Multiple stage IV colorectal cancers in a patient who received multidisciplinary treatment, including chemotherapy and Japanese Kampo medicine: A case report.

FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab is the preferred first-line treatment for right-sided metastatic colorectal cancer with RAS mutation. However, severe adverse events are common in Japanese patients. We report the successful management of multiple stage IV colorectal cancers in a patient who received multidisciplinary treatment, including chemotherapy and Japanese Kampo medicine. A 68-year-old man presented with epigastralgia and appetite loss and was diagnosed with multiple stage IV colorectal cancers. Colonoscopy identified type II tumors in the ascending colon, sigmoid colon, and upper rectum. Histopathological examination of a biopsy specimen revealed well- to moderately differentiated tubular adenocarcinoma. Enhanced computed tomography of the thorax and abdomen showed multiple pulmonary nodules and para-aortic lymph node swelling. Laparoscopic loop-ileostomy was performed to avoid bowel obstruction due to severe stenosis of ascending colon cancer. Intraoperative observation revealed two white nodules suggestive of metastasis in the lateral area of the liver. Therefore, we diagnosed multiple stage IV colorectal cancers with multiple metastases (lung, liver, and distant lymph nodes). His postoperative course was uneventful, and chemotherapy was started. Since the cancer cells harbored a RAS mutation, he received FOLFOXIRI plus bevacizumab. Japanese Kampo medicine consisting of Hangeshashinto and Juzen-taiho-to, to prevent diarrhea and fatigue, was administered daily. After 12 courses of chemotherapy, though circumferential stenosis still existed in the ascending colon, the tumors in the sigmoid colon and upper rectum were unclear. Enhanced computed tomography showed shrinkage of the pulmonary nodules and para-aortic lymph node; therefore, laparoscopic-assisted ileocecal resection was performed. The postoperative histopathological examination revealed moderately differentiated adenocarcinoma. The patient recovered uneventfully, and Kampo medicine consisting of Ninjin'yoeito was administered for postoperative weakness. Administration of adjuvant chemotherapy in this patient led to a near complete response that has been maintained without recurrence for 2 years and 8 months without reduced quality of life.

Efficacy of Juzen-taiho-to against vincristine-induced toxicity in dogs.

Vincristine, one of the anti-cancer drugs used in veterinary practice, has adverse hematological and gastrointestinal effects in dogs. Juzen-taiho-to is a traditional Chinese medicine used for patients with anorexia in human medicine. However, the protective effects of Juzen-taiho-to against anti-cancer drug-induced toxicity in dogs have not been investigated. We therefore examined whether the administration of Juzen-taiho-to to dogs affects gastric motility, and vincristine-induced gastrointestinal and hematological toxicity. The study was composed of three trials. In the first trial, Juzen-taiho-to (450 mg/kg/day) was orally administered to five dogs. In the second and third trials, vincristine (0.75 mg/m2) was intravenously administered to each dog in the absence or presence of Juzen-taiho-to (450 mg/kg/day). During these trials, gastric motility and blood parameters were assessed. Juzen-taiho-to increased gastric motility and improved vincristine-induced gastrointestinal, but not hematological, adverse effects in dogs. This study suggested that Juzen-taiho-to may be applicable for gastrointestinal care in dogs receiving chemotherapy.

Possible anti-oxidative effects of long-term administration of Juzen-taiho-to in dogs.

It is known that oxidative stress is related to disease in humans and dogs. Many traditional Chinese medicines have been reported to have anti-oxidative effects, but there are no reports that they have anti-oxidative effects in dogs. In this study, we examined the anti-oxidative effects of Juzen-taiho-to, a traditional Chinese medicine, in dogs. Five healthy female beagle dogs (38-41 months of age weighing 8.6-10.7 kg) were orally administered Juzen-taiho-to at 450 mg/kg with food for 28 days. Blood samples were taken from all five dogs on days 0, 7, 14, 21, and 28. Using the blood samples, improvement of the antioxidant level as assessed by the biological antioxidant potential (BAP), reduced oxidative stress level as assessed by derivatives of reactive oxygen metabolites (d-ROMs), and improvement of blood fluidity were examined. Regarding the antioxidant level and blood fluidity, no significant difference was observed, but the oxidative stress level on days 14, 21, and 28 was significantly lower than that on day 0. Thus, Juzen-taiho-to may have anti-oxidative effects in dogs by reducing oxidative stress and be useful for oxidative stress-related diseases in dogs.

