Association between Outpatient Visits and Initiating Medication among Elderly Patients after an Osteoporotic Vertebral Fracture.

PURPOSE: A treatment gap exists in vertebral fracture (VF) patients. An outpatient visit is a necessary step to initiate treatment. The study aimed to evaluate factors associated with an outpatient visit following a VF diagnosis, and the association between the interval of an outpatient visit after VF diagnosis and its impact on prescribing of anti-osteoporosis medications (AOMs). METHODS: Subjects 65 years and older from Tianliao Township in Taiwan with newly diagnosed VF between 2009 and 2010 were included. Information about outpatient visits and AOMs prescriptions were derived from the National Health Insurance Research database and followed up for 2 years. Factors associated with outpatient visits and the initiation of AOMs were assessed using the multivariable Cox proportional regression model analysis. The receiver operating characteristic curve (ROC curve) was analyzed to determine the predictive effects of the interval between an outpatient visit following the diagnosis of a new VF on initiating AOMs and the potential optimal cutoff point. RESULTS: Of 393 participants, 42.2% had outpatient visits within 2 years after a new VF diagnosis, for which the mean interval was 4.8 ± 4.8 months. Patients who were female and reported a current use of supplements were positively associated with visits after a new VF diagnosis, but the bone mineral density (BMD) T-score was negatively associated with visits. Furthermore, 140 (35.6%) patients had initiated AOMs within 2 years after the diagnosis of a new VF. It was found that a higher BMD T-score and a longer interval between an outpatient visit following diagnosis was negatively associated with initiation of AOMs. The ROC curve analysis showed outpatient visits within 3 months after a VF diagnosis had the highest Youden index and maximum area under the curve. CONCLUSIONS: Patients who were female, were currently taking supplements, and those who had a lower BMD T-score were more likely to visit doctors after being diagnosed with a new VF. Furthermore, a lower BMD T-score and a shorter interval, within 3 months and not more than 8 months, between an outpatient visit following the diagnosis of VF increased the likelihood of being prescribed AOMs.

Baicalein Exerts Therapeutic Effects against Endotoxin-Induced Depression-like Behavior in Mice by Decreasing Inflammatory Cytokines and Increasing Brain-Derived Neurotrophic Factor Levels.

Inflammation plays an important role in the pathophysiology of depression. This study aims to elucidate the antidepressant effect of baicalein, an anti-inflammatory component of a traditional Chinese herbal medicine (Scutellaria baicalensis), on lipopolysaccharide (LPS)-induced depression-like behavior in mice, and to investigate the underlying mechanisms. In vitro, baicalein exhibited antioxidant activity and protected macrophages from LPS-induced damage. The results of the tail suspension test and forced swimming test (tests for despair potential in mice) showed the antidepressant effect of baicalein on LPS-treated mice. It also substantially decreased the production of pro-inflammatory cytokines, including IL-6, TNF-α, MCP-1, and eotaxin, elicited by LPS in the plasma. Baicalein downregulated NF-κB-p65 and iNOS protein levels in the hippocampus, demonstrated its ability to mitigate neuroinflammation. Additionally, baicalein increased the levels of the mature brain-derived neurotrophic factor (mBDNF) in the hippocampus of LPS-treated mice, and elevated the ratio of mBDNF/proBDNF, which regulates neuronal survival and synaptic plasticity. Baicalein also promoted the expression of CREB, which plays a role in a variety of signaling pathways. In summary, the findings of this study demonstrate that the administration of baicalein can attenuate LPS-induced depression-like behavior by suppressing neuroinflammation and inflammation induced by the peripheral immune response.

Association between Albuminuria and Different Body Constitution in Type 2 Diabetes Patients: Taichung Diabetic Body Constitution Study.

