Experimental and clinical trial investigations of phyto-extracts, phyto-chemicals and phyto-formulations against oral lichen planus: A systematic review.

ETHNOPHARMACOLOGICAL RELEVANCE: Bio-assay guided phytoextracts and derived phytoconstituents reported having multipotent biological activities and nearly 60-80% of the global population still using natural regimens as an alternative therapeutic source. This study focused on the ethnopharmacological and experimental evidence of natural remedies that are effective in treating oral lichen planus (OLP), a chronic T-cell mediated autoimmune disease that is associated with oral cancer transmission. AIM OF THE REVIEW: A number of studies have shown that antioxidants and antiinflammatory phytoextracts and phyto-constituents are effective against OLP. In this systematic review, we summarize the details of experimentally assessed ancient Traditional Chinese Medicine (TCM), Indian Ayurveda or Ayurvedic Medicine, and Japanese Kampo Medicine (JKM) regimens (crude extracts, individual phytochemicals, and phyto-formulations) that reduce oral lesion, severity index and pain associated with OLP based on studies conducted in vivo, in vitro, and in randomized controlled trials (RCTs). MATERIALS AND METHODS: Experimental, clinical and RCT investigation reports were gathered and presented according to PRISMA-2020 format. Briefly, the information was obtained from PubMed, ScienceDirect, Wiley journal library, Scopus, Google Scholar with ClinicalTrials.gov (a clinical trial registry database operated by the National Library of Medicine in the United States). Further, individual phytochemical structures were verified from PubChem and ChemSpider databases and visualized by ChemDraw 18.0 software. RESULTS: We summarized 11 crude phytoextracts, 7 individual phytochemicals, 9 crude formulations, 8 specific TCM and JKM herbal cocktails, and 6 RCTs/patents corroborated by multiple in vitro, in vivo and enzyme assay methods. Briefly, plants and their family name, used plant parts, reported phytochemicals and their chemical structure, treatment doses, and duration of each experiment were presented more concisely and scientifically. CONCLUSION: Documentation of evidence-based natural ethnomedicines or remedies could be useful for promoting them as potential, cost-effective and less toxic alternatives or as complementary to commonly prescribed steroids towards the control of OLP.

Historical Study for the Differences of Processing of Pinellia ternata Tuber Between China and Japan.

Pinellia Tuber (the dried tuber of Pinellia ternata (Thunb.) Makino [Araceae]) (PT) is a crude drug used in traditional Chinese medicine (TCM) and Japanese Kampo medicine. PT is subjected to additional processing before use in TCM because of its toxic, while the processing has not been used in Kampo medicine. The aim of this study is to clarify the reason why the differences about the processing of PT between TCM and Kampo medicine have been appeared. We investigated successive literatures published in China and in Japan from the Han dynasty to the modern age. The descriptions about the processing of PT in China had appeared since the Later Han dynasty as washing, and after that, various processing methods have been recorded, such as boiling, steaming, making cakes, and fermenting to prepare PT malt (PTM) with various drug additives. The objective of the processing for PT was not only to remove its toxicity but to change drug properties, and several kinds of processed PT had been developed to treat different types of "phlegm" in the Ming dynasty. The current Chinese Pharmacopoeia recommends the use of processed PT to avoid the toxicity, and registers unprocessed PT as well as three kinds of processed PT except for PTM which had been deleted in 2015 edition. These processing methods for PT have been established in the Qing dynasty. The oldest description in Japan was appeared in 1363, and the processing methods had been influenced by the literatures in the Song dynasty. After that, the processed PT in Japan had mainly been PTM until the 18th century. In 1738, Shuan Kagawa wrote that PT should not be processed because its pharmacological effects disappeared and the toxicity of PT disappeared by preparing its decoction without processing. Then, the processing of PT has been unpopular, and the Japanese Pharmacopoeia has registered PT since 1939 without any processing. Compared to TCM, Japanese Kampo medicine has tended to avoid ideologism based on traditional knowledge and to adopt positivism. This policy has reflected the differences in the processing of PT between Kampo medicine and TCM.

