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Objective: The study aimed to evaluate the improvement of patient knowledge of warfarin use, satisfaction with pharmacists, and the quality of international normalized ratio (INR) control after the implementation of an anticoagulant clinic (ACC) service.Methods: This was a prospective single-group pre- and post-comparison study. Patients who were at least 20 years of age and participated in a pharmacist-managed ACC service were enrolled from February 2012 to September 2015. Each participant completed a self-administered questionnaire before and after the ACC service to evaluate changes in warfarin knowledge. Another questionnaire was distributed after the ACC to evaluate participants' satisfaction with the pharmacist service in the ACC. The INR levels before and after the ACC intervention were obtained to calculate the proportion of time spent in the therapeutic INR range (time in therapeutic range, TTR). Paired t-tests were used to compare changes in participants' knowledge related to warfarin use. Multiple linear regressions were performed to explore the predictors associated with the participants' knowledge scores and TTR after the ACC intervention.Results: One hundred and forty-eight participants were enrolled in this study. A significant improvement (31.5%,p

Among engineered nanomaterials, CeO2 nanoparticles (NPs) are of particular interest due to their unique properties. These NPs’ anti-oxidative and auto-reduction natures also render them promising in scavenging reactive oxygen species (ROS). In this study, different synthesis methods of CeO2 NPs were studied: an NH4OH precipitation method, a NaOH precipitation method, and a microwave hydrothermal synthesis. Among these methods, the one-pot facile NH4OH method outperformed the others. The synthesized CeO2 NPs were determined to be highly monodispersed 13 nm crystallites with a pH at the potential of zero point charge (pHzpc) of 2.2. The valence states of Ce in CeO2 NPs were 3 + and 4 + were determined. The synthesized CeO2 NPs remained stable over 2 days in a medium containing FBS and over 3 days in NaCl solutions. The auto-reduction oxidation cycles of our CeO2 NPs were able to scavenge ROS multiple times. The cytotoxicity of NPs showed CeO2 NPs did not have a significant toxic effect on neuro2A cells. Owing to its synthesis of NPs of small size, with anti-oxidative/auto-reduction nature, with stability in cell culture media, and an absence of cytotoxicity toward neuroblastoma cells, this novel method proves promising as a method to generate CeO2 NPs for biomedical applications.

Extremely high doses of erythropoietin (EPO) has been used for neuroprotection in ischemia–reperfusion brain injury to deliver sufficient amounts of EPO across the blood–brain barrier (BBB); however, harmful outcomes were observed afterward. We aimed to test the ability of HBHAc (heparin-binding haemagglutinin adhesion c), an intracellular delivery peptide for macromolecules, as an EPO carrier across the BBB. The cellular internalization and transcytosis ability of HBHAc-modified EPO (EPO-HBHAc) were evaluated in bEnd.3 cells and in the bEnd.3/CTX TNA2 co-culture BBB model, respectively. Subsequently, the NMDA-induced-toxicity model and ischemia–reperfusion rat model were used to understand the neuronal protective activity of EPO-HBHAc. The biodistribution of EPO-HBHAc was demonstrated in rats by the quantification of EPO-HBHAc in the brain, plasma, and organs by ELISA. Our results demonstrate that EPO-HBHAc exhibited significantly higher cellular internalization in dose- and time-dependent manners and better transcytosis ability than EPO. In addition, the transported EPO-HBHAc in the co-culture transwell system maintained the neuronal protective activity when primary rat cortical neurons underwent NMDA-induced toxicity. The calculated cerebral infarction area of rats treated with EPO-HBHAc was significantly reduced compared to that of rats treated with EPO (29.9 ± 7.0% vs 48.9 ± 7.9%) 24 h after occlusion in 3VO rat experiments. Moreover, the EPO amount in both CSF and damaged cortex from the EPO-HBHAc group was 4.0-fold and 3.0-fold higher than the EPO group, respectively. These results suggest that HBHAc would be a favorable tool for EPO brain delivery and would further extend the clinical applications of EPO in neuroprotection. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-020-00845-2) contains supplementary material, which is available to authorized users.

Objectives To assess treatment patterns of statin and/or ezetimibe and possible statin intolerance among patients initiating statin or statin plus ezetimibe and with clinical atherosclerotic cardiovascular disease (ASCVD) or diabetes mellitus (DM) in Taiwan. Methods A retrospective cohort study using Taiwan's 2005 to 2013 National Health Insurance Research Database (NHIRD) was conducted. Patients with history of clinical ASCVD or DM (without previous clinical ASCVD) and initiating statin or statin plus ezetimibe therapy during 2006 to 2012 were identified. The treatment initiation date was defined as index date. Treatment patterns (including discontinuation, reinitiation, subtraction, switching, and augmentation), adherence (medication possession ratio [MPR]), persistence (gap no greater than 60 d) of statin and/or ezetimibe, and possible statin intolerance during 12-month follow-up from the index date were examined. Results Among patients initiating statin or statin plus ezetimibe, 11 092 patients with history of clinical ASCVD and 31 100 patients with DM but without clinical ASCVD were analysed. The discontinuation, reinitiation, and switching rates among patients with clinical ASCVD were 54.0%, 11.3%, and 25.7% during 12-month follow-up period, respectively. Among patients with DM, the rates were 57.5%, 14.2%, and 28.5%. The MPRs of statin among clinical ASCVD and DM cohorts were 0.62 and 0.60, respectively. As for ezetimibe, the MPRs were 0.56 and 0.59. Persistence to statin treatment was 46.1% among ASCVD patients and 42.6% among DM patients. Among the ASCVD and DM cohorts, possible statin intolerance was observed among 19.9% and 21.4% of patients, respectively. Conclusions Large number of patients with either ASCVD or DM discontinued lipid-lowering therapies with suboptimal adherence and persistence among Taiwanese population. There is a large unmet medical need to provide safe and more effective therapies, which can be used in combination with statins or alone, to reduce the risk of CV events and improve outcomes in high-risk patients.

