Antibacterial and Immunosuppressive Effects of OPS-2071, a Candidate Therapy for Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract. Although many types of drug are used, clinical outcomes are still unsatisfactory. Previous studies have suggested that intestinal bacteria are involved in the pathogenesis of IBD. Accordingly, in an IBD model we evaluated the therapeutic effects of OPS-2071, a low-absorption quinolone antibacterial agent indicated for intestinal infection, and investigated its mechanism of action. METHODS: The therapeutic effects of OPS-2071 and comparison therapies were evaluated using naive CD4 + T cell-transfer IBD model mice. In vitro inhibition of LPS-induced TNF-α production and inhibitory effects on T cell responses stimulated using anti-CD3/CD28 antibody-loaded beads were evaluated using mouse splenocytes and human peripheral blood mononuclear cells. In addition, in vitro activities against bacteria implicated in IBD pathogenesis were tested. RESULTS: OPS-2071 dose-dependently decreased both colonic weight/length ratio and the colitis histological score as compared with the vehicle group. The therapeutic effect of OPS-2071 was equivalent to that of anti-IL-12/23 (p40) antibody. In vitro, OPS-2071 suppressed TNF-α production induced by LPS stimulation and T cell responses in a dose-dependent manner. At high concentrations, these effects were comparable to those of existing immunosuppressive agents, such as prednisolone, in both mouse and human cells. OPS-2071 also showed antibacterial activity against IBD-related bacteria. CONCLUSIONS: Our results suggest that OPS-2071 had both immunosuppressive and antibacterial effects. This dual effect makes OPS-2071 a unique and promising candidate for IBD.

Novel Gut Microbiota Modulator, Which Markedly Increases Akkermansia muciniphila Occupancy, Ameliorates Experimental Colitis in Rats.

BACKGROUND: Since gut microbiota is involved in the pathogenesis of inflammatory bowel disease (IBD), antibiotics or probiotics may be attractive options for the treatment of IBD. Akkermansia muciniphila is expected as a next-generation probiotic for IBD, and OPS-2071 is a novel quinolone with potent antibacterial activity against Clostridioides difficile. AIMS: The aim of this study is to assess the potential of OPS-2071 as a gut microbiota modulator for IBD. METHODS: Minimum inhibitory concentrations of several bacteria in the human intestinal microbiota were determined. Microbiota changes in the feces were typed using metagenomic analysis after oral administration of OPS-2071 (100 mg/kg) twice a day to normal rats. The amounts of mucin were determined using the Fecal Mucin Assay Kit. The effects of OPS-2071 (1, 3, 10 mg/kg) twice a day on fecal symptoms and fecal microbiota were evaluated in a colitis rat model induced by free access to drinking water containing 3% dextran sulfate sodium for 10 days. RESULTS: OPS-2071 showed notably low antibacterial activity against only A. muciniphila in spite of higher antimicrobial activity against other strains of intestinal bacteria. OPS-2071 rapidly and dramatically increased the occupancy of A. muciniphila as well as the amount of mucin in the feces of normal rats. OPS-2071 (10 mg/kg) significantly suppressed the exacerbation of stool scores, especially the bloody stool score, with the increase in A. muciniphila occupancy. CONCLUSIONS: OPS-2071 is expected to be a new therapeutic option for IBD as a gut microbiota modulator by significantly increasing A. muciniphila occupancy.

Detection and quantification of human-specific mRNA from hepatocyte-like cells derived from dental pulp using real-time polymerase chain reaction.

OBJECTIVES: We quantified viable hepatocyte-like cells (HLCs) administered via portal or tail veins in the livers and lungs of immunodeficient rats using real-time reverse transcription polymerase chain reaction (RT-PCR) and human glyceraldehyde 3-phosphate dehydrogenase (GAPDH) primers. METHODS: Immunodeficient rats were infused with HLCs via portal or tail veins. mRNA was quantified based on the route of cell administration and the presence of liver injury. RESULTS: Human-specific GAPDH mRNA primers detected 0.1 pg human RNA in 100 ng (1:106) of rat liver RNA. When infused into the portal vein, the quantity of HLC mRNA reduced to 5% 3 h after infusion. Most HLCs were entrapped in the lungs when infused via the tail vein and decreased to approximately 10% 6 h after infusion. A small number of HLCs made it to the liver but disappeared rapidly, regardless of liver injury. 24 h after infusion, viable HLCs were detected only in the lungs of rats with liver injury (P < 0.05). CONCLUSIONS: The quantity of viable human cells in immunodeficient rats was estimated using real-time RT-PCR and primers specific to human mRNA.

