title: Safety, pharmacodynamics and pharmacokinetics of TPI 1020 in smokers with asthma.
abstract: BACKGROUND
  TPI 1020 is a novel compound with potential for anti-neutrophil effects. TPI 1020 exerts its effects by a dual mechanism of action involving corticosteroid activity and controlled donation of nitric oxide.
  
  
  OBJECTIVE
  We assessed the safety, pharmacodynamic and pharmacokinetic activity of ascending doses of TPI 1020 compared to budesonide in asthma.
  
  
  METHODS
  Smokers with mild asthma (n=27) were randomized to receive either 600mcg of TPI 1020 (n=13) or 400mcg of budesonide (n=14) bid for 2weeks followed by 1200 and 800mcg bid, respectively, for an additional week.
  
  
  RESULTS
  There was no serious adverse event and all but one adverse event were mild or moderate (severe headache with budesonide). Patients receiving TPI 1020 reported three-fold fewer treatment-emergent AEs (n=13) than those receiving budesonide (n=39). TPI 1020 had similar effects as budesonide on FEV(1), PEF, rescue medication, asthma scoring system, methacholine response, sputum eosinophils and exhaled NO. Sputum neutrophils (%) tended to decrease more with TPI 1020 (32.6% decrease versus 3.7% increase for budesonide); the decrease occurring only in patients with high neutrophils at baseline. A significant difference favoring TPI 1020 was noted for CRP. Budesonide caused a statistically significant decrease in 24h urinary free cortisol over 22days (median of 4.4-2.8mcg/ml, p=0.01) whereas TPI 1020 had no such effect (4.4-5.8mcg/ml), suggesting lower systemic corticosteroid exposure following TPI 1020 treatment.
  
  
  CONCLUSIONS
  TPI 1020 appears safe in asthmatic smokers and warrants further investigation in respiratory conditions.
authors.affiliation: Centre de Recherche, Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie de l'Université Laval, Québec, QC G1V 4G5, Canada. lpboulet@med.ulaval.ca
authors.forename: Louis-Philippe
authors.initials: LP
authors.lastname: Boulet
authors.forename: Catherine
authors.initials: C
authors.lastname: Lemière
authors.forename: Gail
authors.initials: G
authors.lastname: Gauvreau
authors.forename: Ron
authors.initials: R
authors.lastname: Olivenstein
authors.forename: Diane
authors.initials: D
authors.lastname: Lougheed
authors.forename: Bruno
authors.initials: B
authors.lastname: Paradis
authors.forename: Paul
authors.initials: P
authors.lastname: O'Byrne
authors.forename: René
authors.initials: R
authors.lastname: Pageau
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Renzi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001249:Asthma / Q000188:drug therapy; D019819:Budesonide / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D018375:Neutrophil Activation / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D013183:Sputum / Q000166:cytology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; C492926:NCX 1020; D009569:Nitric Oxide; D019819:Budesonide