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Adrenomedullin Receptor

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François Harel – One of the best experts on this subject based on the ideXlab platform.

  • PulmoBind Imaging Measures Reduction of Vascular Adrenomedullin Receptor Activity with Lack of effect of Sildenafil in Pulmonary Hypertension
    Scientific Reports, 2019
    Co-Authors: Nassiba Merabet, Alain Fournier, François Harel, Quang T Nguyen, Myriam Létourneau, Mohamed Jalloul Nsaibia, Yan Fen Shi, Jeanclaude Tardif, Jocelyn Dupuis

    Abstract:

    Endothelial dysfunction is a core pathophysiologic process in pulmonary arterial hypertension (PAH). We developed PulmoBind (PB), a novel imaging biomarker of the pulmonary vascular endothelium. 99mTechnetium (99mTc)-labelled PB binds to Adrenomedullin Receptors (AM1) densely expressed in the endothelium of alveolar capillaries. We evaluated the effect of sildenafil on AM1 Receptors activity using 99mTc-PB. PAH was induced in rats using the Sugen/hypoxia model and after 3 weeks, animals were allocated to sildenafil (25 or 100 mg/kg/day) for 4 weeks. 99mTc-PB uptake kinetics was assessed by single-photon emission computed tomography. PAH caused right ventricular (RV) hypertrophy that was decreased by low and high sildenafil doses. Sildenafil low and high dose also improved RV function measured from the tricuspid annulus plane systolic excursion. Mean integrated pulmonary uptake of 99mTc-PB was reduced in PAH (508% · min ± 37, p 

  • pulmobind imaging measures reduction of vascular Adrenomedullin Receptor activity with lack of effect of sildenafil in pulmonary hypertension
    Scientific Reports, 2019
    Co-Authors: Nassiba Merabet, Alain Fournier, François Harel, Quang T Nguyen, Myriam Létourneau, Mohamed Jalloul Nsaibia, Yan Fen Shi, Jeanclaude Tardif

    Abstract:

    Endothelial dysfunction is a core pathophysiologic process in pulmonary arterial hypertension (PAH). We developed PulmoBind (PB), a novel imaging biomarker of the pulmonary vascular endothelium. 99mTechnetium (99mTc)-labelled PB binds to Adrenomedullin Receptors (AM1) densely expressed in the endothelium of alveolar capillaries. We evaluated the effect of sildenafil on AM1 Receptors activity using 99mTc-PB. PAH was induced in rats using the Sugen/hypoxia model and after 3 weeks, animals were allocated to sildenafil (25 or 100 mg/kg/day) for 4 weeks. 99mTc-PB uptake kinetics was assessed by single-photon emission computed tomography. PAH caused right ventricular (RV) hypertrophy that was decreased by low and high sildenafil doses. Sildenafil low and high dose also improved RV function measured from the tricuspid annulus plane systolic excursion. Mean integrated pulmonary uptake of 99mTc-PB was reduced in PAH (508% · min ± 37, p < 0.05) compared to controls (630% · min ± 30), but unchanged by sildenafil at low and high doses. Lung tissue expressions of the AM1 Receptor components were reduced in PAH and also unaffected by sildenafil. In experimental angio-proliferative PAH, sildenafil improves RV dysfunction and remodeling, but does not modify pulmonary vascular endothelium dysfunction assessed by the Adrenomedullin Receptor ligand 99mTc-PB.

  • Molecular imaging of the human pulmonary vascular endothelium in pulmonary hypertension: a phase II safety and proof of principle trial
    European Journal of Nuclear Medicine and Molecular Imaging, 2017
    Co-Authors: François Harel, Alain Fournier, Xavier Levac, Myriam Létourneau, Vincent Finnerty, David Langleben, Steve Provencher, Gad Abikhzer, Quang T. Nguyen, Jean Guimond

    Abstract:

