The fibrin-derived peptide Bbeta15-42 is cardioprotective in a pig model of myocardial ischemia-reperfusion injury.
OBJECTIVE
The fibrin-derived peptide Bbeta15-42 has been shown to reduce infarct size in rodent models of ischemia-reperfusion injury. To increase its potential for translation into the clinic, we studied the effects of Bbeta15-42 in pigs, whose coronary anatomy is similar to that of humans. In addition, we evaluated the pharmacokinetics and safety of Bbeta15-42 in several species, including humans.


METHODS
Animal study and phase I trial.


METHODS
University hospital and contract research laboratories.


METHODS
Pigs/healthy volunteers.


METHODS
Male farm-bred Landrace pigs were subjected to 1 hr of left anterior descending coronary artery occlusion followed by 3 hrs of reperfusion. At the time of reperfusion, Bbeta15-42 (2.4 mg/kg, n = 6) or random peptide (control; 2.4 mg/kg, n = 6) was administered as an intravenous bolus. As a positive control, pigs were subjected to ischemic preconditioning (n = 6). Cardiac damage and hemodynamics were recorded. Biodistribution and pharmacokinetics of Bbeta15-42 were determined in rats and dogs. In a phase I trial involving 30 male healthy volunteers, pharmacokinetics and safety were tested in a randomized, double-blinded, placebo-controlled, parallel-group, single ascending dose study.


RESULTS
Bbeta15-42 and ischemic preconditioning significantly reduced myocardial infarct size and troponin I levels. Bbeta15-42 also reduces interleukin-6 levels, underlining its anti-inflammatory properties. Furthermore, in humans, the pharmacokinetics of the peptide Bbeta15-42 were comparable to those of animals, and no serious adverse effects were observed.


CONCLUSIONS
Bbeta15-42 elicits cardioprotection in pigs and is clinically safe in phase I testing of humans. This study confirms the new concept of a pathogenic role of fibrin derivatives in myocardial reperfusion injury, which can be inhibited by peptide Bbeta15-42.
Roesner
Jan P
JP
Department of Anaesthesia, University Hospital Rostock, Germany.
Petzelbauer
Peter
P
Koch
Alexander
A
Mersmann
Jan
J
Zacharowski
Paula A
PA
Boehm
Olaf
O
Reingruber
Sonja
S
Pasteiner
Waltraud
W
Mascher
Daniel
D
Wolzt
Michael
M
Barthuber
Carmen
C
Nöldge-Schomburg
Gabi E F
GE
Scheeren
Thomas W L
TW
Zacharowski
Kai
K
D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D002316:Cardiotonic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004285:Dogs; D004311:Double-Blind Method; D064420:Drug-Related Side Effects and Adverse Reactions; D005338:Fibrin Fibrinogen Degradation Products / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D010446:Peptide Fragments / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D015427:Reperfusion Injury / Q000517:prevention & control*; D013552:Swine; D014018:Tissue Distribution
D002316:Cardiotonic Agents; D005338:Fibrin Fibrinogen Degradation Products; D010446:Peptide Fragments; C033786:fibrinogen Bbeta (15-42)