Anti-inflammatory and anti-pruritic effects of Chi-Huang Solution in a murine model of allergic contact dermatitis.

ETHNOPHARMACOLOGICAL RELEVANCE: In treating atopic dermatitis, multi-mode management is adopted, including trying to avoid the allergens, controlling and preventing secondary infections, and using drugs to control itching. At present, most of the commonly used anti-pruritic drugs in the clinic are single-target and lead to serious side effects. Many studies have shown that a variety of traditional Chinese medicines have significant anti-inflammatory and anti-pruritic effects, and have the characteristics of multiple components, multiple targets, and multiple effects. AIM OF THE STUDY: The study aimed to explore the anti-inflammatory and anti-pruritic effects of the Chi-Huang Solution in a murine model of Allergic contact dermatitis (ACD). This study considers the effectiveness of the Chi-Huang Solution for external use on skin to provide an experimental basis for the clinical development and application of Chinese medicine and related preparations for Canine atopic dermatitis (CAD). MATERIALS AND METHODS: Forty-two male SPF C57BL/6 mice were randomly divided into control group (n = 6), ACD model group (n = 6), HAC control group (n = 6), and 4 Chi-Huang Solution groups (n = 6 in each group). With SADBE induce the murine model of ACD chronic pruritus, and initially evaluate whether the model is successful by counting scratching behavior, measuring the skin fold thickness and skin lesion score within 1 h. After treating the ACD model mice with deionized water, HAC, 1CH, 2CH, 3CH, and 4CH for 7 days, behavioral changes were used to evaluate the anti-pruritic effect. The skin fold thickness, skin lesion score, and spleen index were used to evaluate the anti-inflammatory effect of the Chi-Huang Solution. H.E. staining was used for the epidermal thickness measurement and pathological evaluation. RT-qPCR was used to analyze the mRNA expression of related inflammatory factors such as IL-1ß, TNF-α, IL-33, IL-4, IL-17A, CXCL10, and its receptor CXCR3 in the skin of the lesion site, as well as to detect the mRNA expression of pruritus-related genes such as TRPV1, TRPA1, and GRP in DRG. RESULTS: After the treatment of low-dose (0.1 g/mL) and medium-dose (0.2 g/mL) Chi-Huang Solution, the scratching times both decreased significantly (P < 0.05), meanwhile the medium-dose Chi-Huang Solution had an obvious effect on reducing scratches/scab score (P < 0.05). Moreover, no matter what dose it takes, all Chi-Huang Solution can alleviate the epidermal thickening (P < 0.05) and the infiltration of mast cells in the ACD murine model of ACD. It is worth mentioning that the count of mast cells in the dermis was significantly down-regulated after the treatment of medium-dose Chi-Huang Solution (P < 0.005). Furthermore, Chi-Huang Solution can significantly down-regulate the mRNA expression of related inflammatory factors in the skin, and reduce the mRNA expression of pruritus-related genes, such as TRPA1, TRPV1, and GRP in the spinal cord. CONCLUSIONS: The results indicated that Chi-Huang Solution for external use exhibits significant anti-inflammatory and anti-pruritic effects on SADBE-induced ACD chronic pruritus murine models. Chi-Huang Solution might emerge as an effective drug for the treatment of CAD and high-dose Chi-Huang Solution (0.4 g/ml) has better comprehensive effects.

Aristolochic acid and the risk of cancers in patients with type 2 diabetes: Nationwide population-based cohort study.

BACKGROUND: Both aristolochic acid (AA) exposure and diabetic can increase risk of certain cancers,whetherAAexposureincreases cancer risk in diabetic patientsisunknown. The purpose of this study was to investigate the association between the use of Chinese herbal products containing AA and the risk of cancer in diabetic patients. METHODS: A cohort study was conducted using the National Health Insurance Research Database in Taiwan. Patients older than 18 years who were diagnosed with diabetes between 1997 and 2010 were enrolled in our cohort. The use of Chinese herbal products containing AA was recorded from the beginning of 1997 until the ban of herbs containing AA in November 2003. Patients were individually tracked to identify cancer incidence between 1997 and 2013. Only patients who visited traditional Chinese medicine clinics between 1997 and 1 year before the end of follow-up were included in the cohort to ensure comparability. Cox proportional hazards regression was used to calculate the hazard ratio for the association between the use of Chinese herbal products containing AA and the occurrence of cancer. RESULTS: Among the 430 377 male and 431 956 female patients with diabetes enrolled in our cohort, 37 554 and 31 535 cancer diagnoses were recorded during the study period, respectively. The use of AA-containing herbal products was associated with a significantly higher risk of liver, colorectum, kidney, bladder, prostate, pelvis, and ureter cancer in a dose-dependent manner. An increased risk of extrahepatic bile duct cancer in women was also associated with AA exposure at doses of more than 500 mg. CONCLUSIONS: Association between AA exposure and the risk of some cancers were found in this study. AA exposure might increase risk of kidney,bladder,pelvis, ureter,liver,colorectum,andprostatecancer in all patientsandextrahepatic bile duct cancerin women.

