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 investigate the effects of multiple doses of Shugan jieyu capsules on the pharmacokinetics of voriconazole， rivaroxaban and apixaban in rats. METHODS Male SD rats were randomly divided into voriconazole group （30 mg/kg）， rivaroxaban group （2 mg/kg）， apixaban group （0.5 mg/kg）， Shugan jieyu capsules+voriconazole group （145 mg/kg+30 mg/kg）， Shugan jieyu capsules+rivaroxaban group （145 mg/kg+2 mg/kg）， Shugan jieyu capsules+apixaban group （145 mg/kg+0.5 mg/kg）， with 6 rats in each group. After the rats in each group were consecutively administered solvent （0.5% sodium carboxymethyl cellulose solution） or Shugan jieyu capsules by intragastric gavage for 8 days， they were respectively given voriconazole， rivaroxaban and apixaban solution by intragastric gavage on the 8th day. Blood samples were then collected at different time points （in voriconazole group， rivaroxaban group and corresponding drug combination groups， blood was collected before administration and at 0.17， 0.34， 0.5， 0.75， 1， 1.5， 2， 3， 4， 5， 6， 8， 10 and 12 hours post-administration； in apixaban group and corresponding drug combination group， blood was collected before administration and at 0.08， 0.17， 0.25， 0.34， 0.5， 0.75， 1， 3， 5， 7， 10 and 12 hours post-administration）. Ultra-high performance liquid chromatography-tandem mass spectrometry method was employed to determine the mass concentrations of voriconazole， rivaroxaban and apixaban in rat plasma. The main pharmacokinetic parameters of these drugs were calculated using a non-compartmental model， and the comparisons were made between groups. RESULTS Compared with single drug group， after multiple administrations of Shugan jieyu capsules， AUC0－t， AUC0－∞ and cmax of voriconazole were significantly decreased， while CLz/F was significantly increased， and tmax was also significantly prolonged （P＜0.05）. For rivaroxaban and apixaban， their tmax values were both significantly prolonged （P＜0.05）. However， there were no statistically significant differences in the other pharmacokinetic parameters between the two groups （P＞0.05）. CONCLUSIONS The combination of Shugan jieyu capsules can decrease the exposure， increase the clearance， and delay the peak concentration of oral voriconazole. However， it does not affect the exposure levels of rivaroxaban and apixaban， but it does delay the time to reach peak concentration for both drugs.

ObjectiveTo investigate the influence of empagliflozin combined with donafenib or lenvatinib on the pharmacokinetic parameters of each drug， and to provide a reference for combined medication in clinical practice. MethodsA total of 48 healthy male Sprague-Dawley rats were divided into 8 groups： empagliflozin group 1 and 2， donafenib group， lenvatinib group， donafenib pretreatment+empagliflozin group， lenvatinib pretreatment + empagliflozin group， empagliflozin pretreatment+donafenib group， and empagliflozin pretreatment+lenvatinib group， with 6 rats in each group. The doses of empagliflozin， donafenib， and lenvatinib were 2.5 mg/kg， 40 mg/kg， and 1.2 mg/kg， respectively. The rats in the empagliflozin group， donafenib group， and lenvatinib group were given a blank solvent by gavage for 7 consecutive days， followed by a single dose of empagliflozin， donafenib， or lenvatinib on day 7 after the administration of the blank solvent； the rats in the pretreatment groups were given the pretreatment drug by gavage for 7 consecutive days， followed by a single dose of drug combination on day 7 after administration of the pretreatment drug. Blood samples were collected at different time points， and plasma was separated to measure the concentration of each drug. A validated ultra-performance liquid chromatography-tandem mass spectrometry method was used to measure the plasma concentrations of donafenib， lenvatinib， and empagliflozin， and a non-compartmental model was used to calculate the main pharmacokinetic parameters of each drug （area under the plasma concentration-time curve ［AUC］， time to peak ［T_max］， peak concentration ［C_max］， and half-life time ［t_1/2］）. 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 the empagliflozin group， the donafenib pretreatment+empagliflozin group had significant increases in the AUC_0-t and AUC_0-∞ of empagliflozin （P=0.011 and 0.008）， while the lenvatinib pretreatment+empagliflozin group had no significant change in the AUC of empagliflozin， with a slightly shorter T_max （P=0.019）. Compared with the donafenib group， the empagliflozin pretreatment+donafenib group had significant increases in the AUC_0-t and AUC_0-∞ of donafenib （P=0.027 and 0.025）， as well as a significant increase in C_max （P=0.015） and significant reductions in CLz/F and Vz/F （P=0.005 and 0.004）； compared with the lenvatinib group， the empagliflozin pretreatment+lenvatinib group had a reduction in the t_1/2 of lenvatinib by approximately 5 hours （P=0.002）， with a trend of reduction in AUC_0-t （P0.05）. ConclusionEmpagliflozin combined with donafenib may alter the pharmacokinetic parameters of both drugs， leading to a significant increase in the exposure levels of both drugs， and efficacy and adverse reactions should be monitored during co-administration. There are no significant changes in the exposure levels of empagliflozin and lenvatinib during co-administration.

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.

