Efficacy of keishibukuryogan for hot flashes in prostate cancer patients receiving androgen deprivation therapy: a sub-analysis focusing on hormonal and cytokine levels.

Background: The current study attempted to elucidate the mechanisms of keishibukuryogan (TJ-25) efficacy by focusing on hormonal and cytokine levels. This is a sub-analysis of serum hormonal and cytokine levels extracted from the single-arm prospective study. Methods: Twenty-five participants were administrated TJ-25 at a dose of 2.5 g three times daily for 12 weeks, and competed for a diary of their hot flashes conditions. Various hormonal and cytokine values, including interleukin (IL)-8 and tumor necrosis factor-α (TNF-α), were measured at the baseline and 12-week visits. The correlation of hot flashes with hormonal and cytokine levels at baseline was investigated. As part of the responder analyses, all participants were divided into two groups based on the median baseline values of all hormones and cytokines at baseline, and the change amounts in strength and frequency of hot flashes from baseline to 12-week visits in both groups were compared. Furthermore, a correlation in change amounts (Δ values) by TJ-25 administration between hot flashes and each parameter was also conducted. Results: Hot flashes intensity was inversely related to estradiol levels (r=-0.433, P=0.019), and frequency was inversely related to progesterone levels (r=-0.415, P=0.025). In the responder analyses, the effectiveness of TJ-25 for hot flash strength increased in the patients with higher levels of TNF-α at baseline (P=0.0372). TJ-25 was more efficient in frequency in the patients with higher levels of IL-8 (P=0.0312). TJ-25 efficacy, on the other hand, was not significantly associated with changes in any hormonal or cytokine levels between the baseline and 12-week visits. However, ΔIL-8 and ΔTNF-α were not significantly correlated with Δstrength and Δfrequency of hot flashes by TJ-25 administration. Conclusions: Hot flashes were inversely correlated with estradiol and progesterone levels. TJ-25 was more effective in patients with higher TNF-α and IL-8 levels, with no significant change in serum levels caused by the treatment. The suggestive mechanism for the effects of keishibukuryogan is that this drug doesn't suppress the production of IL-8 and TNF-α, but may inhibit some actions of these cytokines.

Beneficial effect of Gyejibokryeong-hwan on climacteric syndrome with blood stasis pattern: A randomized, double-blinded, placebo-controlled clinical pilot trial.

Background: Gyejibokryeong-hwan (GBH), a herbal mixture that is widely used for climacteric syndrome, is studied for its efficacy; however, no study evaluated the GBH indication, which is a blood-stasis pattern based on traditional Chinese medicine theory. Methods: This is a randomized, double-blinded, placebo-controlled clinical pilot trial. Fifty subjects with climacteric syndrome were recruited and randomly assigned to GBH group or placebo group. Subjects were administered GBH or placebo granules for 4 weeks followed by 4 weeks of observation period. For the primary outcome, the Menopause Rating Scale (MRS) was evaluated. For the secondary outcomes, quality of life, degrees of abdominal resistance and tenderness, blood-stasis pattern questionnaire and degree of upward movement of Qi were evaluated. Results: After 4-week intervention, the mean change of total MRS score significantly decreased in the GBH group compared to the placebo group (p = 0.037). The quality of life related to physical health (p = 0.008) and blood-stasis pattern (p = 0.018) significantly improved in the GBH group but not in the placebo group. Conclusion: Our findings provide evidence of the feasibility of recruiting subjects with GBH indications and show that GBH may have clinical efficacy for the treatment of menopausal symptoms, especially urogenital symptoms, without any significant adverse events. Trial registration: Clinical Research Information Service (CRIS identifier: KCT0002170).

