Abstract W P404: Magnetic Particle Surface Characteristics Associated with Bradykinin Upregulation: Cause of Hypotension in the Magnetically-Enhanced Diffusion (MED) of Intravenous tPA in Acute Ischemic Stroke Feasibility Trial
Background: Hypotension during treatment was observed in some subjects in a first in man study of MED. The MED system uses an external magnet and magnetic particles to enhance diffusion of intravenous tPA and speed lysis. While free iron and dextran have been associated with hypotension for commercial iron products, the MED magnetic particles use a PEG coating and possesses nearly no free iron. One potential cause for the hypotension was surface charge, similar to acute hypotension reported with dialysis blood filters and liposomes.
Methods: Several preclinical experiments were conducted to investigate IgE and complement mediated allergic responses, dose rate vs. dose, baroreflex, and bradykinin upregualtion. Two particle lots were evaluated: Lot A (negatively charged, used in pilot clinical study) and lot B (50% smaller, neutral behavior). For the bradykinin investigation, particle boluses were administered in the presence of a bradykinin blocker (HOE-140) or ACE-I. Mean arterial pressure (MAP) and heart rate (HR) were monitored with acute hypotension defined as a significant drop in MAP over 30s.
Results: Studies show a dose-rate relationship to hypotension, not total dose, for lot A only. Baroreflex, IgE, and complement mediated allergic mechanisms were deemed unlikely. While rabbits appeared immune to the response, pigs reliably showed a ~30% MAP decline using the lot A particles, and not for lot B. ACE-I premedication resulted in a stronger response whereas HOE-140 premedication prevented hypotension (Figure). HR appeared to be largely unaffected in the study.
Conclusion: It is believed this study represents the first published relationship between bradykinin upregulation and surface characteristics (charge and/or area). Modification of the magnetic particle surface appears to prevent hypotension. The results may provide a new understanding of hypotension reported with other IV iron compounds.
Author Disclosures: C. Derdeyn: Ownership Interest; Modest; Pulse Therapeutics. Consultant/Advisory Board; Modest; Microvention, Penumbra, Silk Road, Pulse Therapeutics. B. Campbell: None. C. Bladin: None. C. Levi: None. M. Parsons: None. P. Panagos: Speakers' Bureau; Modest; Genentech. Ownership Interest; Modest; Pulse Therapeutics. Consultant/Advisory Board; Modest; Pulse Therapeutics. F.M. Creighton: Employment; Significant; Pulse Therapeutics. Ownership Interest; Significant; Pulse Therapeutics.
- © 2015 by American Heart Association, Inc.