Efficacy of intrathecal liposomal fasudil for experimental cerebral vasospasm after subarachnoid hemorrhage.
OBJECTIVE
To investigate the safety and efficacy of liposomal fasudil in a sustained-release form for the prevention of cerebral vasospasm after subarachnoid hemorrhage (SAH).


METHODS
Eighteen rats were divided into three groups, each of which received 2.5 mg/kg of liposomal fasudil, 5 mg/kg of liposomal fasudil, or drug-free liposomes after SAH. Next, experimental SAH was induced in 15 dogs by injection of autologous arterial blood into the cisterna magna twice after baseline vertebral angiography. In six dogs, 0.94 mg/kg of liposomal fasudil was injected into the cisterna magna (treatment group). In four dogs, drug-free liposomes were similarly injected (placebo group), and the remaining five dogs were not treated with liposomal injection after SAH (control group). Angiography was repeated on Day 7, and cerebrospinal fluid was collected before the dogs were killed.


RESULTS
A high dose of liposomal fasudil caused no significant changes in mean arterial blood pressure and did not induce seizures during the observation period. Gross and microscopic examination of the brains revealed no abnormalities, but severe vasospasm was noted in the rat basilar artery, mainly in the group treated with drug-free liposomes. Likewise, in the canine placebo and control groups, significant vasospasm occurred in the basilar artery on Day 7. In the treatment group, vasospasm in the basilar artery was significantly ameliorated (P < 0.01). In vivo, 90% of fasudil was released from liposomes in the cerebrospinal fluid.


CONCLUSIONS
A single injection of intrathecal liposomal fasudil is safe and effective for the prevention of vasospasm in experimental SAH.
Takanashi
Y
Y
Department of Neurosurgery, Yokohama City University School of Medicine, Yokohama, Japan. ytaka@med.yokohama-cu.ac.jp
Ishida
T
T
Meguro
T
T
Kiwada
H
H
Zhang
J H
JH
Yamamoto
I
I
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000473:pathology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D008081:Liposomes; D051381:Rats; D013345:Subarachnoid Hemorrhage / Q000473:pathology*; D016896:Treatment Outcome; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*; D020301:Vasospasm, Intracranial / Q000473:pathology*
D008081:Liposomes; D014665:Vasodilator Agents; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C049347:fasudil