Objective. Albuminuria in type 2 diabetes mellitus (T2DM) patients increases the risk of diabetic nephropathy, the leading cause of end-stage renal disease worldwide. Because albuminuria is modifiable, identifying relevant risk factors could facilitate prevention and/or management. This cross-sectional study investigated whether body constitution (BC) independently predicts albuminuria. Method. Patients with T2DM (n = 846) received urinalysis, a blood test, and diabetic retinopathy examination. Albuminuria was defined by an elevated urinary albumin/creatinine ratio (≥30 µg/mg). BC type (Yang deficiency, Yin deficiency, and Phlegm stasis) was assessed using a body constitution questionnaire (BCQ). Traditional risk factors for albuminuria were also recorded. Odds ratios (ORs) of albuminuria for BC were estimated using multivariate logistic regression. Results. Albuminuria was more prevalent in patients with Yang deficiency or Phlegm stasis (both P < 0.01). After adjustment, patients with both Yang deficiency and Phlegm stasis exhibited a significantly higher risk of albuminuria (OR = 3.037; 95% confidence interval = 1.572-5.867, and P < 0.001). Conclusion. BC is strongly associated with albuminuria in T2DM patients. Using a BCQ to assess BC is noninvasive, convenient, and inexpensive and can provide information for health care professionals to identify T2DM patients who are at a high risk of albuminuria.

Yang Deficiency Body Constitution Acts as a Predictor of Diabetic Retinopathy in Patients with Type 2 Diabetes: Taichung Diabetic Body Constitution Study.

Objective. Diabetic retinopathy (DR), the most common microvascular complication of diabetes mellitus (DM), can cause severe visual impairment and blindness. To prevent the development of DR, identifying the associated risk factors for patient classification is critical. We conducted a cross-sectional study to determine whether body constitution (BC) is an independent predictor of DR. Method. 673 type 2 DM (T2DM) patients were recruited from a medical center, all received DR examination and body constitution questionnaire to assess BC. Other risk factors for DR were also recorded, including life style, history of diabetes, and blood pressure, etc. Multiple logistic regression analysis was conducted to calculate the odds ratios (ORs) for DR. Results. The prevalence of DR was significantly lower in Yang deficiency patients compared with non-Yang deficiency patients (24.69% versus 38.18% P = 0.02). After adjusting for other risk factors, we observed that patients exhibiting Yang deficiency BC were less likely to present with DR (OR = 0.531; 95% confidence interval = 0.312-0.903, P = 0.018). Conclusion. In addition to traditional risk factors, Yang deficiency BC might be an independent predictor of DR among T2DM patients and the results can be used as evidence for traditional Chinese medicine patient classification.

Logistic-AFT location-scale mixture regression models with nonsusceptibility for left-truncated and general interval-censored data.

In conventional survival analysis there is an underlying assumption that all study subjects are susceptible to the event. In general, this assumption does not adequately hold when investigating the time to an event other than death. Owing to genetic and/or environmental etiology, study subjects may not be susceptible to the disease. Analyzing nonsusceptibility has become an important topic in biomedical, epidemiological, and sociological research, with recent statistical studies proposing several mixture models for right-censored data in regression analysis. In longitudinal studies, we often encounter left, interval, and right-censored data because of incomplete observations of the time endpoint, as well as possibly left-truncated data arising from the dissimilar entry ages of recruited healthy subjects. To analyze these kinds of incomplete data while accounting for nonsusceptibility and possible crossing hazards in the framework of mixture regression models, we utilize a logistic regression model to specify the probability of susceptibility, and a generalized gamma distribution, or a log-logistic distribution, in the accelerated failure time location-scale regression model to formulate the time to the event. Relative times of the conditional event time distribution for susceptible subjects are extended in the accelerated failure time location-scale submodel. We also construct graphical goodness-of-fit procedures on the basis of the Turnbull-Frydman estimator and newly proposed residuals. Simulation studies were conducted to demonstrate the validity of the proposed estimation procedure. The mixture regression models are illustrated with alcohol abuse data from the Taiwan Aboriginal Study Project and hypertriglyceridemia data from the Cardiovascular Disease Risk Factor Two-township Study in Taiwan.

Value of preapproval safety data in predicting postapproval hepatic safety and assessing the legitimacy of class warning.