Epidemiology of chronic kidney disease of undetermined aetiology in Taiwanese farmers: a cross-sectional study from Changhua Community-based Integrated Screening programme.

OBJECTIVES: Chronic kidney disease of undetermined or non-traditional aetiology (CKDu or CKDnT) has been reported in Mesoamerica among farmers under heat stress. Epidemiological evidence was lacking in Asian countries with similar climatic conditions. The objective of this study was to investigate the prevalence of CKDu and possible risk factors. METHODS: We used the data from the Changhua Community-based Integrated Screening programme from 2005 to 2014, which is the annual screening for chronic diseases in Taiwan's largest rice-farming county since 2005. Our study population included farmers and non-farmers aged 15-60 years. CKDu was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2 at age under 60 years without hypertension, diabetes, proteinuria, haematuria or using Chinese herbal medicine. We estimated the adjusted prevalence OR (POR) of CKDu by farmers, age, sex, education, urbanisation, smoking, body mass index, hyperuricaemia, hyperlipidaemia, heart disease and chronic liver disease. RESULTS: 5555 farmers and 35 761 non-farmers were included in this study. CKDu accounted for 48.9% of all CKD cases. The prevalence of CKDu was 2.3% in the farmers and 0.9% in the non-farmers. The crude POR of CKDu in farmers compared with non-farmers was 2.73 (2.13-3.50), and the adjusted POR was 1.45 (1.10-1.90). Dehydration (blood urea nitrogen-to-creatinine ratio >20) was found in 22% of the farmers and 14% of the non-farmers. CONCLUSIONS: Farmers in subtropical Asian countries are at increased risk of CKDu. Governments should take the CKDu epidemics seriously and provide farmers with occupational health education programmes on thermal hazards.

Team-based care improves quality of diabetes care -Family Practice Integrated Care Project in Taiwan.

BACKGROUND: The Family Practice Integrated Care Project (FPICP) is a team-based program in Taiwan initiated in 2003. This study investigates the influence of FPICP on the quality of diabetes care. METHODS: This population-based cohort study used Taiwan's National Health Insurance Administration data on FPICP (fiscal year 2015-2016, with follow-up duration of one year). Participants included diabetic patients aged ≥30 in primary care clinics. We used conditional logistic regression modeling of patient characteristics and annual diabetes examinations and compared FPICP participants with non-participating candidates. Main outcome measures included completion of annual diabetes examinations, including glycated hemoglobin (A1c), low-density lipoprotein (LDL), urine microalbumin (MAU), routine urinalysis (UR), and fundus examination (FE). RESULTS: The sample included 298,208 FPICP participants and 478,778 non-participating candidates. After 1:1 propensity score matching, the examination completion rates for FPICP participants and non-participants, respectively, were 94.4% versus 93.6% in A1c, 84.2% versus 83.8% in LDL, 61.9% versus 60.1% in MAU, 59.2% versus 58.0% in UR, and 30.1% versus 32.4% in FE. CONCLUSION: Our findings indicate that a program like FPICP helps improve the quality of diabetes care through regular examinations of Alc, LDL, MAU, and UR.

Family physician system in Taiwan.

Following economic development and increasing healthcare demand, Taiwan has not only built a universal healthcare coverage payment system in 1995, but has also developed an accountable family physician system, called the Family Practice Integrated Care Project (FPICP), to deal with the pressures of an ageing society, since 2003. The community healthcare group-based family physician system is not only an important milestone for the development of family medicine in Taiwan but may also even serve as a global example for future family doctor systems. In this review, we aim to review the development of family medicine in Taiwan, the implementation and achievement of the FPICP, as well as the future prospects of system-based healthcare system. We firmly believe that only when the family physician system is well developed and put into practice with person-centered, family as a care unit, and community-oriented holistic care, can the objective of "everyone has their own family doctor" and sustainable operation of National Health Insurance be achieved.

