The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin reduces thrombolytic-induced intracerebral hemorrhage in embolized rabbits.
Statins were designed as cholesterol-lowering drugs for the prevention of coronary artery disease. It is estimated that there are currently 33.5 million U.S. patients on chronic statin treatment regimens. Recently, statins have been shown to have pleiotropic including anti-inflammatory and neuroprotective effects. In this study, we assessed the pharmacological effects of simvastatin administered alone and in combination with tissue plasminogen activator (tPA) on measures of ischemia and hemorrhage in large clot embolized New Zealand white rabbits. For these studies, simvastatin (20 mg/kg, SC in DMSO) was administered 24 and 4 h prior to large clot embolization in order to achieve a "loading dose" pretreatment with the drug. In combination studies, tPA (3.3 mg/kg, IV) was administered 1 h following embolization. Intravenous tPA administration significantly increased hemorrhage volume by 175% (p=0.015) and hemorrhage incidence by 60% (p>0.05) compared to control, but did not affect infarct incidence or volume. Simvastatin treatment significantly decreased tPA-induced hemorrhage incidence (p=0.022) and volume (p=0.0001) following embolization. The study suggests that simvastatin treatment blocks or attenuates mechanisms involved in tPA-induced hemorrhage. Based upon our results, patients on simvastatin treatment may have significantly reduced tPA-induced side effects should they require tPA administration following an embolic stroke.
Department of Neuroscience, University of California San Diego, 9500 Gilman Drive MTF316, La Jolla, CA 92093-0624, USA. plapchak@ucsd.edu
Paul A
PA
Lapchak
Moon Ku
MK
Han
D000818:Animals; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D004195:Disease Models, Animal; D004347:Drug Interactions / Q000502:physiology; D004359:Drug Therapy, Combination; D005343:Fibrinolytic Agents / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D020766:Intracranial Embolism / Q000188:drug therapy; D008297:Male; D011300:Preoperative Care / Q000379:methods; D011817:Rabbits; D051381:Rats; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D015912:Thrombolytic Therapy / Q000009:adverse effects; D010959:Tissue Plasminogen Activator / Q000009:adverse effects / Q000037:antagonists & inhibitors
D005343:Fibrinolytic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D010959:Tissue Plasminogen Activator