生物活性

• 描述Angiotensin receptor blockade and neprilysin (NEP) inhibition together offer potential benefits for the treatment of hypertension and heart failure. LCZ696, composed of valsartan and sacubitril with a molar ratio of 1:1, is an oral bioactive, dual-acting angiotensin receptor-neprilysin inhibitor (ARNi) for the treatment of hypertension and heart failure^[3]. H9C2 cells were pretreated with LCZ696 at concentrations of 1, 10, or 30 μM for 30 min and then stimulated with high glucose (HG) for 48 h. HG- or diabetes-induced JNK/p38MAPK phosphorylation and NF-kB nuclear translocation were inhibited by the administration of LCZ696^[4]. Oral administration of LCZ696 caused dose-dependent increases in atrial natriuretic peptide immunoreactivity (due to NEP inhibition) in Sprague-Dawley rats and provided sustained, dose-dependent blood pressure reductions in hypertensive double-transgenic rats^[3]. Adult male Sprague–Dawley rats were randomized to treatment for 4 weeks with LCZ696 (68 mg/kg body weight perorally; myocardial infarction (MI) -ARNi, n=11), and the degree of fibrosis both in noninfarcted remote myocardium and in the peri-infarct zone was significantly reduced^[5].

• 动物研究
  剂量	Mice: 60 mg/kg[3] (p.o.), 6 mg/kg[4] (p.o.) Rat: 2 mg/kg - 60 mg/kg[5] (p.o.) Beagle dog: 15 mg/kg, 45 mg/kg[6] (p.o.)
  给药途径	p.o.

• 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
  NCT03608085	Heart Failure	Not Applicable	Recruiting	May 31, 2019	United States, Rhode Island ... more >> Ocean State Research Institute Recruiting Providence, Rhode Island, United States, 02908 Contact: Mary Ford    401-273-7100 ext 3674    Mary.Ford@va.gov    Principal Investigator: Tracey H Taveira, Pharm.D.          Sub-Investigator: Philip Haines, MD          Sub-Investigator: Wen-Chih Wu, MD          Providence VAMC Recruiting Providence, Rhode Island, United States, 02908 Contact: Melanie R Parent, Ba    401-273-7100 ext 6293    Melanie.Parent@va.gov    Principal Investigator: Tracey H Taveira, Pharm.D. Collapse <<
  NCT03717688	Diabetes Hear... more >>t Failure Collapse <<	Phase 4	Recruiting	January 31, 2019	Denmark ... more >> University of Copenhagen Recruiting Copenhagen, Denmark, 2100 Contact: Peter Plomgaard, MD, PhD    35451397    Peter.Plomgaard@regionh.dk    Principal Investigator: Peter Plomgaard, MD, PhD Collapse <<
  NCT02470403	Elevated Body Mass Index	Phase 2	Completed	-	United States, Nebraska ... more >> Novartis Investigative Site Lincoln, Nebraska, United States, 68502 Collapse <<

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• 参考文献

• [1] von Lueder TG, Wang BH, et al. Angiotensin receptor neprilysin inhibitor LCZ696 attenuates cardiac remodeling and dysfunction after myocardial infarction by reducing cardiac fibrosis and hypertrophy. Circ Heart Fail. 2015 Jan;8(1):71-8.

  [2] Gu J, Noe A, Chandra P, et al. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J Clin Pharmacol. 2010 Apr;50(4):401-14.

  [3] Gu J, Noe A, Chandra P, Al-Fayoumi S, Ligueros-Saylan M, Sarangapani R, Maahs S, Ksander G, Rigel DF, Jeng AY, Lin TH, Zheng W, Dole WP. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J Clin Pharmacol. 2010 Apr;50(4):401-14. doi: 10.1177/0091270009343932. Epub 2009 Nov 23. PMID: 19934029.

  [4] Ge Q, Zhao L, Ren XM, Ye P, Hu ZY. LCZ696, an angiotensin receptor-neprilysin inhibitor, ameliorates diabetic cardiomyopathy by inhibiting inflammation, oxidative stress and apoptosis. Exp Biol Med (Maywood). 2019 Sep;244(12):1028-1039. doi: 10.1177/1535370219861283. Epub 2019 Jul 1. PMID: 31262190; PMCID: PMC6879777.

  [5] von Lueder TG, Wang BH, Kompa AR, Huang L, Webb R, Jordaan P, Atar D, Krum H. Angiotensin receptor neprilysin inhibitor LCZ696 attenuates cardiac remodeling and dysfunction after myocardial infarction by reducing cardiac fibrosis and hypertrophy. Circ Heart Fail. 2015 Jan;8(1):71-8. doi: 10.1161/CIRCHEARTFAILURE.114.001785. Epub 2014 Oct 31. PMID: 25362207.

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