A substructure-based screening approach to uncover N-nitrosamines in drug substances.

Drug substances are at risk of contamination with N-nitrosamines (NAs), well-known carcinogenic agents, during synthesis processes and/or long-term storage. Therefore, in this study, we developed an efficient data-based screening approach to systemically assess marketed products and investigated its scalability for benefiting both regulatory agencies and pharmaceutical industries. A substructure-based screening method employing DataWarrior, an open-source software, was established to evaluate the risks of NA impurities in drug substances. Eight NA substructures containing susceptible amino sources for N-nitrosation have been identified as screening targets: dimethylamine (DMA), diethylamine, isopropylethylamine, diisopropylamine, N-methyl-2-pyrrolidone, dibutylamine, methylphenylamine, and tetrazoles. Our method detected 192 drug substances with a theoretical possibility of NA impurity, 141 of which had not been reported previously. In addition, the DMA moiety was significantly dominant among the eight NA substructures. The results were validated using data from the literature, and a high detection sensitivity of 0.944 was demonstrated. Furthermore, our approach has the advantage of scalability, owing to which 31 additional drugs with suspected NA-contaminated substructures were identified using the substructures of 1-methyl-4-piperazine in rifampin and 1-cyclopentyl-4-piperazine in rifapentine. In conclusion, the reported substructure-based approach provides an effective and scalable method for the screening and investigation of NA impurities in various pharmaceuticals and might be used as an ancillary technique in the field of pharmaceutical quality control for risk assessments of potential NA impurities.

Up-regulation of cofilin-1 in cell senescence associates with morphological change and p27kip1 -mediated growth delay.

Morphological change is an explicit characteristic of cell senescence, but the underlying mechanisms remains to be addressed. Here, we demonstrated, after a survey of various actin-binding proteins, that the post-translational up-regulation of cofilin-1 was essential for the reduced rate of actin depolymerization morphological enlargement in senescent cells. Additionally, up-regulated cofilin-1 mainly existed in the serine-3 phosphorylated form, according to the 2D gel immunoblotting assay. The up-regulation of cofilin-1 was also detected in aged mammalian tissues. The over-expression of wild-type cofilin-1 and constitutively phosphorylated cofilin-1 promoted cell senescence with an increased cell size. Additionally, senescent phenotypes were also reduced by knockdown of total cofilin-1, which led to a decrease in phosphorylated cofilin-1. The senescence induced by the over-expression of cofilin-1 was dependent on p27Kip1 , but not on the p53 and p16INK4 expressions. The knockdown of p27Kip1 alleviated cell senescence induced by oxidative stress or replicative stress. We also found that the over-expression of cofilin-1 induced the expression of p27Kip1 through transcriptional suppression of the transcriptional enhancer factors domain 1 (TEAD1) transcription factor. The TEAD1 transcription factor played a transrepressive role in the p27Kip1  gene promoter, as determined by the promoter deletion reporter gene assay. Interestingly, the down-regulation of TEAD1 was accompanied by the up-regulation of cofilin-1 in senescence. The knockdown and restoration of TEAD1 in young cells and old cells could induce and inhibit p27Kip1 and senescent phenotypes, respectively. Taken together, the current data suggest that cofilin-1/TEAD1/p27Kip1 signaling is involved in senescence-related morphological change and growth arrest.

Beneficial Effects of Hydroalcoholic Extract from Rosa Roxburghii Tratt Fruit on Hyperlipidemia in High-Fat-Fed Rats.

BACKGROUND: Rosa roxburghii Tratt fruit is extensively used as a medicinal and edible resource in China due to its unique bioactivities. In this research, we aimed to characterize its phenolic acid composition and investigate the potential hypolipidemic effect of this plant in a rat model of hyperlipidemia. METHODS: We evaluated the effects of hydroalcoholic extract of Rosa roxburghii Tratt fruit (HRT) on serum lipids, body weight, activities of lipoprotein metabolism and antioxidant enzymes, and gene expression of lipid metabolism in hyperlipidemic rats. RESULTS: HRT significantly reduced body weight gain and decreased serum and liver lipid levels in the hyperlipidemic rats. In addition, HRT treatment improved the activities of antioxidant enzymes, lipoprotein lipase, and hepatic lipase, downregulated the mRNA and protein expressions of sterol regulatory element-binding protein 1c and acetyl CoA carboxylase, and upregulated the mRNA and protein expressions of peroxisome proliferator-activated receptor α and low-density lipoprotein receptor in hepatic tissue. CONCLUSIONS: The results showed that Rosa roxburghii Tratt fruit is rich in phenolic acids, and that it exerted lipid lowering effects in the hyperlipidemic rats.

Evaluation of depression and anxiety in empty nose syndrome after surgical treatment.

