Background In recent years,the incidence of coronary heart disease(CHD)has continued to rise,and its comorbidity with hyperlipidemia significantly increases the mortality risk in patients.Statin monotherapy faces limi...Background In recent years,the incidence of coronary heart disease(CHD)has continued to rise,and its comorbidity with hyperlipidemia significantly increases the mortality risk in patients.Statin monotherapy faces limitations in efficacy for some patients and raises potential safety concerns.Ezetimibe,as a novel lipid-modulating agent,exhibits potential advantages in the treatment of hyperlipidemia.Based on this,the present study investigated the therapeutic efficacy of ezetimibe in CHD patients with hyperlipidemia,as well as its effects on lipid metabolism and the amelioration of atherosclerosis.Methods In this study,150 clinical cases with CHD and hyperlipidemia admitted in our hospital from July 2022 to July 2024 were collected for retrospective analysis.According to different treatment methods,they were randomly divided into the Atorvastatin group(control group,n=75)and the Atorvastatin+Ezetimibe group(experimental group,n=75).Control group received atorvastatin monotherapy,while experimental group were administered additional ezetimibe as an adjunct to the atorvastatin-based treatment regimen.The clinical efficacy of the two treatment groups was analyzed,including cardiac function-related parameters such as the cardiac index(CI),cardiac output(CO),left ventricular ejection fraction(LVEF)and left ventricular end-diastolic diameter(LVEDD)before and after treatment.The observed indicators encompassed coronary angiography findings,the Gensini score for assessing coronary stenosis severity,the inflammatory marker high-sensitivity C-reactive protein(hs-CRP),and lipid profile parameters including total cholesterol(TC),triglycerides(TG),high-density lipoprotein cholesterol(HDL-C),and low-density lipoprotein cholesterol(LDL-C).Additionally,the occurrence of adverse reactions during treatment was monitored.Results After treatment,the total effective rate in experimental group was significantly higher than that in control group,with a statistically significant difference(P<0.05).In the comparison of the baseline data,both groups showed marked improvements in CI,CO,LVEF,and HDL-C.However,at the same time points,the experimental group demonstrated significantly better results in these parameters than control group(P<0.05).Additionally,LVEDD,LDL-C,hs-CRP and Gensini scores were significantly reduced after treatment in both groups compared to pretreatment levels.Moreover,at identical time points,the aforementioned parameters in the experimental group demonstrated significantly greater reductions compared to control group(P<0.05).Regarding safety assessment,comparative analysis of adverse drug reaction(ADR)incidence rates between the two treatment groups revealed no statistically significant difference(P>0.05).Conclusions In patients with CHD complicated by hyperlipidemia,ezetimibe demonstrates significant therapeutic advantages.It effectively enhances treatment efficacy,regulates lipid profiles,improves cardiac function,and mitigates the progression of atherosclerosis.This regimen exhibits a favorable safety profile and holds substantial clinical value for both therapeutic processes and rehabilitation outcomes in this patient population.展开更多
Objective: To evaluate the bioequivalence (BE) of two fixed-dose combination (FDC) formulations of Rosuvastatin and Ezetimibe: Cresadex® EZE 20/10 mg (Abbott Laboratories) as the reference formulation (R), and Ra...Objective: To evaluate the bioequivalence (BE) of two fixed-dose combination (FDC) formulations of Rosuvastatin and Ezetimibe: Cresadex® EZE 20/10 mg (Abbott Laboratories) as the reference formulation (R), and Racor® Duo 20/10 mg (Laboratorios Leti, S.A.V.) as the test formulation (T). Method: A randomized, single-dose, two-period, two-sequence, open-label, crossover design was employed. Subjects received a single oral dose of either the Test or Reference formulation under fasting conditions, with a 12-day washout period between treatments. Male subjects aged 18 - 45 years with normal health and laboratory values were included. Exclusion criteria encompassed any medical