A Case of Laryngeal Venous Malformation Successfully Treated with Keishibukuryogan and Daiokanzoto / 日本東洋医学雑誌

Laryngeal venous malformation has a risk of airway obstruction due to its enlargement or bleeding. It requires treatment such as sclerotherapy, laser treatment or surgery. However, adult-type laryngeal venous malformation occurs frequently in the upper part of the glottis, and causes almost no symptoms except when it occurs in the vocal cords. So some patients do not wish to undergo surgery. This time, we describe a case of an asymptomatic laryngeal venous malformation patient who did not wish to receive laser treatment, and was significantly improved by Kampo medicine. The patient was a 69-year-old man. He consulted us because of an accidental laryngeal mass on upper gastrointestinal endoscopy during a medical examination, but he had no particular pharyngeal symptoms. A venous malformation was found in the upper part of the right glottis, and we recommended him laser treatment. But he did not wish it because he had no symptoms. We considered the condition of static blood (oketsu), and administered keishibukuryogan for 7 weeks, but there was no change. Since he had constipation, we administered daiokanzoto together with keishibukuryogan, and his bowel movement improved. Thirteen weeks after the beginning of the combined use, the venous malformation also remarkably reduced.

Japanese herbal Kampo medicine, Keishibukuryogan, for chronic subdural hematoma - Prospective observational study.

Background: Pharmacological treatment for chronic subdural hematoma (CSDH) recurrence prevention after surgery is under debate. CSDH may be related to suidoku (fluid disturbance) from the Japanese herbal kampo perspective. Goreisan (GRS) treats suidoku and is used to prevent a postoperative recurrence. However, not all CSDHs are liquid, and some have structures such as trabecula, hematoma, and clots, suggesting oketsu (blood stasis). Therefore, we prospectively investigated the keishibukuryogan (KBG) effectiveness, which treats oketsu, for CSDH recurrence prevention and hematoma resolution compared to GRS. Methods: We prospectively prescribed KBG 7.5 g/day for 12 CSDH patients after burr-hole surgery. As a control cohort, we retrospectively collected 48 patients treated by GRS 7.5 g/day. The recurrence within 1 month and the hematoma thickness after 1 month were evaluated. Results: The median age was 84 years old. All the patients' symptoms improved after surgery. The median preoperative midline shift and mean hematoma thicknesses were 6.0 mm and 23.75 mm. Those at 1 month were 2.0 mm and 11.43 mm. The recurrence rate was not significantly different between the KBG cohort (1 of 12) and the GRS cohort (4 of 48) (P = 0.999). The KBG's noninferiority to GRS regarding the hematoma thickness at 1 month was statistically proven; KBG (12.26 mm) and GRS (11.20 mm). Conclusion: The recurrence rate at 1 month was not different between the KBG and GRS cohorts. The hematoma thickness at 1 month in the KBG cohort was not statistically inferior to that in the GRS cohort.

Efficacy and safety of Gyejibokryeong-hwan (GBH) in major depressive disorder: study protocol for multicentre randomised controlled trial.

BACKGROUND: Gyejibokryeong-hwan (GBH) is an herbal medicine composed of five herbs. It has been widely used to treat gynaecological diseases in traditional East Asian medicine. Recent animal studies suggest antidepressant effects of GBH. In this trial, we explore the efficacy and safety of GBH in patients with major depressive disorder and to identify the optimal dose for the next phase III trial. METHODS: This trial will enrol 126 patients diagnosed with major depressive disorder and not treated with antidepressants. Participants will be randomised to receive a high or a low dose of GBH or placebo granules. The study drugs will be administered three times a day, for 8 weeks. The 17-item Hamilton Depression Rating Scale (HDRS) will be used to measure the severity of depressive symptoms at weeks 2, 4, 6, 8, and 12. The primary efficacy endpoint is the change from baseline in HDRS-17 total score post-treatment at week 8. Analysis of covariance will be based on the baseline HDRS-17 total score and site as the covariates. Safety assessment will be based on the frequency of adverse events. The severity and causality of the study drug will be assessed. DISCUSSION: This study is designed to evaluate the efficacy and safety of GBH granules compared with placebo in patients with major depressive disorder. TRIAL REGISTRATION: Clinical Research Information Service KCT0004417 . Registered on November 1, 2019 (prospective registration).

