Posttreatment with adenovirus-mediated gene transfer of calcitonin gene—related peptide to reverse cerebral vasospasm in dogs

2002 ◽  
Vol 97 (1) ◽  
pp. 136-142 ◽  
Author(s):  
Motoyoshi Satoh ◽  
Eddie Perkins ◽  
Hitoshi Kimura ◽  
Jiping Tang ◽  
Yi Chun ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Cerebral Vasospasm ◽  
Treated Group ◽  
Positive Staining ◽  
Cmv Promoter ◽  
Content Type ◽  
Related Peptide ◽  
Arterial Blood ◽  
Blood Injection ◽  
Fine Print

Object. Gene transfer to cerebral vessels is a promising new therapeutic approach for cerebral vasospasm after subarachnoid hemorrhage (SAH). This study was undertaken to explore whether a delayed treatment with adenovirus encoding the prepro-calcitonin gene—related peptide (CGRP), 2 days after initial blood injection, reduces cerebral vasospasm in a double-hemorrhage model of severe vasospasm in dogs. Methods. In 20 dogs, arterial blood was injected into the cisterna magna on Days 0 and 2. Thirty minutes after the second blood injection, the animals received either adenovirus encoding the prepro-CGRP gene (AdCMVCGRP—treated group, eight dogs) or adenovirus encoding the β-galactosidase gene (AdCMVβgal—treated group, six dogs) under the cytomegalovirus (CMV) promoter. One group of dogs did not receive treatment and served as controls (control SAH group, six dogs). Angiography was performed on Days 0 and 7 to assess cerebral vasospasm. On Day 7 following angiography, the animals were killed and their brains were stained with X-gal to detect the distribution of gene expression. Cerebrospinal fluid (CSF) was also tested for CGRP immunoreactivity. Severe vasospasm was observed in control SAH dogs on Day 7, and the mean basilar artery (BA) diameter was 53.4 ± 5.5% of the value measured on Day 0. Treatment with AdCMVβgal did not alter vasospasm (the BA diameter was 55 ± 3.9% of that measured on Day 0). The leptomeninges and adventitia of the BAs of dogs treated using AdCMVβgal demonstrated positive staining with X-gal. High levels of CGRP were measured in CSF from dogs that received AdCMVCGRP. In the group treated with AdCMVCGRP, vasospasm was significantly reduced (the BA diameter was 78.2 ± 5.3% of that measured on Day 0, p < 0.05 compared with the control SAH group and the AdCMVβgal group). Conclusions. In a model of severe vasospasm in dogs, gene transfer of CGRP after injection of blood attenuated cerebral vasospasm after SAH.

Prostaglandin metabolism in experimental cerebral vasospasm

1981 ◽  
Vol 55 (5) ◽  
pp. 779-785 ◽  
Author(s):  
Yukio Maeda ◽  
Eiichi Tani ◽  
Tsumoru Miyamoto
Keyword(s):  
Platelet Aggregation ◽  
Cerebral Vasospasm ◽  
Basilar Artery ◽  
Content Type ◽  
Arterial Blood ◽  
Intracisternal Injection ◽  
Blood Injection ◽  
Canine Basilar Artery ◽  
Layer Chromatography ◽  
Fine Print

✓ Experimental cerebral vasospasm was produced in the canine basilar artery by an intracisternal injection of fresh autogenous arterial blood, and prostaglandins generated in spastic and nonspastic arteries were assessed by thin-layer chromatography. Prostaglandins synthesized in normal arteries were 6-keto-prostaglandin (PG)F1α, PGF2α, PGE2, and PGD2; 6-keto-PGF1α was the most abundant prostaglandin. The study of platelet aggregation suggested that prostacyclin (PGI2)-like activity was manufactured by the normal basilar artery. At 5 minutes after the intracisternal blood injection, no significant changes were evident in syntheses of prostaglandins generated by spastic artery. However, PGE2 synthesis was significantly increased in spastic artery 2 days after the intracisternal blood injection, and 6-keto-PGF1α and PGF2α synthesis and PGE2 synthesis were significantly decreased and increased, respectively, in spastic artery 6 days after the intracisternal blood injection. No significant changes were found in syntheses of 6-keto-PGF1α, PGF2α, and PGE2 manufactured by nonspastic arteries at any stage. Formation of thromboxane B2 was not detected in normal, spastic, or nonspastic arteries.

