ArchiveThis article studies growth of China's listed biopharmaceutical companies. According to the Shenyin Wanguo industry classification criteria, 36 biopharmaceutical listed companies were selected, and 12 financial indicators were used to establish a growth index evaluation system. The factor analysis method was used to calculate the comprehensive growth scores of listed companies. The results show that the companies with comprehensive scores above 0.5 account for about 16.7%. The overall calculation result shows that the development space of the biopharmaceutical industry is relatively large, and the growth of China's biopharmaceutical listed companies still remain to improve. Combined with the results of factor analysis, we make recommendations, such as precise strategic planning and main business strengthening; improving talent introduction, increasing R&D investment; complying beneficial policies, and seizing development opportunities.
The relationship between the profit level and knowledge output of Chinese pharmaceutical manufacturing industry is empirically analyzed, aiming to provide reference for them to improve the profit level and knowledge output.
The relevant data of Chinese pharmaceutical manufacturing industry from 1995 to 2018 were selected, the total profit to represent the profit level and the number of valid invention patents to represent the knowledge output were used. The co-integration test was established using VAR model. Granger causality test, impulse response analysis and variance decomposition were used to explore the relationship between the two.
The profit level of Chinese pharmaceutical manufacturing industry has a long-term and significantly positive effect on knowledge output. The total profit increased by 1%, and the number of valid invention patents increased by 1.480 2%. This positive promotion effect has a certain lag, which is 2 years. Knowledge output also has a long-term significant positive promotion effect on profit level. The number of valid invention patents increased by 1%, and the total profit increased by 0.675 6%, but this promotion effect was not obvious.
This paper clarifies the usage frequency and the success rate of invalidation of various articles of patent law based on statistical analysis of the invalidation cases of drugs polymorphism patents in recent years. The paper also sumed up and sorted out some viewpoints involved in the corresponding cases, in order to provide a certain reference for pharmaceutical companies to apply for crystal patents.
As a cooperative innovation organization, the strategic alliance of industrial technology innovation is suitable for the overall innovation circumstance of pharmaceutical industry in China. By establishing the payment matrix of single game and repeated game, this paper analyzes the factors in the construction of trust mechanism of technology innovation strategic alliance in pharmaceutical industry. The results show that the information completeness, the number of games and the size of external forces are the key to the construction of trust mechanism, and the corresponding countermeasures are put forward. The results will provide some reference for the stable operation of strategic alliance.
“Guidance on Pharmaceutical Development of Paediatric Medicines” was issued by National Medical Products Administration on December 2020, aiming to encourage and facilitate the development and accessibility of paediatric medicines. This paper provides a detailed interpretation of the guidance, combined with the drafting process of the guidance and the current state of the pharmaceutical development level in China. The paper is intended to help applicants getting a better understanding of the scientific and technical requirements for pharmaceutical development of paediatric medicines.
In order to standardize the expression of the strength of Chinese patent medicine (CPM), the connotation, significance, characteristics and standard expression of CPM strengths are systematically summarized and analyzed in this paper. Furthermore, the related issues which need to be paid attention to in the implementation of “Technical Guideline for Strengths Expression of Chinese Patent Medicines” are discussed, and the following suggestions are put forward: According to the requirements of “Technical Guideline for Strengths Expression of Chinese Patent Medicine”, the theoretical amount (or marked amount) of prescription composition in each dosage should be indicated in the strengths of CPM. Drug strengths have nothing to do with the types of excipients used. It is suggested that the strengths should be reasonably expressed according to prescription composition, dosage form, usage and other characteristics of CPM. Drug strengths and capacity specification should be distinguished to facilitate the registration and management of drugs and to clarify the scope of powers of National Medical Product Administration and the Provincial Medical Product Administration. The strengths of CPM should be expressed according to the equivalent amount of decoction pieces in each dosage, which does not affect the check of capacity difference of the product.
To study the effect of arecoline on rat embryo cartilage development in vitro, so as to explore the embryonic teratogenicity of arecoline.
