Sodium-glucose co-transporter 2(SGLT2)inhibitors are a new class of oral hypoglyce-mic drugs with definite hypoglycemic effects,low risk of hypoglycemia,cardiovascular protection,and kidney benefits.In recent years,SGLT2 inhibi-tors have been widely used in clinical practice,and their interactions with other drugs have gradually attracted attention.The SGLT2 inhibitors commonly used in China's clinic include canagliflozin,dapa-gliflozin,empagliflozin,ertugliflozin and hena-gliflozin currently,they are mainly metabolized by the phase Ⅱ metabolic enzyme uridine diphos-phate glucuronosyltransferase(UGT),and various transporters are involved in the disposal of SGLT2 inhibitors in vivo.This article reviews the pharma-cokinetic characteristics of different SGLT2 inhibi-tors mentioned above,as well as their pharmacoki-netic interaction studies with various drugs such as statins,antineoplastic drugs,antimicrobials,nonste-roidal anti-inflammatory drugs and traditional Chi-nese medicine,in order to promote the safe and ra-tional use of SGLT2 inhibitors in clinical practice.

ObjectiveTo investigate the effect of sorafenib and donafenib on the pharmacokinetics of ertugliflozin in rats， and to provide a theoretical basis for drug combination in clinical practice. MethodsA total of 24 male Sprague-Dawley rats were randomly divided into groups A， B， C， and D， with 6 rats in each group. The rats in groups A and B were given sorafenib control solvent and sorafenib （100 mg/kg）， respectively， by gavage for 7 consecutive days， followed by ertugliflozin （1.5 mg/kg） by gavage on day 7. Blood samples were collected from the angular vein plexus at different time points， and ultra-performance liquid chromatography-tandem mass spectrometry was used to determine the mass concentration of ertugliflozin and plot the plasma concentration-time curves， while the non-compartment model in DAS 2.1.1 software was used to calculate related pharmacokinetic parameters. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups. ResultsCompared with group A， group B had significant increases in the AUC_0-t and AUC_0-∞ of the plasma concentration-time curve of ertugliflozin （both P<0.05）， significant prolongation of t_1/2， MRT_0-t， and MRT_0-∞ （all P<0.05）， and a significant reduction in CL_Z/F （P<0.05）. Compared with group C， group D had significant increases in the AUC_0-t and AUC_0-∞ of ertugliflozin （both P<0.05）， significant prolongation of T_max， t_1/2， MRT_0-t， and MRT_0-∞ （all P<0.01）， and significant reductions in V_Z/F and CL_Z/F （both P<0.05）. ConclusionBoth sorafenib and donafenib can affect the pharmacokinetics of ertugliflozin in rats and significantly increase the plasma exposure of ertugliflozin. The efficacy and adverse drug reactions of ertugliflozin should be closely monitored during combined use in clinical practice and the dose should be adjusted when necessary to avoid the potential risk of drug interaction.

OBJECTIVE To investigate the effects of ertugliflozin on pharmacokinetic of sorafenib and donafenib in rats and explore the mechanism. METHODS Twenty-four male SD rats were randomly divided into four groups， with 6 rats in each group. Groups A and B were respectively gavaged with 0.5% sodium carboxymethyl cellulose solution and ertugliflozin （1.5 mg/kg） for 7 consecutive days， and both were given sorafenib （100 mg/kg） on the 7th day. Groups C and D were administered intragastrically in the same way as those in Groups A and B， respectively， for the first 7 days； after the drug administration on the 7th day， all rats in Groups C and D were further gavaged with donafenib （40 mg/kg）. Blood samples were collected at different time points before and after administration of sorafenib or donafenib， the concentrations of sorafenib in plasma of rats in groups A and B and donafenib in groups C and D were determined by UPLC-MS/MS method. The pharmacokinetic parameters were calculated by DAS 2.1.1 software. Six additional rats were randomly divided into blank control group and ertugliflozin group， with three rats in each group. Blank control group was given 0.5% sodium carboxymethyl cellulose intragastrically， while rats in ertugliflozin group were given ertugliflozin （1.5 mg/kg） once a day for 7 consecutive days. After the last administration， the mRNA expression levels of uridine diphosphate glucuronosyl transferase 1A7 （UGT1A7）， breast cancer resistance protein （BCRP）， and P-glycoprotein （P-gp） in the liver and small intestine tissues of the rats were detected. RESULTS Compared with group A， the AUC0-t， AUC0-∞， cmax， tmax， MRT0-t and MRT0-∞ of sorafenib in group B were decreased significantly， while CL and V were increased significantly. Compared with group C， the AUC0-t， AUC0-∞ ， tmax， cmax and MRT0-t of Δ donafenib in group D were decreased significantly， while V and CL were increased significantly （P＜0.05）. mRNA expression of UGT1A7， P-gp and BCRP in the liver tissue and small intestine of rats were not significantly affected after intragastric administration of ertugliflozin for 7 consecutive days. CONCLUSIONS Ertugliflozin can affect the pharmacokinetics of sorafenib and donafenib in rats and decrease the plasma exposure of them significantly. However， its mechanism of action may not be through the regulation of related metabolic enzymes and transporters. When using drugs in combination clinically， one should be vigilant about the potential for disease progression due to poor therapeutic effects.

