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Aim: To evaluate the effectiveness of yokukansan, a traditional Japanese medicine, as treatment for nocturia due to sleep disorders. Methods: In this study, we included patients diagnosed with nocturia due to sleep disorders, evaluated using the Pittsburgh Sleep Quality Index (PSQI). Participants received 2.5 g of yokukansan, three times daily, for 12 weeks. We evaluated the changes in the overactive bladder (OAB) symptom score (OABSS), hours of undisturbed sleep (HUS), and PSQI score. In addition, patients were categorized based on the severity of their sleep disorders, and we divided patients into two groups according to whether the severity of the disorder was downgraded after treatment: the improved and unchanged groups. Results: Among 35 patients with a mean ± standard deviation age of 73.2 ± 10.5 years, yokukansan administration was associated with significant improvements in nighttime urinary frequency (from 3.8 ± 2.1 to 2.1 ± 1.9), total OABSS score (from 4.9 ± 1.8 to 2.9 ± 1.9), OABSS urgency score (from 1.3 ± 1.0 to 0.7 ± 0.9), HUS (from 2.2 ± 0.6 to 3.5 ± 1.1 h), and global PSQI score (from 11.9 ± 3.1 to 10.0 ± 1.4; all p < 0.001). In addition, significant improvements were noted in both the improved and unchanged groups in terms of the total OABSS, nocturia, and urgency scores. Furthermore, yokukansan treatment was related to improved global PSQI scores in both groups (improved group: from 10.8 ± 0.7 to 8.6 ± 0.5, p = 0.001; unchanged group: from 12.3 ± 3.4 to 10.4 ± 1.3, p = 0.004). Conclusion: Yokukansan may effectively ameliorate nocturia due to sleep disorders. [ABSTRACT FROM AUTHOR]

Objectives: Managing perioperative anxiety improves postoperative recovery significantly by reducing postoperative pain. However, little is known about association between preoperative anxiety and postoperative pain in oral surgical procedures. In the present study, we examined the effect between preoperative anxiety and postoperative pain in mandibular third molar extraction and the anxiolytic effect of Yokukansan (YKS) during the perioperative period. Materials and methods: We conducted a prospective cohort study from September 2021 to May 2022. For patients with a complaint of insomnia on the day before surgery, 2.5 g per package of YKS was administered before sleep on the day before surgery. Twelve patients were administered YKS, and 23 patients were not (non‐YKS). Results: Perioperative anxiety was assessed by the Hospital Anxiety and Depression Scale (HADS) and amylase in saliva, and perioperative pain was assessed by the Numerical Rating Scale (NRS) and the total number of times pain medication. There were no significant differences in HADS and amylase in saliva between the YKS and non‐YKS. The median postoperative NRS was 5 for YKS and 7 for non‐YKS. The maximum use of pain medication was 16 in YKS and 24 in non‐YKS. Although no significant difference was observed in the anxiolytic effects and the improvement of postoperative pain during the perioperative period of mandibular third molar extraction between patients who took YKS and those who did not, NRS and the maximum use of pain medication were less in the YKS patients. Conclusions: Therefore, YKS may be useful for managing postoperative pain through the preoperative anxiolytic effect in oral surgical procedures. [ABSTRACT FROM AUTHOR]

Background: The source of yokukansan (YKS) is thought to be Baoying‐Jinjiang (Hoeikinkyōroku in Japanese) by Xue Ji. YKS was originally designed for children and indicated for spasms, clenching of teeth, digestive dysfunction due to mental instability, and insomnia. Key Findings: YKS formula consists of seven types of crude drugs. Clinical studies have revealed that YKS exerts physiological effects including the treatment of behavioral and psychiatric symptoms of dementia (BPSD), preoperative sedation and anxiety, and postoperative delirium. A meta‐analysis showed that YKS could improve BPSD and daily living activities; however, no improvement in cognitive function was observed. Preclinical studies have also reported that YKS modulates neuronal pathways in the central nervous system, including the serotonergic, glutamatergic, GABAergic, and other neurotransmitter pathways. The incidence of adverse events associated with YKS was 5.17%, with the major adverse effect being pseudoaldosteronism. Routine blood sampling is considered for hypokalemia prevention. Conclusion: YKS is useful for BPSD and perioperative mental instability. The modulation of the serotonergic and glutamatergic neural pathways is one of mechanisms. Pseudoaldosteronism is one of the side effects. [ABSTRACT FROM AUTHOR]