Objective To determine and compare the risk of cardiovascular events and mortality of febuxostat and allopurinol use. Patients and Methods We conducted a cohort study using the Taiwan National Health Insurance Research Database. New users of febuxostat and allopurinol between April 1, 2012 and December 31, 2015 were identified, and the two groups were 1:1 matched by propensity score, benzbromarone use history, renal impairment, and time of drug initiation. The risk of major adverse cardiovascular events (MACEs), venous thromboembolism (VTE), heart failure (HF) hospitalization, atrial fibrillation hospitalization, cardiovascular (CV) death, and all-cause mortality was assessed using Cox proportional hazards models. The dose-response relationship between xanthine oxidase inhibitor use and adverse CV outcomes were also determined. Results A total of 44,111 patients were included for each group, and all baseline covariates were well matched. Febuxostat users were at a significantly higher risk for HF hospitalization (hazard ratio [HR], 1.22; 95% CI, 1.13-1.33), atrial fibrillation hospitalization (HR, 1.19; 95% CI, 1.05-1.36), and CV death (HR, 1.19; 95% CI, 1.03-1.36) than allopurinol users, whereas no difference was found for the major adverse cardiac events composite endpoint, venous thromboembolism, myocardial infarction, ischemic stroke, and all-cause mortality. The elevated risk of HF hospitalization was consistent throughout the primary and sensitivity analyses. In addition, febuxostat increased the risk of adverse CV outcomes in a dose-dependent manner. Conclusion The use of febuxostat, compared with allopurinol, was associated with a significantly increased risk of adverse CV events. Higher febuxostat doses had a greater impact. Further studies are needed to investigate the mechanisms linking febuxostat to adverse CV outcomes.

Objectives In children, supraventricular tachycardia is the most common form of arrhythmia, and propafenone is an effective class Ic antiarrhythmic agent used in this population. No suitable paediatric-specific, dosing-flexible preparation is available in Taiwan. The objective of this study was to develop a formulation of propafenone oral suspension prepared from commercially available propafenone tablets and commercially available oral syrup vehicles for related patients. Methods An oral suspension of propafenone hydrochloride at a concentration of 10 mg/mL was prepared by mixing finely grounded propafenone hydrochloride tablets and a 1:1 mixture of Ora-Plus and Ora-Sweet. The beyond-use date was determined by analysing the samples stored at room temperature or 2–8℃ at time 0 and on days 7, 14, 21, 28, 35, 42, 56, and 90. Parameters to be inspected included appearance, pH measurement, high-performance liquid chromatography analysis, and microbial limit tests. Results On the basis of the physicochemical and microbial stability results, the 10 mg/mL oral suspension of propafenone hydrochloride was stable at 2–8℃ and room temperature for at least 90 days. The suspension did not exhibit significant changes in drug concentration or pH level at any time point. Moreover, no apparent changes or microbial contaminations were observed for at least 90 days. Conclusions Propafenone hydrochloride in a 10 mg/mL oral suspension prepared by diluting fine powder with a 1:1 mixture of Ora-Plus and Ora-Sweet and stored in high-density polyethylene bottles and has a beyond-use date of 90 days when stored at 2–8℃ or room temperature. This finding enables us to improve the accuracy of dosage administration and reduce the risk of medication errors affecting the paediatric population.

Drug delivery into the central nervous system (CNS) is a brilliant research field, and the development of protein production and purification procedures for novel therapeutic proteins is crucial. Erythropoietin (EPO) is a glycoprotein with tremendous neuroprotective potential, but its bulky size prevents easy penetration across the blood-brain barrier (BBB). EPO-HBHAc is a promising cell-penetrating peptide modified protein for CNS diseases, necessitating an appropriate in vitro BBB model for further evaluation. The plasmid of EPO-HBHAc was constructed by DNA recombinant technology, and the Chinese Hamster Ovary (CHO-K1) cell expression system was selected to generate target proteins. His-tag and size exclusion purification were used to purify the target protein from the cell-conditioned medium; target proteins were further evaluated by western blotting and Coomassie blue staining. Moreover, the endothelial cells (bEnd.3) and astrocytes (CTX TNA2) were used to generate the in vitro BBB model, and transepithelial electrical resistance (TEER) and paracellular diffusion were measured to evaluate barrier integrity. The EPO-HBHAc plasmid was successfully constructed, and a stable cell line expressing EPO-HBHAc was generated. A higher protein expression level was observed in serum-containing medium than in serum-free medium. His-tag purification is not sufficient to remove impurities from target proteins, and thus size exclusion purification was performed to increase the purity of the protein of interest. In contrast, a higher TEER value and lower paracellular diffusion were observed in the co-culture model than in the mono-culture model. Furthermore, the higher TEER value was observed in inserts with a larger growth area (4.67 cm2) than in those with a smaller area (0.33 cm2). In conclusion, we demonstrated that some critical points might impact protein production and the in vitro BBB model construction in this study. Importantly, our research will provide valuable information in the field of CNS drug delivery.

