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Jie Chen,1,* Yen-Ming Huang,1– 3,* Hsun-Yu Chan,4 Mon-Chiao Chen,5 Yunn-Fang Ho1,2 1School of Pharmacy, College of Medicine, National Taiwan University, Taipei, 100025, Taiwan; 2Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, 100025, Taiwan; 3Department of Pharmacy, National Taiwan University Hospital, Taipei, 100229, Taiwan; 4Department of Industrial Education, National Taiwan Normal University, Taipei, 106308, Taiwan; 5Adam’s Drug Store, Taipei, 111049, Taiwan*These authors contributed equally to this workCorrespondence: Yunn-Fang Ho, Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, No. 33, Linsen South Road, Zhongzheng District, Taipei, 100025, Taiwan, Tel +886 2 33668794, Fax +886 2 33668780, Email yfho@ntu.edu.twBackground: Easy and adequate access to community pharmacies is key to eliminating primary barriers to the utilization of medicines and healthcare services. The location of community pharmacies is important for patients and providers when choosing and opening a pharmacy, but only a handful of studies investigate factors associated with the geographical distribution of pharmacies. This study aimed to identify decisive factors for location selection when starting a pharmacy among districts/townships in Taiwan.Methods: This cross-sectional mixed mode study employed an explanatory sequential design, beginning with a quantitative analysis of national datasets, and followed by a qualitative analysis of structured interviews. The national data were extracted from the Taiwan government database of 2020, and the qualitative interviews were conducted with 10 community pharmacists through a snowball sampling in 2021. A multiple linear regression was conducted to identify salient predictors of the number of community pharmacies in each of the 368 districts/townships in Taiwan, including population density, median annual household income, number of physician offices, area, and proportion of female residents of each district/township. Ten chief pharmacists were interviewed to share viewpoints on the decision-making process of their selection of current pharmacy practice sites. Inductive thematic analysis was performed to extract factors pertinent to location selection for pharmacy operations and services.Results: Confirmed by quantitative and qualitative data, population density, numbers of physician offices, median annual household income, pharmacy operation type, and type of retail locations are key determinants for site selection in considering opening a new community pharmacy.Conclusion: The study uncovers salient factors associated with the choice of community pharmacy location in Taiwan and proposes the adequate number of physician offices that a community pharmacy can collaborate with. In addition, pharmacists should prudently consider if their preferred service features match the needs of residents.Keywords: community pharmacy, physician office, location, mixed mode

Background A powerful way to nurture and strengthen professionalism is by accruing practice-based experiences. However, few studies in Taiwan have evaluated the impacts of experiential learning programmes on pharmacy students’ views on professionalism − the core of quality healthcare practices and services. This study aimed to measure changes in perceptions of and attitudes towards professionalism among third-year pharmacy students following an introductory-intermediate experiential learning course. Methods A single-group pre- and postcourse comparative study using a self-administered survey was conducted in 2017. Pharmacy students in their third year of a six-year programme were eligible to participate in this study. We used a 28-item questionnaire with a 10-point Likert-type scale to assess students’ professionalism. Among them, 10 items were employed to assess students’ perceived importance of professionalism in pharmacy practice, and another 18 items adapted from the Pharmacy Professionalism Instrument were used to evaluate students’ attitudes towards pharmacy professionalism. An independent t test was performed to compare the differences in students’ anonymous survey responses before and after the course, with an a priori level of statistical significance of 0.05. Results Fifty-two pharmacy students participated in the study. They showed significant improvement in three tenets of professionalism, namely, altruism (p = 0.035), accountability (p = 0.026), and duty (p = 0.002), after completing the 5-week experiential course. Conclusions Pharmacy students’ attitudes towards professionalism were modifiable by purposely designed experiential learning programme in the community setting. Such experiences may help socialize students with positive attitudes towards altruism, accountability, and duty.

To evaluate the impact of a tailored Symptom Allergy Indication Direction Self-care (SAIDS) counseling by pharmacists on consumers' correct understanding of over-the-counter (OTC) medication use.This study used a time-based sampling of two independent cohorts at a single community pharmacy in Taiwan for two years beginning in December 2018. In the control cohort, participants received conventional counseling for the OTCs they selected. In the intervention cohort, participants received SAIDS counseling along with pointing out OTC package label instructions. A paper-and-pencil survey was administered face-to-face to evaluate participants' understanding for the correct use of OTCs. Descriptive statistics and chi-square tests were used to evaluate the effect of the SAIDS approach on cohorts' understanding of OTC use.Compared with conventional OTC counseling, participants reported better understanding regarding potential side effects of OTCs that they acquired (p 0.001) and were more aware of strategies to cope with the associated side effects (p 0.001).Despite the time constraints that pharmacists often can offer to each customer, the SAIDS counseling approach may refine the structure and effectiveness of pharmacists' OTC counseling skills and thereby improve consumers' understanding of their ailments and self-care medications in Taiwan.

An estimate of one third of preventable medication errors occurred annually due to patients' misunderstanding of use instructions. To safeguard consumers' over-the-counter (OTC) medicine use and to develop future initiatives, this study evaluated the use, comprehensibility and clarity of the information labels on OTC packages from consumers' perspectives in Taiwan. This cross-sectional study was conducted at 29 community pharmacies; 50 pharmacy clerkship students helped participant enrolment from June to September 2017. Participants (n = 470) were 20 years old or above, Mandarin speaking, and with specific OTC purchases. A face-to-face survey was administered to investigate the degree to which participants read the package labels and their comprehension of correct medicine use. An 11-item survey was used to measure participants' specific OTC purchases (3 items), the use (2 items), comprehensibility (1 item) and clarity (2 items) of OTC package labels, in addition to the sociodemographic information (3 items). Participants were also solicited to provide opinions regarding package label redesign. Descriptive statistics and logistic regressions were applied for analyses. Findings show that most (84.0%) participants read instruction labels before use, with indications (79.4%), drug names (64.5%) and dosage and administration (59.8%) being the top reads. Only 30.0% of the participants fully understood how to take the medicines correctly. Younger (OR = 1.033, p < .001) and female participants (OR = 1.965, p = .014) with a higher level of education (OR = 1.940, p = .034) tended to read package label information prior to purchase or use. Younger participants (OR = 1.030, p < .001) and those who read OTC medicine labels before use (OR = 2.317, p = .004) were more likely to correctly understand medicine use. The findings indicate that older, male adults with a lower level of education should be targeted to ensure their correct understanding of OTC labels. Pharmacists should recite pertinent label information and, concomitantly, ensure consumers' understanding when providing medicine counselling.