Prevention of cerebral vasospasm after SAH with a thromboxane synthetase inhibitor, OKY-1581

1982 ◽  
Vol 57 (1) ◽  
pp. 74-82 ◽  
Author(s):  
Tomio Sasaki ◽  
Susumu Wakai ◽  
Takao Asano ◽  
Kintomo Takakura ◽  
Keiji Sano
Keyword(s):  
Cerebral Vasospasm ◽  
Morphological Changes ◽  
Content Type ◽  
Synthetase Inhibitor ◽  
Thromboxane Synthetase Inhibitor ◽  
Thromboxane Synthetase ◽  
Basilar Arteries ◽  
Blood Injection ◽  
Subarachnoid Blood ◽  
Fine Print

✓ The efficacy of thromboxane synthetase inhibitor in the prevention of cerebral vasospasm after subarachnoid hemorrhage (SAH) was evaluated in a prolonged experiment using dogs. Changes in the diameter of the basilar artery were followed by angiography, and morphological changes were studied by photomicroscopy and electron microscopy. As a thromboxane synthetase inhibitor, OKY-1581 (sodium-(E)-3-(4(-3-pyridylmethyl)phenyl)-2-methylacrylate)was used. Dogs received intravenous injections of 160 mg of OKY-1581 dissolved in 2 ml of physiological saline immediately after subarachnoid blood injection. Subsequently, the animals received continuous intravenous infusion of the drug at the rate of 4 gm/50 ml/24 hours until sacrifice 4 days after induction of SAH. Control dogs received subarachnoid blood injection without treatment with OKY-1581. Angiographic examination revealed that the late spasm was almost completely abolished by the treatment with OKY-1581. Early spasm was also prevented, but the drug's effect was less prominent than it was on the late spasm. Morphological study revealed degenerative changes in the endothelium and myonecrotic changes in the tunica media following SAH in the basilar arteries of the treated as well as the untreated dogs. However, corrugation of the internal elastic lamina was almost completely absent in the treated dogs. The above results indicate that a disproportionate synthesis of thromboxane A2 plays an important role in the evolution of chronic cerebral vasospasm following SAH, and that drugs such as OKY-1581 that selectively inhibit thromboxane synthetase might be useful in the prevention of vasospasm.

Subarachnoid hemorrhage—induced upregulation of the 5-HT1B receptor in cerebral arteries in rats

2003 ◽  
Vol 99 (1) ◽  
pp. 115-120 ◽  
Author(s):  
Jacob Hansen-Schwartz ◽  
Natalie Løvland Hoel ◽  
Cang-Bao Xu ◽  
Niels-Aage Svendgaard ◽  
Lars Edvinsson
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Real Time ◽  
Cerebral Vasospasm ◽  
Cerebral Arteries ◽  
Specific Treatment ◽  
Content Type ◽  
Sequence Of Events ◽  
Arterial Blood ◽  
Receptor Phenotype ◽  
Fine Print

Object. Cerebral vasospasm following subarachnoid hemorrhage (SAH) leads to reduced blood flow in the brain. Inspired by organ culture—induced changes in the receptor phenotype of cerebral arteries, the authors investigated possible changes in the 5-hydroxytryptamine (HT) receptor phenotype after experimental SAH. Methods. Experimental SAH was induced in rats by using an autologous prechiasmatic injection of arterial blood. Two days later, the middle cerebral artery (MCA), posterior communicating artery (PCoA), and basilar artery (BA) were harvested and examined functionally with the aid of a sensitive in vitro pharmacological method and molecularly by performing quantitative real-time reverse transcription—polymerase chain reaction (PCR). In the MCA and BA the 5-HT1B receptor was upregulated, as determined through both functional and molecular analysis. In response to selective 5-HT1 receptor agonists both the negative logarithm of the 50% effective concentration was increased (one log unit in the MCA and one half unit in the BA), as was the agonist's potency (increased by 50% in the MCA and doubled in the BA). In addition, the authors found an approximately fourfold increase in the number of copies of messenger RNA coding for the 5-HT1B receptor as determined by quantitative real-time PCR. In the PCoA no upregulation of the 5-HT1B receptor was observed. Conclusions. Changes in the receptor phenotype in favor of contractile receptors may well represent the end stage in a sequence of events leading from SAH to the actual development of cerebral vasospasm. Insight into the mechanism of upregulation may provide new targets for developing specific treatment against cerebral vasospasm.

