ArchiveTo establish a scientific applicability evaluation index system of real-world data (RWD), and provide a quantitative analysis basis for the transformation of RWD into real-world evidence (RWE).
Hierarchical extraction analysis of factors affecting the applicability of RWD was carried out by studying domestic and international guides, documents and literature. Analytic hierarchy process (AHP) and group eigenvalue method (GEM) were used in combination to establish the hierarchical structures of the selected indicators, expert scoring matrix was constructed, and MATLAB software for index system was used to compute the weights.
Applicability evaluation index was constructed from two aspects: relevance and reliability. Relevance included five sub-criteria level indexes and 26 specific evaluation indicators: data source and sample, exposure/intervention and event outcome definition, integration of multi-source data, regulatory requirements, ethics. Reliability consisted of three sub-criteria level indexes and 27 specific evaluation indicators: data validity, quality control, and quality assurance.
When gathering and applying RWD, attention should be paid to the data source, validity, and quality control, to ensure that the data is closely related to the demand and is reliable, and then to upgrade the applicability from RWD to RWE.
To investigate the status of clinical trials registered on ClinicalTrials.gov on diseases in the list of rare diseases in China and analyze the registration characteristics.
All clinical trials involved in the list of rare diseases in China were searched on ClinicalTrials.gov from inception to April 5th, 2022. The relevant information of clinical trial registration was collected, and WPS Office was used for data analysis.
A total of 12 904 rare disease-related clinical trials were screened out, and the overall trend was increasing year by year. The information of clinical trial stages was missing a lot, and the sample size was mainly 0~100 cases. The types of trials were mainly interventional studies (9 042 trials, 70.1%) and observational studies (3 760 trials, 29.1%). There were three main statuses of trials: completed (6 467 trials, 50.1%), recruiting (2 388 trials, 18.5%), and unknown status (1 207 trials, 9.4%). The number of drug therapy trials was the largest (5 992 trials, 46.3%). The countries/regions participating in clinical trials were mainly developed countries in Europe and the United States. All of the top three single/multi-center rare disease-related clinical trials were conducted in European and American countries. There were a small percentage of clinical trials conducted in China (460 trials, 3.6%), but the proportion of single center-clinical trials was the highest (260 trials, 56.5%). The research institutions were mainly universities and medical institutions, and in China they were mainly medical institutions (358 trials, 77.8%). The sponsoring institutions were mainly European and American countries. The design of rare disease-related clinical trials was mainly non-randomized, open label and parallel allocation of therapeutic regimens. The outcome indicators were mainly related to safety and efficacy.
The development of clinical trials of rare diseases in China is on the rise, but there is a big gap with European and American countries. We should establish a systematic research and development incentive mechanism and introduce relevant laws and regulations as soon as possible to promote the high-quality development of clinical trials of rare diseases.
Drug re-evaluation system has been developed in some developed countries for many years. In these countries, unique and mature drug re-evaluation systems have been established to make up for the insufficiency of pre-market research and review and further improve the safety and effectiveness of drugs. The importance of drug re-evaluation has been repeatedly verified in the practice of developed countries. China is establishing a pharmacovigilance system and should take advantage of the situation to establish a drug re-evaluation system adapted to China's national conditions, maintain focus on the safety of drugs throughout the life cycle, and ensure the medication safety of Chinese people. The post-marketing re-evaluation system in Japan has been developed for more than 40 years, and it is full of reference. This paper reviews the historical origin of Japan's post-marketing re-evaluation system, systematically analyzes Japan's post-marketing re-evaluation system from the aspects of object and period, change of laws and regulations, responsible subjects, and implementation procedures and so on. In the last part, practical suggestions are put forward for the construction of China's drug re-evaluation system.
