ArchiveThis paper analyzed the relationship between the early resolution of patent disputes and the patent linkage regime in United States and conducted research on the judicial application of “artificial infringement” under § 271(e)(2), the disputes and legal reasoning of United States courts in regard to the issues that whether the Paragraph Ⅳ statement is a necessary prerequisite to determine jurisdiction and whether to extend the infringement object to the later-issued patents. Based on the perception of the function of the mechanism for early resolution of patent disputes in the United States, the status quo of China's pharmaceutical reformation policy, its legislation and legal practice in the field of pharmaceuticals, this paper proposed a better path to build the dispute resolution mechanism under the ongoing drug patent linkage system in China, that is, to solve the patent disputes between the brand-name company and the generic drug company in the specific case related to disputes over confirming the absence of infringement on patent rights, and to provide opportunity for the drug patentees to petition administrative objections.
Lactotol was first registered by Novartis in Switzerland in 1985. Its trade name is Importal. It is used for the treatment of hyperammonemia caused by hepatic encephalopathy. On February 12, 2020, it was approved by the US FDA for the treatment of chronic idiopathic constipation in adults. Its trade name is Pizensy. Latitol can increase the defecation frequency of patients, and the treatment efficacy for chronic idiopathic constipation in adults is not inferior to that of rubiprostone. The most common adverse reactions are upper respiratory tract infection, abdominal distension and diarrhea. The mechanism of action, pharmacokinetics, effectiveness, and safety of lactitol were reviewed in this article.
In August 2020, the Center for Drug Evaluation of National Medical Products Administration issued the “Guideline of the research and validation of the terminal sterilization and aseptic process of chemical injections (for trial implementation)”. In this article, based on the draft and revision of the guideline, some important glossaries of the steam sterilization process and decision tree for sterilization choices for chemical injections were clarified, concerns of the research and validation of the steam sterilization process were discussed, and the main points of amendments and the new contents were analyzed and sorted out, in order to provide more references for the follow-up study on consistency evaluation of generic chemical injections.
To study the anti-hyperuricemic efficacy, assess the safety of compound CC18013, and explore its possible mechanism related to xanthine oxidase (XOD) inhibition.
By establishing the acute and chronic hyperuricemic mice models and use of febuxostat as the positive control drug, the effect of CC18013 on serum uric acid levels was detected; the XOD inhibiting ability of CC18013 was determined using in vitro XOD model. The effect of CC18013 on serum and tissue XOD activity in hyperuricemic mice was measured. The interaction between CC18013 and XOD was analyzed by molecular-docking. The body weight change and general state of the mice were observe after a single dose treatment of CC18013.
CC18013 dose-dependently reduced serum uric acid levels in vivo, with the lowest effective dose of 0.5 mg·kg-1. Its IC50 value of XOD inhibition in vitro was 4.6 nmol·L-1. Moreover, it significantly inhibited XOD activity in liver and small intestine. Molecular-docking result indicated that it had a strong interaction with XOD. It showed no evident toxicity under the single dose of 500 mg·kg-1.
CC18013 is an XOD inhibitor with strong anti-hyperuricemic effect and high safety.
Depression is a type of mental illness that seriously endangers the physical and mental health of humans. The clinical manifestations are marked and lasting symptoms such as depressed mood, low mood, slow thinking and other symptoms. However, its pathogenesis and the therapeutic target is still unclear. Exosomes are lipid bilayer cystic vesicles carrying biological information molecules such as lipids, proteins, DNA, and miRNAs, which mediate information transmission between cells and regulate the expression of related signal pathways. At present, the study of exosomal miRNAs in depression is relatively extensive, providing new application prospects for early diagnosis and treatment of depression. In this paper, we mainly reviewed the latest research progress in exosomal miRNAs in depression.
In recent years, the incidence of malignant tumors has been increasing. After conventional treatments such as surgical resection, chemotherapy, and radiotherapy, many patients' conditions are still not effectively controlled. Therefore, exploring new treatment methods has become the focus of tumor prevention and control. The role of photoimmunotherapy (PIT) in solid tumor research is becoming more and more prominent. Photoimmunoconjugate (PIC) has the ability of tumor-specific recognition and high cytotoxicity. This article reviews the progress in the development of such novel molecular targeted drugs in the past decade, and the results from the study of using porphyrin, chlorin e6 (Ce6), phthalocyanine dye (IR700) and other photosensitizer conjugated monoclonal antibodies (MAbs) as photosensitizing drugs were discussed respectively.
