-
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 -
Minerva Anestesiologica May 2014
Topics: Acute Lung Injury; Almitrine; Bronchodilator Agents; Female; Humans; Male; Nitric Oxide; Pulmonary Circulation; Respiratory System Agents
PubMed: 24280828
DOI: No ID Found -
Biochemical Pharmacology Jan 2021The outbreak of a novel coronavirus (SARS-CoV-2) has caused a major public health concern across the globe. SARS-CoV-2 is the seventh coronavirus that is known to cause... (Review)
Review
The outbreak of a novel coronavirus (SARS-CoV-2) has caused a major public health concern across the globe. SARS-CoV-2 is the seventh coronavirus that is known to cause human disease. As of September 2020, SARS-CoV-2 has been reported in 213 countries and more than 31 million cases have been confirmed, with an estimated mortality rate of ∼3%. Unfortunately, a drug or vaccine is yet to be discovered to treat COVID-19. Thus, repurposing of existing cancer drugs will be a novel approach in treating COVID-19 patients. These drugs target viral replication cycle, viral entry and translocation to the nucleus. Some can enhance innate antiviral immune response as well. Hence this review focuses on comprehensive list of 22 drugs that work against COVID-19 infection. These drugs include fingolimod, colchicine, N4-hydroxycytidine, remdesivir, methylprednisone, oseltamivir, icatibant, perphanizine, viracept, emetine, homoharringtonine, aloxistatin, ribavirin, valrubicin, famotidine, almitrine, amprenavir, hesperidin, biorobin, cromolyn sodium, and antibodies- tocilzumab and sarilumab. Also, we provide a list of 31 drugs that are predicted to function against SARS-CoV-2 infection. In summary, we provide succinct overview of various therapeutic modalities. Among these 53 drugs, based on various clinical trials and literature, remdesivir, nelfinavir, methylpredinosolone, colchicine, famotidine and emetine may be used for COVID-19. SIGNIFICANCE: It is of utmost important priority to develop novel therapies for COVID-19. Since the effect of SARS-CoV-2 is so severe, slowing the spread of diseases will help the health care system, especially the number of visits to Intensive Care Unit (ICU) of any country. Several clinical trials are in works around the globe. Moreover, NCI developed a recent and robust response to COVID-19 pandemic. One of the NCI's goals is to screen cancer related drugs for identification of new therapies for COVID-19. https://www.cancer.gov/news-events/cancer-currents-blog/2020/covid-19-cancer-nci-response?cid=eb_govdel.
Topics: Adenosine Monophosphate; Alanine; Anti-Inflammatory Agents; Antioxidants; Antiviral Agents; Drug Repositioning; Humans; SARS-CoV-2; Treatment Outcome; Virus Internalization; COVID-19 Drug Treatment
PubMed: 33191206
DOI: 10.1016/j.bcp.2020.114296 -
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 -
Anaesthesia, Critical Care & Pain... Aug 2020
Topics: Almitrine; Betacoronavirus; COVID-19; Coronavirus Infections; Humans; Nitric Oxide; Oxygen Consumption; Pandemics; Pneumonia, Viral; Respiratory Distress Syndrome; Respiratory System Agents; Retrospective Studies; SARS-CoV-2; Vasoconstrictor Agents
PubMed: 32505755
DOI: 10.1016/j.accpm.2020.05.014 -
Temperature (Austin, Tex.) 2018During severe septic shock and/or severe acute respiratory distress syndrome (ARDS) patients present with a limited cardio-ventilatory reserve (low cardiac output and... (Review)
Review
During severe septic shock and/or severe acute respiratory distress syndrome (ARDS) patients present with a limited cardio-ventilatory reserve (low cardiac output and blood pressure, low mixed venous saturation, increased lactate, low PaO2/FiO2 ratio, etc.), especially when elderly patients or co-morbidities are considered. Rescue therapies (low dose steroids, adding vasopressin to noradrenaline, proning, almitrine, NO, extracorporeal membrane oxygenation, etc.) are complex. Fever, above 38.5-39.5°C, increases both the ventilatory (high respiratory drive: large tidal volume, high respiratory rate) and the metabolic (increased O2 consumption) demands, further limiting the cardio-ventilatory reserve. Some data (case reports, uncontrolled trial, small randomized prospective trials) suggest that control of elevated body temperature ("fever control") leading to normothermia (35.5-37°C) will lower both the ventilatory and metabolic demands: fever control should simplify critical care management when limited cardio-ventilatory reserve is at stake. Usually fever control is generated by a combination of general anesthesia ("analgo-sedation", light total intravenous anesthesia), antipyretics and cooling. However general anesthesia suppresses spontaneous ventilation, making the management more complex. At variance, alpha-2 agonists (clonidine, dexmedetomidine) administered immediately following tracheal intubation and controlled mandatory ventilation, with prior optimization of volemia and atrio-ventricular conduction, will reduce metabolic demand and facilitate normothermia. Furthermore, after a rigorous control of systemic acidosis, alpha-2 agonists will allow for accelerated emergence without delirium, early spontaneous ventilation, improved cardiac output and micro-circulation, lowered vasopressor requirements and inflammation. Rigorous prospective randomized trials are needed in subsets of patients with a high fever and spiraling toward refractory septic shock and/or presenting with severe ARDS.
