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Liposomal encapsulation of trans-crocetin enhances oxygenation in patients with COVID-19-related ARDS receiving mechanical ventilation.

ABSTRACT: Current therapeutic treatments improving the impaired transportation of oxygen in acute respiratory distress syndrome (ARDS) have been found to be relevant and beneficial for the therapeutic treatment of COVID-19 patients suffering from severe respiratory complications. Hence, we report the preclinical and the preliminary results of the Phase I/II clinical trial of LEAF-4L6715, a liposomal nanocarrier encapsulating the kosmotropic agent trans-crocetin (TC), which, once injected, enhance the oxygenation of vascular tissue and therefore has the potential to improve the clinical outcomes of ARDS and COVID-19 in severely impacted patients. We demonstrated that the liposomal formulation enabled to increase from 30 min to 48 h the reoxygenation properties of free TCs in vitro in endothelial cells, but also to improve the half-life of TC by 6-fold in healthy mice. Furthermore, we identified 25 mg/kg as the maximum tolerated dose in mice. This determined concentration led to the validation of the therapeutic efficacy of LEAF-4 L6715 in a sepsis mouse model. Finally, we report the preliminary outcomes of an open-label multicenter Phase I/II clinical trial (EudraCT 2020-001393-30; NCT04378920), which was aimed to define the appropriate schedule and dosage of LEAF-4L6715 and to confirm its tolerability profile and preliminary clinical activity in COVID-19 patients treated in intensive care unit.

SUBMITTER: Mertes PM

PROVIDER: S-EPMC8225316 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Liposomal encapsulation of trans-crocetin enhances oxygenation in patients with COVID-19-related ARDS receiving mechanical ventilation.

Mertes Paul-Michel PM Collange Olivier O Coliat Pierre P Banerjee Mainak M Diringer Marie-Charlotte MC Roche Anne A Delabranche Xavier X Chaban Vitaliy V Voegelin Manon M Bernard Alexandre A Sartori Valérie V Laurent Nina N Velten Michel M Dhindsa Navreet N Defuria Jason J Kim Gwangseong G Xu Zhenghong Hannah ZH Theodorou Marina M Huang Zhaohua Richard ZR Khalifa Kaniz K Geng Bolin B Niyikiza Clet C Moyo Victor V Gizzi Patrick P Villa Pascal P Detappe Alexandre A Pivot Xavier X

Journal of controlled release : official journal of the Controlled Release Society 20210624

Current therapeutic treatments improving the impaired transportation of oxygen in acute respiratory distress syndrome (ARDS) have been found to be relevant and beneficial for the therapeutic treatment of COVID-19 patients suffering from severe respiratory complications. Hence, we report the preclinical and the preliminary results of the Phase I/II clinical trial of LEAF-4L6715, a liposomal nanocarrier encapsulating the kosmotropic agent trans-crocetin (TC), which, once injected, enhance the oxyg ...[more]

PMID: 34175365

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Project description:BackgroundLung-protective ventilation is key in bridging patients suffering from COVID-19 acute respiratory distress syndrome (ARDS) to recovery. However, resource and personnel limitations during pandemics complicate the implementation of lung-protective protocols. Automated ventilation modes may prove decisive in these settings enabling higher degrees of lung-protective ventilation than conventional modes.MethodProspective study at a Swiss university hospital. Critically ill, mechanically ventilated COVID-19 ARDS patients were allocated, by study-blinded coordinating staff, to either closed-loop or conventional mechanical ventilation, based on mechanical ventilator availability. Primary outcome was the overall achieved percentage of lung-protective ventilation in closed-loop versus conventional mechanical ventilation, assessed minute-by-minute, during the initial 7 days and overall mechanical ventilation time. Lung-protective ventilation was defined as the combined target of tidal volume <8 ml per kg of ideal body weight, dynamic driving pressure <15 cmH2O, peak pressure <30 cmH2O, peripheral oxygen saturation ≥88% and dynamic mechanical power <17 J/min.ResultsForty COVID-19 ARDS patients, accounting for 1,048,630 minutes (728 days) of cumulative mechanical ventilation, allocated to either closed-loop (n = 23) or conventional ventilation (n = 17), presenting with a median paO2/ FiO2 ratio of 92 [72-147] mmHg and a static compliance of 18 [11-25] ml/cmH2O, were mechanically ventilated for 11 [4-25] days and had a 28-day mortality rate of 20%. During the initial 7 days of mechanical ventilation, patients in the closed-loop group were ventilated lung-protectively for 65% of the time versus 38% in the conventional group (Odds Ratio, 1.79; 95% CI, 1.76-1.82; P < 0.001) and for 45% versus 33% of overall mechanical ventilation time (Odds Ratio, 1.22; 95% CI, 1.21-1.23; P < 0.001).ConclusionAmong critically ill, mechanically ventilated COVID-19 ARDS patients during an early highpoint of the pandemic, mechanical ventilation using a closed-loop mode was associated with a higher degree of lung-protective ventilation than was conventional mechanical ventilation.

