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Alex Kleinjan - One of the best experts on this subject based on the ideXlab platform.
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PDE3-inhibitor Enoximone prevented mechanical ventilation in patients with SARS-CoV-2 pneumonia.
Experimental lung research, 2021Co-Authors: Jan Beute, Pieter Boermans, Bart Benraad, Jan Telman, Zuzana Diamant, Alex KleinjanAbstract:Standard care in severe SARS-CoV-2 pneumonia complicated by severe dyspnea and respiratory failure, consists of symptom reduction, ultimately supported by mechanical ventilation. Patients with seve...
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pde3 inhibition reduces epithelial mast cell numbers in allergic airway inflammation and attenuates degranulation of basophils and mast cells
Frontiers in Pharmacology, 2020Co-Authors: Jan Beute, Hedwika Nastiti, Keerthana Ganesh, Steve Hockman, Robin Hoogenboom, Jelle Folkerts, Marco W J Schreurs, Rudi W Hendriks, Alex KleinjanAbstract:textabstractEpithelial mast cells are generally present in the airways of patients with allergic asthma that are inadequately controlled. Airway mast cells (MCs) are critically involved in allergic airway inflammation and contribute directly to the main symptoms of allergic patients. Phosphodiesterase 3 (PDE3) tailors signaling of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which are critical intracellular second messenger molecules in various signaling pathways. This paper investigates the pathophysiological role and disease-modifying effects of PDE3 in mouse bone marrow-derived MCs (bmMCs), human LAD2- and HMC1 mast cell lines, human blood basophils, and peripheral blood-derived primary human MCs (HuMCs). In a chronic house dust mite (HDM)-driven allergic airway inflammation mouse model, we observed that PDE3 deficiency or PDE3 inhibition (PDE3i) therapy reduced the numbers of epithelial MCs, when compared to control mice. Mouse bone marrow-derived MCs (bmMCs) and the human HMC1 and LAD2 cell lines predominantly expressed PDE3B and PDE4A. BmMCs from Pde3−/− mice showed reduced loss of the degranulation marker CD107b compared with wild-type BmMCs, when stimulated in an immunoglobulin E (IgE)-dependent manner. Following both IgE-mediated and substance P-mediated activation, PDE3i-pretreated basophils, LAD2 cells, and HuMCs, showed less degranulation than diluent controls, as measured by surface CD63 expression. MCs lacking PDE3 or treated with the PDE3i Enoximone exhibited a lower calcium flux upon stimulation with ionomycine. In conclusion PDE3 plays a critical role in basophil and mast cell degranulation and therefore its inhibition may be a treatment option in allergic disease.
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pde3 inhibition reduces epithelial mast cell numbers in allergic airway inflammation and attenuates degranulation of basophils and mast cells
Frontiers in Pharmacology, 2020Co-Authors: Jan Beute, Hedwika Nastiti, Keerthana Ganesh, Steve Hockman, Robin Hoogenboom, Jelle Folkerts, Marco W J Schreurs, Rudi W Hendriks, Vivica Bos, Alex KleinjanAbstract:Epithelial mast cells are generally present in the airways of patients with allergic asthma that are inadequately controlled. Airway mast cells (MCs) are critically involved in allergic airway inflammation and contribute directly to the main symptoms of allergic patients. Phosphodiesterase 3 (PDE3) tailors signaling of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which are critical intracellular second messenger molecules in various signaling pathways. This paper investigates the pathophysiological role and disease-modifying effects of PDE3 in mouse bone marrow-derived MCs (bmMCs), human LAD2- and HMC1 mast cell lines, human blood basophils, and peripheral blood-derived primary human MCs (HuMCs). In a chronic house dust mite (HDM)-driven allergic airway inflammation mouse model, we observed that PDE3 deficiency or PDE3 inhibition (PDE3i) therapy reduced the numbers of epithelial MCs, when compared to control mice. Mouse bone marrow-derived MCs (bmMCs) and the human HMC1 and LAD2 cell lines predominantly expressed PDE3B and PDE4A. BmMCs from Pde3-/- mice showed reduced loss of the degranulation marker CD107b compared with wild-type BmMCs, when stimulated in an immunoglobulin E (IgE)-dependent manner. Following both IgE-mediated and substance P-mediated activation, PDE3i-pretreated basophils, LAD2 cells, and HuMCs, showed less degranulation than diluent controls, as measured by surface CD63 expression. MCs lacking PDE3 or treated with the PDE3i Enoximone exhibited a lower calcium flux upon stimulation with ionomycine. In conclusion PDE3 plays a critical role in basophil and mast cell degranulation and therefore its inhibition may be a treatment option in allergic disease.
