, Yamaguchi, Rui, Imoto, Seiya, Miyano, Satoru and Watanabe, Kenji

（Mary Ann Liebert, Inc., publishers） 20 （ 5 ） A47 - A47 2014年

研究論文（国際会議プロシーディングス）, 査読有り

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Kampo Traditional Pattern Diagnosis and the Clustering Analysis of Patients with Insomnia

Yuko, Horiba, Tetsuhiro, Yoshino and Kenji, Watanabe

（Mary Ann Liebert, Inc., publishers） 20 （ 5 ） A47 - A47 2014年

研究論文（国際会議プロシーディングス）, 査読有り

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Kampo Extract of Shinbuto Improved Refractory Diarrhea in Milroy's Disease 汉方真武汤提取物 - 缓解米洛病引起的顽固性腹泻

Yuko Horiba, Tetsuhiro Yoshino and Kenji Watanabe

Global Advances in Health and Medicine 2 （ 1 ） 14 - 17 2013年02月

研究論文（学術雑誌）, 共著, 査読有り

慢性膵炎による膵外分泌機能不全に投与したパンクレリパーゼが有効と考えられた1例

吉野鉄大, 竹内哲, 新井潤, 鈴木考治, 陶経緯 and 鈴木英雄

消化と吸収 35 （ 3 ） 309 - 312 2013年

ISSN 0389-3626

パンクリレパーゼは日本初の高力価パンクレアチン製剤であり、膵外分泌機能不全に対して現段階で唯一適応を持つ薬剤である。症例は78歳男性。下痢、6ヵ月後より貧血、血圧低下によるふらつき、転倒が出現し、さらに全身の浮腫と胸腹水を認めるようになり、利尿薬が開始された。膵萎縮とびまん性の石灰化、BT-PABA試験で膵外分泌能の低下(6時間値33%)が確認されたため慢性膵炎による膵外分泌機能不全と診断された。成分栄養剤と既存の消化酵素配合剤では浮腫、低蛋白血症の改善は限定的であったが、高力価消化酵素剤であるパンクレリパーゼ1,800mg/日を投与したところ、4週間後には下痢、低蛋白血症、貧血、浮腫の改善を認め、利尿薬も漸減、終了することができた。耐糖能異常を含め明らかな副作用を認めなかった。現在もパンクレリパーゼの内服を継続しており、症状の再発を認めていない。(著者抄録)

続発性無月経に烏薬順気散が有効だった一例

吉野鉄大, 堀場裕子 and 渡辺賢治

日本東洋医学雑誌 64 （ 4 ） 227 - 230 2013年

ISSN 0287-4857

症例は37歳の女性。半年前のオステオパシー施術後からの無月経を主訴に当院漢方クリニックを受診した。首から腰にかけての背部痛、頸椎・肩・手・膝・足関節のクリック、筋肉のこわばりを伴ったが、日常生活は送れていた。発病前の月経周期には異常なく、産婦人科、整形外科では異常所見を認めなかった。中間証、寒証で疼痛に伴う気うつによる症状と捉え、烏薬順気散料去白姜蚕加附子(煎じ)を開始した。1ヵ月後に関節症状や冷えが軽快し、3ヵ月後に月経が再開した。烏薬順気散の原典にある婦人血風は、古典の記載から無月経と解釈しうる。漢方医学において、無月経に対する気うつの関与が指摘されてはいるが、一般的には血の症状と考えられ、補血薬や駆お血薬を用いることが多い。続発性無月経の病態には血の異常だけでなく、気の異常が密接に関係しており、気剤も治療の重要な選択肢となりうることが再確認された。(著者抄録)

経腟採卵後の下腹部痛・発熱・頻尿、尿失禁に漢方治療が奏効した一例

吉野鉄大, 堀場裕子, 水口雄貴, 佐藤卓, 末岡浩 and 渡辺賢治

日本東洋医学雑誌 64 （ 3 ） 173 - 176 2013年

ISSN 0287-4857

経腟採卵後の著明な膀胱血腫に対して血腫除去を行った後の、日単位での変化に対する随証治療で改善をみた急性疾患の1例を報告する。症例は44歳女性。朝、体外受精のために静脈麻酔下に経腟超音波下採卵を施行し昼過ぎに帰宅した。同日夕方に、右下腹部痛、血尿、頻尿、尿失禁、発熱、悪寒が出現したため救急外来を受診し、超音波で膀胱内に径45mm程度の血腫を認めたため入院となった。膀胱洗浄後に膀胱内持続還流、抗菌薬、止血薬を投与した。右下腹部痛は持続し、第5病日に発熱が再発した。浮脈、腹力中等度、右下腹部痛、頻尿、尿失禁、便秘傾向から大黄牡丹皮湯エキスを投与し、歯痕と入院時からの下腿浮腫を水毒とし五苓散料エキスを併用した。第6病日、右下腹部痛はほぼ消失、頻尿、尿失禁は軽減し、軟便になった。発熱時の発汗、脈浮虚、腹力虚より桂枝湯エキスに転方し、軽度の頻尿、尿失禁より猪苓湯エキスを併用すると汗が持続的に出て発熱を認めなくなり、頻尿、尿失禁も消失した。第7病日、全身状態良好となったため退院となった。(著者抄録)

Statistical analysis of hie (cold sensation) and hiesho (cold disorder) in kampo clinic

Yoshino, T., Katayama, K., Munakata, K., Horiba, Y., Yamaguchi, R., Imoto, S., Miyano, S. and Watanabe, K.