Abundance of Plant-Associated Gammaproteobacteria Correlates with Immunostimulatory Activity of Angelica sinensis.

Background: Angelica sinensis is a medicinal plant known for a variety of biological effects, including its ability to stimulate innate immune cells in humans. Recent studies indicate that the immunostimulatory activity of A. sinensis arises from microbe-associated molecular patterns (MAMPs) of plant-associated bacteria. However, it is unknown which bacterial taxa in A. sinensis are responsible for the production of immunostimulatory MAMPs. Methods: Samples of A. sinensis were subjected to a cell-based assay to detect monocyte-stimulation and 16S ribosomal RNA amplicon sequencing, which revealed their immunostimulatory activity and microbial communities. The resulting data were analyzed by Linear discriminant analysis effect size (LEfSe), an online biostatistical tool for metagenomic biomarker discovery, to identify the bacterial taxonomical features correlated with the immunostimulatory activity. Results: A series of bacterial taxa under Gammaproteobacteria correlated positively with the immunostimulatory activity, whereas several Gram-positive taxa and Betaproteobacteria correlated negatively with the activity. Conclusions: The identified bacterial taxa set a new stage to characterize immunostimulatory MAMPs in plants.

Randomized controlled trial of juzen-taiho-to in children with recurrent acute otitis media.

OBJECTIVE: Recurrent acute otitis media (AOM) in young children is rapidly increasing worldwide. Repeated antibiotic use leads to antibiotic-resistant pathogen development. Complementary and alternative medicine approaches have been suggested as a supplemental treatment option to conventional antimicrobial medicine. This randomized, parallel-group, open-label, non-herbal medicine controlled trial assessed the efficacy of a traditional Japanese herbal medicine, juzen-taiho-to (JTT) for AOM prevention in otitis-prone children. METHODS: Children prone to recurrent AOM aged 6-48 months were recruited from 26 otolaryngology clinics in Japan and received conventional AOM treatment based on Japanese guidelines with or without 2 daily oral doses of JTT (0.10-0.25g/kg/day). The mean number of AOM episodes, coryza episodes, and duration of total antibiotic administration per month were compared during 3-month intervention. RESULTS: At least one episode of AOM was diagnosed in 71% of JTT-group and 92% of control participants during follow-up. JTT administration reduced the frequency of AOM episodes by 57% compared with children who received conventional treatment alone (0.61±0.54 vs. 1.07±0.72 AOM instances/month; P=0.005) and also significantly decreased number of coryza episodes (P=0.015) and total antibiotic administration (P=0.024). CONCLUSIONS: This is the first report of recurrent AOM prevention by herbal medication. JTT appears to effectively prevent recurrent AOM in children. Subsequent double-blind studies are needed to confirm the beneficial effects of JTT on recurrent AOM and upper respiratory tract infections.

The translational aspect of complementary and alternative medicine for cancer with particular emphasis on Kampo.

Complementary and alternative medicine (CAM) including Japanese Kampo is known to have anticancer potential. An increasing number of cancer survivors are using CAM for disease prevention, immune system enhancement, and symptom control. Although there have been abundant previous clinical reports regarding CAM, scientific investigations aimed at acquiring quantifiable results in clinical trials, as well as basic research regarding CAM, have only recently been undertaken. Recent studies suggest that CAM enhancement of immune function is related to cytokines. This review provides a translational aspect of CAM, particularly Hozai in Kampo from both scientific and clinical points of view for further development of CAM for cancer treatment.

Immunostimulatory lipid nanoparticles from herbal medicine.