"Kambakutaisoto" and Emotional Instability Associated With Premenstrual Syndrome.

Many women suffer from premenstrual syndrome (PMS), which can be considered a modern illness in this busy society; mental symptoms, such as irritability, often affect the surroundings and result in loss of self-confidence. The symptoms of PMS are diverse, and it is often difficult to treat psychiatric and social symptoms with low-dose estrogen progestin combination drug (LEP) alone. Selective serotonin reuptake inhibitors (SSRIs) are also effective; however, many are unable to take them owing to their side effects. "Kambakutaisoto" is a Kampo medicine consisting of "jujube," "licorice," and "wheat," which is often described as "food"; however, it is highly effective in treating emotional instability attributed to PMS in sensitive young women. There are many reports on the effects of kambakutaisoto; the molecular nutritional findings of kambakutaisoto, which has dramatic effects despite its mild composition of crude drugs, have also been reported, suggesting an association with premenstrual exacerbation of functional hypoglycemia. A narrative review of its clinical effects on PMS and the results of molecular nutrition studies was performed.

Clinical Risk Factors of Licorice-Induced Pseudoaldosteronism Based on Glycyrrhizin-Metabolite Concentrations: A Narrative Review.

Licorice, the dried root or stolon of Glycyrrhiza glabra or G. ularensis, is commonly used worldwide as a food sweetener or crude drug. Its major ingredient is glycyrrhizin. Hypokalemia or pseudoaldosteronism (PsA) is one of the most frequent side effects of licorice intake. Glycyrrhizin metabolites inhibit type 2 11ß-hydroxysteroid dehydrogenase (11ßHSD2), which decomposes cortisol into inactive cortisone in the distal nephron, thereby inducing mineralocorticoid receptor activity. Among the several reported glycyrrhizin-metabolites, 18ß-glycyrrhetyl-3-O-sulfate is the major compound found in humans after licorice consumption, followed by glycyrrhetinic acid. These metabolites are highly bound to albumin in blood circulation and are predominantly excreted into bile via multidrug resistance-associated protein 2 (Mrp2). High dosage and long-term use of licorice are constitutional risk factors for PsA. Orally administered glycyrrhizin is effectively hydrolyzed to glycyrrhetinic acid by the intestinal bacteria in constipated patients, which enhances the bioavailability of glycyrrhizin metabolites. Under hypoalbuminemic conditions, the unbound metabolite fractions can reach 11ßHSD2 at the distal nephron. Hyper direct-bilirubin could be a surrogate marker of Mrp2 dysfunction, which results in metabolite accumulation. Older age is associated with reduced 11ßHSD2 function, and several concomitant medications, such as diuretics, have been reported to affect the phenotype. This review summarizes several factors related to licorice-induced PsA, including daily dosage, long-term use, constipation, hypoalbuminemia, hyper direct-bilirubin, older age, and concomitant medications.

Kambakutaisoto Treatment for Children With Night Crying and Arousal Parasomnias Developed During Prolonged Hospitalization for Hematological and Oncological Diseases.

OBJECTIVE: The lack of an established treatment standard prompted an examination of whether kambakutaisoto, an herbal formula, is effective for non-rapid eye movement (NREM)-related parasomnias and night crying (provisionally defined as an infantile form of arousal parasomnia). METHODS: This study included 137 children aged median 4.1 years (range, 0.02-18.5) who were admitted for hematological and oncological diseases. RESULTS: Of 137, 3 children developed recurrent episodes of NREM-related parasomnias, and 3 developed night crying. The proportion of children with night-crying/parasomnia receiving invasive procedures was significantly higher than those without (100% vs. 47%, P = .013). All 6 children with night crying/parasomnia received kambakutaisoto at a dose of 0.13-0.22 g/kg per os and responded from the start of administration with a significant reduction in the number of episodes. No adverse effects were observed. CONCLUSION: Kambakutaisoto may be a safe and promising therapy for night crying and NREM-related parasomnias in children.

