title: Maximum renal responses to renin inhibition in healthy study participants: VTP-27999 versus aliskiren.
abstract: BACKGROUND
  Renin inhibition with aliskiren induced the largest increases in renal plasma flow (RPF) in salt-depleted healthy volunteers of all renin-angiotensin system (RAS) blockers. However, given its side-effects at doses higher than 300 mg, no maximum effect of renin inhibition could be established. We hypothesized that VTP-27999, a novel renin inhibitor without major side-effects at high doses, would allow us to establish this.
  
  
  RESULTS
  The effects of escalating VTP-27999 doses (75-600 mg) on RPF, glomerular filtration rate (GFR), and plasma RAS components were compared with those of 300 mg aliskiren in 22 normal volunteers on a low-sodium diet. VTP-27999 dose-dependently increased RPF and GFR; its effects on both parameters at 600 mg (increases of 18 ± 4 and 20 ± 4%, respectively) were equivalent to those at 300 mg, indicating that a maximum had been reached. The effects of 300 mg aliskiren (increases of 13 ± 5 and 8 ± 6%, respectively; P < 0.01 vs. 300 and 600 mg VTP-27999) resembled those of 150 mg VTP-27999. VTP-27999 dose-dependently increased renin, and lowered plasma renin activity and angiotensin II to detection limit levels. The effects of aliskiren on RAS components were best comparable to those of 150 mg VTP-27999.
  
  
  CONCLUSIONS
  Maximum renal renin blockade in healthy, salt-depleted volunteers, requires aliskiren doses higher than 300 mg, but can be established with 300 mg VTP-27999. To what degree such maximal effects (exceeding those of angiotensin-converting enzyme inhibitors and AT1-receptor blockers) are required in patients with renal disease, given the potential detrimental effects of excessive RAS blockade, remains to be determined.
authors.affiliation: aDepartment of Medicine bDepartment of Radiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA cDivision of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands dVitae Pharmaceuticals Inc., Fort Washington, Pennsylvania eDepartment of Internal Medicine, University of Toledo, Toledo, Ohio, USA.
authors.forename: Ebrahim
authors.initials: E
authors.lastname: Barkoudah
authors.forename: Bibi S
authors.initials: BS
authors.lastname: van Thiel
authors.forename: Naomi D L
authors.initials: ND
authors.lastname: Fisher
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gregg
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
authors.forename: George V
authors.initials: GV
authors.lastname: Moukarbel
authors.forename: Norman K
authors.initials: NK
authors.lastname: Hollenberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000577:Amides / Q000008:administration & dosage / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002219:Carbamates / Q000008:administration & dosage / Q000494:pharmacology*; D004311:Double-Blind Method; D005260:Female; D005650:Fumarates / Q000008:administration & dosage / Q000494:pharmacology*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D011446:Prospective Studies; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects*; D055815:Young Adult; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D002219:Carbamates; D005650:Fumarates; D010880:Piperidines; D012083:Renin; D000092502:Renin Inhibitors; C582069:methyl (2-((3-chlorophenyl)(1-((2-(methylamino)-3-(tetrahydro-2H-pyran-3-yl)propyl)carbamoyl)piperidin-3-yl)methoxy)ethyl)carbamate; C446481:aliskiren