Randomized double-blind placebo-controlled study of an angiotensin immunotherapeutic vaccine (PMD3117) in hypertensive subjects.
Immunization against components of the renin-angiotensin system offers a potential alternative to daily medication in some patients with hypertension or heart failure. Our primary objective was to determine whether a sustained antibody titre to Ang I (angiotensin I) can be achieved in hypertensive patients. The secondary objective was to determine whether the antibodies block the renin system. Patients (n=27) with essential hypertension responsive to an ACEi (angiotensin-converting enzyme inhibitor) or ARB (angiotensin blocker) were randomly assigned to receive three or four injections of the Ang I vaccine PMD3117 or aluminium hydroxide (Alhydrogel trade mark ) over a 6 week period. Antibody titre was measured prior to each injection and every 30 days until disappearance. Indices of renin blockade were changes in renin and aldosterone (blood and urine) and a within-patient comparison of the pre- and post-vaccination rise in 24 h ambulatory blood pressure after 2 weeks of withdrawal of ACEi or ARB. The anti-(Ang I) antibody titre rose from the second injection in both regimes and peaked on day 64. Median half-life was 85 (95% CI, 44 and 153) days (where CI is confidence interval). Vaccination did not influence blood pressure, but significantly blunted the fall in plasma renin following withdrawal of ACEi or ARB. At 42 days after the first injection, aldosterone excretion was decreased by PMD3117 to 6 (95% CI, 1 and 31)% of values in patients receiving Alhydrogel trade mark (P=0.012). In patients with essential hypertension, PMD3117 generated a prolonged antibody response to Ang I. Biochemical measurements show evidence of blockade of the renin system, but higher titres will be required to achieve a decrease in blood pressure.
Brown
Morris J
MJ
Clinical Pharmacology Unit, Addenbrooke's Centre for Clinical Investigation, Box 110, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK. morris.brown@cai.cam.ac.uk
Coltart
John
J
Gunewardena
Kulasiri
K
Ritter
James M
JM
Auton
Timothy R
TR
Glover
James F
JF
D000293:Adolescent; D000328:Adult; D000368:Aged; D000450:Aldosterone / Q000378:metabolism; D000536:Aluminum Hydroxide / Q000009:adverse effects / Q000276:immunology; D000803:Angiotensin I / Q000276:immunology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000276:immunology; D000809:Angiotensins / Q000037:antagonists & inhibitors; D000906:Antibodies / Q000276:immunology; D001794:Blood Pressure / Q000502:physiology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000276:immunology; D007074:Immunoglobulin G / Q000032:analysis; D008297:Male; D008875:Middle Aged; D012083:Renin / Q000276:immunology / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000276:immunology*; D014611:Vaccination / Q000379:methods; D014612:Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*
D000806:Angiotensin-Converting Enzyme Inhibitors; D000809:Angiotensins; D000906:Antibodies; D007074:Immunoglobulin G; D014612:Vaccines; D000450:Aldosterone; D000536:Aluminum Hydroxide; D000803:Angiotensin I; D012083:Renin