Dodecafluoropentane Emulsion Extends Window for tPA Therapy in a Rabbit Stroke Model.

Abstract

Dodecafluoropentane emulsion (DDFPe) nanodroplets are exceptional oxygen transporters and can protect ischemic brain in stroke models 24 h without reperfusion. Current stroke therapy usually fails to reach patients because of delays following stroke onset. We tested using DDFPe to extend the time window for tissue plasminogen activator (tPA). Longer treatment windows will allow more patients more complete stroke recovery. We test DDFPe to safely extend the time window for tPA thrombolysis to 9 h after stroke. With IACUC approval, randomized New Zealand white rabbits (3.4-4.7 kg, n = 30) received angiography and 4-mm blood clot in the internal carotid artery for flow-directed middle cerebral artery occlusion. Seven failed and were discarded. Groups were IV tPA (n = 11), DDFPe + tPA (n = 7), and no therapy controls (n = 5). DDFPe (0.3 ml/kg, 2 % emulsion) IV dosing began at 1 h and continued at 90 min intervals for 6 doses in one test group; the other received saline injections. Both got standard IV tPA (0.9 mg/kg) therapy starting 9 h post stroke. At 24 h, neurological assessment scores (NAS, 0-18) were determined. Following brain removal percent stroke volume (%SV) was measured. Outcomes were compared with Kruskal-Wallis analysis. For NAS, DDFPe + tPA was improved overall, p = 0.0015, and vs. tPA alone, p = 0.0052. For %SV, DDFPe + tPA was improved overall, p = 0.0003 and vs. tPA alone, p = 0.0018. NAS controls and tPA alone were not different but %SV was, p = 0.0078. With delayed reperfusion, DDFPe + tPA was more effective than tPA alone in preserving functioning brain after stroke. DDFPe significantly extends the time window for tPA therapy.

• Authors: W C Culp, A T Brown, J D Lowery, M C Arthur, P K Roberson, R D Skinner
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 52 Issue 2 Pg. 979-84 (Oct 2015) ISSN: 1559-1182 [Electronic] United States
• PMID: 26055229 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Emulsions
• Fibrinolytic Agents
• Fluorocarbons
• Neuroprotective Agents
• perfluoropentane
• Tissue Plasminogen Activator

Topics

• Animals
• Cerebral Hemorrhage (chemically induced)
• Disease Models, Animal
• Drug Administration Schedule
• Drug Evaluation, Preclinical
• Emulsions
• Female
• Fibrinolytic Agents (administration & dosage, therapeutic use, toxicity)
• Fluorocarbons (administration & dosage, therapeutic use)
• Infarction, Anterior Cerebral Artery (drug therapy, pathology)
• Infarction, Middle Cerebral Artery (drug therapy, pathology)
• Infusions, Intravenous
• Male
• Neuroprotective Agents (administration & dosage, therapeutic use)
• Rabbits
• Random Allocation
• Reperfusion Injury (prevention & control)
• Single-Blind Method
• Thrombolytic Therapy (adverse effects, methods)
• Time Factors
• Tissue Plasminogen Activator (administration & dosage, therapeutic use, toxicity)