Gut Microbiota and Bile Acids Mediate the Clinical Benefits of YH1 in Male Patients with Type 2 Diabetes Mellitus: A Pilot Observational Study.

Our previous clinical trial showed that a novel concentrated herbal extract formula, YH1 (Rhizoma coptidis and Shen-Ling-Bai-Zhu-San), improved blood glucose and lipid control. This pilot observational study investigated whether YH1 affects microbiota, plasma, and fecal bile acid (BA) compositions in ten untreated male patients with type 2 diabetes (T2D), hyperlipidemia, and a body mass index ≥ 23 kg/m2. Stool and plasma samples were collected for microbiome, BA, and biochemical analyses before and after 4 weeks of YH1 therapy. As previous studies found, the glycated albumin, 2-h postprandial glucose, triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels were significantly improved after YH1 treatment. Gut microbiota revealed an increased abundance of the short-chain fatty acid-producing bacteria Anaerostipes and Escherichia/Shigella. Furthermore, YH1 inhibited specific phylotypes of bile salt hydrolase-expressing bacteria, including Parabacteroides, Bifidobacterium, and Bacteroides caccae. Stool tauro-conjugated BA levels increased after YH1 treatment. Plasma total BAs and 7α-hydroxy-4-cholesten-3-one (C4), a BA synthesis indicator, were elevated. The reduced deconjugation of BAs and increased plasma conjugated BAs, especially tauro-conjugated BAs, led to a decreased glyco- to tauro-conjugated BA ratio and reduced unconjugated secondary BAs. These results suggest that YH1 ameliorates T2D and hyperlipidemia by modulating microbiota constituents that alter fecal and plasma BA compositions and promote liver cholesterol-to-BA conversion and glucose homeostasis.

Chinese Herbal Medicine, Guilu Erxian Glue, as Alternative Medicine for Adverse Side Effects of Chemotherapy in Doxorubicin-Treated Cell and Mouse Models.

Doxorubicin (DOX), a chemotherapeutic drug, often causes many adverse side effects in patients with cancer, such as weight loss, motor disability, blood circulation defects, myelosuppression, myocardial injury, joint degeneration, and bone loss. The Chinese herbal medicine Guilu Erxian Glue (GEG) has been used in the prevention and treatment of osteoarthritis and osteoporosis for hundreds of years, with considerably fewer side effects. We expected that GEG could serve as a protective and beneficial alternative treatment for DOX-induced adverse side effects. In this study, we evaluated whether GEG can alleviate DOX-induced weight loss, motor disability, abnormal blood circulation, myelosuppression, myocardial injury, joint degeneration, and bone loss by using chemotherapy models of synoviocyte cell line HIG-82 and mice. Moreover, we examined the antioxidant capacity of GEG by using DPPH (1,1-diphenyl-2-picrylhydrazyl) free-radical scavenging. Our results revealed that GEG treatment can significantly enhance DPPH free-radical scavenging and reduce DOX-induced cytotoxicity in synoviocyte HIG-82 cells. In addition, GEG treatment for 2 weeks can significantly relieve weight loss, enhance exhaustive exercise capacity, improve blood circulation, alleviate myocardial oxidative stress and inflammation, and strengthen the tibias of DOX-treated mice. Thus, we suggest that GEG treatment can be a protective and alternative therapy for alleviating chemotherapy-related side effects such as weight loss, motor disability, blood circulation defects, and bone loss.

Associations Between Using Chinese Herbal Medicine and Long-Term Outcome Among Pre-dialysis Diabetic Nephropathy Patients: A Retrospective Population-Based Cohort Study.

