ABSTRACT
OBJECTIVE To establish the drug-induced liver injury （DILI） surveillance and assessment system （DILI-SAS）， and to improve the diagnostic efficiency of clinical DILI. METHODS The DILI-SAS was constructed by using natural language processing technology to mine and utilize all inpatient medical record data， and combined with Roussel Uclaf causality assessment method （RUCAM）. The medical records of 19 445 hospitalized patients from August 2022 to January 2023 were detected to verify the performance of the system and manually analyze the basic data of patients with DILI and the distribution of the first suspected drugs. RESULTS The overall accuracy rate of the DILI-SAS system was 91.95%， and the recall rate was 93.20%. Seventy-five DILI cases were detected， and the DILI incidence rate was 385.70/100 000 people. The efficiency of DILI monitoring by human- computer coupling was increased by about 60 times of manual monitoring； males （61.33%） and patients over 60 years old （56.00%） were the most common in the 75 cases of DILI. The clinical type of liver injury was hepatocyte injury （69.33%）， the incubation period was mainly 5-90 days after treatment （62.67%）， and the RUCAM score between 3 and 5 was the most common （66.67%）； pharmacological distribution of the first suspected drugs was mainly dihydropyridines， HMG CoA reductase inhibitors， proton pump inhibitors， etc. The specific drugs were atorvastatin， omeprazole， ceftriaxone， metronidazole and other drugs. CONCLUSIONS The establishment of DILI-SAS can improve the evaluation efficiency on the basis of ensuring the accuracy degree， and provide a solution for the early identification， diagnosis and evaluation of clinical DILI.
ABSTRACT
The cell cycle is a complex process that involves DNA replication, protein expression, and cell division. Dysregulation of the cell cycle is associated with various diseases. Cyclin-dependent kinases (CDKs) and their corresponding cyclins are major proteins that regulate the cell cycle. In contrast to inhibition, a new approach called proteolysis-targeting chimeras (PROTACs) and molecular glues can eliminate both enzymatic and scaffold functions of CDKs and cyclins, achieving targeted degradation. The field of PROTACs and molecular glues has developed rapidly in recent years. In this article, we aim to summarize the latest developments of CDKs and cyclin protein degraders. The selectivity, application, validation and the current state of each CDK degrader will be overviewed. Additionally, possible methods are discussed for the development of degraders for CDK members that still lack them. Overall, this article provides a comprehensive summary of the latest advancements in CDK and cyclin protein degraders, which will be helpful for researchers working on this topic.
Subject(s)
Humans , Cell Cycle/physiology , Cell Division , Cyclin-Dependent Kinases/metabolism , Cyclins/metabolismABSTRACT
OBJECTIVE To expl ore the clinical significance of folic acid metabolic gene detection in methotrexate （MTX） treatment of acute myeloid leukemia （AML）. METHODS Therapeutic drug monitoring （TDM）pharmacists participated in the treatment process of an AML patient who had neurotoxic side effects such as dizziness ，headache，and vomiting after intrathecal injection of MTX. According to the results of the test of the folic acid metabolic gene MTHFR C677T（rs1801133）（mutant homozygous）and the results of MTX blood concentration monitoring （＜0.05 μmol/L），combined with clinical manifestations ，it was recommended to stop MTX ，give intravenous drip of calcium folinate for rescue ，and consider using azacytidine for follow-up treatment. RESULTS The doctor took the advice of TDM pharmacist ，and the above symptoms were significantly relieved after the patient rescued for 2 times and successfully discharged from the hospital. CONCLUSIONS For AML patients who meet the indications and receive intrathecal injection of MTX ，drug metabolism genetics testing and MTX drug concentration monitoring can be performed before medication ，which helps doctors and pharmacists evaluate the feasibility of drug treatment options and reduce medical risks.
