Paeoniflorin, a constituent of Kami-shoyo-san, suppresses blood glucose levels in postmenopausal diabetic mice by promoting the secretion of estradiol from adipocytes.

Ovarian functional deterioration in women with climacteric disorders increases the prevalence of type 2 diabetes (T2D). Therefore, we revealed that paeoniflorin (PF), an ingredient of paeony root (PR), which is a constituent of Kami-shoyo-san (KS), promotes glucose uptake by increasing estradiol secretion from adipocytes. Adipocytes differentiated from 3T3-L1 cells were incubated in culture medium containing the extracts of KS, PR, KS excluding PR (KS-PR), or PF for 5 d at 37 °C and 5% CO2. The estradiol and glucose concentrations in the medium were determined using enzyme-linked immunosorbent assay (ELISA). Next, PF (1 or 10 mg/kg) was subcutaneously injected into ovariectomized mice (12-week-old, ICR strain) once daily for 19 d to perform the glucose tolerance test and determine blood estradiol and adiponectin levels. The release of estradiol from 3T3-L1 adipocytes was significantly increased by KS, PR, KS-PR, and PF, and the increased estradiol level caused by KS was significantly decreased by excluding PF from KS (KS-PR). Glucose concentration in the medium was significantly decreased by KS and PF. In in vivo experiments, the 10 mg/kg PF-treated group showed significantly suppressed blood glucose levels at 0 and 30 min after d-glucose loading by intraperitoneal injection. These findings indicate that KS, which includes PR-containing PF as the main ingredient, may have the potential to prevent T2D caused by ovarian dysfunction in menopausal women by increasing estradiol secretion from adipocytes.

Kami-shoyo-san ameliorates sociability deficits in ovariectomized mice, a putative female model of autism spectrum disorder, via facilitating dopamine D1 and GABAA receptor functions.

ETHNOPHARMACOLOGICAL RELEVANCE: Kami-shoyo-san (KSS) is a Kampo formula used clinically for menopause-related symptoms in Japan. However, the effect of KSS on autism spectrum disorder (ASD), a developmental disorder with a higher prevalence in males than in females, has not been reported yet. AIM OF THE STUDY: It is accepted generally that dysfunction in the GABAergic system is associated with pathogenesis of ASD. In our previous study, a decrease in brain allopregnanolone (ALLO), a positive allosteric GABAA receptor modulator, induced ASD-like symptoms such as impaired sociability-related performance and increased repetitive self-grooming behavior in male mice, and that KSS ameliorated these behavioral abnormalities via GABAA receptor- and dopamine D1 receptor-mediated mechanisms. In this study, to better understand a gender difference in the prevalence of ASD, we examined whether dissection of ovary (OVX), a major organ secreting progesterone in females, causes ASD-like behaviors in a manner dependent on brain ALLO levels, and if so, how KSS affects the behaviors. MATERIALS AND METHODS: Six-week-old ICR female mice received ovariectomy, and KSS (74 mg/kg and 222 mg/kg, p.o.) were treated before 1 h starting each behavioral test. The sociability, social anxiety-like behavior, and self-grooming behavior were analyzed by the resident-intruder test, mirror chamber test, and open field test, respectively. After finishing the behavioral experiment, the ALLO content in the brain was measured by ELISA. Furthermore, we examined the effects of OVX on the neuro-signaling pathways in the prefrontal cortex and striatum by Western blotting. RESULTS: The results revealed that OVX induced sociability deficits and social anxiety-related behaviors, but not repetitive self-grooming behavior, and that these behavioral changes were accompanied not only by a decrease of brain ALLO levels, but also by impairment of CREB- and CaMKIIα-mediated neuro-signaling in the prefrontal cortex. Moreover, the administration of KSS had no effect on the brain ALLO level, but significantly ameliorated the OVX-induced behavioral and neurochemical changes via facilitation of GABAA receptor and dopamine D1 receptor-mediated neurotransmission. CONCLUSIONS: These findings suggest that a decrease in gonadal hormone-derived ALLO plays a major role in ASD-like behaviors in female mice and that KSS is beneficial for the treatment of ASD in females.

