title: Acute hemodynamic effects and preload-dependent cardiovascular profile of the partial phosphodiesterase inhibitor nanterinone in patients with mild to moderate heart failure.
abstract: Nanterinone (UK-61,260) is a novel positive inotropic and balanced-type vasodilating drug, only partially based on phosphodiesterase III inhibition. Preliminary data from controlled studies suggest satisfactory long-term efficacy and safety. As its acute hemodynamic effects in humans are unknown, an oral dose of 2 mg nanterinone was studied in 14 patients with heart failure (NYHA class II-III) on chronic diuretic and angiotensin-converting enzyme (ACE) inhibitor treatment. Before the study, patients were on a 2 g salt-balanced diet, and they received their last medication 16 hours before each study day. Hemodynamic measurements were carried out before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours after administration of the study drug. All patients received placebo and nanterinone on 2 consecutive days. Following nanterinone, systemic vascular resistance decreased immediately from 1699 +/- 82 (mean +/- SEM) at baseline to 1368 +/- 80 at 1 hour. Changes persisted for 12 hours. Concomitantly, there was an immediate and significant fall in pulmonary wedge pressure to 38% of baseline at 1.5 hours, together with a 20% reduction in pulmonary artery pressure. Heart rate remained unchanged and arterial pressures showed only a short, significant decrease. Cardiac index rose significantly from 2.28 +/- 0.15 at baseline to a highest value of 2.65 +/- 0.14 1/min/m2 at 1 hour. Changes persisted for 3 hours. Placebo had no effect on these variables. As, in view of its potential venodilating properties, hemodynamic improvement by nanterinone may depend on pre-existing left ventricular filling pressure, patients were subsequently grouped according to baseline pulmonary wedge pressure of > 12 mmHg (H-PCWP) and < or = 12 mmHg (L-PCWP). Cardiac index improved by 26% in H-PCWP and by 17% in L-PCWP (NS). In contrast, PCWP fell more markedly in H-PWCP than in L-PCWP (40% and 23%, respectively, p < 0.05). Thus, oral nanterinone results in a significant acute hemodynamic improvement and is well tolerated. Although changes in left ventricular filling pressure are more pronounced in patients with elevated pre-existing PCWP, cardiac pump function improves equally in patients with normal or low left ventricular filling pressure at baseline.
authors.affiliation: Sticares Cardiovascular Research Foundation, Rotterdam, The Netherlands.
authors.forename: W J
authors.initials: WJ
authors.lastname: Remme
authors.forename: M
authors.initials: M
authors.lastname: van der Ent
authors.forename: G L
authors.initials: GL
authors.lastname: Bartels
authors.forename: D
authors.initials: D
authors.lastname: van Schelven
authors.forename: D C
authors.initials: DC
authors.lastname: van Hoogenhuyze
authors.forename: X H
authors.initials: XH
authors.lastname: Krauss
authors.forename: H A
authors.initials: HA
authors.lastname: Kruijssen
authors.forename: C J
authors.initials: CJ
authors.lastname: Storm
mesh_terms: D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D004232:Diuretics / Q000008:administration & dosage; D004656:Enalapril / Q000008:administration & dosage; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016037:Single-Blind Method; D014655:Vascular Resistance / Q000187:drug effects; D018487:Ventricular Dysfunction, Left
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D004232:Diuretics; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D015363:Quinolones; C061526:nanterinone; D004656:Enalapril