At present, our country is facing the unfavorable situation that our independent innovation capability is weak and the key core technologies are subject to foreign countries. The complicated domestic and foreign environment makes it more urgent to reverse the "neck sticking" situation. General Secretary Xi Jinping delivered an important speech at the Central Economic Work Conference, demanding to "solve a number of ‘neck sticking’ problems as soon as possible". This study sorted out the definitions of "neck sticking" from different perspectives in previous studies, combined the differences and connections between "neck sticking" technology and other technologies, and analyzed the conceptual connotation of "neck sticking". It was proposed to define the "neck sticking" technology from multiple dimensions, such as national strategy, technology criticality, technology gap, and industry criticality, and build an evaluation index system of "neck sticking" based on above four dimensions. Finally, combined with our national conditions and domestic and foreign environment, some thoughts were put forward to solve the "neck sticking" problem in the field of biomedicine.
To develop a highly sensitive, efficient, and stable cell-based platform for detection of anti-adeno-associated virus 8 (AAV8) neutralizing antibody titer in monkey plasma and perform preliminary validation of the relevant performance of the method.
In vitro, an equal volume of diluted monkey plasma was incubated with AAV8-Luciferase and then the mixture was added to a 96-well plate lined with HEK293 cells and incubated overnight to infect HEK293 cells; after cell lysis, the cells were added to a firefly luciferase reporter gene assay and the fluorescence signal (RLU) was detected using ELISA to assess the plasma levels of anti-AAV8 neutralising antibodies and subsequently obtain the corresponding antibody titres. The assay's sensitivity (LOD) and titer reproducibility, precision, method robustness and sample stability were preliminary were preliminary validated.
A highly sensitive, efficient and stable method for the detection of anti-AAV8 neutralizing antibody titer in monkey plasma at the cellular level was developed and preliminarily validated. The LOD value of the method was 10.36 ng·mL-1. The repeatability, precision and method robustness of the titer assay were good, and the positive control samples were stable after being placed at room temperature and 2 ℃~8 ℃ for 24 h and after freeze-thawing for 6 times at -65 ℃~-90 ℃/room temperature.
It has been preliminarily validated that the method can be used for the analysis and detection of anti-AAV8 neutralizing antibody titer in monkey plasma, which is useful for grasping the process of drug treatment and adjusting the treatment protocol in time and is suggestive for the development of AAV8 serotype gene therapy drugs and individualized treatment.
While significant advancements have been made in recent years in target identification and drug discovery, there is a general lack of validated targets for diseases. In the meantime, the number of new molecular entities approved per year has dramatically declined over the past decades. There is still much room for further improvement to optimize the drug discovery process. Activity-based protein profiling (ABPP) is a chemical proteomic method for functional investigation of complex proteomes directly in native biological systems. ABPP is widely used for target identification and drug discovery by using chemical probes that label active site residues in proteins. This review summarizes the design strategy of ABPP and introduces the related applications of ABPP technology in the field of target identification and drug discovery.
Compared with other administration methods such as intravenous injection, oral administration is simple and feasible with low medical cost and high safety, and can relieve the pain of patients and enhance humanistic care. However, due to the harsh gastrointestinal environment, many oral drugs cannot reach their target sites with effective concentrations to exert therapeutic effects. Therefore, there are many challenges in developing oral drugs. Exosomes are extracellular vesicles secreted by cells, which transport proteins, nucleic acids, miRNA and other bioactive substances to receptor cells for intercellular communication. Recently, a number of researchers have reported that vesicles with structures similar to those secreted by mammalian cells can be extracted from vegetables, fruits and dairy products, and named them as food-derived exosomes (FDEs). FDEs have attracted wide attention due to their low immunogenicity, high biocompatibility, non-toxic and environmental properties. This review summarizes the medical application of FDEs as oral preparations, hoping to provide theoretical reference for the development and application of oral preparations based on FDEs.
