Association of the AhR, ARNT, and AhRR gene polymorphisms and cord blood AhR levels with elevated cord blood IgE susceptibility in Taiwan mother-infant pairs: a nested case-control study.

The roles of aryl hydrocarbon receptor (AhR), AhR-nuclear translocator (ARNT), and AhR repressor (AhRR) genes in the elevation of cord blood IgE (CbIgE) remained unclear. Our aims were to determine the polymorphisms of AhR, ARNT, and AhRR genes, cord blood AhR (CBAhR) level, and susceptibility to elevation of CbIgE. 206 infant-mother pairs with CbIgE>=0.35 IU/ml and 421 randomly selected controls recruited from our previous study. Genotyping was determined using TaqMan assays. Statistical analysis showed AhR rs2066853 (GG vs. AA+AG: adjusted OR (AOR)=1.5, 95%CI=1.10-2.31 and AOR=1.60, 95%CI=1.06-2.43, respectively) and the combination of AhR rs2066853 and maternal total IgE (mtIgE)>=100 IU/ml were significantly correlated with CbIgE>=0.35 IU/ml or CbIgE>=0.5 IU/ml. CBAhR in a random subsample and CbIgE levels were significantly higher in infants with rs2066853GG genotype. We suggest that infant AhR rs2066853 and their interactions with mtIgE>=100 IU/ml significantly correlate with elevated CbIgE, but AhRR and ARNT polymorphisms do not.

Association between acid-suppressive drug use and atopic dermatitis in patients with upper gastrointestinal diseases: A population-based retrospective cohort study.

WHAT IS KNOWN AND OBJECTIVE: Proton-pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs) are two of the most widely used acid-suppressive drugs (ASDs). Some studies have reported that prenatal ASD exposure may increase the risk of asthma and other allergic diseases. This study investigated the effects of ASDs on the risk of atopic dermatitis in patients with upper gastrointestinal diseases. METHODS: This population-based retrospective cohort study used data of 289,850 patients with at least two diagnoses of upper gastrointestinal diseases (UGIDs) between 1 January 2001 and 31 December 2005, from Taiwan's National Health Insurance Research Database. The AD risks among ASD users and nonusers were compared. Differences in sociodemographic characteristics and potential covariates were examined. AD hazard ratios were estimated, and groups were compared using Cox proportional hazards regression analysis after adjustment for age, sex and other covariates. RESULTS AND DISCUSSION: In total, 109,980 patients were included. The adjusted hazard ratio (HR) of AD risk in ASD users relative to that in nonusers was 1.52 (95% confidence interval [CI]: 1.40-1.64, p < 0.001). For a dose-effect sub-analysis, patients were divided into four groups based on their defined daily dose. ASDs dose-dependently affected the AD risk (p for trend <0.01). Furthermore, the adjusted HR of the AD risk among ASD nonusers was 2.30 (95% CI: 2.06-2.57) relative to that in the comparison group (ASD nonusers without UGIDs). Among patients with UGIDs, ASD users had a higher AD risk than ASD nonusers. A subgroup analysis revealed only H2RA use was associated with an increased AD risk (adjusted HR 1.70, 95% CI: 1.53-1.89, p < 0.001). WHAT IS NEW AND CONCLUSIONS: These results indicate that the use of H2RAs was associated with an increased risk of AD among patients with UGIDs, and the increase in risk appeared to be dose-dependent. ASDs should be used only in situations where clear clinical benefits can be obtained.

Effect of catechin and commercial preparation of green tea essence on the pharmacokinetics of l-dopa in rabbits.

