title: Evaluation of the safety and efficacy of TY-51924 in patients with ST elevated acute myocardial infarction - Early phase II first in patient pilot study.
abstract: BACKGROUND
  In myocardial ischemia-reperfusion injuries, the involvement of the Na(+)/H(+) exchanger (NHE) is considered to be one of the pathogenic mechanisms following reperfusion. TY-51924 is a novel hydrophilic NHE inhibitor with a lower risk of central neurotoxicity than previous NHE inhibitors. This open-label, dose-escalating study was undertaken to investigate the safety, efficacy, and pharmacokinetics of TY-51924 in patients with ST-elevation myocardial infarction (STEMI).
  
  
  METHODS
  Consent was obtained from a total of 30 patients with first anterior STEMI. After 12 patients were determined to be ineligible, the remaining 18 patients, each of whom was undergoing primary percutaneous coronary intervention (pPCI), received TY-51924 intravenously up to 10, 20, or 30mg/kg as the low-, medium-, or high-dose groups, respectively (n=6 in each group). The primary endpoints were safety (up to 7 days) and plasma drug concentration. The myocardial salvage index (MSI) was measured by (201)Tl/(123)I-beta-methyl-p-iodophenyl pentadecanoic acid single photon emission computed tomography (SPECT) 3-5 days after pPCI.
  
  
  RESULTS
  No side effects were observed. Plasma drug concentrations increased dose-dependently, and were subsequently eliminated rapidly. MSIs were 0.118, 0.335, and 0.192 in the low-, medium-, and high-dose groups, respectively. In additional analysis, the combined MSIs in the medium- and high-dose groups were significantly higher than those in the low-dose group, in patients with a longer time from symptom onset to reperfusion (p=0.0247).
  
  
  CONCLUSIONS
  No side effects were observed even at the highest dose with this novel hydrophilic NHE inhibitor. Therefore, TY-51924 is thought to be safe in patients with STEMI, even at the highest dose. Potential cardioprotective effects of intravenous TY-51924 might be expected based on the results obtained for the MSIs using SPECT at 20-30mg/kg. However, further large-scale, double-blind, placebo-controlled clinical studies are required to confirm the efficacy and safety implied in the current study.
authors.affiliation: Department of Cardiology, Nihon University Itabashi Hospital, Tokyo, Japan. Electronic address: takayama.tadateru@nihon-u.ac.jp.
authors.forename: Tadateru
authors.initials: T
authors.lastname: Takayama
authors.affiliation: Division of Cardiology, Yokohama City University Medical Center, Yokohama, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kimura
authors.affiliation: Division of Cardiology, Funabashi Municipal Medical Center Heart and Vascular Institute, Funabashi, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Fukuzawa
authors.affiliation: Department of Cardiology, Nagoya Daini Red Cross Hospital, Nagoya, Japan.
authors.forename: Haruo
authors.initials: H
authors.lastname: Hirayama
authors.affiliation: Department of Cardiology, Ogaki Municipal Hospital, Ogaki, Japan.
authors.forename: Takahito
authors.initials: T
authors.lastname: Sone
authors.affiliation: Cardiovascular Division, Osaka National Hospital, Osaka, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Ueda
authors.affiliation: Kansai Rosai Hospital Cardiovascular Center, Hyogo, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Uematsu
authors.affiliation: Division of Coronary Artery Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Ishihara
authors.affiliation: Division of Cardiology, Saiseikai Kumamoto Hospital Cardiovascular Center, Kumamoto, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Nakao
authors.affiliation: Department of Cardiology, Nihon University Hospital, Tokyo, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Matsumoto
authors.affiliation: Department of Cardiology, Yokohama Ekisaikai Hospital, Yokohama, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Kosuge
authors.affiliation: Division of Advanced Cardiovascular Image Analysis, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Hiro
authors.affiliation: Department of Clinical Research, National Cerebral and Cardiovascular Center, Suita, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Asakura
authors.affiliation: Research & Development Department, TOA EIYO Ltd., Saitama, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kaneko
authors.affiliation: Research & Development Department, TOA EIYO Ltd., Saitama, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Yokoi
authors.affiliation: Department of Medicine, Division of Cardiology, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hirayama
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D005260:Female; D006146:Guanidines / Q000008:administration & dosage* / Q000097:blood; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000601:surgery; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000209:etiology; D009206:Myocardium / Q000473:pathology; D062645:Percutaneous Coronary Intervention; D010865:Pilot Projects; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013463:Sulfuric Acid Esters / Q000008:administration & dosage* / Q000097:blood; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: C000592017:3-guanidinocarbonyl-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta(b)pyridine-9-ylmethyl sulfuric acid; D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; D013463:Sulfuric Acid Esters
keywords: Acute myocardial infarction; Cardioprotection; NHE inhibitor; Percutaneous coronary intervention; Reperfusion injury