ArchiveThere are many unmet clinical needs of antidepressants, such as slow onset of action and low remission rate. The high degree of difficulty in its research and development is related to the high cost of research and the limitations of current understanding of the pathogenesis of major depressive disorder. To facilitate pharmaceutical research and development practitioners and to keep abreast of the frontiers of antidepressant research and expand research ideas, this paper summarizes the clinical research status and pipeline analysis of antidepressants, and sorts out the current global antidepressant clinical research trends and clinical research direction of antidepressants in China.
This paper combs and analyzes the drug patent infringement cases in China from 1995 to October 2020. The empirical analysis was carried out from the dimensions of the year of case acceptance, the subject of litigation, the type of drug involved, the level of adjudication and the case conclusion. According to the above statistical analysis, the number of patent infringement cases of chemical drugs in China is the largest, accounting for 53.3%, followed by that of traditional Chinese drugs and biological drugs in China, accounting for 30.7% and 16%, respectively. In drug patents in China, the "basic patents" of drugs are mostly held by foreign companies that own the original patented drugs. They build patent portfolio around the "basic patents" and actively use patent litigation strategy. Combined with empirical research, this paper discusses the specific strategies of patent work of pharmaceutical companies in China.
The curative effect is the vitality of Traditional Chinese Medicine (TCM). The evaluation of curative effect is the main bottleneck restricting the development of TCM, and syndrome curative effect is the characteristic of TCM's curative effect. However, there is still a lack of scientific and feasible clinical efficacy evaluation system of TCM for the treatment of migraine. Based on accurate positioning and combining the characteristics of TCM with the evidence-based evaluation system, we can construct a reasonable clinical efficacy evaluation system and promote the transformation of TCM from experience to evidence. By summarizing the previous clinical research of our team, the author preliminarily constructed a set of clinical efficacy evaluation system of TCM for treating migraine with TCM connotation, in order to break down the barrier of TCM clinical efficacy evaluation for migraine and promote the development of TCM clinical research.
In order to implement the new regulatory policy for radiopharmaceuticals and adapt to the new trend of industry and development of nuclear medicine, this research combining with the working experience of radiopharmaceutical inspection proposes, suggests on the development of inspection institutions and the effective connection between supervision and inspection using review of regulations and literature, expert interviews. It is recommended that the provincial drug inspection agencies should accelerate to expand the qualification of radiopharmaceutical inspection in order to meet the requirement of territorial supervision and solve the problems that do not match the current industrial development. It is also recommended to clarify the requirements for the initiation of production license inspection and medical institution filing inspection, further improve the working procedures for the connection between supervision and inspection, and effectively play the supporting role of inspection technology.
Abrocitinib is a selective small-molecule Janus kinase-1 inhibitor. It was approved by the U.S. FDA for the treatment of adults with refractory, moderate-to-severe atopic dermatitis on January 14, 2022. It is the third oral JAK inhibitors for atopic dermatitis in the world, slightly later than baricitinib and upadacitinib developed by Incyte and AbbVie, respectively. Although the U.S. FDA label contains a black box warning against JAK inhibitors, safety data from clinical trials reveal a manageable tolerability and longer-term safety. This paper introduces the mechanism of action, dosage and administration, pharmacokinetics, clinical studies and safety evaluation of the drug.
Camptothecin is a kind of quinoline alkaloid and is also a natural topoisomerase I inhibitor isolated from Camptotheca involucrata. After complexing with topoisomerase I-DNA, camptothecin prevents DNA replication and RNA synthesis, indicating an anti-tumor effect. Clinical studies have shown that camptothecin and its derivatives have good antitumor activity. However, the high toxicity and low bioavailability limited its clinical application. Novel drug delivery systems can make up the defects through enhancing the drug stability, bioavailability and targeting ability to improve the anti-tumor effect, which can help reduce the toxicity, and solve the problems of camptothecins to a certain extent. This paper analyzes and summarizes the research progress of camptothecin-based antitumor drug delivery systems in recent published literatures, in order to provide theoretical guidance and suggestion for the development of new preparations of camptothecins that meet the needs of clinical applications.
