Latest ArticlesThe efficacy of interleukin (IL)-2 in tumor immunotherapy is remarkable, but its adverse reactions greatly limit its further clinical application. In recent years, researchers have tried to improve or regulate the receptor selectivity of IL-2, that is, selectively bias the activation of IL-2Rβγ and reduce or even completely do not bind to IL-2Rα, so as to preferentially activate CD8+ T cells with tumor killing function and maximize the immune activation of IL-2. The main development strategies of receptor biased IL-2 include polyethylene glycol chemical modification and site-specific mutation technology. Currently, the drugs under research include NKTR-214, THOR-707, SHR-1916, TransConIL-2β/γ, 8MW2311,RG7461, FSD13, IBI363, etc. But none of them have been successfully developed yet. Further in-depth research on their mechanisms of action is required, or various drug development strategies need to be used in combination.
The use of polyethylene glycol (PEG) modified drugs or nano-carriers is a widely accepted method that can effectively improve therapeutic effects of drugs in vivo. However, PEGylated drugs are usually immunogenic in vivo and can trigger the secretion of anti-PEG immunoglobulin IgG and IgM, leading to a significant increase in blood clearance efficiency of drugs and the occurrence of hypersensitivity reactions. The physicochemical properties of PEG molecules,drugs, or drug carriers will affect the secretion of anti-PEG antibodies, and the PEG modification density and administration frequency will also affect the immunogenicity of PEGylated drugs. Optimizing the causes and influencing factors is an effective method to improve the immunogenicity of PEGylated drugs in vivo. PEG alternative biomaterial is a new direction of drug research and development.
Isavuconazole is the latest triazole broad-spectrum antifungal drug that has been approved for the treatment of invasive aspergillosis and mucormycosis in adults. When isavuconazole was initially marketed abroad, many international guidelines did not recommend or weakly recommended it for routine therapeutic drug monitoring. However, a number of recent studies and expert consensus have emphasized that specific populations can be monitored for the use of isavuconazole based on clinical needs. Based on domestic and international real-world studies, this article provided a review of the specific situations leading to therapeutic drug monitoring of isavuconazole, including liver insufficiency, abnormal body mass index, children, CYP3A5*1/*3 genotypes, multi-drug therapy, long-term medication, and receiving special treatment or medication regimens, in order to provide reference for the clinical rational application of isavuconazole.
As the first dual receptor agonist of glucose-dependent insulin-stimulating polypeptide and glucagon-like peptide-1 used for chronic weight management, tirzepatide achieves weight loss by delaying gastric emptying and reducing energy intake, and its therapeutic effect on obesity is significant and its safety is high. Tirzepatide can also improve a variety of cardiometabolic risk factors, such as reducing blood sugar, lowering blood pressure, and improving blood lipids. In the future,it is expected to treat obesity with cardiovascular and cerebrovascular diseases, respiratory diseases, liver diseases, etc, with broad application prospects. This article reviewed the pharmacokinetics, mechanism of weight loss, clinical application and safety of tirzepatide.
To investigate the impact of erianin on the development of pancreatic cancer by regulating cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) signal pathway.
SW1990 cells were divided into control group, low-, medium- and high-concentration erianin groups (10, 20, 40 nmol·L-1), RU.521 (cGAS inhibitor)group (1 μmol·L-1), and erianin (40 nmol·L-1) +RU.521 (1 μmol·L-1) group. The proliferation was detected by CCK-8 method, and apoptosis was detected by flow cytometry. The migration and invasion of SW1990 cells were detected by scratch test and Transwell test, respectively. Western blot was applied to detect the protein expressions of cyclin D1, Bcl-2 associated X protein (Bax), matrix metalloproteinase (MMP)-2, MMP-9, cGAS and STING in SW1990 cells. SW1990 cells were co-cultured with NK cells for 48 hours, the levels of granzyme B and perforin (PF) in co-culture supernatant were detected by ELISA, and NK cell killing activity was detected.
