Considering the frequent use of netupitant in polytherapy,the elucidation of its oxidative metabolization pattern is of major importance.However,there is a lack of published research on the redox behavior of this nove...Considering the frequent use of netupitant in polytherapy,the elucidation of its oxidative metabolization pattern is of major importance.However,there is a lack of published research on the redox behavior of this novel neurokinin-1 receptor antagonist.Therefore,this study was performed to simulate the intensive hepatic biotransformation of netupitant using an electrochemically driven method.Most of the known enzyme-mediated reactions occurring in the liver(i.e.,N-dealkylation,hydroxylation,and Noxidation)were successfully mimicked by the electrolytic cell using a boron-doped diamond working electrode.The products were separated by reversed-phase high-performance liquid chromatography and identified by high-resolution mass spectrometry.Aside from its ability to pinpoint formerly unknown metabolites that could be responsible for the known side effects of netupitant or connected with any new perspective concerning future therapeutic indications,this electrochemical process also represents a facile alternative for the synthesis of oxidation products for further in vitro and in vivo studies.展开更多
BACKGROUND A new,oral fixed dose combination of highly selective neurokinin-1 receptor antagonist,netupitant with 5HT3 receptor antagonist,netupitant and palonosetron(NEPA)was approved in India for prevention of chemo...BACKGROUND A new,oral fixed dose combination of highly selective neurokinin-1 receptor antagonist,netupitant with 5HT3 receptor antagonist,netupitant and palonosetron(NEPA)was approved in India for prevention of chemotherapy induced nausea and vomiting(CINV).AIM To assess effectiveness of NEPA in real-world scenario.METHODS We retrospectively assessed the medical records and patient dairies of adult patients who received highly emetogenic or moderately emetogenic chemotherapy(HEC/MEC)and treated with NEPA(Netupitant 300 mg+Palanosetron 0.50 mg)for prevention of CINV.Complete response(CR)was defined as no emesis or no requirement of rescue medication in overall phase(0 to 5 d),acute phase(0-24 h)and delayed phase(2 to 5 d).RESULTS In 403 patients included in the analysis,mean age was 56.24±11.11 years and 55.09%were females.Breast cancer(25.06%)was most common malignancy encountered.HEC and MEC were administered in 54.6%and 45.4%patients respectively.CR in overall phase was 93.79%whereas it was 98.01%in acute CINV and 93.79%in delayed CINV.Overall CR in HEC and MEC groups was 93.63%and 93.98%respectively.CR was more than 90%in different chemotherapy cycles except in group of patients of cycle 4 where CR was 88.88%.CONCLUSION NEPA is a novel combination that is effective in preventing CINV in up to 93%cases treated with highly emetogenic or moderately emetogenic chemotherapy.This study brings the first real-life evidence of its effectiveness in India population.展开更多
Objective:Chemotherapy-induced nausea and vomiting(CINV)are common with doxorubicin-cyclophosphamide(AC)chemotherapy.Recommended antiemetic regimens incorporate neurokinin-1 receptor antagonist(NK1 RA),5-hydroxytrypta...Objective:Chemotherapy-induced nausea and vomiting(CINV)are common with doxorubicin-cyclophosphamide(AC)chemotherapy.Recommended antiemetic regimens incorporate neurokinin-1 receptor antagonist(NK1 RA),5-hydroxytryptamine type-3 receptor antagonist(5 HT3 RA),corticosteroid,and dopamine antagonists.This post-hoc analysis compared results of 3 prospective antiemetic studies conducted among Chinese breast cancer patients who received(neo)adjuvant AC,in order to identify optimal antiemetic prophylaxis.Methods:A total of 304 patients were included:Group 1,ondansetron/dexamethasone(D1);Group 2,aprepitant/ondansetron/dexamethasone(D1);Group 3,aprepitant/ondansetron/dexamethasone(D1–3);Group 4,aprepitant/ondansetron/dexamethasone(D1–3)/olanzapine;and Group 5,netupitant/palonosetron/dexamethasone(D1–3).Antiemetic efficacies of Groups 3,4,and 5 during cycle 1 of AC were individually compared with Group 1.In addition,emesis outcomes of patients in Groups 3 and 5,and those of Groups 2 and 3,were compared.Results:When comparing efficacies of a historical doublet(5 HT3 RA/dexamethasone)with triplet antiemetic regimens(NK1 RA/5 HT3 RA/dexamethasone)with/without olanzapine,complete response(CR)percentages and quality of life(QOL)in overall phase of cycle 1 AC were compared between Group 1 and the other groups:Group 1 vs.3,41.9%vs.38.3%(P=0.6849);Group 1 vs.4,41.9%vs.65.0%(P=0.0107);and Group 1 vs.5,41.9%vs.60.0%(P=0.0460).Groups 4 and 5 achieved a better QOL.When comparing netupitant-based(Group 3)with aprepitant-based(Group 5)triplet antiemetics,CR percentages were 38.3%vs.60.0%,respectively(P=0.0176);Group 5 achieved a better QOL.When comparing 1 day(Group 2)vs.3 day(Group 3)dexamethasone,CR percentages were 46.8%and 38.3%,respectively(P=0.3459);Group 3 had a worse QOL.Conclusions:Aprepitant-containing triplets were non-superior to doublet antiemetics.Netupitant-containing triplets and adding olanzapine to aprepitant-containing triplets were superior to doublets.Netupitant/palonosetron/dexamethasone was superior to aprepitant/ondansetron/dexamethasone.Protracted administration of dexamethasone provided limited additional benefit.展开更多
基金The authors gratefully acknowledged the financial support for part of this work by the German Research Foundation(DFG,Grant No.:KA 1093/7-2,Bonn,Germany)as well as Iuliu Hațieganu University(Internal Grant No.:5200/19/01.03.2017)a grant of the Romanian Ministry of Education and Research,CCCDI-UEFISCDI(Project No.:PNe-Ⅲ-P2-2.1-PED-2019-5473)within PNCDIⅢ.