Background: Chronic kidney disease (CKD) has become a worldwide burden due to the high co-morbidity and mortality. Diabetic nephropathy (DN) is one of the leading causes of CKD, and pre-dialysis is one of the most critical stages before the end-stage renal disease (ESRD). Although Chinese herbal medicine (CHM) use is not uncommon, the feasibility of using CHM among pre-dialysis DN patients remains unclear. Materials and methods: We analyzed a population-based cohort, retrieved from Taiwan's National Health Insurance Research Database, to study the long-term outcome of using CHM among incident pre-dialysis DN patients from January 1, 2004, to December 31, 2007. All patients were followed up to 5 years or the occurrence of mortality. The risks of all-cause mortality and ESRD were carried out using Kaplan-Meier and competing risk estimation, respectively. Further, we demonstrated the CHM prescriptions and core CHMs using the Chinese herbal medicine network (CMN) analysis. Results: A total of 6,648 incident pre-dialysis DN patients were analyzed, including 877 CHM users and 5,771 CHM nonusers. With overlap weighing for balancing all accessible covariates between CHM users and nonusers, we found the use of CHM was associated with lower all-cause mortality (0.22 versus 0.56; log-rank test: p-value <0.001), and the risk of mortality was 0.42 (95% CI: 0.36-0.49; p-value <0.001) by adjusting all accessible covariates. Further, the use of CHM was associated with a lower risk of ESRD (cause-specific hazard ratio: 0.59, 95%CI: 0.55-0.63; p-value <0.001). Also, from the 5,901 CHM prescriptions, we found Ji-Sheng-Shen-Qi-Wan, Astragalus mongholicus Bunge or (Astragalus membranaceus (Fisch.) Bge.), Plantago asiatica L. (or Plantago depressa Willd.), Salvia miltiorrhiza Bunge, and Rheum palmatum L. (or Rheum tanguticum (Maxim. ex Regel) Balf., Rheum officinale Baill.) were used as core CHMs for different CHM indications. Use of core CHMs was associated with a lower risk of mortality than CHM users without using core CHMs. Conclusions: The use of CHM seemed feasible among pre-dialysis DN patients; however, the beneficial effects still need to be validated by well-designed clinical trials.

Ketoanalogue supplements reduce mortality in patients with pre-dialysis advanced diabetic kidney disease: A nationwide population-based study.

BACKGROUND & AIMS: Metabolism dysregulation and protein energy wasting occur in patients with chronic kidney disease (CKD) and are associated with poor survival, especially in patients prior to starting dialysis. Accumulating evidence indicates that dietary supplementation with ketoanalogues (KAs, a mixture of branched-chain amino acids) exerts a variety of beneficial effects for patients with CKD. However, the role of KAs in diabetic kidney disease (DKD), one of the major causes of CKD, is still controversial. The aim of this study was to explore the impact of KA supplements on survival in patients with stage 5 DKD who have not yet started dialysis (DKD-5-ND). METHODS: We analyzed a nationwide cohort retrieved from the National Health Insurance Research Database in Taiwan to study the long-term impact of KA supplements in patients with DKD-5-ND. We enrolled 15,782 incident pre-dialysis DKD patients between January 1, 2004 and December 31, 2007. Landmark analysis was used to eliminate immortal bias, and overlap weighting was used to balance differences between the KA users and nonusers in the beginning. The primary study endpoint was all-cause mortality, and the occurrence of permanent dialysis (presenting the end-stage renal disease, ESRD) and major adverse cardiovascular events (MACEs) was also evaluated. All patients were followed for five years or until death. RESULTS: The prevalence of KA usage in the DKD-5-ND patients was 6.3%. The 5-year all-cause mortality rate in the KA users was lower than that in the nonusers (34.7% vs 42.7%). After adjusting for known covariates, the KA users still had a lower risk of mortality (adjusted hazard ratio [aHR]: 0.73, 95% confidence interval [CI]: 0.66-0.82). In addition, the incidence of ESRD was also slightly lower among the KA users (90.9% for users vs 91.2% for nonusers, adjusted cause-specific hazard ratio [aCSHR]: 0.65, 95% CI: 0.61-0.69), and the occurrence of MACEs was lower (adjusted incidence rate ratios [aIRR]: 0.76, 95% CI: 0.67-0.86). Although the all-cause mortality was higher among patientsolder than 70 years (60.5% for KA users vs 46.5% for nonusers) the risk reduction seemed prominent among older patients (aHR: 0.65, 95% CI: 0.56-0.76 for patients aged ≥70 years; aHR: 0.82, 95% CI: 0.71-0.96 for patients aged < 70 years). The reduction in risks of mortality was consistent in subgroup analysis and sensitivity tests. CONCLUSIONS: The use of KA supplements seemed to be beneficial for patients with DKD-5-ND; further in-depth analysis of using KA for these patients is warranted.

Identifying the Chinese Herbal Medicine Network and Core Formula for Allergic Rhinitis on a Real-World Database.