    Purpose The Adrenomedullin Receptor is densely expressed in the pulmonary vascular endothelium. PulmoBind, an Adrenomedullin Receptor ligand, was developed for molecular diagnosis of pulmonary vascular disease. We evaluated the safety of PulmoBind SPECT imaging and its capacity to detect pulmonary vascular disease associated with pulmonary hypertension (PH) in a human phase II study. Methods Thirty patients with pulmonary arterial hypertension (PAH, n  = 23) or chronic thromboembolic PH (CTEPH, n  = 7) in WHO functional class II ( n  = 26) or III ( n  = 4) were compared to 15 healthy controls. Lung SPECT was performed after injection of 15 mCi ^99mTc-PulmoBind in supine position. Qualitative and semi-quantitative analyses of lung uptake were performed. Reproducibility of repeated testing was evaluated in controls after 1 month. Results PulmoBind injection was well tolerated without any serious adverse event. Imaging was markedly abnormal in PH with ∼50% of subjects showing moderate to severe heterogeneity of moderate to severe extent. The abnormalities were unevenly distributed between the right and left lungs as well as within each lung. Segmental defects compatible with pulmonary embolism were present in 7/7 subjects with CTEPH and in 2/23 subjects with PAH. There were no segmental defects in controls. The PulmoBind activity distribution index, a parameter indicative of heterogeneity, was elevated in PH (65% ± 28%) vs. controls (41% ± 13%, p  = 0.0003). In the only subject with vasodilator-responsive idiopathic PAH, PulmoBind lung SPECT was completely normal. Repeated testing 1 month later in healthy controls was well tolerated and showed no significant variability of PulmoBind distribution. Conclusions In this phase II study, molecular SPECT imaging of the pulmonary vascular endothelium using ^99mTc-PulmoBind was safe. PulmoBind showed potential to detect both pulmonary embolism and abnormalities indicative of pulmonary vascular disease in PAH. Phase III studies with this novel tracer and direct comparisons to lung perfusion agents such as labeled macro-aggregates of albumin are needed. Clinical trial ClinicalTrials.gov, NCT02216279

Jocelyn Dupuis – One of the best experts on this subject based on the ideXlab platform.

  • PulmoBind Imaging Measures Reduction of Vascular Adrenomedullin Receptor Activity with Lack of effect of Sildenafil in Pulmonary Hypertension
    Scientific Reports, 2019
    Co-Authors: Nassiba Merabet, Alain Fournier, François Harel, Quang T Nguyen, Myriam Létourneau, Mohamed Jalloul Nsaibia, Yan Fen Shi, Jeanclaude Tardif, Jocelyn Dupuis

    Abstract:

    Endothelial dysfunction is a core pathophysiologic process in pulmonary arterial hypertension (PAH). We developed PulmoBind (PB), a novel imaging biomarker of the pulmonary vascular endothelium. 99mTechnetium (99mTc)-labelled PB binds to Adrenomedullin Receptors (AM1) densely expressed in the endothelium of alveolar capillaries. We evaluated the effect of sildenafil on AM1 Receptors activity using 99mTc-PB. PAH was induced in rats using the Sugen/hypoxia model and after 3 weeks, animals were allocated to sildenafil (25 or 100 mg/kg/day) for 4 weeks. 99mTc-PB uptake kinetics was assessed by single-photon emission computed tomography. PAH caused right ventricular (RV) hypertrophy that was decreased by low and high sildenafil doses. Sildenafil low and high dose also improved RV function measured from the tricuspid annulus plane systolic excursion. Mean integrated pulmonary uptake of 99mTc-PB was reduced in PAH (508% · min ± 37, p 

  • Evaluation of pulmonary perfusion by SPECT imaging using an endothelial cell tracer in supine humans and dogs.
    EJNMMI Research, 2016
    Co-Authors: Xavier Levac, Alain Fournier, Jocelyn Dupuis, Myriam Létourneau, Sophie Marcil, Vincent Finnerty, Quang T. Nguyen, François Harel

    Abstract:

