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Omecamtiv

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https://www.readbyqxmd.com/read/29792814/perspectives-of-a-myosin-motor-activator-agent-with-increased-selectivity
#1
Peter Nanasi, Istvan Komaromi, Janos Almassy
Clinical treatment of heart failure is still not fully solved. A novel class of agents, the myosin motor activators, acts directly on cardiac myosin resulting in an increased force generation and prolongation of contraction. Omecamtiv mecarbil, the lead molecule of this group, is now in human 3 phase displaying promising clinical performance. However, omecamtiv mecarbil is not selective to myosin, since it readily binds to and activates cardiac ryanodine receptors (RyR-2), an effect that may cause complications is case of overdose...
May 24, 2018: Canadian Journal of Physiology and Pharmacology
https://www.readbyqxmd.com/read/29783950/effects-of-the-cardiac-myosin-activator-omecamtiv-mecarbil-on-severe-chronic-aortic-regurgitation-in-wistar-rats
#2
Bachar El-Oumeiri, Kathleen Mc Entee, Filippo Annoni, Antoine Herpain, Frédéric Vanden Eynden, Pascal Jespers, Guido Van Nooten, Philippe van de Borne
BACKGROUND: Aortic regurgitation (AR) is a valvular disease that can lead to systolic heart failure. Treatment options besides cardiac surgery are limited and consequently severe AR is associated with higher mortality and morbidity when not operated. In this investigation, we examined the effects of a novel cardiac myosin activator, Omecamtiv-mecarbil (OM), in rats with chronic severe AR. METHODS: AR was created by retrograde puncture of the aortic valve leaflets in 20 adults Wistar rats...
May 21, 2018: BMC Cardiovascular Disorders
https://www.readbyqxmd.com/read/29741611/crispr-cas9-editing-in-human-pluripotent-stem-cell-cardiomyocytes-highlights-arrhythmias-hypocontractility-and-energy-depletion-as-potential-therapeutic-targets-for-hypertrophic-cardiomyopathy
#3
Diogo Mosqueira, Ingra Mannhardt, Jamie R Bhagwan, Katarzyna Lis-Slimak, Puspita Katili, Elizabeth Scott, Mustafa Hassan, Maksymilian Prondzynski, Stephen C Harmer, Andrew Tinker, James G W Smith, Lucie Carrier, Philip M Williams, Daniel Gaffney, Thomas Eschenhagen, Arne Hansen, Chris Denning
Aims: Sarcomeric gene mutations frequently underlie hypertrophic cardiomyopathy (HCM), a prevalent and complex condition leading to left ventricle thickening and heart dysfunction. We evaluated isogenic genome-edited human pluripotent stem cell-cardiomyocytes (hPSC-CM) for their validity to model, and add clarity to, HCM. Methods and results: CRISPR/Cas9 editing produced 11 variants of the HCM-causing mutation c.C9123T-MYH7 [(p.R453C-β-myosin heavy chain (MHC)] in 3 independent hPSC lines...
May 8, 2018: European Heart Journal
https://www.readbyqxmd.com/read/29707029/cardiac-myosin-activators-for-heart-failure-therapy-focus-on-omecamtiv-mecarbil
#4
REVIEW
Edgardo Kaplinsky, Gordon Mallarkey
Heart failure continues to be a major global health problem with a pronounced impact on morbidity and mortality and very limited drug treatment options especially with regard to inotropic therapy. Omecamtiv mecarbil is a first-in-class cardiac myosin activator, which increases the proportion of myosin heads that are tightly bound to actin and creates a force-producing state that is not associated with cytosolic calcium accumulation. Phase I and phase II studies have shown that it is safe and well tolerated...
2018: Drugs in Context
https://www.readbyqxmd.com/read/29278207/omecamtiv-mecarbil-a-myosin-motor-activator-agent-with-promising-clinical-performance-and-new-in-vitro-results
#5
Peter Nanasi, Istvan Komaromi, Marta Gaburjakova, Janos Almassy
Clinical treatment of heart failure is still suffering from limited efficacy and unfavorable side effects. The recently developed group of agents, the myosin motor activators, act directly on cardiac myosin resulting in an increased force generation and prolongation of contraction. The lead molecule, omecamtiv mecarbil is now in human phase 3. In addition to the promising clinical data published so far, there are new in vitro results indicating that the effect of omecamtiv mecarbil on contractility is rate-dependent...