Objective:To evaluate the predictive value of whole blood cell derived inflammatory marker (including systemic immunoinflammatory index (SII), systemic inflammatory response index (SIRI), neutrophil count/lymphocyte count (NLR), platelet count/lymphocyte count (PLR), and monocyte count/lymphocyte count (MLR)) and in combination with N-terminal pro-B-type natriuretic peptide (NT-proBNP) on the prognosis of patients with chronic heart failure.Methods:This study was a retrospective cohort study. Patients with chronic heart failure hospitalized in the Department of Cardiovascular Medicine, Nanfang Hospital, Southern Medical University from January 2019 to August 2022 were enrolled. Patients were followed up and were divided into survival group and death group according to the follow-up results. Clinical characteristics of the two groups were compared. Receiver operating characteristic (ROC) curve was used to determine the optimal cut-off value of each whole blood cell derived inflammatory marker for predicting all-cause death in patients with chronic heart failure. Kaplan-Meier survival curve was drawn, and log-rank test was used to compare the difference in survival of chronic heart failure patients with different levels of whole blood cell derived inflammatory markers. Univariate and multivariate Cox proportional hazards models were used to analyze the effects of whole blood cell derived inflammatory markers and NT-proBNP on the all-cause death of patients with chronic heart failure. ROC curve was used to analyze the predictive value of whole blood cell derived inflammatory markers combined with NT-proBNP on the prognosis of patients with chronic heart failure.Results:A total of 324 patients with heart failure aged (64.76±13.78) years were enrolled, with 212 males (65.43%). 297 patients (91.67%) completed follow-up, 27 patients (8.33%) were lost to follow-up. The follow-up time was 24.0 (18.0, 41.8) months. There were 258 patients in the survival group and 66 patients in the death group. The optimal cut-off values of SII, SIRI, NLR, PLR and MLR determined by ROC curve were 739.83, 1.65, 3.14, 151.95 and 0.37, respectively. Kaplan-Meier survival curve analysis showed that patients with chronic heart failure with high levels of SII (≥739.83), SIRI (≥1.65), NLR (≥3.14), PLR (≥151.95) and MLR (≥0.37) had higher incidence of all-cause death than patients with low levels of inflammatory markers (all P<0.001). Multivariate Cox proportional hazard regression analysis showed that age ( HR=1.04, 95% CI 1.01-1.06, P=0.002), NT-proBNP ( HR=2.93, 95% CI 1.64-5.23, P<0.001), SII≥739.83 ( HR=3.27, 95% CI 1.18-9.02, P=0.022) and PLR≥151.95 ( HR=2.67, 95% CI 1.02-6.96, P=0.045) were independent predictors of all-cause death in patients with chronic heart failure. ROC curve analysis showed that the predictive value of SII and PLR combined with NT-proBNP ( AUC=0.850) for the prognosis of patients with chronic heart failure was better than that of SII ( AUC=0.779)、PLR ( AUC=0.782)、NT-proBNP ( AUC=0.727) and CRP ( AUC=0.668) alone (all P<0.001). Conclusions:Whole blood cell derived inflammatory markers——SII, PLR, and NT-pro BNP were independently associated with all-cause death in patients with chronic heart failure. SII and PLR can independently predict the prognosis of patients with chronic heart failure, combination of SII and PLR with NT-pro BNP has better predictive value for the prognosis of patients with chronic heart failure.