Validation and standardization of DNA extraction and library construction methods for metagenomics-based human fecal microbiome measurements.

BACKGROUND: Validation and standardization of methodologies for microbial community measurements by high-throughput sequencing are needed to support human microbiome research and its industrialization. This study set out to establish standards-based solutions to improve the accuracy and reproducibility of metagenomics-based microbiome profiling of human fecal samples. RESULTS: In the first phase, we performed a head-to-head comparison of a wide range of protocols for DNA extraction and sequencing library construction using defined mock communities, to identify performant protocols and pinpoint sources of inaccuracy in quantification. In the second phase, we validated performant protocols with respect to their variability of measurement results within a single laboratory (that is, intermediate precision) as well as interlaboratory transferability and reproducibility through an industry-based collaborative study. We further ascertained the performance of our recommended protocols in the context of a community-wide interlaboratory study (that is, the MOSAIC Standards Challenge). Finally, we defined performance metrics to provide best practice guidance for improving measurement consistency across methods and laboratories. CONCLUSIONS: The validated protocols and methodological guidance for DNA extraction and library construction provided in this study expand current best practices for metagenomic analyses of human fecal microbiota. Uptake of our protocols and guidelines will improve the accuracy and comparability of metagenomics-based studies of the human microbiome, thereby facilitating development and commercialization of human microbiome-based products. Video Abstract.

Effect of lidocaine with adrenaline and landiolol on hemodynamics in spontaneously hypertensive rats.

Administration of local anesthetics with adrenaline can cause tachycardia and hypertension. This study assessed whether combined administration of landiolol with adrenaline and lidocaine would induce local anesthesia without causing hemodynamic changes. Normal saline (NS), lidocaine with adrenaline (LA), and lidocaine with adrenaline and landiolol (LLA) were injected into Wistar Kyoto (WKY/Izm) or spontaneously hypertensive (SHR/Izm) rats, followed by measurement of the pulse rate (PR), and the systolic, diastolic and mean blood pressures (SBP, DBP and MBP). In the LLA group, the increase in PR was significantly suppressed in both SHR/Izm and WKY/Izm rats relative to those in the LA group. Although SBP was significantly reduced in WKY/Izm rats given LLA, relative to those given NS or LA, it was elevated in SHR/Izm rats given LLA. Landiolol-induced changes in PR may be due to blockade of adrenaline-induced ß1 receptor stimulation, which suppresses cardiac hyperactivity, whereas the early surge of blood pressure in SHR/Izm rats given LLA may be due to the dominant alpha-adrenergic effects of ß1 receptor inhibition. The anti-adrenergic effects of LLA were safe and effective in WKY/Izm rats, although the unexpected early hypertensive surge in SHR/Izm rats indicates the need for caution.

Investigation of fluctuations in blood glucose level due to dietary restrictions during impacted mandibular third molar extraction under intravenous sedation: effect of perioperative glucose administration.

OBJECTIVE: We aimed to investigate the usefulness of glucose administration for maintaining perioperative glycemic control in patients with dietary restrictions during 4 h prior to impacted mandibular third molar extraction under intravenous sedation. METHODS: Fifty-four individuals scheduled to undergo extraction of impacted mandibular third molars under intravenous sedation, with preoperative blood glucose levels (GL) of 70-110 mg/dL, were evaluated and divided into 3 groups (n = 18 each): control group receiving glucose-free sodium lactate Ringer's solution, perioperative GL group receiving 100 mL of 5% glucose solution immediately after local anesthesia, and postoperative GL group receiving 100 mL of 5% glucose solution immediately after surgery completion. Blood glucose levels, systolic blood pressure, diastolic blood pressure, and heart rate were measured. RESULTS: Glucose levels of those in the control and perioperative GL groups decreased within the standard range 90 min after surgery, compared with the preoperative blood glucose level. However, in the postoperative GL group, glucose levels were similar to the preoperative levels. Systolic and diastolic blood pressure and heart rate were not affected by glucose administration, and sedation could be maintained without an invasive procedure. CONCLUSIONS: Following a restriction on eating and drinking 4 h prior to surgery, the blood glucose level gradually decreased in the perioperative period but remained within the reference range until 90 min following surgery. The administration of 100 mL 5% glucose solution immediately after surgery was sufficient for the prevention of postoperative hypoglycemia. This approach may be useful for perioperative glycemic control during third molar extraction.

