OBJECTIVE To explore the method of preparation of 99m↑Tc labeled AntiVEGF McAb 5-FU loaded polylactic acid nanoparticles （99m↑TC-5-FU-Ab-NPs）, and investigate the biological distribution of the nanoparticles in hu...OBJECTIVE To explore the method of preparation of 99m↑Tc labeled AntiVEGF McAb 5-FU loaded polylactic acid nanoparticles （99m↑TC-5-FU-Ab-NPs）, and investigate the biological distribution of the nanoparticles in human gastric carcinoma xenografts. METHODS Anti-VEGF monoclonal antibodyes （MCAB）in 5-FU-Ab-NPs were labeled with 99m↑Tc using a modified Schwarz method. After isolation of the 99m↑TC-5-FU-Ab-NPs using a Sephadex G-250 column, the labeling percentage and radiochemical purity were determined using paper chromatography. The immunocempetence of the 99m↑TC-5-FU-Ab-NPs as tumor markers was determined using ELISA and immunohistochemistry. 99m↑TC-5-FU-Ab-NPs （experimental group）, 99m↑Tc-labelled murine multiclonal IgG loaded polylactic acid and nanoparticles （control group） were injected via the tail vein into SCID mice bearing human gastric carcinoma. A radio-immunity ECT image was developed at 2 and 6 h after the injection. Following the ECT imaging, the mice were sacrificed, their tissue and tumor radioactivity distribution determined, and percentage of the injected-dose per gram （%ID/g） and tumor/ nontumor （T/NT） ratio calculated. High performance liquid chromatography （HPLC） was used to determine the 5-FU concentration in the tumor tissue and blood in the mice of both groups. RESULTS The percentage of 99m↑TC-5-FU-Ab-NPs labeling was 90%-95%. There was no obvious decrease in the antibody activity before and after labeling. The radio-immuno-imaging （RII） showed that the tumor image had developed 2 h after injection of the 99m↑TC-5-FU-Ab-NPs, and with time it was clearer at the 6th hour following the injection. The %lD/g of the tumor tissue at both 2 h and 6 h after the injection was significantly higher compared to the control group. The tumor %lD/g and the tumor to blood activity ratio （TB） of the experimental group at 6 h following the injection increased compared to that at 2 h, and at the same time, 5-FU concentration in the tumor of the experimental group continuously increased over time, and showed a significant difference compared to the 5-FU concentration in the tumor of the control group. CONCLUSION The 99m↑TC-5-FU-Ab-NPs prepared in this study are adequate to meet the demands of the RII, and the immune targeting ability of the anti-VEGF MCAB is reliable. Six hours after injection, the 99m↑TC-5-FU-Ab-NPs showed a relatively high specific concentration shadow in the human gastric carcinoma xenografts.展开更多
Chiglitazar(Carfloglitazar)is a novel peroxisome proliferator-activated receptor(PPAR)pan-agonist that has shown promising effects on glycemic control and lipid regulation in patients with type 2 diabetes.In this rand...Chiglitazar(Carfloglitazar)is a novel peroxisome proliferator-activated receptor(PPAR)pan-agonist that has shown promising effects on glycemic control and lipid regulation in patients with type 2 diabetes.In this randomized phase 3 trial,we compared the efficacy and safety of chiglitazar with sitagliptin in patients with type 2 diabetes who had insufficient glycemic control despite a strict diet and exercise regimen.Eligible patients were randomized(1:1:1)to receive chiglitazar 32 mg(n=245),chiglitazar 48 mg(n=246),or sitagliptin 100 mg(n=248)once daily for 24 weeks.The primary endpoint was the change in glycosylated hemoglobin A_(1C)(HbA_(1c))from baseline at week 24 with the non-inferiority of chiglitazar over sitagliptin.Both chiglitazar and sitagliptin significantly reduced HbA1c at week 24 with values of-1.40%,-1.47%,and-1.39%for chiglitazar 32 mg,chiglitazar 48 mg,and sitagliptin 100 mg,respectively.Chiglitazar 32 and 48 mg were both non-inferior to sitagliptin 100 mg,with mean differences of-0.04%(95%confidential interval(Cl)-0.22 to 0.15)and-0.08%(95%Cl-0.27 to 0.10),respectively.Compared with sitagliptin,greater reduction in fasting and 2-h postprandial plasma glucose and fasting insulin was observed with chiglitazar.Overall adverse event rates were similar between the groups.A small increase in mild edema in the chiglitazar 48 mg group and slight weight gain in both chiglitazar groups were reported.The overall results demonstrated that chiglitazar possesses good efficacy and safety profile in patients with type 2 diabetes inadequately controlled with lifestyle interventions,thereby providing adequate supporting evidence for using this PPAR pan-agonist as a treatment option for type 2 diabetes.展开更多
