Background GW117(N-(2-(6-chloro-7-deuteromethoxynaphthalen-1-yl)ethyl)acetamide)is a dual-acting agent(MT1/MT2 agonist,5-HT_(2C)antagonist)with prior evidence of antidepressant efficacy and favourable safety.Aims To p...Background GW117(N-(2-(6-chloro-7-deuteromethoxynaphthalen-1-yl)ethyl)acetamide)is a dual-acting agent(MT1/MT2 agonist,5-HT_(2C)antagonist)with prior evidence of antidepressant efficacy and favourable safety.Aims To preliminarily evaluate the efficacy and safety of GW117 in major depressive disorder(MDD)and to explore the optimal dosing.Methods A total of 280 eligible patients aged 18-65years with MDD were randomly assigned(1:1:1:1)to8 weeks of double-blind treatment with fixed doses of GW117 tablets(20,40,60 mg/day)or placebo.The primary endpoint was the change from baseline to Week 8 in the total score of the Hamilton Rating Scale for Depression-17item(HAMD-17).Key secondary endpoints included changes in the Montgomery-?sberg Depression Rating Scale(MADRS)total score over the same period.Results In the full analysis set(n=276),GW117 showed numerically greater reductions versus placebo in the HAMD-17 and MADRS total scores,as well as higher response rates at Week 8.However,these differences did not reach statistical significance,potentially due to a high placebo response and other contributing factors.In a post hoc analysis of an optimal subgroup(baseline HAMD-17>24 or insomnia factor>4),GW117 showed efficacy in improving multidimensional symptoms,including insomnia.The 20 mg dose demonstrated a significant3.66-point greater reduction in MADRS(p=0.026)and a23.16%higher response rate(p=0.013)compared with placebo.GW117 was well-tolerated,with no cases of alanine aminotransferase or aspartate aminotransferase exceeding 3×the upper limit of normal and no concerning safety signals reported.Conclusions This exploratory study found that GW117demonstrated encouraging antidepressant efficacy and a favourable safety profile in patients with MDD.Although differences versus placebo did not reach statistical significance in the overall population,GW11720 mg monotherapy showed significant improvements in multidimensional depressive symptoms,including insomnia,in the optimal response subgroup.No hepatotoxicity was reported,supporting its promising therapeutic potential for further clinical development.展开更多
Hyperthyroidism refers to a clinical state that results from inappropriately hight hyroid hormone levels in the tissues;.Ⅰ-131 therapy plays a critical role and provides a remarkable curative effect in targeting thyr...Hyperthyroidism refers to a clinical state that results from inappropriately hight hyroid hormone levels in the tissues;.Ⅰ-131 therapy plays a critical role and provides a remarkable curative effect in targeting thyroid diseases. Thyroid cells can take up isotope I-131, which emits not only beta rays but also展开更多
Peptide receptor radionuclide therapy(PRRT)with radiolabeled SSTR2 agonists is a treatment option that is highly effective in controlling metastatic and progressive neuroendocrine tumors(NETs).Previous studies have sh...Peptide receptor radionuclide therapy(PRRT)with radiolabeled SSTR2 agonists is a treatment option that is highly effective in controlling metastatic and progressive neuroendocrine tumors(NETs).Previous studies have shown that an SSTR2 agonist combined with albumin binding moiety Evans blue(denoted as^(177)Lu-EB-TATE)is characterized by a higher tumor uptake and residence time in preclinical models and in patients with metastatic NETs.This study aimed to enhance the in vivo stability,pharmacokinetics,and pharmacodynamics of^(177)Lu-EB-TATE by replacing the maleimide-thiol group with a polyethylene glycol chain,resulting in a novel EB conjugated SSTR2-targeting radiopharmaceutical,^(177)Lu-LNC1010,for PRRT.In preclinical studies,^(177)Lu-LNC1010 exhibited good stability and SSTR2-binding affinity in AR42J tumor cells and enhanced uptake and prolonged retention in AR42J tumor xenografts.Thereafter,we presented the first-in-human dose escalation study of^(177)Lu-LNC1010 in patients with advanced/metastatic NETs.^(177)Lu-LNC1010 was well-tolerated by all patients,with minor adverse effects,and exhibited significant uptake and prolonged retention in tumor lesions,with higher tumor radiation doses than those of^(177)Lu-EB-TATE.Preliminary PRRT efficacy results showed an 83%disease control rate and a 42%overall response rate after two^(177)Lu-LNC1010 treatment cycles.These encouraging findings warrant further investigations through multicenter,prospective,and randomized controlled trials.展开更多