Marko Fiege - One of the best experts on this subject based on the ideXlab platform.
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phosphodiesterase iii inhibition with amrinone leads to contracture development in skeletal muscle preparations of malignant hyperthermia susceptible swine
European Journal of Anaesthesiology, 2005Co-Authors: Marko Fiege, F Wappler, Ralf Weisshorn, M U Gerbershagen, Kerstin Kolodzie, Schulte Am J EschAbstract:SummaryBackground and objective:The phosphodiesterase-III (PDE-III) inhibitor Enoximone-induced marked contractures in skeletal muscle specimens of malignant hyperthermia (MH) susceptible (MHS) human beings and swine. Whether this is a substance specific effect of Enoximone or caused by inhibition o
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phosphodiesterase iii inhibition with amrinone leads to contracture development in skeletal muscle preparations of malignant hyperthermia susceptible swine
European Journal of Anaesthesiology, 2005Co-Authors: Marko Fiege, F Wappler, Ralf Weisshorn, M U Gerbershagen, Kerstin Kolodzie, Schulte Am J EschAbstract:SummaryBackground and objective: The phosphodiesterase-III (PDE-III) inhibitor Enoximone-induced marked contractures in skeletal muscle specimens of malignant hyperthermia (MH) susceptible (MHS) human beings and swine. Whether this is a substance specific effect of Enoximone or caused by inhibition of PDE-III remained unclear. Therefore, the effects of the PDE-III inhibitor amrinone in porcine MH normal (MHN) and MHS skeletal muscles were investigated.Methods: MH-trigger-free general anaesthesia was performed in eight MHS and eight MHN swine. The MH status of the swine was determined by detection of the Arg615–Cys point mutation on chromosome 6 indicating MH susceptibility. Skeletal muscle specimens were excised for the in vitro contracture tests with amrinone. Amrinone was added cumulatively every 5 min to muscle specimens in order to obtain organ bath concentrations between 20 and 400 μmol L−1. The in vitro effects of amrinone on muscle contractures and twitches were measured.Results: Amrinone-induced contractures in all skeletal muscle preparations. MHS muscles developed contractures at significantly lower bath concentrations of amrinone than MHN muscles. Contractures of MHS compared to MHN muscles were significantly larger at bath concentrations of 80, 100, 150, 200 and 400 μmol L−1 amrinone. Muscle twitches remained unchanged up to and including 200 μmol L−1 amrinone.Conclusions: Inhibition of PDE-III in general elicited higher contractures in MHS than in MHN muscles. Therefore, a contribution of PDE-III and the cyclic adenosine monophosphate (cAMP) system in the pathophysiology of MH must be suspected.
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In vitro and in vivo effects of the phosphodiesterase-III inhibitor Enoximone on malignant hyperthermia-susceptible swine.
