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Kanitani M.,Tsumura Research Laboratories | Nishimura N.,Bozo Research Center Inc | Edamoto H.,Bozo Research Center Inc | Kase Y.,Tsumura Research Laboratories
Journal of Toxicologic Pathology | Year: 2016

Keishibukuryogan is a traditional Japanese medicine widely administered to patients with menopausal symptoms. Because humans use it on a long-term basis, we believed that a carcinogenicity study was warranted. We orally administered keishibukuryogan (TJ-25) extract powder to 6-week-old Sprague-Dawley rats [Crl:CD(SD)], which were divided into four dosage groups-0 (water for injection), 100, 500 and 2,500 mg/kg/day for 24 months. We found that TJ-25 did not affect the survival rate of either sex. Furthermore, it did not affect the clinical condition of the rats, number of superficial tumors found by palpation, body weight, food consumption, hematology, or gross pathological findings. The severity of degeneration of muscle fiber in the femoral skeletal muscle increased slightly in males and females in the 2,500 mg/kg/day group, but TJ-25 did not increase the number of tumors found on histopathological examination. In our study, oral administration of TJ-25 extract powder in rats for 24 months was not associated with an increased incidence of tumors. © 2016 The Japanese Society of Toxicologic Pathology.


Furukawa N.,Kawasaki University of Medical Welfare | Manabe N.,Kawasaki Medical School | Kase Y.,Tsumura Research Laboratories | Hattori T.,Tsumura Research Laboratories | And 3 more authors.
Autonomic Neuroscience: Basic and Clinical | Year: 2013

Purpose: Abnormal proximal gastric relaxation is one of the causes of functional dyspepsia. The purpose of this study is to use a barostat in conscious dogs to determine the effects of rikkunshito, which is considered to have beneficial effects on functional dyspepsia, on the proximal stomach. Methods: Eight beagles were used. A gastrocutaneous fistula and force transducers were surgically implanted in the middle corpus and gastric antrum and duodenum, respectively. After a recovery period, a plastic bag was inserted through the gastrocutaneous fistula and the proximal stomach was distended using a barostat. First, four dogs were used to investigate the pressure-volume relation in the fasted and postprandial phases. Second, the stomachs of four different dogs were continuously distended at minimal distending pressure +. 2. mm. Hg, and 5. min later were infused with warmed liquid rikkunshito (2. g/20. mL) or water through the gastrocutaneous fistula. Finally, changes in the proximal gastric volume and gastrointestinal motility were observed. Results: The proximal stomach was significantly more pliable in the postprandial phase than in the fasted phase. The proximal gastric volume increased immediately after liquid infusion under constant pressure in both phases and duodenal motility was accelerated. The effect of rikkunshito was significantly greater and lasted longer than that of water. No significant difference between the effects during the fasted or postprandial phase and no change in the gastric antrum motility were observed when rikkunshito was infused. Conclusion: These results indicate that rikkunshito accelerates duodenal motility and relaxes the proximal stomach. © 2013 Elsevier B.V.


Wang L.,University of California at Los Angeles | Mogami S.,Tsumura Research Laboratories | Karasawa H.,University of California at Los Angeles | Yamada C.,Tsumura Research Laboratories | And 4 more authors.
Peptides | Year: 2014

We previously reported that ghrelin prevented l-dopa (LD)-induced inhibition of gastric emptying (GE) of a non-nutrient solution in rats. Parkinson's disease treatment involves the combined administration of l-dopa with the enzyme l-amino acid decarboxylase inhibitor, carbidopa (CD) to reduce peripheral formation of dopamine. We investigated the effect LD/CD given orogastrically (og) on GE of a non-nutrient or nutrient meal and whether og pretreatment with rikkunshito, a kampo medicine clinically used to treat gastroparesis, influenced LD/CD effect on GE and postprandial antral and duodenal motility in conscious rats. LD/CD (20/2 mg kg-1) decreased significantly GE to 26.3 ± 6.0% compared to 61.2 ± 3.2% in og vehicle monitored 20-min after a non-nutrient meal and to 41.9 ± 5.8% compared to 72.9 ± 5.2% in og vehicle monitored 60 min after a nutrient meal. Rikkunshito (0.5 or 1.0 g kg-1) reduced the LD/CD (20/2 mg kg-1) inhibition of GE of non-nutrient meal (36.9 ± 7.4% and 46.6 ± 4.8% respectively vs. 12.1 ± 7.4% in og vehicle plus LD/CD) while having no effect alone (56.6 ± 8.5%). The ghrelin antagonist, [d-Lys3]-GHRP-6 (1 mg kg-1) injected intraperitoneally partially reversed rikkunshito preventive effect on LD/CD-inhibited GE. Rikkunshito (1.0 g kg-1) blocked LD/CD (20/2 mg kg -1)-induced delayed GE of a nutrient meal and the reduction of postprandial antral motility. In 6-hydroxydopamine-induced Parkinson's disease rat model, rikkunshito (1.0 g kg-1, og) also prevented LD/CD-inhibited gastric emptying of a nutrient meal and enhanced fasting plasma levels of acylated ghrelin. These data indicate that oral rikkunshito alleviates the delayed GE induced by LD/CD in naïve and PD rat model in part through ghrelin-related mechanisms. © 2014 Elsevier Inc.


