PMID- 31708774
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200929
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 10
DP  - 2019
TI  - Phase I Trial of Pyragrel, a Novel Thromboxane Synthetase Inhibitor, to Evaluate 
      the Safety, Tolerability, and Pharmacokinetics in Healthy Volunteers.
PG  - 1231
LID - 10.3389/fphar.2019.01231 [doi]
LID - 1231
AB  - Background and Objective: Inhibition of thrombosis and platelet aggregation 
      through a thromboxane synthetase inhibitor proved to be an effective and 
      promising treatment for cardiovascular and/or cerebrovascular disease (CCVD) 
      patients. This phase I study evaluated the safety, tolerability, and 
      pharmacokinetics of sodium pyragrel, a novel thromboxane A(2) synthetase 
      inhibitor, in healthy volunteers. Methods: A total of 84 healthy Chinese 
      volunteers were enrolled in the study and randomized into one of five dosing 
      regimens of intravenous pyragrel, which were single ascending dose (30 to 300 
      mg), multiple doses (pyragrel 180 mg once daily on Day 1 and Day 6, twice daily 
      from Day 2 to Day 5), 3x3 Latin square crossover (60, 120, 240 mg), and a 
      continuous dose (360 mg in 24 h), respectively. Plasma concentrations were 
      determined using HPLC-MS/MS. Pharmacokinetics parameters were calculated with 
      non-compartment analysis. Results: The maximum plasma concentrations of pyragrel 
      were essentially reached at the end of the 3 h infusion. The pharmacokinetic 
      process of pyragrel and two main metabolites (BBS and BJS) is linear over the 
      30-300 mg dose range, with no significant accumulation on multiple doses. The 
      urinary excretion of pyragrel accounted for more than 70% of the total drug 
      amount. Preliminary pharmacodynamic results demonstrated that the production of 
      urinary 11-D-HTXB(2) was time- and dose-dependently inhibited by single i.v. dose 
      of pyragrel. Conclusions: Pyragrel was well tolerated after single ascending 
      doses up to 300 mg, multiple doses of 180 mg, and continuous administration of 
      360 mg within 24 h. No drug-related, serious adverse drug reactions occurred 
      during the five-part study. The most common pyragrel-related adverse events (AEs) 
      were total bilirubin (TB)/direct bilirubin (DB) elevations with a relatively low 
      incidence rate and seemed to be dose independent. Given the acceptable safety and 
      appropriate pharmacokinetic properties of sodium pyragrel proven in this study, 
      continued clinical development is warranted. The study was registered at 
      http://www.chictr.org.cn (ChiCTR-IID-16010159).
CI  - Copyright (c) 2019 Zou, Zuo, Huang, Hua, Yang, Yang, Guo, Tan, Chen, Chu, Pei and 
      Yang.
FAU - Zou, Chan
AU  - Zou C
AD  - Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South 
      University, Changsha, China.
FAU - Zuo, Xiaocong
AU  - Zuo X
AD  - Department of Pharmacy, The Third Xiangya Hospital, Central South University, 
      Changsha, China.
FAU - Huang, Jie
AU  - Huang J
AD  - Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South 
      University, Changsha, China.
FAU - Hua, Ye
AU  - Hua Y
AD  - Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical 
      University, Urumqi, China.
FAU - Yang, Shuang
AU  - Yang S
AD  - Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South 
      University, Changsha, China.
FAU - Yang, Xiaoyan
AU  - Yang X
AD  - Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South 
      University, Changsha, China.
FAU - Guo, Can
AU  - Guo C
AD  - Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South 
      University, Changsha, China.
FAU - Tan, Hongyi
AU  - Tan H
AD  - Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South 
      University, Changsha, China.
FAU - Chen, Jun
AU  - Chen J
AD  - Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South 
      University, Changsha, China.
FAU - Chu, Zhaoxing
AU  - Chu Z
AD  - Innovative Drug Design and Evaluation Center, Hefei Industrial Pharmaceutical 
      Institute Co., Ltd, Anhui, China.
FAU - Pei, Qi
AU  - Pei Q
AD  - Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South 
      University, Changsha, China.
FAU - Yang, Guoping
AU  - Yang G
AD  - Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South 
      University, Changsha, China.
LA  - eng
PT  - Journal Article
DEP - 20191024
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC6821791
OTO - NOTNLM
OT  - pharmacodynamics
OT  - pharmacokinetics
OT  - phase I trial
OT  - pyragrel
OT  - safety
EDAT- 2019/11/12 06:00
MHDA- 2019/11/12 06:01
PMCR- 2019/10/24
CRDT- 2019/11/12 06:00
PHST- 2019/05/01 00:00 [received]
PHST- 2019/09/27 00:00 [accepted]
PHST- 2019/11/12 06:00 [entrez]
PHST- 2019/11/12 06:00 [pubmed]
PHST- 2019/11/12 06:01 [medline]
PHST- 2019/10/24 00:00 [pmc-release]
AID - 10.3389/fphar.2019.01231 [doi]
PST - epublish
SO  - Front Pharmacol. 2019 Oct 24;10:1231. doi: 10.3389/fphar.2019.01231. eCollection 
      2019.