conditions, recent surgery, drug or alcohol use, and hypersensitivity to the study drugs. Blood samples were collected at pre-dose and multiple post-dose time points and analyzed using a validated LC-MS/MS method to quantify Rosuvastatin and Ezetimibe concentrations in plasma. Descriptive statistics were used to summarize pharmacokinetic (PK) parameters. ANOVA was conducted to compare the ln-transformed values of Cmax, AUC0−t, and AUC0−∞. Schuirmann’s two one-sided t-tests were applied to assess bioequivalence (BE). Results: The 90% Confidence Intervals for the ln-transformed ratios of Cmax, AUC0−t, and AUC0−∞ fell within the acceptance range of 80% to 125%, demonstrating bioequivalence between the Test and Reference formulations. Both formulations were well-tolerated, with no serious adverse events reported. Conclusions: The results of this study confirm the bioequivalence of the two tested FDC Rosuvastatin/Ezetimibe formulations: Cresadex® EZE (Abbott Laboratories) and Racor® Duo (Laboratorios Leti, S.A.V.). These findings endorse the therapeutic interchangeability of these products, providing clinicians with greater flexibility in the treatment of hyperlipidemia.展开更多
AIM： To assess whether treatment with insulinsensitizing agents （ISAs） in combination with ezetimibe and valsartan have greater effect on hepatic fat content and lipid peroxidation compared to monotherapy in the me...AIM： To assess whether treatment with insulinsensitizing agents （ISAs） in combination with ezetimibe and valsartan have greater effect on hepatic fat content and lipid peroxidation compared to monotherapy in the methionine choline-deficient diet （MCDD） rat model of non-alcoholic fatty liver disease （NAFLD）. METHODS： Rats （n = 6 per group） were treated with different drugs, including MCDD only, MCDD diet with either metformin （200 mg/kg）, rosiglitazone （3 mg/kg）, metformin plus rosiglitazone （M＋R）, ezetimibe （2 mg/ kg）, valsartan （2 mg/kg）, or combination of all drugs for a total of 15 wk. Liver histology, lipids, parameters of oxidative stress and TNF-alpha were measured. RESULTS： Fatty liver （FL） rats demonstrated severe hepatic fatty infiltration （〉 91% fat）, with an increase in hepatic TG （＋1263%, P 〈 0.001）, hepatic cholesterol （＋245%, P 〈 0.03）, hepatic MDA levels （＋225%, P 〈 0.001）, serum TNF-alpha （17.8 ＋ 10 vs 7.8 ＋ 0.0, P 〈 0.001）, but a decrease in hepatic alpha tocopherol （-74%, P 〈 0.001） as compared to the control rats. Combination therapy with all drugs produced a significant decrease in liver steatosis （-54%）, hepatic TG （-64%）, hepatic cholesterol （-31%） and hepatic MDA （-70%）, but increased hepatic alpha tocopherol （＋443%） as compared to FL rats. Combination therapy with ISA alone produced a smaller decrease in liver steatosis （-32% vs -54%, P 〈 0.001） and in hepatic MDA levels （-55% vs -70%, P 〈 0.01）, but a similar decrease in hepatic lipids when compared with the all drugs combination. TNF-alpha levels decreased significantly in all treatment groups except in ISA group. CONCLUSION： Combination therapies have a greater effect on liver fat content as compared to monotherapy. Rosiglitazone appears to improve hepatic steatosis to a greater extent than metformin.展开更多
AIM: To investigate whether ezetimibe ameliorates hepatic steatosis and induces autophagy in a rat model of obesity and type 2 diabetes. METHODS: Male age-matched lean control LETO and obese and diabetic OLETF rats we...AIM: To investigate whether ezetimibe ameliorates hepatic steatosis and induces autophagy in a rat model of obesity and type 2 diabetes. METHODS: Male age-matched lean control LETO and obese and diabetic OLETF rats were administered either PBS or ezetimibe(10 mg/kg per day) via stomach gavage for 20 wk. Changes in weight gain and energy intake were regularly monitored. Blood and liver tissue were harvested after overnight fasting at the end of study. Histological assessment was performed in liver tissue. The concentrations of glucose, insulin, triglycerides(TG), free fatty acids(FFA), and total cholesterol(TC) in blood and TG, FFA, and TG in livertissue were measured. m RNA and protein abundance involved in autophagy was analyzed in the liver. To investigate the effect of ezetimibe on autophagy and reduction in hepatic fat accumulation, human Huh7 hepatocytes were