A novel drug delivery system as prophylaxis for cerebral vasospasm

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Acta Neurochir (2001) [Suppl]77: 213-215 Springer-Verlag 2001

A Novel Drug Delivery System as Prophylaxis for Cerebral Vasospasm Y. Takanashi!, T. Ishida 2 , T. Meguro 3 , M. J. Kirchmeier 2 , T. M. Allen 2 , and J. H. Zhang 3 1 Department

of Neurosurgery, Yokohama City University School of Medicine, Yokohama, Japan of Pharmacology, University of Alberta, Edmonton, Alberta, Canada J Department of Neurosurgery, University of Mississippi Medical Center, Jackson, Mississippi, USA 2 Department

Introduction Experimental work has extensively demonstrated that calcium antagonists can reverse established an­ giographically identified vasospasm when administered by the intrathecal route, despite being ineffective when administered by the peripheral route [3, 5]. However, the effective time in the therapeutic window may be temporary even if bolus application by intrathecal route was feasible. Therefore, externalized ventricular catheter or repeated lumbar puncture is needed to keep a therapeutic drug concentration in the cerebrospinal fluid (CSF), which is troublesome in a clinical setting. We have devised that a sustained-release fonn of a protein kinase inhibitor, Fasudil, can maintain a ther­ apeutic concentration in the CSF within a therapeutic window. The purpose of this study was to devise a nove) drug delivery system which can be directly ap­ plied into the CSF, and then to clarify the preventive effect of liposome-entrapped Fasudil on cerebral vas­ ospasm in a rat modeL KeYlV(Jrds: Cerebral vasospasm; drug delivery systems; fasudil; rat.

Materials and Methods Preparation ofLiposomes

Liposomes were prepared according to the method of Allen [1]. The mean diameter of liposomes which was detennined by dynamic light scattering was in the range of 110 ± 10 nm. Fasudil (Sigma Chemical Co., St. Louis, MO) was loaded into the liposomes at a phospholipid (PL): Fasudil ratio of 1:0.4 (w/w) and

incubated for 1 hour at 6SOC. Spectrophotometry O. = 320 nm) finally detennined the concentration of the liposome-entrapped FasudiL

Releasing Property of Liposome-Entrapped Fasudil in Vitro

The in vitro drug-release kinetics of the liposome­ entrapped Fasudil was measured in control CSF (Sigma Chemical Co., St. Louis, MO) for 7 days. The concentration of the Fasudil in liposomes was deter­ mined by spectrophotometry (A. 320 nm) at the various time points.

Experimental Model of SAH and Study Design

Male Sprague-Dawley rats weighing 350-400 g were used for the experiments. Subarachnoid hemor­ rhage (SAH) in rats was induced by double autologous blood injection via cisterna magna [4]. On day 2 fol­ lowing second blood injection, treated rats (n = 10) received 0.4 mg liposome-entrapped Fasudil via the cisterna magna. Likewise, control rats (n = 10) re­ ceived drug-free liposomes. The drug-free liposomes contained the same amount of PL as the liposome­ entrapped Fasudil. Sham-operated animals (n 3) were used for normal caliber of rat basilar arteries. On day 7 after SAH, the basilar artery was removed for measurement by light microscopy and the concen­ tration of liposome-entrapped Fasudil in the CSF was examined. Finally, the caliber of each sample was expressed as the percentage to the caliber of the nonnal basilar artery.

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Y. Takanashi et al.

Table 1. Caliher Change on Rat Basilar Artery'

Treated group Average diameter ofrat basilar artery (%)*

86.6

± 4.8

Control group 65.9

± 7.21.1

* When normal caliber rat basilar artery obtained from the sham-operated group is expressed as 100%, caliber of each group is shown as mean ± standard deviation (I P < 0.001 vs. treated group, 1 p < 0.001 vs. Sham-operated group).