Efficacy of Kampo Medical Treatment Focused on Kami-syoyo-san against Premenstrual Syndrome (PMS) / 日本東洋医学雑誌

Approximately 40% of women during the course of their menstrual cycles suffer from premenstrual syndrome (PMS). The cause of this syndrome is unknown, furthermore diagnostic criteria and treatments have not been established. Kampo medicines were applied using Kami-shoyo-san as a first choice, and several other alternative Kampo medicines, to 33 PMS patient cases. To evaluate the effectiveness of this therapy, PMS scores were recorded prior to treatment. Patients' scores were recorded as; score 0 (symptomless), score 1 (endurable), score 2 (unbearable without medicine), as well as the five major characteristics of PMS, 1) psychiatric symptoms, 2) headache, 3) breast pain, 4) swelling, 5) lower abdominal pain or lumbago. The scores were verified subsequent to two menstrual cycles. Kampo medicine was found to be effective in 24 cases, with scores declining in average from 4.4 to 1.5. Further treatments were requested in 4 cases, moreover, 5 cases were discounted altogether. Thus Kampo medicine proved to be a very useful method for patients suffering from PMS.

Evaluation of the Effect of Kampo(herbal) Medicine to Diminish Climacteric Symptoms Induced by the GnRH Agonist / 日本東洋医学雑誌

In the hormonal treatment of uterine myomas, which are estrogen dependent, GnRH agonist (GnRHa) therapy has become widespread. However, GnRHa therapy causes uncomfortable or harmful side effects such as climacteric symptoms. The aim of this study is to evaluate the effect of Kampo (herbal) medicine to diminish climacteric symptoms induced by the GnRHa. Twenty-six patients with symptomatic uterine myoma were recruited, and informed consent was obtained from all subjects. Leuprolide acetate depot 3.75mg (LA) as GnRHa was given with subcutaneous injection every four weeks for six months. After LA therapy was initiated, Toki-shakuyaku-san, Kami-shoyo-san, or Keishi-bukuryo-gan was given from the second month of treatment. Climacteric symptoms were evaluated with Simplified Menopausal Index, which was improved for Japanese women. In the present study, we found all three Kampo medicines were useful. In particular, Kami-shoyo-san was useful for climacteric symptoms induced by LA. Also, LA therapy combined with Keishi-bukuryo-gan had beneficial effects in uterine myomas. However, the precise mechanism by which results were achieved remains unclear. Therefore, further research may be necessary to evaluate the ability of Kampo medicines to diminish climacteric symptoms induced by GnRHa.

A Case of Chronic Hepatitis C, in which Elimination of Hepatitis C Virus was Achieved by Kampo Treatment / 日本東洋医学雑誌

Chronic hepatitis C has a high incidence of proceeding to liver cirrhosis, and a natural healing from chronic hepatitis C is extremely rare. We observed a case of chronic hepatitis type C, in which the virus was eliminated after Kampo treatment. The patient was a 37-year-old female who underwent a blood transfusion following delivery of her first child in 1982. In January 1983, she became aware of general malaise, and was diagnosed as having chronic hepatitis. She was treated with Stronger Neo Minophagen C, but her symptoms and laboratory data were unchanged. A liver biopsy disclosed chronic active hepatitis in 1988, and she was transferred to our hospital for Kampo treatment in May. Although the symptoms rapidly disappeared after treatment with the Kampo formulas, Hochu-ekki-to and Keishi-bukuryo-gan, her transamilase values did not change. Her transamilase level decreased gradually after the prescription was changed to Saiko-keishi-to-go-Toki-shakuyaku-san-ryo, and returned to normal after her prescription was changed to Kami-shoyo-san-ryo in May 1996.<br>Concerning HCV-RNA in the serum, in March 1995, when Saiko-keishi-to-go-Toki-shakuyaku-san was administered, the amount of HCV-RNA in the serum was 10⁴ Kcopies/ml. But that was less than the detectable sensitivity in April 1998. We believe this to be a case in which elimination of HCV was achieved by Kampo treatment alone.