Funakushi N.,Juntendo University | Yamaguchi T.,Juntendo University | Yamaguchi T.,Tsumura Research Laboratories | Jiang J.,Juntendo University | And 8 more authors.
Archives of Dermatological Research | Year: 2011

Yokukansan (YKS) has been used in Japan as a remedy for neurosis, insomnia, and children with night crying. In a previous study, we reported that YKS controls scratching behavior and inhibits the development of atopic dermatitis (AD)-like lesions in NC/Nga mice. In this study, we investigated the effects of YKS on the development of AD-like lesions in socially isolated NC/Nga mice compared with the effects of fexofenadine and elucidated the mechanism of the ameliorating effect of YKS on the skin lesions. Ten-week-old male NC/Nga mice were divided into three groups (n = 5/group): the conventional control, the YKS-treated, and the fexofenadine-treated groups, and were kept isolated under conventional conditions for 6 weeks. Measurements were made of dermatitis scores and transepidermal water loss (TEWL), scratching and grooming behaviors. Immunohistochemistry and mRNA levels were also evaluated. We performed similar experiments under specific pathogen free (SPF) conditions that served as a SPF control. YKS and fexofenadine inhibited the aggravation of skin lesions and decreased TEWL, but only YKS decreased the numbers of scratching and pathologic grooming behaviors. Immunohistochemistry and RT-PCR revealed that N-methyl-d-aspartate (NMDA) receptor expression was increased in the skin of conventional control mice and was decreased in YKS-treated mice. Glutamate transporter-1 (GLT-1) mRNA levels were decreased in the skin of conventional control mice and were increased in YKS-treated mice. The results indicate that YKS ameliorates AD-like skin lesions in NC/Nga mice through a mechanism distinct from that of fexofenadine. Furthermore, the effects of YKS are suggested to be mediated via glutamate signaling in the skin lesions. © The Author(s) 2011.


Yakabi K.,Saitama University | Sadakane C.,Tsumura Research Laboratories | Noguchi M.,Tsumura Research Laboratories | Ohno S.,Saitama University | And 6 more authors.
Endocrinology | Year: 2010

Although chemotherapy with cisplatin is a widely used and effective cancer treatment, the undesirable gastrointestinal side effects associated with it, such as nausea, vomiting, and anorexia, markedly decrease patients' quality of life. To elucidate the mechanism underlying chemotherapy-induced anorexia, focusing on the hypothalamic ghrelin secretion-anorexia association, we measured hypothalamic ghrelin secretion in fasted and cisplatin-treated rats. Hypothalamic ghrelin secretion changes after vagotomy or administration of cisplatin. Cisplatin + rikkunshito, a serotonin 2C receptor antagonist or serotonin 3 receptor antagonist, was investigated. The effects of intracerebroventricular (icv) administration of ghrelin or the serotonin 2C receptor antagonist SB242084 on food intake were also evaluated in cisplatin-treated rats. Hypothalamic ghrelin secretion significantly increased in 24-h-fasted rats compared to freely fed rats and was markedly reduced 24 and 48 h after cisplatin treatment in cisplatin-treated rats compared to saline-treated rats, although their plasma ghrelin levels were comparable. In cisplatin-treated rats, icv ghrelin administration reversed the decrease in food intake, vagotomy partially restored hypothalamic ghrelin secretion, and hypothalamic serotonin 2C receptor mRNA expression increased significantly. Administration of rikkunshito (an endogenous ghrelin enhancer) or a serotonin 2C receptor antagonist reversed the decrease in hypothalamic ghrelin secretion and food intake 24 h after cisplatin treatment. Cisplatin-induced anorexia is mediated through reduced hypothalamic ghrelin secretion. Cerebral serotonin 2C receptor activation partially induces decrease in hypothalamic ghrelin secretion, and rikkunshito suppresses cisplatin-induced anorexia by enhancing this secretion. Copyright © 2010 by The Endocrine Society.

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