Objective: To clarify the fetal safety of herbal Kampo medicines, including Hange‐koboku‐to, Koso‐san, Nyoshin‐san, Yokukansan, Yokukansan‐kachinpi‐hange, Saiko‐keishikankyo‐to, Keishi‐karyukotu‐borei‐to, and Kanbaku‐taisou‐to, when administered to pregnant women with depression using a large healthcare administrative database. Methods: We extracted data from the JMDC Claims Database (2005–2018) for this retrospective cohort study of pregnant women aged 19 years or older admitted to obstetric clinics or hospitals for delivery. Participants were classified into four groups: those without depression, those diagnosed with depression without medication, those given Kampo medicines for depression, and those given western medicines for depression. Neonatal outcomes (congenital anomalies, low birth weight, and preterm birth) were considered as the safety outcome measures. Results: We identified 179 707 eligible mothers. The adverse outcomes did not differ significantly between participants receiving Kampo medicine and those not diagnosed with depression during pregnancy. The proportion of low‐birth‐weight neonates did not differ significantly between the Kampo medicine and non‐depression groups (adjusted odds ratio [aOR] 1.28; 95% confidence interval [CI] 0.86–1.91), but was significantly higher in the unmedicated depression group (aOR 1.31; 95% CI 1.07–1.61) and western medicine group (aOR 1.47; 95% CI 1.18–1.83). Conclusion: Kampo medicines are safe for treating depression during pregnancy without increasing the incidence of congenital anomalies, low birth weight, or preterm birth. [ABSTRACT FROM AUTHOR]

Aim: Rapid eye movement sleep behaviour disorder (RBD) is characterized by abnormal behaviours accordant with nightmares during rapid eye movement sleep and is considered a prodromal marker of dementia with Lewy body. Most common in the elderly population, RBD is generally treated with clonazepam (CZP), a long‐term acting benzodiazepine antiepileptic. As such, alternative drugs for RBD are urgently needed to minimize the adverse effects peculiar to benzodiazepines. The efficacy of yokukansan (YKS), a traditional Japanese herbal medicine, on RBD was initially reported by Shinno et al. in 2008. However, no study has compared YKS with CZP. Therefore, this study aimed to clarify the possibility of using YKS as an alternative to CZP. Methods: This was a retrospective cohort study conducted at Jikei University Affiliated Hospital. The subjects were selected from 36 outpatients who had been diagnosed with RBD based on the International Classification of Sleep Disorders, third edition. Of the 23 who met the inclusion criteria but not the exclusion criteria, 11 were treated with YKS monotherapy, and 12 were treated with CZP monotherapy. The primary outcome was the total score on the Japanese version of the Rapid Eye Movement Sleep Behaviour Disorder Questionnaire (RBDQ‐JP), and the secondary outcomes were the scores from the eight‐item Short‐Form Health Survey and factors 1 and 2 of the RBDQ‐JP. Results: The mean total RBDQ‐JP score significantly improved from 52.5 to 21.7 (P = 0.002) after treatment with YKS (mean dosage: 3.0 g/day), which was similar to the change after CZP treatment (from 43.8 to 21.3). On RBDQ‐JP factor 1 (dream content), the mean score on five of six items significantly improved after treatment with YKS. There was no significant change in Short‐Form Health Survey scores after treatment with either drug. Potassium concentrations were within the normal range in patients treated with YKS. Conclusions: The present results suggest that a small amount of YKS may be an alternative to CZP for RBD, without remarkable adverse events. Further study is needed to prospectively clarify the efficacy and safety of YKS in more detail. [ABSTRACT FROM AUTHOR]

