ArchiveSince joining the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 2017, China has gradually strengthened the research on the extrapolation of overseas clinical trial data. Standardization of bridging studies and international multi-center clinical trials will become the trend of the times. Extrapolation of overseas clinical trial data is particularly important in the registration process of drugs that have been listed overseas and not listed in China. Usually, the Center for Drug Evaluation of NMPA needs to consider the completeness of clinical trial packages to determine whether a drug is racially sensitive and whether bridging studies are needed. At present, to investigate the influence of ethnic factors on the acceptability of overseas clinical trials, the ICH E5 (R1) Guidelines are generally followed internationally. In addition, the United States, Japan, the European Union, and other ICH member states have issued their own relevant regulations or guidelines. This article introduces the basis and key points of current review of overseas clinical trial data in China, summarizes and analyzes the design of bridging studies based on international experience, and finally puts forward reasonable suggestions for extrapolation of overseas clinical trial data in China.
It has been nearly 40 years since the Hatch-Waxman Act was enacted in 1984. Generics have developed tremendously during this period, which shows the importance of promoting the development of generics. The Hatch-Waxman Act is important, but it is not the whole story of how generics develop in the United States. After the promulgate of Hatch-Waxman Act, the development mechanism of generic drugs in the United States did not stick to the original state, but continuously made dynamic adjustments in many aspects, including combating misconduct in abbreviated new drug application (ANDA) to standardize the procedures, greatly improving the time efficiency for ANDA, establishing a generic drug replacement mechanism, establishing two patent invalidation procedures [inter parte review (IPR) and post grant review (PGR)], revising the Orange Book, exclusivity period, containment period, etc. to improve patent links system, and establishing a drug price negotiation system and a drug inflation penalty system. China should shorten the period of drug patent reexamination and invalidation examination. The first generic drug exclusivity period system should be coordinated with anti-monopoly. A user payment system should be established in China, but innovative drugs can be exempted. The drug approval and review mechanism, patent law, anti-monopoly law and other fields need to work together to continuously track and improve relevant systems.
The aim of the article was to clarify the factors affecting the investment in cooperation and innovation in different sub-sectors of China's pharmaceutical manufacturing industry and its mechanism of action, and provide a reference for improving the level of investment in this field. Based on the relevant indicator data of different sub-sectors of China's pharmaceutical manufacturing industry from 2009 to 2019, the factor analysis method is used to empirically analyze the impact of the summarized factors on the investment in cooperative innovation. It was found that internal investment in research and development funds, investment in scientific and technological activities, investment in new product development, profitability, effective invention patents, and government funding all have a positive impact on investment in cooperative innovation in different sub-sectors of China's pharmaceutical manufacturing industry. Their impact on biopharmaceutical manufacturing industry is greater than that on chemical manufacturing industry, followed by the Chinese patent medicine manufacturing industry. Whereas the degree of enterprise openness has a negative impact on the investment in cooperation and innovation in different sub-sectors of the Chinese pharmaceutical manufacturing industry.
To establish a "three-in-one" traditional Chinese medicine registration review evidence system, the formation of a traditional Chinese medicine theoretical evidence evaluation system is crucial. The existing traditional Chinese medicine theory evidence system is still immature, lack of standardized retrieval steps for the retrieval of ancient documents, and the evaluation elements of the evidence are not comprehensive enough. So the retrieval process of ancient documents was standardized in this study. Propose six elements of DSPMRE to clarify retrieval issues and needs, and the integrity of the documents, the source and consensus of literature were innovatively proposed to be the three elements of evidence evaluation. Recommendations were made on the level of traditional Chinese medicine theoretical evidence to improve the three key links, i.e., literature retrieval, analysis and evaluation, and classified recommendation, thus to build a traditional Chinese medicine theoretical evidence system that supports the research and development and registration approval of new Chinese medicines under the triple-combination system.
Myelofibrosis (MF) is a myeloproliferative neoplasms (MPN), usually accomplies with thrombocytopenia, severely impacts the life quality of patients and presents a risk for leukemic transformation. Pacritinib is a kind of Janus activated kinase 2 (JAK2) and Fms-like tyrosine kinase 3 (FLT3) inhibitor. U.S. FDA has granted accelerated approval for pacritinib capsules (Vonjo), on Feb 28, 2022, in the treatment of adult patients with the platelet (blood clotting cells) levels below 50 000·μL-1 who have a rare form of bone marrow disorder known as intermediate or high-risk primary and secondary myelofibrosis. The oral dose of 200 mg twice daily showed good clinical efficacy and manageable safety. In this paper, the mechanism of action, pharmacodynamics, pharmacokinetics, safety, and clinical efficacy of daridorexant are reviewed.