Effect of keishibukuryogan combined with tocopherol nicotinate on sperm parameters in patients with a varicocele.

OBJECTIVE: To evaluate the efficacy of keishibukuryogan, a traditional Kampo formula known to be an anti-Oketsu (impaired microcirculation and non-physiological blood congestion) drug, in combination with an anti-oxidant for the treatment of varicoceles. METHODS: We retrospectively analyzed 119 patients with palpable and subclinical varicoceles who were treated with 7.5 g/day of keishibukuryogan and 600 mg/day of tocopherol nicotinate. Their motile sperm concentrations at the start of medication and after 3 months were compared. As a subgroup analysis, a comparison test was carried out between patients with a high-grade varicocele and those with a low-grade varicocele. RESULTS: The mean age of the study patients was 35.6 years. Among them, 17, 41, 44 and 17 had subclinical, grade 1, grade 2 and grade 3 varicoceles, respectively. Overall, the differences in motile sperm concentration (millions/mL) before and after treatment were not significant (median 0.58, 95% confidence interval -0.12 to 1.56; P = 0.115). The results of the subgroup analysis showed that the motile sperm concentration in patients with a low-grade varicocele significantly increased (median 1.21, 95% confidence interval 0.45-2.47; P = 0.024); however, no significant improvements were seen in patients with a high-grade varicocele. CONCLUSIONS: The results of the present study showed that the combination of keishibukuryogan and an anti-oxidant had a limited effect on varicoceles, but they suggest that it is effective for the treatment of low-grade varicoceles.

A Case of Kampo Medicine Treatment for Acute Antebrachial Compartment Syndrome in the Arm Caused with Percutaneous Coronary Intervention Via Radial Artery / 日本東洋医学雑誌

After percutaneous coronary intervention (PCI), the patient developed symptoms of pain, sensory impairment, paralysis, pallor of the skin, and pain during passive extension, and was diagnosed with PCI-induced antebrachial compartment syndrome. Since it was considered to be blood stasis and water stasis in Oriental medicine, we administered jidabokuippo and keishibukuryogan to the patient. Then the subjective and objective symptoms improved promptly, and the symptoms disappeared by the 10th day after the operation. The patient was able to discontinue jidabokuippo 14 days after the operation. It was suggested that the symptomatic treatment with Kampo medicine is effective for compartment syndrome.

The Effective of Keishibukuryogan on Uterine Subinvolution after Childbirth: NRCT / 日本東洋医学雑誌

The uterus starts shrinking after giving birth and returns to its size prior to pregnancy one month postpartum. However, absence of this natural shrinking is called uterine subinvolution. There are two types of subinvolution : organic and functional. Removal of the cause is the first option for organic subinvolution. Conversely, most cases of functional subinvolution require drug treatment. This study included patients with subinvolution caused by accumulation of lochia with a uterine cavity width of 15 mm or more during a 14-day postpartum checkup. These patients were categorized into the control, keishibukuryogan, and ergometrine maleate groups ; therapeutic intervention was performed. A comparative study was conducted to determine the presence of subinvolution during the 1-month medical screening. There was no difference in the rate of uterine cavity shrinkage between the ergometrine maleate group and the control group. However, the keishibukuryogan group had a significantly higher reduction rate than the ergometrine maleate group. Furthermore, the keishibukuryogan group showed a tendency of higher shrinking rate when compared with the control group (76.1 ± 17.1% vs 65.8 ± 25.4%, 68.3 ± 22.9%, p = 0.0101, p = 0.0709). Additionally, no difference in the reduction rate of the fundal height was noted among the groups. These results suggest that although keishibukuryogan has little effect on reducing the uterine size, however, it has the effect of lochia accumulated within the uterine cavity.

Clinical and genetic characteristics of Keishi-Bukuryo-Gan syndrome: an analysis of 5 cases.