incubated with ezetimibe(10 μmol/L) together with or without palmitic acid(PA, 0.5 mmol/L, 24 h). Transmission electron microscopy(TEM) was employed to demonstrate effect of ezetimibe on autophagy formation. Autophagic flux was measured with bafilomycin A1, an inhibitor of autophagy and following immunoblotting for autophagy-related protein expression.RESULTS: In the OLETF rats that received ezetimibe(10 mg/kg per day), liver weight were significantly decreased by 20% compared to OLETF control rats without changes in food intake and body weight(P < 0.05). Lipid parameters including TG, FFA, and TC in liver tissue of ezetimibe-administrated OLETF rats were dramatically decreased at least by 30% compared to OLETF controls(P < 0.01). The serum glucose, insulin, HOMA-IR, and lipid profiles were also improved by ezetimibe(P < 0.05). In addition, autophagy-related m RNA expression including ATG5, ATG6, and ATG7 and the protein level of microtubule-associated protein light chain 3(LC3) were significantly increased in the liver in rats that received ezetimibe(P < 0.05). Likewise, for hepatocytes cultured in vitro, ezetimibe treatment significantly decreased PA-induced fat accumulation and increased PA-reduced m RNA and protein expression involved in autophagy(P < 0.05). Ezetimibe-increased autophagosomes was observed in TEM analysis. Immunoblotting analysis of autophagy formation with an inhibitor of autophagy demonstrated that ezetimibe-increased autophagy resulted from increased autophagic flux. CONCLUSION: The present study demonstrates that ezetimibe-mediated improvement in hepatic steatosis might involve the induction of autophagy.展开更多
Non-alcoholic fatty liver disease (NAFLD) encompasses a histological spectrum ranging from simple steatosis to steatohepatitis,advanced fibrosis and inflammatory changes.Ezetimibe inhibits cholesterol absorption from ...Non-alcoholic fatty liver disease (NAFLD) encompasses a histological spectrum ranging from simple steatosis to steatohepatitis,advanced fibrosis and inflammatory changes.Ezetimibe inhibits cholesterol absorption from the intestinal lumen into enterocytes.The molecular target of ezetimibe is the sterol transporter Niemann-Pick C1-like 1 protein (NPC1L1).Human NPC1L1 is abundantly expressed in the liver and may facilitate the hepatic accumulation of cholesterol.Ezetimibe ex-erts beneficial effects on several metabolic variables.Ezetimibe treatment attenuates hepatic steatosis and is beneficial in terms of NAFLD biochemical markers.The combination of ezetimibe with other interventions may also be beneficial in NAFLD patients.Our group inves-tigated the ezetimibe-orlistat combination treatment in overweight and obese patients with hypercholeste-rolemia,with beneficial effects on NAFLD biochemical markers.These results are promising for patients with NAFLD,who usually have increased cardiovascular disease risk and need a multifactorial treatment.How-ever,it should be mentioned that most results are from animal studies and,although modest elevation of liver function tests may raise the suspicion of NAFLD,none of these tests are sensitive to establish the diagnosis of NAFLD with great accuracy.展开更多
A simple, sensitive and specific liquid chromatography-tandem mass spectrometry method was developed for simultaneous quantification of ezetimibe and simvastatin in rat plasma. The deuterium isotopes： ezetimibe d4 an...A simple, sensitive and specific liquid chromatography-tandem mass spectrometry method was developed for simultaneous quantification of ezetimibe and simvastatin in rat plasma. The deuterium isotopes： ezetimibe d4 and simvastatin d6 were used as internal standards for ezetimibe and simvastatin, respectively. MS/MS detection involved a switch of electron spray ionization mode from negative to positive at retention time 3.01 rain. Samples were extracted from plasma by liquid-liquid extraction using tertiary butyl methyl ether. Chromatographic separation was achieved with Agilent Eclipse XBD-CIs column using mobile phase that consisted of a mixture of ammonium acetate （pH4.5; 10 mM）-acetonitrile （25：75 v/v）. The method was linear and validated over the concentration range of 0.2--40.0 ng/rnL for simvastatin and 0.05-15.0 ng/mL for ezetimibe. The transitions selected were m/z 408.3→271.1 and m/z 412.0→275.10 for ezetimibe and ezetimibe d4, and m/z 419.30 → 285.20 and rrdz 425.40 →199.20 for simvastatin and simvastatin d6. Intra- and inter-batch precisions for ezetimibe were 1.6-14.8% and 2.1-13.4%; and for simvastatin 0.94-9.56% and 0.79-12%, respectively. The proposed method was sensitive, selective, precise and accurate for the quantification of ezetimibe and simvastatin simultaneously in rat plasma. The method was successfully applied to a pharmacokinetic study by oral co-administration of ezetimibe and simvastatin in SD rats.展开更多
