Perfan (enoximone) / Sanofi - LARVOL DELTA

Assessing institutional responsibility in scientific misconduct: A case study of enoximone research by Joachim Boldt. (PubMed, Clin Trials) - "The current guidelines of the Committee on Publication Ethics for retraction are inadequate for large-scale scientific misconduct. Comprehensive ethics training, regular audits, and transparent reporting are essential to ensure the credibility of published research."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure

Levosimendan, a Promising Pharmacotherapy in Cardiogenic Shock: A Comprehensive Review. (PubMed, Eur Cardiol) - "By synthesising evidence from numerous studies, a comparison of levosimendan over traditional inotropic agents, such as enoximone, dobutamine, dopamine and norepinephrine, is highlighted. Safety profiles and adverse effects are critically assessed to provide a balanced view of the therapeutic window provided by levosimendan. The review concludes that levosimendan is a valuable addition to the therapeutic strategy against CS, with the potential to improve patient outcomes."

Journal • Review • Cardiovascular

Aerosol of Enoximone/Hydroxypropyl-β-Cyclodextrin Inclusion Complex, Biopharmaceutical Evidence for ARDS Applicability. (PubMed, Pharmaceutics) - "This study offers a promising advance in the optimization of enoximone delivery to the lungs."

Journal • Acute Respiratory Distress Syndrome • Asthma • Chronic Obstructive Pulmonary Disease • Immunology • Infectious Disease • Novel Coronavirus Disease • Pulmonary Disease • Respiratory Diseases

Enoximone alleviates atopic dermatitis-like skin inflammation via inhibition of type 2 T helper cell development. (PubMed, Int Immunopharmacol) - "Collectively, the results demonstrate that Enox alleviates AD-like skin inflammation by inhibiting T-cell development. Thus, Enox may be a therapeutic candidate for the treatment of AD."

Journal • Allergy • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • Inflammation • GATA3

Cyclic nucleotide phosphodiesterases: therapeutic targets in cardiac hypertrophy and failure (PubMed, Med Sci (Paris)) - "Although PDE3 inhibitors such as milrinone or enoximone can be used clinically to improve systolic function and relieve the symptoms of acute CHF, their chronic use has proved detrimental. In this review, we describe cAMP and cGMP signalling in cardiomyocytes and present the different families of PDEs expressed in the heart and their modifications in pathological cardiac hypertrophy and HF. We also review results from preclinical models and clinical data indicating the use of specific PDE inhibitors or activators that may have therapeutic potential in CI."

Journal • Review • Cardiovascular • Congestive Heart Failure • Heart Failure

UNLOAD-HF: Unloading in Heart Failure Cardiogenic Shock (clinicaltrials.gov) - P=N/A | N=456 | Not yet recruiting | Sponsor: Amsterdam UMC, location VUmc | Trial completion date: Dec 2026 ➔ Jul 2028 | Trial primary completion date: Feb 2026 ➔ Oct 2027

Trial completion date • Trial primary completion date • Cardiovascular • Congestive Heart Failure • Heart Failure

A plea for personalization of the hemodynamic management of septic shock. (PubMed, Crit Care) - "Based on pharmacologic properties, we suggest as the first test a limited dose of dobutamine, to add enoximone or milrinone in the second line and substitute or add levosimendan if inefficient. Regarding adjunctive therapies, while hydrocortisone is nowadays advised in patients receiving high doses of vasopressors, patients responding to corticosteroids may be identified in the future by the analysis of selected cytokines or specific transcriptomic endotypes. To conclude, although some general rules apply for shock management, a personalized approach should be considered for hemodynamic monitoring and support."

Journal • Review • Septic Shock

Cyclic nucleotide phosphodiesterases as therapeutic targets in cardiac hypertrophy and heart failure. (PubMed, Nat Rev Cardiol) - "Although PDE3 inhibitors, such as milrinone or enoximone, have been used clinically to improve systolic function and alleviate the symptoms of acute HF, their chronic use has proved to be detrimental. In this Review, we describe cAMP and cGMP signalling in cardiomyocytes and present the various PDE families expressed in the heart as well as their modifications in pathological cardiac hypertrophy and HF. We also appraise the evidence from preclinical models as well as clinical data pointing to the use of inhibitors or activators of specific PDEs that could have therapeutic potential in HF."