: To analyze the clinical and genetic characteristics of children with Keishi-Bukuryo-Gan (KBG) syndrome. The clinical and genetic data of 5 children with KBG syndrome admitted in Children's Hospital Affiliated of Zhengzhou University from November 2018 to September 2020 were retrospectively analyzed. Five children were all males who came from four different families. All children presented triangular face, bushy eyebrows, thin upper lip, large or delayed closure of anterior fontanel, and abnormal bone development. Four cases had growth retardation, large ears, thick ear lips; 3 cases had large central incisors; 2 cases had congenital heart disease; 2 cases had abnormal skin changes; 2 cases had genital changes; and 2 cases became grumpy. Liver and kidney function,thyroid function, blood gas analysis and electrolyte of the children were all in the normal range. Three children received bone age examination, and all showed bone age lag. Two cases showed backward myelination of white matter in MRI. Whole exome sequencing revealed that all 5 children had heterozygous mutations in the gene, among which c.6836_6837delTG, c.5866C>T, and c.6270delT were newly discovered mutation sites. None of the parents of probands were found to carry the mutations in gene. Two cases achieved height catch-up and cognitive improvement after treatment with recombinant human growth hormone. KBG syndrome is characterized by a wide spectrum of phenotypes, and large or delayed closure of the anterior fontanel, large ears and thick ear lips may be the main manifestations of the disease in infants and young children. gene mostly presents spontaneous mutations, and early application of growth hormone therapy can achieve height catch-up and cognitive improvement without obvious adverse reactions.

A Review on the Mechanism and Application of Keishibukuryogan.

The concept of "blood stasis" - called yu xie in Chinese, Oketsu in Japanese - is one of the unique pathophysiology of traditional medicine that originated in China and inherited in Korea and Japan. This concept is related to the multiple aspects of hemodynamic disorders brought on by quantitative and qualitative changes. It theorizes that the quantitative changes of "blood stasis" are related to peripheral circulatory insufficiency. When chronic qualitative changes of "blood stasis" produce stagnant blood that turns into a pathological product, it could cause inflammation and lead to organic changes. Trauma induced hematomas, that are considered to be a quantitative change of blood, are also a form of blood stasis. The basic medicine research on Keishibukuryogan (KBG)-a Japanese name in Traditional Japanese Medicine (Kampo) for one of the most common anti- "blood stasis" prescriptions, also known as gui-zhi-fu-ling-wan (GFW) in Chinese in Traditional Chinese Medicine (TCM)-indicated that the initiation of quantitative changes was closely related to loss of redox balances on endothelial function induced by oxidative stress. The following qualitative changes were related to coagulopathy, hyper viscosity; anti-platelet aggregation, lipid metabolism; a regulation of systemic leptin level and/or lipid metabolism, inflammatory factor; cyclooxygenase-1,2 (COX-1, 2), interleukin-6, 8 tumor necrosis factor-α, macrophage infiltration, hyperplasia, tissue fibrosis and sclerosis caused by transforming growth factor-ß1 and fibronectin, the dysfunction of regulated cell deaths, such as, apoptosis, autophagy, ferroptosis and ovarian hormone imbalance. Clinically, KBG was often used for diseases related to Obstetrics and Gynecology, Endocrine Metabolism, Rheumatology and Dermatology. In this review, we give an overview of the mechanism and its current clinical application of KBG through a summary of the basic and clinical research and discuss future perspective.

Effective Use of Keishibukuryogan in Subcutaneous Hematoma after Implantable Cardiac Device Surgery in Two Cases.

Keishibukuryogan is a Kampo medicine that induces vasodilation and improves the blood flow velocity in subcutaneous blood vessels. We herein report two cases in which keishibukuryogan completely diminished subcutaneous hematoma after cardiac resynchronization therapy pacemaker implantation and defibrillator battery replacement within a month. Keishibukuryogan can be a good option for treating or preventing subcutaneous hematoma after surgical procedures for devices.