Chiglitazar(Carfloglitazar)is a novel non-thiazolidinedione(TZD)structured peroxisome proliferatoractivated receptor(PPAR)pan-agonist that has shown promising effects on glycemic control and lipid regulation in patien...Chiglitazar(Carfloglitazar)is a novel non-thiazolidinedione(TZD)structured peroxisome proliferatoractivated receptor(PPAR)pan-agonist that has shown promising effects on glycemic control and lipid regulation in patients with type 2 diabetes in previous clinical studies.This randomized phase 3 trial aimed to compare the efficacy and safety of chiglitazar with placebo in patients with type 2 diabetes with insufficient glycemic control by strict diet and exercise alone.Eligible patients were randomly assigned to receive chiglitazar 32 mg(n=167),chiglitazar 48 mg(n=166),or placebo(n=202)once daily.The primary endpoint was the change in glycosylated hemoglobin A_(1c)(HbA_(1c))at week 24 with superiority of chiglitazar over placebo.The results showed that both chiglitazar 32 and 48 mg resulted in significant and clinically meaningful reductions in HbA_(1c),and placebo-adjusted estimated treatment differences at week 24 for chiglitazar 32 and 48 mg were-0.87%(95%confidential interval(CI):-1.10 to-0.65;P<0.0001)and-1.05%(95%CI:-1.29 to-0.81;P<0.0001),respectively.Secondary efficacy parameters including glycemic control,insulin sensitivity and triglyceride reduction were also significantly improved in the chiglitazar groups.The overall frequency of adverse events and study discontinuation attributable to adverse events were similar among the groups.Low incidences of mild edema and body weight gain were reported in the chiglitazar dose groups.The results from this phase 3 trial demonstrated that the PPAR pan-agonist chiglitazar possesses an overall good efficacy and safety profile in patients with type 2 diabetes inadequately controlled with lifestyle interventions,thereby providing adequate supporting evidence for using this PPAR pan-agonist as a treatment option for type 2 diabetes.展开更多
基金the grants as fol-lows:The Problems-Tackling Program in Sci-ence and Technology of Guangzhou City,Chi-na(No.2003 Z 3-E0381)National Foundationof Natural Science,China(No.30670951)+1 种基金Guangdong Foundation of Natural Science,Guangdong,China(No.06021322)TheProblems-Tackling Program in Science andTechnology of Guangdong Province,China(No.2005 B31211002).
文摘OBJECTIVE To explore the method of preparation of 99m↑Tc labeled AntiVEGF McAb 5-FU loaded polylactic acid nanoparticles （99m↑TC-5-FU-Ab-NPs）, and investigate the biological distribution of the nanoparticles in human gastric carcinoma xenografts. METHODS Anti-VEGF monoclonal antibodyes （MCAB）in 5-FU-Ab-NPs were labeled with 99m↑Tc using a modified Schwarz method. After isolation of the 99m↑TC-5-FU-Ab-NPs using a Sephadex G-250 column, the labeling percentage and radiochemical purity were determined using paper chromatography. The immunocempetence of the 99m↑TC-5-FU-Ab-NPs as tumor markers was determined using ELISA and immunohistochemistry. 99m↑TC-5-FU-Ab-NPs （experimental group）, 99m↑Tc-labelled murine multiclonal IgG loaded polylactic acid and nanoparticles （control group） were injected via the tail vein into SCID mice bearing human gastric carcinoma. A radio-immunity ECT image was developed at 2 and 6 h after the injection. Following the ECT imaging, the mice were sacrificed, their tissue and tumor radioactivity distribution determined, and percentage of the injected-dose per gram （%ID/g） and tumor/ nontumor （T/NT） ratio calculated. High performance liquid chromatography （HPLC） was used to determine the 5-FU concentration in the tumor tissue and blood in the mice of both groups. RESULTS The percentage of 99m↑TC-5-FU-Ab-NPs labeling was 90%-95%. There was no obvious decrease in the antibody activity before and after labeling. The radio-immuno-imaging （RII） showed that the tumor image had developed 2 h after injection of the 99m↑TC-5-FU-Ab-NPs, and with time it was clearer at the 6th hour following the injection. The %lD/g of the tumor tissue at both 2 h and 6 h after the injection was significantly higher compared to the control group. The tumor %lD/g and the tumor to blood activity ratio （TB） of the experimental group at 6 h following the injection increased compared to that at 2 h, and at the same time, 5-FU concentration in the tumor of the experimental group continuously increased over time, and showed a significant difference compared to the 5-FU concentration in the tumor of the control group. CONCLUSION The 99m↑TC-5-FU-Ab-NPs prepared in this study are adequate to meet the demands of the RII, and the immune targeting ability of the anti-VEGF MCAB is reliable. Six hours after injection, the 99m↑TC-5-FU-Ab-NPs showed a relatively high specific concentration shadow in the human gastric carcinoma xenografts.