Anesthesiology, 2003Co-Authors: Marko Fiege, F Wappler, Ralf Weisshorn, M U Gerbershagen, Kerstin Kolodzie, Jochen Schulte Am EschAbstract:BACKGROUND In human skeletal muscles, the phosphodiesterase-III inhibitor Enoximone induces in vitro contracture development, and it has been suggested that Enoximone could trigger malignant hyperthermia (MH). In this study, the in vitro and in vivo effects of Enoximone in MH-normal (MHN) and MH-susceptible (MHS) swine were investigated. METHODS Malignant hyperthermia trigger-free general anesthesia was performed in MHS and MHN swine. Skeletal muscle specimens were excised for an in vitro contracture test with 0.6 mm Enoximone. Thereafter, MHS and MHN swine were exposed to cumulative administration of 0.5, 1, 2, 4, 8, 16, and 32 mg/kg Enoximone intravenously. Clinical occurrence of MH was defined by a Pco(2) greater than 70 mmHg, a pH less than 7.20, and an increase in body temperature of more than 2.0 degrees C. RESULTS Enoximone induced marked contractures in all MHS muscle specimens in vitro. In contrast, only small or no contracture development was observed in MHN muscle specimens, without an overlap in contractures between MHS and MHN muscles. However, in vivo, no clinical differences were found between MHS and MHN swine following cumulative Enoximone doses. According to the defined criteria, none of the swine developed MH during the experiment. Furthermore, high Enoximone doses induced progressive circulatory insufficiency, and after receiving 32 mg/kg Enoximone, all animals died of cardiovascular failure. CONCLUSIONS The cumulative Enoximone doses used in this study were 30- to 50-fold higher than therapeutic doses in humans. Enoximone does not trigger MH in genetically determined swine. However, Enoximone might be useful for in vitro diagnosis of MH.
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Effects of the phosphodiesterase-III inhibitor Enoximone on skeletal muscle specimens from malignant hyperthermia susceptible patients
Journal of clinical anesthesia, 2000Co-Authors: Marko Fiege, F Wappler, Ralf Weisshorn, Jens Scholz, Verena Von Richthofen, Jochen Schulte Am EschAbstract:Abstract Study Objectives: To study the in vitro effects of the phosphodiesterase-III inhibitor Enoximone on skeletal muscle specimens from malignant hyperthermia susceptible (MHS) and normal (MHN) patients. Design: Prospective study. Setting: Malignant hyperthermia (MH) laboratory at a university hospital. Patients: 47 patients with clinical suspicion for MH undergoing in vitro contracture test (IVCT) for diagnosis of MH susceptibility. Interventions: Biopsies of M. quadriceps femoris were performed in adult patients with a 3-in-1 nerve block and in children with trigger-free general anesthesia. Measurements and Main Result: Patients were first classified as MHS or MHN by the IVCT according to the protocol of the European MH Group (EMHG). Patients with equivocal results (MHE) or with neuromuscular diseases were excluded from the study. Enoximone was added to the organ bath to surplus vital muscle specimens in single bolus concentrations of 0.4, 0.6, 0.8, or 1.6 mmol/L. The in vitro effects of Enoximone on muscle contractures and twitch were measured. Seventeen patients were classified as MHS and 30 as MHN by the EMHG criteria. Enoximone induced contractures in skeletal muscles in a dose-dependent manner. Contractures of MHS compared to MHN muscle specimens were significantly larger at all concentrations used in this study. No overlap in maximum contractures was seen between MHS and MHN muscles at a bath concentration of 0.6 mmol/L Enoximone only. Conclusions: Diagnosis of MH by an IVCT test with a single bolus administration of Enoximone seems to be possible using a concentration of 0.6 mmol/L. The findings of this study may indicate an involvement of the phosphodiesterase-III and cAMP system in pathogenesis of MH. Further in vivo investigation should determine the trigger potency of Enoximone in MH susceptible individuals.
Jan Beute - One of the best experts on this subject based on the ideXlab platform.
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PDE3-inhibitor Enoximone prevented mechanical ventilation in patients with SARS-CoV-2 pneumonia.
Experimental lung research, 2021Co-Authors: Jan Beute, Pieter Boermans, Bart Benraad, Jan Telman, Zuzana Diamant, Alex KleinjanAbstract:Standard care in severe SARS-CoV-2 pneumonia complicated by severe dyspnea and respiratory failure, consists of symptom reduction, ultimately supported by mechanical ventilation. Patients with seve...