Objective:To evaluate the predictive value of whole blood cell derived inflammatory marker (including systemic immunoinflammatory index (SII), systemic inflammatory response index (SIRI), neutrophil count/lymphocyte count (NLR), platelet count/lymphocyte count (PLR), and monocyte count/lymphocyte count (MLR)) and in combination with N-terminal pro-B-type natriuretic peptide (NT-proBNP) on the prognosis of patients with chronic heart failure.Methods:This study was a retrospective cohort study. Patients with chronic heart failure hospitalized in the Department of Cardiovascular Medicine, Nanfang Hospital, Southern Medical University from January 2019 to August 2022 were enrolled. Patients were followed up and were divided into survival group and death group according to the follow-up results. Clinical characteristics of the two groups were compared. Receiver operating characteristic (ROC) curve was used to determine the optimal cut-off value of each whole blood cell derived inflammatory marker for predicting all-cause death in patients with chronic heart failure. Kaplan-Meier survival curve was drawn, and log-rank test was used to compare the difference in survival of chronic heart failure patients with different levels of whole blood cell derived inflammatory markers. Univariate and multivariate Cox proportional hazards models were used to analyze the effects of whole blood cell derived inflammatory markers and NT-proBNP on the all-cause death of patients with chronic heart failure. ROC curve was used to analyze the predictive value of whole blood cell derived inflammatory markers combined with NT-proBNP on the prognosis of patients with chronic heart failure.Results:A total of 324 patients with heart failure aged (64.76±13.78) years were enrolled, with 212 males (65.43%). 297 patients (91.67%) completed follow-up, 27 patients (8.33%) were lost to follow-up. The follow-up time was 24.0 (18.0, 41.8) months. There were 258 patients in the survival group and 66 patients in the death group. The optimal cut-off values of SII, SIRI, NLR, PLR and MLR determined by ROC curve were 739.83, 1.65, 3.14, 151.95 and 0.37, respectively. Kaplan-Meier survival curve analysis showed that patients with chronic heart failure with high levels of SII (≥739.83), SIRI (≥1.65), NLR (≥3.14), PLR (≥151.95) and MLR (≥0.37) had higher incidence of all-cause death than patients with low levels of inflammatory markers (all P<0.001). Multivariate Cox proportional hazard regression analysis showed that age ( HR=1.04, 95% CI 1.01-1.06, P=0.002), NT-proBNP ( HR=2.93, 95% CI 1.64-5.23, P<0.001), SII≥739.83 ( HR=3.27, 95% CI 1.18-9.02, P=0.022) and PLR≥151.95 ( HR=2.67, 95% CI 1.02-6.96, P=0.045) were independent predictors of all-cause death in patients with chronic heart failure. ROC curve analysis showed that the predictive value of SII and PLR combined with NT-proBNP ( AUC=0.850) for the prognosis of patients with chronic heart failure was better than that of SII ( AUC=0.779)、PLR ( AUC=0.782)、NT-proBNP ( AUC=0.727) and CRP ( AUC=0.668) alone (all P<0.001). Conclusions:Whole blood cell derived inflammatory markers——SII, PLR, and NT-pro BNP were independently associated with all-cause death in patients with chronic heart failure. SII and PLR can independently predict the prognosis of patients with chronic heart failure, combination of SII and PLR with NT-pro BNP has better predictive value for the prognosis of patients with chronic heart failure.