Medical institutions usually ensure the quality of medications by reviewing manufacturing documents and examining the appearance of the drugs. However, these mechanisms may not be robust enough to confirm the quality of the medications used. To evaluate the quality of medicines used at a medical center in Taiwan, a total of 190 new or formulary drugs were analyzed in a period from April 2004 to June 2010. For each medication, at least one test in the pharmacopeia or pharmaceutical manufacturers' specifications was chosen according to the dosage form or clinical requirement. A total of 437 tests were conducted. The overall failure rate was 5.8% (11/190) among all the drug products tested. Higher failure rates were seen in drugs with special dosage forms (12.5%) or dubious quality (7.7%). Although the failure rates of domestic brand-name drugs (9.1%, 2/22) and imported generic drugs (16.7%, 1/6) appeared to be higher than those of imported brand-name drugs (0%, 0/29) and domestic generic drugs (6.0%. 8/ 133), there was no significant difference among the various groups by Fisher's exact test due to the small sample size. Nevertheless, this study shows that there are still some substandard medicines in the market. The quality of imported brand-name drugs was shown to be unquestionable. The quality of domestic generic drugs was found to be equivalent to that of domestic brand-name or imported generic drugs. In-house laboratory analysis is an effective method that can be used together with the review of manufacturing documents to ensure the quality of drugs used at health-care institutions.

Background/purpose The pharmacokinetics of vancomycin in patients who undergo sustained low efficiency daily diafiltration (SLEDD-f) is not clear. This study aimed to determine the appropriate vancomycin dosage regimen for patients receiving SLEDD-f. Methods This prospectively observational study enrolled critically ill patients older than 18 years old that used SLEDD-f as renal replacement therapy and received vancomycin treatment. An 8-h SLEDD-f was performed with FX-60 (high-flux helixone membrane, 1.4 m2). Serial blood samples were collected before, during, and after SLEDD-f to analyse vancomycin serum concentrations. Effluent fluid samples (a mixture of dialysate and ultrafiltrate) were also collected to determine the amount of vancomycin removal. Results Seventeen patients were enrolled, and 10 completed the study. The amount of vancomycin removal was 447.4 ± 88.8 mg (about 78.4 ± 18.4% of the dose administered before SLEDD-f). The vancomycin concentration was reduced by 57.5 ± 14.9% during SLEDD-f, and this reduction was followed by a rebound with duration of one to three hours. The elimination half-life of vancomycin decreased from 64.1 ± 35.7 h before SLEDD-f to 7.0 ± 3.0 h during SLEDD-f. Conclusion Significant amount of vancomycin removed during SLEDD-f. Despite the existence of post-dialysis rebound, a sufficient supplemental dose is necessary to maintain therapeutic range.

Objectives The immunomodulatory effects of statins may reduce the immune response induced by influenza vaccines. However, evidence regarding the effect of statin use on the effectiveness of seasonal influenza vaccines against medically attended acute respiratory illness (MAARI) in the elderly remains scarce. Methods We conducted a retrospective cohort study using data from Taiwan’s National Health Insurance Research Database. Elderly adults aged ≧ 66 years who were vaccinated with seasonal influenza vaccines during the 2007–2008 to 2012–2013 influenza seasons were enrolled for this analysis. We compared the risk of MAARI between statin and non-statin users. Propensity score matching and conditional logistic regression models were used to analyze the data. Results A total of 440,180 elderly were included in this study. In general, the risk of MAARI was higher in statin users than non-statin users (odds ratio [OR]: 1.03, 95% confidence interval [CI]: 1.02–1.05). Statin exposure after vaccination was associated with a higher risk of MAARI (OR: 1.05, 95% CI: 1.02–1.07). Among different statin agents, simvastatin and lovastatin use was associated with a significant increase in the risk of MAARI (ORsimvastatin: 1.14, 95% CI: 1.10–1.18; ORlovastatin: 1.18, 95% CI: 1.12–1.25). Conclusions Statin exposure, especially simvastatin and lovastatin, was associated with a higher risk of MAARI in the seasonal influenza vaccinated elderly. Future studies exploring the differences between individual statins and mechanisms of their immunomodulatory effects are necessary.

BACKGROUND Previous studies suggested that acute respiratory infection (ARI) could trigger stroke and that use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with increased risk of stroke. In many countries, NSAIDs have been widely used among patients with ARI or common cold for pain and fever relief. However, studies evaluating whether NSAIDs use during ARI episodes may further increase the risk of stroke were very limited. METHODS AND RESULTS During 2007 to 2011, 29 518 patients with an incident hospitalization of stroke were identified. The date of admission was defined as the index date. Using case-crossover design, we compared the following exposure status between the case period (1- to 7-d period before the index date) and matched control period (366- to 372-d period before the index date): NSAIDs use during ARI episodes, ARI episodes without NSAIDs use, NSAIDs use only, or no exposure. Multivariable conditional regression models were used to estimate odds ratios adjusting potential confounders. The results suggested that NSAIDs use during ARI episodes was associated with a 2.3-fold increased risk of stroke (ischemic: adjusted odds ratio, aOR 2.27, 95% confidence interval, 95% CI, 2.00-2.58; hemorrhagic: aOR 2.28, 95% CI, 1.71-3.02). We also determined that parenteral NSAIDs were associated with much higher risk of stroke in patients with ARI. CONCLUSIONS Nonsteroidal anti-inflammatory drugs use during ARI episodes, especially parenteral NSAIDs use, was associated with a further increased risk of stroke.