OBJECTIVE: The objective of this study was to systematically evaluate whether preapproval safety data for nonhepatotoxic drugs and hepatotoxic drugs can be compared to improve preapproval prediction of postapproval hepatic safety and to assess the legitimacy of applying class warnings. METHODS: Drugs within a therapeutic class that included at least one drug that had been withdrawn from the market because of liver toxicity or had a warning of potential liver toxicity issued by major regulatory agencies, and at least one drug free from such regulatory action, were identified and divided into two groups: drugs with and drugs without regulatory action. Preapproval clinical data [including the elevation rates of alanine aminotransferse (ALT) and withdrawal due to liver toxicity, the number of patients with combined elevation of ALT and bilirubin, and liver failure] and nonclinical data (including chemical structures, metabolic pathways, and other significant findings in animal studies) were compared between the two groups. RESULTS: Six drug classes were assessed in this study: thiazolidinediones, cyclooxygenase-2 inhibitors, fluoroquinolones, catechol-O-methyltransferase (COMT) inhibitors, leukotriene receptor inhibitors, and endothelin receptor antagonists. In two classes (COMT inhibitors and endothelin receptor antagonists), drugs with regulatory action had significantly higher rates of ALT elevation of more than threefold and greater numbers of patients with combined elevation of ALT and bilirubin than drugs without regulatory action. Drugs with regulatory action also had chemical structures or metabolic pathways associated with the toxicity. The legitimacy of class warnings was refuted in all six classes of drugs. CONCLUSION: Preapproval safety data may help predict postapproval hepatic safety and can be used to assess the legitimacy of applying class warnings.

Pharmacokinetics of felodipine extended-release tablets in healthy Taiwanese subjects: a retrospective review.

The objective of this study was to investigate the pharmacokinetics of felodipine (CAS 72509-76-3) in healthy male Taiwanese subjects. This is a retrospective review of five felodipine pharmacokinetic studies completed in Taiwan. A total of 100 evaluable healthy Taiwanese males were enrolled in these studies. The subjects received 5 mg (n = 80) or 10 mg (n = 20) of Plendil (felodipine extended-release tablets; felodipine ER) once daily for 6 days. The mean +/- SD t(max,ss,) CG(max,ss) and AUG(tau) of dose normalized to 10 mg felodipine was 3.32 +/- 1.33 h, 13.12 +/- 5.34 nmol/L and 136.33 +/- 63.18 nmol x h/L, respectively. By using Kolmogorov-Smirnov's test and probit plots, the results indicated that the frequency distribution of AUC/dose, C(min)/dose and CL/F was bimodal. Compared to data from the literature, the mean C(max,ss) and AUG(tau) of 5 mg felodipine in healthy young Taiwanese subjects were similar to or slightly lower than data from Swedish, Danish, Turkish and Canadian studies in healthy young subjects who received 10 mg felodipine. Comparable C(max) values and approximately 30% lower AUC values were observed when comparing the 5 mg Taiwanese data to data in healthy elderly German subjects who also received 5 mg felodipine. Taiwanese subjects might have lower CYP3A4 activity to metabolize felodipine, which is similar to the phenomenon observed with nifedipine.

Electrophysiologic, pharmacokinetic, and pharmacodynamic values indicating a higher risk of torsades de pointes.

Torsades de pointes (TdP) is a major safety concern with drugs that are submitted for regulatory approval. The study aimed to identify the electrophysiological, pharmacokinetic, and pharmacodynamic values indicating a higher risk of TdP. A number of QT-prolonging drugs were assigned to 2 groups. Group 1 consisted of drugs that had been withdrawn or suspended from the market because of unacceptable TdP risk or for which numerous reports of TdP had been published. Group 2 included drugs for which there had been isolated reports or no report. The results showed that drugs in group 1 induced greater inhibition of human ether-a-go-go-related gene (HERG) potassium current or the rapid component of the delayed rectifier potassium current (I(kr)), had lower half-maximal inhibitory concentration (IC50) values for inhibition of HERG/I(kr), and induced greater QTc increases in humans. The cutoff values indicating a higher risk of TdP included an increase in action potential duration greater than 10% at concentration lower than 300 nM, inhibition of HERG/I(kr) greater than 30% at therapeutic concentration, IC50 lower than 2 µM, a mean QTc increase greater than 15.5 milliseconds in monotherapy and 12.0 milliseconds with concurrent use of metabolic inhibitors, and an upper bound of its 95% confidence interval greater than 21 milliseconds in monotherapy and 19.4 milliseconds in the presence of metabolic inhibition.

Electrocardiographic monitoring for QT prolongation in patients treated with ziprasidone--a claims database approach.