As a new drug carrier, albumin nanoparticles have many characteristics, such as biodegradability, biocompatibility, non-toxicity and non-immunogenicity, and it has shown unique tumor targeting mechanism. Most of anti-tumor drugs are water-insoluble, poor drugability of preparation, and of high adverse reaction. For the purpose of changing its physical and chemical properties and reducing the adverse effects, albumin nanoparticles are often applied as carrier to deliver anti-tumor drug. The surface modification of albumin nanoparticles and coating of plasma membrane greatly enhance the drug targeting, improve the solubility, reduce the toxicity, prolong in vivo circulation, and even enhance the efficacy of drugs. In this paper, the preparation process and surface modification of albumin nanoparticles are reviewed in order to provide reference for the study of related drugs of albumin nanoparticles.
Hepatocellular carcinoma (HCC) is the main pathological type of primary liver cancer, accounting for 75%~85%, and most of the patients are diagnosed late with poor prognosis. The treatment choices of advanced HCC are limited, sorafenib and other targeted drugs can only prolong the overall survival of patients to about one year, which is difficult to meet the clinical needs, so it is urgent to develop new treatment methods. Nivolumab further prolongs the overall survival of patients, and it was the first immune checkpoint inhibitor (ICI) approved for the treatment of advanced HCC, which also opened the prelude of immunotherapy for advanced HCC. Subsequent clinical studies indicated that immune checkpoint inhibitors (ICIs) combined with other therapies such as targeted therapy, local treatment, systemic chemotherapy could not only enhance the efficacy, but also had no significant increase in adverse reactions. In conclusion, ICIs have broad application prospects in the treatment of advanced HCC, and combination therapy will be the main treatment for advanced HCC.
Paclitaxel, the first natural plant-derived chemical approved by the US FDA, is a broad-spectrum antitumor drug with good antitumor activity. However, due to its complex chemical structure, disadvantages such as poor water solubility and poor absorption limit its widespread clinical application. Therefore, how to improve its water solubility, bioavailability and targeting effect in tumor tissues has been a difficult and important issue to be solved. In this article, we briefly reviewed the research progress of paclitaxel prodrugs that improve its water solubility and targeting in recent years.
Rheumatism immunity disease is one of the chronic diseases which affect health seriously. A series of biological agents targeting cytokines have greatly improved the prognosis and quality of life of patients, but still can not meet the needs of disease treatment, thus searching new drugs has become an important task in the treatment of rheumatoid immune diseases. JAK-STAT is an important signaling pathway, which is involved in the development of many autoimmune diseases. JAK inhibitors can block the production of a variety of inflammatory cytokines and have anti-inflammatory and immunomodulatory effects. JAK inhibitors are gaining increasing attention in the field of rheumatologic disorders. In this review, the application status and prospect of these drugs in autoimmune diseases are summarized for the first time.
To summarize and analyze the current situation of safety reporting requirements of drug clinical trial institutions in China after the implementation of the new “Good Clinical Practice” (GCP).
Data processing and statistical analysis were conducted on the reporting procedures and management requirements of safety events issued by 98 drug clinical trial institutions.
Fifty institutions (51.0%) required investigators to submit suspected unexpected serious adverse reactions (SUSAR) to ethics committees. A high proportion of institutions did not specify the media and time limit for SUSAR submission. There were 36 (36.7%) institutions that differentiated the time limit for SUSAR submission from sponsors to at least one role of investigators, ethics or trial management departments. The time limit for SUSAR at own hospitals was shorter than that from other hospitals and 7 or 15 d was the most common time limit. Forty-two (42.9%) institutions required investigators to report severe adverse events (SAE) to ethics committees and/or trial management departments.
Drug clinical trial institutions have timely updated the safety reporting requirements which focus on SUSAR and other safety events at own hospitals. It is necessary to further improve the clarity and convenience of safety reporting procedures and explore the management mechanism of safety events at the institution level.
To investigate the protective effect of PPARα agonist WY14643 on stress-induced liver injury.