Background: Cognitive dysfunction is often accompanied by behavioral and psychological symptoms of dementia (BPSD) in patients with Alzheimer's disease and other forms of senile dementia. BPSD include agitation, aggression, and hallucinations. BPSD have a serious effect on the quality of life of dementia patients and their caregivers, but effective drug therapy for BPSD has not been identified as yet. Typical and atypical antipsychotics that are used for the treatment of BPSD are known to cause a variety of extrapyramidal adverse events. Yokukansan (YKS, Yi‐gan san in Chinese) is a Japanese traditional herbal (kampo) medicine that is used to alleviate night‐crying and irritation in children, as well as to treat neurosis and insomnia. It is currently also used to treat BPSD. Methods: In this review, we summarize the pharmacological effects of YKS in the context of BPSD. Conclusion: YKS is expected to be useful in treating and/or preventing BPSD. [ABSTRACT FROM AUTHOR]

ABSTRACT: Aim: The effectiveness of traditional Japanese herbal medicine (kampo) is gradually attracting worldwide attention. Although yokukansan has been shown to be clinically effective in suppressing maternal post‐partum depression, the safety of maternal yokukansan treatment in newborn infants has not been fully established. Methods: Herein we examined the effect of maternal yokukansan treatment on neuronal circuit formation using somatosensory maps in the cerebral cortex of the newborn mouse brain. Results: Somatosensory maps in newborn mouse pups were formed normally at postnatal day (P)5, even though yokukansan was given to lactating mouse dams. Paroxetine injected into pups strongly inhibited somatosensory map formation in mouse pups at P5, whereas paroxetine injected into lactating dams did not inhibit somatosensory map formation in pups. Yokukansan also did not affect the timing of somatosensory map formation in mouse pups at P3 and P4. Conclusion: Maternal yokukansan treatment does not have apparent adverse effects on somatosensory map formation in the brain of mouse pups. [ABSTRACT FROM AUTHOR]

Aim Yokukansan ( YKS), a traditional herbal medicine, has been used to treat behavioral and psychological symptoms of dementia ( BPSD). The present study is the first double-blind, randomized, placebo-controlled trial to determine the efficacy and safety of YKS for the treatment of BPSD in Alzheimer's disease ( AD). Methods A total of 22 sites consisting of clinics, hospitals and nursing homes participated. A total of 145 patients with AD were randomized. Active YKS (7.5 g/day) and placebo were supplied to 75 and 70 participants, respectively. The primary outcome measure was the 4-week change in total score of the Neuropsychiatric Inventory Brief Questionnaire Form ( NPI-Q), an instrument that evaluates BPSD. Secondary outcome measures included 12-week changes in NPI-Q scores, changes in NPI-Q subcategory scores and total scores of the Mini-Mental-State Examination. Results Four-week changes in NPI- Q total scores did not differ significantly between the treatment and placebo groups. There were also no significant differences between groups in 12-week changes in total NPI- Q scores, NPI- Q subcategory scores or total Mini-Mental-State Examination scores. However, a subgroup with fewer than 20 points on the Mini-Mental-State Examination at baseline showed a greater decrease in 'agitation/aggression' score in the YKS group than in the placebo group ( P = 0.007). No serious adverse effects were observed during the study. Conclusions Our data did not reach statistical significance regarding the efficacy of YKS against BPSD; however, YKS improves some symptoms including 'agitation/aggression' and 'hallucinations' with low frequencies of adverse events. Geriatr Gerontol Int 2017; 17: 211-218 [ABSTRACT FROM AUTHOR]