Reproducibility is an important issue in biological characterization of drug candidates and natural products. It is not uncommon to encounter cases in which supposedly the same sample exhibits very different biological activities. During our characterization of macrophage-stimulatory lipids from herbal medicine, it was found that the potency of these lipids could vary substantially from experiment to experiment. Further analysis of this reproducibility issue led to the discovery of solvent-dependent nanoparticle formation by these lipids. While larger nanoparticles (approximately 100 nm) of these lipids showed modest macrophage-stimulatory activity, smaller nanoparticles (<10 nm) of the same lipids exhibited substantially higher potency. Thus, the study revealed an unexpected link between nanoparticle formation and macrophage-stimulatory activity of plant lipids. Although nanoparticles have been extensively studied in the context of vehicles for drug delivery, our finding indicates that drugs themselves can form nanoassemblies, and their biological properties may be altered by the way they assemble.

Preventive Effects of Juzen-taiho-to on Endometrial Carcinogenesis in Mice / 日本東洋医学雑誌

Two experiments were conducted to determine effects of Juzen-taiho-to on endometrial carcinogenesis in mice. In the first experiment, Juzen-taiho-to treatment (2 weeks) decreased the levels of estradiol-17 β (E₂)-stimulated expression of c-fos/jun mRNA and their oncoproteins, determined by reverse transcription-polymerase chain reaction and Southern blot analysis, and immunohistochemical method, in the uteri of ovarectomized mice. For the second experiment, 93 female ICR mice were given N-methyl-N-nitrsourea (MNU) solution (1mg/100g body wt.) and normal saline (as controls) into their left and right uterine corpora, respectively, and were divided into four groups. Group 1 was given 0.2% Juzen-taiho-to and 5 ppm E₂-containing diet. Group 2 was given 5ppm E₂-containing diet alone. Group 3 was exposed to 0.2% Juzen-taiho-to containing diet alone. Group 4 was kept on the basal diet alone and treated as a control. Juzen-taiho-to treatment significantly decreased incidences of the uterine endometrial atypical (P<0.01), complex (P<0.05) and simple hyperplasias (P<0.01), under estrogenic stimulation. It is suggested that Juzen-taiho-to has an inhibitory effect on E₂-related endometrial carcinogenesis in mice, relevantly through suppression of estrogeninduced c-fos/jun-expression.

KAMPO Medicine for the Self-Medication Age / 日本東洋医学雑誌

Kampo medicines, boiling water extracts of several kinds of herbal medicines, has been widely used for the clinical treatments in Japan. This medicine was created in China and brought to Japan via Korean peninsula at 5th century and has followed an independent course of development in Japan. But a modern scientific knowledge on Kampo medicines are still lacking, so this precious properties are slighted by modern medical treatment.<br>Last twenty five years, we have investigated the Kampo medicine chemically and pharmacologically to change this situation. In this paper, few topics will be discussed as shown bellow.<br>1) Difference between Kampo medicines and modern western medicines<br>2) Structural transformation of ingredients of crude drug<br>3) What is Kampo medicines based on components<br>4) Biological evaluation of some Kampo medicines<br>a. Effects of Sho-saiko-to toward the expression of P450mRNA<br>b. Effects of some Kampo formula toward the AD models<br>c. Effects of some Kampo formula toward the rheumatic models

Effect of Juzen-taiho-to on the Serum Alanine Aminotransferase Levels in Patients with HCV-associated Chronic Hepatitis or Liver Cirrhosis / 日本東洋医学雑誌

Although the combined administration of glycyrrhizin (SNMC) and ursodeoxycholic acid (UDCA) is usually used for intractable patients with active HCV-associated chronic hepatitis (HCV-CH) or cirrhosis (LC), there are many cases that do not respond to this combination therapy. In this study, we examined the effects of adding Juzen-taiho-to (TJ-48) to lower the serum alanine aminotransferase (s-ALT=s-GPT) levels in such cases. Methods: The average s-ALT levels for 6 months were compared before and after 7.5g of Juzen-taiho-to was added to the combined therapy of SNMC and UDCA for 9 HCV-CH and 12 HCV-LC patients. In some cases, the effectiveness of the therapy over 12 months was also evaluated. Results: In the HCV-CH cases s-ALT levels were significantly decreased in 3 of 9 (33%) cases in 6 months (about 30 INU in average). In the HCV-LC cases, s-ALT levels were significantly decreased in 5 of 12 (42%) cases in 6 months (more than 40 INU in average). There were some patients whose s-ALT levels decreased significantly after 6 months. As to the improvement of clinical symptoms, general fatigability improved in 12 out of 20 cases (60%) and anorexia improved in 10 out of 19 cases (53%). Conclusions: Juzen-taiho-to (TJ-48, 7.5g daily) added to the combined therapy of SNMC and UDCA may be an effective therapy for intractable cases of active HCV-CH or LC.

