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Open Access

Acute hemodynamic response to single oral doses of BAY 60-4552, a soluble guanylate cyclase stimulator, in patients with biventricular heart failure

  • Veselin Mitrovic1Email author,
  • B Swidnicki1,
  • Ardeschir Ghofrani2,
  • Wolfgang Mück3,
  • Nina Kirschbaum4,
  • Joachim Mittendorf5,
  • Johannes-Peter Stasch6,
  • Georg Wensing3,
  • Reiner Frey3 and
  • Silvia Lentini3
BMC Pharmacology20099(Suppl 1):P51

https://doi.org/10.1186/1471-2210-9-S1-P51

Published: 11 August 2009

Background

BAY 60-4552 is a direct soluble guanylate cyclase (sGC) stimulator that acts independently of nitric oxide (NO). In preclinical studies BAY 60-4552 exhibited potent vasorelaxing properties and end-organ protective effects. Secondary pulmonary hypertension is a determinant of morbidity and mortality in patients with biventricular heart failure (bivHF). Weassumed that BAY 60-4552 would improve cardiopulmonary hemodynamics by restoring functionality of the NO/sGC/cGMP pathway and be well tolerated in patients with bivHF.

Methods

This study evaluated safety, tolerability and invasive hemodynamics of 1, 2.5, 5, 7.5 and 10 mg oral BAY 60-4552 in patients with bivHF (LVEF ≤ 45%, mean pulmonary artery pressure (mPAP) ≥ 25 mmHg, pulmonary capillary wedge pressure [PCWP] ≥ 18 mmHg).

Results

31 male and 11 female patients (65 ± 11 years; BMI 27.4 ± 4.4) were included. Mean hemodynamic parameters at baseline were PCWP: 23.9 ± 4.5 mmHg; right atrial pressure (RAP): 10.6 ± 4.3 mmHg; mPAP: 35.7 ± 8 mmHg; systolic blood pressure (SBP): 119.2 ± 17.4 mmHg; systemic vascular resistance (SVR): 1721 ± 534 dyn•s•cm-5; heart rate (HR): 70.6 ± 11.2 bpm; and cardiac index (CI): 1.99 ± 0.48 L/min/m2. Table 1 summarizes peak changes in invasive hemodynamics aftersingle dosesof 2.5, 7.5 and 10 mg. No relevant HR increase was observed. BAY 60-4552 was safe and well tolerated with mild adverse events (asymptomatic hypotension, n = 1; transient facial flushing, n = 5; mild headache, n = 4). Pharmakokinetic parameters were linear and mean elimination half-life ranged between 14 – 20 h.
Table 1

Changes in hemodynamic parameters

 

2.5 mg (n = 7)

7.5 mg (n = 12)

10 mg (n = 12)

PCWP [mmHg]

-7.3 ± 2.8 [-28 ± 10%]

-8.4 ± 3.1 [-36 ± 13%]

-9.3 ± 2.5 [-43 ± 11%]

MPAP [mmHg]

-8.9 ± 6.1 [-22 ± 12%]

-8.0 ± 3.3 [-24 ± 9%]

-7.3 ± 3.3 [-23 ± 8%]

RAP [mmHg]

-3.1 ± 3.5 [-26 ± 29%]

-4.3 ± 1.9 [-40 ± 15%]

-4.0 ± 2.3 [-39 ± 15%]

SVR [dyn•s•cm-5]

-378 ± 550 [-15 ± 21%]

-523 ± 293 [-33 ± 15%]

-546 ± 267 [-31 ± 12%]

CI [L/min/m2]

+0.3 ± 0.3 [+17 ± 22%]

+0.6 ± 0.4 [+31 ± 22%]

+0.7 ± 0.5 [+33 ± 25%]

Changes from baseline (absolute and [relative] mean ± SD) of invasive hemodynamics after oral administration of 2.5, 7.5 and 10 mg BAY60-4552, p < 0.05 (for each change from baseline).

Conclusion

In patients with bivHF, oral administration of BAY 60-4552 was well tolerated and mediated a potent vasodilation. Biventricular pre- and afterload were improved, which resulted in a significant increase in cardiac index. These first clinical results with an oral sGC stimulator in patients with bivHF demonstrate the potential of this new therapeutic principle.

Authors’ Affiliations

(1)
Department of Cardiology, Kerckhoff Heart Center
(2)
Department of Internal Medicine, Medical Clinic II/V, University Hospital Giessen and Marburg GmbH
(3)
Clinical Pharmacology
(4)
Global Biostatistics
(5)
Medicinal Chemistry
(6)
Cardiology Research, Bayer Schering Pharma AG, Pharma Research Centre

Copyright

© Mitrovic et al; licensee BioMed Central Ltd. 2009

This article is published under license to BioMed Central Ltd.

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