To study the bioactivity determination method of human insulin from transgenic cell using in-cell Western technology.
Using CHO-INSR B1284 cells as the target cell, different concentrations of human insulin were used as the stimulants. In-cell Western was used to measure the phosphorylation of human insulin receptor, and the bioactivity of human insulin was determined. According to the 2020 edition 9401 biological products bioactivity/potency determination method verification guiding principles in the General Rules of the fourth part of Chinese Pharmacopoeia, the established method was validated in terms of specificity, precision and durability. The national standard of recombinant human insulin was used as the benchmark to evaluate the relative potency of human insulin drug substance and other insulin analogues.
Different concentrations of human insulin indicated effect on CHO-INSR B1284 cells in a dose-dependent manner. The samples of five potent concentrations were detected for 8 times. The geometric means of the relative potency were (63.76±4.38)%, (78.01±5.97)%, (99.52±4.62)%, (122.84±7.49)% and (151.71±8.81)%, respectively. The relative bias of five potency level were within ±5%, the corresponding geometric coefficient of variations (GCV,%) were lower than 11%, and the upper confidence limit of GCV were all lower than 20%. The bioactivity of human insulin and insulin analogues can be effectively detected using this method.
The in vitro bioactivity determination of human insulin using the In-cell Western was of good specificity, accuracy and precision, which can be used as a routine bioassay method of human insulin.
The COVID-19 pandemic highlights the necessity of stockpiling rapid-response vaccine technology. Represented by nucleic acid vaccine and viral vector vaccine, the vaccine platform technology only needs the virus gene sequence to start research and development, and can rapidly expand production in a short period of time. It shows huge potential capacity of preventing and controlling emerging infectious diseases that spread fast, and affect a wide range of people who generally lack immunity. However, due to the rapid development of this field, few domestic literatures have described relevant concepts, definitions, and classifications. This review combed the related literatures and documents, summarized the definition, development and application of vaccine platform technology and explained its important role for emergent research and development of emerging infectious diseases. It provided scientific basis and suggestions for China to build up strategic stockpiles of related vaccine platform technologies and improve the capability of preparedness and response to emerging infectious diseases.
Alzheimer's disease (AD) is a chronic degenerative disease of the central nervous system, characterized by β-amyloid deposition and abnormal phosphorylation of Tau protein, while its etiology and pathogenesis have not been fully elucidated. The most common presentation of AD is of an elderly individual with progressive problems of memory impairment, cognitive dysfunction, mental symptoms, and loss of living ability. Dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is a highly evolutionary conserved protein kinase, which is related to retardation, neurodegeneration, severe cognitive impairment, and early onset AD. Compelling data have implicated that DYRK1A phosphorylates a variety of substrates on serine or threonine residues, thereby regulating the different cellular processes involved in brain development and function. Thus, DYRK1A might be a promising target for the prevention and treatment of AD, as it is implicated in the formation of senile plaques, neurofibrillary tangles, oxidative stress injury and inflammatory responses. In this paper, we reviews the structure, distribution, and function of DYRK1A, as well as its role in the pathogenesis of AD, in order to provide a theoretical basis for the treatment of AD.
Cancer has always been a major disease that threatens human lives. Traditional treatment modalities cannot guarantee efficient killing of tumor cells and good prognosis after treatment, mainly because people do not have sufficient understanding of tumors and their microenvironment. In recent years, with the advancement of tumor research, the mechanism of tumorigenesis and the impact of tumors on human immune system have become hot topics of research. Various preclinical tumor models have been developed, including in vivo models represented by patient tumor-derived xenograft models (PDX) and in vitro models represented by organoid microarrays, which have different functions in preclinical tumor research and play important roles. As a convenient and effective tool, preclinical tumor models play an irreplaceable role in exploring tumor-immune system interactions, preclinical evaluation of anti-tumor drugs, and discovery of biomarkers for immunotherapy.
Chronic inflammation is considered as a potential pathological state, which is the long-term presence of low concentrations of inflammatory factors in the body and continuous infection of the body, manifested by aggregation and infiltration of monocytes, lymphocytes and other cells, tissue proliferation, lesions, etc. Research shows that chronic inflammation can mediate cancer, diabetes, cardiovascular, nervous system, inflammatory bowel disease, lung disease and other diseases. Curcumin is an active component of polyphenols extracted from turmeric, a traditional Chinese medicine. It has significant anti-inflammatory activity, and its efficacy in controlling or treating a variety of chronic inflammatory diseases has been widely reported. On the other hand, inflammation-related signaling pathways, such as JAKs/STATs, PI3K/AKT/mTOR, Wnt/β-catenin, NF-κB, MAPK/ERK, etc., play key roles in the pathogenesis of various chronic inflammatory diseases. Signaling molecules in the pathway are considered to be important targets of new therapeutic approaches, and curcumin can participate in related inflammation-related signaling pathways to produce anti-inflammatory effects. In this paper, the pharmacological studies of curcumin in chronic inflammatory diseases in the past five years and the regulatory role of curcumin in the inflammatory signaling pathway were reviewed, to provide a reference for the research and development of curcumin in the prevention and treatment of chronic inflammatory diseases.
