Lin-Chau Chang

Determining estrogens using surface-assisted laser desorption/ionization mass spectrometry with silver nanoparticles as the matrix

We describe the application of silver nanoparticles (Ag NPs) as matrices for the determination of three estrogens using surface-assisted laser desorption/ionization mass spectrometry (SALDI-MS). Because Ag NPs have extremely high absorption coefficients (1.2 × 108 M−1 cm−1) at 337 nm, they are effective SALDI matrices when using a nitrogen laser. Three tested estrogens—estrone (E1), estradiol (E2), and estriol (E3)—adsorb weakly onto the surfaces of the Ag NPs, through van der Waals forces. After centrifugation, the concentrated analytes adsorbed on the Ag NPs were subjected directly to SALDI-MS analyses, with the limits of detection for E1, E2, and E3 being 2.23, 0.23, and 2.11 µM, respectively. The shot-to-shot and batch-to-batch variations for the three analytes were less than 9% and 13%, respectively. We validated the practicality of this present approach through the quantitation of E2 in human urine. Using this approach, we determined the concentration of E2 in a sample of a pregnant woman’s urine to be 0.16 ± 0.05 µM (n = 10).

Adiponectin: a biomarker of obesity-induced insulin resistance in adipose tissue and beyond

Adiponectin is one of the most thoroughly studied adipocytokines. Low plasma levels of adiponectin are found to associate with obesity, metabolic syndrome, diabetes and many other human diseases. From animal experiments and human studies, adiponectin has been shown to be a key regulator of insulin sensitivity. In this article, we review the evidence and propose that hypo-adiponectinemia is not a major cause of obesity. Instead, it is the result of obesity-induced insulin resistance in the adipose tissue. Hypo-adiponectinemia then mediates the metabolic effects of obesity on the other peripheral tissues, such as liver and skeletal muscle and may also exert some direct effects on end-organ damage. We propose that deciphering the molecular details governing the adiponectin gene expression and protein secretion will lead us to more comprehensive understanding of the mechanisms of insulin resistance in the adipose tissue and provide us new avenues for the therapeutic intervention of obesity and insulin resistance-related human disorders.

The Clinical Implications of Blood Adiponectin in Cardiometabolic Disorders

Adipose tissue is now accepted by the scientific and medical community to be a genuine endocrine organ, in addition to its classical role as an energy store. Adiponectin is one of the many adipocytokines that are secreted almost exclusively by adipose tissue. Alteration in blood adiponectin concentrations has been linked to many human diseases in numerous cross-sectional and prospective studies. In this review, we describe briefly the biological effects of adiponectin as revealed by basic scientific investigations. We also summarize the principles of blood adiponectin assays. Overall, lower blood adiponectin concentration is found in subjects with obesity, type 2 diabetes mellitus, dyslipidemia, and hypertension. These medical conditions are components of the metabolic syndrome and major risk factors for accelerated atherosclerosis. Plasma adiponectin levels are also expected to be lower in subjects with cardiovascular diseases, such as coronary artery disease, ischemic stroke and peripheral artery disease. Congestive heart failure (CHF) and cardiac arrhythmia are common end points in cardiovascular diseases. Surprisingly, higher blood adiponectin levels are frequently reported to predict mortality associated with CHF. Few human data regarding adiponectin and cardiac arrhythmia are available. Higher blood adiponectin level has been documented only in atrial fibrillation. We also summarize data on the role of the high molecular weight (HMW) isoforms of adiponectin and the effects of clinical treatment on the levels of total or HMW adiponectin. Whether adiponectin is a risk marker or a risk factor for the diseases reviewed in this article, and in many other human diseases, and their detailed pathogenic links awaits further investigation.

Interfacial properties of Pluronics and the interactions between Pluronics and cholesterol/DPPC mixed monolayers.