Aims To examine the association between statin use before and after intracranial haemorrhage (ICH) and the risk of poststroke epilepsy (PSE). Methods Patients with new-onset ICH between 2004 and 2012 were identified from the Taiwan National Health Insurance Research Database. The main outcome was the occurrence of epilepsy after stroke. Multivariable Cox regression modelling was used to estimate the association between statin use and the risk of PSE, with poststroke medication exposures being treated as time-dependent variables. Results A total of 7435 patients with ICH were enrolled with a median follow-up of 17.6 months. Within the study cohort, 709 patients developed PSE. Poststroke, but not prestroke, stain use was associated with a reduced risk of PSE (adjusted hazard ratio 0.62, 95% confidence interval 0.42-0.90, P = 0.01). In subanalyses, a trend of a dose-response relationship was observed. A significant PSE risk reduction was correlated with a higher cumulative statin dose. Moreover, the risk of PSE was lower in patients receiving moderate-to-high-intensity statin therapy (adjusted hazard ratio 0.37, 95% confidence interval 0.18-0.75, P = 0.01). Lipophilic and hydrophilic statins were similar with regard to their associations with the reduced risk of PSE. Conclusions Statin therapy may reduce the risk of PSE after ICH, especially with moderate-to-high therapy intensity. Further research is needed to understand the mechanisms underlying the potential protective effects of statins against PSE in this patient population.

The majority of patient safety incidents cited in the latest Taiwan Patient Safety Reporting System Annual Report were medication-related, with human factors and communication issues identified as the key underlying causes of these incidents. Focusing on inpatient settings, the complex yet multiprofessional-linked drug supply scheme currently in place in medical institutions in Taiwan is described, with the aim of facilitating the accessibility and appropriateness of medication use by detailing the responsibilities of each professional role. Institutional medication management and use comprise several sequential and interconnected stages, including formulary management and drug procurement, medication storage, physician prescribing, pharmacist dispensing, nurse administration, and efficacy-and-safety monitoring and reporting. The principal tasks and personnel duties at each stage are addressed. In summary, institutional drug distribution and control is an intricate process that involves multiple processes and a diverse array of professionals and administrative staff. It is imperative to actively engage the relevant parties, especially through in-service training, in order to understand their essential roles and responsibilities and to enable communication and collaboration among stakeholders in the drug distribution chain. Implementing the appropriate initiatives in a timely manner will help establish an effective and robust safe-medication-use system.跨專業環環相扣守護安全用藥—以住院藥品管理為例.「臺灣病人安全通報系統」2017年年報資料顯示，國內醫療機構通報之異常事件以藥物問題為最大宗，而「人為」與「溝通」是重要因素。本文以涵蓋層面多元的住院藥品供應為例，從機構處方集的藥品品項評選與採購、藥品儲存、處方開立、調劑作業、給藥作業，到用藥後之藥品療效與不良反應監測及異常事件通報等，分階段探討醫療機構之藥品管理與使用，並闡述各階段之工作要旨，說明相關專業各別擔負的職責或可扮演的角色，期有助各司其職，共同確保「有藥用」且「用對藥」。整體而言，醫療機構之藥品供應與管理事務複雜，不僅流程涵蓋多重步驟，管理與使用更牽涉到行政單位與醫療團隊多樣專業，值得相關成員共同關注與瞭解，而以教育訓練強化醫療人員之守護用藥安全認知與增進專業人員間之良性互動與協同合作，在合宜措施與及時推動下，共謀奠立可長可久安全用藥體系。.

Statins possess neuroprotective effects. However, real-world evidence supporting their utility in post-stroke epilepsy (PSE) prevention is limited. The association between statin use, including timing of prescribing (pre-stroke vs post-stroke), type (lipophilicity, intensity of therapy) and dose intensity, and risk of developing PSE were investigated by studying Taiwanese health claims (2003–2013). Patients with new-onset ischaemic stroke were identified. The main outcome was a diagnosis of epilepsy after ischaemic stroke. According to pre-stroke statin use, groups of current users, former users, and non-users were compared using ANOVA. An extended Cox regression model was utilized to estimate the hazard ratio (HR) of PSE, with post-stroke statin use and certain comedications as time-dependent variables. Serial sensitivity analyses were performed to ensure study robustness. Of the 20,858 ischaemic stroke patients, 954 (4.6%) developed PSE. Post-stroke statin use (adjusted HR (aHR) 0.55; 95% confidence interval 0.46–0.67, p