Ezetimibe is the f irst member of a new family of lipid- lowering drugs that inhibits uptake of dietary and bili- ary cholesterol. It was approved by the FDA in 2002 for hypercholesterolemia alone or in combination wi...Ezetimibe is the f irst member of a new family of lipid- lowering drugs that inhibits uptake of dietary and bili- ary cholesterol. It was approved by the FDA in 2002 for hypercholesterolemia alone or in combination with statins. Its use has been spreading over the last years. Ezetimibe was considered a safe drug. We report a case of a woman who developed a serious hepatocellular drug-induced liver disease after 4 mo therapy with 10 mg daily of ezetimibe. After withdrawal of the drug, the patient recovered slowly. Ezetimibe may produce seri- ous toxic hepatitis and prompt withdrawal is mandatory in case of a signif icant abnormality in liver testing after beginning or during treatment with ezetimibe.展开更多
AIM： To investigate the prevalence of cholelithiasis among patients treated with ezetimibe. METHODS： A retrospective, case-control study based on computerized medical records from patients of the Clalit Health Servi...AIM： To investigate the prevalence of cholelithiasis among patients treated with ezetimibe. METHODS： A retrospective, case-control study based on computerized medical records from patients of the Clalit Health Services, Sharon-Shomron region, from 2000 to 2009. Patients 20-85 years of age, who had been treated with ezetimibe and statins or statins only for at least 6 too, and who had an abdominal ultrasound were included in the study. Collected data included age, gender, ezetimibe treatment duration, presence of hypothyroidism or diabetes, and existence of cholelithiasis as determined by ultrasound. Ex- cluded were subjects after gallbladder resection, with hemolysis, myeloproliferative or inflammatory bowel diseases, and those treated with ursodeoxycholic acid and fibrates. Patients treated with statins and ezeti- mibe （study group） were compared to patients treated with statins only （control group）. RESULTS： The study group included 25 patients and the control group 168. All patients in the study were treated with statins. The study group included 13 males （52%） and 12 females （48%）, the control group 76 males （45%） and 92 （55%） females （P = 0.544）. The groups did not differ in age （mean age： 68 ± 8 years, range 53-85 years vs mean age： 71±8 years, range 51-85 years; P = 0.153） or in the rate of dia- betic and hypothyroid patients [11 （44%） vs 57 （33%）, P = 0.347 in the study group and 5 （20%） vs 23 （14%）, P = 0.449 in the control group, respectively]. Patients in the study group were treated with ezetimibe for an average of 798±379 d. Cholelithiasis was found in 4 （16%） patients in the study group and in 33 （20%） patients in the control group （P = 0.666）. CONCLUSION： Ezetimibe does not appear to influ- ence the prevalence of gallstones.展开更多
uring the laboratory optimization and the late phase manufacturing studies of the cholesterol absorption inhibitor Ezetimibe 1, the formation of several stereoisomers was observed. To study the complete stereoisomer p...uring the laboratory optimization and the late phase manufacturing studies of the cholesterol absorption inhibitor Ezetimibe 1, the formation of several stereoisomers was observed. To study the complete stereoisomer profile of Ezetimibe 1, we have synthesized and completely characterized several key stereoisomers of Ezetimibe 1 for the first time. This study will provide an access to the reference standard of these stereoisomers and may have some implications in the development of new medicines.展开更多