Herbal Medicine Containing Aristolochic Acid and the Risk of Primary Liver Cancer in Patients with Hepatitis C Virus Infection.

BACKGROUND: We investigated the association between taking herbal medicine (HM) containing aristolochic acid (AA) and the risk of primary liver cancer (PLC) among patients with hepatitis C virus (HCV) infection. METHODS: This is a prospective study for the long-term follow-up of a nationwide population-based cohort of patients ages 18 years or older diagnosed with HCV infection during 1997 to 2010. A total of 223,467 HCV-infected patients were identified using the National Health Insurance Research Database in Taiwan. The use of HM containing AA was evaluated among patients who had visited traditional Chinese medicine clinics beginning from 1997 to 1 year prior to the diagnosis of PLC or dates censored (2003). We tracked each individual patient from 1997 to 2013 to identify incident cases of PLC since 1999. RESULTS: During the follow-up period of 3,052,132 person-years, we identified 25,502 PLC cases; this corresponded to an overall incidence rate of 835.5 PLCs per 100,000 person-years. The adjusted HRs were 1.21 [95% confidence interval (CI), 1.18-1.24], 1.48 (95% CI, 1.37-1.59), 1.50 (95% CI, 1.34-1.68), and 1.88 (95% CI, 1.61-2.19) for estimated AA usage groups: 1 to 250, 251 to 500, 501 to 1,000, and more than 1,000 mg, respectively, relative to no AA exposure (reference group). CONCLUSIONS: The current findings suggest that among HCV-positive patients, increasing exposure to AA poses an increased risk of acquiring PLC. IMPACT: AA may increase the risk of PLC in HCV-positive populations.

Stomach Cancer and Exposure to Talc Powder without Asbestos via Chinese Herbal Medicine: A Population-Based Cohort Study.

The present investigation was designed to explore the risk of stomach cancer by oral intake of talc powder without asbestos. We conducted a population-based cohort study on a randomly sampled cohort from Taiwan's health insurance database, with population of 1,000,000. The study participants were followed up through 2013. The outcome event of interest was the diagnosis of stomach cancer. The exposure of interest was the prescription of talc powder. Cox regression analyses were performed respectively. There were 584,077 persons without talc exposure and 21,575 talc users, 1849 diagnosed with stomach cancer. Persons with exposure of talc had a higher hazard ratio of stomach cancer (adjusted hazard ratio, 2.13; 95% confidence interval (CI), 1.54⁻2.94; p < 0.001). Classification by cumulative exposure of talc yielded adjusted hazard ratios of stomach cancer of 1.58 (95% CI, 0.79⁻3.17; p = 0.19) and 2.30 (95% CI, 1.48⁻3.57; p < 0.001) among persons with high (>21 g) and medium (6⁻21 g) exposure of talc, as compared to the low-exposure counterparts. Our data demonstrated positive association between increased risk of stomach cancer and oral intake of talc without asbestos. Despite the absence of dose-response effect, there might be a link between stomach cancer and talc.

Herbal medicine containing aristolochic acid and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection.

It was suspected that aristolochic acid-induced mutations may be associated with hepatitis B virus (HBV), playing an important role in liver carcinogenesis. The purpose of this study was to investigate the association between the use of Chinese herbs containing aristolochic acid and the risk of hepatocellular carcinoma (HCC) among HBV-infected patients. We conducted a retrospective, population-based, cohort study on patients older than 18 years who had a diagnosis of HBV infection between January 1, 1997 and December 31, 2010 and had visited traditional Chinese medicine clinics before one year before the diagnosis of HCC or the censor dates. A total of 802,642 HBV-infected patients were identified by using the National Health Insurance Research Database in Taiwan. The use of Chinese herbal products containing aristolochic acid was identified between 1997 and 2003. Each patient was individually tracked from 1997 to 2013 to identify incident cases of HCC since 1999. There were 33,982 HCCs during the follow-up period of 11,643,790 person-years and the overall incidence rate was 291.8 HCCs per 100,000 person-years. The adjusted hazard ratios (HRs) were 1.13 (95% confidence interval [CI], 1.11-1.16), 1.21 (95% CI, 1.13-1.29), 1.37 (95% CI, 1.24-1.50) and 1.61 (95% CI, 1.40-1.84) for estimated aristolochic acid of 1-250, 251-500, 501-1,000 and more than 1,000 mg, respectively, relative to no aristolochic acid exposure. Our study found a significant dose-response relationship between the consumption of aristolochic acid and HCC in patients with HBV infection, suggesting that aristolochic acid which may be associated with HBV plays an important role in the pathogenesis of HCC.

