Oral enoximone allows the reduction and discontinuation of inhaled steroids and beta2 agonists in asthmatic children.

In the last two decades, improvement on asthma treatment has been merely marginal for both adults and children; inhaled corticosteroids (ICS) combined with ß-2-mimetics remain the main therapy [3,4]. "New" therapies are just variations on ICS or, for children, on various other drugs that were allowed for adult asthma patients (clinicaltrials.gov). Although currently monoclonal antibodies have been introduced to the field, there is still a large therapeutic burden, given the mortality rate and widespread prevalence of uncontrolled asthma [2]. A simple and adequate way to reduce distress and costs would have great merit. PDE3 inhibitor enoximone was used earlier in successful treatment of life-threatening bronchial asthma (status asthmaticus) as well as in preoperative settings to prevent patients with severe asthma from suffering major surgery-related exacerbations; also, translational mice models showed the anti-inflammatory effects when PDE3 was targeted. Both outcomes suggested a beneficial effect of enoximone in severe chronic asthma. We hypothesized that enoximone might also be helpful in patients with severe chronic asthma; hence, we treated (and followed) > 70 patients (age 0-77, all volunteers) with personalized low doses of enoximone (orally), among them 11 minors, who are described here. Both children and adults reported improvement and/or alleviation of their asthma symptoms. All patients reported a better quality of life and greater drug compliance. The drug was well tolerated and showed no/negligible side effects. Notable bonus: asthma-related comorbidities (allergies, eczema, and rhinitis) were reported also to be less severe or even to disappear. The evaluation shows that PDE3 inhibitor enoximone is an adequate alternative for or addition to current asthma therapeutics, as add-on as well as stand-alone, considerably reducing the use of ß-2-mimetics/ICS, with no or negligible side effects. Additional studies are advisable.

Evaluation of Real-Life Investigational Use of Enoximone in Asthma, the Third Step in Drug Repurposing: A Preliminary Report.

Background: The population of uncontrolled asthma patients represents a large therapeutic burden. The PDE3-inhibitor enoximone is a strong and quick bronchodilator and is known to successfully treat life-threatening bronchial asthma (status asthmaticus). Translational mice models showed anti-inflammatory effects when PDE3 was targeted. Methods: Here, we investigated the effectiveness of PDE3-inhibitor enoximone as oral treatment for chronic asthma in a real-life off-label setting. Investigational use of PDE3-inhibitor enoximone: 51 outpatients (age 18-77) with chronic asthma were followed using off-label personalized low doses of the PDE3-inhibitor enoximone. Duration of treatment was 2-8 years. Results: Four groups could be distinguished as follows: The first group includes patients who use enoximone as an add-on, because it helps them in maintaining a better general wellbeing; they still use their traditional medication (n = 5). The second group consists of patients who use enoximone and were able to phase down their traditional medication without deterioration of their asthma symptoms (n = 11). The third group comprises patients who were able to discontinue their traditional medication and use only enoximone without deterioration of their asthma symptoms (n = 24). The last one has patients who, after having used enoximone for some time, saw their symptoms disappear and now use no medication at all, not even enoximone (n = 11). All patients reported improvement or at least alleviation of their asthma symptoms. All patients reported a better quality of life and greater drug compliance. Conclusion: 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.

PDE3-inhibitor enoximone prevented mechanical ventilation in patients with SARS-CoV-2 pneumonia.

BACKGROUND: 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 severe SARS-CoV-2, a prominent feature of COVID-19, show several similar symptoms to Critical Asthma Syndrome (CAS) patients, such as pulmonary edema, mucus plugging of distal airways, decreased tissue oxygenation, (emergent) exhaustion due to severe dyspnea and respiratory failure. Prior application of elective phosphodiesterase (PDE)3-inhibitors milrinone and enoximone in patients with CAS yielded rapid symptomatic relief and reverted the need for mechanical ventilation, due to their bronchodilator and anti-inflammatory properties. Based on these observations, we hypothesized that enoximone may be beneficial in the treatment of patients with severe SARS-CoV-2 pneumonia and prominent CAS-features. METHODS: In this case report enoximone was administered to four consecutive patients (1 M; 3 F; 46-70 y) with emergent respiratory failure due to SARS-CoV-2 pneumonia. Clinical outcome was compared with three controls who received standard care only. RESULTS: After an intravenous bolus of enoximone 20 mg followed by 10 mg/h via perfusor, a rapid symptomatic relief was observed: two out of four patients recovered within a few hours, the other two (with comorbid COPD GOLD II/III) responded within 24-36 h. Compared to the controls, in the enoximone-treated patients respiratory failure and further COVID-19-related deterioration was reverted and mechanical ventilation was prevented, leading to reduced hospital/ICU time. DISCUSSION: 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.

(Oral) enoximone in asthma.

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.