The aim of this study was to investigate drug interactions of L-dopa/carbidopa with catechin and green tea essence in rabbits following the simultaneous administration via an intramuscular injection of catechin or via an intragastric route for green tea essence with L-dopa/carbidopa. The results indicated that catechin at doses of 10, 20 and 50 mg/kg increased the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-t ) of L-dopa by about 69, 78 and 42%, respectively. The metabolic ratios of the AUC0-t for 3-O-methyldopa (3-OMD)/L-dopa significantly decreased by about 56, 68 and 76% (P < 0.05), respectively. In addition, a single dose of 5/1.25 mg/kg L-dopa/carbidopa was co-administrated with 150 mg/kg green tea essence via an intragastric route with an oral-gastric tube. Comparing the related pharmacokinetic parameters of L-dopa, the clearance and metabolic ratio of L-dopa decreased by 20 and 19% (P < 0.05), respectively. In conclusion, catechin and green tea essence can significantly affect the metabolism of L-dopa by the catechol-O-methyltransferase (COMT) metabolic pathway. Catechin can enhance L-dopa bioavailability, and both catechin and green tea essence decreased 3-OMD formation. Therefore, catechin and green tea essence may increase L-dopa efficacy for Parkinson's disease treatment.

In Vitro and Vivo Identification, Metabolism and Action of Xenoestrogens: An Overview.

Xenoestrogens (XEs) are substances that imitate endogenous estrogens to affect the physiologic functions of humans or other animals. As endocrine disruptors, they can be either synthetic or natural chemical compounds derived from diet, pesticides, cosmetics, plastics, plants, industrial byproducts, metals, and medications. By mimicking the chemical structure that is naturally occurring estrogen compounds, synthetic XEs, such as polychlorinated biphenyls (PCBs), bisphenol A (BPA), and diethylstilbestrol (DES), are considered the focus of a group of exogenous chemical. On the other hand, nature phytoestrogens in soybeans can also serve as XEs to exert estrogenic activities. In contrast, some XEs are not similar to estrogens in structure and can affect the physiologic functions in ways other than ER-ERE ligand routes. Studies have confirmed that even the weakly active compounds could interfere with the hormonal balance with persistency or high concentrations of XEs, thus possibly being associated with the occurrence of the reproductive tract or neuroendocrine disorders and congenital malformations. However, XEs are most likely to exert tissue-specific and non-genomic actions when estrogen concentrations are relatively low. Current research has reported that there is not only one factor affected by XEs, but opposite directions are also found on several occasions, or even different components stem from the identical endocrine pathway; thus, it is more challenging and unpredictable of the physical health. This review provides a summary of the identification, detection, metabolism, and action of XEs. However, many details of the underlying mechanisms remain unknown and warrant further investigation.

Increased risk of periodontitis among patients with Crohn's disease: a population-based matched-cohort study.

BACKGROUND: Periodontitis is a frequently cited extraintestinal manifestation of Crohn's disease (CD). Despite a plethora of investigations and a recent meta-analysis linking CD and periodontitis, no study has estimated the risk of periodontitis among CD patients with respect to a comparison group nor has any investigation analyzed the effect of CD-specific medications on the risk of periodontitis. The present cohort study compared CD patients and matched subjects without a history of inflammatory bowel disease (IBD) to estimate the effect of CD and CD-specific pharmaceutical prescriptions on the risk of developing periodontitis by leveraging a population-based dataset in Taiwan. METHODS: We sourced 6657 CD patients and 26,628 comparison subjects without a history of IBD from the Taiwan National Health Insurance Database. Cox proportional hazards regressions were used to estimate the risk of subsequent periodontitis by CD status and pharmaceutical prescription during the follow-up period. RESULTS: After adjusting for socioeconomic status (SES), urbanicity, selected medical co-morbidities, and CD-specific pharmaceutical prescriptions, the hazard ratio (HR) for subsequent periodontitis among patients with CD was 1.36 (95% CI = 1.25-1.48) that of comparison subjects. There was not a significant difference in risk between genders or across ages. Steroids (95% CI = 0.66-0.77) appeared to confer a protective effect and Aspirin, Plavix, and Licodin were marginally protective (95% CI = 0.76-0.95). CONCLUSION: This is the first study to report an increased HR for subsequent periodontitis among CD patients when compared to matched comparison subjects without IBD. The protective effect of some pharmaceuticals may suggest that treatment of CD protects against periodontitis.

Dose-dependent pharmacokinetics and tentative identification of urine metabolites from an isosteviol derivative with anti-hepatitis B activity in rats.