Sodium-glucose co-transporter 2(SGLT2)inhibitors are a new class of oral hypoglyce-mic drugs with definite hypoglycemic effects,low risk of hypoglycemia,cardiovascular protection,and kidney benefits.In recent years,SGLT2 inhibi-tors have been widely used in clinical practice,and their interactions with other drugs have gradually attracted attention.The SGLT2 inhibitors commonly used in China's clinic include canagliflozin,dapa-gliflozin,empagliflozin,ertugliflozin and hena-gliflozin currently,they are mainly metabolized by the phase Ⅱ metabolic enzyme uridine diphos-phate glucuronosyltransferase(UGT),and various transporters are involved in the disposal of SGLT2 inhibitors in vivo.This article reviews the pharma-cokinetic characteristics of different SGLT2 inhibi-tors mentioned above,as well as their pharmacoki-netic interaction studies with various drugs such as statins,antineoplastic drugs,antimicrobials,nonste-roidal anti-inflammatory drugs and traditional Chi-nese medicine,in order to promote the safe and ra-tional use of SGLT2 inhibitors in clinical practice.

Objective To establish mouse models exposed to different doses of neodymium oxide via tracheal instillation,and to investigate the mechanisms underlying brain tissue damage induced by neodymium oxide exposure in mice.Methods Forty-eight male C57/BL6 mice were randomly assigned to four groups:the control group,the low-dose group,the medium-dose group,and the high-dose group.The low-dose,medium-dose,and high-dose groups received 62.5 mg/mL,125 mg/mL,and 250 mg/mL neodymium oxide,respectively,via non-exposed tracheal instillation.The control group received an equivalent volume of saline using the same administration method.After 35 days,the mice were euthanized,and brain tissues were collected.RT-PCR was used to assess the mRNA expression changes of Claudin-5 and Occludin.Western blot analysis was performed to evaluate the expression changes of Claudin-5 and Occludin tight junction proteins,as well as the expression changes of MMP-2 and MMP-9 in the brain tissues.Additionally,the expression of the RhoA/ROCK2 signaling pathway and downstream cofilin protein was examined.Changes in oxidative stress markers,including MDA,T-AOC,and NO,were measured using a kit method.Results The mRNA expression of Claudin-5 was significantly reduced in the middle-dose and high-dose groups compared to the control group(P<0.05).Similarly,the mRNA expression of Occludin was significantly lower in the low-dose,medium-dose,and high-dose groups compared to the control group(P<0.05).Additionally,the protein expression of Claudin-5,MMP-2,and Occludin was significantly decreased in the low-dose,medium-dose,and high-dose groups compared to the control group(P<0.05).The protein expression of MMP-9 and RhoA was also signifi-cantly lower in the medium-dose and high-dose groups compared to the control group(P<0.05).Furthermore,the protein expression of ROCK2 and p-cofilin in the high-dose group was significantly lower than that in the control group(P<0.05).The content of MDA and T-AOC was significantly lower in the medium-dose and high-dose groups compared to the control group(P<0.05),and the content of NO in the high-dose group was significantly lower than that in the control group(P<0.05).Conclusion Exposure to neodymium oxide results in increased permeability of the blood-brain barrier in mice,leading to oxidative stress,inflammatory responses,and activation of the RhoA/ROCK2 signaling pathway.

Objective To establish mouse models exposed to different doses of neodymium oxide via tracheal instillation,and to investigate the mechanisms underlying brain tissue damage induced by neodymium oxide exposure in mice.Methods Forty-eight male C57/BL6 mice were randomly assigned to four groups:the control group,the low-dose group,the medium-dose group,and the high-dose group.The low-dose,medium-dose,and high-dose groups received 62.5 mg/mL,125 mg/mL,and 250 mg/mL neodymium oxide,respectively,via non-exposed tracheal instillation.The control group received an equivalent volume of saline using the same administration method.After 35 days,the mice were euthanized,and brain tissues were collected.RT-PCR was used to assess the mRNA expression changes of Claudin-5 and Occludin.Western blot analysis was performed to evaluate the expression changes of Claudin-5 and Occludin tight junction proteins,as well as the expression changes of MMP-2 and MMP-9 in the brain tissues.Additionally,the expression of the RhoA/ROCK2 signaling pathway and downstream cofilin protein was examined.Changes in oxidative stress markers,including MDA,T-AOC,and NO,were measured using a kit method.Results The mRNA expression of Claudin-5 was significantly reduced in the middle-dose and high-dose groups compared to the control group(P<0.05).Similarly,the mRNA expression of Occludin was significantly lower in the low-dose,medium-dose,and high-dose groups compared to the control group(P<0.05).Additionally,the protein expression of Claudin-5,MMP-2,and Occludin was significantly decreased in the low-dose,medium-dose,and high-dose groups compared to the control group(P<0.05).The protein expression of MMP-9 and RhoA was also signifi-cantly lower in the medium-dose and high-dose groups compared to the control group(P<0.05).Furthermore,the protein expression of ROCK2 and p-cofilin in the high-dose group was significantly lower than that in the control group(P<0.05).The content of MDA and T-AOC was significantly lower in the medium-dose and high-dose groups compared to the control group(P<0.05),and the content of NO in the high-dose group was significantly lower than that in the control group(P<0.05).Conclusion Exposure to neodymium oxide results in increased permeability of the blood-brain barrier in mice,leading to oxidative stress,inflammatory responses,and activation of the RhoA/ROCK2 signaling pathway.