To study the pharmacokinetics of atomoxetine hydrochloride and to evaluate the bioequivalence of domestic generic and reference atomoxetine hydrochloride (25 mg) in healthy Chinese volunteers.
A randomized, open, two-period crossover study with a 7-day washout period was conducted under fasting and fed conditions in healthy Chinese volunteers (24 subjects/condition). Eligible subjects randomly received a 25 mg single dose of either the test or the reference formulation. A serial blood samples were collected over a 36-hour interval following the administration. The concentration of atomoxetine in plasma was determined by validated HPLC-MS/MS method. Noncompartmental model was applied for pharmacokinetic analysis. The geometric mean ratios (GMRs) and the corresponding 90% confidence intervals of Cmax, AUC0-t and AUC0-∞ were acquired for bioequivalence analysis.
The pharmacokinetic parameters of the test and reference capsules under fasting condition are as follows: Cmax are (282.13±91.45) and (271.42±79.44) ng·mL-1; AUC0-t are (2 009.91±1 258.81) and (1 942.78±1 198.58) ng·h·mL-1, AUC0-∞ are (2 051.51±1 306.58) and (1 982.65±1 242.27) ng·h·mL-1. The pharmacokinetic parameters of the test and reference capsules under fed condition are as follows: Cmax are (189.26±77.24) and (185.80±63.09) ng·mL-1; AUC0-t are (1 804.43±1 107.08) and (1 740.68±1 003.93) ng·h·mL-1, AUC0-∞ are (1 847.90±1 164.11) and (1 779.44±1 053.44) ng·h·mL-1. The 90% confidential intervals of the GMRs of Cmax, AUC0-t and AUC0-∞ fell within the bioequivalence criteria (80.00%~125.00%). No serious adverse event was observed.
The domestic atomoxetine hydrochloride was bioequivalence to the reference formulation. Both formulations were generally well tolerated.
To explore the value of neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), and lactate dehydrogenase (LDH) levels in evaluating the benefits of immunotherapy for lung small cell carcinoma with liver metastasis.
From November 2021 to August 2022, the clinical data of 56 patients diagnosed with pulmonary small cell lung carcinoma (SCLC) with liver metastases and treated with chemoradiotherapy combined with programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors in our hospital were collected, and the follow-up was cut in September 2022. Blood routine examinations and LDH values before and after treatment of all patients were collected. The ROC curve was plotted and the optimal cutoff values of NLR, PLR and LDH were determined when the Youden index was maximum. The cases were divided into low indicator score group and high indicator score group respectively. Multivariate Cox regression analysis was used to screen independent predictors of survival after immunotherapy for SCLC liver metastasis.
The levels of NLR and PLR before treatment were related to the objective response rate (ORR) of patients receiving immunotherapy. Through univariate analysis of patients' progression free survival (PFS), we concluded that the risk factors of PFS in patients with liver metastasis were high NLR, high PLR and high LDH. The Cox proportional hazards model was used to analyze the risk factors obtained from the univariate analysis. The independent risk factors of PFS in patients with liver metastasis were high NLR and high LDH.
NLR, PLR and LDH can be used to predict the survival of SCLC after immunotherapy.
To study the protective effect of apigenin (APG) on adriamycin-induced renal injury in rats and explore its mechanism.
Adriamycin nephropathy (AN) model was established by injecting doxorubicin into the tail vein of 60 SD rats, and another 10 rats were given the same volume of vehicle as control group. AN rats were randomly divided into model group, positive control dexamethasone group (DEX group, 0.1 mg·kg-1·d-1), APG low-dose group (APL group, 50 mg·kg-1·d-1), APG medium-dose group (APM group, 100 mg·kg-1·d-1), and APG high-dose group (APH group, 200 mg·kg-1·d-1), 10 rats in each group. The rats in DEX and APG groups were given daily intragastric administration, while those in the normal control group and the model group were administered with APG solvent (0.5% CMC-Na solution) for 60 days. The 24-hour proteinuria (PRO), serum renal function, liver function and other biochemical indicators were measured; the pathological examination of the kidney tissue was carried out by HE staining; the CD68 protein in the kidney tissue was marked by immunohistochemistry, and the aggregation of macrophages in the kidney was detected; the apoptosis of renal cells was detected by TUNEL apoptosis assay; the levels of serum inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA). Lipopolysaccharide (LPS) was used to induce RAW264.7 cell inflammation model, and the inhibitory effect of APG on inflammation at different concentrations was observed; adriamycin was used to induce rat renal tubular epithelial NRK-52E cell injury model, and the effect of APG on cell injury was observed.