Compound 1 (ent-16-oxobeyeran-19-N-methylureido) is a semisynthetic isosteviol derivative that shows anti-hepatitis B virus activity in Huh7 cells by affecting viral DNA transcription and the Toll-like receptor 2/nuclear factor-κB signaling pathway. Thus, the pharmacokinetics and metabolite identification were studied as part of the discovery and development process of compound 1. The pharmacokinetics was evaluated after administration to rats at an intravenous dose of 2 mg/kg, and oral doses of 2, 5 and 10 mg/kg. Plasma concentrations were determined using LC-MS/MS. Moreover, urine samples from rats dosed at 10 mg/kg were scanned for metabolites using UPLC-QTOF-MS/MS. Results for the intravenously administered dose of 2 mg/kg showed that the area under the concentration-time curve was 65,223.31 ± 4269.80 ng min/mL, and the systemic clearance was 0.031 ± 0.0021 L/min. Oral pharmacokinetic parameters were dose-dependent, showing nonproportional increases in the oral AUCs with respective values of 4371.62 ± 3084.81, 22,472.75 ± 9103.33 and 135,141.83 ± 38,934.03 ng min/mL for 2, 5 and 10 mg/kg. The bioavailability was low at 1.5% for 2 mg/kg dose, and at 1.1% for both 5 and 10 mg/kg doses. Metabolites excreted in the urine indicate possible N-oxidation and glucuronide conjugation.

Risk of cancer among HIV-infected patients from a population-based nested case-control study: implications for cancer prevention.

BACKGROUND: The burden of cancer is likely to increase among the human immunodeficiency virus (HIV)-positive population as it ages due to successful antiretroviral therapy (ART). The purpose of this study was to determine the risk of cancer in HIV-infected patients. METHODS: This study was a matched nested case-control study. It was performed using the National Health Insurance Research Database of Taiwan. The control group included non-HIV-infected patients matched by sex, age, and year of enrollment. Logistic regression analyses were performed and simultaneously adjusted for potential confounders (income, urbanization, and Charslon index of comorbidity to evaluate HIV infection as an independent risk of cancer. We calculated the overall and sex-specific standardized incidence ratios (SIR) to investigate the pattern of cancer risk and overall cancer risk in the patients with HIV infection. RESULTS: Of the 1,115 HIV-infected patients, 104 (9.33%) developed cancer during the 11-year follow-up period. The risk of cancer for patients with HIV infection was significant (adjusted odds ratio = 3.89, 95% confidence interval [CI] = 2.92-5.19) after adjustment for potential confounders. There was a significantly increased risk of developing non-Hodgkin lymphoma (SIR = 25.73, 95% CI = 6.83-90.85), cervical cancer (SIR = 4.01, 95% CI = 1.0-16.06), lymphoma (SIR = 20.26, 95% CI = 5.86-70.10), and respiratory and intrathoracic cancer (SIR = 20.09, 95% CI = 2.34-172.09) compared with the control group. In addition, HIV-infected patients were at significant risk for renal, oral, breast, liver, skin, and colorectal cancer. CONCLUSIONS: Patients with HIV infection are at increased risk for several specific cancers. Our results support the implementation of an active and accelerated cancer screening schedule for patients with HIV infection to increase their life span.

Increased risk of stroke among patients with Crohn's disease: a population-based matched cohort study.

BACKGROUND: Crohn's disease (CD) is one type of inflammatory bowel disease (IBD) that has been speculated to share prognostic factors with the development of stroke. There is controversial information in the literature regarding the association between CD and stroke. The present cohort study estimated the risk of subsequent stroke among CD patients compared with matched comparison subjects drawn from a population-based dataset in Taiwan. METHOD: This study drew data from the Taiwan National Health Insurance Database to conduct a historical cohort study. The study cohort comprised 3309 CD patients, and the comparison cohort comprised 13,236 subjects without an IBD. Cox proportional hazards regressions were performed to estimate the risk of subsequent stroke during the follow-up period. We also conducted additional analyses stratifying by age group and gender. RESULTS: After adjusting for selected medical co-morbidities and recent prescriptions of selected pharmaceuticals, the hazard ratio (HR) for subsequent stroke among patients with CD was found to be 1.911 (95% confidence interval (CI) = 1.65-2.22) that of comparison subjects. While we did not detect an association between stroke and CD among patients aged 30-40 years, we did detect increased risks for stroke among CD patients aged 40-50 years (HR = 2.29) and those aged over 50 years (HR = 1.88). We also found women (HR = 2.39) to be at a greater risk than men (HR = 1.50). CONCLUSION: This study reports an increased HR for subsequent stroke among CD patients when compared to matched comparison patients without IBD in an Asian population.