MATERIALS AND METHODS: Patients with a primary diagnosis of AR (ICD-9-CM code: 477.9) in 2010 were included, and the National Health Insurance Research Database in Taiwan was used as the data source. Association rule mining and social network analysis were used to establish and explore the CHM network. Possible molecular pathways of the CHM network were summarized and compared with commonly used western medicine (WM) by conducting overrepresentation analysis in the Reactome pathway database. The potential proteins acted by CHMs were obtained from the CHM ingredient-protein databases, including STITCH, TCMSP, TCMID, and TCM@Taiwan. RESULTS: There were 89,148 AR subjects found in 2010, and a total of 33,507 patients ever used CHM. On an average, 5.6 types of CHMs were utilized per prescription. Xin-Yi-Qing-Fei-Tang was used most frequently (25.5% of 222,279 prescriptions), while Xiao-Qing-Long-Tang with Xin-Yi-San was the most commonly prescribed CHM-CHM combination. Up to six distinctive clusters could be found among the CHM network, and core CHMs could be found for AR, such as Xiao-Qing-Long-Tang and Xin-Yi-Qing-Fei-Tang. A total of 140 molecular pathways were covered by the CHM network (2,432 ingredients from 31 kinds of CHMs), while 39 WMs covered 55 pathways. Among pathways responding to the immune system, WM mainly acted on cytokine signaling-related pathways, while CHM mostly acted on neutrophil/macrophage-related innate pathways and dendritic cell-related adaptive immunity pathways. CONCLUSION: Our study demonstrated and analyzed the CHM network for AR. Core CHM for AR and possible molecular pathways were presented as well, and this information is crucial for researchers to select candidates for CHM-related studies.

Laminar specificity of oscillatory coherence in the auditory cortex.

Empirical evidence suggests that, in the auditory cortex (AC), the phase relationship between spikes and local-field potentials (LFPs) plays an important role in the processing of auditory stimuli. Nevertheless, unlike the case of other sensory systems, it remains largely unexplored in the auditory modality whether the properties of the cortical columnar microcircuit shape the dynamics of spike-LFP coherence in a layer-specific manner. In this study, we directly tackle this issue by addressing whether spike-LFP and LFP-stimulus phase synchronization are spatially distributed in the AC during sensory processing, by performing laminar recordings in the cortex of awake short-tailed bats (Carollia perspicillata) while animals listened to conspecific distress vocalizations. We show that, in the AC, spike-LFP and LFP-stimulus synchrony depend significantly on cortical depth, and that sensory stimulation alters the spatial and spectral patterns of spike-LFP phase-locking. We argue that such laminar distribution of coherence could have functional implications for the representation of naturalistic auditory stimuli at a cortical level.

Traditional Chinese medicine use is associated with lower end-stage renal disease and mortality rates among patients with diabetic nephropathy: a population-based cohort study.

BACKGROUND: Diabetic nephropathy (DN) is a common complication of diabetes mellitus (DM) that imposes an enormous burden on the healthcare system. Although some studies show that traditional Chinese medicine (TCM) treatments confer a protective effect on DN, the long-term impact remains unclear. This study aims to examine end-stage renal disease (ESRD) and mortality rates among TCM users with DN. METHODS: A total of 125,490 patients with incident DN patients from 2004 to 2006 were identified from the National Health Insurance Research Database in Taiwan and followed until 2012. The landmark method was applied to avoid immortal time bias, and propensity score matching was used to select 1:1 baseline characteristics-matched cohort. The Kaplan-Meier method and competing-risk analysis were used to assess mortality and ESRD rates separately. RESULTS: Among all eligible subjects, about 60% of patients were classified as TCM users (65,812 TCM users and 41,482 nonusers). After 1:1 matching, the outcomes of 68,882 patients were analyzed. For the ESRD rate, the 8-year cumulative incidence was 14.5% for TCM users [95% confidence interval (CI): 13.9-15.0] and 16.6% for nonusers (95% CI: 16.0-17.2). For the mortality rate, the 8-year cumulative incidence was 33.8% for TCM users (95% CI: 33.1-34.6) and 49.2% for nonusers (95% CI: 48.5-49.9). After adjusting for confounding covariates, the cause-specific hazard ratio of ESRD was 0.81 (95% CI: 0.78-0.84), and the hazard ratio of mortality for TCM users was 0.48 (95% CI: 0.47-0.50). The cumulative incidence of mortality increased rapidly among TCM users with ESRD (56.8, 95% CI: 54.6-59.1) when compared with TCM users without ESRD (30.1, 95% CI: 29.4-30.9). In addition, TCM users who used TCM longer or initiated TCM treatments after being diagnosed with DN were associated with a lower risk of mortality. These results were consistent across sensitivity tests with different definitions of TCM users and inverse probability weighting of subjects. CONCLUSIONS: The lower ESRD and mortality rates among patients with incident DN correlates with the use of TCM treatments. Further studies about specific TCM modalities or medications for DN are still needed.

Aryl hydrocarbon receptor agonist indigo protects against obesity-related insulin resistance through modulation of intestinal and metabolic tissue immunity.

