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Chest Nov 2022In people with COPD, pulmonary gas-exchange efficiency may be impaired because of abnormal alveolar ventilation (V˙A), capillary perfusion (Q˙c), or both. Both have... (Review)
Review
In people with COPD, pulmonary gas-exchange efficiency may be impaired because of abnormal alveolar ventilation (V˙A), capillary perfusion (Q˙c), or both. Both have been reported in early and mild stages of the disease. Such derangements often accompany significant clinical consequences such as activity-related dyspnea and exercise intolerance. Although much attention has been paid to pharmacologic treatment of mechanical abnormalities in COPD (eg, bronchodilators to deflate the lungs), increasing neurochemical afferent activity, secondary to gas-exchange inefficiency, has remained elusive as a therapeutic target. Hence, in this invited review, we first summarize how dyspnea, leading to poor exercise tolerance in COPD, may be explained by an increased venous admixture resulting from low V˙A/Q˙c, or wasted ventilation related to high V˙A/Q˙c, or both. We review the conflicting evidence supporting current treatments for gas-exchange inefficiency and exercise tolerance that act primarily on V˙A (bronchodilators, antiinflammatory medications) or Q˙c (oral and inhaled vasodilators, almitrine, and supplemental oxygen). Finally, to address the current knowledge and health care gaps, we propose two independent clinical research foci that may lead to a better understanding of the role of pulmonary gas-exchange inefficiency and activity-related dyspnea in COPD: (1) enhanced and deeper phenotyping of patients with COPD with V˙A/Q˙c abnormalities and (2) evaluation of existing and novel pharmacologic treatments to improve gas-exchange inefficiency, exertional dyspnea, and exercise tolerance across the spectrum of COPD severity.
Topics: Humans; Bronchodilator Agents; Pulmonary Disease, Chronic Obstructive; Exercise Test; Exercise; Pulmonary Gas Exchange; Exercise Tolerance; Dyspnea
PubMed: 35390329
DOI: 10.1016/j.chest.2022.03.033 -
Critical Care Medicine Feb 2021
Topics: Almitrine; COVID-19; Humans; Pharmaceutical Preparations; Respiratory Distress Syndrome; Respiratory Insufficiency; SARS-CoV-2
PubMed: 33186137
DOI: 10.1097/CCM.0000000000004765 -
Journal of Infection and Public Health Feb 2022To clarify the work done by using AI for identifying the genomic sequences, development of drugs and vaccines for COVID-19 and to recognize the advantages and challenges... (Review)
Review
OBJECTIVES
To clarify the work done by using AI for identifying the genomic sequences, development of drugs and vaccines for COVID-19 and to recognize the advantages and challenges of using such technology.
METHODS
A non-systematic review was done. All articles published on Pub-Med, Medline, Google, and Google Scholar on AI or digital health regarding genomic sequencing, drug development, and vaccines of COVID-19 were scrutinized and summarized.
RESULTS
The sequence of SARS- CoV-2 was identified with the help of AI. It can help also in the prompt identification of variants of concern (VOC) as delta strains and Omicron. Furthermore, there are many drugs applied with the help of AI. These drugs included Atazanavir, Remdesivir, Efavirenz, Ritonavir, and Dolutegravir, PARP1 inhibitors (Olaparib and CVL218 which is Mefuparib hydrochloride), Abacavir, Roflumilast, Almitrine, and Mesylate. Many vaccines were developed utilizing the new technology of bioinformatics, databases, immune-informatics, machine learning, and reverse vaccinology to the whole SARS-CoV-2 proteomes or the structural proteins. Examples of these vaccines are the messenger RNA and viral vector vaccines. AI provides cost-saving and agility. However, the challenges of its usage are the difficulty of collecting data, the internal and external validation, ethical consideration, therapeutic effect, and the time needed for clinical trials after drug approval. Moreover, there is a common problem in the deep learning (DL) model which is the shortage of interpretability.
CONCLUSION
The growth of AI techniques in health care opened a broad gate for discovering the genomic sequences of the COVID-19 virus and the VOC. AI helps also in the development of vaccines and drugs (including drug repurposing) to obtain potential preventive and therapeutic agents for controlling the COVID-19 pandemic.