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pde3 inhibition reduces epithelial mast cell numbers in allergic airway inflammation and attenuates degranulation of basophils and mast cells
Frontiers in Pharmacology, 2020Co-Authors: Jan Beute, Hedwika Nastiti, Keerthana Ganesh, Steve Hockman, Robin Hoogenboom, Jelle Folkerts, Marco W J Schreurs, Rudi W Hendriks, Vivica Bos, Alex KleinjanAbstract:Epithelial mast cells are generally present in the airways of patients with allergic asthma that are inadequately controlled. Airway mast cells (MCs) are critically involved in allergic airway inflammation and contribute directly to the main symptoms of allergic patients. Phosphodiesterase 3 (PDE3) tailors signaling of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which are critical intracellular second messenger molecules in various signaling pathways. This paper investigates the pathophysiological role and disease-modifying effects of PDE3 in mouse bone marrow-derived MCs (bmMCs), human LAD2- and HMC1 mast cell lines, human blood basophils, and peripheral blood-derived primary human MCs (HuMCs). In a chronic house dust mite (HDM)-driven allergic airway inflammation mouse model, we observed that PDE3 deficiency or PDE3 inhibition (PDE3i) therapy reduced the numbers of epithelial MCs, when compared to control mice. Mouse bone marrow-derived MCs (bmMCs) and the human HMC1 and LAD2 cell lines predominantly expressed PDE3B and PDE4A. BmMCs from Pde3-/- mice showed reduced loss of the degranulation marker CD107b compared with wild-type BmMCs, when stimulated in an immunoglobulin E (IgE)-dependent manner. Following both IgE-mediated and substance P-mediated activation, PDE3i-pretreated basophils, LAD2 cells, and HuMCs, showed less degranulation than diluent controls, as measured by surface CD63 expression. MCs lacking PDE3 or treated with the PDE3i Enoximone exhibited a lower calcium flux upon stimulation with ionomycine. In conclusion PDE3 plays a critical role in basophil and mast cell degranulation and therefore its inhibition may be a treatment option in allergic disease.
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pde3 inhibition reduces epithelial mast cell numbers in allergic airway inflammation and attenuates degranulation of basophils and mast cells
Frontiers in Pharmacology, 2020Co-Authors: Jan Beute, Hedwika Nastiti, Keerthana Ganesh, Steve Hockman, Robin Hoogenboom, Jelle Folkerts, Marco W J Schreurs, Rudi W Hendriks, Alex KleinjanAbstract:textabstractEpithelial mast cells are generally present in the airways of patients with allergic asthma that are inadequately controlled. Airway mast cells (MCs) are critically involved in allergic airway inflammation and contribute directly to the main symptoms of allergic patients. Phosphodiesterase 3 (PDE3) tailors signaling of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which are critical intracellular second messenger molecules in various signaling pathways. This paper investigates the pathophysiological role and disease-modifying effects of PDE3 in mouse bone marrow-derived MCs (bmMCs), human LAD2- and HMC1 mast cell lines, human blood basophils, and peripheral blood-derived primary human MCs (HuMCs). In a chronic house dust mite (HDM)-driven allergic airway inflammation mouse model, we observed that PDE3 deficiency or PDE3 inhibition (PDE3i) therapy reduced the numbers of epithelial MCs, when compared to control mice. Mouse bone marrow-derived MCs (bmMCs) and the human HMC1 and LAD2 cell lines predominantly expressed PDE3B and PDE4A. BmMCs from Pde3−/− mice showed reduced loss of the degranulation marker CD107b compared with wild-type BmMCs, when stimulated in an immunoglobulin E (IgE)-dependent manner. Following both IgE-mediated and substance P-mediated activation, PDE3i-pretreated basophils, LAD2 cells, and HuMCs, showed less degranulation than diluent controls, as measured by surface CD63 expression. MCs lacking PDE3 or treated with the PDE3i Enoximone exhibited a lower calcium flux upon stimulation with ionomycine. In conclusion PDE3 plays a critical role in basophil and mast cell degranulation and therefore its inhibition may be a treatment option in allergic disease.