Increased risk of stroke among patients with ulcerative colitis: a population-based matched cohort study.

BACKGROUND: The risk of venous thromboembolism (VTE) and the development of atherosclerosis are increased in patients with inflammatory bowel disease (IBD). Ulcerative colitis (UC) is one type of IBD; however, there is controversy in the literature regarding the association between UC and stroke. The present cohort study estimated the risk of subsequent stroke among UC patients compared with that among matched comparison subjects drawn from a population-based data set in Taiwan. METHODS: This investigation analyzed administrative claims data sourced from the Taiwan National Health Insurance Database. Our study consisted of a study cohort comprising 516 UC patients and a comparison cohort of 2,579 subjects without IBD. Cox proportional hazards regressions were performed to estimate the risk of subsequent stroke during the follow-up period. We also conducted additional analyses investigating the risk of subsequent stroke by age group and gender. RESULTS: After adjusting for selected medical co-morbidities and recent prescriptions of selected pharmaceuticals, the hazard ratio (HR) for subsequent stroke among patients with UC was 2.045 (95 % confidence interval (CI) = 1.374-3.043) than that among comparison subjects. While we did not detect an association between stroke and UC among patients aged 30-40 or 40-50 years, we did detect increased risks for stroke among UC patients aged over 50 years (HR = 2.045). We also found the association to remain significant for both men (HR = 2.153) and women (HR = 2.750). CONCLUSIONS: This study detected an increased HR for subsequent stroke among Taiwanese UC patients hen compared to that among matched comparison patients without IBD.

Increased risk of stroke among patients with ankylosing spondylitis: a population-based matched-cohort study.

Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease. Although two prior studies detected increased prevalence ratios of cerebrovascular disease among AS patients, the results of the two studies investigating AS and stroke are in conflict. Therefore, the present cohort study set out to estimate the risk of subsequent stroke in AS patients compared with matched controls using a population-based dataset in Taiwan. This investigation analyzed administrative claims data sourced from the Taiwan National Health Insurance Database. Our study consisted of a study cohort comprising 1,479 AS patients and a comparison cohort of 5,916 subjects without AS. Cox proportional hazards regressions were performed to estimate the risk of subsequent stroke during the follow-up period. We also conducted additional analyses investigating the risk of subsequent stroke by gender and pharmaceutical prescription. After adjusting for chronic lower respiratory diseases, type 2 diabetes mellitus, hypertension, hyperlipidemia, renal disease, coronary heart disease, atrial fibrillation, income, and urbanization, compared with comparison patients, the hazard ratio for subsequent stroke among patients with AS was 2.3 (95 % CI 1.9-2.8). We also stratified our results by both gender and pharmaceutical prescription, but did not find a statistically significant difference for the risk of subsequent stroke either between men and women, or between AS patients taking various pharmaceutical regimens and the overall AS population. This is the first study to report an increased hazard ratio for subsequent stroke among AS patients when compared with matched comparison patients without AS.

Association Between Statin Use and the Incidence of Clinically Diagnosed Osteoarthritis: A Nationwide Retrospective Cohort Study in Taiwan.

