ArchiveThere is high similarity between real-world study (RWS) and the clinical practice of traditional Chinese medicine (TCM). RWS can be used as one of the methods to collect the empirical data of human use normatively, and generate high-quality empirical evidence of human use of TCM. From the perspective of the whole life cycle of TCM, RWS can not only help to choose the subject and set up the project, optimize the strategy of TCM research and develop (R&D), shorten the R&D period, guide the pharmacological and toxicological research and clinical trial design, improve the research efficiency, but also continuously explore the clinical value and extend the life cycle of products. In view of the deficiencies in the quality of real-world data and the methodology for using real-world data needing to be standardized, it is necessary to clean up the data to form applicable analysis data, and form the truth through standardized methodological design, well organized implementation, and reasonable statistical analysis. Exploring the safety and effectiveness of TCM with the real-world evidence would support the research and development of new TCM products with human experience.
This paper analyzed the situation of patent applications of anti-tumor traditional Chinese medicine (TCM) in China in order to provide suggestions for the research, development, utilization and innovation of anti-tumor TCM. The Patentics patent database was used as the data source to search and analyze the patent application of anti-tumor TCM in China. The patent applications of anti-tumor TCM in China mainly experienced three stages: steady development (2000—2012), rapid outbreak (2013—2015) and slowing down (2016-present). However, the quality of patent applications showed an opposite trend, resulting in a low patent effective rate (21%). The quality of the patents applied by modern pharmaceutical enterprises and universities showed a higher level. The patent applications of pharmaceutical enterprises mainly focused on the extract of TCM and preparation process, while universities mainly focused on TCM composition and compound preparations. In an overall view, the patent application quality of anti-tumor TCM in China is relatively low, we should improve the patent quality, learn from the foreign patent layout experience, enhance the ability of university-enterprise collaborative innovation, and promote the inheritance and development of TCM.
The research and development process of osimertinib was prompted by new drug expedited programs in the US, which resulted in the highly coincident time periods of drug registration and patent examination. Based on the review of the research and development process and patent strategy of osimertinib, the opportunities and challenges of pioneering new drugs and follow-on drugs under the global trend of accelerating approval process were analyzed. The exploration of special patent examination management such as creating a fast-track for drugs undergoing clinical trials was proposed to strengthen the protection of innovations.
According to the spirit of the “implementation opinion on comprehensive strengthening of the drug regulatory capacity construction” issued by the General Office of the State Council, this article aimed to provide reference for the evaluation benchmark and future direction for the improvement of drug evaluation ability under the strategy of pharmaceutical power. According to the dual organization theory, lessons were drawn from WHO and EMA competence assessment for regulatory authorities, and the drug evaluation ability model was constructed by using two rounds of expert investigation method of Delphi. The drug evaluation ability model was composed of input, process control and output modules, which contained 16 primary indicators of core competency assessment and 58 secondary indicators altogether. It will provide a basis for the assessment of the ability of drug review authority in China in the new period, to find the gap between vision and reality, to improve the ability of drug review from the long-term goal, and to promote the capability development of drug review authority.
Novel designs for early clinical trials of anticancer drugs have received widespread attention and have been applied in drug development. This paper introduced three methods, i.e., algorithm-based designs, model-based designs and model-assisted designs, in single-dose exploration and multiple-dose exploration respectively. Their basic ideas and statistical methods were introduced and then their strengths and weaknesses were explained. These novel designs can not only reduce R&D costs and research time but also determine whether the medicine is effective in clinic earlier, thereby increasing the development efficiency.
A comparative study of two in vitro experimental methods detecting cytokine release was conducted for evaluating methodological choices on whether new drugs cause cytokine release.
Peripheral blood mononuclear cells were incubated with two different methods for 24 hours, after which the expression levels of four cytokines: IL-1β, IL-6, IL-8 and TNF-α were detected by cytometric bead assay.
In solid phase method, IL-1β was significantly released only in OKT3 at 5 μg·well-1 (P<0.05). Significant release of IL-6 was found in two antibodies (P<0.05). There was a significant release of IL-8 and TNF-α at all concentrations of OKT3 and 5 μg·well-1 of TGN1412 (P<0.05). While in liquid phase method, significant release of IL-6 happened in 1 and 5 μg·well-1 of OKT3, as well as 5 μg·well-1 of TGN1412 (P<0.05). There was a significant release of IL-8 at 5 μg·well-1 of TGN1412 (P<0.05). Significant release of TNF-α was found in all concentrations of OKT3 and 5 μg·well-1 of TGN1412 (P<0.05).
