生物活性

• 描述Phosphodiesterases (PDEs) are a family of enzymes that catalyze the hydrolysis of cyclic adenosine monophosphate and cyclic guanosine monophosphate. Roflumilast is a potent inhibitor of both human PDE4B and PDE4D with IC50 values of 0.84 and 0.68nM, respectively, while it showed much less inhibitory activity against other forms of PDEs (IC50 values > 10μM)^[7]. In A549 cells, roflumilast at the dose of 1μM prevented EGF-stimulated increase in MUC5AC mRNA and protein production but did not change the basal MUC5AC expression, and also inhibited EGF-induced phosphorylation of tyrosine residues of different intracellular proteins (i.e. EGF receptor, phospho-p38- and p44/42-MAPK) and the upregulation of EGFR expression. In human isolated bronchus, the presence of 1μM roflumilast inhibited EGF-induced MUC5AC mRNA and protein expression^[8]. In A/J mice expressing wild type cystic fibrosis transmembrane conductance regulator (CFTR) and exposed to cigarette smoke or air, acute roflumilast (30nM) treatment increased CFTR-dependent chloride transport in both smoke- and air-exposed mice as compared to vehicle-treated group. Oral administration of roflumilast (5mg/kg/day, once per day) for five weeks activated CFTR and completely reversed cigarette smoke-induced adverse effects in vivo^[9].
• 作用机制The difluromethoxy group of roflumilast binds at the Q1 pocket of enzyme, while the cyclopropyl methoxy group binds at the Q2 pocket^[7].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  HEK293 cells	-	Function assay	15 min	Inhibition of PDE4 expressed in HEK293 cells coexpressing cyclic nucleotide gated ion channel mutant assessed as inhibition of NECA-induced cAMP production treated 15 mins before NECA challenge measured after 45 mins by FLIPR assay	20378348
  PBMC	-	Function assay	-	Inhibition of TNFalpha production in LPS-stimulated human PBMC preincubated before LPS challenge measured after 4 hrs by enzyme immunoassay, IC50=2e-05 μM	19256507
  sf21 cells	-	Function assay	-	Inhibition of human full length PDE4A4 expressed in baculovirus infected sf21 cells, IC50=0.35 nM	23806553

• 动物研究
  剂量	Guinea pig: 0.04 mg/kg - 4 mg/kg[3] (p.o.) Mice: 1 mg/kg, 5 mg/kg[4] (p.o.), 5 mg/kg - 10 mg/kg[5] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Mice[6] Rats[6] Dogs[6] Monkeys[6] Dose 12 mg/kg 20 mg/kg 2 mg/kg 0.5 mg/kg Administration p.o. p.o. p.o. p.o. F 0.25 0.11 0.19 0.48 Vd 1.9 L/kg 5.1 L/kg 2.1 L/kg 2.1 L/kg T1/2 0.7 h 0.9 h 3.8 h 4.4 h CL 1.8 L/h/kg 3.9 L/h/kg 0.4 L/h/kg 0.3 L/h/kg Cmax 1313 μg/ml 94 μg/ml 106 μg/ml 341 μg/ml AUC0→∞ 1663 μg·h/ml 643 μg·h/ml 1054 μg·h/ml 648 μg·h/ml

• 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
  NCT03762330	Chronic Obstructive Pulmonary ... more >>Disease Collapse <<	Not Applicable	Not yet recruiting	January 2021	-
  NCT02835716	-	-	Recruiting	September 2020	United States, Connecticut ... more >> Millennium Magnetic Technologies, LLC Recruiting Westport, Connecticut, United States, 06880 Contact: Steve Levy, MD    203-423-9494    SL@MilMag.net    Contact: Donald H Marks, MD PhD    9733070364    DHM@MilMag.net Collapse <<
  NCT01730404	COPD	Phase 2	Completed	-	Ireland ... more >> Celerion Belfast, Ireland United Kingdom Parexel, early phases Harrow, United Kingdom Medicines Evaluation Unit Ltd Manchester, United Kingdom Freeman Hospital Newcastle, United Kingdom Nottingham University Hospitals NHS Trust Nottingham, United Kingdom Collapse <<

• 更多
• 参考文献

• [1] Martorana PA, Lunghi B, et al. Effect of roflumilast on inflammatory cells in the lungs of cigarette smoke-exposed mice. BMC Pulm Med. 2008 Aug 28;8:17.

  [2] Hatzelmann A, Schudt C. Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J Pharmacol Exp Ther. 2001 Apr;297(1):267-79.

  [3] Wollin L, Marx D, et al. Roflumilast inhibition of pulmonary leukotriene production and bronchoconstriction in ovalbumin-sensitized and -challenged Guinea pigs. J Asthma. 2005 Dec;42(10):873-8.

  [4] Martorana PA, Beume R, et al. Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke. Am J Respir Crit Care Med. 2005 Oct 1;172(7):848-53. Epub 2005 Jun 16.

  [5] Kasetty G, Papareddy P, et al. Roflumilast Increases Bacterial Load and Dissemination in a Model of Pseudomononas Aeruginosa Airway Infection. J Pharmacol Exp Ther. 2016 Apr;357(1):66-72.

  [6] Roflumilast

  [7] Card GL, England BP, Suzuki Y, Fong D, Powell B, Lee B, Luu C, Tabrizizad M, Gillette S, Ibrahim PN, Artis DR, Bollag G, Milburn MV, Kim SH, Schlessinger J, Zhang KY. Structural basis for the activity of drugs that inhibit phosphodiesterases. Structure. 2004 Dec;12(12):2233-47.

  [8] Mata M, Sarriá B, Buenestado A, Cortijo J, Cerdá M, Morcillo EJ. Phosphodiesterase 4 inhibition decreases MUC5AC expression induced by epidermal growth factor in human airway epithelial cells. Thorax. 2005 Feb;60(2):144-52.

  [9] Raju SV, Rasmussen L, Sloane PA, Tang LP, Libby EF, Rowe SM. Roflumilast reverses CFTR-mediated ion transport dysfunction in cigarette smoke-exposed mice. Respir Res. 2017 Sep 18;18(1):173.

• 更多

• Collapse