Impact of China’s National Centralized Drug Procurement Policy on pharmaceutical enterprises’ financial performance: a quasi-natural experimental study

IntroductionIn China, the interest relationship between pharmaceutical enterprises and medical institutions has harmed the healthy development of pharmaceutical enterprises. In November 2018, the National Centralized Drug Procurement (NCDP) policy was published. The NCDP policy severs the interest relationship and significantly impacts on pharmaceutical enterprises’s financial performance.MethodsUsing the implementation of China’s National Centralized Drug Procurement (NCDP) policy as a quasi-natural experiment, this study evaluated the impact of participation in the NCDP policy on pharmaceutical enterprises’ financial performance. We developed a difference-in-difference model to estimate the change in financial performance after NCDP implementation, based on financial data on Chinese listed pharmaceutical enterprises.ResultsWe found that the bid-winning enterprises’ financial performance significantly improved after participating in NCDP. This may be related to lower costs, market share expansion, and increased research and development investment by the bid-winning enterprises.DiscussionTo further promote the high-quality development of pharmaceutical enterprises in China, the government should expand the variety of drugs on the NCDP list (NCDP drugs), while improving the drug patent protection system and the policies to support the bid-winning enterprises

Association between genetic polymorphisms of cytochrome P450 2C19 and the risk of cerebral ischemic stroke in Chinese

BACKGROUND: Cytochrome P450 (CYP) 2C19 is a very important drug metabolizing enzyme. Although the single nucleotide polymorphisms (SNPs) of CYP2C19 G681A and G636A have been suggested that they may increase the incidence of cardiovascular events, the relationship between SNPs in CYP2C19 and cerebral ischemic stroke (CIS) are unclear. The aim of this study was to investigate the correlation between the distribution of G681A and G636A polymorphisms in CYP2C19 gene and the risk of CIS in Chinese. METHODS: The peripheral blood DNA was extracted from 299 patients with CIS and 295 healthy controls. The genotyping was conducted using the polymerase chain reaction-restriction fragment length polymorphism. The sampled sequencing was applied to verify the correctness of genotyping results. Both the genotype and allele distributions were compared in patients with CIS and healthy controls. RESULTS: The frequencies of CYP2C19 681AA (11.7% vs. 2.7%; P = 0.000), 636AA (4.0% vs. 0.7%; P = 0.007), 636AG (7.0% vs. 2.2%; P = 0.038) genotype, CYP2C19 681A (30.9% vs. 20.8%; P = 0.000) and 636A (13.0% vs. 5.8%; P = 0.000) allele in the CIS group are significantly higher than those in the controls. The frequencies of CYP2C19 681AA (16.7% vs. 8.6%; P = 0.036), CYP2C19 636AA (7.0% vs. 2.2%; P = 0.038) genotype, CYP2C19 681A (36.4% vs. 27.6%; P = 0.023) and CYP2C19 636A (17.5% vs.10.3%; P = 0.010) allele in the recurrent stroke group are significantly higher than those in the first onset group. Multivariate logistic regression analysis of risk factors for cerebral ischemic stroke and recurrent stroke respectively suggests that the CYP2C19 681AA genotype may be an independent risk factor for CIS (OR = 6.179, 95% CI: 2.285 ~ 16.708; P = 0.000) and recurrent stroke (OR = 2.305, 95% CI: 1.121 ~ 4.743; P = 0.023). CONCLUSIONS: The AA genotype and A allele of CYP2C19 G681A may be related to the occurrence and recurrence of cerebral ischemic stroke

Dissecting the roles of DR4, DR5 and c-FLIP in the regulation of Geranylgeranyltransferase I inhibition-mediated augmentation of TRAIL-induced apoptosis

