Development of nicardipine
prolonged-release implants after clipping for preventing cerebral
vasospasm: From laboratory to clinical trial
Currently, there are no drugs supported by sufficient evidence
of efficacy for cerebral vasospasm in patients with subarachnoid
hemorrhage, despite abundant evidence of anti-vasospasm drugs
at an experimental level. We have developed a drug-delivery
system using a vasodilating drug that can be implanted intracranially
at the time of surgery for aneurysm clipping, without systemic
side effects or side effects associated with long-term intrathecal
drug administration through indwelling catheters.
We started our project on 1994 for making slowly-releasing
drug-delivery system in vitro, because cerebral vasospasm
occurs 4-14 days following subarachnoid hemorrhage. A rod-shaped
pellet (1 mm in diameter, 10 mm in length, containing 1 mg
of nicardipine) for animal study was prepared by heat compression.
Release curve from the pellets was adjusted similar to the
time course of cerebral vasospasm by changing the combination
of molecular weight and lactic acid ratio of Copoly(lactic/glycolic
acid) and nicardipine. We presented the efficacy and safety
of this drug delivery system using both canine double hemorrhage
and clot placement model. The mean concentration of nicardipine
in the clots was 1.5x10-4 mol/L on Day 7 and 5.1x10-6 on Day
14. This drug delivery system can prevent vasospasm significantly
in dogs, while maintaining an appropriate concentration of
nicardipine in the clot adjacent to the arteries, since maximal
relaxation is achieved by 10-6 mol/L of nicardipine.
Since October 1999, nicardipine pellets (NPs) (2 mm in diameter,
10 mm in length, containing 4 mg of nicardipine) have been
used to prevent vasospasm in patients with SAH. The study
was approved by the University Ethical Committee, and informed
consent was obtained. A frontotemporal craniotomy and a midline
frontal craniotomy (pterional and anterior interhemispheric
approach) were performed for aneurysms in the internal carotid
artery (ICA), middle cerebral artery (MCA), basilar artery,
anterior communicating artery, and distal anterior cerebral
artery (ACA). NPs were placed in the cistern of the ICA, the
MCA, and/or the ACA, where thick clots existed, and, therefore,
vasospasm related to delayed ischemic neurological deficits
(DIND) was highly probable. The number of pellets and the
location of the placement depended on the amount and site
of the subarachnoid clot in the preoperative CT scans, the
operative field, and the craniotomy. Cerebral vasospasm was
assessed by DIND, and angiography was performed in all patients
on Days 7 to 12. We published a preliminary report on the
efficacy and safety of NPs to prevent vasospasm in 20 SAH
patients. Vasospasm was completely prevented in the arteries
in cisterns with thick clots, where vasospasm was highly expected,
by placing NPs adjacent to the arteries during surgery. In
the first 100 patients treated with NPs, the ratio of DIND,
severe angiographical vasospasm and cerebral infarctions were
7%, 11%, and 5%, respectively. No complications were experienced.
Thirty-two patients with severe SAH and undergoing aneurysm
clipping were included into the single center, randomized,
double-blind trial in Germany. The incidence of angiographic
vasospasm in proximal vessel segments was significantly reduced
after implantation of NPs (73% control versus 7% NPs). Significant
differences occurred also for the majority of distal vessel
segments. Computed tomography scans revealed a lower incidence
of delayed ischemic lesions (47% control versus 14% NPs).
The NPs group demonstrated more favorable modified Rankin
and National Institute of Health Stroke scales as well as
a significantly lower incidence of deaths (38% control versus
6% NPs).
We found that vasospasm is completely prevented in arteries
in cisterns with thick clots, where vasospasm is highly expected,
by placing NPs adjacent to the arteries during surgery. Less
efficacy was found for arteries remote from the placement
of pellets. Implantation of NPs improves clinical outcome
of SAH patients. We consider that this could not be achieved
by developing new drugs but by developing methods to maintain
an appropriate concentration of the drug in the target cerebral
artery and its surrounding environment.
Hidetoshi Kasuya
Tokyo Women's Medical University
Tokyo, Japan
|
| 
| | Dr.
Kasuya is head of the neurosurgery department at Medical Center
East of the Tokyo Women’s Medical University in Tokyo,
Japan. He finished his medical education at Tokushima University
School of Medicine, Tokushima, Japan in 1982. He had neurosurgical
training as a resident at the Department of Neurosurgery,
Tokyo Women’s Medical University, Tokyo, Japan between
1982 and 1987 and received his Board Certification of the
Japan Neurosurgical Society in 1987. He studied the pathogenesis
of cerebral vasospasm following subarachnoid hemorrhage (SAH)
as a research fellow at the Department of Surgery, University
of Alberta, Edmonton, Canada and Department of Neurosurgery,
University of Chicago, USA under the supervision of Prof.
Dr. Bryce Weir between 1990 and 1993.
He started his research in the field of drug-delivery systems
in 1994 and developed a system using a vasodilating drug that
can be implanted intracranially at the time of surgery for
aneurysm clipping in patients with SAH. Vasospasm was completely
prevented in the arteries in cisterns with thick clots, where
it was highly expected (Neurosurgery 42:109-116, 1998, Neurol
Res 22: 634-641, 2000). Since October 1999, he has treated
more than 300 SAH patients with nicardipine prolonged-release
implants (NPRIs) in Japan (Stroke 33: 1011-1015, 2002, Neurosurgery
56: 895-905, 2005, Neurol Med Chir (Tokyo) 47: 389-396, 2007).
No complications were reported. A double-blinded randomized
trial was successfully carried out by Professor Peter Vajkoczy
in Mannheim, Germany (Stroke 38:330-336, 2007, J Neurosurg
110:955-960, 2009). His dream is to manufacture this drug-delivery
system and to save SAH patients from vasospasm related disabling
states .
He became Professor and Head of Department of Neurosurgery,
Medical Center East, Tokyo Women’s Medical University
in 2007.
He has more than 128 peer-reviewed research and clinical articles.
Scientific and professional activities include membership
of the editorial board of Stroke and Translational Stroke
Research. He is also interested in research of intracranial
aneurysm genetics, clinical and pathological characteristics
of meningioma and the pathology of trigeminal neuralgia.
|
|