ABSTRACT
OBJECTIVE： To investigate how pharmacists provide through individualized pharmaceutical care for patients medication therapy management（MTM） combined with medicine gene detection， and to promote rational drug use in clinic.METHODS： A case of elderly comorbidity with acute upper gastrointestinal hemorrhage caused by Warfarin sodium tablets was taken as an example. The patient had a history of type 2 diabetes mellitus and hypertension. Coronary artery bypass grafting was performed two months before admission， and urinary tract infection occurred half a month ago. Medication therapy course was analyzed retrospectively before and after hospitalization； based on gene typing detection of CYP2C9*3 and VKORC1-1639， the individualized dose of Warfarin sodium tablets was evaluated. MTM was perfomed for acute upper gastrointestinal hemorrhage and all medication of patient to formulate individualized medication scheme. RESULTS： The genotyping of warfarin CYP2C9*3 and VKORC1-1639 indicated that the patients were of super slow metabolic type. The recommended dosage of warfarin should be 0.86-1.86 mg/d. Based on MTM analysis of acute upper gastrointestinal hemorrhage， the main causes of acute upper gastrointestinal hemorrhage were Warfarin sodium tablets 3.0 mg/d， poor drug compliance， disease status and co-morbidity and multi-drug combination. Clinical gastrointestinal hemorrhage of the patients were improved after drug withdrawal， anticoagulant drugs was changed into Rivaroxaban tablet，10 mg/d. Through MTM for all drug use in the patient， results of medication reorganization showed that Diltiazem hydrochloride tablet， Amoxicillin/clavulanate potassium dispersible tablet， Compound vitamin tablet were stopped； hypoglycemic drug Glimepiride tablet was changed into Gliquidone tablet； Metoprolol tartrate tablet was changed into Bisoprolol tablet after coronary artery bypass graft； proton pump inhibitor Esomeprazole enteric-coated tablet was changed into Pantoprazole sodium enteric-coated capsule. CONCLUSIONS： The pharmaceutical care mode of MTM combined with medicine gene detection can guide rational drug use in clinic， realize individualized pharmaceutical care， improve patient compliance and prevent problems related to adverse drug reactions.
ABSTRACT
The study was designed to explore the effects of HS060098 on activation of peroxisome proliferator-activated receptors (PPARα, γ and δ) and in the down-regulation of hyperlipidemia in golden hamster. Luciferase gene reporters of PPARα, PPARγ and PPARδ were constructed in HepG2 cells and the green fluorescent protein (GFP) was used as an internal reference. Transfected cells were then cultured with various concentrations of HS060098 for 24 h. The peroxisome proliferator-response element luciferase activity was determined by the dual-luciferase reporter gene assay system. To investigate the lipid-lowering effect of HS060098, hyperlipidemic golden hamsters fed by high-diet were administered orally with HS060098 through prophylactic and therapeutic approaches respectively. The levels of blood lipids such as total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and fat index in hamsters were evaluated. The results showed that HS060098 was a potent activator of PPAR δ with a good selectivity and the median effective concentration (EC 50) is 0.01 μmol·L-1, while no obvious PPARα and PPARγ activation was observed. In the golden hamster, oral administration of HS060098 (5, 10, 20 mg·kg-1·d-1) for 2 weeks, led to a significant decrease the concentrations of plasma TC, TG, LDL-C and fat index (PPPPδ agonist with a significant activity in the prevention and therapy of hyperlipemia in golden hamster.
ABSTRACT
Objective:To establish a method for the determination of 7 residual organic solvents including acetone,2,3 -dimethyl-pentane,3-methylhexane,n-heptane,2,2-dimethylhexane,o-xylene and 2,4,6-trimethylpyridine in Shengxuening tablets. Methods: A headspace gas chromatography method was adopted. The determination was performed on a DB-5MS capillary column ( 30 m × 0. 25 mm,0. 25 μm) with programming temperature. Nitrogen was used as the carrier gas at the flow rate of 2. 5 ml·min-1 . The tem-perature of injector was 200℃,and a flame ionization detector was used as the temperature of 250℃. The containers of headspace in-jector were in equilibrium at 95℃ for 30min. DMF was used as the solvent and an external standard method was used for the determi-nation of the 7 residual solvents. The injection volume was 1 ml. Results:Under the chromatographic conditions, the 7 residual organic solvents could be well separated from each other . The concentration of each solvent showed a good linearity with the peak area within the investigated concentration range (r≥0. 994 4). The average recoveries were 98. 72%-99. 71% (RSD=0. 14%-0. 71%)(n=9). Conclusion:The established method is simple, rapid and sensitive, which can be used for the determination of multiple residual or-ganic solvents in Shengxuening tablets.
