ArchiveTo analyze the absolute lag and relative lag time of new drug approvals in China from 2011 to 2021 and reasons causing the lag, and to preliminarily explore the potential factors that affect the new drug launch lag.
The information on new drugs approved for marketing in China, the United States, the European Union and Japan was collected from 2011 to 2021. The durations between the time when the new drugs approved for marketing in China were first approved for marketing in the world were calculated to analyze absolute lag and relative lag in China. Multiple regression analysis was used to determine the factors related to drug lag.
During the period from 2011 to 2021, a total of 280 new drugs were approved in China, among which 180, 82 and 154 drugs exist absolute lags with the United States, the European Union and Japan, respectively. The median duration of the overall relative lag was 1 359 days. The median length of the lag gradually increased from 2011 to 2014, and reached a peak (3 438 days) in 2014; the median length dropped significantly from 2015 to 2018; the median length in 2019 to 2021 decreased year by year. The overall lag in 2020 and 2021 were below the overall median lag, 1 134 days and 500 days respectively (B=-1 153.840, P<0.05). New drugs in theraprutic area of sensory organs were related to a shorter median approval lag, and new drugs of orphan drug designation (B=441.147, P<0.01) and classified as biological products (B=502.205, P<0.01) were related to a longer median approval lag.
In the past years of 2011—2021, the drug lag issue in China has been significantly improved, but the lag phenomenon still exists in new drugs in various therapeutic fields. Under the background of the new policy implement, key factors to reduce the delay in the launch of new drugs include further improving the quality and efficiency of new drug review and approval, strengthening the communication between government approval agencies and applying companies, connecting with international common rules, and encouraging companies to conduct international multi-center clinical trials.
Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products Draft Guidance for Industry was launched by FDA on March 21, 2022. It provides CAR-T cell specific recommendations regarding chemistry, manufacturing, and control (CMC), pharmacology and toxicology, clinical study design, and other important aspects. To provide references for sponsors, this article mainly introduces the clinical considerations for early-phase development of CAR-T cells for patients with cancer (hematologic malignancies and solid tumors), including study population, treatment plan, clinical pharmacology considerations, safety evaluation and monitoring, CAR-T cell persistence and long term follow-up, and allogeneic CAR-T cells. This article also introduces the information of chimeric antigen receptor T cell products in China, and discusses the similarities and differences of the clinical review of such products by regulatory agencies between China and the United States.
In recent years, microneedle technology has been widely used in the research of transdermal drug delivery due to its unique mechanism of opening the stratum corneum barrier. Nanotechnology has also received extensive attention in the field of transdermal drug delivery due to its excellent solubility enhancement, high drug stability, targeted drug release, and sustained and controlled release properties. However, the researchers found that both technologies have obvious defects in transdermal drug delivery, such as inability of microneedle technology to improve the solubility of poorly soluble drugs, and poor stratum corneum penetration ability of nano-formulations, which will limit the application of the two technologies in transdermal drug delivery. At present, some scholars have tried to combine nano-formulations with microneedles to improve the physicochemical properties of drugs and achieve targeted drug delivery as well as controlled drug release, synergistically enhancing the effect of drug transdermal delivery and promoting the efficient application of drugs. Therefore, this article will briefly introduce the advantages and disadvantages of some microneedles and nano-formulations, and further summarize the advantages, applications, and prospects of nano-formulations combined with microneedles.
As the latest generation of sodium-glucose cotransporter-2 inhibitors (SGLT2i), ertugliflozin (ERT) has stable molecular structure, long half-life, significant hypoglycemic effect and good tolerance. It also has the protective effect of heart independent of its hypoglycemic activity. It is recommended as a priority treatment for the patients with type 2 diabetes mellitus (T2DM) complicated with atherosclerotic cardiovascular disease (ASCVD) in China and abroad. In addition, ERT has a concrete effect on controlling the body weight of T2DM patients, thus also has the value in the treatment of T2DM patients with obesity. However, ERT is not recommended to be used in those T2DM patients with renal insufficiency due to low safety profile.
Primary biliary cholangitis (PBC) is a chronic progressive autoimmune cholestasis, which eventually leads to liver fibrosis and cirrhosis, but the pathogenesis is not totally clear. With the further under standing of the disease and the higher level of clinical diagnosis, the prevalence of PBC in China is on the rise. At present, only ursodeoxycholic acids and obeticholic acid are officially approved for the treatment of PBC around the world, therefore there are limited treatment options and unmet clinical needs. Several drugs with different targets are under development in China and abroad. This paper briefly summarizes the clinical development experiences of the drugs, in order to provide reference for research and evaluation.