Journal • Review • Cardiovascular • Congestive Heart Failure • Heart Failure

The Effects of Enoximone in Acute Exacerbation COPD (clinicaltrials.gov) - P4; N=3; Terminated; Sponsor: Rijnstate Hospital; N=15 ➔ 3; Trial completion date: Mar 2021 ➔ Dec 2021; Not yet recruiting ➔ Terminated; Trial primary completion date: Mar 2021 ➔ Dec 2021; A limited number of inclusions due to the Covid-pandemic

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases

UNLOAD-HF: Mechanical Left Ventricular Unloading in Acute Decompensated Heart Failure (clinicaltrials.gov) - P=N/A; N=456; Not yet recruiting; Sponsor: VU University Medical Center; Initiation date: Dec 2021 ➔ Jun 2022

Trial initiation date • Cardiovascular • Congestive Heart Failure • Heart Failure

Evaluation of Real-Life Investigational Use of Enoximone in Asthma, the Third Step in Drug Repurposing: A Preliminary Report. (PubMed, Can Respir J) - "The evaluation shows that PDE3-inhibitor enoximone is a viable alternative for or addition to current asthma therapeutics, as both add-on and stand-alone, considerably reducing the use of LABAs/SABAs/ICS, with no or negligible side effects. Additional studies are advisable."

Clinical • Journal • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

UNLOAD-HF: Mechanical Left Ventricular Unloading in Acute Decompensated Heart Failure (clinicaltrials.gov) - P=N/A; N=456; Not yet recruiting; Sponsor: VU University Medical Center

New trial • Cardiovascular • Congestive Heart Failure • Heart Failure

MULTIFACETED APPROACH FOR DESENSITIZATION OF A HYPERIMMUNE HEART TRANSPLANTATION RECIPIENT (ESOT 2021) - "She was treated with intravenous inotropic drugs (enoximone 2-2.5 mcg/kg/min), improving clinical status and, after 8 days, entered in macro-area urgency (level 2) due to the difficulty of allocation due to elevated class II PRA. Due to the sliding on inotropic support state, the patient underwent immunoadsorption (IA) (five sessions) and started rituximab (4 doses in two weeks), resulting in a 5% reduction of PRA...Pre-discharge extracorporeal photopheresis (ECP) has been started; she was discharged at home in good clinical conditions and is now in follow-up from 3 months. Intriguingly, after ECP the Donor-Specific Antibody titer abruptly decreased."

Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • Hepatology • Hypertrophic Cardiomyopathy • Infectious Disease • Liver Failure • Septic Shock • Transplantation • Ventricular Tachycardia

Phosphodiesterase-3 Inhibitor Enoximone in SARS-CoV-2 Infection. (PubMed, J Aerosol Med Pulm Drug Deliv) - No abstract available

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Vasoactive pharmacologic therapy in cardiogenic shock: a critical review. (PubMed, J Drug Assess) - "The studies evaluated the comparisons of norepinephrine (NE) vs. dopamine, epinephrine vs. NE, levosimendan vs. dobutamine, enoximone or placebo, and nitric oxide synthase inhibitors (NOSi) vs. placebo. The methodological quality between the studies is variable due to the inherent difficulties to conduct a study in CS. Vasopressors and inotropes continue to have a fundamental role given the lack of pharmacological alternatives."

Journal • Review • Cardiovascular • Myocardial Infarction

The Potential Role of Aerosolized Phosphodiesterase 3 Inhibitor Enoximone in the Management of Coronavirus Disease 2019 Hypoxemia: A Case Report. (PubMed, J Aerosol Med Pulm Drug Deliv) - "Intravenous infusions of phosphodiesterase inhibitors are commonly used as pulmonary vasodilators in the management of pulmonary hypertension. This is the first case showing that inhaled route administration of PDE3 inhibitor enoximone could be important in the management of COVID-19 hypoxemia, to restore perfusion in noninjured part of the lung, improving oxygenation and avoiding risks of systemic infusion."

Clinical • Journal • Hypertension • Infectious Disease • Novel Coronavirus Disease • Pneumonia • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Post-transplant Inotrope Score is Associated with Clinical Outcomes after Adult Heart Transplantation. (PubMed, Clin Transplant) - "High inotrope score post-HTx was observed in recipient congenital heart disease and was associated with a higher risk of mortality and acute kidney injury."

