title: Haemodynamic effects, safety, and pharmacokinetics of human stresscopin in heart failure with reduced ejection fraction.
abstract: OBJECTIVE
  Human stresscopin is a corticotropin-releasing factor (CRF) type 2 receptor (CRFR2) selective agonist and a member of the CRF peptide family. Stimulation of CRFR2 improves cardiac output and left ventricular ejection fraction (LVEF) in patients with stable heart failure (HF) with reduced LVEF. We examined the safety, pharmacokinetics, and effects on haemodynamics and serum biomarkers of intravenous human stresscopin acetate (JNJ-39588146) in patients with stable HF with LVEF ≤ 35% and cardiac index (CI) ≤ 2.5 L/min/m(2).
  
  
  RESULTS
  Sixty-two patients with HF and LVEF ≤ 35% were instrumented with a pulmonary artery catheter and randomly assigned (ratio 3:1) to receive an intravenous infusion of JNJ-39588146 or placebo. The main study was an ascending dose study of three doses (5, 15, and 30 ng/kg/min) of study drug or placebo administered in sequential 1 h intervals (3 h total). Statistically significant increases in CI and reduction in systemic vascular resistance (SVR) were observed with both the 15 ng/kg/min (2 h time point) and 30 ng/kg/min (3 h time point) doses of JNJ-39588146 without significant changes in heart rate (HR) or systolic blood pressure (SBP). No statistically significant reductions in pulmonary capillary wedge pressure (PCWP) were seen with any dose tested in the primary analysis, although a trend towards reduction was seen.
  
  
  CONCLUSIONS
  In HF patients with reduced LVEF and CI, ascending doses of JNJ-39588146 were associated with progressive increases in CI and reductions in SVR without significant effects on PCWP, HR, or SBP.
  
  
  BACKGROUND
  NCT01120210.
authors.affiliation: Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, 645 North Michigan Ave., Suite 1006, Chicago, IL 60611, USA. m-gheorghiade@northwestern.edu
authors.forename: Mihai
authors.initials: M
authors.lastname: Gheorghiade
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Greene
authors.forename: Piotr
authors.initials: P
authors.lastname: Ponikowski
authors.forename: Aldo P
authors.initials: AP
authors.lastname: Maggioni
authors.forename: Jerzy
authors.initials: J
authors.lastname: Korewicki
authors.forename: Cezar
authors.initials: C
authors.lastname: Macarie
authors.forename: Marco
authors.initials: M
authors.lastname: Metra
authors.forename: Jacek
authors.initials: J
authors.lastname: Grzybowski
authors.forename: Serban-Ion
authors.initials: SI
authors.lastname: Bubenek-Turconi
authors.forename: Waldemar
authors.initials: W
authors.lastname: Radziszewski
authors.forename: Allan
authors.initials: A
authors.lastname: Olson
authors.forename: Orlando F
authors.initials: OF
authors.lastname: Bueno
authors.forename: Atalanta
authors.initials: A
authors.lastname: Ghosh
authors.forename: Lawrence I
authors.initials: LI
authors.lastname: Deckelbaum
authors.forename: Lilian Y
authors.initials: LY
authors.lastname: Li
authors.forename: Ayan R
authors.initials: AR
authors.lastname: Patel
authors.forename: Andreas
authors.initials: A
authors.lastname: Koester
authors.forename: Marvin A
authors.initials: MA
authors.lastname: Konstam
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D003346:Corticotropin-Releasing Hormone / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006333:Heart Failure / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D013318:Stroke Volume / Q000502:physiology*; D054832:Urocortins / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D015415:Biomarkers; C426704:UCN3 protein, human; D054832:Urocortins; D003346:Corticotropin-Releasing Hormone
keywords: Corticotropin-releasing factor type 2 receptor; Haemodynamics; Heart failure; Human stresscopin; Pharmacokinetics