Student Potential for Self-assessment in a Clinical Dentistry Practical Training Course on Communication Skills.

This study aimed to investigate student potential for self-assessment in a clinical dentistry practical training course focused on communication skills. Participants were 124 fourth-year students (70 males, 54 females; all Japanese) in 2017 and 2018 at the Nippon Dental University, School of Life Dentistry at Niigata. Participating students belonged to different cohorts in 2017 and 2018. Participants were asked to complete a self-evaluation sheet at the end of each unit of the course. Their self-evaluation scores and the faculty evaluation scores for each student for Units 1-1, 1-2, and 1-3 were statistically analyzed. The results showed that females tended to rate themselves significantly higher than males. Furthermore, there were significant differences in evaluation scores between students and faculty for nine of 11 evaluation items for male students and 10 of 11 items for female students in Unit 1-3. Faculty expectations increased from Unit 1-1 to Unit 1-3, although students were satisfied with their performance and had a sense of achievement. However, students' actual performance was below faculty expectations, suggesting faculty evaluations were stricter than students' self-evaluation. Self-assessment may enhance students' ability for self-directed learning and may also inform how faculty can effectively educate dental students. Dental educators should support students to increase their levels of self-efficacy, which will enhance their self-evaluation skills.

Emotional intelligence score and performance of dental undergraduates.

The purpose of this study was to investigate the relationship between emotional intelligence (EI) and undergraduate dental students' ability to deal with different situations of communication in a clinical dentistry practical training course of communication skills. Fourth-year students in 2012 and in 2013 at the Nippon Dental University School of Life Dentistry at Niigata participated in the survey. The total number of participating students was 129 (88 males and 41 females). The students were asked to complete the Japanese version of the Mayer-Salovey-Caruso Emotional Intelligence Test in communication skills. Female students tended to have significantly higher EI score than males. The EI score in the group with high-grade academic performers was higher than in the low-grade group. The influence of EI on academic performance appeared to be mainly due to the students' ability to accurately perceiving emotions and to their ability to understand emotional issues. The importance of EI may also lie in its ability to parse out personality factors from more changeable aspects of a person's behavior. Although further studies are required, we believe that dental educators need to assume the responsibility to help students develop their emotional competencies that they will need to prosper in their chosen careers. In our conclusion, dental educators should support low achievers to increase their levels of self-confidence instead of concentrating mainly on improving their technical skill and academic performance. This may lead to upgrading their skills for managing emotions and to changing their learning approach.

Trends in percentage of postgraduate dental trainees at dental clinics.

A facilities-group system designed to provide clinical training at dental clinics was developed after postgraduate clinical training became mandatory for dentists in Japan in 2006. As a result, there has been a steady increase in the number of dental clinics collaborating with dental school hospitals under this program. A larger number of dental clinics have also been designated as single-system facilities, program management facilities or collaborating facilities. However, it remains to be determined whether this increase in the number of dental clinics designated as clinical training facilities has led to an increase in the amount of training offered. Therefore, the purpose of this study was to investigate trends in the percentage of postgraduate dental trainees at dental clinics between fiscal years 2006 and 2010. The results showed no significant correlation among (1) the percentage of dental clinics designated as single-system collaborating facilities, (2) the percentage of training programs at dental clinics, and (3) the proportion of training program recruitment offers by dental clinics compared to the total number of recruits. These findings showed that increasing the number of collaborating dental clinics did not lead to an increase in the amount of clinical training at dental clinics. The findings also suggest that increasing the number of single-system or program management dental clinics is important in promoting clinical training at dental clinics.

Oral clarithromycin enhances airway immunoglobulin A (IgA) immunity through induction of IgA class switching recombination and B-cell-activating factor of the tumor necrosis factor family molecule on mucosal dendritic cells in mice infected with influenza A virus.