Objective To investigate the cost-effectiveness of the first patient self-paying pharmacist-assisted warfarin monitoring (PAWM) program in Taiwan. Design A Markov model with a 1-month cycle length and a 20-year time horizon was employed in this study. The model is composed of the following eight states: three no-event states (i.e. 'subtherapeutic,' 'within therapeutic' and 'supratherapeutic' states), two serious adverse events (AEs) (i.e. bleeding and thromboembolism), two sequelae states and death. The likelihood of events, costs and utilities were derived from local databases and literature, if applicable. This study was conducted with a payer's perspective and all costs were discounted with a rate of 3%. Setting A pharmacist-led clinic. Participants A hypothetical cohort of 10 000 participants. Intervention(s) PAWM versus usual care. Main outcome measure(s) Average quality-adjusted life-years (QALYs) gained and cost increments per patient, and incremental cost-effectiveness ratios (ICERs). Results The PAWM program resulted in an average of 0.13 QALYs gained and a cost increment of NT$53 850 (US$1683) per patient. As the ICER (NT$410 749 [US$12 836]) was less than the gross domestic product per capita (NT$631 142 [US$19 723]), the PAWM was considered to be very cost-effective. The sensitivity analyses suggested that our result was robust and that the PAWM program had an 86% probability of being very cost-effective. Conclusions Even if the costs saved from avoiding AEs were thought to be minimal due to the low-medical expenditures in Taiwan, the PAWM program was demonstrated to be economical. According to our findings, the policymakers should consider reimbursing such a service.

Background: Since 2011, Taiwan’s National Health Insurance Administration (NHIA) issued a regulation on the reimbursement to anti-osteoporosis medications (AOMs). This study aimed to evaluate the impact of this regulation in reimbursement on the utilization of AOMs, clinical outcomes and associated medical expenditures of patients with incident hip fractures. Methods: By using the National Health Insurance Research Database (NHIRD), patients with incident hip fracture from 2006 to 2015 were identified as our study cohort. Patients younger than 50 years old or prescribed with AOMs within one year prior to incident fracture were excluded. Outcomes of interest were quarterly estimates of the proportion of patients who received bone mineral density (BMD) examination, who were prescribed AOMs, as well as who encountered subsequent osteoporotic fracture-related visits and associated medical expenditures. Particularly, age- and gender specific estimates were reported. An interrupted time series study design with segmented regression model was used to quantitatively explore the impact of the changes of the reimbursement criteria on the level (immediate) and trend (long-term) changes of these outcomes. Results: Our study enrolled 118 493 patients with incident hip fracture with those patients aged older than 80 years old accounting for the largest proportion. A significantly decreased trend of AOMs prescription rates was observed immediately post regulation except for female aged between 65 and 80, while the long-term pattern showed no significant difference. However, the percentage of patients encountered subsequent osteoporotic fracture-related visit was not statistically different between pre- and post-regulation periods. Noteworthy, the policy regulation was associated with an increasing trend of osteoporotic fracture associated medical expenditures, especially for patients older than 80 years old. Conclusion: The regulation on the reimbursement for AOMs decreased the prescribing rate of AOMs immediately although the effect did not sustain thereafter. However, higher subsequent osteoporotic fracture-related medical expenditures were introduced, especially among those very old population.

The targeted delivery of therapeutic agents is a promising approach to enhance the efficacy and reduce the toxicity of cancer treatments. Understanding the intracellular endocytic mechanisms of a cell penetrating peptide (CPP) in an acidic environment is important for targeted delivery of macromolecules to tumours. In this study, we constructed a pH-sensitive CPP-based delivery system for the intracellular delivery of macromolecules. A pH-sensitive CPP, HBHAc, was fused with a model protein, enhanced green fluorescent protein (EGFP), through recombinant DNA technology. We found that is essential that negatively charged proteoglycans on the cell surface interact with HBHAc-EGFP prior to the cellular uptake of HBHAc-EGFP. The uptake was significantly restricted at 4 °C under pH conditions of both 6.5 and 7.5. The increased positive charge of HBHAc-EGFP under the acidic condition leads to a pH-dependent cellular uptake, and we observed that the internalisation of HBHAc-EGFP was significantly higher at pH 6.5 than at pH 7.5 (

Background Existing studies suggested that concomitant use of calcium channel blockers (CCBs) may interfere with the antiplatelet effect of clopidogrel. The objective of this study was to examine the effect of concomitant use of CCBs and clopidogrel on risks of acute coronary syndrome (ACS) re-hospitalization in patients receiving percutaneous coronary intervention. Methods Using the Taiwan National Health Insurance Research Database, we identified 51 925 patients who were admitted for newly diagnosed ACS, received percutaneous coronary intervention, and used clopidogrel within 1 year after discharge. We further stratified them into three groups based on their uses of guideline-recommended secondary prevention medications for ACS (fully, partially, and non-compliant groups) to assess the potential modification effect of guideline compliance. For each group, we conducted a 1:1 propensity score matching to minimize selection bias. Cox proportional hazard models were used to investigate the effect of concomitant use of CCBs (overall, subclasses, and individual CCBs) and clopidogrel on risks of ACS re-hospitalization. Results Concomitant use of CCBs in patients discharged with clopidogrel was significantly associated with a lower risk of ACS re-hospitalization in the fully compliant group (HRfully compliant = 0.82 [95% confidence interval 0.75–0.89], p