The embryonic limb buds of gestation day 14 timed-pregnant (GD14) rats were taken, and the forelimb buds were cultured in micromass (MM). The teratogenicity of arecoline was determined by the half-proliferation inhibitory concentration (IC50-P), the half-differentiation inhibitory concentration (IC50-D) and their ratios. The hindlimb buds were cultured in organ culture and randomly divided into five experimental groups, i.e., blank control (0 mg·mL-1 arecoline), low-dose (0.1 mg·mL-1 arecoline), middle-dose (1 mg·mL-1 arecoline), high-dose (10 mg·mL-1 arecoline), and positive control group (10 ng·mL-1 5-fluorouracil). They were cultured in vitro for 24, 72, and 120 h, respectively, and then harvested. Morphological scoring was performed under a stereo microscope, and followed by paraffin embedding, sectioning, HE staining and toluidine blue staining to observe the morphology cartilage cells. The effects of arecoline on the expression of bone morphogenetic protein 2 (BMP-2) in each group were studied by immunohistochemistry.
In MM model, according to the ECVAM prediction model, it was determined that arecoline was a developmental toxic chemical and a non-specific weak teratogen. In the limb bud organ model, 1 mg·mL-1 (medium dose) and above concentrations of can cause developmental toxicity arecoline to limb bud organs. Arecoline at 10 mg·mL-1 (high dose) can produce significant toxicity after 24 h of administration. The developmental status of each dose group has a significant measurement correlation after 72 h of culture. It can be seen from the pathological section results that arecoline further affected the proliferation and differentiation of proliferating chondrocytes and hypertrophic chondrocytes, thereby affecting the development of limb buds, palms and limbs. In the immunohistochemical analysis, the expression intensity of BMP-2 was related to the dose of arecoline. The larger the dose of arecoline used, the lower degree of positive expression obtained, reflecting the slowdown of chondrocyte proliferation and differentiation.
Arecoline at concentration over 1 mg·mL-1 inhibited the growth of rat embryonic limb buds and cartilage development in vitro. It can be preliminarily believed that arecoline has weak teratogenicity on embryonic development, and arecoline affected the expression of BMP-2 to inhibit the proliferation and differentiation of chondrocytes directly or indirectly.
Opioid analgesics are still irreplaceable for the treatment of moderate to severe pain, but the usage is limited because of their dependence and other adverse reactions. There is an urgent need for a new generation of efficient and safe opioid analgesics. At present, many studies on the interaction between μ and δ opioid receptors have been reported, and the existence of μ/δ dimer also provides a molecular basis for the receptor interaction. The design of molecules with double activation effect on μ and δ types is the new development direction of opioid drugs with strong analgesic effect and little or weak adverse reactions. In this paper, the research progress of μ/δ dual agonists in recent years is reviewed according to the classification of design strategy of μ/δ dual agonist.
Multitargeted tyrosine kinase inhibitors have shown significant therapeutic effects in antitumor therapy. As one of the most common side effects, hyperlipidemia has drawn increasing attentions. Five similar drugs were selected in this review in order to investigate the relationship between hyperlipidemia and therapeutic outcomes of multitargeted tyrosine kinase inhibitors and further illustrate the underlying mechanisms. The reported occurrences of hyperlipidemia in patients treated with them were summarized and possible mechanisms of treatment-induced hyperlipidemia were discussed, which would benefit for searching optimal targeted patients and designing rational therapeutic schedules to improve the survival benefits of patients with carcinomas.
Janus kinases (JAKs) are a class of non-receptor tyrosine kinases. In the past two decades, small-molecule Janus kinases inhibitors have gradually entered the public vision and received extensive attention from researchers. JAKs can regulate cell proliferation, differentiation, apoptosis, angiogenesis and immunity through JAK-STAT signal pathway formed by Janus kinases and their downstream signal transducers and activators of transcription. The inhibitors of JAKs can be used for prevention and treatment of autoimmune diseases, inflammatory reactions and malignant tumors. At present, nearly ten small-molecule Janus kinases inhibitors have been approved for marketing, and some others are in clinical research stage. This review summarizes the structure of Janus kinase, JAK-STAT signaling pathway, research and development progress and clinical application of JAKs inhibitors in recent years, providing useful reference for the further research and development of this class of inhibitors.