    Pulmonary perfusion is not spatially homogeneously distributed, and its variations could be of diagnostic value in lung vascular disease. PulmoBind is a ligand of the Adrenomedullin Receptor densely expressed in endothelial cells of lung capillaries. The aim of this study was to evaluate spatial distribution of human lung perfusion by using this novel molecular tracer of the pulmonary vascular endothelium. Normal humans (n = 19) enrolled into the PulmoBind phase I trial were studied (Clinicaltrials.gov. NCT01539889 ). They were injected with (99m)Tc-PulmoBind for SPECT imaging. Results were compared with (99m)Tc-PulmoBind in quadruped mammals (dogs, n = 5). Imaging was performed in the supine position and distribution of activity was determined as a function of cumulative voxels along the different anatomical planes. PulmoBind uptake in humans was 58 ± 1 % (mean ± SEM) of the injected dose. Dorsal activity was 18.1 ± 2.1 % greater than ventral, and caudal activity was 25.7 ± 1.6 % greater than cranial. Lateral activity was only mildly higher than medial by 7.0 ± 1.0 %. In supine dogs, similar but higher PulmoBind gradients were present: dorsal 28.6 ± 2.5 %, caudal 34.1 ± 5.0 % and lateral 18.1 ± 2.0 %. The perfused pulmonary circulation of supine humans, assessed by an Adrenomedullin Receptor ligand, is not homogeneously distributed with more prominent distribution in dorsal and caudal regions. It is qualitatively similar to a supine quadruped mammal confirming the presence of a microcirculatory gravitational perfusion gradient detectable with this tracer. Future studies are needed to determine if this novel endothelial cell tracer could be used to detect physiologic and pathologic variations of lung perfusion such as in pulmonary hypertension. ClinicalTrial.gov, NCT01539889.

  • Evaluation of pulmonary perfusion by SPECT imaging using an endothelial cell tracer in supine humans and dogs
    EJNMMI research, 2016
    Co-Authors: Xavier Levac, Alain Fournier, François Harel, Myriam Létourneau, Sophie Marcil, Vincent Finnerty, Quang T. Nguyen, Jocelyn Dupuis

    Abstract:

    Background
    Pulmonary perfusion is not spatially homogeneously distributed, and its variations could be of diagnostic value in lung vascular disease. PulmoBind is a ligand of the Adrenomedullin Receptor densely expressed in endothelial cells of lung capillaries. The aim of this study was to evaluate spatial distribution of human lung perfusion by using this novel molecular tracer of the pulmonary vascular endothelium.

Alain Fournier – One of the best experts on this subject based on the ideXlab platform.

  • PulmoBind Imaging Measures Reduction of Vascular Adrenomedullin Receptor Activity with Lack of effect of Sildenafil in Pulmonary Hypertension
    Scientific Reports, 2019
    Co-Authors: Nassiba Merabet, Alain Fournier, François Harel, Quang T Nguyen, Myriam Létourneau, Mohamed Jalloul Nsaibia, Yan Fen Shi, Jeanclaude Tardif, Jocelyn Dupuis

    Abstract:

    Endothelial dysfunction is a core pathophysiologic process in pulmonary arterial hypertension (PAH). We developed PulmoBind (PB), a novel imaging biomarker of the pulmonary vascular endothelium. 99mTechnetium (99mTc)-labelled PB binds to Adrenomedullin Receptors (AM1) densely expressed in the endothelium of alveolar capillaries. We evaluated the effect of sildenafil on AM1 Receptors activity using 99mTc-PB. PAH was induced in rats using the Sugen/hypoxia model and after 3 weeks, animals were allocated to sildenafil (25 or 100 mg/kg/day) for 4 weeks. 99mTc-PB uptake kinetics was assessed by single-photon emission computed tomography. PAH caused right ventricular (RV) hypertrophy that was decreased by low and high sildenafil doses. Sildenafil low and high dose also improved RV function measured from the tricuspid annulus plane systolic excursion. Mean integrated pulmonary uptake of 99mTc-PB was reduced in PAH (508% · min ± 37, p 

  • pulmobind imaging measures reduction of vascular Adrenomedullin Receptor activity with lack of effect of sildenafil in pulmonary hypertension
    Scientific Reports, 2019
    Co-Authors: Nassiba Merabet, Alain Fournier, François Harel, Quang T Nguyen, Myriam Létourneau, Mohamed Jalloul Nsaibia, Yan Fen Shi, Jeanclaude Tardif