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A pathophysiological role of PDE3 in allergic airway inflammation
JCI insight, 2018Co-Authors: Jan Beute, Melanie Lukkes, Ewout P. Koekoek, Hedwika Nastiti, Keerthana Ganesh, Marjolein J. W. De Bruijn, Steve Hockman, Menno Van Nimwegen, Gert-jan Braunstahl, Louis BoonAbstract:Phosphodiesterase 3 (PDE3) and PDE4 regulate levels of cyclic AMP, which are critical in various cell types involved in allergic airway inflammation. Although PDE4 inhibition attenuates allergic airway inflammation, reported side effects preclude its application as an antiasthma drug in humans. Case reports showed that Enoximone, which is a smooth muscle relaxant that inhibits PDE3, is beneficial and lifesaving in status asthmaticus and is well tolerated. However, clinical observations also showed antiinflammatory effects of PDE3 inhibition. In this study, we investigated the role of PDE3 in a house dust mite-driven (HDM-driven) allergic airway inflammation (AAI) model that is characterized by T helper 2 cell activation, eosinophilia, and reduced mucosal barrier function. Compared with wild-type (WT) littermates, mice with a targeted deletion of the PDE3A or PDE3B gene showed significantly reduced HDM-driven AAI. Therapeutic intervention in WT mice showed that all hallmarks of HDM-driven AAI were abrogated by the PDE3 inhibitors Enoximone and milrinone. Importantly, we found that Enoximone also reduced the upregulation of the CD11b integrin on mouse and human eosinophils in vitro, which is crucial for their recruitment during allergic inflammation. This study provides evidence for a hitherto unknown antiinflammatory role of PDE3 inhibition in allergic airway inflammation and offers a potentially novel treatment approach.
Schulte Am J Esch - One of the best experts on this subject based on the ideXlab platform.
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phosphodiesterase iii inhibition with amrinone leads to contracture development in skeletal muscle preparations of malignant hyperthermia susceptible swine
European Journal of Anaesthesiology, 2005Co-Authors: Marko Fiege, F Wappler, Ralf Weisshorn, M U Gerbershagen, Kerstin Kolodzie, Schulte Am J EschAbstract:SummaryBackground and objective:The phosphodiesterase-III (PDE-III) inhibitor Enoximone-induced marked contractures in skeletal muscle specimens of malignant hyperthermia (MH) susceptible (MHS) human beings and swine. Whether this is a substance specific effect of Enoximone or caused by inhibition o
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phosphodiesterase iii inhibition with amrinone leads to contracture development in skeletal muscle preparations of malignant hyperthermia susceptible swine
European Journal of Anaesthesiology, 2005Co-Authors: Marko Fiege, F Wappler, Ralf Weisshorn, M U Gerbershagen, Kerstin Kolodzie, Schulte Am J EschAbstract:SummaryBackground and objective: The phosphodiesterase-III (PDE-III) inhibitor Enoximone-induced marked contractures in skeletal muscle specimens of malignant hyperthermia (MH) susceptible (MHS) human beings and swine. Whether this is a substance specific effect of Enoximone or caused by inhibition of PDE-III remained unclear. Therefore, the effects of the PDE-III inhibitor amrinone in porcine MH normal (MHN) and MHS skeletal muscles were investigated.Methods: MH-trigger-free general anaesthesia was performed in eight MHS and eight MHN swine. The MH status of the swine was determined by detection of the Arg615–Cys point mutation on chromosome 6 indicating MH susceptibility. Skeletal muscle specimens were excised for the in vitro contracture tests with amrinone. Amrinone was added cumulatively every 5 min to muscle specimens in order to obtain organ bath concentrations between 20 and 400 μmol L−1. The in vitro effects of amrinone on muscle contractures and twitches were measured.Results: Amrinone-induced contractures in all skeletal muscle preparations. MHS muscles developed contractures at significantly lower bath concentrations of amrinone than MHN muscles. Contractures of MHS compared to MHN muscles were significantly larger at bath concentrations of 80, 100, 150, 200 and 400 μmol L−1 amrinone. Muscle twitches remained unchanged up to and including 200 μmol L−1 amrinone.Conclusions: Inhibition of PDE-III in general elicited higher contractures in MHS than in MHN muscles. Therefore, a contribution of PDE-III and the cyclic adenosine monophosphate (cAMP) system in the pathophysiology of MH must be suspected.