Relative importance of hypertension compared with hypervolemia for increasing cerebral oxygenation in patients with cerebral vasospasm after subarachnoid hemorrhage

2005 ◽  
Vol 103 (6) ◽  
pp. 974-981 ◽  
Author(s):  
Andreas Raabe ◽  
Jügen Beck ◽  
Mike Keller ◽  
Hartmuth Vatter ◽  
Michael Zimmermann ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Brain Tissue ◽  
Cerebral Vasospasm ◽  
Moderate Hypertension ◽  
Cerebral Oxygenation ◽  
Brain Oxygenation ◽  
Content Type ◽  
Arterial Blood ◽  
Hypertension Therapy ◽  
Fine Print

Object. Hypervolemia and hypertension therapy is routinely used for prophylaxis and treatment of symptomatic cerebral vasospasm at many institutions. Nevertheless, there is an ongoing debate about the preferred modality (hypervolemia, hypertension, or both), the degree of therapy (moderate or aggressive), and the risk or benefit of hypervolemia, moderate hypertension, and aggressive hypertension in patients following subarachnoid hemorrhage. Methods. Monitoring data and patient charts for 45 patients were retrospectively searched to identify periods of hypervolemia, moderate hypertension, or aggressive hypertension. Measurements of central venous pressure, fluid input, urine output, arterial blood pressure, intracranial pressure, and oxygen partial pressure (PO2) in the brain tissue were extracted from periods ranging from 1 hour to 24 hours. For these periods, the change in brain tissue PO2 and the incidence of complications were analyzed. During the 55 periods of moderate hypertension, an increase in brain tissue PO2 was found in 50 cases (90%), with complications occurring in three patients (8%). During the 25 periods of hypervolemia, an increase in brain oxygenation was found during three intervals (12%), with complications occurring in nine patients (53%). During the 10 periods of aggressive hypervolemic hypertension, an increase in brain oxygenation was found during six of the intervals (60%), with complications in five patients (50%). Conclusions. When hypervolemia treatment is applied as in this study, it may be associated with increased risks. Note, however, that further studies are needed to determine the role of this therapeutic modality in the care of patients with cerebral vasospasm. In poor-grade patients, moderate hypertension (cerebral perfusion pressure 80–120 mm Hg) in a normovolemic, hemodiluted patient is an effective method of improving cerebral oxygenation and is associated with a lower complication rate compared with hypervolemia or aggressive hypertension therapy.

Comparative effectiveness of alpha-blockade and beta-stimulation in modifying experimental basilar arterial spasm

1974 ◽  
Vol 41 (3) ◽  
pp. 300-305 ◽  
Author(s):  
Mitchell R. Smigiel ◽  
Thoralf M. Sundt
Keyword(s):  
Cerebral Vasospasm ◽  
Topical Application ◽  
Comparative Effectiveness ◽  
Arterial Spasm ◽  
Content Type ◽  
Arterial Blood ◽  
Alpha Blockade ◽  
Initial Peak ◽  
Fine Print

✓The comparative effectiveness of isoproterenol (Isuprel), phentolamine (Regitine), and phenoxybenzamine (Dibenzyline) in modifying basilar arterial spasm induced by the topical application of arterial blood was studied in cats. None of these agents was effective in inhibiting initial peak constriction. Each reduced the duration of the vasospasm. The results indicate that both alpha-blockade and beta-stimulation can alter the course of blood-induced cerebral vasospasm.