<p>Abstract</p> <p>Background</p> <p>Geranylgeranyltransferase I (GGTase I) has emerged as a cancer therapeutic target. Accordingly, small molecules that inhibit GGTase I have been developed and exhibit encouraging anticancer activity in preclinical studies. However, their underlying anticancer mechanisms remain unclear. Here we have demonstrated a novel mechanism by which GGTase I inhibition modulates apoptosis.</p> <p>Results</p> <p>The GGTase I inhibitor GGTI-298 induced apoptosis and augmented tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human lung cancer cells. GGTI-298 induced DR4 and DR5 expression and reduced c-FLIP levels. Enforced c-FLIP expression or DR5 knockdown attenuated apoptosis induced by GGTI-298 and TRAIL combination. Surprisingly, DR4 knockdown sensitized cancer cells to GGTI298/TRAIL-induced apoptosis. The combination of GGTI-298 and TRAIL was more effective than each single agent in decreasing the levels of IκBα and p-Akt, implying that GGTI298/TRAIL activates NF-κB and inhibits Akt. Interestingly, knockdown of DR5, but not DR4, prevented GGTI298/TRAIL-induced IκBα and p-Akt reduction, suggesting that DR5 mediates reduction of IκBα and p-Akt induced by GGTI298/TRAIL. In contrast, DR4 knockdown further facilitated GGTI298/TRAIL-induced p-Akt reduction.</p> <p>Conclusions</p> <p>Both DR5 induction and c-FLIP downregulation contribute to GGTI-298-mediated augmentation of TRAIL-induced apoptosis. Moreover, DR4 appears to play an opposite role to DR5 in regulation of GGTI/TRAIL-induced apoptotic signaling.</p

Surface-potential-based compact model for the gate current of p-GaN Gate HEMTs

The gate leakage current of p-GaN gate HEMTs is modeled based on surface potential calculations. The model accurately describes the bias and temperature dependence of the gate leakage. Thermionic emission is the main mechanism of the gate current in forward bias operation while hopping transport component is the main mechanism of gate current in reverse bias operation. This newly developed gate current model was implemented in Verilog-A. A good agreement between the simulations and experimental data demonstrates the accuracy of the model

Epileptiform response of CA1 neurones to convulsant stimulation by cyclothiazide, kainic acid and pentylenetetrazol in anaesthetized rats

AbstractWe have previously reported that cyclothiazide (CTZ) evokes epileptiform activities in hippocampal neurons and induces seizure behavior. Here we further studied in vivo the sensitivity of the hippocampal CA1 neurons in response to CTZ in epileptogenesis in comparison with two other classic convulsants of kainic acid (KA) and pentylenetetrazol (PTZ).CTZ administered intracerebral ventricle (i.c.v.) induced epileptiform activities from an initial of multiple evoked population spikes, progressed to spontaneous spikes and finally to highly synchronized burst activities in hippocampal CA1 neurons. PTZ, when given by subcutaneously, but not by intracerebral ventricle injection, evoked similar progressive epileptiform activities. In contrast, KA given by i.c.v. induced a quick development of epileptiform burst activities and then shortly switched to continuous high frequency firing as acute status epilepticus (ASE). Pharmacologically, alprazolam, a high-potency benzodiazepine ligand, inhibited CTZ and PTZ, but not KA, induced epileptiform burst activities while GYKI 53784, an AMPA receptor antagonist, suppressed CTZ and KA but not PTZ evoked epileptiform activities.In conclusion, CTZ and PTZ induced epileptiform activities are most likely to share a similar progressive pattern in hippocampus with GABAergic mechanism dominant in epileptogenesis, while CTZ model involves additional glutamate receptor activation. KA induced seizure in hippocampus is different to that of both CTA and PTZ. The results from this study indicate that hippocampal neurons respond to various convulsant stimulation differently which may reflect the complicated causes of the seizure in clinics

Jasmine (Jasminum grandiflorum) Flower Extracts Ameliorate Tetradecanoylphorbol Acetate Induced Ear Edema in Mice