For unknown reasons, there is discordance among previous reports with regard to the association of contrast medium (CM) with nephropathy and the incidence of nephropathy after contrast-enhanced CT. This study aimed to determine the frequency of and possible factors related to CM-induced nephropathy in hospitalized patients, with an emphasis on detailing coprescriptions with nephrotoxic potential.Of 1378 inpatients who underwent CT, 208 (15.1%) met the inclusion criteria: receipt of IV iodinated CM and baseline serum creatinine level obtained within 45 days before and within 2 weeks after CT. Patient demographics, clinical characteristics, comorbidity, nephrotoxic comedications (nine classes of drugs), and type of CM administered were retrospectively reviewed. Relationships between CM-induced nephropathy (serum creatinine level increase ≥ 25% or ≥ 0.5 mg/dL after CT) and risk factors were assessed by stepwise multivariate logistic regression.The cohort of 208 subjects had a high number of comorbidities (mean [± SD], 5.8 ± 3.5 diagnoses) and a high rate of receiving nephrotoxic comedications (45.2%). CM-induced nephropathy was detected in 27 (13.0%) patients. Concurrent use of four nephrotoxic agents (odds ratio [OR], 26.250; 95% CI, 3.673-233.993) was the most influential factor associated with CM-induced nephropathy; other predictors included preexisting renal disease (OR, 8.218; 95% CI, 1.622-42.357), baseline serum creatinine level less than 0.7 or greater than or equal to 1.3 mg/dL (OR, 3.463; 95% CI, 1.341-9.025), and hemoglobin level less than 9.3 g/dL (OR, 3.141; 95% CI, 1.087-8.946).Among the known risk factors, such as preexisting renal disease, high serum creatinine level, and low hemoglobin level, a statistically significant association was identified between CM-induced nephropathy and concurrent receipt of four nephrotoxic medications. Relevant preventive measures are warranted for individuals at risk, especially hospitalized patients receiving multiple nephrotoxic medications who require contrast-enhanced CT.

Chronic kidney disease (CKD) differentially affects the pharmacokinetics (PK) of nonrenally cleared drugs via certain pathways (e.g., cytochrome P450 (CYP)2D6); however, the effect on CYP2C8‐mediated clearance is not well understood because of overlapping substrate specificity with hepatic organic anion‐transporting polypeptides (OATPs). This study used physiologically based pharmacokinetic (PBPK) modeling to delineate potential changes in CYP2C8 or OATP1B activity in patients with CKD. Drugs analyzed are predominantly substrates of CYP2C8 (rosiglitazone and pioglitazone), OATP1B (pitavastatin), or both (repaglinide). Following initial model verification, pharmacokinetics (PK) of these drugs were simulated in patients with severe CKD considering changes in glomerular filtration rate (GFR), plasma protein binding, and activity of either CYP2C8 and/or OATP1B in a stepwise manner. The PBPK analysis suggests that OATP1B activity could be decreased up to 60% in severe CKD, whereas changes to CYP2C8 are negligible. This improved understanding of CKD effect on clearance pathways could be important to inform the optimal use of nonrenally eliminated drugs in patients with CKD.

Background A pharmacovigilance database of real-world adverse drug reaction (ADR) reports is helpful for characterising adverse events and identifying new signals after drug approval. Objective This study aimed to analyse trends of ADR reporting in relation to liver injury and to delineate critical factors for suspected drug-related hepatotoxicity with a focus on reports associated with amiodarone. Setting The 2000–2014 Taiwan pharmacovigilance database. Method Relevant Standardized Medical Dictionary for Regulatory Activities queries were used to identify reports associated with liver injury. Information on ADR, patient characteristics, and the verbatim pertaining to amiodarone prescriptions, liver injury, comedications, and comorbidities were extracted and evaluated. Group comparisons between Hy’s Law cases and Temple’s Corollary cases of suspected amiodarone-related hepatotoxicity were performed. Main outcome measure Number and nature of drug-related liver injuries, particularly those associated with amiodarone. Results Of the 98,777 ADR reports over a 15-year period, 4261 (4.3%) were related to liver injury. Sixty-eight reports contained amiodarone prescriptions, but only 49 (1.1%) were eligible for further analysis. Hepatotoxic cases associated with amiodarone mostly occurred within 1 week, exhibited a hepatocellular pattern, and were more common among elderly individuals. Among 23 discernible cases, four (17.4%) recovered fully from liver injury. The critical Hy’s Law cases were associated with shorter height, lower body surface area, and higher average daily doses. Conclusion This study substantiates the importance of ADR reporting. Data pertaining to drug-associated liver injury and factors associated with suspected amiodarone-related hepatotoxicity warrants continual attention in pharmacovigilance for those at risk, especially the elderly.

To examine the association between statin use before and after intracranial haemorrhage (ICH) and the risk of poststroke epilepsy (PSE).Patients with new-onset ICH between 2004 and 2012 were identified from the Taiwan National Health Insurance Research Database. The main outcome was the occurrence of epilepsy after stroke. Multivariable Cox regression modelling was used to estimate the association between statin use and the risk of PSE, with poststroke medication exposures being treated as time-dependent variables.A total of 7435 patients with ICH were enrolled with a median follow-up of 17.6 months. Within the study cohort, 709 patients developed PSE. Poststroke, but not prestroke, stain use was associated with a reduced risk of PSE (adjusted hazard ratio 0.62, 95% confidence interval 0.42-0.90, P = 0.01). In subanalyses, a trend of a dose-response relationship was observed. A significant PSE risk reduction was correlated with a higher cumulative statin dose. Moreover, the risk of PSE was lower in patients receiving moderate-to-high-intensity statin therapy (adjusted hazard ratio 0.37, 95% confidence interval 0.18-0.75, P = 0.01). Lipophilic and hydrophilic statins were similar with regard to their associations with the reduced risk of PSE.Statin therapy may reduce the risk of PSE after ICH, especially with moderate-to-high therapy intensity. Further research is needed to understand the mechanisms underlying the potential protective effects of statins against PSE in this patient population.