Topics: Artificial Intelligence; COVID-19; COVID-19 Vaccines; Drug Development; Humans; Pandemics; SARS-CoV-2; Viral Vaccines
PubMed: 35078755
DOI: 10.1016/j.jiph.2022.01.011 -
Anaesthesia, Critical Care & Pain... Aug 2020
Topics: Almitrine; Betacoronavirus; COVID-19; Coronavirus Infections; Humans; Hypoxia; Pandemics; Pneumonia, Viral; Respiratory Distress Syndrome; Respiratory System Agents; SARS-CoV-2
PubMed: 32653550
DOI: 10.1016/j.accpm.2020.07.003 -
Frontiers in Medicine 2021Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is manifested by an acute respiratory distress syndrome (ARDS) with intense inflammation and endothelial...
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. 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 (PaO/FiO) <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 PaO/FiO 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. Among 20 patients requiring mechanical ventilation during the study period, 12 met the inclusion criteria. Baseline PaO/FiO was 146 ± 48 mmHg. When iNO was combined with almitrine, PaO/FiO rose to 255 ± 90 mmHg (+80 ± 49%, = 0.005), also after almitrine alone: 238 ± 98 mmHg (+67 ± 75%, = 0.02), but not after iNO alone: 185 ± 73 mmHg (+30 ± 5%, = 0.49). No adverse events related to almitrine infusion or iNO was observed. 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.
PubMed: 34277653
DOI: 10.3389/fmed.2021.655763 -
Critical Care Medicine Feb 2021Treating acute respiratory failure in patients with coronavirus disease 2019 is challenging due to the lack of knowledge of the underlying pathophysiology. Hypoxemia may... (Clinical Trial)
Clinical Trial Observational Study
OBJECTIVES
Treating acute respiratory failure in patients with coronavirus disease 2019 is challenging due to the lack of knowledge of the underlying pathophysiology. Hypoxemia may be explained in part by the loss of hypoxic pulmonary vasoconstriction. The present study assessed the effect of almitrine, a selective pulmonary vasoconstrictor, on arterial oxygenation in severe acute respiratory syndrome coronavirus 2-induced acute respiratory distress syndrome.
DESIGN
Single-center retrospective observational study.
SETTING
ICU of Lille Teaching Hospital, France, from February 27, 2020, to April 14, 2020.
PATIENTS
Patients with coronavirus disease 2019 pneumonia confirmed by positive reverse transcriptase-polymerase chain reaction for severe acute respiratory syndrome-coronavirus 2 and acute respiratory distress syndrome according to Berlin definition. Data focused on clinicobiological features, ventilator settings, therapeutics, outcomes, and almitrine-related adverse events.
INTERVENTIONS
Almitrine was considered in patients with severe hypoxemia (Pao2/Fio2 ratio < 150 mm Hg) in addition to the recommended therapies, at an hourly IV delivery of 10 μg/kg/min. Comparative blood gases were done before starting almitrine trial and immediately after the end of the infusion. A positive response to almitrine was defined by an increase of Pao2/Fio2 ratio greater than or equal to 20% at the end of the infusion.
MEASUREMENTS AND MAIN RESULTS
A total of 169 patients were enrolled. Thirty-two patients with acute respiratory distress syndrome received an almitrine infusion trial. In most cases, almitrine was infused in combination with inhaled nitric oxide (75%). Twenty-one patients (66%) were responders. The median Pao2/Fio2 ratio improvement was 39% (9-93%) and differs significantly between the responders and nonresponders (67% [39-131%] vs 6% [9-16%], respectively; p < 0.0001). The 28-day mortality rates were 47.6% and 63.6% (p = 0.39) for the responders and nonresponders, respectively. Hemodynamic parameters remained similar before and after the trial, not suggesting acute cor pulmonale.
CONCLUSIONS
Almitrine infusion improved oxygenation in severe acute respiratory syndrome coronavirus 2-induced acute respiratory distress syndrome without adverse effects. In a multistep clinical approach to manage severe hypoxemia in this population, almitrine could be an interesting therapeutic option to counteract the loss of hypoxic pulmonary vasoconstriction and redistribute blood flow away from shunting zones.
Topics: Almitrine; COVID-19; Critical Care; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Pulmonary Gas Exchange; Respiratory Distress Syndrome; Respiratory System Agents; Retrospective Studies; COVID-19 Drug Treatment
PubMed: 33093279
DOI: 10.1097/CCM.0000000000004711 -
Minerva Anestesiologica Mar 2023Almitrine, a drug enhancing hypoxic pulmonary vasoconstriction, has been proposed as a rescue therapy for refractory hypoxemia in COVID related acute respiratory...