Four Cases of Chronic Constipation Treated with Kami-shoyo-san / 日本東洋医学雑誌

In Japan chronic constipation is divided into two groups: atonic constipation and spastic constipation. Stimulant laxatives are unsuitable for patients with spastic constipation, and routine use of stimulant laxatives over long periods of time should be discouraged. Nevertheless stimulant laxatives are often used continually among these patients because their stools are too hard and infrequent without stimulant laxatives.<br>In this report, we present 4 cases of chronic constipation treated with Kami-shoyo-san. Cases 1, 2 and 3 were patients with spastic constipation and case 1, 3 and 4 had used stimulant laxatives continually. In all cases both stimulant laxatives and Kampo medicines containing Rhei Rhizoma caused adverse effects such as abdominal discomfort and pollakisuria. Kami-shoyo-san improved bowel movement as well as other complaints: irritability, heat in the upper part of the body, painful tension of shoulder muscles, fatigue, dysmenorrhea and pollakisuria. Withdrawal from stimulant laxatives was achieved in the patients except for case 2. In drug treatment of chronic constipation, Kampo medicines such as Kami-shoyo-san seem to be useful in withdrawal from stimulant laxatives.

Clinical Features of Patients with Indefinite Complaints. Comparison between Saiko-ka-ryukotsu-borei-to and Lami-shoyo-san / 日本東洋医学雑誌

Before the administration of conventional medicines, outpatients with indefinite complaints answered 51 questions (six mental categories) from the Cornell Medical Index (CMI) and 43 questions (seven physical categories) from the Abe questionnaire for vegetative syndrome. The subjects of this study were 18 cases with CMI III-IV scores who were effectively treated with Saiko-ka-ryukotsu-borei-to (n=9; SR group) or Kami-shoyo-san (n=9; KS group). In order to compare the clinical features of both groups, the average complaint rates responding to the mental and physical categories were evaluated in each group.<br>Psychologically, the average complaint rates related to depression and tension were high in the SR group, and the average complaint rates related to hyper-sensitivity and anger were high in the KS group. Discriminant analysis revealed that three categories —tension, hyper-sensitivity and depression— contributed to a difference between the SR and KS groups. Physically, the average complaint rates responding to all of 7 categories of the SR group were not significantly different from those of the KS group.

Effects of Kami-shoyo-san on the Indefinite Complaints / 日本東洋医学雑誌

Physical and psychological symptoms were evaluated in 9 cases with unidentified clinical syndromes who were effectively treated with kami-shoyo-san (KS). Before and after administration, the patients were tested with the 43-question Abe questionnaire for vegetative syndrome and 51 questions (M-R) of the Cornell Medical Index. After administering KS for three months, the mean number of physical symptoms decreased from 19.9 to 9.1, and the psychological symptoms decreased from 16.7 to 9.3.<br>In order to clarify the clinical features for which KS is efficacious, the physical and psychological symptoms were divided into 7 and 6 categories, respectively. The average complaint rates responding to those categories before administration were evaluated. Physically, the average complaint rates related to locomotion and fatigue were high, and those related to digestion were low. Psychologically, the average complaint rates related to hypersensitivity and anger were high, and those relating to depression and tension were low.

The Sources of Kampo Formulae, Kami-shoyo-san and its Combination with Shimotsu-to / 日本東洋医学雑誌

The source of Kami-shoyo-san varies in the literature. The current formula contains ten kinds of medicine. Only Shoyo-san is described in “He ji ju fang”. In “Nü ke cuo yao” and “Nei ke zhai yao”, a formula containing eight medicines without ginger and mentha was descrided. It was in “Wan bing hui chun” after Xue Ji that a formula containing ten kinds of medicine was first specified. The source of its combination with Shimotsu-to also varies in the literature. There is no mention of this combination in the “He ji ju fang”. In the “Nei ke zhai yao”, there is a case where eight-medicine formulations in combination with Shimotsu-to were used. Although ten-medicine plus Shimotsu-to are, in fact, described in “Futsugo-yakushitsu-houkan-kuketsu”, my investigation found that such a combination formula was used for general pruritus in “Ryo-chikeiken-hikki” about 90 years previously. I believe that if the process of establishing a formula is complicated, as in the case of Kami-shoyo-san, every activity contributing to each step in establishing the formula is generally included as a part of its source and that any activity, in which a combination of formulae was very effective, is regarded, in principle, as its source.