Effects of Juzen-taiho-to and M-CSF on Thrombocytopenia induced by Anti-cancer Drugs in Gynecologic Malignancies / 日本東洋医学雑誌

We investigated the clinical effect of Juzen-taiho-to and macrophage-colony stimulating factor (M-CSF) on thrombocytopenia induced by anti-cancer chemotherapy in gynecologic malignancies. We discussed 31 courses in 20 patients. Juzen-taiho-to and/or M-CSF were given when indicated from serum platelet level. Twenty-eight courses (90.3%) in 17 patients did not need transfusion of platelet, and 3 courses in 3 patients needed it. It suggested that Juzen-taiho-to and M-CSF might be effective. As platelet-free plasma TGF-β1 level during the treatment of Juzen-taiho-to alone was remarkably increased, it might enhance the antitumoral action. Accordingly, combination treatments of Juzen-taiho-to and M-CSF might be effective for thrombocytopenia induced by anti-cancer chemotherapy.

The Clinical Effect of Jyuzen-Taiho-to for Malaises in Hemodialysis Patients / 日本東洋医学雑誌

In hemodialysis patients, malaise is a common compliant. We tried to use Juzen-taiho-to as a treatment for malaise. Seventeen patients took 5g of Juzen-taiho-to twice a day for 8 weeks, and then responded to questionaires regarding their condition. Twelve patients experienced a decreased feeling of malaise, but 4 patients dropped out of the study, and 1 patient was ineffective. Hemodialysis patients usually feel cold and their skin is dry; these are symptoms of weak Ki (elemental energy) and anemia. Juzen-taiho-to is a medicine for Ki and blood deficiency. Juzen-taiho-to is a useful drug for treatment of malaise in hemodialysis patients.

A Case of Thrombocytopenia arising from Systemic Lupus Erythematosus Effectively Treated with Juzen-Taiho-To / 日本東洋医学雑誌

A patient with systemic lupus erythematosus (SLE), complicated by severe thrombocytopenia was successfully treated with Juzen-taiho-to. The patient was a 38-year-old woman presenting thrombocytopenia in 1974. She was diagnosed as having SLE with the appearance of renal failure in 1975. In 1984, she began blood dialysis due to deterioration of renal function. In addition, she repeatedly suffered from severe bleeding episodes due to thrombocytopenia. In 1989, she visited our clinic to undergo Kampo therapy, with no significant results obtained with any of the formulas tried.<br>In September 1992, she suffered from duodenal ulcer bleeding and stopped Kampo therapy for some time. However, since she began taking Juzen-taiho-to in June 1993, her thrombocytopenia improved and her platelet count stabilized at 10-15×10⁴/mm³. This made it possible to taper the dosage of the steroids being administered. Since July 1994, the prednisolone (PSL) dosage has been 5mg on alternate days. Since July 1995, the anti-DNA antibody was negative. The platelet count has been maintained at 15-20×10⁴/mm³ (as of December, 1996).

Nine Clinical Case Studies using Juzen-taiho-to for the Closure of Fistulae in Children / 日本東洋医学雑誌

Post-inflammatory or post-operative fistula formation is a troublesome complication. As these fistulae are not amenable to closure, surgical excision is usually indicated afterwards. In order to close these fistulae, Juzen-taiho-to was administered to nine children. The location of these fistulae were: cervical region in 1 patient, abdominal wall in 4 patients and external genitalia (perineum) in 4 patients. The fistulae located in the cervical and abdominal regions closed within three weeks of administration, and those located in the external genitalia within six months, including anal fistula. These results suggest the applicability of Juzen-taiho-to for fistula closure.