Evaluation of the pharmacodynamics, pharmacokinetics andsafety of repeated escalating oral doses of S 38844 versus placeboin patients with chronic heart failure and left ventricular systolicdysfunctionA phase II, randomised, double-blind, parallel-group, placebocontrolled, international multicentre study

Start Date29 Oct 2014

Sponsor / Collaborator

Institut de Recherches Intern Servier

NL-OMON36850 / CompletedNot ApplicableIIT

Excretion balance, pharmacokinetics and metabolism of S 38844 after single oral dose administration of [14C]-S 38844 in healthy male volunteers. - 14C-S 38844 ADME study

Start Date15 Jan 2013

Sponsor / Collaborator-

EUCTR2010-020197-42-DE / Not yet recruitingNot ApplicableIIT

Evaluation of the pharmacokinetics, pharmacodynamics and safety of repeated escalating oral doses of a slow release formulation of S 38844 in healthy male volunteersAn open-label, non-randomised, two-group three-period, monocentre study

Start Date20 Aug 2010

Sponsor / Collaborator

Institut de Recherches Intern Servier

100 Clinical Results associated with S-38844

100 Translational Medicine associated with S-38844

100 Patents (Medical) associated with S-38844

Literatures (Medical) associated with S-38844

01 Apr 2021·ESC Heart FailureQ2 · MEDICINE

Transient heart rate reduction improves acute decompensated heart failure‐induced left ventricular and coronary dysfunction

Q2 · MEDICINE

ArticleOA

Author: Mulder, Paul ; Remy‐Jouet, Isabelle ; Nicol, Lionel ; Renet, Sylvanie ; Richard, Vincent ; Thuillez, Christian ; Roussel, Jérôme ; Dumesnil, Anais ; Henry, Jean‐Paul ; Fougerousse, Françoise ; Brakenhielm, Ebba ; Ouvrard‐Pascaud, Antoine ; Peschanski, Nicolas ; Harouki, Najah ; Lachaux, Marianne ; Soulie, Matthieu

AbstractAimsAcute decompensated heart failure (ADHF), a live‐threatening complication of heart failure (HF), associates a further decrease of the already by HF‐impaired cardiac function with an increase in heart rate. We evaluated, using a new model of ADHF, whether heart rate reduction (HRR) opposes the acute decompensation‐related aggravation of cardiovascular dysfunction.Methods and resultsCardiac output (echocardiography), cardiac tissue perfusion (magnetic resonance imaging), pulmonary wet weight, and in vitro coronary artery relaxation (Mulvany) were assessed 1 and 14 days after acute decompensation induced by salt‐loading (1.8 g/kg, PO) in rats with well‐established HF due to coronary ligation. HRR was induced by administration of the If current inhibitor S38844, 12 mg/kg PO twice daily for 2.5 days initiated 12 h or 6 days after salt‐loading (early or delayed treatment, respectively). After 24 h, salt‐loading resulted in acute decompensation, characterized by a reduction in cardiac output (HF: 130 ± 5 mL/min, ADHF: 105 ± 8 mL/min; P < 0.01), associated with a decreased myocardial perfusion (HF: 6.41 ± 0.53 mL/min/g, ADHF: 4.20 ± 0.11 mL/min/g; P < 0.01), a slight increase in pulmonary weight (HF: 1.68 ± 0.09 g, ADHF: 1.81 ± 0.15 g), and impaired coronary relaxation (HF: 55 ± 1% of pre‐contraction at acetylcholine 4.5 10−5 M, ADHF: 27 ± 7 %; P < 0.01). Fourteen days after salt‐loading, cardiac output only partially recovered (117 ± 5 mL/min; P < 0.05), while myocardial tissue perfusion (4.51 ± 0.44 mL/min; P < 0.01) and coronary relaxation (28 ± 4%; P < 0.01) remained impaired, but pulmonary weight further increased (2.06 ± 0.15 g, P < 0.05). Compared with untreated ADHF, HRR induced by S38844 improved cardiac output (125 ± 1 mL/min; P < 0.05), myocardial tissue perfusion (6.46 ± 0.42 mL/min/g; P < 0.01), and coronary relaxation (79 ± 2%; P < 0.01) as soon as 12 h after S38844 administration. These effects persisted beyond S38844 administration, illustrated by the improvements in cardiac output (130 ± 6 mL/min; P < 0.05), myocardial tissue perfusion (6.38 ± 0.48 mL/min/g; P < 0.01), and coronary relaxation (71 ± 4%; P < 0.01) at Day 14. S38844 did not modify pulmonary weight at Day 1 (1.78 ± 0.04 g) but tended to decrease pulmonary weight at Day 14 (1.80 ± 0.18 g). While delayed HRR induced by S38844 never improved cardiac function, early HRR rendered less prone to a second acute decompensation.ConclusionsIn a model mimicking human ADHF, early, but not delayed, transient HRR induced by the If current inhibitor S38844 opposes acute decompensation by preventing the decompensated‐related aggravation of cardiovascular dysfunction as well as the development of pulmonary congestion, and these protective effects persist beyond the transient treatment. Whether early transient HRR induced by If current inhibitors or other bradycardic agents, i.e. beta‐blockers, exerts beneficial effects in human ADHF warrants further investigation.

