A nine cyclic peptide(TCP-1)showed excellent specificity for colon cancer.TCP-1 binds with human tumor tissues at early stages and mice tumor with diameters of 1-4 mm,suggesting that TCP-1 may be used for early diagno...A nine cyclic peptide(TCP-1)showed excellent specificity for colon cancer.TCP-1 binds with human tumor tissues at early stages and mice tumor with diameters of 1-4 mm,suggesting that TCP-1 may be used for early diagnosis of colon cancer.The mechanism of the targeted binding of TCP-1 to colon cancer was also studied using immunoprecipitation,LC-MS and bioinformatics.After screening and identifying of the possible binding target proteins of TCP-1,keratin,typeⅡcytoskeletal 5 was speculated to be the specific binding target protein of TCP-1 in human tumor tissue.Pharmacokinetics studies were conducted to investigate the target-mediated drug disposition of the new tumor-specific peptide by LC-MS/MS.The tissue distribution study showed that TCP-1 was found only in colon tumors(the target site)in tumor mice did not bind to any other tissues.Conjugating TCP-1 to tumor markedly increased its removal rate from blood circulation but mildly extended its staying time in vivo.In tumor mice,a lower AUC of TCP-1(reduced by almost 35%)and 2-fold higher clearance were found compared to that of normal mice.The proposed metabolic pathway of TCP-1 in the kidney was also determined using LC-MS^(n)-IT-TOF.The high specificity and low toxicity of the peptide may be caused by its extremely tight binding to the targets.Potential applications for future clinical use,including MRI and PET/CT were also explored,and this research may promote the development of colon cancer diagnostic technology research and provide new ideas and technical routes for tumor diagnostic technology.展开更多
目的使用药代动力学/药效学模型联合蒙特卡洛模拟评价和优化某院ICU患者应用亚胺培南/西司他丁进行抗感染治疗的给药方案,为ICU合理使用亚胺培南/西司他丁提供参考。方法收集该院2019年1月~2021年12月重症监护病房中常见革兰氏阴性菌药...目的使用药代动力学/药效学模型联合蒙特卡洛模拟评价和优化某院ICU患者应用亚胺培南/西司他丁进行抗感染治疗的给药方案,为ICU合理使用亚胺培南/西司他丁提供参考。方法收集该院2019年1月~2021年12月重症监护病房中常见革兰氏阴性菌药敏试验报告,制订亚胺培南/西司他丁对4种革兰阴性菌治疗的6种给药方案,使用药代动学/药效学模型联合蒙特卡洛模拟的方法进行模拟,计算不同给药方案的达标概率和累积反应分数,优选出最佳的治疗方案。结果亚胺培南/西司他丁治疗4种革兰阴性菌,在“0.5 g q12h”的给药方案中,当最低抑菌浓度(MIC)=2μg·mL^(-1)和MIC=4μg·mL^(-1)时,达标概率(PTA)分别为80.38%和12.93%,均小于90%;在“1 g q12h”的给药方案中,当MIC=4μg·mL^(-1)时,PTA为79.46%。除以上3种情况之外,其他各用药方案,在不同的MIC下模拟的PTA都大于90%。对于鲍曼不动杆菌感染,亚胺培南/西司他丁“0.5 g q12h”和“1 g q12h”两种给药方案的累计反应分数(CFR)分别是44.26%和86.96%,均小于90%,其余4种给药方案的CFR均大于90%;对于铜绿假单胞菌的治疗,“0.5 g q12h”给药方案的CFR为55.41%,其余5种给药方案CFR均大于90%;对于肺炎克雷伯菌和大肠埃希菌感染,6种给药方案的CFR均大于90%。结论该院ICU重症感染患者在使用亚胺培南/西司他丁进行抗感染治疗时,对于鲍曼不动杆菌和铜绿假单胞菌可经验性使用“0.5 g q8h”给药方案;而对于肺炎克雷伯菌和大肠埃希菌感染,可经验性使用“0.5 g q12h”给药方案,目标性治疗则可根据具体MIC值进行给药方案调整,从而减少抗菌药物耐药性和药品不良反应的发生,降低患者的治疗费用。展开更多