OBJECTIVES/HYPOTHESIS: Empty nose syndrome (ENS) is often associated with psychological symptoms. With the absence of psychiatric instruments utilized in the current literature, the assessment of psychological disorder is limited, and the effectiveness of surgical intervention in improving such disorders in ENS are not well understood. The aim of this study was to evaluate the change in depression and anxiety before and after surgical treatment for ENS STUDY DESIGN: Prospective cohort study in a tertiary medical center. METHODS: ENS patients indicated for surgical treatment were enrolled. The Beck Depression Inventory II (BDI-II) and Beck Anxiety Inventory (BAI) questionnaires were completed by these patients before and after surgery to assess the level of depression and anxiety. RESULTS: A total of 20 patients completed the BDI-II and BAI before and after surgical treatment. A majority of patients developed depression and anxiety prior to surgical treatment. The severity of depression and anxiety were significantly decreased following the surgery; the mean scores of both the BDI-II and BAI improved from moderate severity to normal (both P < .001). The preoperative total score was found to be a powerful predictor for the postoperative improvement in both BDI-II and BAI (P < .001). Female patients had significantly worse preoperative scores (P = .005) and greater postoperative improvement (P = .012) in the BDI-II. CONCLUSIONS: Depression and anxiety are psychological disorders prevalent among ENS patients. Surgical treatment for ENS is effective in improving depression and anxiety. Patients with worse preoperative BDI-II and BAI scores as well as female patients may be better candidates for surgical intervention. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:1284-1289, 2016.

Effectiveness of high-intensity interval training on the mental and physical health of people with chronic schizophrenia.

BACKGROUND: Low-volume high-intensity interval training (HIIT) is emerging as a time-efficient exercise strategy for improving cardiorespiratory fitness and for controlling blood sugar levels and hypertension. In addition, patient acceptance of HIIT may improve adherence to exercise programs. This study evaluated the effectiveness of HIIT for improving the mental and physical health of people with chronic schizophrenia. METHODS: Twenty patients attending a psychiatric day care unit volunteered for an 8-week program of HIIT. Blood pressure, resting heart rate, body weight, body mass index, waist and hip circumference, and waist-to-hip ratio were measured weekly. The Positive and Negative Syndrome Scale score was recorded at baseline and at the end of the study. Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) scores were recorded every 2 weeks. RESULTS: Statistically significant changes occurred in the physical and mental parameters measured in the 18 patients who completed the study. Body weight, body mass index, resting heart rate, and pulse pressure decreased significantly. Mean arterial pressure and diastolic blood pressure increased significantly. Mental health scores improved, with the Negative Scale score decreasing from 31.17±5.95 to 27.78±3.57 (P<0.01) and the General Psychopathology Scale score from 14.28±2.16 to 13.00±1.72 (P<0.01). Positive Scale scores changed, but not significantly, from 12.28±2.27 to 12.33±2.00 (P=0.729). Scores on the BDI (from 19.56±15.28 to 15.89±14.33, P<0.001) and BAI (from 13.67±13.83 to 10.06±11.18, P=0.003) both improved significantly. CONCLUSION: This study demonstrated that HIIT has positive effects on the physical and mental health of patients with chronic schizophrenia.

Current controlled drug regulation in Taiwan.

In order to strengthen the management system of medical and scientific use of controlled drugs, Taiwan government referred to the three major drug control treaties of United Nation to formulate the "Controlled Drugs Act" in 1999. There are three kinds of system to manage controlled drugs, including (1) Schedule Management, (2) Licensing Regulation Management and (3) Diversion Control Management, such as the reporting and auditing systems. In this article, the management system of controlled drugs will be discussed thoroughly. Under the "Controlled Drugs Act", the controlled drugs are scheduled by the tendency of their habitual use, drug dependency, abuse, and social hazard. If violating the rule, the administrative sanction is applied. Cases of violations will also be given in this article.

PBAT based nanocomposites for medical and industrial applications.

Poly(butylene adipate-co-terephthalate) (PBAT) based nanocomposites were prepared by melt blending PBAT with 5 and 10 wt.% of clay nanoparticles (unmodified and modified montmorillonites, unmodified and modified fluoro-hectorites, and unmodified sepiolites). All nanocomposites showed a good level of clay distribution and dispersion into PBAT, especially nanocomposites with high clay chemical affinity with the polymer matrix. DSC results showed that addition of layered silicates slightly hindered kinetics and extent of crystallization of PBAT; however, sepiolite particles were able to promote polymer crystallization kinetics and the transformation of the PBAT crystal structure to a more ordered form. Similar increases in the thermal stability of PBAT in nitrogen and air were obtained upon addition of all clays, due to a barrier effect of the clays toward polymer decomposition product ablation. Preliminary biocompatibility tests indicated that PBAT based materials with 10% clay content have good biological safety and display almost no cytotoxicity. The addition of all nanofillers increased the hardness of PBAT matrix. The DMA analysis showed that all nanocomposites presented higher E' values than neat PBAT, indicating that addition of clays improved the mechanical properties of PBAT. For layered silicate nanocomposites, the main influencing factors on the thermo-mechanical properties appeared to be the aspect ratio and dispersion of clay nanoplatelets, rather than polymer/clay chemical affinity. The highest E' values of sepiolite based nanocomposites make this nanoparticle the most attractive material for tissue engineering and environmental industrial applications.