Chinese herbs containing aristolochic acid associated with renal failure and urothelial carcinoma: a review from epidemiologic observations to causal inference.

Herbal remedies containing aristolochic acid (AA) have been designated to be a strong carcinogen. This review summarizes major epidemiologic evidence to argue for the causal association between AA exposure and urothelial carcinoma as well as nephropathy. The exposure scenarios include the following: Belgian women taking slimming pills containing single material Guang Fang Ji, consumptions of mixtures of Chinese herbal products in the general population and patients with chronic renal failure in Taiwan, occupational exposure in Chinese herbalists, and food contamination in farming villages in valleys of the Danube River. Such an association is corroborated by detecting specific DNA adducts in the tumor tissue removed from affected patients. Preventive actions of banning such use and education to the healthcare professionals and public are necessary for the safety of herbal remedies.

Association of blood lead and mercury with estimated GFR in herbalists after the ban of herbs containing aristolochic acids in Taiwan.

OBJECTIVE: This study was undertaken to explore the association of estimated glomerular filtration rate (GFR) with exposure to aristolochic acids (ALAs) and nephrotoxic metals in herbalists after the ban of herbs containing ALAs in Taiwan. METHODS: This cross-sectional study recruited a total of 138 herbalists without end-stage renal disease or urothelial carcinoma from the Occupational Union of Chinese Herbalists in Taiwan in 2007. Aristolochic acid I (ALA-I) was measured by ultra-high-pressure liquid chromatography/ tandem mass spectrometry (UHPLC-MS/MS) and heavy metals in blood samples were analysed by Agilent 7500C inductively coupled plasma-mass spectrometry. Renal function was assessed by using a simplified Modification of Diet in Renal Disease Study equation to estimate GFR. RESULTS: Blood lead was higher in herbal dispensing procedures (p=0.053) and in subjects who self-prescribe herbal medicine (p=0.057); mercury was also higher in subjects living in the workplace (p=0.03). Lower estimated GFR was significantly associated with lead (ß=-10.66, 95% CI -18.7 to -2.6) and mercury (ß=-12.52, 95% CI -24.3 to -0.8) with a significant interaction (p=0.01) between mercury and lead; however, estimated GFR was not significantly associated with high ALA-I level groups, arsenic and cadmium after adjusting for other confounding factors. CONCLUSIONS: We found that lower estimated GFR was associated with blood lead and mercury in herbalists after the ban of herbs containing ALAs in Taiwan. The ALA-I exposure did not show a significant negative association of estimated GFR, which might due to herbalists having known how to distinguish ALA herbs after the banning policy. Rigorous monitoring is still needed to protect herbalists and the general population who take herbs.

Occupational exposure to herbs containing aristolochic acids increases the risk of urothelial carcinoma in Chinese herbalists.

PURPOSE: Aristolochic acid can cause urothelial carcinoma. Herbal remedies containing aristolochic acids were previously categorized as proven group 1 human carcinogens by the WHO cancer agency, the International Agency for Research on Cancer. However, the health effect on workers exposed to aristolochic acid is unclear. Fangchi, a representative herb containing aristolochic acid, is commonly used in the Chinese herbal medicine industry. We determined whether workers exposed to fangchi are at increased risk for urothelial carcinoma. MATERIALS AND METHODS: We designed a case-control study based in a national representative cohort of Chinese herbalists. This study analyzed 6,564 Chinese herbalists employed between 1985 and 1998. All incident cases of urothelial carcinoma that occurred between 1988 and 2001 were defined as the case group. Controls were selected from the baseline cohort in a randomized manner. A total of 24 cases and 140 controls were included in analysis. Information about fangchi exposure was obtained in a questionnaire survey administered in 2002. RESULTS: Processing, selling or dispensing herbs containing fangchi significantly increased the risk of urothelial carcinoma (HR 2.4, 95% CI 1.1-5.3, p = 0.03). This relationship was independent of cigarette smoking or potential arsenic exposure from drinking water from deep wells. CONCLUSIONS: Exposure to the Chinese herbal drug fangchi increases the risk of urothelial carcinoma in herbalists. Appropriate medical monitoring is warranted for workers who have similar exposure.

Increased risks of upper tract urothelial carcinoma in male and female chinese herbalists.