Objective To investigate the effect of amlodipine and levamlodipine on the pharmacokinetics of lenvatinib and related mechanisms.Methods A total of 18 male Sprague-Dawley rats were randomly divided into lenvatinib(1.2 mg/kg)group,amlodipine(1.0 mg/kg)+lenvatinib group,and levamlodipine(0.5 mg/kg)+lenvatinib group,with 6 rats in each group.The rats were pretreated with 0.5%sodium carboxymethyl cellulose,amlodipine or levamlodipine by gavage for 8 days,and lenvatinib was given after the last intragastric administration.Blood samples were collected from the intraocular canthus venous plexus at the specified time points.Ultra-performance liquid chromatography-tandem mass spectrometry was used to measure the plasma concentration of lenvatinib in rats,and a non-compartment model was used to calculate pharmacokinetic parameters.RT-qPCR was used to measure the mRNA expression levels of cytochrome P450 3A1(CYP3A1),P-glycoprotein(P-gp),and breast cancer resistance protein(BCRP)in rat liver tissue.A one-way analysis of variance was used for comparison of normally distributed continuous data between multiple groups,and the Dunnett-t test was used for further comparison between two groups;the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between groups.Results There were significant differences between the three groups in the area under the concentration-time curve AUC0-∞(F=4.567,P<0.05),clearance rate CLz/F(F=5.038,P<0.05),and peak concentration Cmax(F=11.667,P<0.01).Compared with the lenvatinib group,the amlodipine+lenvatinib group had an increase in AUC0-∞ by 36.1%(P<0.05),a reduction in CLz/F by 26.1%(P<0.05),and an increase in Cmax by 56.7%(P<0.01),and the levamlodipine+lenvatinib group had an increase in Cmax by 37.7%(P<0.05).RT-qPCR showed that there were significant differences in the mRNA expression levels of CYP3A1,P-gp,and BCRP between the three groups(F=10.160,5.350,and 5.237,all P<0.05),and compared with the lenvatinib group,the amlodipine+lenvatinib group had significant reductions in the mRNA expression levels of CYP3A1,P-gp,and BCRP in rat liver tissue(all P<0.05),while the levamlodipine+lenvatinib group had a significant reduction in the mRNA expression level of CYP3A1 in rat liver tissue(P<0.05).Conclusion Amlodipine can increase the in vivo exposure of lenvatinib possibly by inhibiting the mRNA expression of CYP3A1,P-gp,and BCRP in the liver,while levamlodipine only increases the peak concentration of lenvatinib.

Cardiac toxicity of anthracycline greatly limit its clinical use,to explore the rule of anthracycline cardiotoxicity and prevention and control strategies of Chinese and western medicine,this paper through the literature search mechanism and drugs is summarized,the mechanism can be divided into oxidative stress,inflammatory reaction,myocardial cell autophagy and DNA damage four categories,the prevention and treatment of western medicine to dc prosamine,ACEI,ARB is given priority to,Chinese medicine can be divided into single medicine,by prescription and proprietary Chinese medicine.On this basis,the combination drug is discussed to prevent cardiotoxicity,and the theoretical basis and research status of the combined application of western medicine,traditional Chinese medicine and Chinese and western medicine are introduced.The results show that it has good feasibility and safety,and can provide reference for the clinical treatment strategy of anthracycline chemotherapy drugs.