Evid Based Complement Alternat Med 2013 398458 2013年

ISSN 1741-427X

A cold sensation (hie) is common in Japanese women and is an important treatment target in Kampo medicine. Physicians diagnose patients as having hiesho (cold disorder) when hie disturbs their daily activity. However, differences between hie and hiesho in men and women are not well described. Hie can be of three types depending on body part where patients feel hie. We aimed to clarify the characteristics of patients with hie and hiesho by analyzing data from new patients seen at the Kampo Clinic at Keio University Hospital between 2008 and 2013. We collected information about patients' subjective symptoms and their severity using visual analogue scales. Of 4,016 new patients, 2,344 complained about hie and 524 of those were diagnosed with hiesho. Hie was most common in legs/feet and combined with hands or lower back, rather than the whole body. Almost 30% of patients with hie felt upper body heat symptoms like hot flushes. Cold sensation was stronger in hiesho than non-hiesho patients. Patients with hie had more complaints. Men with hiesho had the same distribution of hie and had symptoms similar to women. The results of our study may increase awareness of hiesho and help doctors treat hie and other symptoms.

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A Report of 2 Cases of Disseminated Invasive Aspergillosis with Myocarditis in Immunocompromised Patients

T. Yoshino, H. Nishida, T. Takita, M. Nemoto, M. Sakauchi, M. Hatano, K. Koyama, M. Hori and K. Obara

Open Journal of Pathology 3 （ 4 ） 166 - 169 2013年

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Prescription of kampo drugs in the Japanese health care insurance program

Katayama, K., Yoshino, T., Munakata, K., Yamaguchi, R., Imoto, S., Miyano, S. and Watanabe, K.

Evid Based Complement Alternat Med 2013 576973 2013年

ISSN 1741-427X

Kampo medicine or traditional Japanese medicine has been used under Japan's National Health Insurance scheme for 46 years. Recent research has shown that more than 80% of physicians use Kampo in daily practice. However, the use of Kampo from the patient perspective has received scant attention. To assess the current use of Kampo drugs in the National Health Insurance Program, we analysed a total of 67,113,579 health care claim records, which had been collected by Japan's Ministry of Health, Labour and Welfare in 2009. We found that Kampo drugs were prescribed for 1.34% of all patients. Among these, 92.2% simultaneously received biomedical drugs. Shakuyakukanzoto was the most frequently prescribed Kampo drug. The usage of frequently prescribed Kampo drugs differed between the youth and the elderly, males and females, and inpatients and outpatients. Kampo medicine has been employed in a wide variety of conditions, but the prescription rate was highest for disorders associated with pregnancy, childbirth, and the puerperium (4.08%). Although the adoption of Kampo medicine by physicians is large in a variety of diseases, the prescription rate of Kampo drugs is very limited.

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A case of hypoglycemic hemiparesis and literature review

Yoshino, T., Meguro, S., Soeda, Y., Itoh, A., Kawai, T. and Itoh, H.

Ups J Med Sci 2012年01月

ISSN 2000-1967

Abstract An 89-year-old man with diabetes treated with metformin 500 mg/day and glimepiride 4 mg/day was hospitalized because of hypoglycemic right hemiparesis and dysarthria (casual glucose value 1.8 mmol/L), which resolved quickly following administration of 40 mL of 40% dextrose. Hemiparesis is a rare symptom (4.2%) of hypoglycemia. There are about 200 case reports of hypoglycemic hemiparesis. The average glucose level at which hemiparesis developed was 1.8 mmol/L. Right-sided hemiparesis predominated (R 66%; L 34%). On imaging studies, abnormal findings were frequently observed in the internal capsule or splenium of the corpus callosum. The mechanism of hemiparesis is not fully understood. The existence of cases in which hypoglycemia cannot be distinguished from stroke on imaging studies suggests the importance of measurement of the blood glucose level when the symptoms of stroke are first recognized.

