Evaluating Fda Generic Approval After 2017 Agency Initiatives

Importance: Generic drugs play an essential role in the US healthcare system, providing less costly alternatives to branded drugs that are equally effective and safe. The US Food and Drug Administration (FDA) regulatory policies influence the standards for generic drug approval. In 2017, the FDA instituted several initiatives to promote generic drug approval, particularly focused on those with limited competition. Objective: To determine whether the initiatives begun by FDA in 2017 were associated with greater numbers of approvals of generic drugs with limited generic competition and histories of drug shortage. Study Sample and Design: We conducted a cross-sectional study of new drug applications (ANDA) approved by FDA during two one-year periods: July 1st, 2016 to June 30th, 2017 (before the initiatives) and January 1st, 2018 to December 31st, 2018 (after the initiatives). ANDAs were also characterized on the basis of their initial approval year, priority review status and orphan designation status for the original new drug, World Health Organization (WHO) essential medicine status, therapeutic area, drug complexity. Main outcomes and measures: We determined (1) generic competition at the time of ANDA approval; (2) history of drug shortage during the five years before ANDA approval. Results: A total of 1,410 ANDAs were identified, 661 prior to the FDA’s initiatives, 749 afterwards. Overall, there were 336 (23.8%) ANDAs originally approved with priority review status, 183 (13.0%) ANDAs previously approved with orphan drugs status. 262 (18.6%) ANDAs were listed as essential medicine by WHO, and 265 (18.8%) generic approvals were categorized as complex generic drugs. In the pre-period, 234 (35.4%) of the ANDAs approved were determined to have limited competition (≤3 ANDAs), as compared to 237 (31.6%) afterwards (p=0.14). Similarly, 242 (36.6%) of the ANDAs approved in the pre-period had been in shortage during the five years before ANDA approval, as compared to 282 (37.7%) afterwards (p=0.69). In multivariate analysis, approval of generics with limited competition was significantly less likely during the period after the FDA’s initiatives when compared to before (OR=0.76; 95% CI, 0.60-0.97; p=0.02), but there was no significant difference in the approval of generics with histories of drug shortage (OR=1.09; 95% CI, 0.86-1.38; p=0.46). Conclusion and relevance: The FDA’s initiatives in 2017 to promote generic drug approvals had limited impact on the approval of ANDAs for drugs that lacked generic competition and had histories of drug shortage. Additional efforts are needed to promote approval of generic drugs with limited competition

Relationship between trade enhancement, firm characteristics and CSR: key mediating role of green investment

Organisations are increasingly implementing socially responsible strategies in response to increased rivalry in trade and commercial activities. Organisations are expected to increase their profitability through corporate social responsibility (CSR). Hence, this study investigates the relationship between trade enhancement, firm characteristics, and CSR. Further, this study also explored the critical mediating role of green investment (GI). The data were collected from 456 respondents from manufacturing organisations in China through a questionnaire and analysed by partial least square structural equation modelling (PLS-SEM). PLS-SEM results revealed that trade enhancement has a significant positive effect on CSR and GI. GI also has a significant effect on CSR. In comparison, firm characteristics do not have a substantial impact on CSR and GI. However, GI significantly mediates the relationship between trade enhancement, firm characteristics, and CSR. This study provides insights to managers and stakeholders regarding GI and CSR in the Chinese manufacturing industry. Lastly, this study proposes theoretical and practical implications andoffers valuable information for practitioners and policymakers

Sparse Matrix for ECG Identification with Two-Lead Features

Electrocardiograph (ECG) human identification has the potential to improve biometric security. However, improvements in ECG identification and feature extraction are required. Previous work has focused on single lead ECG signals. Our work proposes a new algorithm for human identification by mapping two-lead ECG signals onto a two-dimensional matrix then employing a sparse matrix method to process the matrix. And that is the first application of sparse matrix techniques for ECG identification. Moreover, the results of our experiments demonstrate the benefits of our approach over existing methods

Transitional Zone Index and Intravesical Prostatic Protrusion in Benign Prostatic Hyperplasia Patients: Correlations according to Treatment Received and Other Clinical Data

