Administration mode matters for 5-fluorouracil therapy: Physiologically based pharmacokinetic evidence for avoidance of myelotoxicity by continuous infusion but not intravenous bolus.

AIMS: Pre-emptive prediction to avoid myelosuppression and harmful sequelae is difficult given the complex interplay among patients, drugs and treatment protocols. This study aimed to model plasma and bone marrow concentrations and the likelihood of myelotoxicity following administration of 5-fluorouracil (5-FU) by diverse intravenous (IV) bolus or continuous infusion (cIF) regimens. METHODS: Using physicochemical, in vitro and clinical data obtained from the literature consisting of various regimens and patient cohorts, a 5-FU physiologically based pharmacokinetic (PBPK) model was developed. The predicted and observed PK values were compared to assess model performance prior to examining myelotoxicity potential of IV bolus vs. cIF and DPYD wild type vs. genetic variant. RESULTS: The established model was verified by utilizing 5-FU concentration-time profiles of adequate heterogeneity contributed by 36 regimens from 15 studies. The study provided corroborative evidence to explain why cIF (vs. IV bolus) had lower myelotoxicity risk despite much higher total doses. The PBPK model was used to estimate the optimal dosage in patients heterozygous for the DPYD c.1905 + 1G > A allele and suggested that a dose reduction of at least 25% was needed (compared to the dose in wild-type subjects). CONCLUSION: A verified PBPK model was used to explain the lower myelotoxicity risk of cIF vs. IV bolus administration of 5-FU and to estimate the dose reduction needed in carriers of a DPYD variant. With appropriate data, expertise and resources, PBPK models have many potential uses in precision medicine application of oncology drugs.

Author response to "lack of benefit from low dose computed tomography in screening for lung cancer".

We explain to Dr. Benjamin (corresponding author) about why low-dose computed tomography reduce lung cancer mortality without significantly reducing all-cause mortality. We also conduct an up-to-date meta-analysis to evaluate low-dose computed tomography clinical effectiveness compared with usual care of lung cancer screening.

Effects of low-dose computed tomography on lung cancer screening: a systematic review, meta-analysis, and trial sequential analysis.

BACKGROUND: The Nelson mortality results were presented in September 2018. Four other randomized control trials (RCTs) were also reported the latest mortality outcomes in 2018 and 2019. We therefore conducted a meta-analysis to update the evidence and investigate the benefits and harms of low-dose computed tomography (LDCT) in lung cancer screening. METHODS: Detailed electronic database searches were performed to identify reports of RCTs that comparing LDCT to any other type of lung cancer screening. Pooled risk ratios (RRs) were calculated using random effects models. RESULTS: We identified nine RCTs (n = 97,244 participants). In pooled analyses LDCT reduced lung cancer mortality (RR 0.83, 95% CI 0.76-0.90, I2 = 1%) but had no effect on all-cause mortality (RR 0.95, 95% CI 0.90-1.00). Trial sequential analysis (TSA) confirmed the results of our meta-analysis. Subgroup defined by high quality trials benefitted from LDCT screening in reducing lung cancer mortality (RR 0.82, 95% CI 0.73-0.91, I2 = 7%), whereas no benefit observed in other low quality RCTs. LDCT was associated with detection of a significantly higher number of early stage lung cancers than the control. No significant difference (RR 0.64, 95% CI 0.30-1.33) was found in mortality after invasive procedures between two groups. CONCLUSIONS: In meta-analysis based on sufficient evidence demonstrated by TSA suggests that LDCT screening is superiority over usual care in lung cancer survival. The benefit of LDCT is expected to be heavily influenced by the risk of lung cancer in the different target group (smoking status, Asian) being screened.

Comparison of agomelatine and selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors in major depressive disorder: A meta-analysis of head-to-head randomized clinical trials.

OBJECTIVE: Agomelatine is a new antidepressant with unique melatonin receptor type 1A (MTNR1A) and 1B ( MTNR1B) agonism and serotonergic receptor 5-hydroxytryptamine receptor 2C (5-HT-2C) antagonism. Several studies of patients with major depressive disorder (MDD) have confirmed the superior efficacy and safety of agomelatine in comparison with established treatments, such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). This meta-analysis comprehensively shows the efficacy, acceptability, and safety of agomelatine in comparison with SSRIs and SNRIs used as antidepressants in MDD. METHOD: Comprehensive electronic database searches were performed to identify reports of head-to-head randomized controlled trials that have compared agomelatine with SSRIs or SNRIs in terms of efficacy/effectiveness in treating MDD. Response and remission rates at both acute (6-12 weeks) and follow-up (24 weeks) phases, Clinical Global Impression-Improvement Scale response and remission rates, changes in depression scale scores, improvements in subjective sleep, dropout rates, and side effect rates were extracted and analysed. RESULTS: The meta-analysis included six head-to-head trials involving 1871 patients. In the acute phase, agomelatine had higher response rates (relative risk (RR) 1.08, 95% confidence interval (CI) 1.02-1.15) compared to SSRIs and SNRIs. In the remission analysis, only acute remission rates (RR 1.12, 95% CI 1.01-1.24) significantly differed. The action of agomelatine was superior on the Leeds Sleep Evaluation Questionnaire-Quality of Sleep score (mean difference 4.05, 95% CI 0.61-7.49). Discontinuation due to inefficacy did not differ between agomelatine and SSRIs/SNRIs (RR 0.74, 95% CI 0.42-1.28). Compared to SSRIs and SNRIs, however, agomelatine revealed a lower rate of discontinuation due to side effects (RR 0.38, 95% CI 0.25-0.57). CONCLUSIONS: Agomelatine has significantly higher efficacy and potential acceptability compared to SSRIs and SNRIs when treating MDD. However, the difference in efficacy is not considered clinically relevant. Because of its unique chronobiotic effects, agomelatine may be useful for the management of some MDD patients with circadian disturbance.