Although the results of several studies have underscored the regulatory effect of H1-histamine receptors in cell proliferation of some cancer cell types, its effect in prostate cancers remains unclear. We have therefore studied the effect of terfenadine (an H1-histamine receptor antagonist) in prostate cancer cell lines. Our data demonstrate that terfenadine was effective against PC-3 and DU-145 cells (two prostate cancer cell lines). In contrast, based on the sulforhodamine B assay, loratadine had less potency while fexofenadine and diphenhydramine had little effect. Terfenadine induced the cleavage of Mcl-1 cleavage into a pro-apoptotic 28-kDa fragment and up-regulation of Bak, resulting in the loss of mitochondrial membrane potential (ΔΨm) and the release of cytochrome c and apoptosis-inducing factor into the cytosol. The activation of caspase cascades was detected to be linked to terfenadine action. Bak up-regulation was also examined at both the transcriptional and translational levels, and Bak activation was validated based on conformational change to expose the N terminus. Terfenadine also induced an indirect-but not direct-DNA damage response through the cleavage and activation of caspase-2, phosphorylation and activation of Chk1 and Chk2 kinases, phosphorylation of RPA32 and acetylation of Histone H3; these processes were highly correlated to severe mitochondrial dysfunction and the activation of caspase cascades. In conclusion, terfenadine induced apoptotic signaling cascades against HRPCs in a sequential manner. The exposure of cells to terfenadine caused the up-regulation and activation of Bak and the cleavage of Mcl-1, leading to the loss of ΔΨm and activation of caspase cascades which further resulted in DNA damage response and cell apoptosis.

Combination therapy, which can optimize killing activity to cancers and minimize drug resistance, is a mainstream therapy against hormone-refractory prostate cancers (HRPCs). Rottlerin, a natural polyphenolic component, synergistically increased PC-3 (a HRPC cell line) apoptosis induced by camptothecin (a topoisomerase I inhibitor). Using siRNA technique to knockdown protein kinase C-δ (PKCδ), the data showed that rottlerin-mediated synergistic effect was PKCδ-independent, although rottlerin has been used as a PKCδ inhibitor. Rottlerin potentiated camptothecin-induced DNA fragmentation at S phase and ATM phosphorylation at Ser1981. The effect was correlated to apoptosis (r2 = 0.9). To detect upstream signals, the data showed that camptothecin acted on and stabilized topoisomerase I-DNA complex, leading to the formation of camptothecin-trapped cleavage complexes (TOP1cc). The effect was potentiated by rottlerin. To determine DNA repair capability, the time-related γH2A.X formation was examined after camptothecin removal. Consequently, rottlerin significantly inhibited camptothecin removal-mediated decline of γH2A.X formation at S phase, indicating the impairment of DNA repair activity in the presence of rottlerin. The combinatory treatment of camptothecin and rottlerin induced conformational change and activation of Bax and formation of truncated Bad, suggesting the contribution of mitochondria stress to apoptosis. In summary, the data suggest that rottlerin-mediated camptothecin sensitization is through the augmented stabilization of TOP1cc, leading to an increase of DNA damage stress and, possibly, an impairment of DNA repair capability. Subsequently, mitochondria-involved apoptosis is triggered through Bax activation and truncated Bad formation. The novel discovery may provide an anticancer approach of combinatory use between rottlerin and camptothecin for the treatment of HRPCs.

Emerging evidence shows that the translocation of apoptosis related factors on cellular organelles, such as mitochondria, endoplasmic reticulum, Golgi apparatus and nucleus, has a crucial role in the apoptotic process. We characterized the effect of paclitaxel (Sigma®) on Golgi involved apoptosis in human hormone refractory prostate cancer.FACScan™ flow cytometric analysis was used to determine cell cycle distribution and the subG1 (apoptosis) population. Protein expression and localization were detected by Western blot, confocal microscopic examination and the sucrose gradient separation technique.Paclitaxel induced Golgi apparatus disassembly and interaction between Golgi complexes and mitochondria. Discontinuous sucrose gradient fractionation was used to determine and collect Golgi containing fractions. Data revealed that paclitaxel induced an increase of Cdk1 activity and DR5 expression on the Golgi complex that was associated with increased cleavage of caspase-8, a DR5 downstream factor, and caspase-3 into catalytically active fragments. Data were validated by confocal immunofluorescence microscopy. Golgi associated effects were inhibited by the Cdk1 inhibitor roscovitine (Sigma), suggesting a critical role for Golgi-Cdk1. Also, paclitaxel caused an increase of nuclear but not of Golgi associated PKC-δ activity. The selective PKC-δ inhibitor rottlerin (Sigma) completely inhibited the increase of Golgi-Cdk1 activity, suggesting that nuclear PKC-δ served as an upstream regulator of Golgi-Cdk1.Data suggest that paclitaxel induces nuclear translocation and activation of PKC-δ, which in turn causes Golgi-Cdk1 activation, leading to Golgi associated DR5 up-regulation, and caspase-8 and 3 activation. Golgi mediated signaling cascades facilitate mitochondria involved apoptotic pathways and at least partly explain the anticancer activity of paclitaxel action.

Costunolide is a natural sesquiterpene lactone. We elucidated what to our knowledge is a novel mechanism to highlight its potential in chemotherapy for prostate cancer, particularly androgen refractory prostate cancer.Several pharmacological and biochemical assays were used to characterize the apoptotic signaling pathways of costunolide (ChromaDex™) in prostate cancer cells.Costunolide showed effective antiproliferative activity against hormone dependent (LNCaP) and independent (PC-3 and DU-145) prostate cancer cells (ATCC®) by sulforhodamine B assay, clonogenic test and flow cytometric analysis of carboxyfluorescein succinimidyl ester labeling. In PC-3 cells data showed that costunolide induced a rapid overload of nuclear Ca(2+), DNA damage response and ATR phosphorylation. Costunolide induced G1-phase cell cycle arrest, which was supported by p21 up-regulation and its association with the cyclin dependent kinase 2/cyclin E complex. The association resulted in inhibition of the complex activity and inhibition of Rb phosphorylation. Costunolide mediated effects were substantially inhibited by glutathione, the reactive oxygen species scavenger and glutathione precursor N-acetylcysteine, and the Ca(2+) chelator BAPTA-AM other than the reactive oxygen species scavenger Trolox®. This indicated the crucial role of intracellular Ca(2+) mobilization and thiol depletion but not of reactive oxygen species production in apoptotic signaling.Data suggest that costunolide induces the depletion of intracellular thiols and overload of nuclear Ca(2+) that cause DNA damage and p21 up-regulation. The association of p21 with the cyclin dependent kinase 2/cyclin E complex blocks cyclin dependent kinase 2 activity and inhibits Rb phosphorylation, leading to G1 arrest of the cell cycle and subsequent apoptotic cell death in human prostate cancer cells.

