Transnasal Delivery of the Peptide Agonist Specific to Neuromedin-U Receptor 2 to the Brain for the Treatment of Obesity.

Obesity and metabolic syndrome are threats to the health of large population worldwide as they are associated with high mortality, mainly linked to cardiovascular diseases. Recently, CPN-116 (CPN), which is an agonist peptide specific to neuromedin-U receptor 2 (NMUR2) that is expressed predominantly in the brain, has been developed as a new therapeutic candidate for the treatment of obesity and metabolic syndrome. However, treatment with CPN poses a challenge due to the limited delivery of CPN to the brain. Recent studies have clarified that the direct anatomical connection of the nasal cavity with brain allows delivery of several drugs to the brain. In this study, we confirm the nasal cavity as a promising CPN delivery route to the brain for the treatment of obesity and metabolic syndrome. According to the pharmacokinetic study, the clearance of CPN from the blood was very rapid with a half-life of 3 min. In vitro study on its stability in the serum and cerebrospinal fluid (CSF) indicates that CPN was more stable in the CSF than in the blood. The concentration of CPN in the brain was higher after nasal administration, despite its lower concentrations in the plasma than that after intravenous administration. The study on its pharmacological potency suggests the effective suppression of increased body weight in mice in a dose-dependent manner due to the direct activation of NMUR2 by CPN. This results from the higher concentration of corticosterone in blood after nasal administration of CPN as compared to nasal application of saline. In conclusion, the above findings indicate that the nasal cavity is a promising CPN delivery route to the brain to treat obesity and metabolic syndrome.

[Effect of withdrawal of 5-fluorouracil bolus administration on recovery from neutropenia in colorectal cancer patients treated with mFOLFOX6 chemotherapy-comparison with total dosage reduction].

A combination of oxaliplatin(L-OHP), folinic acid and 5-fluorouracil(5-FU)(mFOLFOX6)has been widely administered to treat advanced or recurrent colorectal cancer. In this regimen, a bolus of 5-FU is administered intravenously, followed by its 46-hr continuous intravenous infusion. For 12 patients who showed neutropenia during mFOLFOX6 chemotherapy at Itami City Hospital, we investigated neutrophil recovery by comparing a patient group treated by the withdrawal of the 5-FU bolus administration(n=6)with a patient group treated by total dose reduction of L-OHP, as well as both the bolus and continuous 5-FU administration(n=6). After two weeks, the neutrophil numbers in the bolus withdrawal group showed a relatively higher value than that in the total dose reduction group[p= 0.032]. For patients showing neutropenia related to mFOLFOX6 chemotherapy, withdrawal of 5-FU bolus administration is suggested to be an effective method of promoting the recovery of neutrophil numbers.