Clinical • Clinical data • Journal • Acute Kidney Injury • Cardiovascular • Heart Failure • Nephrology • Renal Disease • Transplantation • CRP

PDE3-inhibitor enoximone prevented mechanical ventilation in patients with SARS-CoV-2 pneumonia. (PubMed, Exp Lung Res) - "Our preliminary observations suggest that early intervention with the selective PDE3-inhibitor enoximone may help to revert respiratory failure as well as avert mechanical ventilation, and reduces ICU/hospital time in patients with severe SARS-CoV-2 pneumonia. Our findings warrant further research on the therapeutic potential of PDE3-inhibition, alone or in combination with other anti-COVID-19 strategies."

Clinical • Journal • Asthma • Chronic Obstructive Pulmonary Disease • Immunology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

Intravenous and intramuscular therapy in near fatal asthma. A response to Al-Shamrani. (PubMed, Int J Pediatr Adolesc Med) - "Intubation and ventilation prevent coughing but tenacious mucus remains which blocks the bronchi. There are no randomised controlled trials or national asthma guidelines to inform practice at this stage of the disease, especially in under 18 year olds, so case report evidence, experience, common sense, and pharmacological principles must be engaged to save the patient's life."

Journal • Asthma • Immunology • Respiratory Diseases

(Oral) enoximone in asthma. (PubMed, ERJ Open Res) - "PDE-3 inhibitors appear to have a large therapeutic value in asthma treatment; this letter provides some of the insights acquired in recent research https://bit.ly/33D9Dgd."

Journal • Asthma • Immunology • Respiratory Diseases

Inotropic agents and vasodilator strategies for the treatment of cardiogenic shock or low cardiac output syndrome. (PubMed, Cochrane Database Syst Rev) - "At present, there are no convincing data supporting any specific inotropic or vasodilating therapy to reduce mortality in haemodynamically unstable patients with CS or LCOS. Considering the limited evidence derived from the present data due to a high risk of bias and imprecision, it should be emphasised that there is an unmet need for large-scale, well-designed randomised trials on this topic to close the gap between daily practice in critical care of cardiovascular patients and the available evidence. In light of the uncertainties in the field, partially due to the underlying methodological flaws in existing studies, future RCTs should be carefully designed to potentially overcome given limitations and ultimately define the role of inotropic agents and vasodilator strategies in CS and LCOS."

Journal • Review • Cardiovascular • Congestive Heart Failure • Critical care • Heart Failure • Myocardial Infarction

[VIRTUAL] Is lactate clearance a good predictor for the prognosis of ED acutely ill patients? (EUSEM 2020) - "It is important to consider that the use of epinephrine is associated with increases in lactate not related to tissue hypoperfusion but increased glycolysis, glycogenolysis, and stimulation of the Na-K-pump. The balance between oxygen delivery and oxygen demand can be improved by ameliorating oxygen delivery by packed red blood cell transfusions as well as augmenting cardiac output, increasing SaO2 by intubation and improving microcirculatory perfusion by enhancing regional blood flow with, for example, dobutamine, enoximone, or nitroglycerin or by decreasing oxygen demand by mechanical ventilation... The pathophysiology of hyperlactatemia is complex with hypoxic and nonhypoxic mechanisms, often coinciding. Hyperlactatemia is a strong predictor of mortality in diverse populations of critically ill patients. However, it is still unclear how lactate levels influence clinical decision-making regarding admission policies or end-of-life decisions."

Clinical • Critical care • Infectious Disease • Metabolic Disorders • Septic Shock

The Effects of Enoximone in Acute Exacerbation COPD (clinicaltrials.gov) - P4; N=15; Not yet recruiting; Sponsor: Rijnstate Hospital

New P4 trial • Chronic Obstructive Pulmonary Disease

Inotrope Score as a Predictor of Outcome after Adult Heart Transplantation. (PubMed, J Heart Lung Transplant) - "A high inotrope score post-heart transplantation was seen in congenital heart disease recipients. Furthermore, it was associated with a higher risk of requiring renal replacement therapy."

Biomarker • Clinical • Journal • Cardiovascular • Heart Failure • Transplantation

PDE3 Inhibition Reduces Epithelial Mast Cell Numbers in Allergic Airway Inflammation and Attenuates Degranulation of Basophils and Mast Cells. (PubMed, Front Pharmacol) - "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."

Journal • Allergy • Asthma • Immunology • Respiratory Diseases • CD63