Tumor immunotherapy is a major breakthrough in the history of tumor therapy. New immunooncological drugs targeting PD-1/PD-L1 and CAR-T cells have achieved gratifying clinical efficacy. However, due to the complexity and particularity of tumor immune microenvironment, it is difficult for a single target treatment mode to achieve a lasting response. Recurrence, metastasis and resistance are still difficult for most advanced cancer patients to overcome. Recently, PD-(L)1/TGF-β bispecific antibodies have become a hot spot in the research of tumor immunomodulatory drugs, which contains two functional domains and interacts with PD-(L)1 and TGF-β simultaneously to restore the activity of T cells and enhance the immune response. This paper mainly analyzes the clinical research progress of PD-(L)1/TGF-β bifunctional antibodies, which have been developing rapidly in recent years. We further analyze the existing problems and make an outlook on the prospect of dual-target tumor immunotherapy, in order to provide basis and reference for bifunctional or multifunctional drugs.
To systematically explore the correlation between serum tacrolimus trough concentration (C0) and the efficacy in patients with systemic lupus erythematosus (SLE), and to obtain the effective concentration threshold of tacrolimus in such patients, so as to provide reference for the safety and efficacy of clinical medication.
The clinical and laboratory data of SLE patients treated with tacrolimus in our hospital from January 2016 to December 2021 were collected retrospectively, including demographic information (sex, age, height, and weight), course of disease, results of laboratory test, medication, monitoring data on blood concentration and clinical response, and efficacy and safety were evaluated. The correlation between C0 and efficacy was analyzed, and the threshold of effective concentration of tacrolimus was determined by receiver operating characteristic curve (ROC).
A total of 72 patients who met the criteria were included in this study, and 176 monitoring data of C0 (0.1~10.3 ng·mL-1) were collected. There was a weak correlation between daily dose of tacrolimus and C0 (r=0.326). With the prolonging of time of tacrolimus treatment, there was no significant change in C0, and there was significant difference in complement C3 among different blood concentration groups (P<0.05). There was no significant difference in other biochemical indexes. In the effective concentration study, 124 monitoring results of blood concentration in 59 patients with long-term of tacrolimus treatment (tacrolimus >3 months) were analyzed. They were divided into effective group (76 cases) and ineffective group (48 cases) according to clinical manifestations and biochemical indexes. Binary logistics regression analysis showed that C0 had a significant effect on the curative effect of the patients (P<0.001). The area under ROC curve (AUC) is 0.763 (P<0.001, 95%CI: 0.674~0.851).
This study showed that the drug dose affected the blood concentration of tacrolimus in patients with SLE, and there was a correlation between the plasma concentration of tacrolimus and the curative effect. The threshold of its effective concentration was determined by ROC curve analysis, which is 1.55 ng·mL-1.
To analyze the effect of Wuzhi capsule on tacrolimus concentration and clinical efficacy.
The Chinese databases of Wanfang, CNKI and Weipu were searched to collect the relevant studies on the effect of Wuzhi capsule on the plasma concentration and clinical efficacy of tacrolimus in patients with nephrotic syndrome. The literatures that met the standards were included, and the effective data were extracted. SPSS 27.0 statistical software was applied for analysis.
A total of 4 studies were included, and the statistical analysis results showed that Wuzhi capsule improved the plasma concentration of tacrolimus and standardized plasma concentration, and the difference was statistically significant (P<0.05). The 24-hour urine protein level in drug combination group was lower than that in single drug group, and the plasma albumin level was higher.
Wuzhi capsule can significantly improve the plasma concentration of tacrolimus and clinical efficacy in patients with nephrotic syndrome.
To explore and analyze the clinical efficacy and safety of doxazosin mesylate sustained release tablets in the treatment of postoperative bladder spasm after electroprostatectomy (TURP).
A total of 110 patients receiving TURP admitted to our hospital from March 2020 to May 2022 were selected and randomly divided into control and observation groups, with 55 cases in each group. The control group was treated with doxazosin mesylate sustained release tablets after TURP operation, and the observation group was treated with diclofenac sodium supposal anal plug on the basis of oral treatment. The results of occurrence time and frequency of postoperative bladder spasm, visual analog scale (VAS), duration of bladder flushing solution dilution, catheter indwelling time, postoperative hospital stay and incidence of adverse reactions were compared between the two groups.