Pluronics are triblock copolymers of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) with wide range of hydrophilic-lipophilic balance. In order to investigate the relationship between the chemical structures of Pluronics and the interfacial properties at the air-water interface by monolayer techniques, Pluronics L61, P65, F68, P84, P123, L35, and P105 were selected. Since cholesterol influenced substantially the molecular packing stage and the characteristics of cell membranes, the interactions between Pluronics and model cell membranes in the absence and presence of cholesterol were compared. The results of pi-A isotherms and surface elasticities of Pluronic monolayers indicated that the first and second transition like stage were mainly affected by the numbers of EO and PO monomers, respectively. Pluronics with higher hydrophobicities demonstrated larger surface activities and penetration abilities to dipalmitoylphosphatidylcholine (DPPC) monolayers, which might be due to hydrophobic interactions and van der Waals forces. In the presence of cholesterol, hydrogen bonding effects was supposed to exist between the 3beta-hydroxy group of cholesterol and ether oxygen of PEO chains, which led Pluronic F68, with the longest PEO chain herein, to exhibit significantly higher penetration ability. Our findings proposed a theoretical basis for selection of optimized drug carriers and the starting point for further investigations.

Patterns of use and impact of standardised MedDRA query analyses on the safety evaluation and review of new drug and biologics license applications

Purpose Standardised MedDRA Queries (SMQs) have been developed since the early 2000’s and used by academia, industry, public health, and government sectors for detecting safety signals in adverse event safety databases. The purpose of the present study is to characterize how SMQs are used and the impact in safety analyses for New Drug Application (NDA) and Biologics License Application (BLA) submissions to the United States Food and Drug Administration (USFDA). Methods We used the PharmaPendium database to capture SMQ use in Summary Basis of Approvals (SBoAs) of drugs and biologics approved by the USFDA. Characteristics of the drugs and the SMQ use were employed to evaluate the role of SMQ safety analyses in regulatory decisions and the veracity of signals they revealed. Results A comprehensive search of the SBoAs yielded 184 regulatory submissions approved from 2006 to 2015. Search strategies more frequently utilized restrictive searches with “narrow terms” to enhance specificity over strategies using “broad terms” to increase sensitivity, while some involved modification of search terms. A majority (59%) of 1290 searches used descriptive statistics, however inferential statistics were utilized in 35% of them. Commentary from reviewers and supervisory staff suggested that a small, yet notable percentage (18%) of 1290 searches supported regulatory decisions. The searches with regulatory impact were found in 73 submissions (40% of the submissions investigated). Most searches (75% of 227 searches) with regulatory implications described how the searches were confirmed, indicating prudence in the decision-making process. Conclusions SMQs have an increasing role in the presentation and review of safety analysis for NDAs/BLAs and their regulatory reviews. This study suggests that SMQs are best used for screening process, with descriptive statistics, description of SMQ modifications, and systematic verification of cases which is crucial for drawing regulatory conclusions.

The evolution and challenges for the international harmonization of the regulation of pharmaceutical excipients in Taiwan

Excipients, once considered an inert component, have been shown to greatly influence the characteristics of the drug product, such as quality and safety. Functionality-related characteristics of excipients could affect the performance of the drug product. Moreover, the impact of globalization has complicated the issue and made the supervision of supply chain highly important. Taiwan, a member of the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme, makes efforts to harmonize with international regulations and to strengthen the protection of patients through regulatory controls. In order to improve the harmonization and the transparency of regulatory requirements, the aim of the present study was to investigate the regulatory framework and considerations of stringent regulatory authorities and to propose the draft regulatory requirements to the Taiwan Food and Drug Administration for jurisdiction. The proposal which was extensively discussed in the expert committee includes the regulatory considerations to ensure the safety and quality of the excipients and may serve as a platform to facilitate the communication with industries about the current thinking on related issues. Moreover, through the review of the recent guidelines published by the stringent regulatory authorities, the trend of the regulatory considerations was revealed and discussed.