PubMed: 30393754
DOI: 10.1080/23328940.2018.1453771 -
British Journal of Anaesthesia Sep 2005Almitrine combined with inhaled nitric oxide (NO) can prevent hypoxia during one-lung ventilation (OLV). The optimal dose of almitrine that would provide therapeutic... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
BACKGROUND
Almitrine combined with inhaled nitric oxide (NO) can prevent hypoxia during one-lung ventilation (OLV). The optimal dose of almitrine that would provide therapeutic advantage with few side-effects during open-chest OLV has not been established.
METHODS
Forty-two patients undergoing thoracotomy were randomly allocated to three groups: placebo, almitrine 4 microg kg(-1) min(-1) and inhaled NO 10 p.p.m. (ALM4+NO), and almitrine 16 microg kg(-1) min(-1) and inhaled NO 10 p.p.m. (ALM16+NO). Gas exchange, haemodynamic and respiratory variables and plasma concentrations of almitrine and lactate were monitored. Measurements were obtained with the patient awake (baseline), after induction of anaesthesia with two-lung ventilation (control 2LV), 20 min after treatment (2LV+T), and then at 10, 20 and 30 min of OLV (OLV10', OLV20' and OLV30') with FI(O2)1.
RESULTS
In the placebo group, OLV impaired Pa(O2) and increased pulmonary shunt [16 (SD 7) kPa and 42 (10)% respectively]. These improved with ALM4+NO [26 (10) kPa and 31 (7)%; P<0.001]. ALM16+NO further improved PaO2) to 36 (13) kPa (P<0.0001) but gave no improvement in the shunt. Mean pulmonary artery pressure was similar in the placebo and ALM4+NO groups [20 (4) vs 23 (5) mm Hg], whereas it was increased in the ALM16+NO group to 28 (8) mm Hg (P<0.01). Plasma concentrations of almitrine and lactate were unaltered by the treatments.
CONCLUSIONS
Low-dose almitrine (4 microg kg(-1) min(-1)) together with inhaled NO significantly improves oxygenation during open-chest OLV, without modifying pulmonary haemodynamics. An increased dose of almitrine (16 microg kg(-1) min(-1)) with inhaled NO further improves arterial oxygenation, but also increases mean pulmonary artery pressure.