December 22, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29108014/allosteric-modulation-of-cardiac-myosin-dynamics-by-omecamtiv-mecarbil
#6
Shaima Hashem, Matteo Tiberti, Arianna Fornili
New promising avenues for the pharmacological treatment of skeletal and heart muscle diseases rely on direct sarcomeric modulators, which are molecules that can directly bind to sarcomeric proteins and either inhibit or enhance their activity. A recent breakthrough has been the discovery of the myosin activator omecamtiv mecarbil (OM), which has been shown to increase the power output of the cardiac muscle and is currently in clinical trials for the treatment of heart failure. While the overall effect of OM on the mechano-chemical cycle of myosin is to increase the fraction of myosin molecules in the sarcomere that are strongly bound to actin, the molecular basis of its action is still not completely clear...
November 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/29052230/omecamtiv-mercabil-and-blebbistatin-modulate-cardiac-contractility-by-perturbing-the-regulatory-state-of-the-myosin-filament
#7
Thomas Kampourakis, Xuemeng Zhang, Yin-Biao Sun, Malcolm Irving
KEY POINTS: Omecamtiv mecarbil and blebbistatin perturb the regulatory state of the thick filament in heart muscle. Omecamtiv mecarbil increases contractility at low levels of activation by stabilizing the ON state of the thick filament. Omecamtiv mecarbil decreases contractility at high levels of activation by disrupting the acto-myosin ATPase cycle. Blebbistatin reduces contractility by stabilizing the thick filament OFF state and inhibiting acto-myosin ATPase. Thick filament regulation is a promising target for novel therapeutics in heart disease...
January 1, 2018: Journal of Physiology
https://www.readbyqxmd.com/read/29030372/dose-dependent-effects-of-the-myosin-activator-omecamtiv-mecarbil-on-cross-bridge-behavior-and-force-generation-in-failing-human-myocardium
#8
Ranganath Mamidi, Jiayang Li, Kenneth S Gresham, Sujeet Verma, Chang Yoon Doh, Amy Li, Sean Lal, Cristobal G Dos Remedios, Julian E Stelzer
BACKGROUND: Omecamtiv mecarbil (OM) enhances systolic function in vivo by directly binding the myosin cross-bridges (XBs) in the sarcomere. However, the mechanistic details governing OM-induced modulation of XB behavior in failing human myocardium are unclear. METHODS AND RESULTS: The effects of OM on steady state and dynamic XB behavior were measured in chemically skinned myocardial preparations isolated from human donor and heart failure (HF) left ventricle. HF myocardium exhibited impaired contractile function as evidenced by reduced maximal force, magnitude of XB recruitment ( P df ), and a slowed rate of XB detachment ( k rel ) at submaximal Ca2+ activations...
October 2017: Circulation. Heart Failure
https://www.readbyqxmd.com/read/28940010/frequency-dependent-effects-of-omecamtiv-mecarbil-on-cell-shortening-of-isolated-canine-ventricular-cardiomyocytes
#9
Balázs Horváth, Norbert Szentandrássy, Roland Veress, János Almássy, János Magyar, Tamás Bányász, Attila Tóth, Zoltán Papp, Péter P Nánási
Omecamtiv mecarbil (OM) is a myosin activator agent developed for the treatment of heart failure. OM was reported to increase left ventricular ejection fraction and systolic ejection time, but little is known about the effect of heart rate on the action of OM. The present study, therefore, was designed to investigate the effects of OM on unloaded cell shortening and intracellular Ca(2+) ([Ca(2+)]i) transients as a function of the pacing frequency. Isolated cardiomyocytes were stimulated at various frequencies under steady-state conditions...
December 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28834724/omecamtiv-mecarbil-abolishes-length-mediated-increase-in-guinea-pig-cardiac-myofiber-ca-2-sensitivity
#10
Sampath K Gollapudi, Sherif M Reda, Murali Chandra
Omecamtiv mecarbil (OM) is a pharmacological agent that augments cardiac contractile function by enhancing myofilament Ca(2+) sensitivity. Given that interventions that increase myofilament Ca(2+) sensitivity have the potential to alter length-dependent activation (LDA) of cardiac myofilaments, we tested the influence of OM on this fundamental property of the heart. This is significant not only because LDA is prominent in cardiac muscle but also because it contributes to the Frank-Starling law, a mechanism by which the heart increases stroke volume in response to an increase in venous return...