01 Oct 2015·Journal of Cardiovascular PharmacologyQ4 · MEDICINE

Selective Heart Rate Reduction Improves Metabolic Syndrome–related Left Ventricular Diastolic Dysfunction

Q4 · MEDICINE

Article

Author: Le Bouter-Banon, Sabrina ; Monteil, Christelle ; Roussel, Jerome ; Richard, Vincent ; Merabet, Nassiba ; Wecker, Didier ; Remy-Jouet, Isabelle ; Nicol, Lionel ; Thuillez, Christian ; Mulder, Paul ; Henry, Jean-Paul ; Fang, Yuehua

BACKGROUNDEnhanced heart rate observed in metabolic syndrome (MS) contributes to the deterioration of left ventricular (LV) function via impaired LV filling and relaxation, increased myocardial O2 consumption, and reduced coronary perfusion. However, whether heart rate reduction (HRR) opposes LV dysfunction observed in MS is unknown.METHODSWe assessed in Zucker fa/fa rats, a rat model of MS, the cardiovascular effects of HRR induced by the If current inhibitor S38844 (3 mg · kg(-1) · d(-1)).RESULTSDelayed short-term (4 days) and long-term (90 days) HRR induced by S38844 reduced LV end-diastolic pressure and LV end-diastolic pressure-volume relation, increased myocardial tissue perfusion, decreased myocardial oxidized glutathione levels, and preserved cardiac output, without modifying LV end-systolic pressure and LV end-systolic pressure-volume relation, although only long-term S38844 opposed LV collagen accumulation. Long-term S38844 improved flow-induced endothelium-dependent dilatation of mesenteric arteries, while metabolic parameters, such as plasma glucose levels, and Hb1c, were never modified.CONCLUSIONSIn rats with MS, HRR induced by the If inhibitor S38844 improved LV diastolic function and endothelium-dependent vascular dilatation, independent from modifications in metabolic status. Moreover, this improvement in cardiac function involves not only immediate effects such as improved myocardial perfusion and reduced oxidative stress but also long-term effects such as modifications in the myocardial structure.

100 Deals associated with S-38844

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Heart Failure	Phase 2	-	Amgen, Inc.	-
Ventricular Dysfunction, Left	Preclinical	FR	Institut National de la Santé et de la Recherche Médicale	01 Oct 2015
Ventricular Dysfunction, Left	Preclinical	FR	Les Laboratoires Servier SAS	01 Oct 2015
Cardiovascular Diseases	Preclinical	DE	Les Laboratoires Servier SAS	-
Heart Failure	Preclinical	SK	Les Laboratoires Servier SAS	-
Heart Failure	Preclinical	BE	Les Laboratoires Servier SAS	-
Heart Failure	Preclinical	LT	Les Laboratoires Servier SAS	-
Heart Failure	Preclinical	LV	Les Laboratoires Servier SAS	-
Heart Failure	Preclinical	EE	Les Laboratoires Servier SAS	-
Heart Failure	Preclinical	HU	Les Laboratoires Servier SAS	-

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