Topics: Adolescent; Adult; Aged; Almitrine; Anthropometry; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Hemodynamics; Humans; Hypoxia; Intraoperative Complications; Male; Middle Aged; Nitric Oxide; Oxygen; Partial Pressure; Prospective Studies; Respiration, Artificial; Thoracotomy
PubMed: 16024585
DOI: 10.1093/bja/aei194 -
The European Respiratory Journal Dec 1999The combination of inhaled nitric oxide with almitrine bismesylate has been proposed for the management of acute respiratory distress syndrome in order to divert... (Clinical Trial)
Clinical Trial Comparative Study
The combination of inhaled nitric oxide with almitrine bismesylate has been proposed for the management of acute respiratory distress syndrome in order to divert pulmonary blood flow away from poorly ventilated toward well-ventilated areas. The aims of this prospective and comparative study were to: 1) confirm the beneficial effects on oxygenation of this association; 2) evaluate the haemodynamic effects of this association; and 3) evaluate the influence of noradrenaline (a nonspecific vasoconstrictor) on the modification of gas exchange related to inhaled NO and/or almitrine bismesylate. Forty-one sedated paralysed and ventilated patients were investigated. Haemodynamic and blood gas measurements were performed in a fixed order: baseline; inhalation of NO for 30 min.; intravenous infusion of almitrine bismesylate; and concomitant administration of inhaled NO and almitrine bismesylate. Inhaled NO and almitrine bismesylate increased arterial oxygen tension (Pa,O2)/inspiratory oxygen fraction (FI,O2) (p<0.001). The association of inhaled NO with almitrine bismesylate resulted in a dramatic improvement in Pa,O2/FI,O2 (p<0.0001 versus almitrine bismesylate, p<0.05 versus inhaled NO). In patients receiving noradrenalin (n = 19), almitrine bismesylate had no effect on oxygenation. The present study confirmed that the combination of inhaled NO with almitrine bismesylate improved oxygenation, and demonstrated that almitrine bismesylate has no effect on oxygenation in patients receiving noradrenalin.
Topics: Administration, Inhalation; Adult; Aged; Almitrine; Drug Interactions; Drug Therapy, Combination; Female; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Nitric Oxide; Norepinephrine; Prospective Studies; Pulmonary Gas Exchange; Reference Values; Reproducibility of Results; Respiratory Distress Syndrome; Respiratory Function Tests; Respiratory System Agents; Statistics, Nonparametric; Vasoconstrictor Agents
PubMed: 10624756
DOI: 10.1183/09031936.99.14612839 -
World Journal of Clinical Cases May 2021Several reports with clinical, histological and imaging data have observed the involvement of lung vascular function to explain the severe hypoxemia in coronavirus...
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 (PaO/FiO 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 PaO/FiO ratio and total respiratory system compliance during almitrine infusion were measured. For the three patients, the PaO/FiO 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.
PubMed: 34002149
DOI: 10.12998/wjcc.v9.i14.3385 -
Thorax Sep 1990The effects of almitrine bismesylate and medroxyprogesterone acetate on oxygenation during wakefulness and sleep were compared in six patients with chronic obstructive... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
The effects of almitrine bismesylate and medroxyprogesterone acetate on oxygenation during wakefulness and sleep were compared in six patients with chronic obstructive lung disease and carbon dioxide retention. Patients received 1.5 mg/kg almitrine (a peripheral chemoreceptor stimulant), 100 mg of medroxyprogesterone (a central respiratory stimulant), or matched placebo daily for 15 days in random order in a crossover trial. When subjects were awake almitrine increased the ventilatory response to hypoxia and increased arterial oxygen tension (PaO2) to a greater extent than medroxyprogesterone, whereas medroxyprogesterone augmented the ventilatory response to hypercapnia and decreased arterial carbon dioxide tension (PaCO2) to a greater extent than almitrine. Neither drug influenced sleep architecture significantly, except that medroxyprogesterone increased the number of arousals. Almitrine had a more favourable effect than placebo on oxygenation as estimated from arterial oxygen saturation (SaO2) during the different stages of sleep, the number of episodes of hypoxaemia, and the amount of time that SaO2 was below 80%. The only change with medroxyprogesterone by comparison with placebo was a decrease in the number of hypoxaemic episodes. It is concluded that both active drugs improved blood gases during wakefulness, but that 1.5 mg/kg of almitrine is superior to 100 mg of medroxyprogesterone in improving SaO2 during sleep.
Topics: Almitrine; Carbon Dioxide; Chemoreceptor Cells; Humans; Lung Diseases, Obstructive; Male; Medroxyprogesterone; Medroxyprogesterone Acetate; Middle Aged; Oxygen; Pulmonary Ventilation; Sleep; Spirometry; Wakefulness
PubMed: 2145654
DOI: 10.1136/thx.45.9.666