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.

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.

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.

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 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 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.

Objective To comprehensively assess the strengths and weaknesses of the 24 antihypertensive drugs procured as Volume-based Procurement(VBP)and innovator drugs by using quantitative evaluation system,and to provide a reference for doctors and patients in medication guidance and pharmaceutical decision-making.Methods The Quantitative Evaluation Criteria in the"Quick Guide to Drug Evaluation and Selection in Chinese Medical Institutions"were refined and optimized.The 24 selected VBP and innovator antihypertensive drugs were quantitatively evaluated according to the optimized quantitative evaluation system with the help of Chinese and English databases such as China Knowledge Network,Wanfang data,Wipunet,Embased,PubMed,and Metstr,as well as guideline search tools such as Meikang MCDEX,Drugwise Data,Up To Date,Medical Pulse and other databases etc.Results Among the 24 antihypertensive drugs,only four innovator drug evaluation scores were higher than those of drugs selected as VBP,namely felodipine tablets,Fosinopril sodium tablets,indapamide extended-release capsules,Irbesartan hydrochlorothiazide tablets.there were five main differences in the evaluation scores,namely economy,consistency evaluation,drug expiry date,global use,and the status of manufacturing enterprises.It was found that 83%of the VBP drugs had higher evaluation scores than those of the innovator drugs.The economic score of the innovator drug was low,and the difference in the scores was between 1-11 points.Conclusion By using the quantitative evaluation system to evaluate the antihypertensive drugs,the advantages and disadvantages of the innovator and VBP antihypertensive drugs can be assessed comprehensively,and the digital characteristics of antihypertensive drugs can be given,and the evaluation score can provide the reference basis for the guidance and decision-making of medication for doctors and patients.

Objective:To systematically evaluate cardiotoxicity of programmed cell death 1 receptor (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors.Methods:Clinical trials of PD-1/PD-L1 inhibitor alone or in combination with other treatments for tumors were collected by searching related databases at home and abroad (up to March 2, 2019). The methodological quality of studies was evaluated using the internationally accepted Cochrane collaboration′s risk of bias assessment tool. A meta-analysis was performed using RevMan 5.3 software to compare the incidences of cardiotoxicity between PD-1/PD-L1 inhibitors (trial group) and placebo or other antineoplastic agents(control group).Results:A total of 10 randomized controlled trials (RCTs) were enrolled, 9 of which were about PD-1 inhibitor alone or in combination with other antineoplastic agents, and 1 of which was about PD-L1 inhibitor monotherapy. There were a total of 5 291 patients, including 3 022 in the trial group and 2 269 in the control group. Evaluation of the methodological quality for studies showed that 4 RCTs were at high risk of bias and the other 6 were at low risk of bias. The meta-analysis showed that the incidence of cardiotoxicity in the trial group was significantly higher than that in the control group, and the difference was statistically significant[1.13% (34/3 022) vs. 0.22% (5/2 269), RR=2.38, 95 %CI: 1.19 -4.78, P=0.01]. Conclusion:PD-1/PD-L1 inhibitors have the risk of causing heart related adverse events, which should be paid attention to in clinical application.

Objective:To explore the clinical and pathological characteristics of heomlytic-uremic syndrome (HUS) induced by gemcitabine.Methods:The relevant databases abroad were searched up to November 12, 2018. Case reports and clinical research papers about HUS induced by gemcitabine were collected. The patient′s general situation, use of gemcitabine, symptoms of HUS, relevant laboratory test results, renal biopsy results, time from medication to HUS onset, and the treatments and outcomes of HUS were recorded. The clinical and pathological characteristics of HUS induced by gemcitabine were analyzed by descriptive statistical method.Results:A total of 61 patients were enrolled in the study, including 22 males and 35 females with 4 unknown gender. The age of patients ranged from 25 to 81 years. The primary diseases included pancreatic cancer in 22 cases, lung cancer in 18 cases, cholangiocarcinoma in 7 cases, mammary cancer in 5 cases, ovarian cancer in 4 cases, non-Hodgkin′s lymphoma in 2 cases, soft tissue sarcoma in 1 case, bladder cancer in 1 case, and kidney cancer in 1 case. HUS occurred in 2-34 months after the first application of gemcitabine, and the median time was 6 months. The cumulative dose of gemcitabine was 4 000-99 540 mg/m 2 when HUS occurred, and the median cumulative dose was 19 100 mg/m 2. Of the 61 patients, 54 patients developed HUS symptoms, including hypertension (43 cases, 79.6%), peripheral edema (31 cases, 57.4%), and dyspnea (20 cases, 37.0%), and 7 patients were asymptomatic. There were different degrees of increase in serum creatinine and lactate dehydrogenase and decrease in platelet and hemoglobin in 61 patients. Fifteen patients performed renal biopsy and the thrombotic microangiopathy were found in all cases. Gemcitabine were stopped after the occurrence of HUS in all patients, and therapies such as symptomatic treatments, plasmapheresis, hemodialysis, symptomatic treatments+plasmapheresis, symptomatic treatments+glucocorticoid, or rituximab or ikuzumab treatment on the basis of above-mentioned therapy were given. Of the 61 patients, HUS was improved in 34 (55.7%) cases, but 27 patients (44.3%) died within 1-65 months after the occurrence of HUS, of which 13 cases (21.3%) died of HUS. Conclusions:The main clinical manifestations of HUS caused by gemcitabine are hypertension, peripheral edema, and dyspnea. A few patients may be asymptomatic, but all develop abnormal laboratory indicators related to toxuria and hemolysis. The main pathological changes in the kidney are thrombotic microangiopathy. The prognosis of HUS is poor. Severe cases can lead to death.

Objective:To systematically evaluate cardiotoxicity of programmed cell death 1 receptor (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors.Methods:Clinical trials of PD-1/PD-L1 inhibitor alone or in combination with other treatments for tumors were collected by searching related databases at home and abroad (up to March 2, 2019). The methodological quality of studies was evaluated using the internationally accepted Cochrane collaboration′s risk of bias assessment tool. A meta-analysis was performed using RevMan 5.3 software to compare the incidences of cardiotoxicity between PD-1/PD-L1 inhibitors (trial group) and placebo or other antineoplastic agents(control group).Results:A total of 10 randomized controlled trials (RCTs) were enrolled, 9 of which were about PD-1 inhibitor alone or in combination with other antineoplastic agents, and 1 of which was about PD-L1 inhibitor monotherapy. There were a total of 5 291 patients, including 3 022 in the trial group and 2 269 in the control group. Evaluation of the methodological quality for studies showed that 4 RCTs were at high risk of bias and the other 6 were at low risk of bias. The meta-analysis showed that the incidence of cardiotoxicity in the trial group was significantly higher than that in the control group, and the difference was statistically significant[1.13% (34/3 022) vs. 0.22% (5/2 269), RR=2.38, 95 %CI: 1.19 -4.78, P=0.01]. Conclusion:PD-1/PD-L1 inhibitors have the risk of causing heart related adverse events, which should be paid attention to in clinical application.