Results Releasing Property of Liposome-Entrapped Fasudil in Vitro and in Vivo

The release of Fasudil from liposomes in vitro was biphasic. In the first 6 hours at 37°C, approximately 30% of the Fasudil was released from liposomes, and over 7 days, 60% of the contents were gradually re­ leased (n = 3). By contrast, most of the Fasudil in vivo was released from liposomes on day 7 after SAH. Mean CSF concentrations of liposome-entrapped Fasudil in rats were 980 ngjml (n = 7) on day 7. Evaluation of Vasoconstriction on Basilar Artery

Treatment with 0.4 mg liposome-entrapped Fasudil significantly prevented constriction of rat basilar artery (86.6 ± 4.8%) compared to the control group (65.9 ± 7.2%) (Table I).

Discussion We studied in the present experiments that a single intrathecal administration of liposome-entrapped Fasudil significantly ameliorated the vasoconstriction in rat basilar artery and no obvious adverse effect was noted in rat SAH model. The advantage of using liposomes comes from a sustained release of therapeutically relevant concen­ trations of the drug over a therapeutic window. A sus­ tained-release preparation of Fasudil, small enough to be administered in the CSF, could continuously deliver drug into the CSF. The relatively slow release of drug from liposomes mimicks some aspects of drug infu­ sion, including a significant decrease in the toxicity of the free drug. Thus, the therapeutic index of Fasudil was increased by virtue of both an increase efficacy and a decrease in systemic toxicity.

Calcium antagonists by intrathecal route for the treatment of cerebral vasospasm could avoid the potential systemic adverse effect such as hypotension. Therefore, it has been reported that intrathecal route of calcium antagonists has been evaluated for the pre­ vention of cerebral vasospasm [3, 5]. However, the effective therapeutic concentration by intrathecal bolus application may be short, so that externalized ventricular catheter or repeated lumbar puncture must be applied to keep a therapeutic drug concentration in the CSF. These frequent or continuous intrathecal administrations are impractical, especially in a clinical setting. Therefore, a single injection of liposome­ entrapped Fasudil which can be safely delivered in the CSF might be a novel approach for the treatment of cerebral vasospasm following SAH. Many works have confirmed that interaction with blood components and the mononuclear phagocyte system affect the clearance and elimination of lip­ osomes in case of intravenous application [2]. As CSF contains a small amount of blood in case of SAH, it is conceivable that the discrepancy in the releasing rate between in vitro and in vivo might be responsible for blood components in the CSF. However, as little is known about the clearance and elimination of lipo­ somes in the CSF, further studies will be needed to elucidate the optimal drug release rate as well as phar­ macokinetics ofliposomal drugs in the CSF.

Conclusion Treatment with liposome-entrapped Fasudil by a single intrathecal injection has a considerable vaso­ dilating effect. The liposomal drug functioned as a sustained drug release system resulting in free drug concentration within the therapeutic range. The promising results obtained from the current study rep­ resent a major breakthrough in the treatment of cere­ bral vasospasm following SAH.

References 1. Allen TM, Hansen C (1991) Pharmacokinetics of stealth versus

conventional liposomes: effect of dose. Biochim Biophys Acta 1068: 133-141 2. Devine D. Marjan J (1997) The role of immunoproteins in the survival of liposomes in the circulation. Crit Rev Ther Drug Carrier Syst 14: 105-131 3. Gioia A, White R, Bakhtian B, Robertson J (1985) Evaluation of the efficacy of intrathecal nimodipine in canine models of chronic cerebral vasospasm. J Neurosurg 62: 721-728

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A Novel Drug Delivery System as Prophylaxis for Cerebral Vasospasm 4. Suzuki H, Kanamaru K, Tsunoda H, Inada H, Kuroki M, Sun H, Waga S. Tanaka T (1999) Heme oxygenase-l induction as an intrinsic regulation against delayed cerebral vasospasm in rats. I Clin Invest 104: 59-66 5. Voldby B, Petersen 0, Buhl M, Jakobsen p, 0stergaard R (1984) Reversal of cerebral arterial spasm by intrathecal administration

of a calcium antagonist (nimodipine). An experimental study. Acta Neurochir (Wien) 70: 243-254 Correspondence: Yoshihiro Takanashi, M,D., Ph.D., Department of Neurosurgery, Yokohama City University, School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Japan, 236-0004.

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