Utilizing venous occlusion plethysmography to assess vascular effects: A study with buloxibutid, an angiotensin II type 2 receptor agonist
Abstract Buloxibutid (also known as C21) is a potent and selective angiotensin II type 2 receptor (AT2R) agonist, in development for oral treatment of fibrotic lung disease. This phase I, open‐label, pharmacodynamic study investigated vascular effects of buloxibutid in five healthy male volunteers....
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2024-02-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.13735 |
| _version_ | 1797296268623478784 |
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| author | Erik Rein‐Hedin Folke Sjöberg Cecilia Ganslandt Johan Skoog Helene Zachrisson Thomas Bengtsson Carl‐Johan Dalsgaard |
| author_facet | Erik Rein‐Hedin Folke Sjöberg Cecilia Ganslandt Johan Skoog Helene Zachrisson Thomas Bengtsson Carl‐Johan Dalsgaard |
| author_sort | Erik Rein‐Hedin |
| collection | DOAJ |
| description | Abstract Buloxibutid (also known as C21) is a potent and selective angiotensin II type 2 receptor (AT2R) agonist, in development for oral treatment of fibrotic lung disease. This phase I, open‐label, pharmacodynamic study investigated vascular effects of buloxibutid in five healthy male volunteers. Subjects were administered intra‐arterial infusions of buloxibutid for 5 min in ascending doses of 3, 10, 30, 100, and 200 μg/min, infused sequentially in the forearm. Infusions of sodium nitroprusside (SNP) solution in doses of 0.8–3.2 μg/min were administered as a positive control. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Safety and tolerability of intra‐arterial administrations of buloxibutid were evaluated. Following infusion of buloxibutid in doses of 3–200 μg/min, the range of increase in FBF was 27.8%, 17.2%, 37.0%, 28.5%, and 60.5%, compared to the respective baseline. The largest increase was observed in the highest dose group. Infusions of SNP as a positive control, increased FBF 230–320% compared to baseline. Three adverse events (AEs) of mild intensity, not related to buloxibutid or SNP, were reported for two subjects. Two of these AEs were related to study procedures. There were no clinically relevant changes in arterial blood pressure during the study period. Intra‐arterial infusion of buloxibutid in low, ascending doses increased FBF, indicating that buloxibutid may be effective in conditions associated with endothelial dysfunction. Venous occlusion plethysmography was found to be a useful method to explore pharmacodynamic vascular effects of novel AT2R agonists, while avoiding systemic adverse effects. |
| first_indexed | 2024-03-07T22:02:08Z |
| format | Article |
| id | doaj.art-55ff203de6964d7b9a14d27c9990b251 |
| institution | Directory Open Access Journal |
| issn | 1752-8054 1752-8062 |
| language | English |
| last_indexed | 2024-03-07T22:02:08Z |
| publishDate | 2024-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj.art-55ff203de6964d7b9a14d27c9990b2512024-02-24T03:31:30ZengWileyClinical and Translational Science1752-80541752-80622024-02-01172n/an/a10.1111/cts.13735Utilizing venous occlusion plethysmography to assess vascular effects: A study with buloxibutid, an angiotensin II type 2 receptor agonistErik Rein‐Hedin0Folke Sjöberg1Cecilia Ganslandt2Johan Skoog3Helene Zachrisson4Thomas Bengtsson5Carl‐Johan Dalsgaard6CTC Clinical Trial Consultants AB Uppsala SwedenCTC Clinical Trial Consultants AB Uppsala SwedenVicore Pharma AB Stockholm SwedenDepartment of Clinical Physiology and Department of Health, Medicine and Caring Sciences Linköping University Linköping SwedenDepartment of Clinical Physiology and Department of Health, Medicine and Caring Sciences Linköping University Linköping SwedenStatMind AB Lund SwedenVicore Pharma AB Stockholm SwedenAbstract Buloxibutid (also known as C21) is a potent and selective angiotensin II type 2 receptor (AT2R) agonist, in development for oral treatment of fibrotic lung disease. This phase I, open‐label, pharmacodynamic study investigated vascular effects of buloxibutid in five healthy male volunteers. Subjects were administered intra‐arterial infusions of buloxibutid for 5 min in ascending doses of 3, 10, 30, 100, and 200 μg/min, infused sequentially in the forearm. Infusions of sodium nitroprusside (SNP) solution in doses of 0.8–3.2 μg/min were administered as a positive control. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Safety and tolerability of intra‐arterial administrations of buloxibutid were evaluated. Following infusion of buloxibutid in doses of 3–200 μg/min, the range of increase in FBF was 27.8%, 17.2%, 37.0%, 28.5%, and 60.5%, compared to the respective baseline. The largest increase was observed in the highest dose group. Infusions of SNP as a positive control, increased FBF 230–320% compared to baseline. Three adverse events (AEs) of mild intensity, not related to buloxibutid or SNP, were reported for two subjects. Two of these AEs were related to study procedures. There were no clinically relevant changes in arterial blood pressure during the study period. Intra‐arterial infusion of buloxibutid in low, ascending doses increased FBF, indicating that buloxibutid may be effective in conditions associated with endothelial dysfunction. Venous occlusion plethysmography was found to be a useful method to explore pharmacodynamic vascular effects of novel AT2R agonists, while avoiding systemic adverse effects.https://doi.org/10.1111/cts.13735 |
| spellingShingle | Erik Rein‐Hedin Folke Sjöberg Cecilia Ganslandt Johan Skoog Helene Zachrisson Thomas Bengtsson Carl‐Johan Dalsgaard Utilizing venous occlusion plethysmography to assess vascular effects: A study with buloxibutid, an angiotensin II type 2 receptor agonist Clinical and Translational Science |
| title | Utilizing venous occlusion plethysmography to assess vascular effects: A study with buloxibutid, an angiotensin II type 2 receptor agonist |
| title_full | Utilizing venous occlusion plethysmography to assess vascular effects: A study with buloxibutid, an angiotensin II type 2 receptor agonist |
| title_fullStr | Utilizing venous occlusion plethysmography to assess vascular effects: A study with buloxibutid, an angiotensin II type 2 receptor agonist |
| title_full_unstemmed | Utilizing venous occlusion plethysmography to assess vascular effects: A study with buloxibutid, an angiotensin II type 2 receptor agonist |
| title_short | Utilizing venous occlusion plethysmography to assess vascular effects: A study with buloxibutid, an angiotensin II type 2 receptor agonist |
| title_sort | utilizing venous occlusion plethysmography to assess vascular effects a study with buloxibutid an angiotensin ii type 2 receptor agonist |
| url | https://doi.org/10.1111/cts.13735 |
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