OBJECTIVE: To investigate the effect of higher cumulative defined daily dose per year (cDDD/y) compared with lower cDDD/y of statin use in the incidence of any joint osteoarthritis (OA). DESIGN: In this population-based retrospective cohort study, patients who were aged ≥40 years were newly initiated on statin therapy between 2002 and 2011, and had a statin prescription for ≥90 days in the first year of treatment were identified from the 2000 Longitudinal Generation Tracking Database. All patients were separated into groups with higher cDDD/y (>120 cDDD/y) and lower cDDD/y (≤120 cDDD/y; as an active comparator) values. Propensity score matching was performed to balance potential confounders. All recruited patients were followed up for 8 years. Marginal Cox proportional hazard models were used to estimate time-to-event outcomes of OA. RESULTS: Compared with lower cDDD/y use, higher cDDD/y use did not reduce the risk of any joint OA (adjusted hazard ratio, 1.07; 95% confidence interval, 0.99-1.14). Dose-related analysis did not reveal any dose-dependent association. A series of sensitivity analyses showed similar results. Joint-specific analyses revealed that statin did not reduce the incidence of knee, hand, hip, and weight-bearing (knee or hip) OA. CONCLUSIONS: Higher cDDD/y statin use did not reduce the risk of OA in this Taiwanese nationwide cohort study. The complexity of OA pathogenesis might contribute to the ineffectiveness of statin. Repurposing statin with its anti-inflammation properties might be ineffective for OA development, and balancing the catabolism and anabolism of cartilage might be a major strategy for OA prevention.

Association between antihyperlipidemic agents and the risk of chronic periodontitis in patients with hyperlipidemia: A population-based retrospective cohort study in Taiwan.

BACKGROUND: The lipid-lowering and anti-inflammatory effects of statins and fibrates may ameliorate periodontitis. Patients with hyperlipidemia tend to have a worse periodontal status. This study assessed the association between the use of statins/fibrates and the incidence of chronic periodontitis in patients with hyperlipidemia in Taiwan. METHODS: This retrospective cohort study enrolled patients newly diagnosed with hyperlipidemia between 2001 and 2012 from the 2000 Longitudinal Generation Tracking Database and followed them for 5 years. The study population was divided into four groups: statin monotherapy, fibrate monotherapy, combination therapy (both statins and fibrates), and control (neither statins nor fibrates). Each patient in the treatment group was matched at a ratio of 1:1 with a control. Chronic periodontitis risk was compared in the three study arms by using a Cox proportional hazard model. RESULTS: Chronic periodontitis risk was reduced by 25.7% in the combination therapy group compared with the control group (adjusted hazard ratio [aHR], 0.743; 95% confidence interval (CI), 0.678-0.815). Low dose (<360 cumulative defined daily dose [cDDD]) and shorter duration (<2 years) of statin monotherapy seem to be associated with an increased risk of chronic periodontitis; high dose (≥720 cDDD/≥1080 cDDD) and longer duration (≥3 years) of statin/fibrate monotherapy may be correlated with a lower risk of periodontitis. Hydrophobic statin users had a lower chronic periodontitis risk than hydrophilic statin users. CONCLUSION: Chronic periodontitis risk was lower in patients with hyperlipidemia on combination treatment with statins and fibrates, and the risk decreased when patients used statins or fibrates for >3 years.

Association between Antihyperlipidemic Agent Use and Age-Related Macular Degeneration in Patients with Hyperlipidemia: A Population-Based Retrospective Cohort Study.

Several studies have indicated that lipoproteins might contribute to the pathogenesis of age-related macular degeneration (AMD). In this population-based retrospective cohort study, patients with hyperlipidemia were divided into two groups (study groups I and II) based on whether or not they were receiving antihyperlipidemic agents. The comparison group included patients without hyperlipidemia who were randomly selected and matched with study group II patients. A Cox proportional hazard model was used to evaluate the risk of AMD among the groups. Patients with hyperlipidemia receiving antihyperlipidemic agents (study group I, n = 15,482) had a significantly increased AMD risk (adjusted hazard ratio (HR) = 1.23, 95% confidence interval (CI) = 1.04-1.45) compared to those not receiving antihyperlipidemic agents (study group II, n = 15,482). However, with an increase in cumulative exposure, a reduced risk of AMD was observed in patients using a defined daily dose of more than 721, with an adjusted HR of 0.34 (95% CI = 0.22-0.53, p < 0.001). Additionally, the adjusted HR of AMD for study group II was 1.40 (95% CI = 1.20-1.63, p < 0.001) relative to the comparison group (n = 61,928). In conclusion, the study results indicated that patients with hyperlipidemia have a higher AMD risk than patients without hyperlipidemia. Furthermore, patients with hyperlipidemia who received antihyperlipidemic agents had a significantly increased AMD risk. However, a dose-dependent reduction in the risk of AMD was observed in patients with hyperlipidemia using statins or/and fibrates.