PDE3 Inhibition Reduces Epithelial Mast Cell Numbers in Allergic Airway Inflammation and Attenuates Degranulation of Basophils and Mast Cells.

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.

A pathophysiological role of PDE3 in allergic airway inflammation.

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.

Cardiac output measured by uncalibrated arterial pressure waveform analysis by recently released software version 3.02 versus thermodilution in septic shock.

To evaluate the 3.02 software version of the FloTrac/Vigileo™ system for estimation of cardiac output by uncalibrated arterial pressure waveform analysis, in septic shock. Nineteen consecutive patients in septic shock were studied. FloTrac/Vigileo™ measurements (COfv) were compared with pulmonary artery catheter thermodilution-derived cardiac output (COtd). The mean cardiac output was 7.7 L min(-1) and measurements correlated at r = 0.53 (P < 0.001, n = 314). In Bland-Altman plot for repeated measurements, the bias was 1.7 L min(-1) and 95 % limits of agreement (LA) were -3.0 to 6.5 L min(-1), with a %error of 53 %. The bias of COfv inversely related to systemic vascular resistance (SVR) (r = -0.54, P < 0.001). Above a SVR of 700 dyn s cm(-5) (n = 74), bias was 0.3 L min(-1) and 95 % LA were -1.6 to 2.2 L min(-1) (%error 32 %). Changes between consecutive measurements (n = 295) correlated at 0.67 (P < 0.001), with a bias of 0.1 % (95 % limits of agreement -17.5 to 17.0 %). All changes >10 % in both COtd and COfv (n = 46) were in the same direction. Eighty-five percent of the measurements were within the 30°-330° of the polar axis. COfv with the latest software still underestimates COtd at low SVR in septic shock. The tracking capacities of the 3.02 software are moderate-good when clinically relevant changes are considered.

The impact of open versus closed format ICU admission practices on the outcome of high risk surgical patients: a cohort analysis.

BACKGROUND: In the year 2000, the organizational structure of the ICU in the Zaandam Medical Centre (ZMC) changed from an open to a closed format ICU. The objective of this study was to evaluate the effect of this organizational change on outcome in high risk surgical patients. METHODS: The medical records of all consecutive high risk surgical patients admitted to the ICU from 1996 to 1998 (open format) and from 2003 to 2005 (closed format), were reviewed. High-risk patients were defined according to the Identification of Risk in Surgical patients (IRIS) score. Parameters studied were: mortality, morbidity, ICU length of stay (LOS) and hospital LOS. RESULTS: Mortality of ICU patients was 25.7% in the open format group and 15.8% in the closed format group (p = 0.01). Morbidity decreased from 48.6% to 46.1% (p = 0.6). The average length of hospital stay was 17 days in the open format group, and 21 days in the closed format group (p = 0.03). CONCLUSIONS: High risk surgical patients in the ICU are patients that have undergone complex and often extensive surgery. These patients are in need of specialized treatment and careful monitoring for maximum safety and optimal care. Our results suggest that closed format is a more favourable setting than open format to minimize the effects of high risk surgery, and to warrant safe outcome in this patient group.

Cardiac output derived from arterial pressure waveform analysis without calibration vs. thermodilution in septic shock: evolving accuracy of software versions.

BACKGROUND AND OBJECTIVE: We studied the evolution of software in the accuracy of the FloTrac/Vigileo system to measure cardiac output less invasively from arterial pressure waveform analysis without calibration, in comparison with pulmonary artery catheter-derived thermodilution measurements, in patients with septic shock and presumed alterations in vascular tone. METHODS: Nine patients who received a pulmonary artery catheter and were on mechanical ventilation and in sinus rhythm were monitored by the FloTrac/Vigileo. Paired cardiac output measurements by both techniques were analysed for 86 measurements in four patients using the 1.07 software version and 73 measurements in five subsequent patients using the later 1.10 version. RESULTS: For the 1.07 version, bias was -1.6 L min, precision 1.6 L min, limits of agreement -4.8-1.5 L min and error 48%. Measurements correlated at partial r equal to 0.32 (P = 0.003). For the 1.10 version, bias was -1.2 L min, precision 1.1 L min, limits of agreement -3.5-1.0 L min and error 32%. Measurements correlated at partial r equal to 0.90 (P < 0.001 vs. version 1.07). Differences were inversely related to mean cardiac output (P < 0.001, generalized estimating equations), particularly for software version 1.07 vs. 1.10 (P = 0.017, generalized estimating equation). Changes in thermodilution cardiac output over the course of time were also better tracked by the FloTrac/Vigileo when applying the latest software (P < 0.001, generalized estimating equation). CONCLUSIONS: Evolving software versions are thus better able to account for the effect of vascular tone on cardiac output measurements by less invasive waveform analyses without calibration (FloTrac/Vigileo), so that the latter may become useful in the haemodynamic monitoring of septic shock.