Compared with the model group, APM and APH could significantly reduce PRO, plasma total protein (TP), blood urea nitrogen (BUN), and serum creatinine (CRE) contents in the rats after 60 days of treatment, and improve the liver function-related indicators, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the treatment effect of the APH group was better than that of the DEX group; HE staining results showed that APM and APH treatment significantly improved renal tissue lesions; CD68 immunohistochemical and TUNEL apoptosis assay results showed that macrophage aggregation in kidneys of APH group was significantly reduced, cell apoptosis was also improved; the serum levels of inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were significantly reduced in the APH group. The above differences were statistically significant (P<0.05, P<0.01, or P<0.001).
APG can improve adriamycin-induced renal injury in rats, which may be related to its anti-inflammatory and cytoprotective effects.
To evaluate the absorption of pioglitazone hydrochloride (PGH) cocrystals in SD rats and improve the problems of poor solubility and low bioavailability of PGH.
Cocrystals of pioglitazone hydrochloride-para aminobenzoic acid, pioglitazone hydrochloride-para-aminosalicylic acid and pioglitazone hydrochloride-gallic acid were prepared by suspension method. PGH and 3 cocrystals were characterized by a variety of analytical techniques, and the concentration of PGH in rat plasma was determining by high performance liquid chromatography-mass spectrometry (HPLC-MS) to analyze the pharmacokinetic parameters of cocrystals.
The 3 cocrystals all showed good stability and solubility. Cocrystals of pioglitazone hydrochloride-para aminobenzoic acid and pioglitazone hydrochloride-gallic acid could significantly improve the bioavailability, peak concentration (Cmax), and area under the curve (AUC) of oral PGH in rats.
Cocrystallization is an important method to change PGH solubility and absorption characteristics in vivo.
To investigate the compatibility between Shenlu Tablets and drug packaging materials by screening and determination of 20 elements in Shenlu Tablets.
For accelerated testing, the samples were stored at a temperature of 40 ℃ and a relative humidity of 90% for 0, 1, 2, and 3 months. Compatibility study was carried out by comparing the content of elements. At the same time, elemental determination was carried out on the corresponding raw and auxiliary materials of Shenlu Tablets to determine the source of the elements. Elements that were classified as 1, 2A, 2B (As,Cd,Pb,Hg,Co,V,Ni,Ag) were used as risk assessment elements using ICH Q3D. Risk elements in ginseng deer supplements were assessed according to "Chinese Pharmacopoeia" 2020 Edition Fourth General Chapter 9302 Harmful Traditional Chinese Medicine Guidelines.
The 20 elements showed a good linearty, with the correlation coefficient r of 0.997 3~0.999 9, the recovery rate of spiked sample of 92.7%~98.4%, and the recovery rate of drug packaging material of 82.1%~101.7%. The detection limits of all elements were within 0.000 17~0.17 μg·g-1. 19 elements except Hg were detected in Shenlu Tablets. Except for As, Ag, Sb, Hg, Bi, the other 15 elements were detected in the packaging materials used for the patch. Among the raw and auxiliary materials corresponding to Shenlu Tablets, the elements detected in the traditional Chinese medicinal materials are basically the same without obvious element aggregation. The compatibility results show that, compared with the results of the accelerated test in 3 months and in 0 months, six was no obvious migration of each element in the patch and the corresponding packaging material for the three batches of Shenlu Tablets. The maximum theoretical limit of 8 risk elements in Shenlu Tablets was compared with the average content of the accelerated test samples, and the average content of the samples was far less than the maximum theoretical limit L value.
The microwave digestion-ICP-MS was used to determine 20 elements in Shenlu Tablets with high precision, repeatability and stability. There is no significant difference in the contribution of different Chinese herbal medicines to the elements in Shenlu supplement, and there does not exist single source. Combining the results of compatibility and risk analysis, the compatibility between the drug and the packaging material is good, and the risk of element intake is low. This study helps comprehensively evaluate the safety and compatibility of the drug, providing a reference for the quality control of similar drugs and the establishment of element intake risk assessment.
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