BACKGROUND/OBJECTIVES: Low-grade chronic inflammation in visceral adipose tissue and the intestines are important drivers of obesity associated insulin resistance. Bioactive compounds derived from plants are an important source of potential novel therapies for the treatment of chronic diseases. In search for new immune based treatments of obesity associated insulin resistance, we screened for tissue relevant anti-inflammatory properties in 20 plant-based extracts. METHODS: We screened 20 plant-based extracts to assess for preferential production of IL-10 compared to TNFα, specifically targetting metabolic tissues, including the visceral adipose tissue. We assessed the therapeutic potential of the strongest anti-inflammatory compound, indigo, in the C57BL/6J diet-induced obesity mouse model with supplementation for up to 16 weeks by measuring changes in body weight, glucose and insulin tolerance, and gut barrier function. We also utilized flow cytometry, quantitative PCR, enzyme-linked immunosorbent assay (ELISA), and histology to measure changes to immune cells populations and cytokine profiles in the intestine, visceral adipose tissue (VAT), and liver. 16SrRNA sequencing was performed to examine gut microbial differences induced by indigo supplementation. RESULTS: We identifed indigo, an aryl hydrocarbon receptor (AhR) ligand agonist, as a potent inducer of IL-10 and IL-22, which protects against high-fat diet (HFD)-induced insulin resistance and fatty liver disease in the diet-induced obesity model. Therapeutic actions were mechanistically linked to decreased inflammatory immune cell tone in the intestine, VAT and liver. Specifically, indigo increased Lactobacillus bacteria and elicited IL-22 production in the gut, which improved intestinal barrier permeability and reduced endotoxemia. These changes were associated with increased IL-10 production by immune cells residing in liver and VAT. CONCLUSIONS: Indigo is a naturally occurring AhR ligand with anti-inflammatory properties that effectively protects against HFD-induced glucose dysregulation. Compounds derived from indigo or those with similar properties could represent novel therapies for diseases associated with obesity-related metabolic tissue inflammation.

Effects of Positive and Negative Expectations on Human Pain Perception Engage Separate But Interrelated and Dependently Regulated Cerebral Mechanisms.

Expectations substantially influence pain perception, but the relationship between positive and negative expectations remains unclear. Recent evidence indicates that the integration between pain-related expectations and prediction errors is crucial for pain perception, which suggests that aversive prediction error-associated regions, such as the anterior insular cortex (aIC) and rostral anterior cingulate cortex (rACC), may play a pivotal role in expectation-induced pain modulation and help to delineate the relationship between positive and negative expectations. In a stimulus expectancy paradigm combining fMRI in healthy volunteers of both sexes, we found that, although positive and negative expectations respectively engaged the right aIC and right rACC to modulate pain, their associated activations and pain rating changes were significantly correlated. When positive and negative expectations modulated pain, the right aIC and rACC exhibited opposite coupling with periaqueductal gray (PAG) and the mismatch between actual and expected pain respectively modulated their coupling with PAG and thalamus across individuals. Participants' certainty about expectations predicted the extent of pain modulation, with positive expectations involving connectivity between aIC and hippocampus, a region regulating anxiety, and negative expectations engaging connectivity between rACC and lateral orbitofrontal cortex, a region reflecting outcome value and certainty. Interestingly, the strength of these certainty-related connectivities was also significantly associated between positive and negative expectations. These findings suggest that aversive prediction-error-related regions interact with pain-processing circuits to underlie stimulus expectancy effects on pain, with positive and negative expectations engaging dissociable but interrelated neural responses that are dependently regulated by individual certainty about expectations.SIGNIFICANCE STATEMENT Positive and negative expectations substantially influence pain perception, but their relationship remains unclear. Using fMRI in a stimulus expectancy paradigm, we found that, although positive and negative expectations engaged separate brain regions encoding the mismatch between actual and expected pain and involved opposite functional connectivities with the descending pain modulatory system, they produced significantly correlated pain rating changes and brain activation. Moreover, participants' certainty about expectations predicted the magnitude of both types of pain modulation, with the underlying functional connectivities significantly correlated between positive and negative expectations. These findings advance current understanding about cognitive modulation of pain, suggesting that both types of pain modulation engage different aversive prediction error signals but are dependently regulated by individual certainty about expectations.

Immunomodulation Effects of Schizonepeta tenuifolia Briq. on the IgE-Induced Allergic Model of RBL-2H3 Cells.