In the observation group, the duration of postoperative bladder spasm was shorter, the frequency was less, and the VAS score was lower than that in the control group 0 to 24 h, 24 to 78 h and 48 to 72 h after surgery, with statistically significant differences (P<0.05). Compared with the control group, the observation group had a significantly shorter duration of bladder flushing fluid dilution, catheter indwelling time and postoperative hospital stay (P<0.05). There was no significant difference in the incidence of postoperative adverse reactions between the two groups (P>0.05).
The application of doxazosin mesylate combined with diclofenac sodium in the treatment of postoperative bladder spasm after TURP has a singnificant effectwith high safety. It can effectively shorten the occurrence time of bladder spasm, reduce the frequency of incidence, relieve the degree of pain and shorten the duration of clinical symptoms. There is no obvious adverse reactions during medication.
In recent years, pediatric clinical research has been strongly supported by the state in China. The participation of characteristic pediatric clinical research coordinator (CRC) in pediatric clinical research is urgently in need. However, due to the particularity of pediatric patients, pediatric CRC may face a higher dilemma than that of adult clinical research. This article summarizes the basic situation of pediatric CRC in China, analyzes the difficulties faced by pediatric CRC in combination with our own experience, and the possible solutions are put forward. We hope to promote the healthy development of pediatric CRC industry, which can further ensure the quality of clinical trials.
To predict the mechanism of Polygonum multiflorum Thunb. on attenuating lipid metabolism disorder by applying Network Pharmacology and Molecular Docking.
Using software ChemDraw, the chemical constituents of Polygonum multiflorum Thunb. were drawn and documented. Main active ingredients and potential targets of attenuating lipid metabolism disorder were screened out based on the databases like Swiss ADME, Swiss Target Prediction platform and Genecards, and DisGeNET. The drug-active ingredients-potential targets network structure model and PPI network are constructed through the software Cytoscape and STRING database, respectively. Potential targets were analyzed by GO enrichment analysis, KEGG pathway enrichment analysis and visualized. Using software PyMOL and AutoDock, the active ingredients were docked with core target molecules. The body weight and body fat rate of APP/PS1 mice with long-term intragastric administration were measured and the content of serum lipid (TG, TC, HDL-C, LDL-C) were detected.
A total of 30 active ingredients of Polygonum multiflorum Thunb. and 143 potential targets for the treatment of lipid metabolism disorder were obtained. The enrichment analysis shows that the common biological process of Polygonum multiflorum Thunb. and metabolic disorders are related to protein phosphorylation, protein binding, enzyme binding, protein kinase activity biological processes, and the signalling pathways of PI3K-Akt, HIF-1, estrogen are mainly involved in the major therapeutic role. Molecular docking predicts the stable connection structure between the active component and the core targets. The results of animal experiments showed that compared with the model group, there was no significant difference in weight between drug administered groups and the body fat rate decreased significantly (P<0.05). Steaming and sun-buring products had significant effect on the abnormal increase of TG and LDL-C, but crude Polygonum multiflorum Thunb. only had an impact on TG (P<0.05).
Polygonum multiflorum Thunb. has an significant lipid-attenuating effect. The mechanism is predicted to be related with three main active ingredients, including omega-hydroxytroxanin-8-methyl ether, Tricin and Kaempferolare, and PI3K-Akt, HIF-1 and Estrogen signaling pathways are affected through three core targets of EGFR, ESR1 and MMP9.
To extract and separate polysaccharide from Sophora tonkinensis Radix et Rhizoma (SRP), determine the monosaccharide composition and content of SRP, and investigate the antitumor effects of SRP in vitro.
SRP was prepared by water extraction and alcohol precipitation. The contents of polysaccharides, flavonoids, saponins, total phenols and proteins in SRP were determined by UV-Vis spectrophotometry, the contents of alkaloids were determined by high performance liquid chromatography (HPLC), and the content of organic acid was measured by back titration method. The monosaccharide analysis method of SRP was established by HPLC. A Waters X Bridge C18 column (250 mm×4.6 mm,5 μm) was used with acetonitrile: phosphate buffer (0.05 mol·L-1, pH=6.8) at the ration of 18∶82 as mobile phase, the flow rate was 0.8 mL·min-1, the column temperature was 30 ℃, and the detection wavelength was 245 nm. The contents of monosaccharides in SRP were determined and the mole ratio was calculated. MTT assay was used to detect the antitumor effects of SRP in vitro.