Objective The optimal time after hip fracture to start prophylactic anti-osteoporosis medications (AOMs) remains uncertain, especially in real-world practice. Therefore, we investigated how timing of AOMs initiation affects the risk of subsequent osteoporotic fractures, and what factors influence timing of AOMs prescription. Method Patients ≥50 years old with diagnostic codes indicating hospitalization for hip fracture (n = 77,930) were identified from the Taiwan National Health Insurance Research Database; 9986 who were prescribed AOMs ≤1 year after a newly-diagnosed hip fracture were grouped into those who started AOMs from: ≤14 days (very early); 15–84 days (early); 85–252 days (late); and 253–365 days (very late). Associations with fracture-related hospitalizations after an index fracture were analyzed using a multivariate, time-dependent Cox proportional hazards model, and between-group differences compared by log-rank testing. Factors influencing timing of AOMs initiation were elucidated using multivariate logistic regression analyses. Results Compared to AOMs initiation from 15 to 84 days, initiation after 252 days was associated with significantly increased risk of fracture-related hospitalization (HR = 1.93, 95% CI 1.29–2.89). Both sensitivity and pre-specified subgroup analyses yield similar results. Among patients with high adherence to AOMs, the increased risk of subsequent fracture-related hospitalization among very late users was profound (HR = 2.56, 95% CI 1.41–4.64). Conclusion Timing of AOMs initiation was significantly associated with age, index year, index hospital length of stay as well as the accreditation level and geographic region of index hospital. After adjusting factors associated with timing of AOMs initiation and patients' adherence, the anti-fracture benefit of AOMs still depends crucially on the timely initiation of AOMs.

BACKGROUND Active drug surveillance is the proactive process of assessing the adverse drug events (ADEs), but conventional systems lack a seamless workflow. OBJECTIVE This study aims to develop a seamless and online workflow for comparing the safety and effectiveness of drugs in a database of electronic medical records. METHODS We proposed a comprehensive integration process for clinical surveillance using the National Taiwan University Hospital Clinical Surveillance System (NCSS). We studied a practical application of the NCSS that evaluates the drug safety and effectiveness of novel oral-anticoagulants (NOACs) and warfarin by Cohort Tree Analysis in an efficient and interoperable platform. RESULTS We demonstrated a practical example of investigating the differences in effectiveness and safety between NOACs and warfarin in patients with non-valvular atrial fibrillation (AF) using the NCSS. We efficiently identified 2,357 non-valvular AF patients with newly prescribed oral anticoagulants between 2010 and 2015 and further developed one main cohort and two sub-cohorts for separately measuring ischemic stroke as the clinical effectiveness outcome and intracranial hemorrhage as the safety outcome. In the sub-cohort of ischemic stroke, NOACs users exhibited a significantly lower risk of ischemic stroke compared with warfarin users after adjusting for age, sex, comorbidity and co-medication in an intention-to-treat (ITT) analysis (P = 0.01) but exhibited a comparable risk in an as-treated (AT) analysis (P = 0.12) after the 2-year follow-up. In the sub-cohort of intracranial hemorrhage (ICH), NOACs users exhibited a comparable risk of ICH both in ITT (P = 0.68) and AT analyses (P = 0.15). CONCLUSIONS With a seamless and online workflow, the NCSS can serve the critical role of forming associations between evidence and the real world at a medical center in Taiwan.

Background Cardiovascular events associated with oral hypoglycemic agents (OHAs) have raised significant safety concerns. This study assessed the association between dipeptidyl peptidase-4 inhibitors (DPP-4i) and the risk of cardiovascular events in patients with type 2 diabetes mellitus with or without chronic kidney disease (CKD). Study design A retrospective cohort study using Taiwan's National Health Insurance Research Database. Settings and participants Our study included patients with type 2 diabetes who received OHAs between March 1, 2009, and December 31, 2012. All eligible subjects were classified into CKD and non-CKD cohorts and further categorized as the DPP-4i and non-DPP-4i users in each cohort. Methods The DPP-4i and non-DPP-4i groups were matched 1:1 by propensity score to attenuate potential selection bias. Propensity score was estimated by logistic regression, using demographics, co-medications, comorbidities. and adapted diabetic complication severity index at baseline. Outcomes Outcomes of interest included a composite endpoint of ischemic stroke, myocardial infarction, cardiovascular death (major adverse cardiac events [MACE]), and hospitalization for heart failure (hHF). COX proportional hazard models were applied to examine the association between DPP-4i and outcomes of interest. Results We identified 37,641 and 87,604 patients with type 2 diabetes with and without CKD, respectively. After propensity score matching, 8,213 pairs of CKD patients and 12,313 pairs of non-CKD patients were included for analysis. In the CKD cohort, DPP-4i were associated with a 25% increased risk of hHF (DPP-4i vs. non-DPP-4i incidence/1,000 person-years: 15.0 vs. 9.9, HR = 1.25; 95% CI 1.01-1.54, p = 0.037) but not with the risk of MACE (HR = 0.89, p = 0.144). In the non-CKD cohort, DPP-4i were associated with a lower risk of MACE (DPP-4i vs. non-DPP-4i incidence/1,000 person-years: 9.8 vs. 12.6 HR = 0.73; 95% CI 0.61-0.87, p = 0.0007), but not the risk of hHF (HR = 1.09, p = 0.631). Conclusions DPP-4i were found to be associated with decreased risk of MACE in the non-CKD cohort in our study. However, DPP-4i were associated with increased risk of hHF in the CKD cohort. DPP-4i in the CKD cohort should be used cautiously.