A convenient method for the synthesis of ezetimibe analogs as cholesterol absorption inhibitors was described.The key step in the synthesis was the intramolecular ring formation through Mitsunobu reaction.Furthermore,...A convenient method for the synthesis of ezetimibe analogs as cholesterol absorption inhibitors was described.The key step in the synthesis was the intramolecular ring formation through Mitsunobu reaction.Furthermore,a new series of analogs was designed and synthesized.展开更多
A simple and rapid Supercritical Fluid Chromatography (SFC) method has been developed to isolate and characterize R-Isomer of Ezetimi be by using normal phase Chiral Cel OD-H with 250 mm × 30 mm, 5 microns column...A simple and rapid Supercritical Fluid Chromatography (SFC) method has been developed to isolate and characterize R-Isomer of Ezetimi be by using normal phase Chiral Cel OD-H with 250 mm × 30 mm, 5 microns column using a mobile phase system containing super critical fluid carbondi oxide (Co2) and the percentage of 2-Propanol as a mobile phase (85:15) and detection at 230 nm. The isolated R-Isomer is characterized by using UV-vis, FT-IR, ESI-MS, HPLC1H and 13C NMR. The purity of isolated R-Isomer is about 98%.展开更多
文摘Background In recent years,the incidence of coronary heart disease(CHD)has continued to rise,and its comorbidity with hyperlipidemia significantly increases the mortality risk in patients.Statin monotherapy faces limitations in efficacy for some patients and raises potential safety concerns.Ezetimibe,as a novel lipid-modulating agent,exhibits potential advantages in the treatment of hyperlipidemia.Based on this,the present study investigated the therapeutic efficacy of ezetimibe in CHD patients with hyperlipidemia,as well as its effects on lipid metabolism and the amelioration of atherosclerosis.Methods In this study,150 clinical cases with CHD and hyperlipidemia admitted in our hospital from July 2022 to July 2024 were collected for retrospective analysis.According to different treatment methods,they were randomly divided into the Atorvastatin group(control group,n=75)and the Atorvastatin+Ezetimibe group(experimental group,n=75).Control group received atorvastatin monotherapy,while experimental group were administered additional ezetimibe as an adjunct to the atorvastatin-based treatment regimen.The clinical efficacy of the two treatment groups was analyzed,including cardiac function-related parameters such as the cardiac index(CI),cardiac output(CO),left ventricular ejection fraction(LVEF)and left ventricular end-diastolic diameter(LVEDD)before and after treatment.The observed indicators encompassed coronary angiography findings,the Gensini score for assessing coronary stenosis severity,the inflammatory marker high-sensitivity C-reactive protein(hs-CRP),and lipid profile parameters including total cholesterol(TC),triglycerides(TG),high-density lipoprotein cholesterol(HDL-C),and low-density lipoprotein cholesterol(LDL-C).Additionally,the occurrence of adverse reactions during treatment was monitored.Results After treatment,the total effective rate in experimental group was significantly higher than that in control group,with a statistically significant difference(P<0.05).In the comparison of the baseline data,both groups showed marked improvements in CI,CO,LVEF,and HDL-C.However,at the same time points,the experimental group demonstrated significantly better results in these parameters than control group(P<0.05).Additionally,LVEDD,LDL-C,hs-CRP and Gensini scores were significantly reduced after treatment in both groups compared to pretreatment levels.Moreover,at identical time points,the aforementioned parameters in the experimental group demonstrated significantly greater reductions compared to control group(P<0.05).Regarding safety assessment,comparative analysis of adverse drug reaction(ADR)incidence rates between the two treatment groups revealed no statistically significant difference(P>0.05).Conclusions In patients with CHD complicated by hyperlipidemia,ezetimibe demonstrates significant therapeutic advantages.It effectively enhances treatment efficacy,regulates lipid profiles,improves cardiac function,and mitigates the progression of atherosclerosis.This regimen exhibits a favorable safety profile and holds substantial clinical value for both therapeutic processes and rehabilitation outcomes in this patient population.