Tuning open-circuit voltage in organic solar cells by magnesium modified Alq(3).

The low molecular weight tris-(8-hydroxyquinoline) aluminum (Alq(3)) has been incorporated with magnesium (Mg) that altered the nature of its opto-electronic characteristics. The lowering of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) in Mg:Alq(3), compared to pure Alq(3), creates a stronger field (exceeding the exciton binding energy) at the donor-acceptor junction to dissociate the photo-generated exciton and also provides a low barrier for electron transport across the device. In an electron-only device (described in the text), a current enhancement in excess of 10(3), with respect to pure Alq(3), could be observed at 10 V applied bias. Optimized Mg:Alq(3) layer, when introduced in the photovoltaic device, improves the power conversion efficiencies significantly to 0.15% compared to the pure Alq(3) device. The improvement in the photovoltaic performance has been attributed to the superior exciton dissociation and carrier transport.

Non-Markovian dynamics of a microcavity coupled to a waveguide in photonic crystals.

In this paper, the non-Markovian dynamics of a microcavity coupled to a waveguide in photonic crystals is studied based on a semi-finite tight binding model. Using the exact master equation, we solve analytically and numerically the general and exact solution of the non-Markovain dynamics for the cavity coupled to the waveguide in different coupling regime. A critical transition is revealed when the coupling increases between the cavity and the waveguide. In particular, the cavity field becomes dissipationless when the coupling strength goes beyond a critical value, as a manifestation of strong non-Markovian memory effect. The result also indicates that the cavity can maintain in a coherent state with arbitrary small number of photons when it strongly couples to the waveguide at very low temperature. These properties can be measured experimentally through the photon current flowing over the waveguide in photonic crystals.

6-N,N-diphenylaminobenzofuran-derived pyran containing fluorescent dyes: a new class of high-brightness red-light-emitting dopants for OLED.

Dye-doped organic light-emitting diode of ITO/alpha-NPB (70 nm)/Bebq(2)-1 (7 nm)/BCP (5 nm)/Bebq(2) (33 nm)/LiF (1 nm)/Al (150 nm) shows red electroluminescence with the efficiency of 2.9 cd/A at 100 cd/m(2) and maximum brightness of 62000 cd/m(2). The physical organic aspects of the current-induced fluorescent quenching effect are discussed. [structure: see text]

Association of interleukin-6 gene G-174C polymorphism and plasma plasminogen activator inhibitor-1 level in Chinese patients with and without hypertension.

BACKGROUND: The interleukin-6 (IL-6) gene promoter G-174C polymorphism has been associated with insulin resistance, hypertension, and coronary artery disease; however, its relationship with plasma PAI-1 level has not yet been studied. METHODS: The G-174C genotypes and plasma PAI-1 antigen and activity were determined in 424 Chinese subjects, 207 with hypertension and 217 without, to study the possible effects of IL-6 genotypes on the regulation of PAI-1 and blood pressure. RESULTS: Hypertensive patients showed significantly greater percentage of IL-6 GG genotype (51.7% v 33.2%, P < .001) and G allele frequency (71.7% v 59%, P < .001) than normotensive subjects. The GG genotypic group had significantly higher plasma PAI-1 activity (16.1 +/- 9.8 v 12.3 +/- 7.5 IU/mL, P = .03) and antigen (32.4 +/- 23.2 v 23.2 +/- 13.5 ng/mL, P = .01) than the CC genotypic group, with intermediate values in the GC genotypic group (15.9 +/- 9.0 IU/mL and 29.1 +/- 17.5 ng/mL). Multiple linear regression analysis in all study subjects and in normotensive subjects documented an independent dominant effect of IL-6 G-174C gene polymorphism on plasma levels of PAI-1 activity (P = .02 and .01) and antigen (P = .02 and .03) after log transformation and adjustment for confounding factors. CONCLUSIONS: The present study showed a positive association of the IL-6 GG genotype with hypertension and with elevated plasma PAI-1 level in normotensive individuals in a Chinese population in Taiwan. Our findings suggest that the IL-6 gene promoter G-174C polymorphism may affect the regulation of PAI-1 and blood pressure through an inflammatory mechanism.