Arginine depletion strategies, such as pegylated recombinant arginine deiminase (ADI-PEG20), offer a promising anticancer treatment. Many tumor cells have suppressed expression of a key enzyme, argininosuccinate synthetase 1 (ASS1), which converts citrulline to arginine. These tumor cells become arginine auxotrophic, as they can no longer synthesize endogenous arginine intracellularly from citrulline, and are therefore sensitive to arginine depletion therapy. However, since ADI-PEG20 only depletes extracellular arginine due to low internalization, ASS1-expressing cells are not susceptible to treatment since they can synthesize arginine intracellularly. Recent studies have found that several factors influence ASS1 expression. In this study, we evaluated the effect of hypoxia, frequently encountered in many solid tumors, on ASS1 expression and its relationship to ADI-resistance in human MDA-MB-231 breast cancer cells. It was found that MDA-MB-231 cells developed ADI resistance in hypoxic conditions with increased ASS1 expression. To restore ADI sensitivity as well as achieve tumor-selective delivery under hypoxia, we constructed a pH-sensitive cell penetrating peptide (CPP)-based delivery system to carry ADI inside cells to deplete both intra- and extracellular arginine. The delivery system was designed to activate the CPP-mediated internalization only at the mildly acidic pH (6.5–7) associated with the microenvironment of hypoxic tumors, thus achieving better selectivity toward tumor cells. The pH sensitivity of the CPP, HBHAc, was controlled by recombinant fusion to a histidine-glutamine (HE) oligopeptide, generating HBHAc-HE-ADI. The tumor distribution of HBHAc-HE-ADI was comparable to ADI-PEG20 in a mouse xenograft model of human breast cancer cells in vivo. In addition, HBHAc-HE-ADI showed increased in vitro cellular uptake in cells incubated in a mildly acidic pH (hypoxic conditions) compared to normal pH (normoxic conditions), which correlated with pH-sensitive in vitro cytotoxicity in hypoxic MDA-MB-231 and human prostate cancer PC3 cells. Together, we conclude that the HBHAc-HE-based peptide delivery offers a useful means to overcome hypoxia-induced resistance to ADI in breast cancer cells, and to target the mildly acidic tumor microenvironment.

The objective of this study was to explore the pharmacokinetics of vancomycin and determine an appropriate dosage regimen for vancomycin in adult neurosurgical intensive care unit (ICU) patients.First, a 20-month therapeutic drug monitoring database at a medical center was used to retrospectively analyze the pharmacokinetic parameters of vancomycin in adult neurosurgical patients. Significant covariates were selected through Pearson or Spearman correlation tests and multiple linear regressions. Pharmacokinetic models were built using significant covariates to predict vancomycin clearance. Second, a 12-month prospective cohort of neurosurgical ICU patients was recruited to validate the models. Urine and cerebrospinal fluid samples were collected, and vancomycin concentrations were determined using a high-performance liquid chromatography assay. The relation between the model-predicted and observed pharmacokinetic parameters was assessed by Pearson correlation.In the retrospective cohort, 98 sets of peak/trough serum concentrations obtained from 73 patients were analyzed. These patients had a mean age of 54 ± 16 years, an estimated creatinine clearance (eClCr) of 83 ± 29 mL/min, a total vancomycin clearance (ClVan) of 101 ± 41 mL/min, and a volume of distribution (Vd) of 0.93 ± 0.27 L/kg. In a subgroup analysis, the ClVan of ICU patients was higher than the ClVan of non-ICU patients (1.57 ± 0.34-fold versus 1.16 ± 0.32-fold of eClCr, P0.05). Fifteen patients enrolled in the prospective cohort had an average age of 67 ± 12 years, an eClCr of 108 ± 44 mL/min, a ClVan of 112 ± 29 mL/min, and a Vd of 1.03 ± 0.55 L/kg.Adult neurosurgical ICU patients have a significantly elevated ClVan. In this study, 2 dosing equations were derived to achieve optimal serum vancomycin concentrations for this special population.