William T Abraham - One of the best experts on this subject based on the ideXlab platform.
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doi:10.1093/eurheartj/ehp338 CLINICAL RESEARCH
2013Co-Authors: Heart Failure, William T Abraham, Marco Metra, Michael Bohm, Ramon Corbalan, Teresa De Marco, Eric Eichhorn, Jennifer Linseman, David Demets, Sergio V. PerroneAbstract:Effects of low-dose oral Enoximone administration on mortality, morbidity, and exercise capacity in patients with advanced heart failure: the randomized, double-blind, placebocontrolled, parallel group ESSENTIAL trial
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effects of low dose oral Enoximone administration on mortality morbidity and exercise capacity in patients with advanced heart failure the randomized double blind placebo controlled parallel group essential trials
European Heart Journal, 2009Co-Authors: Marco Metra, William T Abraham, Eric J Eichhorn, Michael Bohm, Jennifer V Linseman, Ramon Corbalan, David L Demets, Teresa De Marco, Uri Elkayam, Michael J GerberAbstract:Aims Use of inotropic agents in patients with heart failure (HF) has been limited by adverse effects on outcomes. However, administration of positive inotropes at lower doses and concomitant treatment with beta-blockers might increase benefit–risk ratio. We investigated the effects of low doses of the positive inotrope Enoximone on symptoms, exercise capacity, and major clinical outcomes in patients with advanced HF who were also treated with beta-blockers and other guideline-recommended background therapy. Methods and results The Studies of Oral Enoximone Therapy in Advanced HF (ESSENTIAL) programme consisted of two identical, randomized, double-blind, placebo-controlled trials that differed only by geographic location (North and South America: ESSENTIAL-I; Europe: ESSENTIAL-II). Patients with New York Heart Association class III–IV HF symptoms, left ventricular ejection fraction ≤30%, and one hospitalization or two ambulatory visits for worsening HF in the previous year were eligible for participation in the trials. The trials had three co-primary endpoints: (i) the composite of time to all-cause mortality or cardiovascular hospitalization, analysed in the two ESSENTIAL trials combined; (ii) the 6 month change from baseline in the 6 min walk test distance (6MWTD); and (iii) the Patient Global Assessment (PGA) at 6 months, both analysed in each trial separately. ESSENTIAL-I and -II randomized 1854 subjects at 211 sites in 16 countries. In the combined trials, all-cause mortality and the composite, first co-primary endpoint did not differ between the two treatment groups [hazard ratio (HR) 0.97; 95% confidence interval (CI) 0.80–1.17; and HR 0.98; 95% CI 0.86–1.12, respectively, for Enoximone vs. placebo]. The two other co-primary endpoints were analysed separately in the two ESSENTIAL trials, as prospectively designed in the protocol. The 6MWTD increased with Enoximone, compared with placebo, in ESSENTIAL-I ( P = 0.025, not reaching, however, the pre-specified criterion for statistical significance of P < 0.020), but not in ESSENTIAL-II. No difference in PGA was observed in either trial. Conclusion Although low-dose Enoximone appears to be safe in patients with advanced HF, major clinical outcomes are not improved.