Purpose: The aim of this research was to assess the value of the transitional zone index (TZI) and intravesical prostatic protrusion (IPP) from transrectal ultrasonography in evaluating the severity and progression of disease by analyzing the relationship between the 2 parameters and symptoms, clinical history, and urodynamics in benign prostatic hyperplasia (BPH) patients undergoing different treatment. Materials and Methods: A total of 203 patients receiving medication and 162 patients who underwent transurethral resection of the prostate because of BPH were enrolled in this retrospective analysis. The clinical history and subjective and objective examination results of all patients were recorded and compared after being classified by TZI and IPP level. Linear regression was used to find correlations between IPP, TZI, and urodynamics. Results: The 2 parameters were found to differ significantly between patients receiving medication and patients undergoing surgical therapy (p<0.05). PSA, maximum flow rate (Qmax), detrusor pressure at Qmax (PdetQmax), and the bladder outlet obstruction index (BOOI) differed according to various TZI levels (p<0.05). In addition, the voiding symptom score, Qmax, and BOOI of subgroups with various IPP levels were also significantly different (p<0.05). Both TZI and IPP had significant effects on Qmax, BOOI, and PdetQmax (p<0.05) and the incidence of acute urinary retention (p=0.000). Conclusions: The results demonstrated that both TZI and IPP had favorable value for assessing severity and progression in patients with BPH. Further studies are needed to confirm whether the two parameters have predictive value in the efficacy of BPH treatment and could be considered as factors in the selection of therapy

Auto-adhesive transdermal drug delivery patches using beetle inspired micropillar structures

The patch described in this paper combines the principles of wet adhesion, which is a widely adopted biological adhesion system in nature, with transdermal drug delivery. A biologically inspired micropillar patch was fabricated that is self-adhesive, reusable, and can sustain a controlled drug release. We successfully preloaded the commercial non-steroidal anti-inflammatory generic drug unguents indomethacin, ketoprofen, diclofenac sodium and etofenamate into a polydimethylsiloxane elastomeric matrix and fabricated drug-containing micropillar patches. When examining the drug release kinetics and friction of the patches, we observed that these drug unguents can be released calculably and regularly for several days. Additionally, the drug unguents released from the patch to its attached surface are critical to increase the strength of the patch's adhesion, which is based on capillary attractive forces and is inspired by beetle feet. Here, we create a novel system combining biomimetics and drug delivery that can be modified for use across the biomedical and engineering spectra. Motivation: the objective of the present study was to characterize a micropillar PDMS patch that was inspired by a beetle's wet adhesion as a platform for conducting in vitro release studies. Commercially available non-steroid anti-inflammatory drugs (NSAIDs) were used as the model drugs for our delivery systems. An emphasis was put on quantitatively evaluating the drug release and friction manifestation of these patches

A multi-targeted approach to suppress tumor-promoting inflammation

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes

Small-Molecule Synthetic Compound Norcantharidin Reverses Multi-Drug Resistance by Regulating Sonic Hedgehog Signaling in Human Breast Cancer Cells

Multi-drug resistance (MDR), an unfavorable factor compromising treatment efficacy of anticancer drugs, involves upregulated ATP binding cassette (ABC) transporters and activated Sonic hedgehog (Shh) signaling. By preparing human breast cancer MCF-7 cells resistant to doxorubicin (DOX), we examined the effect and mechanism of norcantharidin (NCTD), a small-molecule synthetic compound, on reversing multidrug resistance. The DOX-prepared MCF-7R cells also possessed resistance to vinorelbine, characteristic of MDR. At suboptimal concentration, NCTD significantly inhibited the viability of DOX-sensitive (MCF-7S) and DOX-resistant (MCF-7R) cells and reversed the resistance to DOX and vinorelbine. NCTD increased the intracellular accumulation of DOX in MCF-7R cells and suppressed the upregulated the mdr-1 mRNA, P-gp and BCRP protein expression, but not the MRP-1. The role of P-gp was strengthened by partial reversal of the DOX and vinorelbine resistance by cyclosporine A. NCTD treatment suppressed the upregulation of Shh expression and nuclear translocation of Gli-1, a hallmark of Shh signaling activation in the resistant clone. Furthermore, the Shh ligand upregulated the expression of P-gp and attenuated the growth inhibitory effect of NCTD. The knockdown of mdr-1 mRNA had not altered the expression of Shh and Smoothened in both MCF-7S and MCF-7R cells. This indicates that the role of Shh signaling in MDR might be upstream to mdr-1/P-gp, and similar effect was shown in breast cancer MDA-MB-231 and BT-474 cells. This study demonstrated that NCTD may overcome multidrug resistance through inhibiting Shh signaling and expression of its downstream mdr-1/P-gp expression in human breast cancer cells