Statistics, Quality Review Issues, and Beyond for Generic Drug Applications in Taiwan

The aim of the present study was to investigate the characteristics and deficiencies listed in the final quality assessment reports of generic drug applications submitted in Taiwan. The basic information of 370 generic drug applications submitted from June 2011 to the end of May 2012 was analyzed, including the dosage forms, classification, location of manufacturing sites of the drug substances and products, as well as deficiencies listed in the final quality assessment reports submitted to the Food and Drug Administration, Department of Health, Executive Yuan in Taiwan (TFDA) for final decisions before the end of September 2012. Statistical analysis demonstrated a variety of submissions concerning a manufacturing aspect. The deficiencies were found to be similar to common deficiencies observed by the US Food and Drug Administration (FDA) and the World Health Organization (WHO), while some issues were mentioned by the European Medicines Agency (EMA) as well. The present article is believed to be the first report to analyze the basic information of generic drug applications in addition to the identification of common deficiencies. These findings may provide an overview on the submissions and regulatory considerations for generic drug applications in Taiwan, which could be useful for applicants in the compilation of their dossiers and could facilitate the approval process.

Recent updates and challenges on the regulation of precision medicine: The United States in perspective

ABSTRACT The rapid progress in “omics”, such as genomics, metabolomics, microbiomics, has paved the path for precision medicine and revolutionized the development of drugs and devices promising to meet unmet medical needs. The aim of the present study was to investigate the current regulatory framework established by the United States Food and Drug Administration (USFDA) and to identify challenges and concerns through study of related literatures in the PubMed database. We found that efforts were made to facilitate the implementation of precision medicine through organizational reform, publication of guidance documents, and continuous post‐market surveillance. The challenges identified included the critical, fundamental structural requirements of databases, essential regulatory considerations for market approval, and the appropriate clinical use such as whole genomic sequencing tests especially for a newborn or even fetus. These issues are worth further research to devise an integral approach involving scientific, ethical, legal, and social considerations. HIGHLIGHTSHarmonization of hardware and software requirements and data sharing rules for “omics” databases is critical.More guidance is needed on clarification of regulatory approval considerations involving evidence supported by “omics”.“Policy‐level interventions” are essential for efficient clinical use of precision medicine. Abbreviations: USFDA: United States Food and Drug Administration; NIH: National Institutes of Health; HER2: human epidermal growth factor receptor 2; NCTR: National Center for Toxicological Research; NGS: next generation sequencing; NCBI: National Center for Biotechnology Information.

Prognostic factors in epithelial ovarian cancer: A population-based study

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<0.001, respectively) in multivariable analysis. For advanced-stage patients, histology (endometrioid type), taxane-based adjuvant chemotherapy, stage, and age at diagnosis had a significant impact on OS (p<0.001, p = 0.020, p<0.001, p<0.001, respectively). In conclusion, taxane-based chemotherapy impacts the outcome of patients with EOC. Personalized medicine may be needed for different histological types of EOC because of their different outcomes.

Development of the risk-based, phased-in approach for the international harmonization of the regulation of container closure systems for drugs in Taiwan

The main concern for container closure systems of drugs is to ensure suitability for the intended use which is associated with issues regarding protection, compatibility, safety, and performance. Among various concerns, leachables may pose a safety hazard to patients, while risks might vary depending on the dosage form and the administration route. Stringent regulatory authorities such as the European Medicines Agency and the United States Food and Drug Administration have established risk-based regulatory requirements and published corresponding guidelines to facilitate implementation. Taiwan, a member of the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme, makes every effort to harmonize with international regulations and to strengthen protection of public health through regulatory controls. The aim of the present study was to investigate the regulatory framework and policies set by stringent regulatory authorities. The strategy proposed for the development of an eventual guideline was sent to the Taiwan Food and Drug Administration for decision. A risk-based, phased-in approach which was extensively discussed in the expert committee was proposed. The approach proposed herein could also serve as a starting point which is worth considered by other countries in which international harmonization is in process.