Fourteen female SD rats were randomly divided into control group (NC) and model group (SLI), 7 in each group. The stress-induced liver injury model was established by the water immersion restraint method. After 21 days of modeling, the morphological changes of liver tissue were observed by HE staining method, serum corticosterone (CORT), alanine transaminase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), total cholesterol (TC), triglyceride (TG) contents were measured by ELISA method, transcriptome sequencing technology was used to find the differentially expressed genes between control group and model group, and qRT-PCR was used to verify the differentially expressed genes. The differentially expressed gene PPARα agonist WY14643 was selected, and 24 SD rats were randomly divided into control group, SLI, WY14643 low-dose group (WYL) and WY14643 high-dose group (WYH). One hour before the daily restraint stress, WYL and WYH groups were intraperitoneally injected with 0.5 and 1 mg·kg-1 of WY14643, respectively. The control group and model group were intraperitoneally injected with the equal doses of saline, and water immersion restraint stress experiment was performed to observe whether WY14643 has anti-stress protective effect and molecular mechanism of liver injury.
ELISA results showed that WY14643 could reduce rat serum CORT, ALT, AST, TNF-α, IL-1β, TC, TG contents. The results of liver HE staining showed that WY14643 could reduce liver damage caused by stress. Western blot results showed that WY14643 could reduce the protein expression of PI3K, AKT and NF-κB in rat liver.
WY14643 can improve the liver damage caused by water immersion restraint stress, and this effect may be related to its inhibition of PI3K/AKT/NF-κB pathway.
To observe the effects of Compound Cortex Phellodendri Fluid on inflammatory factors, nuclear factor-kappa B (NF-κB) and cyclooxygenase-2 (cyclooxygenase-2, COX-2) protein expression in rats with ulcerative colitis (ulcerative colitis, UC), and explore the protective mechanism.
The experimental animals were randomly divided into blank control group, model group and Compound Cortex Phellodendri Fluid group. The UC rat model was established by immune complex method. After 14 days of treatment, the contents of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were determined by ELISA method. Nuclear factor-κB and cyclooxygenase-2 were determined by Western Blot method.
Compared with the blank group, the contents of IL-6 and TNF-α and the expression of NF-κB and COX-2 protein in the model group increased, while the contents of IL-6 and TNF-α, and the expression of NF-κB and COX-2 protein in the Compound Cortex Phellodendri Fluid group decreased.
The protective effect of Compound Cortex Phellodendri Fluid on UC rats may be produced through anti-inflammatory effect.
To optimize the formula of long-circulation liposomes loaded with pulchinenoside B4 (PB4-L) by central composite design-response surface method and characterize the liposomes.
PB4-L were prepared by ethanol injection and the encapsulation efficiency was determined by ultrafiltration centrifugation. The formula of PB4-L was optimized by the four-factor, three-level central composite design-response surface method. The particle size, zeta potential and morphology of PB4-L were characterized by laser particle zeta-sizer and transmission electron microscope. The stability of the liposomes was evaluated.
The optimal formula of PB4-L was as follows: the phospholipid content was 2.4%, the weight ratio of phospholipids to cholesterol was 3∶1, the weight ratio of lipids to drug was 2∶1, and the DSPE-PEG2000 content was 2.4%. The encapsulation efficiency of PB4-L was 76.9%, with a mean particle size of (408.7±1.1) nm, polymer dispersity index (PDI) of 0.16, and zeta potential of (-45.2±0.2) mV. The morphology study of PB4-L showed that the liposomes were round-shaped with good dispersity. PB4-L was stable in 10% FBS-containing medium.
The formula of PB4-L was optimized by central composite design-response surface method. The liposomes were characterized by a high encapsulation efficiency, a uniform particle size distribution and a good serum stability in vitro.
To evaluate the efficacy, safety and economy of nonsteroidal anti-inflammatory drugs (NSAIDs), selective cycleooxygenase-2 receptor inhibitors (COXIBs), glucocorticoids (GC), and colchicine (COLC) in the treatment of acute gout flare by Meta-analysis.
Literature about randomized controlled trails (RCT) using NSAIDs, COXIBs, GC and COLC in the treatment of acute gout flare was searched through Medline, Embase, CENTRAL, CBM and CNKI up to Mar. 2021 and then screened according to the inclusion and exclusion criteria. The data was extracted and assessed for the methodological quality of included studies. Then, Meta-analysis was performed by using R programming and pharmacoeconomics analysis was conducted.
A total of 19 RCTs involving 2 598 patients were included. The results of network Meta-analysis showed that NSAIDs, COXIBs and GC could alleviate patients' pain effectively and improve study joint swelling (P<0.05). COLC had the highest incidence of adverse events among the four kinds of therapeutic drugs. Cost-minimization analysis showed that GC was the most economical treatment.
NSAIDs, COXIBs, GC and COLC can effectively treat acute gout flare, and GC treatment is the most economical.
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