Notolutesins A–J, Dolabrane-Type Diterpenoids from the Chinese Liverwort Notoscyphus lutescens

Ten new dolabrane-type diterpenoids, notolutesins A–J (1–10), were isolated from the Chinese liverwort Notoscyphus lutescens, along with four known compounds. The structures of the new compounds were established on the basis of extensive spectroscopic data, and that of 1 was confirmed by single-crystal X-ray crystallography. The absolute configuration of 1 was determined by comparing its experimental and calculated electronic circular dichroism spectra. All of the isolates were evaluated for their cytotoxicity against a small panel of human cancer cell lines, and compound 1 exhibited an IC50 value of 6.2 μM against the PC3 human prostate cancer cell line

Multifunctional Adaptive NS1 Mutations Are Selected upon Human Influenza Virus Evolution in the Mouse

The role of the NS1 protein in modulating influenza A virulence and host range was assessed by adapting A/Hong Kong/1/1968 (H3N2) (HK-wt) to increased virulence in the mouse. Sequencing the NS genome segment of mouse-adapted variants revealed 11 mutations in the NS1 gene and 4 in the overlapping NEP gene. Using the HK-wt virus and reverse genetics to incorporate mutant NS gene segments, we demonstrated that all NS1 mutations were adaptive and enhanced virus replication (up to 100 fold) in mouse cells and/or lungs. All but one NS1 mutant was associated with increased virulence measured by survival and weight loss in the mouse. Ten of twelve NS1 mutants significantly enhanced IFN-β antagonism to reduce the level of IFN β production relative to HK-wt in infected mouse lungs at 1 day post infection, where 9 mutants induced viral yields in the lung that were equivalent to or significantly greater than HK-wt (up to 16 fold increase). Eight of 12 NS1 mutants had reduced or lost the ability to bind the 30 kDa cleavage and polyadenylation specificity factor (CPSF30) thus demonstrating a lack of correlation with reduced IFN β production. Mutant NS1 genes resulted in increased viral mRNA transcription (10 of 12 mutants), and protein production (6 of 12 mutants) in mouse cells. Increased transcription activity was demonstrated in the influenza mini-genome assay for 7 of 11 NS1 mutants. Although we have shown gain-of-function properties for all mutant NS genes, the contribution of the NEP mutations to phenotypic changes remains to be assessed. This study demonstrates that NS1 is a multifunctional virulence factor subject to adaptive evolution

Modulation of hepatic inflammation and energy-sensing pathways in the rat liver by high-fructose diet and chronic stress

Purpose High-fructose consumption and chronic stress are both associated with metabolic inflammation and insulin resistance. Recently, disturbed activity of energy sensor AMP-activated protein kinase (AMPK) was recognized as mediator between nutrient-induced stress and inflammation. Thus, we analyzed the effects of high-fructose diet, alone or in combination with chronic stress, on glucose homeostasis, inflammation and expression of energy sensing proteins in the rat liver. Methods In male Wistar rats exposed to 9-week 20% fructose diet and/or 4-week chronic unpredictable stress we measured plasma and hepatic corticosterone level, indicators of glucose homeostasis and lipid metabolism, hepatic inflammation (pro- and anti-inflammatory cytokine levels, Toll-like receptor 4, NLRP3, activation of NF kappa B, JNK and ERK pathways) and levels of energy-sensing proteins AMPK, SIRT1 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha). Results High-fructose diet led to glucose intolerance, activation of NF kappa B and JNK pathways and increased intrahepatic IL-1 beta, TNF alpha and inhibitory phosphorylation of insulin receptor substrate 1 on Ser(307). It also decreased phospho-AMPK/AMPK ratio and increased SIRT1 expression. Stress alone increased plasma and hepatic corticosterone but did not influence glucose tolerance, nor hepatic inflammatory or energy-sensing proteins. After the combined treatment, hepatic corticosterone was increased, glucose tolerance remained preserved, while hepatic inflammation was partially prevented despite decreased AMPK activity. Conclusion High-fructose diet resulted in glucose intolerance, hepatic inflammation, decreased AMPK activity and reduced insulin sensitivity. Chronic stress alone did not exert such effects, but when applied together with high-fructose diet it could partially prevent fructose-induced inflammation, presumably due to increased hepatic glucocorticoids