生物活性

• 描述The glucagon-like peptide-1(GLP-1) can potentiate β cell response to glucose for its important role in glucose-stimulated insulin release and thus been frequently used in type 2 diabetes (T2D) clinical therapy. Liraglutide is a potent, long-acting GLP-1 receptor agonist with EC50 value of 61pM, which is usually given , s.c., once daily with the average half-life of 12 hours. In hVEC and C11-STH cells, Liraglutide mediated inhibition of TNFα independent of PKA signaling. Treatment of mice model at 80nM/kg of this drug twice a day for 4 weeks demonstrated a significant improvement in endothelial function with max relaxation of 78.45%. Besides, expression of eNOS in the mice was also significantly increased and the ICAM-1 expression was inhibitedin vivo, suggesting GLP-1R signalling events of Liraglutide mediated by non-PKA . Also in diabetic mice model transplanted with human islets, treatment of them daily with liraglutide (300 μg/kg) showed enhanced initial function of the transplanted human islets without adverse systemic side effects. No additional improvement of the islets was found when the treatment last for >200 days. The lower Human C-peptide plasma levels and slower kinetics of insulin release from the human islets were also observed. When the time last for >240 days, peripheral insulin sensitivity was decreased, suggesting the association between hormone release from the β-cell and long-term treatment with this drug. Meanwhile, the concentration at which the cell apoptosis was increased by direct cytotoxic effects on the β-cell was higher. In a clinical study, 49 T2D patients treated with Liraglutide therapy showed 19% increasing of Mean glucose levels as well as 7% increasing of Mean postprandial glucose levels on Day 1. Meanwhile, the mean body weights of these patients decreased by -3.53kg while the lean body mass, % body fat decreased by -0.47 and -0.37 respectively, suggesting the reduction of timing limitation for liraglutide used in healthcare patients.

• 动物研究
  剂量	Mice: 0.057 mg/kg, 0.118 mg/kg[3] (i.p.), 0.3 mg/kg[4] (i.p.), 0.1 mg/kg - 1 mg/kg[5] (s.c.) Rat: 0.1 mg/kg - 1 mg/kg[6] (s.c.)
  给药途径	i.p., s.c.
  动物药代数据	Animal Mice[7] Rats[7] Monkeys[7] Dose 0.1 mg/kg 0.1 mg/kg 0.12 mg/kg (i.v.) 0.05 mg/kg (s.c.) Administration s.c. s.c. i.v. s.c. Vz 0.05 L/kg (i.v.) T1/2 6.7 h 3.5 h 6.2 h (i.v.) 7.1 h (s.c.) Tmax 6 h 6 h 7.3 h (s.c.) CL 0.0055 L/h/kg (i.v.) Cmax 750 nmol/L 770 nmol/L 600 nmol/L (s.c.) Protein binding (free drug %) 99.5 - 99.7% 95.8 - 98.2% Protein bound (%) 99.3 - 99.8% AUC 11600 nmol·h/L 8700 nmol·h/L 49000 nmol·h/L (i.v.) 9700 nmol·h/L (s.c.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02138045	Diabetes Mellitus, Type 1 ... more >> Type 1 Diabetes Mellitus Collapse <<	Not Applicable	Unknown	February 2017	Denmark ... more >> Mech-Sense, Department of Medical Gastroenterology, Aalborg University Hospital Aalborg, Jutland, Denmark, 9000 Collapse <<
  NCT02014740	-	-	Completed	-	-
  NCT01911468	PCOS Obesity	Phase 4	Completed	-	Slovenia ... more >> University Medical Center Ljubljana Ljubljana, Slovenia, 1000 Collapse <<

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