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1.
EClinicalMedicine ; 52: 101663, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-2041666

ABSTRACT

Background: Severe hypoxemia in patients with COVID-19 pneumonia might result from hypoxic pulmonary vasoconstriction, contributing to ventilation/perfusion (V/Q) mismatch. Because almitrine improves V/Q, it might reduce the risk for mechanical ventilation (MV) in such patients. Our primary objective was to determine the effect of almitrine on the need for MV at day 7. Methods: In a randomised double-blind placebo-controlled trial involving 15 ICUs, patients hospitalized for COVID-19 pneumonia and experiencing acute hypoxemic respiratory failure were randomly assigned to receive 5 days of intravenous low-dose (2 µg.kg-1.min-1) almitrine or placebo. The primary outcome was endotracheal intubation for MV or death within 7 days after randomisation. Secondary outcomes included in-hospital mortality, 28-day mortality, number of ventilator-free days, number of days in the ICU and the hospital, and treatment discontinuation for pre-specified adverse effects. This trial was registered with ClinicalTrials.gov, NCT04357457. Findings: Between September 3, 2020 and September 25, 2021 181 patients were enrolled and randomly assigned to almitrine (n=89) or placebo (n=92). 179 patients (excluding two who withdrew from the study) were included in the intention-to-treat analysis (mean age: 60·1 years; 34% women) and analyzed. On day 7, the primary endpoint occurred in 32 patients assigned to almitrine (36%) and in 37 patients assigned to placebo (41%), for a difference of -4·3% (95% confidence interval: -18·7% to 10·2%). Secondary outcomes (28-day mortality, in-hospital mortality, ventilator-free days at day 28, days in the ICU and the hospital, and treatment discontinuation for pre-specified adverse effects) did not differ between the two groups. Interpretation: In patients with COVID-19 acute hypoxemic respiratory failure, low-dose almitrine failed in reducing the need for MV or death at day 7. Funding: Programme Hospitalier de Recherche Clinique (PHRC COVID 2020) funded by the French Ministry of Health, Les Laboratoires Servier (Suresnes, France) providing the study drug free of charge.

2.
Curr Med Chem ; 2022 Aug 23.
Article in English | MEDLINE | ID: covidwho-2009795

ABSTRACT

Tri and Tetra-substituted Methanes (TRSMs) are a significant structural motif in many approved drugs and prodrugs. There is increasing use of TRSM units in medicinal chemistry, and many derivatives are specifically designed to make drug-target interactions through new chemical space around TRSM moiety. In this perspective, we describe synthetic challenges for accessing a range of functionalized selective TRSMs and their molecular mechanism of action, especially as anti-infectives. Natural anti-infectives like (+)-Bionectin A, B, (+)-Gliocladine C, Balanocarpol having TRSMs selectively and effectively bind to target proteins in comparison to planar motif having more sp2 carbons perhaps due to conformation which reduces the penalty for conformational entropy with the enhancement of three-dimensionality. Properties of repurposed TRSMs like Almitrine, Ifenprodil, Baricitinib and Remdesivir with their recent progress in Covid-19 therapeutics with their mode of action are also delineated. This perspective is expected to deliver a user guide and reference source for scientists, researchers and academicians in pursuing newly designed TRSMs as therapeutics.

4.
Front Med (Lausanne) ; 8: 655763, 2021.
Article in English | MEDLINE | ID: covidwho-1317230

ABSTRACT

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is manifested by an acute respiratory distress syndrome (ARDS) with intense inflammation and endothelial dysfunction leading to particularly severe hypoxemia. We hypothesized that an impaired hypoxic pulmonary vasoconstriction aggravates hypoxemia. The objective of the study was to test the effect of two pulmonary vasoactive drugs on patient oxygenation. Methods: Observational, single-center, open-label study in one intensive care unit (ICU) of the Paris area, realized in April 2020. Eligible patients had coronavirus disease 2019 (COVID-19) and moderate to severe ARDS [arterial partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) <200 mmHg] despite conventional protective ventilation. Exclusion criteria included pulmonary artery hypertension defined by a pulmonary artery systolic pressure (PAPs) >45 mmHg. The assessment of oxygenation was based on PaO2/FiO2 at (1) baseline, then after (2) 30 min of inhaled nitric oxide (iNO) 10 ppm alone, then (3) 30 min combination of iNO + almitrine infusion 8 µg/kg/min, then (4) 30 min of almitrine infusion alone. Results: Among 20 patients requiring mechanical ventilation during the study period, 12 met the inclusion criteria. Baseline PaO2/FiO2 was 146 ± 48 mmHg. When iNO was combined with almitrine, PaO2/FiO2 rose to 255 ± 90 mmHg (+80 ± 49%, p = 0.005), also after almitrine alone: 238 ± 98 mmHg (+67 ± 75%, p = 0.02), but not after iNO alone: 185 ± 73 mmHg (+30 ± 5%, p = 0.49). No adverse events related to almitrine infusion or iNO was observed. Conclusion: Combining iNO and infused almitrine improved the short-term oxygenation in patients with COVID-19-related ARDS. This combination may be of interest when first-line therapies fail to restore adequate oxygenation. These findings argue for an impaired pulmonary hypoxic vasoconstriction in these patients.

