Latest ArticlesDepression is the most common psychological disease at present, but its pathogenesis is complex and has not been fully defined. More and more evidence shows that neuroinflammation plays an important role in the pathogenesis of depression. Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) is the key site of neuroinflammation. Moreover, NLRP3 inflammasome can also mediate cell apoptosis. Therefore, through reviewing the development of research on NLRP3 inflammasome, this paper explores its activation mode, composition, signal pathway regulation mechanism and related inhibitors, so as to provide new ideas and basis for the diagnosis and treatment of depression and the research and development of antidepressants.
Inflammation is a self-defense mechanism which is started when the body is infected or injured. As a common defense mechanism, inflammation is very common in clinic. If not treated in time, it may lead to a variety of more serious diseases. At present, most of the anti-inflammatory drugs used in clinic are chemically synthesized, but their side effects cannot be ignored, which has become an urgent clinical problem to be solved. Plant essential oil is extracted from aromatic plants, which has anti-inflammatory effect. This paper expounds the effective components, mechanism of action, synergy, and safety of plant essential oil for inflammatory pathogens, which can be used for reference for the future direction of scientific research on plant essential oil.
To analyze the pharmacokinetics of bicalutamide (50 mg) in healthy Chinese male volunteers and to evaluate the bioequivalence of domestic generic and reference bicalutamide (CASODEX®) in healthy Chinese male volunteers.
A randomized, open, two-cycle, two-sequence, and cross-over study with a 56-day washout period was conducted under fasting and postprandial conditions in healthy Chinese male volunteers (40 subjects/condition). Eligible subjects randomly received a single 50 mg dose of either the test or the reference formulation. A serial blood samples were collected over a 576-hour interval following drug administration. The concentrations of bicalutamide in EDTA-K2 human plasma were determined by the liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, with non-compartmental model used for pharmacokinetic analysis. The bioequivalence of the two preparations was determined according to whether the 90% confidence interval (CI) of Cmax, AUC0-t and AUC0-∞ geometric mean ratio was within the range of 80.00%~125.00%.
The pharmacokinetic parameters of the test and reference capsules under fasting condition are as follows: Cmax (1 030±196) and (898±167) ng·mL-1; AUC0-t (224 000±42 900) and (196 000±48 400) h·ng·mL-1, AUC0-∞ (243 000±56 900) and (212 000±60 100) h·ng·mL-1. The pharmacokinetic parameters of the test and reference capsules under fed condition are as follows: Cmax (1 260±164) and (1 210±153) ng·mL-1; AUC0-t (245 000±40 700) and (241 000±44 700) h·ng·mL-1; AUC0-∞ (266 000±55 700) and (259 000±57 000) h·ng·mL-1. The 90% confidential intervals of the GMRs of Cmax, AUC0-t and AUC0-∞ fall within bioequivalence criteria (80.00%~125.00%). No serious adverse event was observed.
The domestic bicalutamide formulation is bioequivalent to the reference formulation CASODEX®. Both formulations are generally well tolerated.
To investigate the inhibitory effect and potential mechanism of Yinyanghuo (epimedii folium, EF) alcohol extract on hepatitis B virus (HBV) based on in vitro experiments and network pharmacology.
The wild-type HBV stably replicating cell line HepG 2.2.15 cells were treated with EF alcohol extract and the drug toxicity was evaluated using CCK8 assay. The HBV DNA, HBsAg and HBeAg levels were detected by PCR-fluorescent probe "one-tube method" and ELISA, and the inhibition rate was calculated. The TCMSP and GeneCards databases were used to screen the main active ingredients of EF and HBV-related targets, and the drug-active ingredient-potential disease target network was constructed with Cytoscape software. GO and KEGG enrichment analyses were performed on the core targets using the DAVID database.