Risk factors and underlying mechanisms for liver injury associated with amiodarone remain elusive. This study aimed to investigate the drug-related covariates for acute liver injury by amiodarone—an intriguing compound of high lipophilicity, with a long half-life and notable efficacy. The medical, pharmacy, and laboratory records of new amiodarone users admitted to the cardiac or surgical intensive care units of a medical center were examined retrospectively. A Cox regression model with time-varying dose-related variables of amiodarone was utilized to estimate the hazard ratio (HR) of amiodarone-associated liver injury while adjusting for concomitant therapy and relevant covariates. Of the 131 eligible patients among 6,572 amiodarone users (46,402 prescriptions), 6 were identified as amiodarone-associated liver injury cases. In comparison to controls (n = 125), this liver injury cohort (n = 6) had significantly higher numbers of amiodarone-interacting (2.7 ± 2.0 vs 0.9 ± 0.9 drugs, P = .02) and hepatotoxic (3.8 ± 0.8 vs 2.5 ± 1.7 drugs, P = .03) comedications. The number of comedications with amiodarone-interacting potential (HR 2.07, 95% confidence interval [CI] 1.02−4.22, P = .04) and amiodarone cumulative doses standardized by body surface area (HR 6.82, 95% CI 1.72–27.04, P = .01) were independent risk factors for liver injury associated with amiodarone. Drug-related (amiodarone cumulative dose, interacting drugs) factors were significant predictors of amiodarone-associated acute liver injury. A prudent evaluation of each medication profile is warranted to attain precision medicine at the level of patient care, especially for those treated by medications with complex physicochemical and pharmacokinetic properties, such as amiodarone.

Tubulin and deoxyribonucleic acid (DNA) are two potential targets for the development of cancer chemotherapeutic agents. Mana-Hox is a synthetic derivative of beta-carboline, a structure relevant to marine sponge component, manzamine. In this study, Mana-Hox induced an inhibition of cell proliferation in several types of human cancer cell lines, including androgen-independent prostate cancer PC-3 and DU-145, hepatocellular carcinoma Hep3B and HepG2, and colorectal cancer HT-29 cells. The p53-null PC-3 cells were used for to anticancer mechanisms. Mana-Hox stimulated an increase of ataxia telangiectasia mutated (ATM) phosphorylation on Ser-1981, indicating the induction of DNA double-strand breaks. It also displayed an inhibitory effect on tubulin polymerization using tubulin turbidity assay and immunofluorescence identification. However, it only showed a minor inhibition on the activity of Aurora kinase and histone deacetylase. Mana-Hox induced mitotic arrest of the cell cycle identified by downregulation of cyclin E, cyclin A, and cyclin-dependent kinase 2 (Cdk2) and an increase of MPM-2 expression. Next, it caused Bcl-2 phosphorylation on Ser-70, downregulation of Mcl-1 expression, and activation of caspase-3, leading to apoptotic cell death. Notably, Mana-Hox was not a P-glycoprotein (P-gp) substrate and showed equipotent activity against P-gp-rich cancer cells. We conclude that Mana-Hox induces dual effects on DNA damage and tubulin depolymerization, leading to mitotic arrest and activation of mitochondria-mediated apoptotic pathways. Data provide evidence that the anticancer strategy of dual-action targets could be a potential anticancer approach.

Cancer chemotherapeutic agents that interfere with tubulin/microtubule function are in extensive use. Quinolone is a common structure in alkaloids and its related components exhibit several pharmacological activities. In this study, we have identified the anticancer mechanisms of 2-phenyl-4-quinolone. 2-Phenyl-4-quinolone displayed anti-proliferative effect in several cancer types, including hormone-resistant prostate cancer PC-3, hepatocellular carcinoma Hep3B and HepG2, non-small cell lung cancer A549 and P-glycoprotein-rich breast cancer NCI/ADR-RES cells. The IC(50) values were 0.85, 1.81, 3.32, 0.90 and 1.53 microM, respectively. 2-Phenyl-4-quinolone caused G2/M arrest of the cell-cycle and a subsequent apoptosis. The turbidity assay showed an inhibitory effect on tubulin polymerization. After immunochemical examination, the data demonstrated that the microtubules were arranged irregularly into dipolarity showing prometaphase-like states. Furthermore, 2-Phenyl-4-quinolone induced the Mcl-1 cleavage, the phosphorylation of Bcl-2 and Bcl-xL (12-h treatment), and the caspase activation including caspase-8, -2 and -3 (24-h treatment). The exposure of cells to 2-phenyl-4-quinolone caused Cdk1 activation by several observations, namely (i) elevation of cyclin B1 expression, (ii) dephosphorylation on inhibitory Tyr-15 of Cdk1, and (iii) dephosphorylation on Ser-216 of Cdc25c. Moreover, a long-term treatment (36h) caused the release reaction and subsequent nuclear translocation of AIF. In summary, it is suggested that 2-phenyl-4-quinolone displays anticancer effect through the dysregulation of mitotic spindles and induction of mitotic arrest. Furthermore, participation of cell-cycle regulators, Bcl-2 family of proteins, activation of caspases and release of AIF may mutually cross-regulate the apoptotic signaling cascades induced by 2-phenyl-4-quinolone.