Direct data capture (DDC) by means of digital health technology (DHT) has been played a significant role in the evaluation of clinical benefits in either traditional centralized clinical trials or novel decentralized clinical trials of medicinal products. As a part of e-source data, a trial execution with the regulatory compliance of the DHT is one of the challenges in clinical data flow managements. In the views of developmental trends in GCP and global regulatory and supervisory requirements, DHT applications in clinical trials should meet the validation standards of an e-clinical system, conforming to the ALCOA principle regarding the trial data flow managements with roles and qualifications of relevant stakeholders, such as sponsors, investigators and subjects. In the standpoints of project management views, this paper discusses how the DHT application is complied with regulations, rational monitoring and supervisions on the DHT data flow, and responsibilities of relevant stakeholders, ensuring the approvability of clinical outcomes on DHT-based clinical data by regulatory authorities.
To sort out the previous on-site inspection of clinical trial data by the Center for Food and Drug Inspection (CFDI) of National Medical Products Administration (NMPA), to analyze and discuss the concerns and requirements of common problems in on-site inspection of drug clinical trial data after the implementation of the 2020 Good Clinic Practice (GCP), and to provide reference for the implementation and management of clinical trials.
We collected unqualified situation of the on-site verification of hospital's acceptance of CFDI data since July 22, 2015. A total of 21 items of clinical trials were included, among which 135 items were unqualified. For the common problems in the past non-conformities, the concerns and requirements of the 2020 version of GCP and on-site inspection were analyzed.
The previous unqualified items mainly focused on process records, as well as inspection and inspection of data traceability, program execution, safety event records, management and records of investigational drugs, biological sample circulation management, and the integrity of related data chains. The 2020 GCP and on-site verification points were quite different from the previous requirements regarding common problems in on-site verification of clinical trial data.
Under this new situation, it is necessary to change the previous concepts and rules, and carry out drug clinical trials according to the concerns and requirements of the 2020 version of GCP and the data on-site verification of drug clinical trials.
To investigate whether licorice extracts (LE) combined with iron death inducer Erastin can induce iron death of colorectal cancer cell DLD1 through dipeptidyl peptidase-4 (DPP4).
DLD1 cells were randomly divided into control group, L-LE group (50 μg·mL-1 LE), H-LE group (100 μg·mL-1 LE), H-LE+Erastin group (100 μg·mL-1 LE+30 nmol·L-1 Erastin) and H-LE+Erastin+Sita (DPP4 inhibitor) group (100 μg·mL-1 LE+30 nmol·L-1 Erastin+31.25 μg·mL-1 Sita), with drug interventions for 24 h. Cell cloning assay and Edu-594 cell proliferation test were conducted to determine the cloning and proliferation abilities of the cells. ELISA assay was used to detect the Fe2+ content and DPP4 activity. Flow cytometry was used to detect reactive oxygen species(ROS) content. Western blotting was used to detect the expression of solute carrier family 7 member 11(SLC7A11) and arachidonate lipoxygenase 3(ALOXE3) proteins.
Compared with control group, the cell cloning number decreased while the ROS content increased in L-LE group, H-LE group and H-LE+Erastin group (P<0.05 or P<0.01); and the proliferation ability and Fe2+ content decreased, DPP4 activity and ALOXE3 protein expression increased, SLC7A11 protein expression decreased in H-LE and H-LE+Erastin groups (P<0.05 or P<0.01). Compared with H-LE+Erastin group, the addition of Sita significantly increased cell cloning, proliferation and SLC7A11 protein expression, while significantly decreased Fe2+ content, DPP4 activity, ROS content and ALOXE3 protein expression (P<0.01).
LE combined with Erastin can induce iron death of colorectal cancer (CRC) cell through DPP4.
to investigate the therapeutic effect and possible mechanism of baicalein on ulcerative colitis induced by dextran sulfate sodium salt (DSS) in mice.