Schizonepeta tenuifolia (ST) Briq. is a traditional herbal medicine commonly used to treat allergic skin diseases, where the inflammation process is closely related to symptom severity. This study aimed to explore the immunomodulatory effect of ST by using immunoglobulin E- (IgE-) stimulated RBL-2H3 cell cultures, a common cell line for studying mast cell degranulation and inflammatory cytokine release in vitro. After stimulating the RBL-2H3 cells with IgE, ST at concentrations of 10, 50, or 100 µg/mL was added to the cell cultures. Cell viability, inflammatory cytokines (IL-6, IL-13, IL-4, TNF-α, and IFN-γ), anti-inflammatory cytokine IL-10, and degranulation ability were examined 48 and 72 hours after administration of ST. The markers of inflammation and allergic reaction, IFN-γ, TNF-α, IL-4, and IL-6, were suppressed, especially after treatment with 100 µg/mL ST. However, the anti-inflammation marker IL-10 was also suppressed by ST. Trend analysis showed that a higher ST concentration was associated with lower IFN-γ and TNF-α levels. Moreover, degranulation of RBL-2H3 cells was assessed by measuring the release of ß-hexosaminidase, which was suppressed by ST at 10 µg/mL. This study showed an immunomodulatory effect of ST at the cellular level and suggests the role of ST in treating allergic diseases.

The Efficacy and Safety of a Fixed Combination of Chinese Herbal Medicine in Chronic Urticaria: A Randomized, Double-Blind, Placebo-Controlled Pilot Study.

Background: Chronic urticaria is a bothersome skin disease, and Chinese herbal medicine (CHM) is commonly used as adjuvant therapy. This study aimed to evaluate the effectiveness and safety of the mixture of two CHM formula, Xiao-Feng-San (XFS) and Qing-Shang-Fang-Feng-Tang (QSFFT), in treating urticaria through a randomized, double-blind, placebo-controlled clinical trial. Methods: 78 participants entered the screening phase between November 2012 and August 2015. Participants were randomly and equally allocated in either CHM group (2 gm XFS and 2 gm QSFFT four times a day and 5 mg levocetirizine once daily for 28 days followed by 5 mg levocetirizine once daily alone for 28 days) or control group (placebo and 5 mg levocetirizine daily followed by 5 mg levocetirizine once daily for 28 days alone). Symptom improvement was set as the primary outcome, and the influence on sleep quality and changes in serum markers were used as secondary outcomes. Per protocol design was applied to the final analysis. Results: A total of 56 participants entered the final analysis stage. Participants in the CHM group had more prominent symptom relief on day 56 (the weekly urticaria activity score, UAS7, as 9.9 ± 9.2 vs. 15.6 ± 10.8, p = 0.038). In the CHM group, participants' symptom severity reduced progressively (trend analysis, p < 0.001) while the decreasing trend was less favored in the control group (trend analysis, p = 0.056). The life quality improved gradually in both groups, while the differences between CHM and control groups were statistically insignificant. For urticaria-related cytokines, interferon-γ seemed to decrease positively in the CHM group (about 30.8% reduction from baseline, trend analysis p = 0.013). For safety issue, the CHM prescription was well-tolerated with no noticeable long-term side effects when compared to the control group. At 6-month follow-up of symptom changes after the end of the trial, the CHM group participants reported positive results in no recurrence or ≥50% improvement (36.3% in CHM group vs. 20% in Control group, p = 0.103). Conclusions: The combination of XFS and QSFFT tended to be feasible and tolerable adjuvant therapy for urticaria in addition to standard therapy. However, larger study population with longer follow-up duration may be still needed. Trial registration: NCT01715740 (ClinicalTrials.gov).

Identifying Chinese Herbal Medicine Network for Endometriosis: Implications from a Population-Based Database in Taiwan.

BACKGROUND: Endometriosis is a common but bothersome gynecological disease, and Chinese herbal medicine (CHM) is used for treating endometriosis. The aim of this study is to explore CHM network and core treatments for endometriosis by analyzing nationwide CHM prescription database. METHODS: From 1998 to 2013, the CHM prescriptions made primarily for endometriosis among women diagnosed with endometriosis (ICD-9-CM code: 671) by gynecologists during their reproductive age were collected. CHM network analysis was then carried out by using association rule mining and social network analysis. RESULTS: A total of 12,986 CHM prescriptions made for endometriosis were analyzed. There were 556 kinds of CHM ever used, and, in average, each prescription was composed of 6.2 CHMs. Gui-Zhi-Fu-Ling-Wan (GZFLW) was used most frequently, followed by Cyperus rotundus (28.1% and 18.8% of all prescriptions, resp.). Additionally, the combination of Cyperus rotundus with GZFLW (8.0%) was the most frequently used combination of two CHMs. CHM network showed that GZFLW was the core CHM for endometriosis and graphically demonstrated the extensive coverage of TCM syndromes and pathogenesis of endometriosis. CONCLUSIONS: CHM network provides graphical demonstration and summary of commonly used CHMs for endometriosis, and further studies are warranted based on these findings.