Application status of classical prescription in traditional Chinese medicine and Japanese Kampo medicine / 中草药

Classical prescription is long-lasting which is characterized by simple composition and obvious curative effect. It is popular over China and welcomed by many people. Japanese Kampo medicine and traditional Chinese medicine originated from the same resource but flowed into two branches. Some classical prescription experts are mostly influenced by Japanese Kampo medicine, emphasizing the correspondence between prescriptions and syndromes, physical identification and abdominal diagnosis, which have become the research direction of most classical prescription scholars. Traditional Chinese medicine and Japanese Kampo medicine differ in the dialectical system, application form, dose and dosage form of classical prescription. It is important to have a clear insight of the development status of classical prescription in Chinese medicine and that of Japanese Kampo medicine, understand the differences between them and make full use of advantages and avoid disadvantages. It can provide ideas for the correct development path of classical prescription and reference for the research of preparation of classical prescription in China.

Effects of Osthol Isolated from Cnidium monnieri Fruit on Urate Transporter 1.

(1) Background: Crude drugs used in traditional Japanese Kampo medicine or folk medicine are major sources of new chemical entities for drug discovery. We screened the inhibitory potential of these crude drugs against urate transporter 1 (URAT1) to discover new drugs for hyperuricemia. (2) Methods: We prepared the MeOH extracts of 107 different crude drugs, and screened their inhibitory effects on URAT1 by measuring the uptake of uric acid by HEK293/PDZK1 cells transiently transfected with URAT1. (3) Results: We found that the extract of the dried mature fruit of Cnidium monnieri inhibited urate uptake via URAT1. We isolated and identified osthol as the active ingredient from this extract. Osthol noncompetitively inhibited URAT1 with an IC50 of 78.8 µM. We evaluated the effects of other coumarins and found that the prenyl group, which binds at the 8-position of coumarins, plays an important role in the inhibition of URAT1. (4) Conclusions: Cnidium monnieri fruit may be useful for the treatment of hyperuricemia or gout in traditional medicine, and its active ingredient, osthol, is expected to be a leading compound for the development of new drugs for hyperuricemia.

Japanese Kampo medicine ninjin'yoeito synergistically enhances tumor vaccine effects mediated by CD8+ T cells.

Although Japanese traditional herbal medicine (Kampo) has been widely applied to the treatment of various diseases, including cancer, their mechanisms of action have not yet been elucidated in detail, particularly regarding their role in tumor immunology. The present study investigated the antitumor effects of the Japanese Kampo medicine, ninjin'yoeito (NYT; Ren-Shen-Yang-Rong-Tang in Chinese), which was orally administered with or without an irradiated tumor cell vaccine to a subcutaneous CT26 colon carcinoma tumor model. The irradiated tumor cell vaccine in a prophylactic setting significantly delayed tumor growth in mice fed a control diet, whereas a diet containing NYT alone did not exert any antitumor effects in vivo. However, the inhibition of tumor growth was significantly greater in vaccinated mice fed the NYT diet compared with in vaccinated mice given the control diet. These results suggest that NYT synergistically enhances the effects of the antitumor vaccine. The depletion of cluster of differentiation (CD)8+ T cells abrogated these effects, indicating that antitumor activity required CD8+ T cells. Furthermore, reductions in CD4+ CD25+ and forkhead box protein 3+ T regulatory cell numbers were more apparent between vaccinated mice fed the NYT diet and non-vaccinated mice fed the control diet than between vaccinated mice and non-vaccinated mice fed the control diet, suggesting that the weaker impact of T regulatory cells contributes to the augmentation of antitumor immunity by CD8+ T cells in vaccinated mice fed with NYT. Overall, these results indicate that NYT synergistically enhances the effects of the prophylactic tumor vaccine mediated by CD8+ T cells and that this Japanese Kampo medicine has potential as a useful adjuvant agent for cancer immunotherapy.