Project description:BACKGROUND:Although routine administration of pharmacologic sedation or analgesia during mechanical ventilation in preterm neonates is not recommended, its use in clinical practice remains common. Alpha-2 agonists, mainly clonidine and dexmedetomidine, are used as adjunctive (or alternative) sedative agents alongside opioids and benzodiazepines. Clonidine has not been systematically assessed for use in neonatal sedation during ventilation. OBJECTIVES:To assess whether clonidine administered to term and preterm newborn infants receiving mechanical ventilation reduces morbidity and mortality rates. To compare the intervention versus placebo, no treatment, and dexmedetomidine; and to assess the safety of clonidine infusion for potential harms.To perform subgroup analyses according to gestational age; birth weight; administration method (infusion or bolus therapy); dose, duration, and route of clonidine administration; and pharmacologic sedation as a co-intervention. SEARCH METHODS:We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 12) in the Cochrane Library, MEDLINE via PubMed (1966 to January 10, 2017), Embase (1980 to January 10, 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to January 10, 2017). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials. SELECTION CRITERIA:We searched for randomized controlled trials, quasi-randomized controlled trials, and cluster trials comparing clonidine versus placebo, no treatment, or dexmedetomidine administered to term and preterm newborns receiving mechanical ventilation via an endotracheal tube. DATA COLLECTION AND ANALYSIS:For the included trial, two review authors independently extracted data (e.g. number of participants, birth weight, gestational age, all-cause death during initial hospitalization, duration of respiratory support, sedation scale, duration of hospital stay) and assessed risk of bias (e.g. adequacy of randomization, blinding, completeness of follow-up). This review considered primary outcomes of all-cause neonatal death, all-cause death during initial hospitalization, and duration of mechanical ventilation in days. MAIN RESULTS:One trial, which included 112 infants, met the inclusion criteria for this review. Term newborn infants on mechanical ventilation with the need for continuous analgesia and sedation with fentanyl and midazolam were eligible for enrollment during the first 96 hours of ventilation. Study authors administered clonidine 1 ?g/kg/h or placebo on day 4 after intubation.We found no differences between the two groups in all-cause death during hospitalization (risk ratio [RR] 0.69, 95% confidence interval [CI] 0.12 to 3.98). The quality of the evidence supporting these findings is low owing to imprecision of the estimates (one study; few events). The median (interquartile range) duration of mechanical ventilation was 7.1 days (5.7 to 9.1 days) in the clonidine group and 5.8 days (4.9 to 7.9 days) in the placebo group, respectively (P = 0.070). Among secondary outcomes, we found no differences in terms of duration of stay in the intensive care unit. Sedation scale values (COMFORT) and analgesia scores (Hartwig) during the first 72 hours of infusion of study medication were lower in the clonidine group than in the placebo group. AUTHORS' CONCLUSIONS:At present, evidence is insufficient to show the efficacy and safety of clonidine for sedation and analgesia in term and preterm newborn infants receiving mechanical ventilation.

Dataset Information

Liposomal encapsulation of trans-crocetin enhances oxygenation in patients with COVID-19-related ARDS receiving mechanical ventilation.

Publications

Liposomal encapsulation of trans-crocetin enhances oxygenation in patients with COVID-19-related ARDS receiving mechanical ventilation.

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