Characteristics of traditional Chinese medicine users and prescription analysis for pediatric atopic dermatitis: a population-based study.

BACKGROUND: Atopic dermatitis among children is an important issue due to relapses and skin manifestations. Traditional Chinese medicine (TCM) is commonly used to treat children with atopic dermatitis. The aim of this study was to investigate the characteristics and TCM prescriptions of patients with atopic dermatitis using a nationwide database. METHODS: Children younger than 12 years of age diagnosed with atopic dermatitis, defined as ICD-9-CM codes 691.8 and 692.x, were identified from the database. Data on age, diagnosis codes, area of residence and use of corticosteroids of the TCM users were recorded. Association rule mining was used to analyze the prescriptions used for atopic dermatitis. RESULTS: We identified 13,646 children with atopic dermatitis using TCM in 2007. Female gender (OR: 0.83 for male gender), adolescence (OR: 10.0, 95 % CI: 8.88-11.15) and allergic rhinitis (OR: 2.44, 95 % CI: 2.10-2.85) were associated with the use of TCM. Fewer of the TCM users were prescribed with corticosteroids (35.8 % of all TCM users), but the TCM users had a higher rate of long-term topical corticosteroid therapy (10.6 % for TCM users versus 2.0 % for those who did not use TCM). Chinese herbal medicine (CHM) was used by 93.7 % of all TCM users in 36,398 prescriptions. On average, 5.6 kinds of CHM were used in combination. The relationship between the CHMs constituted a network, in which Xiao-Feng-San was the core treatment for atopic dermatitis. CONCLUSIONS: In this study, we described the characteristics of children with atopic dermatitis who use TCM in Taiwan. and identified the core CHM treatment. Further research on the safety and efficacy of this treatment are still needed.

Identifying Chinese herbal medicine network for treating acne: Implications from a nationwide database.

ETHNO-PHARMACOLOGICAL RELEVANCE: Acne is a highly prevalent inflammatory skin disease which causes patients great psychological stress, especially teenagers. Chinese herbal medicine (CHM) is commonly used to treat acne with personalized but complicated prescriptions. The aim of this study is to determine a CHM network and core CHM treatments for acne by analyzing a nationwide database. MATERIALS AND METHODS: From January 1st to December 31st, 2011, all CHM prescriptions made for acne (ICD-9-CM code: 706.0 or 706.1) were included in this study. Visits with acupuncture, manual therapy or other treatment modalities were excluded, and CHM visits with other diagnoses were also excluded in final analysis. Association rule mining (ARM) and social network analysis (SNA) were used to explore and demonstrate a CHM network. RESULTS: A total of 91,129 patients used traditional Chinese medicine, and 99% of them chose CHM for acne treatment. Most CHM users were teenagers, and there were twice as many female patients as male patients. A total of 279,823 CHM prescriptions were made for acne in 2011. Qing-Shang-Fang-Feng-Tang was the most commonly used CHM (31.2% of all prescriptions), and Zhen-Ren-Huo-Ming-Yin combined with Forsythia suspensa (Thunb.) Vahl. (Lian Qiao) was the most commonly used CHM-CHM combination. Thirty-one important CHM-CHM combinations were identified, and the CHM network could be built. Extensive coverage of the known pathogenesis of acne could be found in the CHM network when incorporating CHM pharmacological mechanisms into the network. Anti-inflammatory and anti-bacterial effects were commonly found in the CHM network, and CHMs with anti-androgen, anti-depressive and skin whitening effects were frequently used in combination. CONCLUSIONS: The CHM combination patterns and core treatments for acne were disclosed in this study by applying network analysis to a CHM prescription database. These results may be beneficial for further bench or clinical studies when choosing target CHM.

Chinese herbal medicine network and core treatments for allergic skin diseases: Implications from a nationwide database.