文摘Objective: To evaluate the bioequivalence (BE) of two fixed-dose combination (FDC) formulations of Rosuvastatin and Ezetimibe: Cresadex® EZE 20/10 mg (Abbott Laboratories) as the reference formulation (R), and Racor® Duo 20/10 mg (Laboratorios Leti, S.A.V.) as the test formulation (T). Method: A randomized, single-dose, two-period, two-sequence, open-label, crossover design was employed. Subjects received a single oral dose of either the Test or Reference formulation under fasting conditions, with a 12-day washout period between treatments. Male subjects aged 18 - 45 years with normal health and laboratory values were included. Exclusion criteria encompassed any medical conditions, recent surgery, drug or alcohol use, and hypersensitivity to the study drugs. Blood samples were collected at pre-dose and multiple post-dose time points and analyzed using a validated LC-MS/MS method to quantify Rosuvastatin and Ezetimibe concentrations in plasma. Descriptive statistics were used to summarize pharmacokinetic (PK) parameters. ANOVA was conducted to compare the ln-transformed values of Cmax, AUC0−t, and AUC0−∞. Schuirmann’s two one-sided t-tests were applied to assess bioequivalence (BE). Results: The 90% Confidence Intervals for the ln-transformed ratios of Cmax, AUC0−t, and AUC0−∞ fell within the acceptance range of 80% to 125%, demonstrating bioequivalence between the Test and Reference formulations. Both formulations were well-tolerated, with no serious adverse events reported. Conclusions: The results of this study confirm the bioequivalence of the two tested FDC Rosuvastatin/Ezetimibe formulations: Cresadex® EZE (Abbott Laboratories) and Racor® Duo (Laboratorios Leti, S.A.V.). These findings endorse the therapeutic interchangeability of these products, providing clinicians with greater flexibility in the treatment of hyperlipidemia.
文摘AIM： To assess whether treatment with insulinsensitizing agents （ISAs） in combination with ezetimibe and valsartan have greater effect on hepatic fat content and lipid peroxidation compared to monotherapy in the methionine choline-deficient diet （MCDD） rat model of non-alcoholic fatty liver disease （NAFLD）. METHODS： Rats （n = 6 per group） were treated with different drugs, including MCDD only, MCDD diet with either metformin （200 mg/kg）, rosiglitazone （3 mg/kg）, metformin plus rosiglitazone （M＋R）, ezetimibe （2 mg/ kg）, valsartan （2 mg/kg）, or combination of all drugs for a total of 15 wk. Liver histology, lipids, parameters of oxidative stress and TNF-alpha were measured. RESULTS： Fatty liver （FL） rats demonstrated severe hepatic fatty infiltration （〉 91% fat）, with an increase in hepatic TG （＋1263%, P 〈 0.001）, hepatic cholesterol （＋245%, P 〈 0.03）, hepatic MDA levels （＋225%, P 〈 0.001）, serum TNF-alpha （17.8 ＋ 10 vs 7.8 ＋ 0.0, P 〈 0.001）, but a decrease in hepatic alpha tocopherol （-74%, P 〈 0.001） as compared to the control rats. Combination therapy with all drugs produced a significant decrease in liver steatosis （-54%）, hepatic TG （-64%）, hepatic cholesterol （-31%） and hepatic MDA （-70%）, but increased hepatic alpha tocopherol （＋443%） as compared to FL rats. Combination therapy with ISA alone produced a smaller decrease in liver steatosis （-32% vs -54%, P 〈 0.001） and in hepatic MDA levels （-55% vs -70%, P 〈 0.01）, but a similar decrease in hepatic lipids when compared with the all drugs combination. TNF-alpha levels decreased significantly in all treatment groups except in ISA group. CONCLUSION： Combination therapies have a greater effect on liver fat content as compared to monotherapy. Rosiglitazone appears to improve hepatic steatosis to a greater extent than metformin.