We previously reported that the macrolide antibiotic clarithromycin (CAM) enhanced the mucosal immune response in pediatric influenza, particularly in children treated with the antiviral neuraminidase inhibitor oseltamivir (OSV) with low production of mucosal antiviral secretory IgA (S-IgA). The aims of the present study were to confirm the effects of CAM on S-IgA immune responses, by using influenza A virus (IAV) H1N1-infected mice treated with or without OSV, and to determine the molecular mechanisms responsible for the induction of mucosal IgA class switching recombination in IAV-infected CAM-treated mice. The anti-IAV S-IgA responses and expression levels of IgA class switching recombination-associated molecules were examined in bronchus-lymphoid tissues and spleens of infected mice. We also assessed neutralization activities of S-IgA against IAV. Data show that CAM enhanced anti-IAV S-IgA induction in the airway of infected mice and restored the attenuated antiviral S-IgA levels in OSV-treated mice to the levels in the vehicle-treated mice. The expression levels of B-cell-activating factor of the tumor necrosis factor family (BAFF) molecule on mucosal dendritic cells as well as those of activation-induced cytidine deaminase and Iµ-Cα transcripts on B cells were enhanced by CAM, compared with the levels without CAM treatment, but CAM had no effect on the expression of the BAFF receptor on B cells. Enhancement by CAM of neutralization activities of airway S-IgA against IAV in vitro and reinfected mice was observed. This study identifies that CAM enhances S-IgA production and neutralizing activities through the induction of IgA class switching recombination and upregulation of BAFF molecules in mucosal dendritic cells in IAV-infected mice.

Attenuation of inducible respiratory immune responses by oseltamivir treatment in mice infected with influenza A virus.

The antiviral neuraminidase inhibitor oseltamivir (OSV) is widely used to suppress viral replication in the treatment of influenza. Here, we report that OSV administration significantly suppressed respiratory mucosal secretory IgA responses with respect to antigen (Ag)-specific antibody (Ab) production and also the induction of Ag-specific IgA Ab-forming cells, but not systemic IgG responses, in weanling mice as a model of pediatric influenza. Neutralizing activities of the airway fluids in oral OSV-treated mice were significantly less than those of sham-treated mice. Our findings suggest the risk of re-infection in patients showing a low mucosal response following OSV treatment.

Altered phospholipid transfer protein gene expression and serum lipid profile by topotecan.

Camptothecin (CPT) and its structural analogues including topotecan and irinotecan, are inhibitors of topoisomerase I. These drugs are clinically active against a broad spectrum of cancers. To understand the genesis of chemotherapeutic resistance to the CPT family of anticancer drugs, we examined by gene expression profiling the pharmacological response to topotecan in the human hepatoma HepG2 cells and found a striking induction of the phospholipid transfer protein (PLTP) gene expression by topotecan. We showed that activation of PLTP gene expression is specific to CPT and its analogues including specific enantiomers that inhibit topoisomerase I. PLTP-mediated lipid transfer to high-density lipoprotein (HDL) is thought to be important for shuttling and redistribution of lipids between lipoproteins, which are normally returned to the liver for metabolism via the reverse cholesterol transport pathway. Hence, we asked whether elevated PLTP levels might increase the transfer of drugs into HDL. We observed that CPT was not accumulated in HDL and other lipoproteins. In addition, topotecan treatment in mice caused a marked reduction in serum HDL that was accompanied by an increase in triglyceride and cholesterol levels. These results showed that PLTP does not mediate the transfer of topoisomerase I inhibitors to serum lipoproteins. However, elevated serum PLTP levels following treatment with topoisomerase I inhibitors in cancer patients may serve as a biomarker for monitoring the development of hypertriglyceridemia and acute pancreatitis.

Prieurianin Causes Weight Loss in Diet-Induced Obese Mice and Inhibits Adipogenesis in Cultured Preadipocytes.

The global increase in the incidence of obesity has emerged as one of the most serious public health risks in recent years. Despite the enormity of the obesity pandemic, there are currently only two FDA-approved therapies for its treatment and these drugs exhibit modest efficacy and have limiting side effects. Prieurianin is a plant limonoid product that deters feeding in insect larvae. We investigated in this study the effects of prieurianin on weight loss and adipogenesis. Our results showed that prieurianin causes weight loss by reducing energy intake in obese mice on high-calorie diet. We also found that prieurianin is anti-adipogenic in cultured preadipocytes and adipocytes by inhibiting proliferation and differentiation of preadipocytes into adipocytes, and induces either dedifferentiation or delipidation of mature adipocytes. Whether prieurianin can potentially be used for obesity treatment in human warrants further investigation.