A total of 42 male BALB/c mice were randomly divided into 6 groups (n=7), including control group, model group, baicalein groups (low-dose, medium-dose and high-dose) and mesalazine group (positive). The UC model of mice was established by 4% DSS. After the model was successfully established, the control group and the model group were given distilled water ad libitum, baicalein suspension of 10, 20, and 40 mg·kg-1, and the positive drug mesalazine 600 mg·kg-1, ig, for 14 days. The disease activity index (DAI) was calculated and evaluated, the changes of colon histopathology were observed by hematoxylin-eosin (HE) staining, and the levels of lipopolysaccharide (LPS) and secretory immunoglobulin A (sIg A) in serum were measured by ELISA. The expression levels of interleukin-6 (IL-6), tumor necrosis factor α (TNF-α) and nuclear factor of activated B(NF-κB) were detected by Western blotting.
Baicalein decreased DAI index of UC mice, decreased the protein expressions of IL-6, TNF-α and NF-κB in colon tissue, decreased the serum levels of LPS, and increased the content of sIg A in serum.
Baicalein reduced the inflammatory response and enhanced the immunity of UC mice, and the mechanism is related to regulating the expression of NF-κB in colon.
To establish the processing method of the classic wine angelica in Wenjing decoction and the HPLC fingerprint of the decoction pieces of angelica in order to provide reference for the follow-up Wenjing decoction preparation research.
By consulting ancient books and combining modern technology and methods, the washing, moisturizing, cutting, drying and other processes were optimized to obtain angelica tablets. The dosage and moistening time of Chinese angelica yellow wine were optimized through single factor investigation. Combining "gentel fire dry" operation key points, three processing parameters, i.e., frying temperature, frying time and frying speed, were observed by L9(34) orthogonal experiment. Taking traits, moisture (%), extract (%) and ferulic acid content (%) as the inspection indicators, the entropy weight method is used to calculate the composite score, and the processing technology of distilled angelica is optimized. The fingerprint of Danggui decoction pieces was established by HPLC using Techmate C18 column (250 mm×4.6 mm, 5 μm), and acetonitrile (A)-0.2% phosphoric acid water (B) was used as the mobile phase system for gradient elution. The detection wavelength was set at 280 nm, the column temperature was 30 ℃, the flow rate was 1.0 mL·min-1.
The best processing method of Angelicae sinensis Radix processed with yellow wine and the HPLC fingerprint of decoction pieces of Angelicae sinensis Radix processed with yellow wine were established, and 4 main common peaks were identified, namely chlorogenic acid, ferulic acid, ligustilide, and ligustalide I. The content determination methods of the four components were established.
The established processing method of Angelicae sinensis Radix using yellow wine is stable and feasible, and its fingerprint can provide a reference for the development and research of Wenjing decoction.
To prepare and optimize the formulation of resveratrol in situ floating gel using common gel materials with high safety and good biocompatibility, in order to obtain a temperature-sensitive gel that can float and continuously release drug in bladder and can be used for bladder perfusion in chemotherapy of bladder cancer.
The gel was prepared by cold dissolution method. Poloxam 407, Poloxam 188, sodium alginate, calcium carbonate and ammonium bicarbonate were used as main excipients. Gelling temperature and gelling time were selected as the indicators to optimize the quantity of poloxamer 407, poloxamer 188 and calcium carbonate in formulation by central combination-response surface method. Temperature sensitivity, floating performance and drug releasing performance of the optimized formulation were evaluated.
The optimal formulation was composed of resveratrol 30%, Poloxam 407 17.2%, Poloxam 188 5.5%, sodium alginate 0.15%, calcium carbonate 0.06%, ammonium bicarbonate 0.15%. The gelling temperature was 28~29 ℃ and the gelling time was 50 s. The drug were released from the gel in a way of diffusion for more than 48 days.
The resveratrol in situ floating gel had the property of continuous drug release for a long time in bladder. It can be used as an alternative form of bladder perfusion chemotherapy in the treatment of bladder cancer to improve patient compliance.