文摘Considering the frequent use of netupitant in polytherapy,the elucidation of its oxidative metabolization pattern is of major importance.However,there is a lack of published research on the redox behavior of this novel neurokinin-1 receptor antagonist.Therefore,this study was performed to simulate the intensive hepatic biotransformation of netupitant using an electrochemically driven method.Most of the known enzyme-mediated reactions occurring in the liver(i.e.,N-dealkylation,hydroxylation,and Noxidation)were successfully mimicked by the electrolytic cell using a boron-doped diamond working electrode.The products were separated by reversed-phase high-performance liquid chromatography and identified by high-resolution mass spectrometry.Aside from its ability to pinpoint formerly unknown metabolites that could be responsible for the known side effects of netupitant or connected with any new perspective concerning future therapeutic indications,this electrochemical process also represents a facile alternative for the synthesis of oxidation products for further in vitro and in vivo studies.
文摘BACKGROUND A new,oral fixed dose combination of highly selective neurokinin-1 receptor antagonist,netupitant with 5HT3 receptor antagonist,netupitant and palonosetron(NEPA)was approved in India for prevention of chemotherapy induced nausea and vomiting(CINV).AIM To assess effectiveness of NEPA in real-world scenario.METHODS We retrospectively assessed the medical records and patient dairies of adult patients who received highly emetogenic or moderately emetogenic chemotherapy(HEC/MEC)and treated with NEPA(Netupitant 300 mg+Palanosetron 0.50 mg)for prevention of CINV.Complete response(CR)was defined as no emesis or no requirement of rescue medication in overall phase(0 to 5 d),acute phase(0-24 h)and delayed phase(2 to 5 d).RESULTS In 403 patients included in the analysis,mean age was 56.24±11.11 years and 55.09%were females.Breast cancer(25.06%)was most common malignancy encountered.HEC and MEC were administered in 54.6%and 45.4%patients respectively.CR in overall phase was 93.79%whereas it was 98.01%in acute CINV and 93.79%in delayed CINV.Overall CR in HEC and MEC groups was 93.63%and 93.98%respectively.CR was more than 90%in different chemotherapy cycles except in group of patients of cycle 4 where CR was 88.88%.CONCLUSION NEPA is a novel combination that is effective in preventing CINV in up to 93%cases treated with highly emetogenic or moderately emetogenic chemotherapy.This study brings the first real-life evidence of its effectiveness in India population.
基金supported by an education grant from Madam Diana Hon Fun Kong Donation for Cancer Research(Grant No.7104870)。
文摘Objective:Chemotherapy-induced nausea and vomiting(CINV)are common with doxorubicin-cyclophosphamide(AC)chemotherapy.Recommended antiemetic regimens incorporate neurokinin-1 receptor antagonist(NK1 RA),5-hydroxytryptamine type-3 receptor antagonist(5 HT3 RA),corticosteroid,and dopamine antagonists.This post-hoc analysis compared results of 3 prospective antiemetic studies conducted among Chinese breast cancer patients who received(neo)adjuvant AC,in order to identify optimal antiemetic prophylaxis.Methods:A total of 304 patients were included:Group 1,ondansetron/dexamethasone(D1);Group 2,aprepitant/ondansetron/dexamethasone(D1);Group 3,aprepitant/ondansetron/dexamethasone(D1–3);Group 4,aprepitant/ondansetron/dexamethasone(D1–3)/olanzapine;and Group 5,netupitant/palonosetron/dexamethasone(D1–3).Antiemetic efficacies of Groups 3,4,and 5 during cycle 1 of AC were individually compared with Group 1.In addition,emesis outcomes of patients in Groups 3 and 5,and those of Groups 2 and 3,were compared.Results:When comparing efficacies of a historical doublet(5 HT3 RA/dexamethasone)with triplet antiemetic regimens(NK1 RA/5 HT3 RA/dexamethasone)with/without olanzapine,complete response(CR)percentages and quality of life(QOL)in overall phase of cycle 1 AC were compared between Group 1 and the other groups:Group 1 vs.3,41.9%vs.38.3%(P=0.6849);Group 1 vs.4,41.9%vs.65.0%(P=0.0107);and Group 1 vs.5,41.9%vs.60.0%(P=0.0460).Groups 4 and 5 achieved a better QOL.When comparing netupitant-based(Group 3)with aprepitant-based(Group 5)triplet antiemetics,CR percentages were 38.3%vs.60.0%,respectively(P=0.0176);Group 5 achieved a better QOL.When comparing 1 day(Group 2)vs.3 day(Group 3)dexamethasone,CR percentages were 46.8%and 38.3%,respectively(P=0.3459);Group 3 had a worse QOL.Conclusions:Aprepitant-containing triplets were non-superior to doublet antiemetics.Netupitant-containing triplets and adding olanzapine to aprepitant-containing triplets were superior to doublets.Netupitant/palonosetron/dexamethasone was superior to aprepitant/ondansetron/dexamethasone.Protracted administration of dexamethasone provided limited additional benefit.