Association between statin use and the risk of gout in patients with hyperlipidemia: A population-based cohort study.

Objective: To investigate the association between statin use and risk of gout in patients with hyperlipidemia. Methods: In this population-based retrospective cohort study, patients ≥20 years and diagnosed as having incident hyperlipidemia between 2001 and 2012 were identified from the 2000 Longitudinal Generation Tracking Database in Taiwan. Regular statin users (incident statin use, having 2 times and ≥90 days of prescription for the first year) and two active comparators [irregular statin use and other lipid-lowering agent (OLLA) use] were compared; the patients were followed up until the end of 2017. Propensity score matching was applied to balance potential confounders. Time-to-event outcomes of gout and dose- and duration-related associations were estimated using marginal Cox proportional hazard models. Results: Regular statin use non-significantly reduced gout risk compared with irregular statin use (aHR, 0.95; 95% CI, 0.90-1.01) and OLLA use (aHR, 0.94; 95% CI, 0.84-1.04). However, a protective effect was noted for a cumulative defined daily dose (cDDD) of >720 (aHR, 0.57; 95% CI, 0.47-0.69 compared with irregular statin use and aHR, 0.48; 95% CI, 0.34-0.67 compared with OLLA use) or a therapy duration of >3 years (aHR, 0.76; 95% CI, 0.64-0.90 compared with irregular statin use and aHR, 0.50; 95% CI, 0.37-0.68 compared with OLLA use). Dose- and duration-dependent associations were consistent in the 5-year sensitivity analyses. Conclusion: Although statin use was not associated with a reduction in gout risk, the protective benefit was observed in those receiving higher cumulative doses or with a longer therapy duration.

Applying the theory of planned behavior to investigate type 2 diabetes patients' intention to receive injection therapy.

Objectives: This study applied the theory of planned behavior (TPB) in shared decision making (SDM) to understand behavioral intention in patients with type 2 diabetes with regard to injection therapy for blood sugar control. Methods: A cross sectional study was conducted. Two hundred and fifty-four patients with type 2 diabetes participated this study and were interviewed by pharmacists in different clinics. A patient decision aid (PDA) entitled "Should I receive injection therapy regarding my type 2 diabetes condition?" was developed for this study and served as interview agenda which comprised 18 items to inquire their willingness to use injection therapy and related considerations during the SDM process. Results: The questionnaires were revised using item analysis, exploratory factor analysis, and a criteria of Cronbach's α > 0.7. This resulted in three constructs for all questionnaires that fit the TPB model. Attitude (ß = 0.432; P < 0.001) and PBC (ß = 0.258; P < 0.001) were directly correlated with intention. TPB explained 35.2% of the variance in intention toward the use of injection therapy. Conclusions: Attitude and PBC toward injection therapy positively and significantly influence the patients' intention to use injection therapy. Practical implications: These findings identify a key association for understanding behavioral intention in patients with type 2 diabetes with regard to blood sugar control during SDM.

Association between GnRH analogue use and atopic diseases in patients with prostate cancer: A population-based retrospective cohort study.