Published data from in vitro assays support the anti-inflammatory effects of jasmine (Jasminum grandiflorum Linn.) but limited studies are reported in animal models. Herein, the anti-inflammatory effects of jasmine flower extracts (JFEs) including ethanol extract (JF-EE), petroleum ether extract (JF-PEE), ethyl acetate extract (JF-EAE), and n-butanol extract (JF-BE) were evaluated in a mouse ear edema model. Acute mouse ear skin inflammation was induced by tetradecanoylphorbol acetate (TPA; 125 µg/mL) and then treated with JFEs (100 mg/mL) or dexamethasone (DEX; 6.25 mg/mL; as a positive control). Jasmine flower extracts alleviated ear edema by reducing TPA-increased ear thickness and ear weight by 30.8% to 64.1% and 24.0% to 47.1%, respectively, whereas DEX showed comparable activity (by 71.8% and 49.1%, respectively). Their anti-inflammatory effects were supported by data from the immunohistochemical assays. Jasmine flower extracts reduced the inflammatory cells (from 5.5- to 9.5-fold) and the expressions of inflammation related enzymes including cyclooxygenase-2 and inhibitor of kappa-B kinase (from 1.9- to 2.8-fold and from 7.1- to 11.0-fold, respectively). Findings from this study showed that JFEs were able to ameliorate TPA-induced mouse skin inflammation. However, future studies on the underlying mechanisms of jasmine flower’s anti-inflammatory effects are warranted

The complete chloroplast genome sequence of Rhododendron fortunei: structural comparative and phylogenetic analysis in the Ericaceae family

Rhododendron fortunei (Ericaceae) possesses valuable horticultural and medicinal values. However, the genomic information on R. fortunei is very limited. In this study, the complete chloroplast genome (cp) of R. fortunei was assembled and annotated, SSR loci were characterised, comparative genomic analysis was carried out, and phylogenetic research was also performed. The results showed that the R. fortunei cp genome was of a typical quadripartite structure (200,997 bp). The lengths of the large single copy region (LSC), the inverted repeat regions (IR), and the small single copy region (SSC) were 109,151 bp, 2,604 bp, and 44,619 bp, respectively. A total of 147 unique genes were identified, including 99 protein-coding genes, 42 tRNA genes, and 6 rRNA genes, respectively. Leucine (11.51%) and cysteine (1.15%) were the highest and lowest representative amino acids, respectively. The total of 30 codons with obvious codon usage bias were all A/U-ending codons. Among the 77 simple sequence repeats, the majority were mononucleotide A/T repeats located in the intergenic spacer region. Five gene regions showed high levels of nucleotide diversity (Pi > 0.03). The comparative genome analysis revealed 7 hotspot intergenic regions (trnI-rpoB, trnTrpl16, rpoA-psbJ, rps7-rrn16, ndhI-rps16, rps16-rps19, and rrn16-trnI), showing great potential as molecular makers for species authentication. Expansion and contraction were detected in the IR region of the R. fortunei cp genome. In the phylogenetic tree, R. fortunei was closely related to R. platypodum. This research will be beneficial for evolutionary and genetic diversity studies of R. fortunei and related species among the Ericaceae family

Karyotype and DNA-Methylation Responses in Myelodysplastic Syndromes following Treatment with Traditional Chinese Formula Containing Arsenic

We have previously shown that arsenic-containing Chinese herbal formula, Qing-Huang powder capsule (containing tetraarsenic tetrasulfide, As4S4), is effective in the treatment of myelodysplastic syndrome (MDS); yet the underlined mechanisms remain unclear. In this study, using standard cytogenetic analysis (G-banded) and global DNA methylation method (ChIP-on-chip assays), we aimed to determine the effect of arsenic-containing Chinese herbal formula on karyotype status and the genomic methylation level in primarily diagnosed MDS patients. Correlation of aberrant DNA methylation and chromosome aberrations in MDS was also investigated. We found that the number of genes with aberrant DNA methylation was highest in MDS patients with normal karyotype, followed by trisomy 8 karyotype, and relatively low in patients with cytogenetic abnormalities other than trisomy 8. Treatment with arsenic-containing Chinese herbal formula had no effects on karyotype status, but resulted in a significant genome-wide demethylation. Our research uncovered a DNA demethylating activity of arsenic-containing Chinese herbal formula in the treatment of MDS