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low dose oral Enoximone enhances the ability to wean patients with ultra advanced heart failure from intravenous inotropic support results of the oral Enoximone in intravenous inotrope dependent subjects trial
American Heart Journal, 2007Co-Authors: Arthur M Feldman, Ron M. Oren, William T Abraham, John P Boehmer, Peter E Carson, Eric J Eichhorn, Edward M Gilbert, Andrew Kao, Carl V Leier, Brian D LowesAbstract:Background We determined whether low-dose oral Enoximone could wean patients with ultra-advanced heart failure (UA-HF) from intravenous (IV) inotropic support. Chronic parenteral inotropic therapy in UA-HF is costly and requires an indwelling catheter. An effective and safe oral inotrope would have value. Methods In this placebo-controlled study, 201 subjects with UA-HF requiring IV inotropic therapy were randomized to Enoximone or placebo. Subjects receiving intermittent IV inotropes were administered study medication of 25 or 50 mg 3 times a day (tid). Subjects receiving continuous IV inotropes were administered 50 or 75 mg tid for 1 week, which was reduced to 25 or 50 mg tid. The ability of subjects to remain alive and free of inotropic therapy was assessed for up to 182 days. Results Thirty days after weaning, 51 (51%) subjects on placebo and 62 (61.4%) subjects in the Enoximone group were alive and free of IV inotropic therapy (unadjusted primary end point P = 0.14, adjusted for etiology P = .17). At 60 days, the wean rate was 30% in the placebo group and 46.5% in the Enoximone group (unadjusted P = .016) Kaplan-Meier curves demonstrated a trend toward a decrease in the time to death or reinitiation of IV inotropic therapy over the 182-day study period (hazard ratio 0.76 [95% CI 0.55-1.04]) and a reduction at 60 days (0.62 [95% CI 0.43-0.89], P = .009) and 90 days (0.69 [95% CI 0.49-0.97], P = .031) after weaning in the Enoximone group. Conclusions Although there was no benefit over placebo in weaning patients from IV inotropes from 0 to 30 days, the EMOTE data suggest that low-dose oral Enoximone can be used to wean a modest percentage of subjects from IV inotropic support for up to 90 days after initiation of therapy.
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combined oral positive inotropic and beta blocker therapy for treatment of refractory class iv heart failure
Journal of the American College of Cardiology, 1998Co-Authors: Simon F Shakar, William T Abraham, Edward M Gilbert, Brian D Lowes, Alastair D Robertson, Lawrence S Zisman, Debra A Ferguson, Michael R BristowAbstract:Abstract Objectives. We sought to assess the effects of combined oral positive inotropic and beta-blocker therapy in patients with severe heart failure. Background. Patients with severe, class IV heart failure who receive standard medical therapy exhibit a 1-year mortality rate >50%. Moreover, such patients generally do not tolerate beta-blockade, a promising new therapy for chronic heart failure. Positive inotropes, including phosphodiesterase inhibitors, are associated with increased mortality when administered over the long term in these patients. The addition of a beta-blocker to positive inotropic therapy might attenuate this adverse effect, although long-term oral inotropic therapy might serve as a bridge to beta-blockade. Methods. Thirty patients with severe heart failure (left ventricular ejection fraction [LVEF] 17.2 ± 1.2%, cardiac index 1.6 ± 0.1 liter/min per m2) were treated with the combination of oral Enoximone (a phosphodiesterase inhibitor) and oral metoprolol at two institutions. Enoximone was given at a dose of ≤1 mg/kg body weight three times a day. After clinical stabilization, metoprolol was initiated at 6.25 mg twice a day and slowly titrated up to a target dose of 100 to 200 mg/day. Results. Ninety-six percent of the patients tolerated Enoximone, whereas 80% tolerated the addition of metoprolol. The mean duration of combination therapy was 9.4 ± 1.8 months. The mean length of follow-up was 20.9 ± 3.9 months. Of the 23 patients receiving the combination therapy, 48% were weaned off Enoximone over the long term. The LVEF increased significantly, from 17.7 ± 1.6% to 27.6 ± 3.4% (p = 0.01), whereas the New York Heart Association functional class improved from 4 ± 0 to 2.8 ± 0.1 (p = 0.0001). The number of hospital admissions tended to decrease during therapy (p = 0.06). The estimated probability of survival at 1 year was 81 ± 9%. Heart transplantation was performed successfully in nine patients (30%). Conclusions. Combination therapy with a positive inotrope and a beta-blocker appears to be useful in the treatment of severe, class IV heart failure. It may be used as a palliative measure when transplantation is not an option or as a bridge to heart transplantation. Further study of this form of combined therapy is warranted.