Effects of subarachnoid hemorrhage on vascular responses to calcitonin gene—related peptide and its related second messengers

1995 ◽  
Vol 83 (3) ◽  
pp. 516-521 ◽  
Author(s):  
Bernhard Sutter ◽  
Satoshi Suzuki ◽  
Adam S. Arthur ◽  
Neal F. Kassell ◽  
Kevin S. Lee
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Second Messengers ◽  
Second Messenger ◽  
Relaxant Effect ◽  
Content Type ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Second Messenger Systems ◽  
Fine Print

✓ Calcitonin gene—related peptide (CGRP) is a potent vasodilator and a primary signaling molecule in neurovascular communication. In the present study, the authors examined cerebrovascular responses to CGRP and its related second messenger systems during cerebral vasospasm induced by subarachnoid hemorrhage (SAH). Tension measurements were performed in vitro on ring strips of basilar arteries obtained from rabbits subjected to artificial SAH and from control (non-SAH) animals. In vessels from SAH animals, which were preconstricted with serotonin, the vasorelaxant response to CGRP was attenuated. Because it has been suggested that vasodilation elicited by CGRP is mediated by cyclic 3′,5′-adenosine monophosphate (cAMP) and/or cyclic 3′,5′-guanosine monophosphate (cGMP), the vascular effects of directly activating these second messenger systems were also examined. The relaxant effect of forskolin, which activates adenylate cyclase directly, was slightly enhanced after SAH. In contrast, the relaxant effect of nitroglycerin (GTN), which activates soluble guanylate cyclase directly, was unchanged after SAH. The attenuation of CGRP-induced vasorelaxation could be the result of a modification in its ability to stimulate the production of second messengers. Experiments testing the capacity of CGRP to elevate cAMP levels showed no significant differences between vessels from non-SAH and SAH animals. Similarly, the resting levels of cAMP and the forskolin-induced elevations of cAMP did not differ between non-SAH and SAH animals. In contrast, cGMP levels were lower in resting and CGRP-treated vessels from SAH animals than in those from non-SAH animals. No significant differences in the levels of cGMP were observed between non-SAH and SAH vessels treated with GTN. This study indicates that CGRP-induced vasodilation is attenuated during vasospasm in a rabbit model of SAH. The findings also demonstrate that vasodilatory responses mediated by cAMP and cGMP are intact, although the levels of cGMP in SAH vessels are reduced. Together, these observations suggest that an attenuation in the capacity of vessels to dilate in response to CGRP occurs during cerebral vasospasm, and this change in CGRP vasoactivity is a result of modifications prior to, or independent of, the elevation of cyclic nucleotide second messengers.

Suramin-induced reversal of chronic cerebral vasospasm in experimental subarachnoid hemorrhage

2002 ◽  
Vol 97 (1) ◽  
pp. 129-135 ◽  
Author(s):  
Hitoshi Kimura ◽  
Toshinari Meguro ◽  
Ahmed Badr ◽  
John H. Zhang
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Tyrosine Kinase ◽  
Cerebral Vasospasm ◽  
Disulfonic Acid ◽  
Control Group ◽  
Content Type ◽  
Basilar Arteries ◽  
Blood Injection ◽  
The Mean ◽  
Fine Print

Object. The naphthylsulfonate derivative suramin is an inhibitor of growth factor receptors (receptor tyrosine kinases) and G protein—coupled P2Y receptors. Both types of these receptors are suspected of being involved in cerebral vasospasm after subarachnoid hemorrhage (SAH). In the current study, the authors examined the therapeutic effects of suramin and a selective P2X-receptor antagonist, pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS), in the reversal of vasospasm in an established canine double-hemorrhage model. Methods. Twenty-four dogs underwent double blood injection into the cisterna magna, with injections given on Days 0 and 2. The dogs were divided randomly into three groups (six animals in each group) to be treated from Days 2 through 6 with the vehicle dimethyl sulfoxide, suramin, or PPADS. An additional group of six dogs received double blood injection without any treatment and served as an SAH control group. The animals were killed on Day 7. Angiography was performed on Day 0 before blood injection and again on Day 7 before the animals were killed. After the death of the animals, the basilar arteries (BAs) were collected for morphological studies and determination of tyrosine kinase expression, and the bloody cerebrospinal fluid (CSF) produced by the hemorrhages was collected for measurement of oxyhemoglobin and adenosine triphosphate (ATP). In the SAH control group, the mean diameter of the BAs on Day 7 was 46.23 ± 6.32% of the value on Day 0 (which served as a reference of 100%). In the DMSO-treated group, the mean residual diameter of the BA was 47.77 ± 0.8% on Day 7 compared with the value on Day 0. Suramin, but not PPADS, increased the residual diameter to 74.02 ± 4.24% on Day 7. On Day 7 the level of ATP in the CSF was decreased and the level of oxyhemoglobin was increased, compared with values measured on Day 0. Suramin, but not PPADS, reduced tyrosine phosphorylation in the spastic BAs. Conclusions. By reducing tyrosine kinase activity, suramin may be useful in the treatment of cerebral vasospasm.