Predicting game-attending behavior in amateur athletes: the moderating role of intention stability.

The theory of planned behavior is a well-established theory in predicting human behavior. However, there is evidence of an inconsistent relationship between intention and behavior. Therefore, the purpose of the current study is to further investigate the gap between intention and behavior. The study proposes intention stability as the moderator. Participants (N = 154, M age = 23 yr., SD = 6.7) were recruited from Internet volleyball forums and local volleyball courts in Taiwan. Multiple hierarchical regression was used to analyze the data. The results indicated that perceived behavioral control significantly predicted game-attending behavior through intention. However, attitude and subjective norms did not significantly predict behavioral intention. In addition, intention stability moderated the relationship between intention and behavior and indicated the relationship between intention and behavior was strong when intention stability was high. On the contrary, when intention stability was low, the relationship between intention and behavior was weak. Implications and applications are discussed.

Preparation of TiO2 nanocrystallite powders coated with 9 mol% ZnO for cosmetic applications in sunscreens.

The preparation of TiO(2) nanocrystallite powders coated with and without 9 mol% ZnO has been studied for cosmetic applications in sunscreens by a co-precipitation process using TiCl(4) and Zn(NO(3))(2)·6H(2)O as starting materials. XRD results show that the phases of anatase TiO(2) and rutile TiO(2) coexist for precursor powders without added ZnO (T-0Z) and calcined at 523 to 973 K for 2 h. When the T-0Z precursor powders are calcined at 1273 K for 2 h, only the rutile TiO(2) appears. In addition, when the TiO(2) precursor powders contain 9 mol% ZnO (T-9Z) are calcined at 873 to 973 K for 2 h, the crystallized samples are composed of the major phase of rutile TiO(2) and the minor phases of anatase TiO(2) and Zn(2)Ti(3)O(8). The analyses of UV/VIS/NIR spectra reveal that the absorption of the T-9Z precursor powders after being calcined has a red-shift effect in the UV range with increasing calcination temperature. Therefore, the TiO(2) nanocrystallite powders coated with 9 mol% ZnO can be used as the attenuate agent in the UV-A region for cosmetic applications in sunscreens.

The Relationships among Proactive Personality, Work Engagement, and Perceived Work Competence in Sports Coaches: The Moderating Role of Perceived Supervisor Support.

Grounded in the job demands-resources model, this study examines the moderating role of supervisor support and the mediating role of sports coaches' work engagement in the relationship between proactive personality and perceived work competence. A total of 261 school sports coaches in Taiwan participated in the study. The results indicated that work engagement positively mediates the relationship between sports coaches' proactive personality and perceived work competence. Separately, supervisor support weakens the link between proactive personality and work engagement but strengthens the relationship between work engagement and perceived work competence; however, taken together, supervisor support weakens the indirect effects of proactive personality on perceived work competence through job engagement. Under the boundary condition of perceived supervisor support, the sports coaches' proactive personality is a critical antecedent of perceived work competence through work engagement. We suggest that proactive sports coaches are assets for schools because they possess the drive and energy for self-improvement, promoting organizational progress automatically.

Phase I, pharmacokinetic, and bone marrow drug-level studies of tri-monthly 48-h infusion of high-dose 5-fluorouracil and leucovorin in patients with metastatic colorectal cancers.

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.

Sports spectator behavior: a test of the theory of planned behavior.

The theory of planned behavior has been applied to sports and exercise behaviors. According to this theory, human intention to take action in a specific context is guided by three antecedents: attitude, subjective norm, and perceived behavioral control. Behavioral intention mediates the relationships between these three considerations and its ultimate performance. However, this theory has seldom been applied to the behaviors of spectators of sporting events. A sample of 269 volleyball spectators in Taiwan was studied to examine whether people's intention mediated their attitudes, subjective norms, and perceived behavioral control toward a given behavior, watching the 2010 Fédération Internationale de Volleyball World Grand Prix in Taipei. Regression analyses did not support behavioral intention as a mediator. This result is discussed in the context of planned behavior.

Appropriateness of ambulatory prescriptions in Taiwan: translating claims data into initiatives.

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 adaptor protein SH2B1ß reduces hydrogen peroxide-induced cell death in PC12 cells and hippocampal neurons.

BACKGROUND: SH2B1ß is a signaling adaptor protein that has been shown to promote neuronal differentiation in PC12 cells and is necessary for the survival of sympathetic neurons. However, the mechanism by which SH2B1ß may influence cell survival is not known. RESULTS: In this study, we investigated the role of SH2B1ß in oxidative stress-induced cell death. Our results suggest that overexpressing SH2B1ß reduced H2O2-induced, caspase 3-dependent apoptosis in PC12 cells and hippocampal neurons. In response to H2O2, overexpressing SH2B1ß enhanced PI3K (phosphatidylinositol 3-kinas)-AKT (protein kinase B) and MEK (MAPK/ERK kinase)-extracellular-signal regulated kinases 1 and 2 (ERK1/2) signaling pathways. We further demonstrated that SH2B1ß was able to reduce H2O2-induced nuclear localization of FoxO1 and 3a transcription factors, which lie downstream of PI3K-AKT and MEK-ERK1/2 pathways. Moreover, overexpressing SH2B1ß reduced the expression of Fas ligand (FasL), one of the target genes of FoxOs. CONCLUSIONS: Overexpressing the adaptor protein SH2B1ß enhanced H2O2-induced PI3K-AKT and MEK-ERK1/2 signaling, reduced nucleus-localized FoxOs and the expression of a pro-apoptotic gene, FasL.