Pokeweed antiviral protein region Gly209-Lys225 is critical for RNA N-glycosidase activity of the prokaryotic ribosome.

Pokeweed antiviral protein (PAP) isolated from Phytolacca americana is a ribosome-inactivating protein (RIP) that has RNA N-glycosidase (RNG) activity towards both eukaryotic and prokaryotic ribosomes. In contrast, karasurin-A (KRN), a RIP from Trichosanthes kirilowii var. japonica, is active only on eukaryotic ribosomes. Stepwise selection of chimera proteins between PAP and KRN indicated that the C-terminal region of PAP (residues 209-225) was critical for RNG activity toward prokaryotic ribosomes. When the region of PAP (residues 209-225) was replaced with the corresponding region of KRN the PAP chimera protein, like KRN, was active only on eukaryotic ribosomes. Furthermore, insertion of the region of PAP (residues 209-225) into the KRN chimera protein resulted not only in the detectable RNG activity toward prokaryotic ribosome, but also activity toward the eukaryotic ribosomes as well that was seven-fold higher than for the original KRN. In this study, the possibility of genetic manipulation of the activity and substrate specificity of RIPs is demonstrated.

Survival analysis of ovarian clear cell carcinoma confined to the ovary with or without comprehensive surgical staging.

Pure-type clear cell carcinoma (CCC) has been recognized as a distinct subtype of ovarian cancer, showing a resistance to chemotherapy and resulting in poor prognosis. Our aim was to evaluate the effects of complete surgical procedures followed by adjuvant chemotherapy for CCC patients whose tumors were confined to the ovary (pT1M0). During the period of 1987-2005, 56 patients with stage I CCC were identified and two cases were excluded due to retroperitoneal lymph node metastasis. A total of 54 patients were enrolled in the study and divided into two groups: Group A (n=38, 1993-2005) underwent complete surgical staging including pelvic and para-aortic lymphadenectomy. Group B (n=16, 1987-1992) underwent a hysterectomy, bilateral salpingo-oopherectomy, omentectomy without comprehensive lymphadenectomy. Every patient received six courses of adjuvant chemotherapy using a platinum agent. Survival analysis was estimated by the Kaplan-Meier method and prognostic factors were evaluated using a Cox regression model. The clinical characteristics of the two groups were similar, except for the rate of conventional platinum-based chemotherapy (p=0.02). Multiple regression survival analysis revealed that the completion of a comprehensive staging operation was the only independent factor for progression-free survival of stage I CCC patients (p=0.03) and that the chemotherapeutic regimen was not a prognostic factor (p=0.43). The present study indicates that we should accomplish complete surgical staging procedures for CCC confined to the ovary.

Clinicopathological significance of WT1 expression in ovarian cancer: a possible accelerator of tumor progression in serous adenocarcinoma.

Recently, oncogenic potential of the WT1 gene has been proposed in some human solid tumors and leukemias. Although previous studies have shown the frequent expression of the WT1 protein in ovarian serous adenocarcinomas (OSAs), its clinicopathologic significance is still unclear. We immunohistochemically examined the expression status of WT1 in 119 OSAs and analyzed the correlation of the intensity of WT1 immunoreactivity with the level of WT1 mRNA expression by quantitative real-time polymerase chain reaction, clinicopathologic variables, expression of p53, Bcl-2, and Ki-67 labeling index (LI). Of 119 OSAs, nuclear WT1 immunoreactivity was positive in 99 (83%), of which 44 (44%) and 55 (56%) exhibited high and low WT1 immunoreactivities, respectively. The quantitative WT1 mRNA levels were significantly correlated with the intensity of WT1 immunoreactivity (P < 0.05). In comparison with WT1-negative OSAs, the WT1-positive OSAs showed a higher grade (P = 0.007), advanced stage (P = 0.018), and higher Ki-67 LI (P < 0.001). Additionally, high WT1 immunoreactivity was correlated with a higher grade (P = 0.003), Ki-67 LI (P = 0.012), Bcl-2 expression (P = 0.003), and poorer patient outcome (5-year survival, 36.5 vs 63.8%, P = 0.008 by log-rank test). The WT1 protein may be an accelerator of the progression of OSA.

Application of expression genomics for predicting treatment response in cancer.