Based on the universality and significance of KRAS mutation in human cancer in recent years, the development of drugs targeting KRAS and KRAS-related drug screening have become the current research hotspots. The research strategies and development status of small-molecule KRAS inhibitors as well as existing effective small-molecule KRAS inhibitors were reviewed in this paper, in favor of providing new ideas and strategies for new drug development of KRAS mutated tumors.
To evaluate the efficacy and safety of injectable cefoperazone sodium and tazobactam sodium (6∶1) for the treatment of moderate to severe acute respiratory bacterial infections.
Totally 237 patients with respiratory tract infections were enrolled in a randomized, double blind, multi-centerand, parallel controlled study, in which 179 in experimental group and 58 in control group ([injectable cefoperazone sodium and tazobactam sodium (4∶1)]. During the screening period, cefoperazone sodium was uniformly injected for 3 d. During the treatment period, the experimental group was given the test drug 3.0 g by intravenous drip twice a day, and the control group was given 2.0 g of control drug by intravenous drip 3 times a day. The results of symptoms, signs, laboratory examination, chest X-ray examination and sputum bacterial culture were observed before and after treatment.
In experiment group and control group, the clinical cure rates were 87.65% and 78.85%, respectively. The bacterial clearance rates were 97.89% and 97.06%. Comprehensive efficacies were 86.32% and 73.53%. Incidences of adverse reaction were 13.79% (24/174 patients) in the test group and 14.29% (8/56 patients) in the control group. The main manifestations were elevated transaminase, leucopenia, eosinophilia and so on. All patients returned to normal after follow-up.
Injectable cefoperazone sodium and tazobactam sodium (6∶1) is proved to be safe and effective in the treatment of moderate to severe acute bacterial infection of respiratory system after large-scale phase Ⅲ clinical trial, providing an effective drug for the control of drug-resistant bacterial infection.
To investigate the in vivo antibacterial activity of fosfomycin combined with imipenem by using the infection model of Galleria mellonella with Klebsiella pneumonia.
Four strains of carbapenem resistant Klebsiella pneumonia (CRKP) and four strains of carbapenem sensitive Klebsiella pneumonia (CSKP) isolated from patients with bloodstream infection were collected from Wuxi Second People's Hospital Affiliated Nanjing Medical University on January to December 2020. The serotypes of Klebsiella pneumoniae capsule were typed by wzi gene sequencing. The virulence model of wax moth was used to calculate the 80% lethal dose of different strains in 96 h, then the antimicrobial susceptibility test of wax borer was carried out to analyze the antibacterial activity of fosfomycin combined with imipenem in vivo. Finally, the bacterial load was detected by the hemolymph test of wax borer.
Wzi gene sequencing showed that the serotypes of all the four CRKP strains were k64. The serotypes of four CSKP strains were K1, K2, K50 and k26, respectively. The in vivo antibacterial activity result of combined drugs showed that when the MIC value of imipenem was ≤8 mg·L-1 and fosfomycin ≤32 mg·L-1 in CRKP group, the antibacterial effect of the combination on two strains was significantly better than that of single drug, and the load clearance rate of hemolymph bacteria was higher. The antibacterial effect of the combination on K1-KP531 and K2-KP532 from high virulence in CSKP group was better than imipenem or fosfomycin alone, with the load clearance rate of hemolymph bacteria lower than that of low virulence strains in CSKP group.
When imipenem MIC≤8 mg·L-1 and fosfomycin was sensitive, fosfomycin and imipenem showed synergistic effect in the Klebsiella pneumoniae infection model of Galleria mellonella.