Temporal changes in perivascular concentrations of oxyhemoglobin, deoxyhemoglobin, and methemoglobin after subarachnoid hemorrhage

1998 ◽  
Vol 88 (3) ◽  
pp. 557-561 ◽  
Author(s):  
Ryszard M. Pluta ◽  
John K. B. Afshar ◽  
Robert J. Boock ◽  
Edward H. Oldfield
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Blood Clot ◽  
Saline Control ◽  
Control Group ◽  
Content Type ◽  
Delayed Cerebral Vasospasm ◽  
Arterial Blood ◽  
Fine Print

Hemoglobin released from hemolysed erythrocytes has been postulated to be responsible for delayed cerebral vasospasm after subarachnoid hemorrhage (SAH). However, the evidence is indirect and the mechanisms of action are unclear. Cerebrovascular tone is regulated by a dynamic balance of relaxing and contracting factors. Loss of the endothelium-derived relaxing factor—nitric oxide in the presence of oxyhemoglobin and overproduction of endothelin-1 stimulated by oxyhemoglobin have been postulated as causes of delayed cerebral vasospasm after SAH. Object. The authors aimed to investigate this hypothesis using in vivo microdialysis to examine time-dependent changes in the perivascular concentrations of oxyhemoglobin, deoxyhemoglobin, and methemoglobin in a primate model of SAH. Methods. Nine cynomolgus monkeys underwent right-sided frontotemporal craniectomy and placement of a semipermeable microdialysis catheter adjacent to the right middle cerebral artery (MCA). Saline (control group, three animals) or an arterial blood clot (SAH group, six animals) was then placed around the MCA and the catheter. Arteriographically confirmed vasospasm had developed in all animals with SAH but in none of the control animals on Day 7. The dialysate was collected daily for 12 days. Levels of oxyhemoglobin, deoxyhemoglobin, and methemoglobin were measured by means of spectrophotometry. Perivascular concentrations of oxyhemoglobin, deoxyhemoglobin, and methemoglobin peaked on Day 2 in the control monkeys and could not be detected on Days 5 to 12. Perivascular concentrations of oxyhemoglobin and deoxyhemoglobin peaked on Day 7 in the SAH group, at which time the concentrations in the dialysate were 100-fold higher than in any sample obtained from the control animals. Methemoglobin levels increased only slightly, peaking between Days 7 and 12, at which time the concentration in the dialysate was 10-fold higher than in samples from the control animals. Conclusions. This study provides in vivo evidence that the concentrations of oxyhemoglobin and deoxyhemoglobin increase in the cerebral subarachnoid perivascular space during the development of delayed cerebral vasospasm. The results support the hypothesis that oxyhemoglobin is involved in the pathogenesis of delayed cerebral vasospasm after SAH and implicate deoxyhemoglobin as a possible vasospastic agent.

Magnesium and experimental vasospasm

2004 ◽  
Vol 100 (1) ◽  
pp. 106-110 ◽  
Author(s):  
R. Loch Macdonald ◽  
Daniel J. Curry ◽  
Yasuo Aihara ◽  
Zhen-Du Zhang ◽  
Babak S. Jahromi ◽  
...  
Keyword(s):  
Magnesium Sulfate ◽  
Cerebral Vasospasm ◽  
Standard Dose ◽  
Cerebral Arteries ◽  
Elevated Serum ◽  
Treated Group ◽  
Dose Finding ◽  
Content Type ◽  
Small Vessels ◽  
Fine Print