A Case of Palmoplantar Pustulosis Successfully Treated with Kampo Medicine Switched Between Fundamental Treatment and Local and Symptomatic Treatment / 日本東洋医学雑誌

We experienced a case of palmoplantar pustulosis in which the patient's dermatological symptoms im­proved after treatment with a combination of bofutsushosan and keishibukuryogan. The patient was a 42-year-old woman. She had been prescribed biotin and a steroid ointment, but her condition did not improve. At her first visit to our Kampo clinic, we observed impetigo, cracks, and scaling on both palms and plantar surfaces. We determined that the patient was of the poisoned organ (zodoku) and stagnant blood (oketsu) constitutions,as outlined in the Ikkando school of medical thought. We prescribed bofutsushosan and keishibukuryogan as fundamental treatment and then in a few days, the patient's dermatological symptoms resolved. The patient later developed hyperthyroidism, which caused her symptoms to worsen again, we therefore switched to shofusan and eppikajutsuto as local and symptomatic treatment, and then she once again improved. Soon after, we returned to keishibukuryogan and bofutsusho for her to maintain remission. Since poisoned organ and stagnant blood constitutions contribute greatly to the Kampo pathology of palmoplantar pustulosis, we believe bofutsushosan and keishibukuryogan are effective formulations for the treatment of this condition. As far as we searched, there were no papers that selected bofutsushosan or blood stasis agents as the main cure from the viewpoint of the poisoned organ constitution and the stagnant blood constitution. Therefore, this case was considered to be a valuable case.

Prolapsed tongue papilloma cured by administration of the traditional Japanese (Kampo) herbal medicine, Keishibukuryogan-ka-yokuinin: A case report.

Squamous papilloma is a benign mass lesion of the oral mucosa. For papillomas of the tongue, surgery is recommended owing to their malignant potential; however, certain complications may be associated with surgery. A traditional Japanese (Kampo) herbal medicine, Keishibukuryogan-ka-yokuinin (KBGY), has been used to treat viral warts and various skin diseases in Japan. Therefore, the effect of KBGY on papillomas is promising. A 49-year-old Japanese man presented with a wart on his tongue that was about 3 months old. He smoked 5 cigarettes per day. He did not drink alcohol. He had no history of malignant illnesses. He was taking alprazolam for panic disorder. The patient was diagnosed with a suspected papilloma of the tongue at the Department of Otolaryngology and was advised to undergo an excision biopsy to exclude malignancy. However, he refused owing to the fear of an invasive procedure. After informed consent was obtained from the patient, KBGY was prescribed. Three months later, the wart on his tongue spontaneously prolapsed. The histopathological diagnosis was squamous papilloma. There was no indication of malignancy, and the patient discontinued Kampo treatment. He has had no recurrence in the past 3 years. KBGY is a combination of Keishibukuryogan and yokuinin (adlay seeds). Keishibukuryogan may be beneficial for skin or oral mucosal remodeling, and yokuinin may have antiviral properties. The present case report suggests the use of KBGY as an appropriate complementary therapy for squamous papilloma.

Effectiveness of Gyejibongnyeong-Hwan for shoulder pain: study protocol for a randomised, wait-list controlled pilot trial.

BACKGROUND: Shoulder pain is an uncomfortable feeling in the muscle around the shoulder. The cause of myalgia is the accumulation of lactic acid in muscles and impaired blood circulation, which is called blood stasis in traditional East Asian medicine. This study aimed to explore the therapeutic effect of Gyejibongnyeong-Hwan (GBH) for shoulder discomfort related to blood stasis before and after treatment. METHODS/DESIGN: This study will be a double-centre, randomised, wait-list controlled pilot trial. Participants with shoulder pain and with a visual analogue scale score of 4 or higher out of 10, blood stasis score of 9 or higher, and triglyceride level of ≥150 mg/dl or total cholesterol level of ≥200 mg/dl will be recruited from two university hospitals. A total of 40 participants will be assigned to the immediate and waiting treatment groups. The immediate treatment group will receive GBH for 8 weeks on enrolment while the waiting treatment group will receive GBH for 8-16 weeks after 8 weeks of controlled waiting. The primary outcome is shoulder pain, and the secondary outcomes are the blood stasis score, blood pressure, ankle-brachial pressure index, brachial-ankle pulse wave velocity, body mass index, waist circumference, indexes of oximetry, and levels of blood lipid, blood sugar, resistin, C-reactive protein, serum amyloid P, and D-dimer. DISCUSSION: The results of this pilot trial will be the bases for a full-scale clinical trial of GBH. TRIAL REGISTRATION: Clinical Research Information Service, KCT0003837. Registered on 23 April 2019. https://cris.nih.go.kr/cris/en/search/search_result_st01.jsp?seq=14258.

