The fibrin-derived peptide Bβ15–42 is cardioprotective in a pig model of myocardial ischemia-reperfusion injury* : Critical Care Medicine

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Laboratory Investigations

The fibrin-derived peptide Bβ15–42 is cardioprotective in a pig model of myocardial ischemia-reperfusion injury*

Roesner, Jan P. MD; Petzelbauer, Peter MD; Koch, Alexander MD; Mersmann, Jan MD; Zacharowski, Paula A. PhD; Boehm, Olaf MD; Reingruber, Sonja PhD; Pasteiner, Waltraud PhD; Mascher, Daniel PhD; Wolzt, Michael MD; Barthuber, Carmen MD; Nöldge-Schomburg, Gabi E. F. MD; Scheeren, Thomas W. L. MD; Zacharowski, Kai MD, PhD

Author Information
Critical Care Medicine 35(7):p 1730-1735, July 2007. | DOI: 10.1097/01.CCM.0000269035.30231.76

Abstract

Objective: 

The fibrin-derived peptide Bβ15–42 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 Bβ15–42 in pigs, whose coronary anatomy is similar to that of humans. In addition, we evaluated the pharmacokinetics and safety of Bβ15–42 in several species, including humans.

Design: 

Animal study and phase I trial.

Setting: 

University hospital and contract research laboratories.

Subjects: 

Pigs/healthy volunteers.

Interventions: 

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, Bβ15–42 (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 Bβ15–42 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.

Measurements and Main Results: 

15–42 and ischemic preconditioning significantly reduced myocardial infarct size and troponin I levels. Bβ15–42 also reduces interleukin-6 levels, underlining its anti-inflammatory properties. Furthermore, in humans, the pharmacokinetics of the peptide Bβ15–42 were comparable to those of animals, and no serious adverse effects were observed.

Conclusions: 

15–42 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 Bβ15–42.

© 2007 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins

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