Insulin degludec and insulin detemir are the third generation of insulin analogues that are chemically modified on long chain aliphatic acid. It is necessary to establish a specific and sensitive liquid chromatography-tandem mass spectrometry method for the determination of amino acid sequences of chemically modified insulin analogues.
The separation was achieved by an ACQUITY UPLC peptide BEH C18 column (100 mm×2.1 mm, 1.7 μm,300 Å) with a mobile phase of 0.1% FA/H2O as Solvent A and 0.1% FA/acetonitrile as Solvent B in a gradient mode. The flow rate was set at 0.3 mL·min-1. MSE was used as the detection mode of mass spectrometry, and the collision energy was 30~40 eV.
The coverage rate of insulin degludec and insulin detemir sequences was good as expected, and the fragment ion y1& was detected by chemical modification. RSD% of ionic strength of medium and high strength ions was within 15%. Both insulin sequences can be effectively distinguished it from other unmodified ones.
A liquid mass spectrometry method for amino acid sequences of adipose-side chain modified insulin analogs with good repeatability, specificity and durability was established, providing reference for the research method of sequence structure of this kind of products.
This article aims to deeply implement the centralized drug volume-based procurement policy issued by the General Office of the State Council, according to "Opinions on Promoting the Normalization of Centralized Bulk Procurement of Drugs" (by State Council Office [2021] No.2), promote rational use of drugs and guarantee the medication safety, as well as ensure the management normalization of centralized procurement of drugs based on the official standard in medical institutions at all levels. In June 2021, the Chinese Pharmacists Association, together with the First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Xuanwu Hospital of Capital Medical University, Shanghai Changzheng Hospital, Guangdong Provincial People's Hospital, Sichuan Provincial People's Hospital, Xijing Hospital of Air Force Military Medical University, the First Bethune Hospital of Jilin University, and Henan Provincial People's Hospital, gathered up 302 scholars as co-leaders from 128 first-class hospitals in 31 provincial areas. The first draft of Consensus of Chinese experts on the Implementation of Scientific Management of National Centralized Drug volume-based Procurement in Medical Institutions, co-authored by those experts, was released to gather public opinions on the official website of the Chinese Pharmacists Association in July 2022. Meanwhile, in order to draw on the scientific management measures taken by medical institutions of different levels to implement the centralized bulk procurement policy, we have collected suggestions from 276 experts and scholars from 201 medical institutions (including 46 community medical institutions) nationwide. It is proved that the reached consensus can be a good reference for wide-range areas. The Consensus is based on the whole process of centralized bulk procurement of drugs carried out in medical institutions, and focuses on the practice, providing individualized and targeted management measures and guidance for rational use of drugs in clinical settings. Refined management of the procurement process have been achieved by doing so, which contributes to the normalization of the centralized bulk procurement.
To analyze the characteristics of perampanel-related treatment emergent adverse events (TEAEs), providing references for clinical rational drug use.
The literatures about TEAEs caused by perampanel were retrieved from databases like CNKI, Wanfang, VIP, PubMed, ScienceDirect and Web of Science. The cases were divided into treatment group and overdose group according to the drug dose.
A total of 20 literatures including 25 cases were reported, with 14 cases in the treatment group and 11 cases in the overdose group. Most TEAEs occurred within 60 days after drug administration in the treatment group (8 cases, 32.00%), mainly involving TEAEs in mental system (7 cases, 28.00%) and nervous system (3 cases, 12.00%). The TEAEs occurred in the treatment group were relieved after withdrawal and/or symptomatic treatment. All TEAEs mainly occurred in nervous system (9 cases, 36.00%) and the mental system (5 cases, 20.00%) on the day of medication in the overdose group, among which 9 cases were completely improved, and 2 cases had sequelae after treatment.
TEAEs caused by perampanel should be paid attention to, and medication education should be strengthened to avoid the occurrence of serious TEAEs and ensure the safety of clinical medication.
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