Efficacy and safety of keishibukuryogan, a traditional Japanese Kampo medicine, for hot flashes in prostate cancer patients receiving androgen deprivation therapy.

BACKGROUND: The efficacy and safety of keishibukuryogan, a traditional Japanese medicine, were investigated for the treatment of hot flashes in prostate cancer (PC) patients receiving androgen deprivation therapy. METHODS: Thirty patients were enrolled and orally administered 2.5 g keishibukuryogan three times daily for 12 weeks. The frequency, strength, and duration of hot flashes were self-evaluated by the patients in a diary every 4 weeks. All patients also completed a questionnaire to determine their aging male symptoms (AMS) scale score and underwent blood biochemical testing. RESULTS: Twenty-five patients completed the 12-week treatment. Hot flash strength significantly improved 4, 8, and 12 weeks after treatment. Their frequency was significantly reduced at the 8-week visit, and duration was significantly shorter after the 8-week visit. In addition, the score of the AMS somatic subscale was improved at the 8- and 12-week visits. Among the somatic items, questions 3 (excessive sweating) and 5 (increased need for sleep) were significantly improved. Obesity, radiation, and a longer duration of PC were predictive factors for treatment response. Prostate specific antigen and total testosterone levels were unchanged, and no patients had severe adverse effects. CONCLUSIONS: Keishibukuryogan was an effective and safe treatment for hot flashes in PC patients.

Prolapsed tongue papilloma cured by administration of the traditional Japanese (Kampo) herbal medicine, Keishibukuryogan-ka-yokuinin: A case report / 中西医结合学报

Squamous papilloma is a benign mass lesion of the oral mucosa. For papillomas of the tongue, surgery is recommended owing to their malignant potential; however, certain complications may be associated with surgery. A traditional Japanese (Kampo) herbal medicine, Keishibukuryogan-ka-yokuinin (KBGY), has been used to treat viral warts and various skin diseases in Japan. Therefore, the effect of KBGY on papillomas is promising. A 49-year-old Japanese man presented with a wart on his tongue that was about 3 months old. He smoked 5 cigarettes per day. He did not drink alcohol. He had no history of malignant illnesses. He was taking alprazolam for panic disorder. The patient was diagnosed with a suspected papilloma of the tongue at the Department of Otolaryngology and was advised to undergo an excision biopsy to exclude malignancy. However, he refused owing to the fear of an invasive procedure. After informed consent was obtained from the patient, KBGY was prescribed. Three months later, the wart on his tongue spontaneously prolapsed. The histopathological diagnosis was squamous papilloma. There was no indication of malignancy, and the patient discontinued Kampo treatment. He has had no recurrence in the past 3 years. KBGY is a combination of Keishibukuryogan and yokuinin (adlay seeds). Keishibukuryogan may be beneficial for skin or oral mucosal remodeling, and yokuinin may have antiviral properties. The present case report suggests the use of KBGY as an appropriate complementary therapy for squamous papilloma.