PURPOSE: Gonadotropin-releasing hormone (GnRH) analogues reduce testosterone levels to castration levels in patients with prostate cancer. However, the role of testosterone in atopic diseases has remained undefined. We aimed to investigate this role. MATERIALS AND METHODS: This retrospective cohort study was conducted using the National Health Insurance Research Database (NHIRD). Patients with prostate cancer were categorized into two groups according to whether they received GnRH analogue treatment (study group I) or not (study group II), and men without prostate cancer and with no GnRH analogue use were defined to comprise the comparison group after their ages and index years were matched with group II. Cox proportional hazard models were used to assess the hazard ratio (HR) of atopic diseases. RESULTS: Group I, group II, and the comparison group comprised 663, 2,172, and 8,688 individuals, respectively. Group I had a significantly lower risk of atopic diseases (adjusted HR: 0.66, 95% CI, 0.49-0.89, p < 0.01) than did group II. A reduced risk of atopic diseases was found when GnRH analogues were prescribed for 2 months (adjusted HR 0.53, 95% CI, 0.29-0.97, p = 0.04) and 2-14 months (adjusted HR 0.66, 95% CI, 0.49-0.89, p = 0.007). No significant difference in the risk of atopic diseases between group II and the comparison group was observed. CONCLUSIONS: A decreased risk of atopic diseases was observed in patients with prostate cancer treated with GnRH analogues. Further studies are warranted to verify the association between testosterone levels and atopic diseases.

Pharmacokinetic Herb-Drug Interactions of Xiang-Sha-Liu-Jun-Zi-Tang and Paclitaxel in Male Sprague Dawley Rats and Its Influence on Enzyme Kinetics in Human Liver Microsomes.

Paclitaxel is a prescribed anticancer drug used to treat various cancers. It is a substrate of cytochrome P-450 (CYP-450) enzymes. Despite its efficacy, paclitaxel has severe side effects. Herbal medicines are commonly used to treat the side effects of chemotherapy. They can be administered before, during, and after chemotherapy. Xiang-Sha-Liu-Jun-Zi Tang (XSLJZT) is a herbal formula commonly used in breast cancer patients. The main purpose of this study was to assess the pharmacokinetic (PK) influence of XSLJZT on paclitaxel PK parameters, determine its effect on CYP-450 enzyme expression, and evaluate its effect on enzyme activity. Sprague Dawley rats were classified into pretreatment and co-treatment groups, where XSLJZT was pre-administered for 3, 5, and 7 days and co-administered 2 h before paclitaxel administration. The rat liver tissues and Hep-G2 cells were used to determine the effects of XSLJZT on CYP3A1/2 and CYP3A4 enzymes respectively. Western blot analysis was used to detect changes in the CYP3A1/2 and CYP3A4 enzymes expression. The influence of XSLJZT on enzyme activity was evaluated using human liver microsomes, and a liquid chromatography-tandem mass spectrometric system was developed to monitor paclitaxel levels in rat plasma. Results demonstrated that XSLJZT increased the area under the concentration versus time curve (AUC) for paclitaxel in pretreatment groups by 2-, 3-, and 4-fold after 3, 5, and 7 days, respectively. In contrast, no significant change in the AUC was observed in the co-treatment group. However, the half-life was prolonged in all groups from 17.11 min to a maximum of 37.56 min. XSLJZT inhibited CYP3A1/2 expression in the rat liver tissues and CYP3A4 enzymes in Hep-G2 cells in a time-dependent manner, with the highest inhibition observed after 7 days of pretreatment in rat liver tissues. In the enzyme kinetics study, XSLJZT inhibited enzyme activity in a competitive dose-dependent manner. In conclusion, there is a potential interaction between XSLJZT and paclitaxel at different co-treatment and pretreatment time points.

Associations of Warfarin Use with Risks of Ischemic Cerebrovascular Events and Major Bleeding in Patients with Hyperthyroidism-Related Atrial Fibrillation.