ETHNO-PHARMACOLOGICAL RELEVANCE: Chinese herbal medicine (CHM) is commonly used to treat skin diseases, but CHM prescription patterns are difficult to understand due to their complexity and inter-connections. This study aimed to demonstrate CHM core treatments and network for treatment of allergic skin diseases by analyzing a nationwide prescription database. MATERIALS AND METHODS: All CHM prescriptions made for atopic dermatitis (with age limitation ≤ 12 years) and urticaria for the entire year of 2011 were included. Association rule mining (ARM) combined with social network analysis (SNA) were used to analyze CHM prescriptions and explore the CHM prescription pattern and network. RESULTS: A total of 27,350 and 97,188 prescriptions for atopic dermatitis and urticaria, respectively, were analyzed. Xiao-Feng-San (XFS) was the most commonly used CHM (32% of prescriptions for atopic dermatitis and 47.4% for urticaria) and was the core treatment for both diseases. Moreover, 42 and 82 important CHM-CHM combinations were identified to establish the CHM network, and XFS with Dictamnus dasycarpus Turcz was the most prevalent (6.4% for atopic dermatitis and 9.1% for urticaria). Traditional Chinese Medicine heat syndrome was most prevalent cause. Extensive anti-inflammation, anti-allergy, anti-oxidation, and anti-bacterial effects were also found among the CHMs. CONCLUSIONS: Network analysis on CHM prescriptions provides graphic and comprehensive illustrations regarding CHM treatment for atopic dermatitis and urticaria. The CHM network analysis of prescriptions is essential to realize the CHM treatments and to select suitable candidates for clinical use or further studies.

Identifying chinese herbal medicine network for eczema: implications from a nationwide prescription database.

Eczema is a highly prevalent dermatological disease that can severely affect the patient's quality of life. Chinese herbal medicine (CHM) is commonly used in combination for eczema due to the complicated pathogenesis. This study aimed to identify a CHM network for the treatment of eczema by using a nationwide database. During 2011, 381,282 CHM prescriptions made for eczema (ICD-9-CM 692.x) were obtained from the National Health Insurance Research Database (NHIRD) in Taiwan and analyzed by using association rule mining and social network analysis. Among 661 available CHMs, 44 important combinations were identified. Among the CHM networks, seven clusters with the predominant traditional Chinese medicine (TCM) pattern were recognized. The largest CHM cluster was used to treat the wind-dampness-heat pattern, and Xiao-Feng-San (24.1% of all prescriptions) was the core of this cluster with anti-inflammation, antioxidation, and antiallergic effects. Lonicera japonica (11.0% of all prescriptions) with Forsythia suspense (17.0% of all prescriptions) was the most commonly used CHM combination and was also the core treatment for treating the heat pattern, in which an antimicrobial effect is found. CHM network analysis is helpful for TCM doctors or researchers to choose candidates for clinical practice or further studies.

Use of traditional Chinese medicine reduces exposure to corticosteroid among atopic dermatitis children: a 1-year follow-up cohort study.

ETHNOPHARMACOLOGICAL RELEVANCE: Atopic dermatitis is a prevalent dermatologic disease in children. Corticosteroid is an important treatment but side effects caused by long-term and excessive use heavily concern patients. Traditional Chinese medicine (TCM) is potentially an alternative treatment and might cause less adverse effects. This nationwide retrospective cohort study aimed to examine the hypothesis that TCM use is associated with lower exposure to corticosteroid. MATERIALS AND METHODS: Children under 12 years of age with ICD-9 codes 691.8 and 692.x were identified as atopic dermatitis patients from 2007/1/1 to 2007/12/31. Corticosteroid use was compared between TCM users and non-users for one-year follow-up by using a general estimation equation model with propensity-score matching. RESULTS: A total of 9012 TCM users were identified and the use of corticosteroid after treatment was compared with matched TCM non-users. Use of TCM significantly reduced exposure to corticosteroids after 1-year follow-up. Among TCM users, the exposure to any corticosteroids was lower (42.1% reduction in TCM users versus 34.5% increase in TCM non-users, relative risk: 0.36; p-Value<0.001), the duration was shorter (relative risk for using corticosteroid more than 14 days: 0.37; p-Value<0.001), and the rate of frequent visits with steroid prescription was also lower. CHM was the most commonly used TCM modality (98.5% of all visits) and Xiao-Feng-San was the most commonly used CHM (33% of all prescriptions) with extensive coverage for pathogenesis of atopic dermatitis. CONCLUSIONS: Lower use rate of corticosteroid can be found after TCM treatment, which can be considered as an integrative therapy for atopic dermatitis. Further studies are warranted on the basis of this study.

Identifying Chinese herbal medicine for premenstrual syndrome: implications from a nationwide database.