The CC50 value of EF alcohol extract alone on HepG 2.2.15 cells was 1.21 mg·mL-1, and the maximum inhibition rates for HBV DNA, HBsAg and HBeAg were 59.54%, 63.07% and 45.73%, respectively (P<0.05). While the control drug tenofovir disoproxil fumarate (TDF) did not show significant inhibition for both HBsAg and HBeAg (inhibition rate <20.00%). The maximum inhibition rate of EF alcohol extract combined with TDF was 93.66% on HBV DNA, and the maximum inhibition rates on HBsAg and HBeAg were 54.97% and 61.28%, respectively (P<0.05). A total of 23 candidate active ingredients of EF and 104 potential targets for HBV treatment were screened by network pharmacology analysis. GO enrichment analysis yielded 624 entries, including 442 biological processes, 73 cellular components and 109 molecular functions; and the KEGG analysis mainly focused on signaling pathways such as cancer pathway, PI3K-Akt, lipids and atherosclerosis, human papillomavirus infection and hepatitis B.
EF can effectively inhibit the replication of wild-type HBV, and the combination of EF and TDF has a synergistic inhibitory effect, especially on antigen inhibition. EF has the characteristics of multi-component and multi-target action against HBV, which can be predicted to play roles through multiple signaling pathways. The findings provide a theoretical basis for subsequent in-depth exploration of the mechanism of EF in the treatment of HBV infection.
To study the mechanism of action of DL-3-N-butylphthalide (NBP) on cerebral small vessel disease in diabetic rats based on Nrf2/HO-1 signaling pathway.
The successfully modeled diabetes rats with cerebrovascular disease were randomly divided into NBP treatment group and model group. The water maze test was carried out. After taking the materials, paraffin sections were stained, dehydrated and sealed. The histological structure of the rat cerebral cortex and the histopathological changes of neurons in this area were observed under a microscope. The expressions of Nrf2 and HO-1 protein in Nrf2/HO-1 signal pathway of brain tissue were detected by Western blot.
Compared with the model group, the escape latency of the rats in the NBP-treated group was shortened gradually on the 1st-4th day in the water maze test. Compared with the model group, the cells of brain tissue in the NBP-treated group were arranged regularly, the nuclei were full and round, and the pyknosis was decreased. Western blot analysis showed that Nrf2 and HO-1 protein expression in the brain tissue of rats treated with NBP was higher than that of the model group.
Nrf2 and HO-1 were increased in the brain tissue of NBP-treated rats, and NBP may play a protective role in the brain by up-regulating the expression of anti-oxidative stress protein.
To investigate the effect and mechanism of Qianggu Tongbi capsules on oxidative stress in rats with osteoarthritis.
Twenty-four SD rats were randomly divided into two groups, 6 of which were used for control group and 18 were used for modeling. After modeling, the 18 rats were randomly divided into model group, Qianggutongbi capsules group, and glucosamine group. Hematoxylin eosin staining (HE) was used to observe the changes of cartilage. Superoxide dismutase (SOD) kit, malondialdehyde (MDA) kit, and nitric oxide (NO) kit were applied to detect the levels of SOD, MDA and NO in serum, respectively. Real time-polymerase chain reaction (RT-PCR) was applied to detect the expressions of nuclear factorerythroid 2-relaxed factor (Nrf2), Kelch-like ECH-associated protein 1 (Keap1), macrophage activation factor (Maf), heme oxygenase-1 (HO-1), and NADPH quinone oxidoreductase 1 (NQO1) in each group. Western blot was used to detect the expressions of Nrf2, Keap1, Maf, HO-1, and NQO1 in each group.
HE staining results showed that there was obvious infiltration of dense inflammatory cells in the cartilage tissue of the model group, while the inflammatory cells in the Qianggu Tongbi capsules group and glucosamine group were significantly reduced compared with the blank control group. Compared with the model group, the levels of antioxidant indexes of Qianggu Tongbi capsules group and glucosamine group increased significantly, while the free radical concentrations decreased significantly (P<0.05). Compared with the model group, the mRNA and protein expression levels of Nrf2, Maf, HO-1, and NQO1 in Qianggu Tongbi capsules group and glucosamine group were significantly up-regulated (P<0.05), while the mRNA and protein expression levels of Keap1 were down-regulated (P<0.05).
Qianggu Tongbi capsules can change the antioxidant indexes in serum by activating the expression of Nrf2-Keap1/ARE pathway-related proteins and mRNA, so as to restore the function of antioxidant stress in rats with osteoarthritis.
