PMID- 30422390
OWN - NLM
STAT- MEDLINE
DCOM- 20200713
LR  - 20200713
IS  - 2160-7648 (Electronic)
IS  - 2160-763X (Linking)
VI  - 8
IP  - 5
DP  - 2019 Jul
TI  - A Randomized, Placebo-Controlled, Multiple-Ascending-Dose Study to Assess the 
      Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Soluble 
      Guanylate Cyclase Stimulator Praliciguat in Healthy Subjects.
PG  - 564-575
LID - 10.1002/cpdd.627 [doi]
AB  - Nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate 
      (cGMP) signaling is central to the regulation of several physiological processes, 
      including blood flow and inflammation. Deficient NO signaling is implicated in 
      multiple diseases. sGC stimulators are small molecules that enhance sGC activity, 
      particularly in combination with NO. In a randomized, placebo-controlled phase 1 
      study, the safety, tolerability, pharmacokinetics, and pharmacodynamics of 
      multiple ascending doses of the sGC stimulator praliciguat were assessed in 
      44 healthy adults. Four cohorts of 11 subjects (8 praliciguat, 3 placebo) 
      received once-daily praliciguat for 14 days before up-titrating for 7 days 
      (treatment sequences: 15/30 mg, 20/40 mg, 30/40 mg, and weight-based). All doses 
      were tolerated. No serious or severe adverse events (AEs) were reported. The most 
      common AEs in praliciguat recipients were headache and symptoms consistent with 
      blood pressure (BP) lowering/vasodilation. There were no laboratory, vital sign, 
      electrocardiographic, or platelet function findings indicative of a safety 
      concern. Pharmacokinetics were dose proportional, with an effective half-life of 
      24-37 hours, supporting once-daily dosing. Praliciguat produced dose-related 
      increases in plasma cGMP consistent with stimulation of sGC. Repeated once-daily 
      dosing showed sustained decreases in BP. Results support evaluation of 
      praliciguat for the treatment of conditions associated with deficient NO 
      signaling.
CI  - (c) 2018 The Authors. Clinical Pharmacology in Drug Development Published by Wiley 
      Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.
FAU - Hanrahan, John P
AU  - Hanrahan JP
AD  - Ironwood Pharmaceuticals Inc., Cambridge, MA, USA.
FAU - Wakefield, James D
AU  - Wakefield JD
AD  - Ironwood Pharmaceuticals Inc., Cambridge, MA, USA.
FAU - Wilson, Phebe J
AU  - Wilson PJ
AD  - Ironwood Pharmaceuticals Inc., Cambridge, MA, USA.
FAU - Mihova, Marina
AU  - Mihova M
AD  - Ironwood Pharmaceuticals Inc., Cambridge, MA, USA.
FAU - Chickering, Jennifer G
AU  - Chickering JG
AD  - Ironwood Pharmaceuticals Inc., Cambridge, MA, USA.
FAU - Ruff, Dennis
AU  - Ruff D
AD  - ICON Early Phase Services LLC, San Antonio, TX, USA.
FAU - Hall, Michael
AU  - Hall M
AD  - Ironwood Pharmaceuticals Inc., Cambridge, MA, USA.
FAU - Milne, G Todd
AU  - Milne GT
AD  - Ironwood Pharmaceuticals Inc., Cambridge, MA, USA.
FAU - Currie, Mark G
AU  - Currie MG
AD  - Ironwood Pharmaceuticals Inc., Cambridge, MA, USA.
FAU - Profy, Albert T
AU  - Profy AT
AD  - Ironwood Pharmaceuticals Inc., Cambridge, MA, USA.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20181113
PL  - United States
TA  - Clin Pharmacol Drug Dev
JT  - Clinical pharmacology in drug development
JID - 101572899
RN  - 0 (Pyrazoles)
RN  - 0 (Pyrimidines)
RN  - EC 4.6.1.2 (Soluble Guanylyl Cyclase)
RN  - H2D2X058MU (Cyclic GMP)
RN  - R1S0H458SA (praliciguat)
SB  - IM
MH  - Adult
MH  - Cross-Over Studies
MH  - Cyclic GMP/blood
MH  - Double-Blind Method
MH  - Female
MH  - Healthy Volunteers
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - *Pyrazoles/adverse effects/blood/pharmacokinetics/pharmacology
MH  - *Pyrimidines/adverse effects/blood/pharmacokinetics/pharmacology
MH  - *Soluble Guanylyl Cyclase
MH  - Young Adult
OTO - NOTNLM
OT  - IW-1973
OT  - cGMP
OT  - large volume of distribution
OT  - nitric oxide
OT  - phase 1b
OT  - praliciguat
OT  - soluble guanylate cyclase
EDAT- 2018/11/14 06:00
MHDA- 2020/07/14 06:00
CRDT- 2018/11/14 06:00
PHST- 2018/05/04 00:00 [received]
PHST- 2018/10/08 00:00 [accepted]
PHST- 2018/11/14 06:00 [pubmed]
PHST- 2020/07/14 06:00 [medline]
PHST- 2018/11/14 06:00 [entrez]
AID - 10.1002/cpdd.627 [doi]
PST - ppublish
SO  - Clin Pharmacol Drug Dev. 2019 Jul;8(5):564-575. doi: 10.1002/cpdd.627. Epub 2018 
      Nov 13.