Rationale, aims and objectives Molecular targeted drugs (MTD), gefitinib and erlotinib, have been proven to provide clinical benefits to advanced stage non-small cell lung cancer (NSCLC) patients. Therefore, access to such medical innovations in time is critical for patients with the right indications. The aim of this study was to explore determinants of the adoption of MTD among NSCLC patients under Taiwan's National Health Insurance (NHI) system. Methods Using Taiwan's Longitudinal Health Insurance Database and Cancer Registry database as the data source, we identified 1555 newly diagnosed NSCLC patients who started their cancer treatment between 2004 and 2009. Patients were categorized into ‘non-MTD’ and ‘MTD’ groups based on the cancer treatment they received. Hierarchical logistic regression was used to explore potential determinants associated with the adoption of MTD by adjusting for patient-, disease-, doctor-, hospital-level characteristics and changes of reimbursement schemes. Results During the study period, 562 (36%) NSCLC patients were classified as the ‘MTD group and 993 (64%) patients were the ‘non-MTD’ group. Hierarchical logistic regression model showed that the elderly were less likely to receive MTD (OR = 0.41; 95% CI: 0.28–0.60). In contrast, patients whose cancer type was adenocarcinoma (OR = 2.99; 95% CI: 2.09–4.26) were more likely to receive MTD. Those who went to private hospitals (OR = 1.75; 95% CI: 1.01–3.03) and hospitals with higher economic scale (OR = 3.00; 95% CI: 1.72–5.25) were more likely to receive MTD as well. Conclusions Our findings suggest that both patient- and hospital-level characteristics significantly affected the adoption of MTD among NSCLC patients.

The overall survival (OS) of patients with ovarian cancer is poor while epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer. The aim of the present study was to evaluate the clinico-pathologic characteristics, especially the prognostic factors, for patients with epithelial ovarian cancer (EOC) in Taiwan. Information about newly diagnosed patients with EOC from 2009 to 2012 was retrieved from the database of the Taiwan Cancer Registry. Data from 2009 to 2013 for the respective cases from the claims database of Taiwan's National Health Insurance and National Death Registry were then retrieved. Potential prognostic factors were analyzed. The mean age at diagnosis of the 2,498 patients was 52.8 years. Serous carcinoma and clear cell carcinoma were diagnosed in 43.3% and 22.8% of the total patients, respectively. For patients with early-stage disease, taxane-based adjuvant chemotherapy, stage I, and younger age at diagnosis led to better overall survival (p = 0.030, p = 0.002, p

BACKGROUND Traditional clinical surveillance relied on the results from clinical trials and observational studies of administrative databases. However, these studies not only required many valuable resources but also faced a very long time lag. OBJECTIVE This study aimed to illustrate a practical application of the National Taiwan University Hospital Clinical Surveillance System (NCSS) in the identification of patients with an osteoporotic fracture and to provide a high reusability infrastructure for longitudinal clinical data. METHODS The NCSS integrates electronic medical records in the National Taiwan University Hospital (NTUH) with a data warehouse and is equipped with a user-friendly interface. The NCSS was developed using professional insight from multidisciplinary experts, including clinical practitioners, epidemiologists, and biomedical engineers. The practical example identifying the unmet treatment needs for patients encountering major osteoporotic fractures described herein was mainly achieved by adopting the computerized workflow in the NCSS. RESULTS We developed the infrastructure of the NCSS, including an integrated data warehouse and an automatic surveillance workflow. By applying the NCSS, we efficiently identified 2193 patients who were newly diagnosed with a hip or vertebral fracture between 2010 and 2014 at NTUH. By adopting the filter function, we identified 1808 (1808/2193, 82.44%) patients who continued their follow-up at NTUH, and 464 (464/2193, 21.16%) patients who were prescribed anti-osteoporosis medications, within 3 and 12 months post the index date of their fracture, respectively. CONCLUSIONS The NCSS systems can integrate the workflow of cohort identification to accelerate the survey process of clinically relevant problems and provide decision support in the daily practice of clinical physicians, thereby making the benefit of evidence-based medicine a reality.

This nationwide study investigated the epidemiology, treatment patterns, and economic burden of osteoporosis and associated fracture in Taiwan. The treatment of osteoporosis is alarmingly suboptimal, considering the significantly increased economic burden of major osteoporotic fracture. Osteoporosis men received lesser anti-osteoporosis drugs but had higher incremental costs attributable to osteoporotic fractures. This nationwide study investigated the epidemiology, treatment patterns, and economic burden of osteoporosis and associated fracture between 2009 and 2013 in Taiwan. We used the National Health Insurance Research Database as our data source. The prevalence of diagnosed osteoporosis and major osteoporotic fractures was calculated annually from 2009 to 2013, stratified by age and gender. Osteoporosis patients who received any prescription of anti-osteoporosis drugs during each fiscal year were defined as osteoporosis patients under treatment. Healthcare utilization and associated direct medical costs were used to quantify the economic burden of osteoporosis. For patients who encountered major osteoporotic fracture, the incremental changes of direct medical costs attributable to fracture using a pre- and post-quasi-experimental design were estimated. Furthermore, we compared the annual direct medical costs of patients who encountered major osteoporotic fracture with those diagnosed osteoporosis only and with the general population. The prevalence of diagnosed osteoporosis increased with age, with the highest rate among those aged 80 and older. Overall, less than one-third of women and only 10% of men received anti-osteoporosis drugs among osteoporosis patients. The annual direct medical costs for osteoporosis patients increased steadily from 2009 to 2013. The total medical costs and incremental change of direct medical costs were higher in men than those in women. We found the treatment of osteoporosis to be alarmingly suboptimal, considering the significantly increased economic burden of major osteoporotic fracture also identified in this study. Osteoporosis men received lesser anti-osteoporosis drugs but had higher incremental costs attributable to major osteoporotic fractures.