The solid phase method is more suitable for T cell receptor monoclonal antibody drugs, the results of which are more reliable in preclinical evaluation. The liquid phase method is simpler to operate, and its simulated environment is closer to human body, but it has higher sensitivity for monoclonal antibodies whose target is not on T cells.
The re-evaluation system of western medicines at home and abroad has been preliminarily formed. It is clear that the post-marketing re-evaluation of drugs must be based on the latest research data of the drugs, the purpose of the re-evaluation should be determined according to the needs of different subjects, and appropriate methods should be selected to carry out the re-evaluation research. Although the post-marketing re-evaluation research of traditional Chinese medicine has made some progress, there are still many problems in this field due to the differences in the theoretical systems of Chinese and Western medicine and the deficiencies of pre-marketing research. This article summarized the status of post-marketing clinical re-evaluation research of traditional Chinese medicine, analyzed the problems, and proposed key technology improvement methods for the post-marketing clinical re-evaluation research of Chinese patent medicines and Chinese herbal medicine pieces. It is hoped that a high-level comprehensive post-marketing clinical re-evaluation system for traditional Chinese medicines based on real world study would be formed based on multi-level, multi-source, multi-method research data and results, which will provide a basis for the rational use of traditional Chinese medicine and the formulation of national drug policies.
Non-alcoholic fatty liver disease (NAFLD) is a liver disease closely related to metabolic syndrome. Hepatic mitochondrial dysfunction, as one of the most important features of NAFLD, leads to simple liver steatosis or progresses to steatohepatitis, and even liver fibrosis, which may eventually induce cirrhosis and hepatocellular carcinoma. However, there is no specific drug for the treatment of NAFLD in clinic. Recent studies found that mitochondrial dysfunction is related to ultrastructural damage, mitochondrial DNA depletion, excessive production of reactive oxygen species, and abnormities of fatty acid oxidation, mitochondrial autophagy, apoptosis, signal transduction. This article reviewed the performance, role, and mechanism of mitochondrial dysfunction in the progression of NAFLD and discussed the therapeutic strategies of NAFLD based on the understanding of mitochondrial dysfunction in NAFLD, providing new ideas for the development of innovative drugs for the prevention and treatment of NAFLD.
Transdermal products have become the research focus for generic pharmaceutical preparations due to their unique advantages relative to other dosage forms and routes of administration. As a result of the complexity of transdermal formulations the bioequivalence study often faces more challenges. Bioequivalence of transdermal patches requires demonstration of pharmacokinetic equivalence along with adhesion studies, skin irritation and sensitization studies and residual analysis of the patch after the intended duration of application, for which domestic authorities have not issued recommendations. This paper provides an overview of the patches approved in global market and systematically expounds general principles for the designing, conducting and evaluating of bioequivalence study of transdermal patches based on guidances addressed by regulatory authorities worldwide and related literatures, which would be referential for domestic sponsors to carry out bioequivalence research of transdermal patches.
To observe the clinical efficacy and safety of butylphthalide injection in the treatment of patients with anterior choroidal artery infarction, as well as the changes of serum high-sensitivity C-reactive protein (hs-CRP) and tumor necrosis factor-α (TNF-α).
Sixty-seven patients with anterior choroidal artery diagnosed in our hospital were selected and randomly divided into butylphthalide group (34 cases) and control group (33 cases). Both groups received antiplatelet aggregation and lipid-lowering therapy, and the butylphthalide group was treated with butylphthalide injection 25 mg (bid) in addition for 14 d. The patients were followed up for 3 month.
The incidence of progressive stroke in the butylphthalide group was significantly lower than that in the control group. The National Institutes of Health Stroke Scale (NIHSS) scores of patients in the butylphthalide group 14 d after treatment were significantly lower than those in the control group. Three months later, the proportion of patients with good prognosis (mRS score≤1, Barthel index score≥90) was significantly higher than that of the control group (P<0.05). The levels of hs-CRP and TNF-α in the two groups were decreased on the 14th day, and the decrease in the butylphthalide group was more significant than that in the control group (P<0.05).
