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Effects of Recombinant Human Angiotensin-Converting Enzyme 2 on Response to Acute Hypoxia and Exercise: A Randomised, Placebo-Controlled Study
- Source :
- Pulmonary Therapy
- Publication Year :
- 2021
-
Abstract
- Introduction Angiotensin-converting enzyme 2 (ACE2) is a key enzyme of the renin-angiotensin system (RAS) that has been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). Enhancing ACE2 activity using GSK2586881, a recombinant form of human ACE2, could be beneficial in diseases such as ARDS but may blunt the hypoxic pulmonary vasoconstriction (HPV) response and potentially impact systemic and tissue oxygenation. This study aimed to evaluate the effect of GSK2586881 0.8 mg/kg on HPV response in healthy adult volunteers during exercise under hypoxic conditions. Methods In this phase I, randomised, double-blind (sponsor open) study, GSK2586881 or placebo was administered as a single intravenous (IV) dose in a two-period crossover design. Treatment periods were separated by a washout period of 3–14 days. The primary endpoint was change from baseline in pulmonary artery systolic pressure (PASP) measured by echocardiography. Secondary endpoints included RAS peptides and oxygen saturation. Results Seventeen adults aged 18–40 years were randomised to treatment. There were no clinically relevant differences (defined as a reduction of ≥ 5 mmHg) in change from baseline in PASP between GSK2586881 and placebo. GSK2586881 was well tolerated, with no serious adverse events, no worsening of hypoxaemia and no evidence of immunogenicity. The study was terminated early after review of the data, which showed that the predefined success criteria had not been met. Following GSK2586881 administration, levels of the RAS peptide angiotensin II decreased while angiotensin (1-7) increased, as expected, indicating that GSK2586881 was pharmacologically active. Conclusions A single IV dose of GSK2586881 0.8 mg/kg was well tolerated but did not impact the acute HPV response in healthy volunteers. Supplementary Information The online version contains supplementary material available at 10.1007/s41030-021-00164-7.
- Subjects :
- Pulmonary and Respiratory Medicine
medicine.medical_specialty
ARDS
GSK2586881
Recombinant human angiotensin-converting enzyme 2
Placebo-controlled study
Placebo
Gastroenterology
Acute hypoxia
Respiratory Care
Internal medicine
Hypoxic pulmonary vasoconstriction
medicine
Pharmacokinetics
rhACE2
Exercise
Original Research
business.industry
medicine.disease
Crossover study
Angiotensin II
Blood pressure
Pharmacodynamics
Angiotensin-converting enzyme 2
Renin-angiotensin system
business
Subjects
Details
- ISSN :
- 23641746
- Volume :
- 7
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Pulmonary therapy
- Accession number :
- edsair.doi.dedup.....8aef9cb8410100a3b2f89c428aa437f3