During tumor progression, multiple genetic changes in the genome vastly alter the transcriptomes of cancers. Some of these changes, including the mutations of various growth regulatory genes as well as alterations in the transcription of a large number of genes, may lead to resistance to treatment. Therefore, capturing such genomic information of the tumors would enable a physician to decide on the course of treatment options clinically available. Currently, it is still not feasible to identify all the genetic mutations that have occurred in a patient's cancer genome. However, the advent of DNA microarray coupled with the completion of the human genome sequence and the identification of all its genes, have made possible genome-wide gene expression profiling of the cancer genome. In this review, we will focus on the application of expression genomics for identifying signature gene expression profiles in primary cancers to predict response to either radio- or chemotherapy. We envision that transcription profiling of the cancer genomes ultimately will not only reveal how altered gene expression results in resistance to treatment, but also be exploited for predicting and personalizing cancer therapy.

Amplicon profiling reveals cytoplasmic overexpression of MUC1 protein as an indicator of resistance to platinum-based chemotherapy in patients with ovarian cancer.

Chromosomal gains of 1q21-q22 and 13q12-q14 were closely related with the chemoresistance of patients with ovarian cancer in our previous CGH (comparative genomic hybridization) study. We conducted the present study to determine the amplified genes on chromosome 1q. Comparisons of relative copy numbers of clinically platinum-sensitive ovarian tumors (CR-group, n=14) and platinum-resistant tumors (PD-group, n=14) were carried out using real-time PCR from ten different gene loci on chromosome 1q. Increased copy numbers were frequently observed in PD-group tumors, especially in the region between WI-8123 and MUC1. Relative copy number of MUC1 over 1.5 was observed in 13 (92%) of 14 PD-group tumors and 3 (21%) of 14 CR-group tumors (p<0.05). Moreover, cytoplasmic expressions of MUC1 protein were significantly higher in PD-group than those in CR-group (p<0.01). We concluded that the cytoplasmic overexpression of MUC1 might be an indicator of resistance to platinum-based chemotherapy and a prognostic marker in ovarian cancer.

Sedation in Japanese dental schools.

There is very little information about the practice of sedation in Japan. Despite the remarkable advances in dentistry, fear and anxiety continue to be significant deterrents for seeking dental services. Most dental procedures can fortunately be undertaken with the aid of sedation. A comprehensive survey of all the dental schools in Japan was carried out to determine what sedation practices were used in Japan. All 29 dental schools in Japan possessed a dedicated department of anesthesiology at the time of this survey. The survey attempted to determine the specific sedation methods (techniques, routes of administration, and agents used in sedation) as well as practices (monitoring, fasting, location, education, and fees involved in sedation). The results indicate that there was a broad range in sedation practices. The Japanese Dental Society of Anesthesiology may wish to examine the findings of this study and may wish to formulate guidelines appropriate for the practice of sedation in Japan. Others may also wish to compare their own practices with those of Japan.

[The efficacy of Shakuyaku-Kanzo-to for peripheral nerve dysfunction in paclitaxel combination chemotherapy for epithelial ovarian carcinoma].

Shakuyaku-Kanzo-to was first medicated for muscular pain which was called Komuragaeri, and it has been reported that it is effective for peripheral nerve dysfunction such as arthralgia and numbness. Recently, Paclitaxel (T) and Carboplatin (J) combination chemotherapy (TJ chemotherapy) has been a standard first-line chemotherapy for epithelial ovarian carcinoma. For the arthralgia and muscular pain occurring in TJ chemotherapy, non-steroid-anti-inflammatory drugs (NSAIDs), Vitamin B12 (VB12) and Shakuyaku-Kanzo-to are the major medications. In this study, we examined twenty-one cases in which arthralgia and muscular pain occurred in TJ chemotherapy (including 16 cases as first-line chemotherapy). In all cases, patients took 7.5 g of Shakuyaku-Kanzo-to orally per day for eight days. We investigated the efficacy of Shakuyaku-Kanzo-to retrospectively with the following results. In nine cases (43%), Shakuyaku-Kanzo-to was effective in reducing pain. Especially in TJ chemotherapy as first-line chemotherapy, Shakuyaku-Kanzo-to was even more effective in reducing pain. We suggested that Paclitaxel combination chemotherapy with Shakuyaku-Kanzo-to taken orally is a more safe and tolerable way to reduce pain in epithelial ovarian carcinoma.