Network pharmacology and molecular docking technology were used to explore the possible mechanism of Compound Shuanghua oral liquid in the treatment of influenza.
The active ingredients of the compound Shuanghua oral liquid were searched through the literature, and the target points of the active ingredients were predicted based on the data platform, after which a compound-target network was constructed. The intersection of the active ingredient targets of the compound Shuanghua oral liquid and the influenza disease targets were taken to obtain the key targets to construct a drug-active ingredient-key target-disease network. Protein interaction analysis was conducted through shared core targets. The protein interaction core (PPI) moderate centrality (DC), intermediate centrality (BC), compact centrality (CC), eigenvector centrality (EC), network centrality (NC) and local average connectivity (LAC) parameters were analyzed to screen the core target genes. The selected main active components of the Compound Shuanghua oral liquid are molecularly docked with the influenza virus neuraminidase target.
Totally 80 active ingredients were obtained corresponding to the targets of Compound Shuanghua oral liquid; 616 action targets, 2 574 influenza-related genes, 243 key targets of Compound Shuanghua oral liquid were predicted in the treatment of influenza, and 23 key core targets were screened from protein interaction core (PPI) analysis, including proto-oncogene tyrosine protein kinase Src (SRC), tyrosine protein kinase JAK1 (JAK1), etc. Enrichment analysis showed the common biological process of compound Shuanghua oral liquid and influenza, which is related to inflammation, cell proliferation and apoptosis. The main pathways of action are tumor necrosis factor signaling pathway, interleukin-17 signaling pathway, apoptosis signaling pathway, Toll-like receptor signaling pathway, and C-type lectin receptor signaling Access, etc. The results of molecular docking show that the main active ingredients have good binding activity with influenza virus neuraminidase.
The mechanism of action for Compound Shuanghua oral liquid may mainly be inhibiting neuraminidase activity, inflammatory response and apoptosis related factors and pathways, acting against influenza, reducing the inflammatory response caused by influenza, so as to achieve the purpose of treating influenza.
To explore the effects of histone deacetylase inhibitor chidamide on the proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) of murine triple-negative breast cancer 4T-1 cells.
CCK-8 method was performed to analyze the effects of chidamide on the proliferation of 4T-1 cells; flow cytometry to detect the effects of chidamide on the cell cycle and apoptosis of 4T-1 cells; Western Blot to detect intracellular histone deacetylase 5, lysine-specifc demethylase 1 and EMT-related proteins E-cadherin, Vimentin, MMP-9, MMP-2 expression; Transwell method to analyze the effect of chidamide on the migration and invasion of 4T-1 cells; HE staining method to observe the pulmonary metastasis of tumor tissues and the toxicity of chidamide on mice; ELISA method to analyze the effect of chidamide on the immune system in mice.
The results of CCK-8 method showed that chidaniline had the ability to prominently inhibit the proliferation of 4T-1 cells, and its 24 h IC50 value was 43.42 μmol·L-1. Chidamide could induce G2/M phase arrest and apoptosis of 4T-1 cells. At the same time, it was found that chidamide distinctly down-regulated the mRNA and protein expression of HDAC5 in 4T-1 cells, but only down-regulated the protein expression of LSD1; in addition, the expressions of EMT-related factors E-cadherin, vimentin, MMP-9, MMP-2 were notably down-regulated. Transwell experiments found that chidamide obviously inhibited the migration and invasion of 4T-1 cells. In vivo, chidamide of 10 mg·kg-1 showed an outstanding suppression effect on the proliferation and pulmonary metastasis of 4T-1 cells in tumor-bearing mice, but did not affect the body weight and the morphology of heart, liver, and kidney tissues.
Chidamide can depress the expression of HDAC5, LSD1 and EMT-related proteins E-cadherin, Vimentin, MMP-9, MMP-2, and inhibit the proliferation and migration of 4T-1 cells both in vivo and in vitro, indicating that chidamide has a great potential for clinical anti-triple-negative breast cancer treatment.
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