Lysis of intracerebral hematoma with stereotactically implanted tissue plasminogen activator polymers in a rabbit model.
OBJECTIVE
Currently no adequate surgical treatment exists for spontaneous intracerebral hemorrhage (ICH). Implantable polymers can be used effectively to deliver therapeutic agents to the local site of the pathological process, thus reducing adverse systemic effects. The authors report the use of stereotactically implanted polymers loaded with tissue plasminogen activator (tPA) to induce lysis of ICH in a rabbit model.


METHODS
Ethylene vinyl acetate (EVAc) polymers were loaded with bovine serum albumin (BSA) only or with BSA plus tPA. In vitro pharmacokinetic (three polymers) and thrombolysis (12 polymers) studies were performed. For the in vivo study, 12 rabbits were fixed in a stereotactic frame, and 0.2 ml of clotted autologous blood was injected into the right frontal lobe parenchyma. After 20 minutes, control BSA polymers were stereotactically implanted at the hemorrhage site in six rabbits, and experimental BSA plus tPA polymers were implanted in six rabbits. Animals were killed at 3 days, and blood clot volume was assessed. The pharmacokinetic study showed release of 146 ng of tPA over 3 days. The tPA activity correlated with in vitro thrombolysis. In the in vivo study, the six animals treated with tPA polymers had a mean (+/- standard error of the mean [SEM]) thrombus volume of 1.43 +/- 0.29 mm3 at 3 days, whereas the six animals treated with blank (BSA-only) polymers had a mean (+/- SEM) thrombus volume of 19.99 +/- 3.74 mm3 (p < 0.001).


CONCLUSIONS
Ethylene vinyl acetate polymers release tPA over the course of 3 days. Stereotactic implantation of tPA-loaded EVAc polymers significantly reduced ICH volume. Polymers loaded with tPA may be useful clinically for lysis of ICH without the side effects of systemic administration of tPA.
Thai
Quoc-Anh
QA
Division of Cerebrovascular Neurosurgery, Department of Neurosurgery, School of Medicine, The Johns Hopkins University, Baltimore, Maryland 21287, USA.
Pradilla
Gustavo
G
Legnani
Federico G
FG
Kretzer
Ryan M
RM
Hsu
Wesley
W
Tamargo
Rafael J
RJ
D000818:Animals; D003692:Delayed-Action Preparations; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006406:Hematoma / Q000188:drug therapy*; D020300:Intracranial Hemorrhages / Q000188:drug therapy*; D014677:Pharmaceutical Vehicles; D011145:Polyvinyls; D011817:Rabbits; D012710:Serum Albumin, Bovine; D013238:Stereotaxic Techniques; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000493:pharmacokinetics
D003692:Delayed-Action Preparations; D005343:Fibrinolytic Agents; D014677:Pharmaceutical Vehicles; D011145:Polyvinyls; C016438:ethylenevinylacetate copolymer; D012710:Serum Albumin, Bovine; D010959:Tissue Plasminogen Activator