Broadening our perspectives on complementary and alternative medicine for menopause: A narrative review.

Complementary and alternative medicine (CAM) is widely used for menopause, although not all women disclose use to their healthcare providers. This narrative review aims to expand providers' understanding of cross-cultural approaches to treating and managing menopause by providing an overarching framework and perspective on CAM treatments. Increased provider understanding and awareness may improve not only provider-patient communication but also effectiveness of treatments. The distinction between illness (what patients suffer) and disease (what physicians treat) highlights the gap between what patients seek and doctors provide, and may help clarify why many women seek CAM at menopause. For example, CAM is often sought by women for whom biomedicine has been unsuccessful or inaccessible. We review the relevance to menopause of three CAM categories: natural products, mind-body practices including meditation, and other complementary health approaches including traditional Chinese medicine (TCM) and Japanese Kampo. Assessing the effectiveness of CAM is challenging because of the individualized nature of illness patterns and associated treatments, which complicate the design of randomized controlled trials. Because many women seek CAM due to inefficacy of biomedical treatments, or cultural or economic marginalization, biomedical practitioners who make an effort to learn about CAM and ask patients about their CAM use or interest may dramatically improve the patient-provider relationship and rapport, as well as harnessing the 'meaning response' (Moerman, 2002) imbued in the clinical encounter. By working with women to integrate their CAM-related health-seeking behaviors and treatments, providers may also boost the efficacy of their own biomedical treatments.

[6]-gingerol and [6]-shogaol, active ingredients of the traditional Japanese medicine hangeshashinto, relief oral ulcerative mucositis-induced pain via action on Na+ channels.

The traditional Japanese herbal medicine hangeshashinto (HST) has beneficial effects for the treatment of oral ulcerative mucositis (OUM) in cancer patients. However, the ingredient-based mechanism that underlies its pain-relieving activity remains unknown. In the present study, to clarify the analgesic mechanism of HST on OUM-induced pain, we investigated putative HST ingredients showing antagonistic effects on Na+ channels in vitro and in vivo. A screen of 21 major ingredients using automated patch-clamp recordings in channel-expressing cells showed that [6]-gingerol and [6]-shogaol, two components of a Processed Ginger extract, considerably inhibited voltage-activated Na+ currents. These two ingredients inhibited the stimulant-induced release of substance P and action potential generation in cultured rat sensory neurons. A submucosal injection of a mixture of [6]-gingerol and [6]-shogaol increased the mechanical withdrawal threshold in healthy rats. In a rat OUM model, OUM-induced mechanical pain was alleviated 30min after the swab application of HST despite the absence of anti-bacterial and anti-inflammatory actions in the OUM area. A swab application of a mixture of [6]-gingerol and [6]-shogaol induced sufficient analgesia of OUM-induced mechanical or spontaneous pain when co-applied with a Ginseng extract containing abundant saponin. The Ginseng extract demonstrated an acceleration of substance permeability into the oral ulcer tissue without an analgesic effect. These findings suggest that Na+ channel blockage by gingerol/shogaol plays an essential role in HST-associated analgesia of OUM-induced pain. This pharmacological mechanism provides scientific evidence supporting the use of this herbal medicine in patients suffering from OUM-induced pain.

Predicting Japanese Kampo formulas by analyzing database of medical records: a preliminary observational study.