PURPOSE: Drug-induced cardiac arrhythmia is a major safety concern for drugs with a potential to prolong the QT interval. The purpose of the study is to examine whether timely electrocardiographic (ECG) monitoring has been performed for patients treated with ziprasidone. METHODS: Out-patient pharmacy claims data abstracted from Taiwan's National Health Insurance Research Database were used to identify patients treated with ziprasidone. Based on the dataset sorted by the encrypted patient identifier and by date, the rates of ECG performed before and during treatment were examined. The intervals between treatment beginning and ECG examination during therapy were calculated. RESULTS: Among 4789 patients ever treated with zipasidone, 229 (4.8%) had ECG performed before treatment. Among 2052 patients treated with a longer duration of ziprasidone, 394 (19.2%) had ECG performed during treatment. They included 64 (3.1%) patients who had it performed within the first 30 days of treatment, 124 (6.0%) within 60 days and 178 (8.7%) within 90 days. The mean interval was 157.4 days (95% confidence interval (CI), 143.0-171.8) between treatment beginning and the first on-therapy ECG examination and was 210.4 days (95%CI, 178.6-242.2) between treatment beginning and the second ECG. CONCLUSIONS: Low rates of ECG examination before and during therapy were noted among patients treated with ziprasidone. It took significant length of time to perform ECG monitoring after treatment was started. Although the patients studied had few risk factors for cardiac arrhythmia, ECG monitoring for patients using ziprasdione could be improved.

A Bayesian approach to evaluating regional treatment effect in a multiregional trial.

A multiregional trial, conducted in more than one region under a common protocol, is a promising strategy making valuable medicines available to patients globally without time lag. When evaluating the treatment effect for each local region, one may wish to utilize information from other regions to enhance the statistical power. This work proposes a Bayesian approach to bridging data across different regions in a multiregional trial to get an improved analysis of treatment effect for a local region. The new proposal has the following distinct features: (1) It performs internal bridging in a multiregional trial, with the degree of bridging automatically determined by the interregional variability of the treatment effect across different regions; (2) it usually ensures the consistency of the conclusions from local and global inference when the treatment effect is virtually homogeneous across regions and is found nonsignificant globally; (3) it generally protects against overbridging of the global information for evaluating the treatment effect in a very small region. Formulas for statistical power of the proposed method are provided. We illustrate the utility of the proposed method by two numerical examples reflecting typical issues we may encounter in evaluating regional treatment effect in a multiregional trial.

A regulatory view of adaptive trial design.

Developing a new medicine is an expensive and time-consuming process. Researchers are interested in applying better designs to expedite the approval of potential medicinal products. Adaptive designs, which allow for some types of prospectively planned mid-study change, can improve the efficiency of a trial and maximize the chance of success. Possible design adaptations of clinical trials include sample size re-estimation, change in primary endpoint, interim dropping of treatment arms, change in statistical hypothesis, and change in the primary analysis. In this article, the regulatory considerations of the methodological issues with respect to adaptive design are discussed. Several examples of design adaptation that the Center for Drug Evaluation has encountered during the past 3 years are presented.

Effects of work-related factors on the breastfeeding behavior of working mothers in a Taiwanese semiconductor manufacturer: a cross-sectional survey.

BACKGROUND: In recent years, the creation of supportive environments for encouraging mothers to breastfeed their children has emerged as a key health issue for women and children. The provision of lactation rooms and breast pumping breaks have helped mothers to continue breastfeeding after returning to work, but their effectiveness is uncertain. The aim of this study was to assess the effects of worksite breastfeeding-friendly policies and work-related factors on the behaviour of working mothers. METHODS: This study was conducted at a large Taiwanese semiconductor manufacturer in August-September 2003. Questionnaires were used to collect data on female employees' breastfeeding behaviour, child rearing and work status when raising their most recently born child. A total of 998 valid questionnaires were collected, giving a response rate of 75.3%. RESULTS: The results showed that 66.9% of survey respondents breastfed initially during their maternity leave, which averaged 56 days. Despite the provision of lactation rooms and breast pumping breaks, only 10.6% mothers continued to breastfeed after returning to work, primarily office workers and those who were aware of their company's breastfeeding-friendly policies. CONCLUSION: In conclusion, breastfeeding-friendly policies can significantly affect breastfeeding behaviour. However, an unfavourable working environment, especially for fab workers, can make it difficult to implement breastfeeding measures. With health professionals emphasizing that the importance of breastfeeding for infant health, and as only females can perform lactation, it is vital that women's work "productive role" and family "reproductive role" be respected and accommodated by society.