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フルルビプロフェンアキセチル脂肪乳剤の反復投与中に発症したMalassezia furfur真菌血症の1例

吉野鉄大, 鈴木考治, 竹内哲, 新井潤, 山口啓二, 大平雅之, 小山和幸 and 小原克之

日本内科学会雑誌 101 （ 11 ） 3226 - 3228 2012年

ISSN 0021-5384

20歳男。14歳時に潰瘍性大腸炎と診断され、PSL、メサラジンを内服中に脳静脈洞血栓症を発症した。潰瘍性大腸炎は悪化しインフリキシマブの導入、白血球除去療法を行いコントロールされていたが、カンジダ口内炎、帯状疱疹、肛門周囲膿瘍などの感染症を繰り返した。禁食継続の上、中心静脈カテーテルからの高カロリー輸液投与とした。肛門周囲膿瘍切開、排膿後の疼痛に対し、フルルビプロフェンアキセチル脂肪乳剤(FA)の頓用を継続したが、第135病日に表皮ブドウ球菌によるカテーテル関連血流感染症を発症した。バンコマイシン投与およびカテーテル交換を行ったが、第149病日に再び発熱を認め、カテーテル抜去したところ、翌日には解熱した。カテーテル逆血培養、抜去したカテーテルの先端のいずれからも酵母様真菌が検出されたため、カンジダ血症と暫定診断し、ミカファンギンを開始し、網膜症、肝膿瘍、脾膿瘍のないことを確認した。PCRの結果から、Malassezia furfurと同定され、同菌によるカテーテル関連血流感染症と診断した。食事開始でFAを中止し以後再発は認めていない。

Usage and attitudes of physicians in Japan concerning traditional Japanese medicine (kampo medicine): a descriptive evaluation of a representative questionnaire-based survey

Moschik, E. C., Mercado, C., Yoshino, T., Matsuura, K. and Watanabe, K.

Evid Based Complement Alternat Med 2012 139818 2012年

ISSN 1741-4288

Kampo medicine has been the primary medical model in Japan until the mid 1800s, regained a prominent role in today's Japanese medical system. Today, 148 herbal Kampo formulas can be prescribed under the national health insurance system, allowing physicians to integrate Kampo in their daily practice. This article aims to provide information about the extent to which Kampo is now used in clinics throughout Japan and about physician's current attitudes toward Kampo. We used the results of a 2008 survey that was administered to physicians throughout Japan (n = 684). The data showed that 83.5% of physicians currently use Kampo in the clinic, although the distribution of physicians who use Kampo differ widely depending on the specialty and provided a breakdown of Kampo usage by specialty. It will be interesting to see how each specialty incorporates Kampo into its respective field as Kampo continues to play a pertinent role in Japanese medical system.

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A patient with Graves' disease who survived despite developing thyroid storm and lactic acidosis

Yoshino, T., Kawano, D., Azuhata, T., Kuwana, T., Kogawa, R., Sakurai, A., Tanjoh, K. and Yanagawa, T.

Ups J Med Sci 2010年08月

ISSN 2000-1967

Abstract A 56-year-old woman with Graves' disease presented with the complaints of diarrhea and palpitations. Physical examination and laboratory data revealed hypothermia and signs of mild hyperthyroidism, heart failure, hepatic dysfunction with jaundice, hypoglycemia, and lactic acidosis. The patient was diagnosed as having developed the complication of thyroid storm in the absence of marked elevation of the thyroid hormone levels, because of the potential hepatic and cardiac dysfunctions caused by heavy alcohol drinking. A year later, after successful treatment, the patient remains well without any clinical evidence of heart failure or hepatic dysfunction. Thyroid storm associated with lactic acidosis and hypothermia is a serious condition and has rarely been reported. Prompt treatment is essential even if the serum thyroid hormone levels are not markedly elevated. We present a report about this patient, as her life could eventually be saved.

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巨大卵巣腫瘍にバセドウ病と著しい肺高血圧症を呈した1例

吉野鉄大, 野崎勲, 西川健一郎, 渡邉昌紀 and 柳川達生

内科 105 （ 2 ） 350 - 352 2010年02月

ISSN 0022-1961

極端な偏食により湿性脚気、大球性貧血、壊血病を呈した1症例

吉野鉄大, 中尾英一, 西川健一郎, 豊田丈夫 and 柳川達生

綜合臨床 58 （ 10 ） 2189 - 2191 2009年10月

ISSN 0371-1900

34歳男。生活は不規則で、この2年間はカップラーメンと卵ご飯しか食べていなかった。1ヵ月前より嘔気と四肢・体幹の痛み、下腹部のつっぱり感が出現し、その後両脚の浮腫が出現して体幹、左腕に拡大してきた。当院内科で低アルブミン・カリウム血症、大球性高色素性貧血を指摘され、翌週の再診時に浮腫の増悪と動悸が出現したため緊急入院となった。腱反射は上下肢とも消失し、CK上昇、葉酸とビタミンB12欠乏に伴う大球性高色素性貧血、BNP高値、便潜血陽性を認め、胸部X線では両側胸水とCTR拡大がみられた。湿性脚気と診断し、ビタミンB1を含む輸液に加え、ビタミンB1、葉酸、ビタミンB12を経口で補給し、利尿剤も併用した。浮腫と胸水は急速に改善したが、浮腫改善に伴って下腿に無痛性の点状紫斑が多発してきた。ビタミンC欠乏による壊血症の併発を考え、ビタミンC、カルバゾクロム、トラネキサム酸内服を開始した。第7病日には貧血の改善と胸水・浮腫の消失を認め、翌々日軽快退院した。

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