SRP, which is brown powder, was obtained by water extraction and alcohol precipitation with a yield of 3.95%. The contents of polysaccharides, flavonoids, saponins, organic acids and total phenols in SRP were 66.08%, 7.17%, 3.45%, 2.54% and 4.33%, respectively. No alkaloids and proteins were detected. SRP was composed of mannose, rhamnose, glucuronic acid, galacturonic acid, glucose, galactose and arabinose. The mole ratios were 1.25∶0.31∶0.28∶0.50∶40.47∶1.00∶10.46, and the percentage of polysaccharide was 64.97%. SRP had inhibitory effect on Hepa1-6, HepG2, HT29 and 4T1 cells in a concentration-dependent manner with IC50 of 770, 1 910, 1 870 and 1 880 μg·mL-1, respectively.
The SRP prepared in this study contained more than 60% polysaccharide and more than 80% known components, among which no alkaloids were detected. HPLC with pre-column derivatization of 1-phenyl-3-methyl-5-pyrazolo has good precision, reproducibility and accuracy, and is suitable for the monosaccharide composion analysis of SRP polysaccharides. SRP is a kind of heteroglycan with glucose and arabinose as the main components. SRP has significant cytotoxic effect by inhibiting tumor cell proliferation, suggesting that it may play a anti-tumor role. This study provides a reference for advancing the basic research of the composition and antitumor effect of SRP.
To prepare and evaluate the polymer micellar thermosensitive gel of Chinese medicine chrysanthemum volatile oil.
The polymer micelles were prepared by the ethanol injection method, and the preparation process was optimized by orthogonal experiments. The morphology, particle size and zeta potential of the polymer micelles were evaluated. The thermosensitive gel was further prepared using poloxamer 407 and poloxamer 188 as the matrix. The rheological properties of the thermosensitive gel were measured by a flat plate rheometer, the irritability of the thermosensitive gel to rabbit eyes was investigated using Draize eye irritation score, and eye tissues were examined by pathological examination.
The optimal preparation process of Chinese medicine chrysanthemum volatile oil polymer micelles thermosensitive gel was as follows: the concentration of chrysanthemum volatile oil was 15 μL·mL-1, the mass ratio of surfactant (TPGS∶phospholipid) was 3∶2, the concentration of surfactant was 37.5 mg·mL-1, and the mass ratio of phospholipids (HSPC∶DSPE-PEG2000) was 1∶1. The polymer micelles were closely arranged, spherical or quasi-spherical with the average particle size of (58.60±2.37) nm and zeta potential of (0.197±0.045) mV. The thermosensitive gel prepared with 21% mass fraction of poloxamer 407 and 3% mass fraction of poloxamer 188 was a pseudoplastic fluid with good rheological properties. The gel was basically non-irritating to rabbit eyes and had no irreversible tissue damage.
The prepared TCM chrysanthemum volatile oil polymer micelle thermosensitive gel has little irritation and good stability.
To investigate the status and tendency of utilization of drugs to prevent chemotherapy-induced nausea and vomiting in Nanjing so as to provide a reference for the management of rational clinical use of these drugs.
The drugs to prevent chemotherapy-induced nausea and vomiting used in 46 hospitals of Nanjing during 2018-2021 were analyzed statistically regarding their types, consumption sum, defined daily doses (DDDs) and defined daily cost (DDC).
The consumption sum of 5-hydroxytryptamine 3 (5-HT3) receptor antagonist in 46 hospitals of Nanjing increased at an average annual rate of 17.78% and 12.39%, respectively, between 2018 and 2020. In 2021, the consumption sum decreased by 46.21%, showing negative growth. The DDDs of 5-HT3 receptor antagonist increased slightly in 2019 and continued to decrease thereafter, with decreasing rates of 2.47% and 1.36%, respectively. The consumption sum and DDDs of the first generation 5-HT3 receptor antagonist decreased, while palonosetron, the second generation 5-HT3 receptor antagonist, increased steadily year by year. The consumption sum and DDDs of neurokinin-1 (NK-1) receptor antagonists increased significantly year by year. Fosaprepitant rapidly occupied the market of NK-1 receptor antagonist, which is about 20% market share in the first year and nearly 90% market share in the second year. In 2021, its DDDs increased by 923.44%. However, the consumption sum and DDDs of Aprepitant decreased significantly year by year.
The drug regimen for preventing chemotherapy-induced nausea and vomiting and the unreasonable application of fosaprepitant in Nanjing should be further paid attention to.
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