基金Supported by Samsung Biomedical Research Institute,Grant No.SBRI C-B1-111-3National Research Foundation of Korea,No.2012R1A1A2009143/2013027171Korean Diabetes Association(to Park CY,2014S-1)
文摘AIM: To investigate whether ezetimibe ameliorates hepatic steatosis and induces autophagy in a rat model of obesity and type 2 diabetes. METHODS: Male age-matched lean control LETO and obese and diabetic OLETF rats were administered either PBS or ezetimibe(10 mg/kg per day) via stomach gavage for 20 wk. Changes in weight gain and energy intake were regularly monitored. Blood and liver tissue were harvested after overnight fasting at the end of study. Histological assessment was performed in liver tissue. The concentrations of glucose, insulin, triglycerides(TG), free fatty acids(FFA), and total cholesterol(TC) in blood and TG, FFA, and TG in livertissue were measured. m RNA and protein abundance involved in autophagy was analyzed in the liver. To investigate the effect of ezetimibe on autophagy and reduction in hepatic fat accumulation, human Huh7 hepatocytes were incubated with ezetimibe(10 μmol/L) together with or without palmitic acid(PA, 0.5 mmol/L, 24 h). Transmission electron microscopy(TEM) was employed to demonstrate effect of ezetimibe on autophagy formation. Autophagic flux was measured with bafilomycin A1, an inhibitor of autophagy and following immunoblotting for autophagy-related protein expression.RESULTS: In the OLETF rats that received ezetimibe(10 mg/kg per day), liver weight were significantly decreased by 20% compared to OLETF control rats without changes in food intake and body weight(P < 0.05). Lipid parameters including TG, FFA, and TC in liver tissue of ezetimibe-administrated OLETF rats were dramatically decreased at least by 30% compared to OLETF controls(P < 0.01). The serum glucose, insulin, HOMA-IR, and lipid profiles were also improved by ezetimibe(P < 0.05). In addition, autophagy-related m RNA expression including ATG5, ATG6, and ATG7 and the protein level of microtubule-associated protein light chain 3(LC3) were significantly increased in the liver in rats that received ezetimibe(P < 0.05). Likewise, for hepatocytes cultured in vitro, ezetimibe treatment significantly decreased PA-induced fat accumulation and increased PA-reduced m RNA and protein expression involved in autophagy(P < 0.05). Ezetimibe-increased autophagosomes was observed in TEM analysis. Immunoblotting analysis of autophagy formation with an inhibitor of autophagy demonstrated that ezetimibe-increased autophagy resulted from increased autophagic flux. CONCLUSION: The present study demonstrates that ezetimibe-mediated improvement in hepatic steatosis might involve the induction of autophagy.
文摘Non-alcoholic fatty liver disease (NAFLD) encompasses a histological spectrum ranging from simple steatosis to steatohepatitis,advanced fibrosis and inflammatory changes.Ezetimibe inhibits cholesterol absorption from the intestinal lumen into enterocytes.The molecular target of ezetimibe is the sterol transporter Niemann-Pick C1-like 1 protein (NPC1L1).Human NPC1L1 is abundantly expressed in the liver and may facilitate the hepatic accumulation of cholesterol.Ezetimibe ex-erts beneficial effects on several metabolic variables.Ezetimibe treatment attenuates hepatic steatosis and is beneficial in terms of NAFLD biochemical markers.The combination of ezetimibe with other interventions may also be beneficial in NAFLD patients.Our group inves-tigated the ezetimibe-orlistat combination treatment in overweight and obese patients with hypercholeste-rolemia,with beneficial effects on NAFLD biochemical markers.These results are promising for patients with NAFLD,who usually have increased cardiovascular disease risk and need a multifactorial treatment.How-ever,it should be mentioned that most results are from animal studies and,although modest elevation of liver function tests may raise the suspicion of NAFLD,none of these tests are sensitive to establish the diagnosis of NAFLD with great accuracy.
文摘A simple, sensitive and specific liquid chromatography-tandem mass spectrometry method was developed for simultaneous quantification of ezetimibe and simvastatin in rat plasma. The deuterium isotopes： ezetimibe d4 and simvastatin d6 were used as internal standards for ezetimibe and simvastatin, respectively. MS/MS detection involved a switch of electron spray ionization mode from negative to positive at retention time 3.01 rain. Samples were extracted from plasma by liquid-liquid extraction using tertiary butyl methyl ether. Chromatographic separation was achieved with Agilent Eclipse XBD-CIs column using mobile phase that consisted of a mixture of ammonium acetate （pH4.5; 10 mM）-acetonitrile （25：75 v/v）. The method was linear and validated over the concentration range of 0.2--40.0 ng/rnL for simvastatin and 0.05-15.0 ng/mL for ezetimibe. The transitions selected were m/z 408.3→271.1 and m/z 412.0→275.10 for ezetimibe and ezetimibe d4, and m/z 419.30 → 285.20 and rrdz 425.40 →199.20 for simvastatin and simvastatin d6. Intra- and inter-batch precisions for ezetimibe were 1.6-14.8% and 2.1-13.4%; and for simvastatin 0.94-9.56% and 0.79-12%, respectively. The proposed method was sensitive, selective, precise and accurate for the quantification of ezetimibe and simvastatin simultaneously in rat plasma. The method was successfully applied to a pharmacokinetic study by oral co-administration of ezetimibe and simvastatin in SD rats.