Background: Medication‐overuse headache (MOH) is one of the most common chronic headache disorders and represents a public health problem. Aim: As we have encountered cases of MOH treated effectively using yokukansan, we planned to analyze the effects of yokukansan on MOH in patients with migraine. Methods: To analyze the effects of yokukansan on MOH in patients with migraine, we planned the study using a double‐blind, randomized, and placebo‐controlled trial. Results: We started to register patients from October 2015, enrolling eight patients in 2015, 35 patients in 2016, 19 patients in 2017, and nine patients as of the time of writing in 2018. We have now collected 71 cases, but recruitment to the trial has not been completed. We need to register more cases to reach the desired number of 80. Conclusion: This article presents the protocol for a double‐blind, randomized, and placebo‐controlled trial to collect evidence of the effects of yokukansan on MOH. The final objective of this study is to reduce headache in MOH while maintaining patient quality of life in good condition. [ABSTRACT FROM AUTHOR]

ABSTRACT Behavioral and psychological symptoms of dementia ( BPSD) occur in approximately 80-90% of patients with dementia. Although antipsychotics are used to treat BPSD, patients often suffer from parkinsonism and impaired activities of daily living ( ADL). In addition, an increased mortality rate has been reported in patients with dementia taking antipsychotics. Thus, Kampo therapy is one alternative to antipsychotic medicines. Yokukansan has been reported to be effective for treatment of agitation/aggression, and irritability/lability in patients with Alzheimer's disease ( AD), dementia with Lewy bodies ( DLB), vascular dementia ( VD), and frontotemporal dementia. In addition, yokukansan is effective for treatment of visual hallucinations in DLB patients. Because DLB patients have hypersensitivity to antipsychotics, and often have severe adverse reactions to these drugs, the beneficial effects and tolerability of yokukansan for DLB patients are particularly significant. Orengedokuto has been reported to be effective for treating irritability and sullenness in patients with VD, and to improve excitement, depression, anxiety, and restlessness in patients with cerebrovascular lesions. Chotosan has been found to be effective for treatment of delirium, insomnia, hallucination, and delusion in patients with VD. Tokishakuyakusan has been reported to improve emotional lability, restlessness, and sleep disturbances in patients with AD and VD. Kampo therapy does not induce extrapyramidal symptoms and anticholinergic symptoms, and has no adverse effects on ADL and cognitive function. In addition, Kampo therapy has been reported to have various neuroprotective effects. Thus, Kampo therapy is safe and promising for patients with BPSD, and should be further utilized for treatment of BPSD. [ABSTRACT FROM AUTHOR]

ABSTRACT Aim Symptoms of dementia are classified into cognitive dysfunction and behavioral and psychological symptoms of dementia, including sleep disturbance. Yokukansan ( YKS) is effective for sleep disturbance in patients with dementia, but the mechanisms are still unclear. In this study, we evaluated sleep disturbance in rats with cerebral ischemia. We investigated the effect of YKS on sleep disturbance in cerebral ischemia-treated rats. Methods Cerebral ischemia was induced by twice occluding both of the common carotid arteries. Wakefulness, non-rapid eye movement ( NREM) sleep, and rapid eye movement ( REM) sleep were classified using electroencephalography and electromyography. mRNA expression of sleep-wakefulness signals were quantified using reverse transcription-polymerase chain reaction. Results Rats with cerebral ischemia had a higher total wakefulness time and lower total NREM sleep time during the light phase. These changes were ameliorated with 1000 mg/kg YKS for 14 days, but not 3 mg/kg donepezil for 7 days. mRNA expression of the prefrontal cortical prostaglandin ( PG) E2 ( EP4) receptor and of the PGD2 ( DP) receptor was increased by cerebral ischemia. Elevated prefrontal cortical EP4 and DP receptor mRNA expression was reduced by YKS treatment. Conclusion Rats with cerebral ischemia had NREM sleep disturbance. YKS might reduce this sleep disturbance by preventing neuroinflammation, and this was mediated by the EP4 and DP receptors in the prefrontal cortex. [ABSTRACT FROM AUTHOR]