August 22, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28775348/mechanistic-and-structural-basis-for-activation-of-cardiac-myosin-force-production-by-omecamtiv-mecarbil
#11
Vicente J Planelles-Herrero, James J Hartman, Julien Robert-Paganin, Fady I Malik, Anne Houdusse
Omecamtiv mecarbil is a selective, small-molecule activator of cardiac myosin that is being developed as a potential treatment for heart failure with reduced ejection fraction. Here we determine the crystal structure of cardiac myosin in the pre-powerstroke state, the most relevant state suggested by kinetic studies, both with (2.45 Å) and without (3.10 Å) omecamtiv mecarbil bound. Omecamtiv mecarbil does not change the motor mechanism nor does it influence myosin structure. Instead, omecamtiv mecarbil binds to an allosteric site that stabilizes the lever arm in a primed position resulting in accumulation of cardiac myosin in the primed state prior to onset of cardiac contraction, thus increasing the number of heads that can bind to the actin filament and undergo a powerstroke once the cardiac cycle starts...
August 4, 2017: Nature Communications
https://www.readbyqxmd.com/read/28506910/omecamtiv-mecarbil-activates-ryanodine-receptors-from-canine-cardiac-but-not-skeletal-muscle
#12
Péter Nánási, Marta Gaburjakova, Jana Gaburjakova, János Almássy
Due to the limited results achieved in the clinical treatment of heart failure, a new inotropic strategy of myosin motor activation has been developed. The lead molecule of myosin activator agents is omecamtiv mecarbil, which binds directly to the heavy chain of the cardiac β-myosin and enhances cardiac contractility by lengthening the lifetime of the acto-myosin complex and increasing the number of the active force-generating cross-bridges. In the absence of relevant data, the effect of omecamtiv mecarbil on canine cardiac ryanodine receptors (RyR 2) has been investigated in the present study by measuring the electrical activity of single RyR 2 channels incorporated into planar lipid bilayer...
August 15, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28375036/new-developments-in-the-pharmacotherapeutic-management-of-heart-failure-in-elderly-patients-concerns-and-considerations
#13
REVIEW
Elles M Screever, Wouter C Meijers, Dirk J van Veldhuisen, Rudolf A de Boer
Heart failure (HF) remains a major public health problem worldwide, affecting approximately 23 million patients, and is predominantly a disease of the elderly population. Elderly patients mostly suffer from HF with preserved ejection fraction (HFpEF), which often presents with multiple co-morbidities and they require multiple medical treatments. This, together with the heterogeneous phenotype of HFpEF, makes it a difficult syndrome to diagnose and treat. Areas covered: Although HF is most abundant in the elderly, this group is still underrepresented in clinical trials, which results in the lack of evidence-based medical regimens...
May 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28357714/the-role-for-cardiovascular-remodeling-in-cardiovascular-outcomes
#14
REVIEW
Nishant Krishna Sekaran, Anna Lisa Crowley, Fernanda Rodrigues de Souza, Elmiro Santos Resende, Sunil V Rao
PURPOSE OF REVIEW: Ischemic and non-ischemic injury to the heart causes deleterious changes in ventricular size, shape, and function. This adverse remodeling is mediated by neurohormonal and hemodynamic alterations and is reflected in non-invasive measures of left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and left ventricular end-diastolic volume (LVEDV). These measures are closely linked to cardiovascular outcomes and have become key surrogate endpoints for evaluating the therapeutic efficacy of contemporary treatments for heart failure with reduced ejection fraction (HFrEF)...
May 2017: Current Atherosclerosis Reports
https://www.readbyqxmd.com/read/28315072/direct-myosin-activation-by-omecamtiv-mecarbil-for-heart-failure-with-reduced-ejection-fraction
#15
REVIEW
Mitchell A Psotka, John R Teerlink
Myosin is the indispensable molecular motor that utilizes chemical energy to produce force for contraction within the cardiac myocyte. Myosin activity is gated by intracellular calcium levels which are regulated by multiple upstream signaling cascades that can be altered for clinical utility using inotropic medications. In contrast to clinically available cardiac inotropes, omecamtiv mecarbil is a novel direct myosin activator developed to augment left ventricular systolic function without the undesirable secondary effects of altered calcium homeostasis...
