Objective:To investigate the effect and the relevant potential mechanism of nonpeptide neurokinin 1(NK1) receptor antagonist L-703,606 in the edema formation after burn injury. Method:1.-703,606 treatment was performe...Objective:To investigate the effect and the relevant potential mechanism of nonpeptide neurokinin 1(NK1) receptor antagonist L-703,606 in the edema formation after burn injury. Method:1.-703,606 treatment was performed in Sprague-Dawley(SD) rats at early stage after deep partial-thickness skin scalding.One hundred and fifty two adult male SI) rats were used in the study and randomly divided into sham scald(SS,n=8),scald control(SC,n=48),and L-703,606 treatment(IT,n=48) groups.The rats in SC and LT groups were subjected to 20%total body surface area(TBSA) deep partial-thickness skin scalding.Modified Evans blue extravasation, tracing electron microscopy by lanthanum nitrate and mean water content assay were employed to observe and detect the changes of vascular permeability,ultrastructure and edema formation in adjacent tissue to the wounds and in the jejuna of rats at early stage(72 h) after scald.Results: The pathological increase of vascular permeability in the periwound tissue and jejunum of rats in LT group were significantly lower than that in SC group(P【0.01),and recuperated earlier. Meanwhile,the changes of water contents of corresponding tissues in LT group were lighter than those in SC group(P【0.01).The ultrastructural changes of the microvessels in the peri-wound tissue of LT group showed that the junctions between microvascular endothelium cells were more narrow than those of SC group,moreover,and the number of opening and the engorgement and cavitation of the vascular endothelium cells decreased,the areosis and edema in perivascular tissue lightened,and the precipitation of the high eletron density lanthanum tracing agent in the interspace of the tissue decreased significantly in LT group.Conclusions:It is concluded that nonpeptide NK1-receptor antagonist L-703,606 could lighten the vascular permeability and edema formation in the periwound tissue and jejunum,and accelerate the normalization process of pathological changes in the tissues of rats after scald.展开更多
Recently, NK1R （Neurokinin-1 receptors） take attention as new and promising target in anticancer drug development area. It has been proved that non-peptide NK1R antagonists L-733,060, aprepitant and L-732,138 inhibi...Recently, NK1R （Neurokinin-1 receptors） take attention as new and promising target in anticancer drug development area. It has been proved that non-peptide NK1R antagonists L-733,060, aprepitant and L-732,138 inhibited tumor growth in several cancer cell lines. For the development of novel NK1R antagonists as antitumor agents, heterocyclic compounds which were previously synthesized by our team, tested for their cytotoxic activities in several cancer cell lines in this study. Among the tested compounds, a benzothiazole derivative BSN-009 inhibited colon cancer cell lines growth by 57.53% by comparing the activity to the control drug aprepitant. Molecular modeling studies such as molecular docking and pharmacophore generation were performed with known NK1R antagonists and BSN-009 by using Discovery Studio 3.5 in order to explain their binding modes to NK1R. BSN-009 may be a good anticancer drug candidate as a possible NK1R antagonist and is worthy to carry on the anticancer studies.展开更多
Chemotherapy-induced nausea and vomiting (CINV) are distressing side effects of chemotherapy. Neurokinin-1 receptor antagonists (NK1-RAs) have been incorporated in the contemporary management of CINV. However, clinica...Chemotherapy-induced nausea and vomiting (CINV) are distressing side effects of chemotherapy. Neurokinin-1 receptor antagonists (NK1-RAs) have been incorporated in the contemporary management of CINV. However, clinical studies on NK1-RAs have shown mixed results in reducing CINV risk. Most studies focused on the use of aprepitant (APR) and casopitant (CAS) in breast cancer patients receiving AC-type (doxorubicin and cyclophosphamide) chemotherapy. In this study, we compared the study design and clinical efficacies of these NK1-RAs in reducing CINV risk. Among the selected eight studies, 4 APR Randomized Controlled Trials (RCTs), 2 APR Observational Studies (OSs) and 2 CAS RCTs were identified. Patient-related characteristics such as the proportion of females (60.0% - 100.0%), age (46.5 - 59.5 years), histories of motion (5.6% - 47.0% in NK1-RA arms) and morning sicknesses (14.2% - 45.0% in NK1-RA arms) and types of antiemetic regimens;as well as chemotherapy-related characteristics such as the proportion of patients on AC chemotherapy (15.0% - 100.0%) varied greatly. In terms of efficacies, both APR and CAS improved overall CR and vomiting in majority of the studies. None of the studies, however, demonstrated that NK1-RA could provide adequate nausea control. To conclude, NK1-RAs are effective in improving vomiting and overall CR, but not useful in controlling nausea or attaining CC, the ideal CINV endpoint. A shift in paradigm is needed for future CINV research. As healthcare providers continue to strive for optimum CINV control in their patients, we hope this review can help them make better informed clinical decisions.展开更多