Object. Interest has developed in the use of magnesium (Mg++) as a neuroprotectant and antivasospastic agent. Magnesium may increase cerebral blood flow (CBF) and reduce the contraction of cerebral arteries caused by various stimuli. In this study the authors tested the hypothesis that a continuous intravenous infusion of Mg++ reduces cerebral vasospasm after experimental subarachnoid hemorrhage (SAH). Methods. A dose-finding study was conducted in five monkeys (Macaca fascicularis) to determine what doses of intravenous MgSO4 elevate the cerebrospinal fluid (CSF) concentrations of Mg++ to vasoactive levels and to determine what effects these doses have on the diameters of cerebral arteries, as shown angiographically. After a standard dose of MgSO4 had been selected it was then administered in a randomized, controlled, blinded study to 10 monkeys (five animals/group) with SAH, beginning on Day 0 and continuing for 7 days, at which time angiography was repeated. A 0.086-g/kg bolus of MgSO4 followed by an infusion of 0.028 g/kg/day MgSO4 significantly elevated serum and CSF levels of Mg++ (five monkeys). Magnesium sulfate significantly elevated the serum level of total Mg++ from a control value of 0.83 ± 0.04 mmol/L to 2.42 ± 1.01 mmol/L on Day 7 and raised the CSF level from 1.3 ± 0.04 mmol/L to 1.76 ± 0.14 mmol/L. There was no angiographic evidence of any effect of MgSO4 on normal cerebral arteries. After SAH, the vasospasm in the middle cerebral artery was not significantly reduced (46 ± 8% in the MgSO4-treated group compared with 35 ± 6% in the placebo [vehicle]-treated group, p > 0.05, unpaired t-test). Conclusions. Magnesium sulfate did not significantly reduce cerebral vasospasm after SAH in the doses tested. An investigation of SAH is warranted mainly to test whether a benefit can be achieved by neuroprotection or by augmentation of CBF by dilation of small vessels and/or collateral pathways.

Effects of MAPK inhibitors on cerebral vasospasm in a dog double hemorrhage model

2000 ◽  
Vol 93 (6) ◽  
pp. 1041-1047 ◽  
Author(s):  
Robert Tibbs ◽  
Alexander Zubkov ◽  
Kazuya Aoki ◽  
Toshinari Meguro ◽  
Ahmed Badr ◽  
...  
Keyword(s):  
Cerebral Vasospasm ◽  
Autologous Blood ◽  
Treated Group ◽  
Mitogen Activated Protein Kinase ◽  
Potential Candidate ◽  
Content Type ◽  
Mitogen Activated Protein ◽  
Mapk Inhibitors ◽  
Fine Print

Object. Mitogen-activated protein kinase (MAPK) may be involved in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage. This study was conducted to investigate the ability of the MAPK inhibitors PD98059 and U-0126 to reverse vasospasm in a double-hemorrhage model in dogs.Methods. Twenty-two adult mongrel dogs of either sex, each weighing 18 to 24 kg, were divided randomly into four groups: control SAH (four dogs), vehicle- (dimethyl sulfoxide, six dogs), PD-98059— (six dogs), and U-0126—treated groups (six dogs). The double-hemorrhage model was created by an autologous blood injection into the cisterna magna on Days 0 and 2. An intracisternal injection of MAPK inhibitors was administered once per day on Days 3 through 6. Cerebral angiography was performed on Days 0 and 7 before the animals were killed. Western blot analysis was used to study the effects of hemorrhage and drug treatment on the MAPK immunoprecipitation.Severe vasospasm developed in the dogs in the control and vehicle-treated groups (basilar artery [BA] diameter reduction 46.6 ± 5.5% and 49.3 ± 4.6%, respectively). In the PD-98059—treated group, most of the dogs developed mild vasospasm (18.9 ± 6.2%). In the U-0126—treated group, severe vasospasm was observed despite treatment (39.6 ± 6.4%). The PD-98059 but not the U-0126 abolished MAPK immunoprecipitation in the spastic BAs. However, treatment with either PD-98059 or U-0126 improved the clinical scores of the dogs.Conclusions. The present study is the first in which the effects of MAPK inhibitors on vasospasm have been investigated in vivo. The authors demonstrate that MAPK may play a role in vasospasm and that PD-98059 is a potential candidate for the treatment of cerebral vasospasm.

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