    Abstract:

    Endothelial dysfunction is a core pathophysiologic process in pulmonary arterial hypertension (PAH). We developed PulmoBind (PB), a novel imaging biomarker of the pulmonary vascular endothelium. 99mTechnetium (99mTc)-labelled PB binds to Adrenomedullin Receptors (AM1) densely expressed in the endothelium of alveolar capillaries. We evaluated the effect of sildenafil on AM1 Receptors activity using 99mTc-PB. PAH was induced in rats using the Sugen/hypoxia model and after 3 weeks, animals were allocated to sildenafil (25 or 100 mg/kg/day) for 4 weeks. 99mTc-PB uptake kinetics was assessed by single-photon emission computed tomography. PAH caused right ventricular (RV) hypertrophy that was decreased by low and high sildenafil doses. Sildenafil low and high dose also improved RV function measured from the tricuspid annulus plane systolic excursion. Mean integrated pulmonary uptake of 99mTc-PB was reduced in PAH (508% · min ± 37, p < 0.05) compared to controls (630% · min ± 30), but unchanged by sildenafil at low and high doses. Lung tissue expressions of the AM1 Receptor components were reduced in PAH and also unaffected by sildenafil. In experimental angio-proliferative PAH, sildenafil improves RV dysfunction and remodeling, but does not modify pulmonary vascular endothelium dysfunction assessed by the Adrenomedullin Receptor ligand 99mTc-PB.

  • Molecular imaging of the human pulmonary vascular endothelium in pulmonary hypertension: a phase II safety and proof of principle trial
    European Journal of Nuclear Medicine and Molecular Imaging, 2017
    Co-Authors: François Harel, Alain Fournier, Xavier Levac, Myriam Létourneau, Vincent Finnerty, David Langleben, Steve Provencher, Gad Abikhzer, Quang T. Nguyen, Jean Guimond

    Abstract:

    Purpose The Adrenomedullin Receptor is densely expressed in the pulmonary vascular endothelium. PulmoBind, an Adrenomedullin Receptor ligand, was developed for molecular diagnosis of pulmonary vascular disease. We evaluated the safety of PulmoBind SPECT imaging and its capacity to detect pulmonary vascular disease associated with pulmonary hypertension (PH) in a human phase II study. Methods Thirty patients with pulmonary arterial hypertension (PAH, n  = 23) or chronic thromboembolic PH (CTEPH, n  = 7) in WHO functional class II ( n  = 26) or III ( n  = 4) were compared to 15 healthy controls. Lung SPECT was performed after injection of 15 mCi ^99mTc-PulmoBind in supine position. Qualitative and semi-quantitative analyses of lung uptake were performed. Reproducibility of repeated testing was evaluated in controls after 1 month. Results PulmoBind injection was well tolerated without any serious adverse event. Imaging was markedly abnormal in PH with ∼50% of subjects showing moderate to severe heterogeneity of moderate to severe extent. The abnormalities were unevenly distributed between the right and left lungs as well as within each lung. Segmental defects compatible with pulmonary embolism were present in 7/7 subjects with CTEPH and in 2/23 subjects with PAH. There were no segmental defects in controls. The PulmoBind activity distribution index, a parameter indicative of heterogeneity, was elevated in PH (65% ± 28%) vs. controls (41% ± 13%, p  = 0.0003). In the only subject with vasodilator-responsive idiopathic PAH, PulmoBind lung SPECT was completely normal. Repeated testing 1 month later in healthy controls was well tolerated and showed no significant variability of PulmoBind distribution. Conclusions In this phase II study, molecular SPECT imaging of the pulmonary vascular endothelium using ^99mTc-PulmoBind was safe. PulmoBind showed potential to detect both pulmonary embolism and abnormalities indicative of pulmonary vascular disease in PAH. Phase III studies with this novel tracer and direct comparisons to lung perfusion agents such as labeled macro-aggregates of albumin are needed. Clinical trial ClinicalTrials.gov, NCT02216279