BACKGROUND
Almitrine, a drug enhancing hypoxic pulmonary vasoconstriction, has been proposed as a rescue therapy for refractory hypoxemia in COVID related acute respiratory distress syndrome (C-ARDS). We aimed at investigating the response to almitrine depending on the cause of ARDS (COVID vs. non-COVID).
METHODS
Monocenter retrospective study from 2014 to 2021. All patients diagnosed with moderate to severe ARDS and treated with almitrine as rescue therapy for refractory hypoxemia were studied. Factor independently associated with oxygenation response to almitrine infusion were determined.
RESULTS
Sixty patients with ARDS and treated with almitrine were analyzed, 36 (60%) due to SARS-CoV-2 infection and 24 (40%) due to other causes. Baseline PaO2/FiO2 was 78 [61-101] mmHg, 76% had at least one prone positioning before the start of almitrine infusion. Median PaO2/FiO2 increased by +38 [7-142] mmHg (+61% [10-151]) after almitrine infusion. PaO2/FiO2 increased by +134 [12-186] mmHg in non-COVID ARDS (NC-ARDS) and by +19 [8-87] mmHg in C-ARDS. The increase in PaO2/FiO2 was lower in C-ARDS than in NC-ARDS (P=0.013). In multivariable analysis, C-ARDS, non-invasive ventilation and concomitant use of norepinephrine were independently associated with a decreased oxygenation response to almitrine infusion.
CONCLUSIONS
Our study reports a highly variable response to almitrine infusion in ARDS patients with refractory hypoxemia. Independent factors associated with a reduced oxygenation response to almitrine infusion were: COVID ARDS, concomitant use of norepinephrine, and non-invasive ventilatory strategy.
Topics: Humans; Almitrine; Retrospective Studies; COVID-19; SARS-CoV-2; Hypoxia; Respiratory Distress Syndrome; Norepinephrine
PubMed: 36287391
DOI: 10.23736/S0375-9393.22.16736-2 -
EClinicalMedicine Oct 2022Severe hypoxemia in patients with COVID-19 pneumonia might result from hypoxic pulmonary vasoconstriction, contributing to ventilation/perfusion (V/Q) mismatch. Because...
Effect of intravenous almitrine on intubation or mortality in patients with COVID-19 acute hypoxemic respiratory failure: A multicentre, randomised, double-blind, placebo-controlled trial.
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.min) 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.
PubMed: 36157895
DOI: 10.1016/j.eclinm.2022.101663 -
Alzheimer's Research & Therapy Jan 2024Specific peripheral proteins have been implicated to play an important role in the development of Alzheimer's disease (AD). However, the roles of additional novel...
BACKGROUND
Specific peripheral proteins have been implicated to play an important role in the development of Alzheimer's disease (AD). However, the roles of additional novel protein biomarkers in AD etiology remains elusive. The availability of large-scale AD GWAS and plasma proteomic data provide the resources needed for the identification of causally relevant circulating proteins that may serve as risk factors for AD and potential therapeutic targets.
METHODS
We established and validated genetic prediction models for protein levels in plasma as instruments to investigate the associations between genetically predicted protein levels and AD risk. We studied 71,880 (proxy) cases and 383,378 (proxy) controls of European descent.
RESULTS
We identified 69 proteins with genetically predicted concentrations showing associations with AD risk. The drugs almitrine and ciclopirox targeting ATP1A1 were suggested to have a potential for being repositioned for AD treatment.
CONCLUSIONS
Our study provides additional insights into the underlying mechanisms of AD and potential therapeutic strategies.
Topics: Humans; Alzheimer Disease; Proteomics; Risk Factors; Blood Proteins; Biomarkers; Genome-Wide Association Study
PubMed: 38212844
DOI: 10.1186/s13195-023-01378-4 -
Annals of Intensive Care Nov 2020In COVID-19 patients with severe acute respiratory distress syndrome (ARDS), the relatively preserved respiratory system compliance despite severe hypoxemia, with...
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 (PaO/FiO 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 PaO/FiO 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.
PubMed: 33150525
DOI: 10.1186/s13613-020-00769-2