225Ac is one of the most promising radionuclides in alpha particle targeting therapy (targeted alpha therapy, TAT). The alpha particles produced by 225Ac decay have the characteristics of higher linear energy transfer, shorter tissue action distance, less side effects and so on. Therefore, TAT drugs such as small molecules and antibodies labeled with 225Ac have good application prospects in tumor treatment. This paper introduces the decay properties and sources of 225Ac, summarizes the commonly used chelating agents for 225Ac labeling, exemplifies the process of 225Ac labeling, and summarizes the application of 225Ac-labeled compounds in non-clinical and clinical research in the past three years. Finally, the challenges and prospects of 225Ac-labeled TAT drugs are analyzed, which provides a basis for the follow-up development of TAT drugs.
Photodynamic therapy (PDT) is a tumor treatment method that uses photosensitizers to convert oxygen into reactive oxygen species and stimulate multiple pathways to kill cells. PDT can break through some limitations in tumor treatment with the help of nano-drug delivery system, but it still cannot solve the key problem of poor biocompatibility of photosensitizers. The cell membrane-modified biomimetic nano-drug delivery system formed by introducing natural cell membrane into nano-drug delivery system can give full play to the low immunogenicity of the cell membrane, improve the biocompatibility of photosensitizers, and enhance the anti-tumor effect of PDT. This review focuses on the progress of nanoparticles modified with cancer cell membrane, red blood cell membrane, leukocyte membrane and hybrid cell membrane, and their applications in PDT against tumors. The advantages and disadvantages of every type of cell membrane-modified nanoparticles based on PDT have been summarized to provide reference for its clinical application.
To investigate the mechanism of drug resistance occurring in hepatocellular carcinoma treated with sorafeinib from epigenetic perspective, and examine the effect of sensitivity of sorafeinib on hepatocellular carcinoma after in vita combination of epigenetic drug decitabine (DAC), so as to provide new ideas and methods for clinical treatment of hepatocellular carcinoma.
The GEPIA 2 database was used to retrieve information of 508 primary hepatocellular liver cancer patients, and the correlation between the expression of OATP1B3 and survival time was analyzed by Kaplan-Meier method. The methylation rate of SLCO1B3 promoter was detected by bisulfite methylation method. RT-qPCR and Western blot were used to detect the expression changes of cancer cell lines OATP1B3 before and after liver DAC treatment. RTCA-eSight experiment was performed to monitor the effect of sorafeinib in combination with DAC on the proliferation of hepatocellular carcinoma cells. Changes in the uptake of sorafeinib by hepatocellular carcinoma cells after the combination of the two drugs were detected by experimental LC-MS/MS.
The results of GEPIA2 database analysis showed that the overall survival rate of patients with hepatocellular carcinoma with high OATP1B3 expression was significantly higher than those with low expression. Bisulfite methylation sequencing showed that the promoter methylation rate of SLCO1B3 was higher in Hep3B and HepG2. RT-qPCR and Western blot showed that the mRNA and protein expressions of OATP1B3 in hepatocellular carcinoma cell lines Hep3B and HepG2 were relatively low, and the expression of OATP1B3 was upregulated after incubation with DAC. RTCA-eSight experiment showed that DAC combination treatment significantly enhanced the effect of sorafeinib on Hep3B and HepG2 inhibition. LC-MS/MS determination showed that the uptake of HEK293-OATP1B3 on sorafeinib was 2.10 times higher than that of HEK293-Wild. The uptake of sorafeinib by Hep3B and HepG2 was increased by 1.87-fold and 2.47-fold after being combined with DAC.
DAC can inhibit SLCO1B3 DNA methylation, up-regulate the expression of OATP1B3, improve the capacity of sorafenib transport, increase the accumulation of sorafenib in liver cancer cells, and enhance the sensitivity of liver cancer cells, so as to reverse the resistance of sorafenib.
To screen potential small-molecule inhibitors of monkeypox virus thymidylate kinase from traditional Chinese medicine databases using virtual screening technology.