ABSTRACT
Objective: To develop an HPLC-DAD method for the simultaneous determination of danshensu, protocatechuic acid, vanillic acid, salvianolic acid B, and hydroxysafflor yellow A (HYSA) in cerebral ischemic injury of rats, in order to provide an accurate and reliable analytical method to study the pharmacokinetics. Methods: The middle cerebral artery occlusion (MCAO) model was established, in which all the rats were iv injected with the active constituents in Danhong Injection simultaneously (danshensu, protocatechuic aldehyde, salvianolic acid B, and HYSA). The analysis of the measured components' plasma concentration was carried at 30℃ on the reversed-phase column of Agilent Eclipse XDB-C18 (150 mm×4.6 mm, 5 μm) and eluted with acetonitrile and water containing 0.4% phosphate acid as mobile phase in gradient mode. Detection wavelengths were 280 nm for danshensu, protocatechuic acid, vanillic acid, salvianolic acid B and 403 nm for HYSA. The propyl p-hydroxybenzoate was used as the internal standard (IS). Results: Protocatechuic aldehyde rapidly metabolized in MCAO rats, but its metabolites, protocatechuic acid and vanillic acid, were easily detected. The linear ranges of danshensu, protocatechuic acid, vanillic acid, salvianolic acid B, and HYSA were 0.35-140 (R2=0.9998), 0.15-60 (R2=0.9990), 0.05-20 (R2=0.9988), 0.25-100 (R2=0.9996), and 0.075-30 mg/L (R2=0.9985), respectively. The mean recoveries were between 80% and 120% and the RSD value of intra-day and inter-day was less than 10%. The results of stability meet the requirements for biopharmaceutical analysis. The main pharmacokinetic parameters of danshensu, protocatechuic acid, vanillic acid, salvianolic acid B and HYSA were as follows: AUC0~∞ were (1143.862±230.840), (427.024±59.293), (135.785±47.631), (418.631±66.242), (288.788±87.809) mg·min/L and t1/2z were (71.496±29.067), (82.379±26.279), (40.331±6.006), (125.164±59.709), (177.577±112.836) min. Conclusion: The method is simple, rapid, precise and stable, which can be used to the pharmacokinetic studies on the compatibilities of danshensu, protocatechuic aldehyde, salvianolic acid B, and HYSA in MCAO rats.
ABSTRACT
To study the pharmacokinetic process of Danshensu in cerebal ischemia injury model rats and the correlation with its anti-cerebral ischemia effect. In this study, the middle cerebral artery occlusion (MCAO) model was established, in which all of the rats were intravenously injected of Danshensu at a single dose of 40 mg x kg(-1). The HPLC-DAD method was applied to determine the plasma concentration of Danshensu at different time points and draw the drug-time curve. Meanwhile, the superoxide dismutase (SOD) and the lactate dehydrogenase (LDH) activity were determined to draw the time-effect curve. The DAS 3.2. 6 software was used to process the data, analyze their correlation, compare the pharmacokinetic difference between model and normal rats after the administration of the same doses of Danshensu and the changes in pharmacodynamic indicators of model rats after the administration, and evaluate the effect of Danshensu in treating the cerebral ischemia disease. According to the results, the pharmacokinetic processes of Danshensu in the cerebral ischemia-reperfusion and normal rats were consistent to the two-compartment model. The main pharmacokinetic parameters were: t1/2alpha were (0.267 +/- 0.026), (0.148 +/- 0.020) h;t1/2beta were (1.226 +/- 0.032), (1.182 +/- 0.082) h; AUC0-infinity were (42.168 +/- 4.007), (26.881 +/- 1.625) mg x L(-1) x h. After the cerebral ischemia-reperfusion, the activity of SOD decreased and the activity of LDH increased. Danshensu could inhibit the decrease in the SOD activity and the increase in the LDH activity within a certain period of time. This indicated that Danshensu could stay longer in cerebral ischemia-reperfusion rats than in normal rats and eliminated more slowly, which reflected the rationality of Danshensu in the clinical treatment of cerebral ischemia diseases. Danshensu's effect against the cerebral ischemic injury may be related with its level in vivo. Its plasma concentration is positively related to the SOD activity and negatively related to the LDH activity.