Cytochrome P450IIE1 (CYP2E1), an ethanol-inducible cytochrome P450 enzyme, is expressed in the basal ganglia and is probably involved in the activation of neurotoxicants, producing free radical metabolites and resulting in oxidative stress. To examine the association between CYP2E1 polymorphism and the risk of Parkinson's disease (PD), we performed a case-control study on a large population of Taiwanese PD patients, focusing especially on early-onset PD patients (onset at, or before, the age of 50). Two hundred and thirty-four PD patients and 251 age- and sex-matched controls were recruited. A much higher frequency of the uncommon c2 allele was seen in our control subjects than in Caucasians (0.23 vs. 0.02). There were no significant differences between PD patients and controls in the distribution of either allelic or genotype frequencies. Our results suggest that CYP2E1 is not a major or independent determinant in the occurrence of PD in Taiwanese.

Objective: Reports suggest that catechol- O -methyltransferase (COMT L/L ) (Val 158 /Met) and monoamine oxidase B (MAOB) intron 13 genotype polymorphism is associated with PD. To understand the ethnicity-specific effects of genetic polymorphism, we performed a case-control study of the association between PD susceptibility and polymorphism of MAOB and COMT, both separately and in combination, in Taiwanese. Methods: Two hundred twenty-four patients with PD and 197 controls, matched for age, sex, and birthplace, were recruited. MAOB and COMT polymorphism genotyping was performed by using PCR-based restriction fragment length polymorphism (RFLP) analyses. χ 2 , OR, and Fisher’s exact tests were used to compare differences in allelic frequencies and genotypes. Results: The MAOB G genotype ( G in men and G/G in women) was associated with a 2.07-fold increased relative risk of PD. COMT polymorphism, considered alone, showed no correlation with PD risk; however, a significant synergistic enhancement was found in PD patients harboring both the COMT L and MAOB G genotypes. Conclusions: These results suggest that, in Taiwanese, PD risk is associated with MAOB G intron 13 polymorphism, and this association is augmented in the presence of the COMT L genotype, indicating an interaction of these two dopamine-metabolizing enzymes in the pathogenesis of sporadic PD. However, the relatively low frequencies of these combined genotypes in our study necessitates confirmation with a larger sample size.

Hormone-refractory metastatic prostate cancer (HRMPC), which is metastatic and resistant to hormone therapy, is an intractable problem in clinical treatment. Anthraquinone-based natural products and synthetic compounds have shown anticancer activity. However, cardiac toxicity is a major adverse reaction in these compounds. CC-36, a unique anthraquinone derivative, displayed higher antiproliferative activity in HRMPC than that in H9c2 cardiomyoblasts and normal prostate cells with the selectivity of five and twelve times, respectively. CC-36 caused G1 arrest of the cell cycle associated with an upregulation of p21 and downregulated levels of cyclin D1 and cyclin E expressions. Immunoprecipitation assay and Western blotting analysis showed that CC-36 triggered an increase of TSC1/TSC2 association and suppressed the phosphorylation of mammalian target of rapamycin (mTOR) (Ser2448) and p70 ribosomal protein S6 kinase (p70S6K) (Thr389), indicating the inhibition of both kinases' activities. CC-36 induced liver kinase B1 (LKB1) phosphorylation at Thr189, leading to LKB1 translocation from nucleus to cytosol for AMPKα phosphorylation (Thr172) and the kinase activation. The signaling pathway was validated using small interfering RNA (siRNA) technique with LKB1 knockdown. The combination treatment of MK2206 (a specific Akt inhibitor) with CC-36 showed a synergistic apoptosis in PC-3 cells indicating a potential combination strategy for LKB1 activators. Taken together, the data suggest that CC-36 displays anti-HRMPC activity through the activation of LKB1-AMPK pathway, leading to an inhibition of mTOR signaling and the induction of G1 arrest of the cell cycle. The combination use of Akt inhibitors with agents acting through LKB1-AMPK-mTOR pathway is a potential strategy for HRMPC treatment.

We have developed a method for the rapid isolation of hepatocyte nuclei, which employs gentle homogenization and centrifugation conditions, and involves minimal processing time. The purified nuclei were morphologically unaltered when observed by light and electron microscopy. No significant contamination from cytoplasm or mitochondria was detected when assessed by marker enzymes. Membrane transport function, measured as ATP-dependent calcium uptake, was intact. This isolation method was devised to be applicable to studies that involve measurement of uptake and active transport of a variety of substances by the cell nucleus.

Background: Esophageal cancer has been associated with oral bisphosphonate use, but current data are conflicting and devoid of Asian studies where esophageal squamous carcinoma prevails. Methods: We assessed the association between dose intensity, stratified by use duration (observation period) and exposure frequency, of oral bisphosphonates and the risk of esophageal cancer using 16,204 esophageal cancer cases and 64,816 malignancy-free controls identified from the population-based National Health Insurance Research Database of Taiwan from 1997 to 2008. Results: Neither duration nor frequency of bisphosphonate exposures was positively correlated to esophageal cancer risk. The ORs for rare users of 1-, 3-, 5-year observation periods were 3.86, 2.58, and 2.27, respectively (P < 0.001). Similar trend of descending ORs was also observed for rare-, frequent-, and regular users of 1-year observation period (ORs = 3.86, 1.93, and 0.95, respectively). Conclusion: Our data suggest that bisphosphonates are not likely risk factors for esophageal cancer in Taiwan. Impact: The study shows no evidence of an association between bisphosphonate use and esophageal cancer risk from Asian perspective. Cancer Epidemiol Biomarkers Prev; 21(6); 993–5. ©2012 AACR.

