Progress in Dodecafluoropentane Emulsion as a Neuroprotective Agent in a Rabbit Stroke Model

by Woods, S. D.; Skinner, R. D.; Ricca, A. M.; Brown, A. T.; Lowery, J. D.; Borrelli, M. J.; Lay, J. O.; Culp, W. C.

Dodecafluoropentane emulsion (DDFPe) in 250 nm nanodroplets seems to swell modestly to accept and carry large amounts of oxygen in the body at > 29 A degrees C. Small particle size allows oxygen delivery even into hypoxic tissue unreachable by erythrocytes. Using permanent cerebral embolic occlusion in rabbits, we assessed DDFPe dose response as a neuroprotectant at 7 and 24 h post-embolization without lysis of arterial obstructions and investigated blood pharmacokinetics. New Zealand White rabbits (N = 56) received cerebral angiography and embolic spheres (diameter = 700-900 mu m) occluded middle and/or anterior cerebral arteries. Intravenous DDFPe dosing (2 % w/v emulsion) began at 60 min and repeated every 90 min until sacrifice at 7 or 24 h post-embolization. Seven-hour groups: (1) control (embolized without treatment, N = 6), and DDFPe treatment: (2) 0.1 ml/kg (N = 7), (3) 0.3 ml/kg (N = 9), (4) 0.6 ml/kg (N = 8). Twenty-four-hour groups: (5) control (N = 16), and DDFPe treatment: (6) 0.1 ml/kg (N = 10). Infarcts as percent of total brain volume were determined using vital stains on brain sections. Other alert normal rabbits (N = 8) received IV doses followed by rapid arterial blood sampling and GC-MS analysis. Percent infarct volume means significantly decreased for all DDFPe-treated groups compared with controls, p = < 0.004 to < 0.03. Blood DDFP (gas) half-life was 1.45 A +/- 0.17 min with R = 0.958. Mean blood clearance was 78.5 A +/- 24.9 ml/min/kg (mean A +/- SE). Intravenous DDFPe decreases ischemic stroke infarct volumes. Blood half-life values are very short. The much longer therapeutic effect, > 90 min, suggests multiple compartments. Lowest effective dose and maximum effective therapy duration are not yet defined. Rapid development is warranted.

Journal
Molecular Neurobiology
Volume
48
Issue
2
Year
2013
Start Page
363-367
URL
https://dx.doi.org/10.1007/s12035-013-8495-6
ISBN/ISSN
1559-1182; 0893-7648
DOI
10.1007/s12035-013-8495-6