Butylphthalide injection can not only reduce the incidence of progression in patients with anterior choroidal artery infarction, but also has better long-term clinical efficacy and can bring higher quality of life to the patients. The mechanism may be related to reducing the levels of hs-CRP and TNF-α and inhibiting inflammatory reaction.
The “subcenter contract” is the basis of multi-center research initiated by investigators. It is a crucial contract document for agreeing on the mutual power and responsibilities of the various institutions participating in the study. This paper analyzed the general characteristics of 158 subcenter contracts for investigator initiated trials (IIT) and assessed the common problems. All the 158 IIT subcenter contracts were in Chinese text, most contracts were signed with university affiliated hospitals and prefecture-level hospitals, most contracts were signed with oncology hospitals and general hospitals, and most of the contracts adopted unified templates of the leading units. Among the 40 template contracts, the common problems were as follows: 45.9% of the contracts did not mention the way of providing research drugs, 51.3% did not specify the adverse drug reaction monitoring and reporting responsibilities during the study, 60% did not mention the subject damage liability, 50% did not state who were responsible for data preservation after the end of the study, misplacement of the regulations that IIT should follow or refer to, missing or unclear key elements of the contract, unclear responsibility for clinical research and supervision, etc. According to the above analysis results, this paper respectively put forward thoughts and suggestions on the legal and regulatory basis to be followed by IIT, the provision of research drugs, adverse reaction monitoring report, the confidentiality and preservation of research data, intellectual property sharing, subject damages, and the key elements of research contract.
To explore the roles of standardized judgement, risk assessment and emergency treatment of hypersensitivity reactions (HSRs) of anti-tumor monoclonal antibody drugs.
The literature of anti-tumor drugs, monoclonal antibodies and HSRs was retrieved from China National Knowledge Infrastructure (CNKI) and PubMed from January 1, 2010 to October 1, 2021. The definition and classification of HSRs, risk factors and novel treatment were analyzed.
A total of 63 pieces of literature were included, of which 22.1% did not clearly define the type of HSRs. The frequencies of infusion reactions of Fully Human Mab and Humanized Mab were reported to be 56.7% and 43.1%, respectively. The frequency of reported HSRs in intravenous drugs was significantly higher than that in subcutaneous ones (88.5% vs 11.5%); the frequency of HSRs reported in patients was significantly higher than that in healthy subjects (58.7% vs 20.2%).
The terminology of HSRs needs to be standardized. The degree of risk could be related to the drug characteristic, the method of administration, and the population of medication. The treatment of acute HSRs needs to be standardized, systematized and individualized. Rapid drug desensitization (RDD) might be novel and beneficial treatment for tumor patients.
To observe the effect of panax notoginseng saponins (PNS) on the differentiation of CD4+ T cells into regulatory T (Treg) cells and preliminarily explore its relationship with regulating cellular fatty acid oxidation metabolism.
The spleen cells of C57BL/6 mice were isolated and CD4+ T cells were cultured in vitro by magnetic beads sorting. The optimal concentration of PNS was screened by the CCK-8 method and its effect on cell viability was tested. Then the cells were divided into control group and PNS intervention groups (5, 10, 20 μg·mL-1). After corresponding drug intervention, the proportion of Treg cells was detected by using flow cytometry, the level of β-hydroxybutyric acid (BHBA) in the supernatant was measured by using ELISA, cellular carnitine palmitoyl transferase 1A (CPT-1A) mRNA expression was detected by using q-PCR, and the expression of CPT-1A protein was detected by using Western Blot method.
The differentiation ratio of Treg cells and BHBA level in the supernatants significantly increased in the PNS intervention groups (5, 10, 20 μg·mL-1). The increasing expressions of CPT-1A mRNA and protein in the cells were also observed in the PNS intervention groups.
Certain concentrations of PNS can significantly promote the differentiation of mouse CD4+ T cells into Treg cells, and its mechanism may be related with promoting the fatty acid oxidation of CD4+ T cells.
To establish real-time PCR methods for the detection of residual SV40LTA&E1A and plasmids in the quality control of CAR-T cell therapy products, as well as the assay of reference plasmid calibration by microfluidic digital PCR technology.
SV40LTA&E1A were detected in one tube at the same time by multiplex TaqMan probe PCR. In view of the fact that it was hard to unify the standard of residue detection because multiple plasmid systems (four or five plasmids) existed in the current lentiviral packaging technologies, primers were designed from the significant sequence homology of replicon of those plasmids. Meanwhile, digital PCR method was validated.
