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1.
Preprint in English | EuropePMC | ID: ppcovidwho-294592

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2), a transmembrane protein, is the main entry point for certain coronaviruses including the new coronavirus SARS-CoV-2 to enter cells. Synthesizing the PET imaging probe Al 18 F-DX600-BCH which is high-affinity ACE2 is aim to detect the expression of ACE2 in body and monitor the therapeutic effect. The Al 18 F-DX600-BCH was obtained manually with a 20.4% ± 5.2% radiochemical yield without attenuation correction and an over 99% purified radiochemical purity, being stable in vitro within 4 hours and cleared rapidly in blood (the half-lives of the distribution phase and clearance phase were 2.12 min and 25.31 min, respectively). Results of both biodistribution and PET imaging showed that Al 18 F-DX600-BCH was highly accumulated in the kidney (SUV kidney/normal > 50), and specific uptake in testis (SUV testis/normal > 10) was observed in rat images. The kidney (++), gastrointestinal (++) and bronchial (+++) cells were evidenced of ACE2 positive by IHC staining of rats. A total of 10 volunteers were enrolled and received PET/CT 1 hour and 2 hours after injection or dynamic PET/CT during 0-330 seconds (NCT04542863), from which strong radioactivity accumulation was mostly observed in the genitourinary system (SUV renal cortex = 32.00, SUV testis = 4.56), and moderate accumulation in conjunctiva and nasal mucosa for several cases. This work firstly reported the probe Al 18 F-DX600-BCH targeting ACE2, conducting preliminary preclinical experiments and a total of 10 clinical transformations, which demonstrated the potential and possibility of non-invasive mapping of ACE2. Trial registration: ClinicalTrials.gov NCT04542863. Registered 9 September 2020.

2.
Preprint in English | EuropePMC | ID: ppcovidwho-293272

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2), a transmembrane protein, is the main entry point for certain coronaviruses including the new coronavirus SARS-CoV-2 to enter cells. Synthesizing the PET imaging probe Al 18 F-DX600-BCH which is high-affinity ACE2 is aim to detect the expression of ACE2 in body and monitor the therapeutic effect. The Al 18 F-DX600-BCH was obtained manually with a 20.4% ± 5.2% radiochemical yield without attenuation correction and an over 99% purified radiochemical purity, being stable in vitro within 4 hours and cleared rapidly in blood (the half-lives of the distribution phase and clearance phase were 2.12 min and 25.31 min, respectively). Results of both biodistribution and PET imaging showed that Al 18 F-DX600-BCH was highly accumulated in the kidney (SUV kidney/normal > 50), and specific uptake in testis (SUV testis/normal > 10) was observed in rat images. The kidney (++), gastrointestinal (++) and bronchial (+++) cells were evidenced of ACE2 positive by IHC staining of rats. A total of 10 volunteers were enrolled and received PET/CT 1 hour and 2 hours after injection or dynamic PET/CT during 0-330 seconds (NCT04542863), from which strong radioactivity accumulation was mostly observed in the genitourinary system (SUV renal cortex = 32.00, SUV testis = 4.56), and moderate accumulation in conjunctiva and nasal mucosa for several cases. This work firstly reported the probe Al 18 F-DX600-BCH targeting ACE2, conducting preliminary preclinical experiments and a total of 10 clinical transformations, which demonstrated the potential and possibility of non-invasive mapping of ACE2. Trial registration: ClinicalTrials.gov NCT04542863. Registered 9 September 2020.

3.
Adv Sci (Weinh) ; 8(16): e2100965, 2021 08.
Article in English | MEDLINE | ID: covidwho-1281195

ABSTRACT

Rapid progress has been made to identify and study the causative agent leading to coronavirus disease 2019 (COVID-19) but many questions including who is most susceptible and what determines severity remain unanswered. Angiotensin-converting enzyme 2 (ACE2) is a key factor in the infection process of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In this study, molecularly specific positron emission tomography imaging agents for targeting ACE2 are first developed, and these novel agents are evaluated in vitro, in preclinical model systems, and in a first-in-human translational ACE2 imaging of healthy volunteers and a SARS-CoV-2 recovered patient (NCT04422457). ACE2 expression levels in different organs in live subjects are quantitatively delineated and observable differences are measured in the patient recovered from COVID-19. Surprising sites of uptake in the breast, reproductive system and very low uptake in pulmonary tissues are reported. This novel method can add a unique tool to facilitate SARS-CoV-2 related research and improve understanding of this enigmatic disease. Molecular imaging provides quantitative annotation of ACE2, the SARS-CoV-2 entry receptor, to noninvasively monitor organs impacted by the COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , COVID-19/virology , Peptides/pharmacokinetics , SARS-CoV-2/metabolism , Animals , COVID-19/pathology , Cells, Cultured , Female , Gallium Radioisotopes/pharmacokinetics , Humans , Male , Mice , Positron Emission Tomography Computed Tomography , Protein Binding , SARS-CoV-2/isolation & purification , SARS-CoV-2/pathogenicity , Tissue Distribution , Xenograft Model Antitumor Assays
4.
Clin Infect Dis ; 73(2): e445-e454, 2021 07 15.
Article in English | MEDLINE | ID: covidwho-640452

ABSTRACT

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) can manifest in rapid decompensation and respiratory failure with elevated inflammatory markers, consistent with cytokine release syndrome for which IL-6 blockade is an approved treatment. METHODS: We assessed effectiveness and safety of IL-6 blockade with tocilizumab in a single-center cohort of patients with COVID-19 requiring mechanical ventilation. The primary endpoint was survival probability postintubation; secondary analyses included an ordinal illness severity scale integrating superinfections. Outcomes in patients who received tocilizumab compared with tocilizumab-untreated controls were evaluated using multivariable Cox regression with propensity score inverse probability of treatment weighting (IPTW). RESULTS: 154 patients were included, of whom 78 received tocilizumab and 76 did not. Median follow-up was 47 days (range, 28-67). Baseline characteristics were similar between groups, although tocilizumab-treated patients were younger (mean: 55 vs 60 years), less likely to have chronic pulmonary disease (10% vs 28%), and had lower D-dimer values at time of intubation (median: 2.4 vs 6.5 mg/dL). In IPTW-adjusted models, tocilizumab was associated with a 45% reduction in hazard of death (HR, .55; 95% CI, .33-.90) and improved status on the ordinal outcome scale [OR per 1-level increase, .58; .36-.94). Although tocilizumab was associated with an increased proportion of patients with superinfections (54% vs 26%; P < .001), there was no difference in 28-day case fatality rate among tocilizumab-treated patients with versus without superinfection (22% vs 15%; P = .42). Staphylococcus aureus accounted for ~50% of bacterial pneumonia. CONCLUSIONS: In this cohort of mechanically ventilated COVID-19 patients, tocilizumab was associated with lower mortality despite higher superinfection occurrence.


Subject(s)
COVID-19 , Respiration, Artificial , Antibodies, Monoclonal, Humanized , COVID-19/drug therapy , Humans , SARS-CoV-2 , Treatment Outcome
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