BACKGROUND/PURPOSE: It has been shown that herbs that contain aristolochic acid induce urological cancer. Chinese herbalists have easy access to such herbs. Our previous mortality study has shown a significantly increased risk of urological cancer in female but not male herbalists. To re-examine this risk in male herbalists, the incidence of urological cancer was analyzed. METHODS: We enrolled all 6550 Chinese herbalists in Taiwan registered during 1985-2000, and we retrospectively followed the development of cancer until 2001 by analysis of data collected from the Taiwan Cancer Registry. Standardized incidence ratios (SIRs) were calculated for urological cancers in herbalists and compared with those for the general population in Taiwan. RESULTS: There were 30 newly diagnosed cases of urological cancer and most of them were transitional cell carcinoma (93.1%). The mean age at diagnosis for urothelial carcinoma was 51.6 years, and 51.9% were in the upper urinary tract. After adjustment for age and sex, the SIR for all urological cancers was 3.51 [(95% confidence interval (CI): 2.37-5.01]. When stratified by location, the SIRs for kidney and upper urinary tract cancers and bladder cancer were 4.24 (95% CI: 2.47-6.80) and 2.86 (95% CI: 1.52-4.89), respectively. When analyzed by sex, the SIRs for all urological cancers, kidney and upper urinary tract cancers, and bladder cancer were also significantly increased in male herbalists. CONCLUSION: The significant risk of urothelial carcinoma noted in male herbalists increases our suspicion that this is an occupational disease that renders regular health assessment of herbalists an urgent necessity.

Occupational kidney disease among Chinese herbalists exposed to herbs containing aristolochic acids.

OBJECTIVE: Many Chinese herbs contain aristolochic acids (ALAs) which are nephrotoxic and carcinogenic. The objective of this study was to identify whether exposure to herbs containing ALAs increased the risk of kidney disease among Chinese herbalists. METHODS: A nested case-control study was carried out on 6538 Chinese herbalists registered between 1985 and 1998. All incident cases of chronic renal failure reported to the Database of Catastrophic Illness of the National Health Insurance Bureau between 1995 and 2000 were defined as the case group. Up to four controls without renal failure were randomly matched to each case by sex and year of birth. A structured questionnaire survey was administered between November and December 2002. The Mantel-Haenszel method and conditional logistic regression were used to estimate the risks. RESULTS: 40 cases and 98 matched controls were included in the final analysis. After adjusting for age, frequent analgesic use, and habitual consumption of alcohol, fermented or smoked food, we found manufacturing and selling Chinese herbal medicine (OR 3.43, 95% CI 1.16 to 10.19), processing, selling or dispensing herbal medicines containing Fangji (OR 4.17, 95% CI 1.36 to 12.81), living in the workplace (OR 3.14, 95% CI 1.11 to 8.84) and a history of taking of herbal medicines containing Fangji (frequently or occasionally) (OR 5.42, 95% CI 1.18 to 24.96) were significantly associated with renal failure. CONCLUSION: Occupational exposure to and consumption of herbs containing ALAs increases the risk of renal failure in Chinese herbalists.

Increased mortality risk for cancers of the kidney and other urinary organs among Chinese herbalists.

BACKGROUND: A national survey in Taiwan has shown that Chinese herbal therapy increases the risk of chronic kidney disease. However, it is unknown whether herbal therapy will increase the risk of urological cancers. The purpose of this study was to determine whether Chinese herbalists are at higher risk for urological cancers. METHODS: We studied all Chinese herbalists in Taiwan that were registered in the Chinese Herbalist Labor Union between 1985 and 2000. We retrospectively followed their survival status and causes of death using the National Mortality Registry Database from 1985 to 2004. Standardized mortality ratios (SMRs) for urological cancers in herbalists were calculated and compared with those of the general population of Taiwan. RESULTS: A total of 6548 Chinese herbalists were enrolled and 88,289 person-years were accrued during the observation period. After adjustment for age and sex, the SMR for urological cancers was significantly higher for Chinese herbalists than for the general population (SMR = 3.10; 95% CI: 1.41-5.87). When further stratified by location, the SMR for kidney cancer and other urinary organ cancers (SMR = 3.81; 95% CI: 1.39-8.28) except bladder cancer (SMR = 2.26; 95% CI: 0.47-6.59) were significantly higher for the Chinese herbalists. The SMR for chronic and unspecified nephritis, renal failure, and renal sclerosis were also significantly higher for herbalists (SMR = 2.40; 95% CI: 1.40-3.84). CONCLUSIONS: Chinese herbalists have a significantly higher risk for urological cancers. This increased risk among herbalists highlights the urgent need for safety assessments of Chinese herbs.