Good specificity and quantitative limits of 2.80×10 copies·μL-1 (SV40LTA) and 2.98×10 copies·μL-1 (E1A) were achieved in the SV40LTA&E1A PCR method. The quantitative limit was 2.80×10 copies·μL-1 for plasmids detection method. The quantitative calculation results of plasmid copy number concentration of SV40LTA and E1A were 2.80×108 copies·μL-1 and 2.98×108 copies·μL-1, corresponding to 1.06×108 copies·μL-1 (SV40LTA) and 1.21×108 copies·μL-1 (E1A) by digital PCR method.
The SV40LTA&E1A and residual plasmid PCR detection methods have good specificity, sensitivity and accuracy. The calibration results of classical absorption method are about twice times larger than those by digital PCR method.
The preferred method for measuring aerodynamic particle size distribution (APSD) is cascade impactor. The next generation impactor (NGI) is a relatively new instrument among cascade impactors (CI), which has been included in the pharmacopoeia of various countries, however, there are still many problems in the process of methodology validation due to the cumbersome and complex operation of the method. In this study, the established CI method was systematically validated to reduce the variability of method, which could be used for the quality control of inhalers.
The APSD of ambroxol hydrochloride inhalation solution was determined by NGI, the drug contents at different stages were determined by high performance liquid chromatography (HPLC) method, and aerodynamic statistical parameters were calculated by the CITDS software. The methodology investigation included the establishment of HPLC method, determination of NGI nebulization time, re-entrainment, robustness of flow velocity, inter-stage drug loss, instrument calibration and leakage test, recovery rate, influence of diluent, repeatability and intermediate precision, temperature and humidity, etc.
The adopted HPLC method could be used for the assay of ambroxol hydrochloride; the nebulization time of APSD was determined to be 1 min; the inter-stage drug loss was not greater than 2% of the total nebulized drug amount; the instrument was calibrated and no leakage was detected. The total recoveries were over 95.0%. The source of diluent had no effect on APSD determination results. The established method had good repeatability and intermediate precision. In the laboratory environment (20 ℃~25 ℃) temperature had no effect on the experimental results. Humidity (30% and 50%) had certain influence on the measured results.
NGI was used to establish the method for the determination of APSD of ambroxol hydrochloride inhalation solution, and systematic validation was finished. It was proved that the precision and recovery of the method are good, and the method variability is small, which is suitable for the determination of APSD of ambroxol hydrochloride inhalation solution. This study provided a reference and basis for the establishment and verification of aerodynamic particle size distribution determination, and this method can be used for the quality control of inhaled preparations.
To investigate the clinical characteristics of severe drug eruption induced by antibacterial drugs and provide aid for their safe use in clinical practice.
Case reports of severe cutaneous adverse reactions induced by antibacterial drugs were retrieved from Medline, CNKI and Wanfang databases from inception to December 31, 2020. The clinical features of these ADRs were summarized and analyzed. The risk factors were analyzed by binary Logic regression.
A total of 241 cases were collected, including 131 males (54.4%) and 110 females (45.6%). Severe cutaneous adverse reactions (SCARs) occurred in all age groups. The median onset time of antibacterial drugs-induced SCARs was 2 d and the median duration was 15 d. The main allergenic drugs were penicillin (55/21.7%), fluoroquinolones (46/18.2%), cephalosporins (39/15.4%), and glycopeptides (25/9.9%). Patients with toxic epidermal necrolysis (TEN) had a higher risk of death than Steven Johnson syndrome (SJS) [odd ratio (OR)=0.263, P=0.006] and exfoliative dermatitis (ED) (OR=0.52, P=0.016) (P<0.05); patients treated with glucocorticoid (OR=0.117, P=0.027) or immunoglobulin (OR=0.042, P=0.001) had a lower risk of death than treated with symptomatic supportive care. There was no statistical difference between glucocorticoid combined with immunoglobulin therapy and symptomatic supportive therapy (OR=0.899, P=0.950).
The mortality of severe drug eruption caused by antimicrobial drugs is high, so it is necessary to strengthen the monitoring of early signs in clinical practice, and immediately stop using suspicious drugs, and choose alternative antimicrobial drugs with different structures to avoid the recurrence of severe cutaneous adverse reactions.
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