We previously reported that the addition of orally administered yokukansan ( YKS), a traditional Japanese herbal medicine, to the standard regimen using histamine H1-receptor inhibitors was effective in controlling refractory chronic urticaria, but the mechanism remained unknown. YKS has also been reported to be effective on inhibiting the development of atopic dermatitis-like skin lesions in NC/Nga mice. As known, the release of various chemical mediators including histamine from degranulated mast cells is strongly related to the mechanism of these diseases. Thus the purpose of this study was to examine the mechanisms behind the medicinal effects of YKS on mast cells using an in vitro system and rat basophil leukemia ( RBL-2H3) cells. The degree of degranulation was measured by β-hexosaminidase secretion assay and intracellular calcium influx assay. ELISA for cytokines ( TNF-α and IL-4) was also conducted using cell culture media. Furthermore, we investigated the effects of YKS on the expression of adhesion molecules ( ICAM-1, VCAM-1, E-selectin) and cytokine production ( IL-8) in human dermal microvascular endothelial cells using gene-transcriptional- and immunohisotoligical analysis. We found that YKS inhibited secretion of β-hexosaminidase, intracellular calcium increase, production of TNF-α and ICAM-1 expression, and that several YKS ingredients may be the key effectors. In conclusion, YKS may suppress several mast cell functions such as degranulation and calcium increase that eventually inhibits the release of proinflammatory cytokines. Furthermore, YKS suppresses ICAM-1 expression on human microvascular endothelial cells. These findings may promote our understanding of the beneficial effects of YKS on mast cell-associated allergic diseases. [ABSTRACT FROM AUTHOR]

Background The major pathogenic factors involved in nocturnal enuresis are nocturnal polyuria, small bladder capacity and/or detrusor overactivity, and a high arousal threshold. Desmopressin is the first-line therapy for the patients with diuresis-dependent nocturnal enuresis. Yokukansan, a traditional Japanese medicine, has been used in Japan to treat patients with nervousness, insomnia, and children with night terrors and temper tantrums. We experienced the positive effect of Yokukansan in some of the patients who did not respond well to desmopressin therapy. Methods In total, 32 children with monosymptomatic nocturnal enuresis with nocturnal polyuria were treated with oral desmopressin melt tablets, which were approved for clinical use in Japan on 29 May 2012. This treatment was effective for 14 of them. For the rest ( n = 18), Yokukansan was introduced in combination with desmopressin. Results Yokukansan was effective for 12 out of the 18 cases. Conclusions: Yokukansan should be a candidate for the medication of nocturnal enuresis. [ABSTRACT FROM AUTHOR]