基金the Chinese National and Provincial Major Project for New Drug Innovation(National:2008ZX09101-002,2013ZX09401301Provincial:2011A080501010)Shenzhen Municipal Major Project(2010-1746)。
文摘Chiglitazar(Carfloglitazar)is a novel peroxisome proliferator-activated receptor(PPAR)pan-agonist that has shown promising effects on glycemic control and lipid regulation in patients with type 2 diabetes.In this randomized phase 3 trial,we compared the efficacy and safety of chiglitazar with sitagliptin in patients with type 2 diabetes who had insufficient glycemic control despite a strict diet and exercise regimen.Eligible patients were randomized(1:1:1)to receive chiglitazar 32 mg(n=245),chiglitazar 48 mg(n=246),or sitagliptin 100 mg(n=248)once daily for 24 weeks.The primary endpoint was the change in glycosylated hemoglobin A_(1C)(HbA_(1c))from baseline at week 24 with the non-inferiority of chiglitazar over sitagliptin.Both chiglitazar and sitagliptin significantly reduced HbA1c at week 24 with values of-1.40%,-1.47%,and-1.39%for chiglitazar 32 mg,chiglitazar 48 mg,and sitagliptin 100 mg,respectively.Chiglitazar 32 and 48 mg were both non-inferior to sitagliptin 100 mg,with mean differences of-0.04%(95%confidential interval(Cl)-0.22 to 0.15)and-0.08%(95%Cl-0.27 to 0.10),respectively.Compared with sitagliptin,greater reduction in fasting and 2-h postprandial plasma glucose and fasting insulin was observed with chiglitazar.Overall adverse event rates were similar between the groups.A small increase in mild edema in the chiglitazar 48 mg group and slight weight gain in both chiglitazar groups were reported.The overall results demonstrated that chiglitazar possesses good efficacy and safety profile in patients with type 2 diabetes inadequately controlled with lifestyle interventions,thereby providing adequate supporting evidence for using this PPAR pan-agonist as a treatment option for type 2 diabetes.
基金grants from Chinese National and Provincial Major Project for New Drug Innovation(National:2008ZX09101-002 and 2013ZX09401301Provincial:2011A080501010)Shenzhen Municipal Major Project(2010-1746)。
文摘Chiglitazar(Carfloglitazar)is a novel non-thiazolidinedione(TZD)structured peroxisome proliferatoractivated receptor(PPAR)pan-agonist that has shown promising effects on glycemic control and lipid regulation in patients with type 2 diabetes in previous clinical studies.This randomized phase 3 trial aimed to compare the efficacy and safety of chiglitazar with placebo in patients with type 2 diabetes with insufficient glycemic control by strict diet and exercise alone.Eligible patients were randomly assigned to receive chiglitazar 32 mg(n=167),chiglitazar 48 mg(n=166),or placebo(n=202)once daily.The primary endpoint was the change in glycosylated hemoglobin A_(1c)(HbA_(1c))at week 24 with superiority of chiglitazar over placebo.The results showed that both chiglitazar 32 and 48 mg resulted in significant and clinically meaningful reductions in HbA_(1c),and placebo-adjusted estimated treatment differences at week 24 for chiglitazar 32 and 48 mg were-0.87%(95%confidential interval(CI):-1.10 to-0.65;P<0.0001)and-1.05%(95%CI:-1.29 to-0.81;P<0.0001),respectively.Secondary efficacy parameters including glycemic control,insulin sensitivity and triglyceride reduction were also significantly improved in the chiglitazar groups.The overall frequency of adverse events and study discontinuation attributable to adverse events were similar among the groups.Low incidences of mild edema and body weight gain were reported in the chiglitazar dose groups.The results from this phase 3 trial demonstrated that the PPAR pan-agonist chiglitazar possesses an overall good efficacy and safety profile in patients with type 2 diabetes inadequately controlled with lifestyle interventions,thereby providing adequate supporting evidence for using this PPAR pan-agonist as a treatment option for type 2 diabetes.