The use of oral anticoagulants for patients with new-onset hyperthyroidism-related atrial fibrillation (AF) is controversial. We aimed to evaluate the clinical benefits of warfarin therapy in this population. This retrospective cohort study used a data-cut of Taiwan Health and Welfare Database between 2000 and 2016. We compared warfarin users and nonusers among AF patients with hyperthyroidism. We used 1:2 propensity score matching to balance covariates and Cox regression model to calculate hazard ratios (HRs). The primary outcome was risk of ischemic stroke/transient ischemic attack (TIA), and the secondary outcome was major bleeding. After propensity score matching, we defined 90 and 168 hyperthyroidism-related AF patients with mean (SD) age of 59.9 ± 13.5 and 59.2 ± 14.6 in the warfarin-treated group and untreated group separately. The mean (SD) CHA2DS2-VASc scores for the two groups were 2.1 ± 1.6 and 1.8 ± 1.5, respectively. Patients with hyperthyroidism-related AF receiving warfarin had no significant risk of ischemic stroke/TIA (adjusted HR: 1.16, 95% confidence interval [CI]: 0.52-2.56, p = 0.717) compared to nonusers. There was a comparable risk of major bleeding between those receiving warfarin or not (adjusted HR: 0.91, 95% CI: 0.56-1.47, p = 0.702). The active-comparator design also demonstrated that warfarin use had no significant association with the risk of stroke/TIA versus aspirin use (adjusted HR: 2.43; 95% CI: 0.68-8.70). In conclusion, anticoagulation therapy did not have a statistically significant benefit on ischemic stroke/TIA nor risk of bleeding, among patients with new-onset hyperthyroidism-related AF under a low CHA2DS2-VASc score, by comparing those without use.

Transformation of isosteviol lactam by fungi and the suppressive effects of its transformed products on LPS-induced iNOS expression in macrophages.

From the screening of 21 microbial strains, Absidia pseudocylindrospora ATCC 24169 and Aspergillus niger BCRC 32720 were found to reproducibly transform isosteviol lactam (4α-carboxy-13α-amino-13,16-seco-ent-19-norbeyeran-16-oic acid 13,16-lactam) (3) into various compounds. Preparative-scale transformation of 3 with Abs. pseudocylindrospora yielded two new hydroxylated compounds (4 and 5), with conservation of the lactam ring. Preparative-scale transformation of 3 with Asp. niger afforded seven new compounds, 6 and 9-14, together with the known compounds 7 and 8. A single-crystal X-ray diffraction experiment confirmed the structure of 14. The suppressive effects of compounds 1-14 on the lipopolysaccharide-induced expression of the inducible nitric oxide synthase gene in RAW 264.7 macrophages were examined by a reverse-transcription real-time PCR analysis. With the exception of 7, all other compounds significantly reduced levels of iNOS mRNA relative to control cells, which were induced by LPS alone. Compounds 2, 3, and 5 were similar in activity to dexamethasone, while 9 was more potent.

Use of gastric acid-suppressive agents increases the risk of dementia in patients with upper gastrointestinal disease: A population-based retrospective cohort study.

BACKGROUND: Prescriptions for gastric acid-suppressive agents, including proton-pump inhibitors (PPIs) and histamine type-2 receptor antagonists (H2RAs), are rising. However, little data exist regarding their association with dementia in the Asian population. The objective of this study was thus to investigate the impact of the use of PPIs and H2RAs on the risk of dementia in an Asian population with upper gastrointestinal disease (UGID). METHODS: We conducted a population-based retrospective cohort study with a 10-year follow-up using data from 2000 to 2015 derived from Taiwan's Longitudinal Health Insurance Database. We included 6711 patients with UGID receiving gastric acid-suppressive agents, 6711 patients with UGID not receiving agents, and 6711 patients without UGID or treatment thereof, all at least 20 years of age. Groups were matched for age, sex, and index date. The association between gastric acid-suppressive agent use and dementia was analyzed using a Cox proportional hazards regression model adjusted for potential confounders. RESULTS: The adjusted hazard ratio (aHR) of dementia for patients with UGID receiving gastric acid-suppressive agents compared with patients with UGID without gastric acid-suppressive agents was 1.470 (95% confidence interval [CI] 1.267-1.705, p < 0.001). Both PPIs and H2RAs increase the risk of dementia (PPIs: aHR 1.886 [95% CI 1.377-2.582], p < 0.001; H2RAs: aHR 1.357 [95% CI 1.098-1.678], p < 0.01), with PPIs exhibiting significantly greater risk (aHR 1.456 [95% CI 1.022-2.075], p < 0.05). CONCLUSIONS: Our results demonstrate an increased risk of dementia in patients with UGID receiving gastric acid-suppressive agents, including PPIs and H2RAs, and the use of PPIs was associated with a significantly greater risk than H2RA use.