Based on the published monkeypox virus thymidylate kinase sequence, the three-dimensional structure of monkeypox virus thymidylate kinase was constructed using homology modeling technology, and multiple rounds of screening were performed using docking-based virtual screening technology, including high-throughput virtual screening, standard precision virtual screening, high precision virtual screening and Prime MMGBSA.
Fifteen compounds with potential inhibitory activity against monkeypox virus thymidylate kinase were obtained by screening. The binding modes of compounds MOL002468, MOL009538, MOL000416 and MOL009237 with thymidylate kinase were analyzed for receptor-ligand interactions including hydrogen bonding, hydrophobic interactions, conjugation and salt bridges.
A virtual screening strategy for monkeypox virus thymidylate kinase was successfully constructed in order to discover new drugs that can be used to prevent and treat monkeypox virus, promoting further development and utilization of traditional Chinese medicine databases.
To develop the national reference standards of 1,1,1,2-tetrafluoroethane as the excipient of medicinal aerosol and its impurities thus to improve the standard of quality control.
The national reference standards of 1,1,1,2-tetrafluoroethane and its main impurities 1,1,2,2-tetrafluoroethane, pentafluoroethane, pentafluorochloroethane and 1,1,1-trifluoroethane were sub-packaged in liquid state directly. The structures were confirmed by IR, MS and MR spectroscopy, the moisture was determined by Coulomb method, the tightness of the package was confirmed by immersion in water. The content of each substance was calculated by mass balance method．Homogeneity and stability were investigated by F test and linear fitting respectively, and the content of 1,1,1,2-tetrafluoroethane was confirmed by multiple laboratories simultaneously.
The contents of 1,1,1,2-tetrafluoroethane, 1,1,2,2-tetrafluoroethane, pentafluoroethane, pentafluorochloroethane and 1,1,1-trifluoroethane were 100.0%, 99.9%, 99.7%, 99.2%, and 99.9%, respectively, with good homogeneity and stability.
In this study, the national reference standards of 1,1,1,2-tetrafluoroethane and its main impurities were developed for the first time, where 1,1,1,2-tetrafluoroethane can be applied for content determination, and the other substances can be applied for the inspection of related substances.
To establish a method of accelerated release of brexpiprazole sustained release microspheres for injection in vitro and discuss the in vivo and in vitro relationship, so as to provide reference for prescription screening and quality control of this preparation.
The effects of surfactant type, salt type and temperature on the release behavior were investigated by the method of constant temperature water bath. The in vitro accelerated release method was finally determined by the analysis of distinguishing ability and in vivo and in vitro relationship (IVIVR).
A method for accelerated release of pH 7.4 HEPES (containing 0.2% cetyltrimethylammonium bromide) at 45 ℃ in vitro was established, which showed a good correlation with in vivo release (r2>0.99).
The method of accelerated release in vitro established in this paper can guide prescription screening and process modification in all stages of drug development, and it is of great significance for product quality control.
To prepare the β-cyclodextrin inclusion complexes of volatile oil in Qizhu granules.
The technology parameters like inclusion time, inclusion temperature, and the ratio of volatile oil to β-cyclodextrin in the preparation process of inclusion complexes were investigated by single factor experiment with inclusion rate as the index. With inclusion rate and inclusion yield as indexes, Box-Behnken response surface method was used to optimize the preparation process of inclusion complexes. Thin-layer chromatography, infrared spectroscopy and differential scanning calorimetry were utilized to characterize the inclusion complexes.
The optimal conditions were as follows: 9∶1 for volatile oils-(β-cyclodextrin) ratio, 64 ℃ for inclusion temperature, and 1 h for inclusion time. The inclusion rate and yield of the obtained inclusion complexes were 90.68% and 80.40%, respectively. All characterization results revealed the formation of inclusion complexes.
The established method is stable and feasible, which can be used for preparing the β-cyclodextrin inclusion complexes of volatile oil in Qizhu granules．
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