A Single Dose-Escalation Study to Evaluate the Safety and Pharmacokinetics of Orally Administered Des-Aspartate Angiotensin I in Healthy Subjects.
Des-aspartate-angiotensin I (DAA-I) is an endogenous angiotensin peptide and a prototype angiotensin receptor agonist (ARA). It acts on the angiotensin AT1receptor and antagonises the deleterious actions of angiotensin II. DAA-I attenuates animal models of human disease in which angiotensin II has been implicated, such as cardiac hypertrophy, neointima formation, arteriosclerosis, renal failure, post-infarction injuries, diabetes, viral infection, chemical-induced inflammation, heat stroke, cancer, and gamma radiation lethality. DAA-I crosses Caco-2 cells and is effective at sub-nanomolar concentrations. These two properties are responsible for its oral efficacy. A single dose-escalation study was conducted to evaluate the safety, tolerability and pharmacokinetics of orally administered DAA-I in 18 healthy subjects. DAA-I was safe and well tolerated by the subjects, who were administered either 0.08, 0.70 or 1.50 mg/kg of the compound. The heart rate and systolic and diastolic blood pressures determined at each post-dose measurement remained within the clinically acceptable range. Across all cohorts, DAA-I had no substantial effect on blood pressures compared with placebo. Electrocardiographs (ECGs) were normal, and none of the subjects complained of chest discomfort. All clinical laboratory tests obtained before and after DAA-I and placebo treatment were normal. Pharmacokinetic analysis over a 12-h period following DAA-I administration did not show any increase of its level beyond basal concentration. This is in line with studies showing that intravenously administered DAA-I is rapidly metabolized and has a short half-life. We postulate that, during its short systemic sojourn, DAA-I exerts its actions via biased agonism on the angiotensin AT1receptor.The ClinicalTrial.gov assignment number for this study is NCT02666196.
Department of Medicine, National University of Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 10, Singapore, 119228, Singapore.
Ko-Onn
KO
Lee
Department of Medicine, National University of Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 10, Singapore, 119228, Singapore.
Chin-Meng
CM
Khoo
Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore, Singapore.|Clinical Pharmacology Core, Sing Health, Singapore, Singapore.|Office of Clinical Sciences, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore.
Balram
B
Chowbay
Biostatistics Unit, Yong Loo Lin School of Medicine, National University Health System, 1E Kent Ridge Road, NUHS Tower Block Level 11, Singapore, 119228, Singapore.
Yiong-Huak
YH
Chan
Department of Pharmacology, Yong Loo Lin School of Medicine, Block MD 3 Level 4 #04-01, 16 Medical Drive, Singapore, 117600, Singapore. simmk@alumni.nus.edu.sg.
Meng-Kwoon
MK
Sim
D000284:Administration, Oral; D000328:Adult; D000803:Angiotensin I / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult
C529402:des-aspartate-angiotensin I; D000803:Angiotensin I
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