Objective.The aim of this population-based study is to examine the adverse events (AE) associated with longitudinal systemic glucocorticoid (GC) use among an ethnic Chinese systemic lupus erythematosus (SLE) cohort.Methods.Our study subjects were patients with newly diagnosed SLE aged 18 and older who received at least 1 prescription of systemic GC between 2001 and 2012 from Taiwan’s National Health Insurance Research Database (NHIRD). The earliest prescription date of systemic GC for each subject was defined as the index date. For each subject, we calculated the average prednisolone-equivalent dose and the medication possession ratio (MPR) of GC use every 90 days for each patient after the index date. Patients with a diagnosis of AE (defined by the International Classification of Diseases-9-Clinical Modification diagnosis code) during the followup were also identified from the NHIRD. Generalized estimating equations adjusted for propensity score were applied to examine the association between longitudinal GC use and risks of prespecified AE (musculoskeletal, gastrointestinal, ophthalmologic, infectious, cardiovascular, neuropsychiatric, metabolic, and dermatologic diseases).Results.We identified 11,288 patients with SLE (mean followup: 6.28 yrs). Higher doses and higher MPR of GC were associated with increased risk of osteonecrosis [adjusted OR (aOR) 2.87–9.09]. Similar results were found regarding the risk of osteoporosis (aOR 1.71–3.67), bacterial infection (aOR 2.12–3.89), Cushingoid syndrome (aOR 6.51–62.03), and sleep disorder (aOR 1.42–3.59).Conclusion.To our knowledge, this is the first study to show that the dose and intensity of longitudinal use of GC were both associated with risk of AE among a nationwide Asian SLE cohort.

Recombinant arginine deiminase (rADI) has been used in clinical trials for arginine-auxotrophic cancers. However, the emergence of rADI resistance, due to the overexpression of argininosuccinate synthetase (AS), has introduced an obstacle in its clinical application. Here, we have proposed a strategy for the intracellular delivery of rADI, which depletes both extracellular and intracellular arginine, to restore the sensitivity of rADI-resistant cancer cells. In this study, the C terminus of heparin-binding hemagglutinin adhesion protein from Mycobacterium tuberculosis (HBHAc), which contains 23 amino acids, was used to deliver rADI into rADI-resistant human breast adenocarcinoma cells (MCF-7). Chemical conjugates (l- and d-HBHAc-SPDP-rADI) and a recombinant fusion protein (rHBHAc-ADI) were produced. l- and d-HBHAc-SPDP-rADI showed a significantly higher cellular uptake of rADI by MCF-7 cells compared to that of rADI alone. Cell viability was significantly decreased in a dose-dependent manner in response to l- and d-HBHAc-SPDP-rADI treatments. In addition, the ratio of intracellular concentration of citrulline to arginine in cells treated with l- and d-HBHAc-SPDP-rADI was significantly increased by 1.4- and 1.7-fold, respectively, compared with that obtained in cells treated with rADI alone (p < 0.001). Similar results were obtained with the recombinant fusion protein rHBHAc-ADI. Our study demonstrates that the increased cellular uptake of rADI by HBHAc modification can restore the sensitivity of rADI treatment in MCF-7 cells. rHBHAc-ADI may represent a novel class of antitumor enzyme with an intracellular mechanism that is independent of AS expression.

Objective This case-control study investigated the association between statin use and liver injury using Taiwan's National Health Insurance Research Database. Methods Our study subjects included 4165 cases (patients who had been admitted with a primary diagnosis of liver injury between 2002 and 2009) and 16 660 age-matched, sex-matched and index date-matched controls. Multivariable conditional regression models were used to estimate the association between statin use and liver injury. Results Users of statins were not associated with risk of liver injury (adjusted odds ratio [aOR] 1.04; 95% confidence interval [0.90–1.19]) when compared with nonusers. Nevertheless, a higher dose of statin (≥1 defined daily dose; aOR 1.55 [1.14–2.11]) and use of rosuvastatin before event of liver injury (aOR 1.38 [1.03–1.85]) were significantly associated with liver injury. Conclusions This population-based study extends previous evidence by exploring the potential association between statins use and risk of liver injury. Overall, we found that statin was not associated with risk of liver injury. Nevertheless, special concern should be paid to those who used statin ≥1 defined daily dose and rosuvastatin. Copyright © 2014 John Wiley & Sons, Ltd.

In some cancer cells, translocation of cytochrome c (Cyt c) from mitochondria to the cytoplasma is inhibited. This inhibition prevents cells from undergoing apoptotic cell death and can lead to uncontrolled cell growth. Increasing cytoplasmic concentration of Cyt c can induce apoptosis in cancer cells as a strategy of cancer therapy. Here we proposed a galactosylated albumin based carrier for intracellular delivery of Cyt c to hepatocarcinoma cells. Galactosylated albumin is recognized by highly expressed asialoglycoprotein receptors (ASGPR) on hepatocarcinoma cells and is further internalized into cells via receptor mediated endocytosis. Cyt c was chemically conjugated to galactosylated albumin with a reducible disulfide linker in order to release Cyt c from the carrier inside cells. We tested cellular uptake and cytotoxicity of Cyt c conjugates in ASGPR positive and negative hepatocarcinoma cells. The results showed galatosylated albumin significantly increased cellular uptake in both cell types resulting in cytotoxicity in a dose dependent manner through the induction of apoptosis. The lack of ASGPR specific uptake might be due to other carbohydrate-recognizing receptors expressed on tumor cells. In general, our work has shown that intracellular delivery of Cyt c to tumor cells can be an alternative therapeutic approach and galactosylated albumin can be a protein drug carrier for intracellular delivery.