2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28223517/heart-failure-drug-changes-the-mechanoenzymology-of-the-cardiac-myosin-powerstroke
#16
John A Rohde, David D Thomas, Joseph M Muretta
Omecamtiv mecarbil (OM), a putative heart failure therapeutic, increases cardiac contractility. We hypothesize that it does this by changing the structural kinetics of the myosin powerstroke. We tested this directly by performing transient time-resolved FRET on a ventricular cardiac myosin biosensor. Our results demonstrate that OM stabilizes myosin's prepowerstroke structural state, supporting previous measurements showing that the drug shifts the equilibrium constant for myosin-catalyzed ATP hydrolysis toward the posthydrolysis biochemical state...
March 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27974808/heart-failure-phase-ii-trial-results-of-omecamtiv-mecarbil
#17
Gregory B Lim
No abstract text is available yet for this article.
February 2017: Nature Reviews. Cardiology
https://www.readbyqxmd.com/read/27914656/chronic-oral-study-of-myosin-activation-to-increase-contractility-in-heart-failure-cosmic-hf-a-phase-2-pharmacokinetic-randomised-placebo-controlled-trial
#18
RANDOMIZED CONTROLLED TRIAL
John R Teerlink, G Michael Felker, John J V McMurray, Scott D Solomon, Kirkwood F Adams, John G F Cleland, Justin A Ezekowitz, Assen Goudev, Peter Macdonald, Marco Metra, Veselin Mitrovic, Piotr Ponikowski, Pranas Serpytis, Jindrich Spinar, János Tomcsányi, Hans J Vandekerckhove, Adriaan A Voors, Maria Laura Monsalvo, James Johnston, Fady I Malik, Narimon Honarpour
BACKGROUND: Impaired contractility is a feature of heart failure with reduced ejection fraction. We assessed the pharmacokinetics and effects on cardiac function and structure of the cardiac myosin activator, omecamtiv mecarbil. METHODS: In this randomised, double-blind study, done at 87 sites in 13 countries, we recruited patients with stable, symptomatic chronic heart failure and left ventricular ejection fraction 40% or lower. Patients were randomly assigned equally, via an interactive web response system, to receive 25 mg oral omecamtiv mecarbil twice daily (fixed-dose group), 25 mg twice daily titrated to 50 mg twice daily guided by pharmacokinetics (pharmacokinetic-titration group), or placebo for 20 weeks...
December 10, 2016: Lancet
https://www.readbyqxmd.com/read/27779469/dose-dependent-electrophysiological-effects-of-the-myosin-activator-omecamtiv-mecarbil-in-canine-ventricular-cardiomyocytes
#19
N Szentandrassy, B Horvath, K Vaczi, K Kistamas, L Masuda, J Magyar, T Banyasz, Z Papp, P P Nanasi
Omecamtiv mecarbil (OM) is a myosin activator agent recently developed for treatment of heart failure. Although its action on extending systolic ejection time and increasing left ventricular ejection fraction is well documented, no data is available regarding its possible side-effects on cardiac ion channels. Therefore, the present study was designed to investigate the effects of OM on action potential morphology and the underlying ion currents in isolated canine ventricular myocytes using sharp microelectrodes, conventional patch clamp, and action potential voltage clamp techniques...
August 2016: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
https://www.readbyqxmd.com/read/27769970/evolving-therapies-for-the-management-of-chronic-and-acute-decompensated-heart-failure
#20
REVIEW
Jennifer C Cook, Richard H Tran, J Herbert Patterson, Jo E Rodgers
PURPOSE: The pharmacology, clinical efficacy, and safety profiles of evolving therapies for the management of chronic heart failure (HF) and acute decompensated heart failure (ADHF) are described. SUMMARY: HF confers a significant financial burden despite the widespread use of traditional guideline-directed medical therapies such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and aldosterone receptor antagonists, and the rates of HF-related mortality and hospitalization have remained unacceptably high...
November 1, 2016: American Journal of Health-system Pharmacy: AJHP
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