5.
World J Clin Cases ; 9(14): 3385-3393, 2021 May 16.
Article in English | MEDLINE | ID: covidwho-1232704

ABSTRACT

BACKGROUND: Several reports with clinical, histological and imaging data have observed the involvement of lung vascular function to explain the severe hypoxemia in coronavirus disease 2019 (COVID-19) patients. It has been hypothesized that an increased pulmonary blood flow associated with an impairment of hypoxic pulmonary vasoconstriction is responsible for an intrapulmonary shunt. COVID-19 may lead to refractory hypoxemia (PaO2/FiO2 ratio below 100 mmHg) despite mechanical ventilation and prone positioning. We hypothesized that the use of a pulmonary vasoconstrictor may help decrease the shunt and thus enhance oxygenation. CASE SUMMARY: We report our experience with three patients with refractory hypoxemia treated with almitrine to enhance oxygenation. Low dose almitrine (Vectarion®; Servier, Suresnes, France) was started at an infusion rate of 4 µg × kg/min on a central line. The PaO2/FiO2 ratio and total respiratory system compliance during almitrine infusion were measured. For the three patients, the PaO2/FiO2 ratio time-course showed a dramatic increase whereas total respiratory system compliance was unchanged. The three patients were discharged from the intensive care unit. The intensive care unit length of stay for patient 1, patient 2 and patient 3 was 30 d, 32 d and 31 d, respectively. Weaning from mechanical ventilation was performed 13 d, 18 d and 15 d after almitrine infusion for patient 1, 2 and 3, respectively. We found no deleterious effects on the right ventricular function, which was similar to previous studies on almitrine safety. CONCLUSION: Almitrine may be effective and safe to enhance oxygenation in coronavirus disease 2019 patients. Further controlled studies are required.

6.
Ann Intensive Care ; 10(1): 151, 2020 Nov 04.
Article in English | MEDLINE | ID: covidwho-992558

ABSTRACT

BACKGROUND: In COVID-19 patients with severe acute respiratory distress syndrome (ARDS), the relatively preserved respiratory system compliance despite severe hypoxemia, with specific pulmonary vascular dysfunction, suggests a possible hemodynamic mechanism for VA/Q mismatch, as hypoxic vasoconstriction alteration. This study aimed to evaluate the capacity of inhaled nitric oxide (iNO)-almitrine combination to restore oxygenation in severe COVID-19 ARDS (C-ARDS) patients. METHODS: We conducted a monocentric preliminary pilot study in intubated patients with severe C-ARDS. Respiratory mechanics was assessed after a prone session. Then, patients received iNO (10 ppm) alone and in association with almitrine (10 µg/kg/min) during 30 min in each step. Echocardiographic and blood gases measurements were performed at baseline, during iNO alone, and iNO-almitrine combination. The primary endpoint was the variation of oxygenation (PaO2/FiO2 ratio). RESULTS: Ten severe C-ARDS patients were assessed (7 males and 3 females), with a median age of 60 [52-72] years. Combination of iNO and almitrine outperformed iNO alone for oxygenation improvement. The median of PaO2/FiO2 ratio varied from 102 [89-134] mmHg at baseline, to 124 [108-146] mmHg after iNO (p = 0.13) and 180 [132-206] mmHg after iNO and almitrine (p < 0.01). We found no correlation between the increase in oxygenation caused by iNO-almitrine combination and that caused by proning. CONCLUSION: In this pilot study of severe C-ARDS patients, iNO-almitrine combination was associated with rapid and significant improvement of oxygenation. These findings highlight the role of pulmonary vascular function in COVID-19 pathophysiology.

8.
JACC Case Rep ; 2(9): 1311-1314, 2020 Jul 15.
Article in English | MEDLINE | ID: covidwho-599457

ABSTRACT

Coronavirus disease-19 (COVID-19)-related severe acute respiratory distress syndrome can lead to acute cor pulmonale. We report a case of acute cor pulmonale secondary to severe COVID-19 acute respiratory distress syndrome diagnosed with transesophageal echocardiography. Almitrine infusion allowed rapid enhancement of right ventricular function as well as improvement in oxygenation. (Level of Difficulty: Intermediate.).

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