Evaluation of Various Anti-oketsu Kampo Formulae—Tokakujokito,Keishibukuryogan and Tokishakuyakusan—for Microcirculation by Live Imaging / 日本東洋医学雑誌

Oketsu is a characteristic pathophysiology in Kampo and traditional East Asian medicine that includes mul­tiple aspects of hemodynamic disorder. Anti­-oketsu drugs or the Kampo formulation used for oketsu show sig­nificant clinical effects on various disorders; however, their underlying mechanisms still remain unclear. We aimed to clarify the characteristics of the pharmacological effects of anti-­oketsu drugs on the microcirculation using a microscopic live imaging technique. Three Kampo formulations, namely tokakujokito, keishibukuryo­gan, and tokishakuyakusan were orally administrated to C57BL/6 mice at a dose of 300 mg/kg diluted in dis­tilled water. Live imaging was performed on the subcutaneous vessels of the mice, including the arteries (di­ameter > 50 μm), arterioles (diameter 10-50 μm) and capillaries (diameter < 10 μm). Tokakujokito widely increased erythrocyte flow velocity and blood flow volume from arteries to capillaries within 60 min of ad­ministration. The effects of keishibukuryogan on the vasodilation of the arterioles were remarkable, and con­tinued up to 120 min after administration. The pharmacological target of tokishakuyakusan was the capillaries, increasing their erythrocyte velocity and blood flow volume;its effect was more slowly expressed than those of the other formulations. Our results clearly demonstrate the sequential and special effects of anti-­oketsu drugs on hemodynamics. These differences may provide pharmacological information on the clinical usage of traditional Kampo formulations.

Ten Patients with General Fatigue Associated with Blood Stagnation Successfully Treated with Kampo Formulae, Keishibukuryogan and/or Tokakujokito / 日本東洋医学雑誌

In Kampo medicine, general fatigue is categorized as a symptom caused by qi deficiency according to the qi-blood-­water criteria. However, in some patients with general fatigue, formulae for qi deficiency are not ef­fective, and this might be because their chronic symptoms are associated with blood stagnation. Recently, we encountered ten patients (M/F 1/9, mean age 46 years, range 23-55 years) with general fatigue that was im­proved by agents for treating blood stagnation, such as keishibukuryogan and/or tokakujokito. These patients, who were mostly of medium build, complained of neck or shoulder stiffness (9/10), consti­pation (5/10), and blushing or hot flushes (5/10). They had no problem with appetite, except that 5 patients tended to overeat. Remarkable sublingual collateral vessels (8/10), paraumbilical tenderness (9/10) and periorbital dark circles (5/10) were observed on physical examination. The tongue and abdominal signs improved or had disappeared after treatment for 3 to 8 months. Our results suggest that patients with general fatigue, but who present with symptoms associated with blood stagnation, could be treated with drugs for blood stagnation such as keishibukuryogan and/or tokakujokito.

Current state of yusho and prospects for therapeutic strategies.

The mass food poisoning incident yusho occurred in Japan in 1968. It was caused by the ingestion of rice bran oil contaminated with polychlorinated biphenyls and various dioxins and dioxin-like compounds including polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDFs). Notably, PCDFs were found to contribute to approximately 65% of the total toxicity equivalent in the blood of yusho patients. Lipophilic dioxins are retained in the body for a longer period than previously estimated. Victims suffered from characteristic skin manifestations associated with non-specific systemic symptoms, neurological symptoms, and respiratory symptoms. The severe symptoms seen in the initial phase subsequently faded, but recently, improvements have scarcely been observed. The Yusho Group has been researching treatments for this condition. Several clinical trials with chelating agents or dietary fibers aimed at accelerating the excretion of compounds. While some treatments increased dioxin excretion, none provided satisfactory symptom relief. Concurrently, various phytochemicals and herbal extracts have been found to possess biological activities that suppress dioxin-induced toxicity via aryl hydrocarbon receptor or activate the antioxidant nuclear factor-erythroid 2-related factor-2 (NRF2) signal pathway, making them promising therapeutic candidates. Here, we summarize the current status of yusho and findings of clinical trials for yusho patients and discuss the treatment prospects.