BACKGROUND Increasing evidence suggests that mitochondria play a central role in regulating cell apoptosis. Survivin, an inhibitor of apoptosis protein (IAP) family member, mediates resistance to cancer chemotherapy particularly in prostate cancers. Therefore, development of anticancer agents targeting mitochondria and survivin is a potential strategy. METHOD Cell proliferation was examined by sulforhodamine B, CFSE staining, and clonogenic assays. Mitochondrial membrane potential (ΔΨm) and reactive oxygen species (ROS) were detected by flow cytometric analysis. Protein expression was detected by Western blot. RNA levels were examined by reverse transcription polymerase chain reaction assay. Overexpression of constitutively active Akt was also used in this study. RESULTS Ardisianone, a natural benzoquinone derivative, displayed anti-proliferative and apoptotic activities against human hormone-refractory prostate cancer cells (HRPC), PC-3, and DU-145. Ardisianone dramatically induced mitochondrial damage, identified by downregulation of Bcl-2 family proteins, ROS production, and loss of ΔΨm. Ardisianone also inhibited Akt and mTOR/p70S6K pathways and induced a fast downregulation of survivin, leading to activation of mitochondria-involved caspase cascades. Overexpression of constitutively active Akt partly rescued ardisianone-mediated apoptotic signaling cascades. Furthermore, a long-term treatment of ardisianone caused an increase of endoplasmic reticulum (ER) stress, upregulation of cIAP1 and cIAP2, and apoptosis-inducing factor (AIF)-mediated caspase-independent apoptosis. CONCLUSIONS The data suggest that the ardisianone induces apoptosis in human prostate cancers through mitochondrial damage stress, leading to the inhibition of mTOR/p70S6K pathway, downregulation of Bcl-2 family members, degradation of survivin, and activation of caspase cascades. The data provide evidence supporting that ardisianone is a potential anticancer agent against HRPCs. Prostate 73: 133–145, 2013. © 2012 Wiley Periodicals, Inc.

The knockdown of Pim-1 or inhibition of Pim-1 activity significantly increased c-H2A.X expression. The effect was correlated to apoptosis and was attributed to the inhibition of nonhomologous DNA-end-joining (NHEJ) repair activity supported by the following observations: (1) inhibition of ATM and DNA-PKcs activities, (2) down-regulation of Ku expression and nuclear localization and (3) decrease of DNA end-binding of both Ku70 and Ku80. The data suggest that Pim-1 plays a crucial role in the regula-tion of NHEJ repair. In the absence of Pim-1, the ability of DNA repair significantly decreases when exposed to paclitaxel, leading to severe DNA damage and apoptosis.

Background: The incidence of end-stage renal disease (ESRD) in Taiwan ranks highest in the world, but the incidence of Chinese herb nephropathy (CHN) is unknown in this country where Chinese herb use is common. Methods: The etiologies of incident ESRD cases from 2000 to 2004 in a single tertiary referral medical center in Taiwan were independently reviewed by two nephrologists through medical records and telephone interview. Patients with obvious causes of ESRD were not diagnosed with CHN, in spite of Chinese herb use. Three categories of CHN (A, B and C) were defined according to the stringency of evidence. Results: Obvious causes of ESRD were identified in 1,359 out of 1,696 newly diagnosed ESRD patients. Among the remainders, 263 had histories of Chinese herb use; 164 patients (mean age 52.7 ± 13.2 years, female 71.6%) had CHN (category A: 51, category B: 38 and category C: 75). Among the three categories, there was no difference in age, gender, body mass index (BMI) or elapsed time from Chinese herb use to the detection of renal failure. In comparison with non-CHN patients (n = 99), more CHN patients were female, had lower BMI, lower blood pressure, shorter duration of Chinese herb use, less severe proteinuria, smaller kidney size, lower levels of hemoglobin and higher serum chloride levels (all p values Conclusion: Based on highly stringent diagnostic criteria, nearly 10% of incident ESRD cases were due to CHN. CHN represents a significant cause of ESRD in Taiwan.

Background Appropriate prescribing is fundamental to successful pharmacotherapy. The status of current ambulatory medication practices in medicine and pharmacy would be better understood through an analysis of community pharmacy prescription claims. Objective The aims of the study were to investigate patterns of the types of prescriptions claimed by community pharmacies, undetected prescription errors by community pharmacists, and associated factors of prescription errors. Setting A population-based claims database of prescriptions dispensed by community pharmacies in Taiwan. Methods Ambulatory prescriptions were randomly sampled and reassessed for prescribing appropriateness by medical center pharmacists using explicit criteria. Demographics of patients, physicians, care facilities, and prescription/dispensing details were assessed and used to identify associated factors for prescription errors using descriptive analyses as well as logistic regression. Main outcome measures Erroneous prescriptions prescribed by physicians, and dispensed and claimed through community pharmacies. Results The study included analyses of 3065 prescriptions dispensed in community pharmacies resulting from 1003 patient visits, mostly to physician or dental clinics (99.5%). Prescribing characteristics, patterns, and examples of prescription errors are described. Prescription errors were identified in 18.3% (n = 560) of prescriptions and 34.9% (n = 350) of patient visits. Potential prescribing errors included errors of omission (25.5%), errors of commission (53.4%), and others (21.1%). The top three errors were incorrect dosage (27.5%), missing indication (23.6%), and insufficient or unavailable drug information (18.9%). Drugs most frequently associated with prescription errors included antihistamines, hormones, and gastrointestinal agents. Prescription were also higher in the central and eastern regions of Taiwan. Pediatricians accounted for a disproportionate number of prescription errors. Conclusion Prescription errors are prevalent in ambulatory care in Taiwan, and differential practice standards exist between community and hospital services. This disparity needs to be reconciled by pertinent initiatives to enhance community-hospital and pharmacist-general practitioner communication and interprofessional educational efforts to improve medication use and safety.