基金supported by the CAMS Innovation Fund for Medical Sciences(CIFMS,No.2021-I2M-1-027)National Natural Science Foundation of China(Nos.T2192972,81402997)+2 种基金Key Project of Beijing Natural Science Foundation(No.7181007)National High-tech Research and Development Plan(863 Plan,No.2014AA020803)Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study(No.Z141102004414062)。
文摘A nine cyclic peptide(TCP-1)showed excellent specificity for colon cancer.TCP-1 binds with human tumor tissues at early stages and mice tumor with diameters of 1-4 mm,suggesting that TCP-1 may be used for early diagnosis of colon cancer.The mechanism of the targeted binding of TCP-1 to colon cancer was also studied using immunoprecipitation,LC-MS and bioinformatics.After screening and identifying of the possible binding target proteins of TCP-1,keratin,typeⅡcytoskeletal 5 was speculated to be the specific binding target protein of TCP-1 in human tumor tissue.Pharmacokinetics studies were conducted to investigate the target-mediated drug disposition of the new tumor-specific peptide by LC-MS/MS.The tissue distribution study showed that TCP-1 was found only in colon tumors(the target site)in tumor mice did not bind to any other tissues.Conjugating TCP-1 to tumor markedly increased its removal rate from blood circulation but mildly extended its staying time in vivo.In tumor mice,a lower AUC of TCP-1(reduced by almost 35%)and 2-fold higher clearance were found compared to that of normal mice.The proposed metabolic pathway of TCP-1 in the kidney was also determined using LC-MS^(n)-IT-TOF.The high specificity and low toxicity of the peptide may be caused by its extremely tight binding to the targets.Potential applications for future clinical use,including MRI and PET/CT were also explored,and this research may promote the development of colon cancer diagnostic technology research and provide new ideas and technical routes for tumor diagnostic technology.
文摘目的使用药代动力学/药效学模型联合蒙特卡洛模拟评价和优化某院ICU患者应用亚胺培南/西司他丁进行抗感染治疗的给药方案,为ICU合理使用亚胺培南/西司他丁提供参考。方法收集该院2019年1月~2021年12月重症监护病房中常见革兰氏阴性菌药敏试验报告,制订亚胺培南/西司他丁对4种革兰阴性菌治疗的6种给药方案,使用药代动学/药效学模型联合蒙特卡洛模拟的方法进行模拟,计算不同给药方案的达标概率和累积反应分数,优选出最佳的治疗方案。结果亚胺培南/西司他丁治疗4种革兰阴性菌,在“0.5 g q12h”的给药方案中,当最低抑菌浓度(MIC)=2μg·mL^(-1)和MIC=4μg·mL^(-1)时,达标概率(PTA)分别为80.38%和12.93%,均小于90%;在“1 g q12h”的给药方案中,当MIC=4μg·mL^(-1)时,PTA为79.46%。除以上3种情况之外,其他各用药方案,在不同的MIC下模拟的PTA都大于90%。对于鲍曼不动杆菌感染,亚胺培南/西司他丁“0.5 g q12h”和“1 g q12h”两种给药方案的累计反应分数(CFR)分别是44.26%和86.96%,均小于90%,其余4种给药方案的CFR均大于90%;对于铜绿假单胞菌的治疗,“0.5 g q12h”给药方案的CFR为55.41%,其余5种给药方案CFR均大于90%;对于肺炎克雷伯菌和大肠埃希菌感染,6种给药方案的CFR均大于90%。结论该院ICU重症感染患者在使用亚胺培南/西司他丁进行抗感染治疗时,对于鲍曼不动杆菌和铜绿假单胞菌可经验性使用“0.5 g q8h”给药方案;而对于肺炎克雷伯菌和大肠埃希菌感染,可经验性使用“0.5 g q12h”给药方案,目标性治疗则可根据具体MIC值进行给药方案调整,从而减少抗菌药物耐药性和药品不良反应的发生,降低患者的治疗费用。