To establish an 1H quantitative nuclear magnetic resonance (1H qNMR) method for determination of noracetildenafil.
1H qNMR spectra were obtained in CDCL3 by using Bruker Ascend 600 spectrometer with noesyigld1d pulse sequence, the relaxation delay time was 30 s, and 32 scans were recorded.
The signals δ8.15 and 9.14 of noracetildenafil and δ6.09 of 1,3,5-Trimethoxybenzene were used for quantitation. Linear regression of areas ratio (As/Ar) versus mass ratio (Ws/Wr) of δ8.15 and 6.09 yielded a correlation coefficient of 0.999 1 and regression equation of y=0.119 7x+0.003 4, the replicability RSD was 1.66% (n=5), the repeatability RSD was 0.76% (n=5), and the determined content was 97.48%. Linear regression of areas ratio (As/Ar) versus mass ratio (Ws/Wr) at δ9.14 and 6.09 yielded a correlation coefficient of 0.999 1 and regression equation of y=0.116 8x+0.004 5, the replicability RSD was 1.69% (n=5), the repeatability RSD was 0.43% (n=5), and the content of noracetildenafil was 95.35%. The result determined by 1H qNMR method (96.42%) was consistent with the results by mass balance method (96.54%) and HPLC assay method (97.07%).
The established 1H qNMR method can be used for the quantitative determination of noracetildenafil. It is accurate and rapid and could be complementary with the mass balance method for the assay of reference substances.
To explore the adverse reactions of risdiplam based on Public Data Open Project of the US Food and Drug Administration (OpenFDA) in order to provide reference for clinical drug safety.
The relevant data of risdiplam were searched and extracted from the OpenFDA database from August 7, 2020 to May 31, 2022. And the report odds ratio (ROR) and proportional report odds ratio (PRR) were applied for signal detection.
A total of 844 adverse event (ADE) reports with risdiplam as a primary suspicious drug were retrieved, and 68 adverse drug reactions (ADR) risk signals were detected, including positional vertigo, decreased oxygen saturation, tachycardia, and accelerated heart rate, which were not labeled in package insert. Top 5 ADE reports were product storage errors, gastrointestinal dysfunction, muscle weakness, diarrhea and weakness. Top 5 ADES in signal strength included diaper dermatitis, positional vertigo, respiratory tract infection virus, product temperature drift, and skin contact exposure.
It is helpful to use real-world data for assessing the potential adverse reactions of risdiplam, suggesting clinicians to monitor specific adverse events and conduct further drug safety evaluations. The signal strength of positional vertigo is high and is not mentioned in the instruction manual, thus it is necessary for clinicians to pay close attention.
To provide suggestions for the improvement of China's drug priority review and approval system.
Japan's pioneer designation system was analyzed through literature survey compared with China's drug priority review and approval situation.
The Japanese pioneer designation system has facilitated the research and development of new drugs in Japan, accelerated the speed of new drug launches, and allowed Japan to extensively participate in international multicenter clinical trials.
China should actively participate in international multicenter clinical trials, designate specialized personnel to fully manage the marketing application process and promote the synergy of multiple priority review and approval mechanisms.
The health decision will be impacted by the selection of different comparators that influence the results of the comparative effectiveness and incremental cost-effectiveness analysis. With the application of health technology assessment in assistent of health decision-making, the selection of comparators has gradually received stakeholders' attention. Focusing on the comparators selection, this study systematically reviews the health technology assessment guidelines and comparator selection guidelines published by seven countries and regions including China Taiwan, Japan, the United Kingdom, Germany, Canada, Australia, the United States and international organizations based on a literature review. Meanwhile, taking the selection of comparators as an example in the health technology evaluation report of chimeric antigen receptor T-cell (CAR-T) immunotherapy therapies when applying for medical insurance access in different countries, the international experience is summarized from the selection process, criteria, methods, usage and other dimensions. To deal with the current issues discussed in this study, the decision-making departments and stakeholders need to determine the comparators before the beginning of the evaluation, establish a two-way communication and feedback mechanism, determine the selection criteria and methods based on different decision-making purposes and uses, and select flexible response options for special circumstances, so as to provide reference for optimizing the selection of comparators in drug value evaluation.
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