The primary aim of the high-dose 5-fluorouracil (5-FU) and leucovorin (LV; HDFL48) phase I study was to determine the maximum tolerated dose and dose-limiting toxicity of 5-FU and LV with modified tri-monthly 48-h continuous infusion of high-dose 5-FU/LV in patients with metastatic colorectal cancer. The study also determined the pharmacokinetic parameters of 5-FU, especially steady-state plasma and bone marrow (BM) concentrations. Eligibility included serum triglyceride of more than or equal to 70 mg/dl, adequate BM function, and the major typical trial criteria. Sixteen patients who were enrolled received tri-monthly 5-FU at 2500 mg/m²/48 h/week (with 500 then 250 mg/m²/48 h/week escalation by a conventional 3-3 schema up to 3750 mg/m²/48 h/week) and LV at 300 mg/m²/48 h on days 1, 8, and 15 during a regular 28-day cycle. The maximum tolerated dose of 5-FU was 3750 mg/m²/48 h/week with this tri-monthly schedule. Dose-limiting toxicities were grade III neutropenia with more than 1-week delay of the next cycle, grade III mucositis, diarrhea, and hand-foot syndrome for more than 3 days. The regimen maintains significant concentration differences between steady-state plasma and BM concentrations (8.06 ± 6.39 vs. 2.89 ± 1.01 μmol/l, P=0.021) as measured by high-performance liquid chromatography. Toxicities were of minor grade and were tolerable, with minimal myelotoxicity significantly associated with low steady-state BM concentration. None had 5-FU-related hyperammonemic encephalopathy. Three patients had an objective partial response (18.8%, 95% confidence interval: 4-46%) and two of the 14 patients, who had failed HDFL24 (2600 mg/m²/24 h/week), had a partial response to HDFL48 (14.3% partial response, 95% confidence interval 2-43%). Median progression-free survival and overall survival were 4.1 months (range: 1.8-12.5) and 10.5 months (range: 2.7-32.1), respectively. The efficacy and low myelotoxicity of HDFL48 were attributed to the sustained adequate steady-state plasma concentration and an average 2.63-fold concentration gradient between plasma and BM compartments at steady state. The recommended 5-FU dose for use in future trials was 3500 mg/m²/48 h/week, with a fixed dose of LV at 300 mg/m²/48 h/week.

Aims To evaluate the possible herb–drug interaction of St. John's wort (SJW) extracts with indinavir in rats and to set up a model for characterizing pre-systemic sites for the interactions between orally administered herbs and pharmaceuticals. Main Methods The in vivo pharmacokinetic study and in situ single-pass intestinal perfusion model were employed in the research. Plasma indinavir concentration and cytochrome P 450 3A activities were measured by high-pressure liquid chromatography and spectrophotometric assays, respectively. Key findings Oral administration of either 150 or 300 mg/day SJW for 15 days significantly reduced indinavir plasma levels with certain pharmacokinetic parameter changes. The cytochrome P 450 3A analysis suggested that this interaction was attributable to the induction of indinavir metabolism. Further perfusion study demonstrated that both small intestine and the liver contributed significantly to the reduction of indinavir bioavailability and was flow rate-dependent. Moreover, the small intestine was the major site for the pre-systemic metabolism of indinavir, whether with or without SJW pretreatment. Significance Herb–drug pharmacokinetic interactions between SJW and indinavir can be clearly observed in the Wistar rat model. Particularly, the respective first-pass effect contributed by the small intestine and the liver could be differentiated and quantified. The application of the animal model to investigating herb–drug interactions or other relevant research purposes is envisioned.

Background/PurposeFirst-pass effect has been an important concern for oral pharmaceuticals. An in vivo system was developed for measuring different concentrations of pharmaceuticals in the portal vein and hepatic vein (via the inferior vena cava) for delineating presystemic metabolism under different perfusion rates by using indinavir as an exemplary agent.MethodsAn in situ single-pass intestinal perfusion technique was modified from previous studies to concomitantly obtain portal and hepatic venous bloods. Portal and hepatic venous samples were simultaneously taken from rats at appropriate time points using the perfusion model of 1 mg/mL indinavir at flow rates of 0.05, 0.1, 0.5 and 1.0 mL/min. The indinavir concentrations were assayed by binary-gradient high-pressure liquid chromatography with UV detection.ResultsThe mean indinavir concentrations in portal vein concentration−time profiles at different perfusion times under various flow rates were all higher than those obtained for hepatic veins. At flow rates of 0.5 and 1.0 mL/min, in particular, the area under the curve (AUC) and maximal concentration (C max) of indinavir absorption were significantly different between portal veins and hepatic veins (p < 0.05), indicating considerable hepatic involvement in the presystemic extraction of indinavir. The system also has potential for use when estimating the hepatic extraction ratio (E H) and hepatic clearance (Cl H).ConclusionThis in vivo approach could provide another useful tool for improving our basic understanding of the absorption kinetics and hepatic metabolism of pharmaceuticals under development and facilitating the clinical application of such.

The disposition and biliary excretion of omeprazole was investigated following i.v. administration to rats at 10 mg/kg. We used a microdialysis technique coupled to a validated microbore HPLC system to monitor the levels of protein-unbound omeprazole in rat blood, brain and bile, constructing the relationship of the time course of the presence of omeprazole. Microdialysis probes were simultaneously inserted into the jugular vein toward right atrium, the brain striatum and the bile duct of the male Sprague-Dawley rats for biological fluid sampling after the administration of omeprazole (10 mg/kg) through the femoral vein. The concentration-response relationship from the present method indicated linearity (r2>0.995) over a concentration range of 0.01-50 microg/ml for omeprazole. Intra-assay and inter-assay precision and accuracy of omeprazole fell well within the predefined limits of acceptability. Following omeprazole administration, the blood-to-brain coefficient of distribution was 0.15, which was calculated as the area under the concentration versus time curve (AUC) in the brain divided by the AUC in blood (k=AUCbrain/AUCblood). The blood-to-bile coefficient of distribution (k=AUCbile/AUCblood) was 0.58. The decline of unbound omeprazole in the brain striatum, blood and bile fluid suggests that there was rapid exchange and equilibration between the compartments of the peripheral and central nervous systems. In addition, the results indicated that omeprazole was able to penetrate the blood-brain barrier and undergo hepatobiliary excretion.