BACKGROUND: Premenstrual syndrome (PMS) occurs in women during their reproductive age with a quite negative impact on their daily lives. Women with PMS experience a wide range of physical or psychological symptoms and seek treatment for them. Chinese herb medicine (CHM) is commonly used for PMS and the goal of this study is to investigate the prescription patterns of CHM for PMS by using a nationwide database. METHODS: Prescriptions of CHM were obtained from two million beneficiaries randomly sampled from the National Health Insurance Research Database, a nationwide database in Taiwan. The ICD-9 code 625.4 was used to identify patients with PMS. Association rule mining and social network analysis were used to explore both the combinations and the core treatments for PMS. RESULTS: During 1998-2011, a total of 14,312 CHM prescriptions for PMS were provided. Jia-Wei-Xiao-Yao-San (JWXYS) was the CHM which had the highest prevalence (37.5% of all prescriptions) and also the core of prescription network for PMS. For combination of two CHM, JWXYS with Cyperus rotundus L. was prescribed most frequently, 7.7% of all prescriptions, followed by JWXYS with Leonurus heterophyllus Sweet, 5.9%, and Cyperus rotundus L. with Leonurus heterophyllus Sweet, 5.6%. CONCLUSIONS: JWXYS-centered CHM combinations were most commonly prescribed for PMS. To the best of our knowledge, this is the first pharmaco-epidemiological study to review CHM treatments for PMS. However, the efficacy and safety of these commonly used CHM were still lacking. The results of this study provide valuable references for further clinical trials and bench studies.

Hedyotis diffusa Combined with Scutellaria barbata Are the Core Treatment of Chinese Herbal Medicine Used for Breast Cancer Patients: A Population-Based Study.

Traditional Chinese medicine (TCM), which is the most common type of complementary and alternative medicine (CAM) used in Taiwan, is increasingly used to treat patients with breast cancer. However, large-scale studies on the patterns of TCM prescriptions for breast cancer are still lacking. The aim of this study was to determine the core treatment of TCM prescriptions used for breast cancer recorded in the Taiwan National Health Insurance Research Database. TCM visits made for breast cancer in 2008 were identified using ICD-9 codes. The prescriptions obtained at these TCM visits were evaluated using association rule mining to evaluate the combinations of Chinese herbal medicine (CHM) used to treat breast cancer patients. A total of 37,176 prescriptions were made for 4,436 outpatients with breast cancer. Association rule mining and network analysis identified Hedyotis diffusa plus Scutellaria barbata as the most common duplex medicinal (10.9%) used for the core treatment of breast cancer. Jia-Wei-Xiao-Yao-San (19.6%) and Hedyotis diffusa (41.9%) were the most commonly prescribed herbal formula (HF) and single herb (SH), respectively. Only 35% of the commonly used CHM had been studied for efficacy. More clinical trials are needed to evaluate the efficacy and safety of these CHM used to treat breast cancer.

Investigation on Chinese herbal medicine for primary dysmenorrhea: implication from a nationwide prescription database in Taiwan.

OBJECTIVE: Primary dysmenorrhea is a common gynecological condition, for which Chinese herbal medicine (CHM) has been widely used in addition to western medicine. The aim of this study is to explore CHM commonly used to treat dysmenorrhea in young Chinese women. DESIGN: Observational retrospective study. SETTING: The National Health Insurance Research Database in Taiwan. POPULATION: Women aged from 13 to 25 years with single diagnosis of primary dysmenorrhea. METHODS: CHM prescriptions made for primary dysmenorrhea women during 1998-2008 were extracted to build up CHM prescription database. Association rule mining was used to explore the prevalent CHM combination patterns in treating primary dysmenorrhea. MAIN OUTCOME MEASURES: Prevalence and mechanisms of CHM combinations. RESULTS: Totally 57,315 prescriptions were analyzed and, on average, 5.3 CHM was used in one prescription. Dang-Gui-Shao-Yao-San (DGSYS) was the most commonly used herbal formula (27.2%), followed by Jia-Wei-Xiao-Yao-San (JWXYS) (20.7%) and Wen-Jing-Tang (WJT) (20.5%). Corydalis yanhusuo and Cyperus rotundus were the most commonly used single herb, found in 33.1% and 29.2% of all prescriptions. Additionally, C. yanhusuo with C. rotundus is the most commonly used two CHM in combination, accounting for 14.24% of all prescriptions, followed by DGSYS with C. yanhusuo (10.47%). Multi-target effects on primary dysmenorrhea, such as analgesia, mood modifying and hormone adjustment, were found among commonly prescribed CHM in this study. CONCLUSIONS: This study discovered the potential importance of C. yanhusuo, C. rotundus and DGSYS in treating primary dysmenorrhea. Further clinical trials or bench studies are warranted based on the results.