文摘Ezetimibe is the f irst member of a new family of lipid- lowering drugs that inhibits uptake of dietary and bili- ary cholesterol. It was approved by the FDA in 2002 for hypercholesterolemia alone or in combination with statins. Its use has been spreading over the last years. Ezetimibe was considered a safe drug. We report a case of a woman who developed a serious hepatocellular drug-induced liver disease after 4 mo therapy with 10 mg daily of ezetimibe. After withdrawal of the drug, the patient recovered slowly. Ezetimibe may produce seri- ous toxic hepatitis and prompt withdrawal is mandatory in case of a signif icant abnormality in liver testing after beginning or during treatment with ezetimibe.
文摘AIM： To investigate the prevalence of cholelithiasis among patients treated with ezetimibe. METHODS： A retrospective, case-control study based on computerized medical records from patients of the Clalit Health Services, Sharon-Shomron region, from 2000 to 2009. Patients 20-85 years of age, who had been treated with ezetimibe and statins or statins only for at least 6 too, and who had an abdominal ultrasound were included in the study. Collected data included age, gender, ezetimibe treatment duration, presence of hypothyroidism or diabetes, and existence of cholelithiasis as determined by ultrasound. Ex- cluded were subjects after gallbladder resection, with hemolysis, myeloproliferative or inflammatory bowel diseases, and those treated with ursodeoxycholic acid and fibrates. Patients treated with statins and ezeti- mibe （study group） were compared to patients treated with statins only （control group）. RESULTS： The study group included 25 patients and the control group 168. All patients in the study were treated with statins. The study group included 13 males （52%） and 12 females （48%）, the control group 76 males （45%） and 92 （55%） females （P = 0.544）. The groups did not differ in age （mean age： 68 ± 8 years, range 53-85 years vs mean age： 71±8 years, range 51-85 years; P = 0.153） or in the rate of dia- betic and hypothyroid patients [11 （44%） vs 57 （33%）, P = 0.347 in the study group and 5 （20%） vs 23 （14%）, P = 0.449 in the control group, respectively]. Patients in the study group were treated with ezetimibe for an average of 798±379 d. Cholelithiasis was found in 4 （16%） patients in the study group and in 33 （20%） patients in the control group （P = 0.666）. CONCLUSION： Ezetimibe does not appear to influ- ence the prevalence of gallstones.
基金Sichuan Provincial Science and Technology Support Program (No. 2011SZ0014)
文摘uring the laboratory optimization and the late phase manufacturing studies of the cholesterol absorption inhibitor Ezetimibe 1, the formation of several stereoisomers was observed. To study the complete stereoisomer profile of Ezetimibe 1, we have synthesized and completely characterized several key stereoisomers of Ezetimibe 1 for the first time. This study will provide an access to the reference standard of these stereoisomers and may have some implications in the development of new medicines.
文摘A convenient method for the synthesis of ezetimibe analogs as cholesterol absorption inhibitors was described.The key step in the synthesis was the intramolecular ring formation through Mitsunobu reaction.Furthermore,a new series of analogs was designed and synthesized.
文摘A simple and rapid Supercritical Fluid Chromatography (SFC) method has been developed to isolate and characterize R-Isomer of Ezetimi be by using normal phase Chiral Cel OD-H with 250 mm × 30 mm, 5 microns column using a mobile phase system containing super critical fluid carbondi oxide (Co2) and the percentage of 2-Propanol as a mobile phase (85:15) and detection at 230 nm. The isolated R-Isomer is characterized by using UV-vis, FT-IR, ESI-MS, HPLC1H and 13C NMR. The purity of isolated R-Isomer is about 98%.
