bay-58-2667 and Hypotension

Cinaciguat (BAY 58-2667) is a novel soluble guanylate cyclase activator. This study evaluated the haemodynamic effect and safety of cinaciguat added to standard therapy in patients with acute decompensated heart failure (ADHF).. In this placebo-controlled, phase IIb study (NCT00559650), 139 patients admitted with ADHF, pulmonary capillary wedge pressure (PCWP) ≥18 mmHg, left ventricular ejection fraction <40%, and a pre-existing need for invasive haemodynamic monitoring were randomized 2:1 to cinaciguat:placebo (continuous i.v. infusion). The dose was titrated for 8 h and maintained for 16-40 h (starting dose: 100 μg/h). At 8 h, mean PCWP changed from 25.7 ± 5.0 mmHg by -7.7 mmHg with cinaciguat and from 25.0 ± 5.3 mmHg by -3.7 mmHg with placebo (P < 0.0001). The mean right atrial pressure changed from 12.4 ± 5.3 mmHg by -2.7 mmHg with cinaciguat and from 11.8 ± 4.9 mmHg by -0.6 mmHg with placebo (P= 0.0019). Cinaciguat also decreased the pulmonary and systemic vascular resistance and the mean arterial pressure, and increased the cardiac index (all P < 0.0001 vs. placebo). Systolic blood pressure changed by -21.6 ± 17.0 mmHg with cinaciguat and -5.0 ± 14.5 mmHg with placebo. Adverse events were experienced by 71 and 45% of patients receiving cinaciguat and placebo, respectively. No adverse effects on the 30-day mortality were seen; however, the trial was stopped prematurely due to an increased occurrence of hypotension at cinaciguat doses ≥200 µg/h.. Cinaciguat unloaded the heart in patients with ADHF. However, high doses were associated with hypotension.

Topics: Acute Disease; Benzoates; Dose-Response Relationship, Drug; Double-Blind Method; Early Termination of Clinical Trials; Female; Glomerular Filtration Rate; Guanylate Cyclase-Activating Proteins; Heart Failure; Hemodynamics; Humans; Hypotension; Infusions, Intravenous; Male; Middle Aged; Tachycardia, Ventricular; Treatment Outcome

Cinaciguat (BAY 58-2667) is the first of a new class of soluble guanylate cyclase activators in clinical development for acute decompensated heart failure. We aimed to assess the hemodynamic effects, safety, and tolerability of intravenous cinaciguat in patients with acute decompensated heart failure (pulmonary capillary wedge pressure > or =18 mm Hg).. After initial dose finding (part A; n=27), cinaciguat was evaluated in the nonrandomized, uncontrolled proof-of-concept part of the study (part B; n=33) using a starting dose of 100 microg/h, which could be titrated depending on hemodynamic response. Patients were categorized as responders if their pulmonary capillary wedge pressure decreased by > or =4 mm Hg compared with baseline. Final doses of cinaciguat after 6 hours of infusion in part B were 50 microg/h (n=2), 200 microg/h (n=12), and 400 microg/h (n=16). Compared with baseline, a 6-hour infusion of cinaciguat led to significant reductions in pulmonary capillary wedge pressure (-7.9 mm Hg), mean right atrial pressure (-2.9 mm Hg), mean pulmonary artery pressure (-6.5 mm Hg), pulmonary vascular resistance (-43.4 dynes . s . cm(-5)), and systemic vascular resistance (-597 dynes . s . cm(-5)), while increasing heart rate by 4.4 bpm and cardiac output by 1.68 L/min. The responder rate was 53% after 2 hours, 83% after 4 hours, and 90% after 6 hours. Cinaciguat was well tolerated, with 13 of 60 patients reporting 14 drug-related treatment-emergent adverse events of mild to moderate intensity, most commonly hypotension.. Cinaciguat has potent preload- and afterload-reducing effects, increasing cardiac output. Further investigation of cinaciguat for acute decompensated heart failure is warranted.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Benzoates; Blood Pressure; Cardiac Output; Enzyme Activation; Female; Guanylate Cyclase; Heart Failure; Heart Rate; Hemodynamics; Humans; Hypotension; Infusions, Intravenous; Male; Middle Aged; Pulmonary Wedge Pressure; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Vascular Resistance; Vasodilator Agents

Cinaciguat, a soluble guanylate cyclase (sGC) activator, was under clinical development for use in acute decompensated heart failure (ADHF), but was discontinued due to occurrence of hypotension. We hypothesized that short-term activation of sGC in ADHF patients would exert a vasodilative effect without hypotension irrespective of disease state, using a novel short-acting sGC activator, TY-55002. The objective of this study was to investigate the vasodilation and hemodynamic effects of TY-55002 in comparison with those of cinaciguat. TY-55002 and cinaciguat activated both normal and heme-oxidized sGC in a dose-dependent manner and caused rapid relaxation of phenylephrine-contracted rat aorta. However, TY-55002 had a milder effect than cinaciguat in enhancing the dose-activity response between normal and oxidized sGC. Therefore, we suggest that the pharmacological effect of TY-55002 is less subject than cinaciguat to oxidative stress associated with complications such as cardiovascular disease or diabetes. In normal dogs, the effects of intravenous TY-55002 or cinaciguat on blood pressure were evaluated in conjunction with the plasma concentrations of the compounds, and pharmacokinetic (PK)-pharmacodynamic (PD) analyses were carried out. The plasma-to-effect-site transfer rate constant (Ke

Topics: Animals; Benzoates; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Female; Half-Life; Heart Failure; Hemodynamics; Humans; Hypotension; Male; Models, Biological; Rats; Rats, Sprague-Dawley; Soluble Guanylyl Cyclase; Time Factors; Treatment Outcome; Vasodilation; Vasodilator Agents

Oxidative stress, a central mediator of cardiovascular disease, results in loss of the prosthetic haem group of soluble guanylate cyclase (sGC), preventing its activation by nitric oxide (NO). Here we introduce Apo-sGC mice expressing haem-free sGC. Apo-sGC mice are viable and develop hypertension. The haemodynamic effects of NO are abolished, but those of the sGC activator cinaciguat are enhanced in apo-sGC mice, suggesting that the effects of NO on smooth muscle relaxation, blood pressure regulation and inhibition of platelet aggregation require sGC activation by NO. Tumour necrosis factor (TNF)-induced hypotension and mortality are preserved in apo-sGC mice, indicating that pathways other than sGC signalling mediate the cardiovascular collapse in shock. Apo-sGC mice allow for differentiation between sGC-dependent and -independent NO effects and between haem-dependent and -independent sGC effects. Apo-sGC mice represent a unique experimental platform to study the in vivo consequences of sGC oxidation and the therapeutic potential of sGC activators.

Topics: Animals; Benzoates; Blood Pressure; Cardiovascular System; Gene Knock-In Techniques; Guanylate Cyclase; Heme; Hypertension; Hypotension; Mice; Mice, Transgenic; Muscle, Smooth, Vascular; Nitric Oxide; Oxidative Stress; Platelet Aggregation; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Tumor Necrosis Factor-alpha