文摘Objective:To investigate the effect and the relevant potential mechanism of nonpeptide neurokinin 1(NK1) receptor antagonist L-703,606 in the edema formation after burn injury. Method:1.-703,606 treatment was performed in Sprague-Dawley(SD) rats at early stage after deep partial-thickness skin scalding.One hundred and fifty two adult male SI) rats were used in the study and randomly divided into sham scald(SS,n=8),scald control(SC,n=48),and L-703,606 treatment(IT,n=48) groups.The rats in SC and LT groups were subjected to 20%total body surface area(TBSA) deep partial-thickness skin scalding.Modified Evans blue extravasation, tracing electron microscopy by lanthanum nitrate and mean water content assay were employed to observe and detect the changes of vascular permeability,ultrastructure and edema formation in adjacent tissue to the wounds and in the jejuna of rats at early stage(72 h) after scald.Results: The pathological increase of vascular permeability in the periwound tissue and jejunum of rats in LT group were significantly lower than that in SC group(P【0.01),and recuperated earlier. Meanwhile,the changes of water contents of corresponding tissues in LT group were lighter than those in SC group(P【0.01).The ultrastructural changes of the microvessels in the peri-wound tissue of LT group showed that the junctions between microvascular endothelium cells were more narrow than those of SC group,moreover,and the number of opening and the engorgement and cavitation of the vascular endothelium cells decreased,the areosis and edema in perivascular tissue lightened,and the precipitation of the high eletron density lanthanum tracing agent in the interspace of the tissue decreased significantly in LT group.Conclusions:It is concluded that nonpeptide NK1-receptor antagonist L-703,606 could lighten the vascular permeability and edema formation in the periwound tissue and jejunum,and accelerate the normalization process of pathological changes in the tissues of rats after scald.
文摘Recently, NK1R （Neurokinin-1 receptors） take attention as new and promising target in anticancer drug development area. It has been proved that non-peptide NK1R antagonists L-733,060, aprepitant and L-732,138 inhibited tumor growth in several cancer cell lines. For the development of novel NK1R antagonists as antitumor agents, heterocyclic compounds which were previously synthesized by our team, tested for their cytotoxic activities in several cancer cell lines in this study. Among the tested compounds, a benzothiazole derivative BSN-009 inhibited colon cancer cell lines growth by 57.53% by comparing the activity to the control drug aprepitant. Molecular modeling studies such as molecular docking and pharmacophore generation were performed with known NK1R antagonists and BSN-009 by using Discovery Studio 3.5 in order to explain their binding modes to NK1R. BSN-009 may be a good anticancer drug candidate as a possible NK1R antagonist and is worthy to carry on the anticancer studies.
文摘Chemotherapy-induced nausea and vomiting (CINV) are distressing side effects of chemotherapy. Neurokinin-1 receptor antagonists (NK1-RAs) have been incorporated in the contemporary management of CINV. However, clinical studies on NK1-RAs have shown mixed results in reducing CINV risk. Most studies focused on the use of aprepitant (APR) and casopitant (CAS) in breast cancer patients receiving AC-type (doxorubicin and cyclophosphamide) chemotherapy. In this study, we compared the study design and clinical efficacies of these NK1-RAs in reducing CINV risk. Among the selected eight studies, 4 APR Randomized Controlled Trials (RCTs), 2 APR Observational Studies (OSs) and 2 CAS RCTs were identified. Patient-related characteristics such as the proportion of females (60.0% - 100.0%), age (46.5 - 59.5 years), histories of motion (5.6% - 47.0% in NK1-RA arms) and morning sicknesses (14.2% - 45.0% in NK1-RA arms) and types of antiemetic regimens;as well as chemotherapy-related characteristics such as the proportion of patients on AC chemotherapy (15.0% - 100.0%) varied greatly. In terms of efficacies, both APR and CAS improved overall CR and vomiting in majority of the studies. None of the studies, however, demonstrated that NK1-RA could provide adequate nausea control. To conclude, NK1-RAs are effective in improving vomiting and overall CR, but not useful in controlling nausea or attaining CC, the ideal CINV endpoint. A shift in paradigm is needed for future CINV research. As healthcare providers continue to strive for optimum CINV control in their patients, we hope this review can help them make better informed clinical decisions.