BACKGROUND: Approximately 90 % of physicians in Japan use Kampo medicine in daily practice. However, it is a challenge for physicians who do not specialize in Kampo medicine to select a proper Kampo formula out of the 148 officially approved formulas, as the decision relies on traditional measurements and traditional medicine pattern diagnoses. The present study tries to evaluate the feasibility of a decision support system for frequently used Kampo formulas. METHODS: Our study included 393 patients who visited the Kampo Clinic at Keio University Hospital for the first time between May 2008 and March 2013. We collected medical records through a browser-based questionnaire system and applied random forests to predict commonly prescribed Kampo formulas. RESULTS: The discriminant rate was the highest (87.0 %) when we tried to predict a Kampo formula from two candidates using age, sex, body mass index, subjective symptoms, and the two essential and predictable traditional medicine pattern diagnoses (excess-deficiency and heat-cold) as predictor variables. The discriminant rate decreased as the candidate Kampo formulas increased, with the greatest drop occurring between three (76.7 %) and four (47.5 %) candidates. Age, body mass index, and traditional medicine pattern diagnoses had higher importance according to the characteristics of each Kampo formula when we utilized the prediction model, which predicted a Kampo formula from among three candidates. CONCLUSIONS: These results suggest that our decision support system for non-specialist physicians works well in selecting appropriate Kampo formulas from among two or three candidates. Additional studies are required to integrate the present statistical analysis in clinical practice.

The traditional Japanese medicine hangeshashinto alleviates oral ulcer-induced pain in a rat model.

OBJECTIVE: Recent studies have demonstrated that mouthwash made with the traditional Japanese medicine hangeshashinto exhibits anti-inflammatory action and alleviates oral mucositis scores, including pain complaints, in patients undergoing chemoradiotherapy. However, no study has demonstrated the mechanism underlying how hangeshashinto provides pain relief in oral ulcers. DESIGN: The analgesic effects on pain-related behaviors following the topical application of hangeshashinto were evaluated in an oral ulcer rat model treated with acetic acid using recently developed methods. Indomethacin, the representative anti-inflammatory agent, was intraperitoneally administered. The tissue permeability of the oral mucosa was histologically evaluated after applying the fluorescent substance FluoroGold. RESULTS: The topical application of hangeshashinto in ulcerative oral mucosa suppressed mechanical pain hypersensitivity over 60 min, without any effects on healthy mucosa. The same drug application also inhibited oral ulcer-induced spontaneous pain. Indomethacin administration failed to block the mechanical pain hypersensitivity, though it did largely block spontaneous pain. Topical anesthesia with lidocaine showed hyposensitivity to mechanical stimulation in healthy mucosa. In the ulcer regions in which the oral epithelial barrier was destroyed, deep parenchyma was stained with FluoroGold, in contrast to healthy oral mucosa, in which staining was limiting to the superficial site. CONCLUSIONS: Hangeshashinto leads to long-lasting analgesic effects, specifically in the ulcer region by destroying the epithelial barrier. Hangeshashinto alleviates oral ulcer-induced pain in inflammation-dependent and/or independent manner.

The Origin of Japanese Kampo Medicine and the Outlook of Its Clinical Research / 国际中医中药杂志

On the basis of summing up the relative works of Japanese journals,this article emphasized introducing the Japanese Kampo Medicine schools,the actuality of Japanese Kampo Medicine clinical researches and the outlook of the Kampo Medicine.This article aimed at making clinicians and researchers understand the form of Japanese Kampo Medichue and thinking method of Japanese Kampo Medicine school,hoping to provide reference for clinical treatment and research.

The Tradition and the Development of the Japanese Kampo-Medicine / 日本東洋医学雑誌

The historical circumstances about the application of the Japanese Kampo-medicine on the point of clinical view are the following that the original directions of the Chinese medical classics have been strictly adhered in China while the directions of those have been remarkably developed in Japan after the import. Now the Japanese Kampo-medecine are based upon these recent developments as well as the current pharmacological studies. Several clinical casereports are demonstrated who are treated with Daisaiko-to, Hachimijio-gan, and Hochuekki-to.<br>Finally the noteworthy opinions by Sensai Nagayo who laid the foundation of the medical system in modern Japan are quoted from his autobiography. Namely the really valuable new medicine should be established with the combination of both the western medicine and the Kampo-medicine.