Compared with the control group, the cell proliferation rate,the rate of scratch healing, the number of invasive cells were decreased in the low-, medium- and high-concentration erianin groups, the protein expressions of cyclin D1, MMP-2, MMP-9 were decreased, the apoptosis rate was increased, and the protein expressions of Bax, cGAS and STING were decreased in a concentration-dependent manner (P<0.05), while the change trends of the above indexes in the RU.521 group were opposite (P<0.05). Compared with the high-concentration erianin group, the cell proliferation rate, scratch healing rate, the number of invasive cells, and the protein expressions of cyclin D1,MMP-2, MMP-9, Bax, cGAS and STING in the erianin +RU.521 group were increased, and the apoptosis rate was decreased (P<0.05). In the co-culture experiment, compared with the control group, the levels of granzyme B and PF and NK cell killing activity in the cell supernatant of the low-, medium- and high-concentration erianin groups were increased in a concentration-dependent manner (P<0.05), while the change trends of corresponding indexes in the RU.521 group were opposite (P<0.05).Compared with the high-concentration erianin group, the levels of granzyme B and PF and NK cell killing activity in the erianin+RU.521 group were decreased (P<0.05).
Erianin may inhibit the proliferation, migration, invasion,and immune escape of pancreatic cancer cells and promote cell apoptosis by activating cGAS-STING signaling pathway.
To investigate the effects of cordycepin on cartilage repair, serum inflammatory factors and oxidative stress in rats with osteoarthritis.
Forty-five rats were randomly divided into control group, model group and low-,medium-, and high-dose cordycepin groups (10, 20, and 50 mg·kg·d-1 by gavage) . The knee osteoarthritis model has been established using Hulth method. One week after modeling, rats in each group were administered the corresponding doses of cordycepin by gavage for 28 days. HE staining and Alcian blue staining were used to observe and compare the cartilage morphology of each group. MicroCT was used to detect and calculate the bone volume fraction, bone area fraction, trabecular bone thickness and trabecular bone number. The expression of cartilage matrix protein was detected by Western blot. The contents of interleukin (IL)-6, tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1 and IL-10 in serum of rats were determined by ELISA. The levels of oxidative stress markers in serum were detected by the kits.
Compared with the control group, cartilage tissue were showed significant pathological damage in the model group, bone volume fraction and bone area fraction were increased, and trabecular thickness and number were decreased (P<0.05); the protein expression levels of sex determining region Y-frame protein 9 (SOX-9), aggrecan, and collagenⅡ were decreased (P<0.05); the levels of IL-6, TNF-α, and MCP-1 in serum were increased, SOD and GSH activity were decreased, and MDA content was increased (all P<0.05). Compared with the model group, the pathological damage of knee cartilage tissue were significantly alleviated in the medium- and high-dose cordycepin groups, the bone volume fraction and bone area fraction were decreased, and trabecular thickness and number were increased ( P<0.05); the protein expression levels of SOX-9, aggrecan, and collagen Ⅱ were increased (P<0.05); serum IL-6, TNF-α, MCP-1 contents were decreased, IL-10 content was increased, MDA content was decreased, and SOD and GSH activity were increased (all P<0.05), showing a dose-dependent trend.
Cordycepin can reduce cartilage damage in rats with osteoarthritis by reducing inflammation and oxidative stress.
To explore the effect of cyclosporin blood drug concentration on the efficacy and safety of cyclosporin on patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the transplant bin.
Clinical medical records of 94 allo-HSCT patients were collected. The first day of stem cell infusion was +1 day (d), and the transplantation time was divided into four groups: group A (-9 d to -1 d), group B (+1 d to +7 d,) group C (+8 d to +14 d) and group D (+15 d to +21 d). The plasma concentration of cyclosporin and its influencing factors,cell implantation, liver and kidney function indexes, acute graft-versus-host disease (aGVHD), and the occurrence of cyclosporin-related adverse reactions were observed in different periods and their relationships with the plasma concentration of cyclosporin were analysed. Receiver operating characteristic (ROC) curve was used to analyze the value of serum concentration of cyclosporin at different time periods in predicting safety.