OBJECTIVE To systematically evaluate the effectiveness of different treatment regimens as first-line treatment for metastatic urothelial carcinoma （UC） using a network meta-analysis （NMA） approach. METHODS Electronic databases including PubMed， the Cochrane Library， Embase， Wanfang Data， CNKI， and VIP were searched for randomized controlled clinical trials （RCTs） on first-line treatment for metastatic UC from January 1， 2010 to January 31， 2024. After literature screening and data extraction， a risk of bias assessment of included studies was conducted. R software （version 4.3.2） was used to perform the NMA. RESULTS A total of 11 RCTs involving 14 treatment interventions were included. No significant differences were noted in objective response rate among groups， with the combination of pembrolizumab， gemcitabine and cisplatin having the highest probability of ranking first. Regarding progression-free survival （PFS） and overall survival （OS）， no significant differences were observed among groups， while enfortumab vedotin combined with pembrolizumab showed a trend towards better PFS extension compared to gemcitabine combined with cisplatin [HR＝0.45， 95%CI（0.20，1.06）， P＝0.049]， and it had the highest probability of ranking first in both PFS and OS. CONCLUSIONS The combination of enfortumab vedotin and pembrolizumab may have an advantage in prolonging survival in the first-line treatments for metastatic UC.

A number of drugs for the treatment of type 2 diabetes mellitus(T2DM)are currently under clinical investigation,including the sodium-dependent glucose transporters 2(SGLT2)inhibitor rongliflozin,the SGLT1/2 inhibitor LIK066,the di-peptidyl peptidase-4(DPP-4)inhibitor DBPR108,the glucagon-likepeptide-1 receptor(GLP-1R)ago-nist CJC-1134-PC,the G-protein-coupled receptor 40(GRP40)agonist SCO-267 and the Glucokinase(GK)agonist PB201.This article briefly reviews the clinical research progress of drugs targeting the above targets in the field of T2DM treatment,in or-der to provide reference for the treatment of T2DM patients.

Objective To standardize the management of clinical trials in our hospital,reduce the incidence of protocol deviations,and provide a reference for improving the quality of clinical trials.Methods The healthcare failure mode and effect analysis(HFMEA)method was used to determine the potential failure modes of the current protocol deviation.The frequency,severity and detectability of failure modes were quantified and evaluated.The risk priority number(RPN)was calculated and the corresponding improvement measures were proposed.The RPN values before and after the implementation of HFMEA were statistically analyzed to evaluate the improvement effect.Results After the implementation of HFMEA activities,the RPN values of 14 potential failure modes decreased significantly(P<0.05);The risk level of 12 potential failure modes decreased.The HFMEA team members'ability in finding and solving problems,communication and cooperation were significantly improved.Conclusions The implementation of HFMEA activities contributes to the management of protocol deviation in clinical trials,can effectively reduce the occurrence of protocol deviation,and provides experience for improving the quality of drug clinical trials.

Objective To explore the application effect of medication therapy management(MTM)services on the treatment of childhood asthma.Methods A total of 107 children aged 5-11 with asthma who visited the Cough and Asthma Pharmacy Clinic of Hebei General Hospital from July to December 2022 were selected,and randomly divided into the control group(50 cases)and the intervention group(52 cases).The control group of children only received single inhalation medication education services at the first visit.The intervention group received standardized MTM services throughout the entire process.The economic,clinical and human outcomes(ECHO)model was used to analyze the differences between the two groups of children in economic(medication costs,cost-effectiveness ratio),clinical(ACT score,correct rate of inhaled preparation,number of asthma attacks)and humanistic(EQ-5D-5L utility value,Morisky medication compliance,patient satisfaction)results before the intervention,3 months after the intervention,and 6 months after the intervention,evaluate the application effect of MTM services in children with asthma.Results Compared with the control group,there was no significant difference between the two groups before the intervention.After the intervention,the children in the intervention group showed statistically significant differences in economic,clinical,and humanistic outcomes(P<0.05).Conclusions The MTM service led by pharmacists can benefit children with asthma from multiple dimensions such as economy,clinical practice,and humanities.This not only enables long-term effective control of asthma in children,but also enhances pharmacist pharmacy specialist service capabilities.

Objective A comprehensive evaluation of oral anticoagulants(OACs)was conducted using the A Quick Guideline for Drug Evaluation and Selection in Chinese Medical Institutions(the Second Edition),to provide a reference for drug selection and clinical medication decisions in medical institutions.Methods Evaluation evidence was collected,and the drugs included in the evaluation were quantified on four dimensions of clinical properties(efficiency and safety),pharmaceutical properties,economy and others.Results All oral anticoagulants included in the evaluation had a score of 70 or higher in the comprehensive evaluation,while warfarin had the highest overall score.Clinical properties and pharmacologic properties were identified as the core attributes for drug selection evaluation.When considering only these factors,edoxaban received the highest score.Conclusion OACs are the preferred option for patients requiring long-term anticoagulation therapy.Various OACs offer distinct clinical advantages.Utilizing the Guidelines(Second Edition)for oral anticoagulant selection and evaluation can offer visual evidence for drug selection and promote the scientific,rational,and safe use of drugs in clinical management.