ABSTRACT Uncaria Hook (UH) alkaloids are involved in the beneficial effects of Yokukansan. However, the pharmacokinetics of UH alkaloids after oral administration of Yokukansan has not yet been sufficiently investigated. Therefore, we developed and validated a sensitive and specific high-performance liquid chromatography with tandem mass spectrometry (LC/MS/MS) method for the simultaneous quantitation of seven UH alkaloids (corynoxeine, isocorynoxeine, rhynchophylline, isorhynchophylline, hirsutine, hirsuteine and geissoschizine methyl ether) in rat plasma and brain. After protein precipitation with acetonitrile, chromatographic separation was performed using an Ascentis Express RP-amide column, with gradient elution with 0.2% formic acid and acetonitrile at 0.3 mL/min. All analytes in the plasma and brain showed good linearity over a wide concentration range ( r > 0.995). Intra-day and inter-day variations of each constituent were 8.6 and 8.0% or less in the plasma, and 14.9 and 15.0% or less in the brain, respectively. The validated LC/MS/MS method was applied in the pharmacokinetic studies of UH alkaloids after oral administration of Yokukansan to rats. In the plasma, rhynchophylline, hirsutine, hirsuteine and geissoschizine methyl ether were detected, but only geissoschizine methyl ether was detected in the brain. These results suggest that geissoschizine methyl ether is an important constituent of the pharmacological effects of Yokukansan. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effect of Yokukansan (YKS) on the impairment of spatial memory and cholinergic involvement in a rat model of early-phase Alzheimer's disease (AD). In this model, rats underwent four-vessel transient cerebral ischemia and then were treated with beta amyloid oligomers injected intracerebroventricularly once daily for 7 days. These animals showed memory impairment in an eight-arm radial maze task without histological evidence of apoptosis but with a decrease in expression of hippocampal dynamin 1, an important factor in synaptic vesicle endocytosis. Oral administration of YKS for 2 weeks significantly increased the number of correct choices and decreased the number of error choices in the eight-arm radial maze task ( P < 0.05). Moreover, YKS significantly increased high K+-evoked potentiation of acetylcholine (ACh) release ( P < 0.05) and significantly increased the expression of dynamin 1 ( P < 0.01) in the hippocampus. The ameliorative effect of YKS on spatial memory impairment in our rat model of early-phase AD may be mediated in part by an increase in ACh release and modulation of dynamin 1 expression, leading to improved synaptic function. Future studies will determine whether YKS is similarly useful in the treatment of memory defects in patients diagnosed with early-stage AD. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objectives There is currently no meta-analysis of the efficacy and tolerability of Yokukansan in the treatment of behavioral and psychological symptoms of dementia. Method We used information obtained from the PubMed and Cochrane Library databases until October 2012. We conducted a systematic review and meta-analysis of individual patient data from randomized controlled trials comparing Yokukansan with usual care (UC, i.e., controls). Standardized mean difference and weighted mean difference were calculated. All studies used the Neuropsychiatric Inventory (NPI) for the evaluation of behavioral and psychological symptoms of dementia. Results Four relevant studies (total n = 236) were identified. Yokukansan was superior to UC in the reduction of total NPI scores ( p = 0.0009, weighted mean difference =−7.20, I2 = 0%). In addition, Yokukansan was more efficacious in reducing scores on the NPI subscale (delusions, hallucinations, and agitation/aggression) than UC ( p < 0.00001-0.0009). Yokukansan treatment also improved activities of daily living scores compared with UC ( p = 0.04, standardized mean difference = −0.32, I2 = 0%). Mini-mental state examination scores did not differ between the Yokukansan and UC treatment groups. Yokukansan was not different from UC regarding discontinuation due to any cause. Conclusion Our results suggest that Yokukansan has a beneficial effect on NPI and on ADL scores and that Yokukansan seems to be a well-tolerated treatment. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the efficacy of Yokukansan in improving behavioral symptoms of frontotemporal dementia. This study was a prospective, open-label trial of daily Yokukansan for 4 weeks in 20 frontotemporal dementia patients. Yokukansan treatment was found to significantly improve scores for the Neuropsychiatric Inventory and the Stereotypy Rating Inventory. No adverse effects or significant changes in physical findings and laboratory data occurred except for hypokalemia in two cases. The results indicate that Yokukansan can alleviate the behavioral symptoms of frontotemporal dementia. (The clinical trial registration number is UMIN000002704). [ABSTRACT FROM AUTHOR]

Herein, we present five cases with frontotemporal dementia whose behavioral symptoms were improved by Yokukansan, a traditional Japanese medicine (Kampo). All five patients were prescribed Yokukansan (7.5 g/day) to reduce their symptoms. The patients' symptoms were evaluated comprehensively using the Neuropsychiatric Inventory (NPI) and the Stereotypy Rating Inventory (SRI) before and 4 weeks after Yokukansan treatment. The mean (± SD) scores on the NPI and the SRI before treatment were 55.6 ± 5.4 and 22.2 ± 6.5, respectively. After treatment, these scores were 30.0 ± 7.8 and 11.6 ± 7.5, respectively. Yokukansan was effective for the treatment of clinical symptoms in all five patients without adverse effects and significant changes in laboratory data. Although antipsychotic drugs have been used to control behavioral symptoms, their associated adverse effects frequently impact on the activities of daily living and quality of life of treated patients. The present cases suggest significant improvement of behavioral symptoms in frontotemporal dementia with Yokukansan treatment, leading to probable benefit of the use of Yokukansan in individuals with frontotemporal dementia. [ABSTRACT FROM AUTHOR]