The concentration of cyclosporin in allo-HSCT patients was 128 (99,160) ng·mL-1, with statistically significant differences between different time periods (P<0.001). In allo-HSCT patients, the implantation rate of leukocyte, platelet, and neutrophil in +21 d was 94%, 64%, and 51%, respectively. The incidence of liver injury, kidney injury, and aGVHD was 47% (44/94), 71% (67/94), and 16% (15/94), respectively. ROC analysis showed that the warning value of cyclosporin blood concentration in the group A for liver injury and kidney injury was 128.5 ng·mL-1 and 113.5 ng·mL-1, respectively, while the area under the curve was 0.712 (95%CI：0.578 to 0.847，P=0.002) and 0.752 (95%CI：0.637 to 0.868，P<0.001), respectively.
There are many factors affecting the blood concentration of cyclosporin which can affect the clinical efficacy and safety. Timely and accurate monitoring of cyclosporin blood concentration can better guide the clinical treatment of allo-HSCT patients in the transplant bin.
To explore the research hotspots and development trends of global drug regulatory science, and to provide reference for promoting the sustainable development of drug regulatory science in China.
The literatures related to drug regulatory science published from 1991 to 2023 was searched from Web of Science database, and the contents of time distribution, author, institution, country / region and keywords were analyzed by CiteSpace 5.8.R3.
A total of 540 papers were included, and the annual number of published papers showed a stable growth trend. Foreign regulatory scientific research started early, and now it has formed a relatively complete regulatory scientific development system, and formed a relatively close cooperative relations among countries and institutions. Drug regulatory science research has evolved from an initial stage to a stage of refined research around new tools, standards, and methods; research hotspots include drug development, risk assessment, biomarkers, etc.
China’s drug regulatory authorities can increase policy guidance, strengthen basic theoretical research and applied capacity building, promote interdisciplinary joint research, and build a multidisciplinary academic exchange platform in order to accelerate the development of drug regulatory science.
AIM To evaluate the effectiveness, safety and economy of lorlatinib in anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) patients, and provide evidence for clinical treatment. METHODS Databases such as PubMed, Cochrane Library, CNKI, Wanfang Data, and VIP and Health Technology Assessment (HTA) related websites were searched to collect HTA reports, systematic evaluation/meta-analysis and pharmacoeconomic evaluation of loratinib for ALK positive NSCLC. Select the literature according to the inclusion and exclusion criteria, extract the data, and evaluate the literature quality. Qualitative description was performed. RESULTS A total of 16 literatures were included, involving 11 systematic review/meta-analysis and 5 pharmacoeconomic evaluation. In terms of effectiveness，compared with other ALK-tyrosine kinase inhibitors (TKIs) and chemotherapy as first-line treatment, lorlatinib significantly prolonged the progression free survival (PFS) in ALK positive NSCLC patients. Compared with chemotherapy as a second- or third-line treatment, lorlatinib significantly prolonged PFS and overall survival. In terms of safety, there was no statistical difference among the ALK-TKIs and chemotherapy in the incidence of adverse events (AEs) of grade≥3, but the incidence of lorlatinib was relatively high. In regards to the serious AEs and AEs leading to treatment discontinuation, lorlatinib was the lowest. In terms of economy, lorlatinib was not cost-effectiveness compared to ensartinib and crizotinib in China, but lorlatinib was cost-effectiveness compared to chemotherapy as a second- or third-line treatment in Greece and Sweden. CONCLUSION Lorlatinib shows good efficacy and safety for ALK positive NSCLC, but its cost-effectiveness after price reduction in China needs further evaluation.
Malignant lymphoma (ML) is a heterogeneous malignant tumor in the hematological system, the existing treatment methods can not meet the clinical needs, and the rapid rise of new treatment schemes has improved the survival benefits of patients with recurrent or refractory ML. Antibody-drug conjugate (ADC), as a new type of highly effective anti-tumor drug composed of monoclonal antibodies specifically targeting tumor cell surface antigens, coupled with small molecular cytotoxic loads through chemical connectors, has attracted much attention in the application prospect of malignant lymphoma. Several ADCs have been approved for the treatment of ML, including brentuximab vedotin, inotuzumab ozogamicin, moxetumomab pasudotox, polatuzumab vedotinands, loncastuximab tesirine, etc. These drugs can exert anti-tumor effects by targeting CD30, CD22, CD79b, CD19, etc. on the surface of tumor cells with good efficacy and safety.
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