文摘Background GW117(N-(2-(6-chloro-7-deuteromethoxynaphthalen-1-yl)ethyl)acetamide)is a dual-acting agent(MT1/MT2 agonist,5-HT_(2C)antagonist)with prior evidence of antidepressant efficacy and favourable safety.Aims To preliminarily evaluate the efficacy and safety of GW117 in major depressive disorder(MDD)and to explore the optimal dosing.Methods A total of 280 eligible patients aged 18-65years with MDD were randomly assigned(1:1:1:1)to8 weeks of double-blind treatment with fixed doses of GW117 tablets(20,40,60 mg/day)or placebo.The primary endpoint was the change from baseline to Week 8 in the total score of the Hamilton Rating Scale for Depression-17item(HAMD-17).Key secondary endpoints included changes in the Montgomery-?sberg Depression Rating Scale(MADRS)total score over the same period.Results In the full analysis set(n=276),GW117 showed numerically greater reductions versus placebo in the HAMD-17 and MADRS total scores,as well as higher response rates at Week 8.However,these differences did not reach statistical significance,potentially due to a high placebo response and other contributing factors.In a post hoc analysis of an optimal subgroup(baseline HAMD-17>24 or insomnia factor>4),GW117 showed efficacy in improving multidimensional symptoms,including insomnia.The 20 mg dose demonstrated a significant3.66-point greater reduction in MADRS(p=0.026)and a23.16%higher response rate(p=0.013)compared with placebo.GW117 was well-tolerated,with no cases of alanine aminotransferase or aspartate aminotransferase exceeding 3×the upper limit of normal and no concerning safety signals reported.Conclusions This exploratory study found that GW117demonstrated encouraging antidepressant efficacy and a favourable safety profile in patients with MDD.Although differences versus placebo did not reach statistical significance in the overall population,GW11720 mg monotherapy showed significant improvements in multidimensional depressive symptoms,including insomnia,in the optimal response subgroup.No hepatotoxicity was reported,supporting its promising therapeutic potential for further clinical development.
基金supported by a fund from the Key Project of Natural Science Foundation of Tianjin [16JCZDJC36100]Medical and Health Technology Innovation Project of the Chinese Academy of Medical Sciences [2017-I2M-1-016]+2 种基金Fundamental Research Funds for the Central Universities [3332018116]PUMC Youth Fund [3332015101]Fundamental Research Funds for CAMS&PUMC [2016ZX310074]
文摘Hyperthyroidism refers to a clinical state that results from inappropriately hight hyroid hormone levels in the tissues;.Ⅰ-131 therapy plays a critical role and provides a remarkable curative effect in targeting thyroid diseases. Thyroid cells can take up isotope I-131, which emits not only beta rays but also
基金supported by the National Natural Science Foundation of China(No.82071961)Fujian Research and Training Grants for Young and Middle-aged Leaders in Healthcare,Key Scientific Research Program for Yong Scholars in Fujian(No.2021ZQNZD016,China)+5 种基金Fujian Natural Science Foundation for Distinguished Young Scholars(No.2022D005,China)Innovation of Science and Technology,Fujian Province(No.2021Y9134,China)National University of Singapore(No.NUHSRO/2020/133/Startup/08,NUHSRO/2023/008/NUSMed/TCE/LOA,NUHSRO/2021/034/TRP/09/Nanomedicine)National Medical Research Council(No.MOH-001388-00,MOH-001041,CG21APR1005,Singapore)Singapore Ministry of Education(No.MOE-000387-00,Singapore)National Research Foundation(No.NRF-000352-00,Singapore).
文摘Peptide receptor radionuclide therapy(PRRT)with radiolabeled SSTR2 agonists is a treatment option that is highly effective in controlling metastatic and progressive neuroendocrine tumors(NETs).Previous studies have shown that an SSTR2 agonist combined with albumin binding moiety Evans blue(denoted as^(177)Lu-EB-TATE)is characterized by a higher tumor uptake and residence time in preclinical models and in patients with metastatic NETs.This study aimed to enhance the in vivo stability,pharmacokinetics,and pharmacodynamics of^(177)Lu-EB-TATE by replacing the maleimide-thiol group with a polyethylene glycol chain,resulting in a novel EB conjugated SSTR2-targeting radiopharmaceutical,^(177)Lu-LNC1010,for PRRT.In preclinical studies,^(177)Lu-LNC1010 exhibited good stability and SSTR2-binding affinity in AR42J tumor cells and enhanced uptake and prolonged retention in AR42J tumor xenografts.Thereafter,we presented the first-in-human dose escalation study of^(177)Lu-LNC1010 in patients with advanced/metastatic NETs.^(177)Lu-LNC1010 was well-tolerated by all patients,with minor adverse effects,and exhibited significant uptake and prolonged retention in tumor lesions,with higher tumor radiation doses than those of^(177)Lu-EB-TATE.Preliminary PRRT efficacy results showed an 83%disease control rate and a 42%overall response rate after two^(177)Lu-LNC1010 treatment cycles.These encouraging findings warrant further investigations through multicenter,prospective,and randomized controlled trials.
