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1.
Eur J Neurol ; 27(6): 1039-1047, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32149450

RESUMEN

BACKGROUND AND PURPOSE: We investigated the effectiveness of intravenous thrombolysis (IVT) in acute ischaemic stroke (AIS) patients with large vessel or distal occlusions and mild neurological deficits, defined as National Institutes of Health Stroke Scale scores < 6 points. METHODS: The primary efficacy outcome was 3-month functional independence (FI) [modified Rankin Scale (mRS) scores 0-2] that was compared between patients with and without IVT treatment. Other efficacy outcomes of interest included 3-month favorable functional outcome (mRS scores 0-1) and mRS score distribution at discharge and at 3 months. The safety outcomes comprised all-cause 3-month mortality, symptomatic intracranial hemorrhage (ICH), asymptomatic ICH and severe systemic bleeding. RESULTS: We evaluated 336 AIS patients with large vessel or distal occlusions and mild stroke severity (mean age 63 ± 15 years, 45% women). Patients treated with IVT (n = 162) had higher FI (85.6% vs. 74.8%, P = 0.027) with lower mRS scores at hospital discharge (P = 0.034) compared with the remaining patients. No differences were detected in any of the safety outcomes including symptomatic ICH, asymptomatic ICH, severe systemic bleeding and 3-month mortality. IVT was associated with higher likelihood of 3-month FI [odds ratio (OR), 2.19; 95% confidence intervals (CI), 1.09-4.42], 3-month favorable functional outcome (OR, 1.99; 95% CI, 1.10-3.57), functional improvement at discharge [common OR (per 1-point decrease in mRS score), 2.94; 95% CI, 1.67-5.26)] and at 3 months (common OR, 1.72; 95% CI, 1.06-2.86) on multivariable logistic regression models adjusting for potential confounders, including mechanical thrombectomy. CONCLUSIONS: Intravenous thrombolysis is independently associated with higher odds of improved discharge and 3-month functional outcomes in AIS patients with large vessel or distal occlusions and mild stroke severity. IVT appears not to increase the risk of systemic or symptomatic intracranial bleeding.


Asunto(s)
Isquemia Encefálica , Accidente Cerebrovascular , Administración Intravenosa , Anciano , Isquemia Encefálica/tratamiento farmacológico , Femenino , Fibrinolíticos/uso terapéutico , Humanos , Hemorragias Intracraneales , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Accidente Cerebrovascular/tratamiento farmacológico , Trombectomía , Terapia Trombolítica , Resultado del Tratamiento
2.
AJNR Am J Neuroradiol ; 44(6): 634-640, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37169541

RESUMEN

BACKGROUND AND PURPOSE: Surgical clipping and endovascular treatment are commonly used in patients with unruptured intracranial aneurysms. We compared the safety and efficacy of the 2 treatments in a randomized trial. MATERIALS AND METHODS: Clipping or endovascular treatments were randomly allocated to patients with one or more 3- to 25-mm unruptured intracranial aneurysms judged treatable both ways by participating physicians. The study hypothesized that clipping would decrease the incidence of treatment failure from 13% to 4%, a composite primary outcome defined as failure of aneurysm occlusion, intracranial hemorrhage during follow-up, or residual aneurysms at 1 year, as adjudicated by a core lab. Safety outcomes included new neurologic deficits following treatment, hospitalization of >5 days, and overall morbidity and mortality (mRS > 2) at 1 year. There was no blinding. RESULTS: Two hundred ninety-one patients were enrolled from 2010 to 2020 in 7 centers. The 1-year primary outcome, ascertainable in 290/291 (99%) patients, was reached in 13/142 (9%; 95% CI, 5%-15%) patients allocated to surgery and in 28/148 (19%; 95% CI, 13%-26%) patients allocated to endovascular treatments (relative risk: 2.07; 95% CI, 1.12-3.83; P = .021). Morbidity and mortality (mRS >2) at 1 year occurred in 3/143 and 3/148 (2%; 95% CI, 1%-6%) patients allocated to surgery and endovascular treatments, respectively. Neurologic deficits (32/143, 22%; 95% CI, 16%-30% versus 19/148, 12%; 95% CI, 8%-19%; relative risk: 1.74; 95% CI, 1.04-2.92; P = .04) and hospitalizations beyond 5 days (69/143, 48%; 95% CI, 40%-56% versus 12/148, 8%; 95% CI, 5%-14%; relative risk: 0.18; 95% CI, 0.11-0.31; P < .001) were more frequent after surgery. CONCLUSIONS: Surgical clipping is more effective than endovascular treatment of unruptured intracranial aneurysms in terms of the frequency of the primary outcome of treatment failure. Results were mainly driven by angiographic results at 1 year.


Asunto(s)
Embolización Terapéutica , Procedimientos Endovasculares , Aneurisma Intracraneal , Humanos , Aneurisma Intracraneal/diagnóstico por imagen , Aneurisma Intracraneal/cirugía , Resultado del Tratamiento , Insuficiencia del Tratamiento , Procedimientos Endovasculares/métodos , Embolización Terapéutica/métodos
3.
Neurosurgery ; 41(6): 1385-91; discussion 1391-2, 1997 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-9402590

RESUMEN

OBJECTIVE: Iron catalyzed generation of injurious free radicals has been implicated in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). The present study assessed the effects of the iron chelator deferiprone on cerebral vasospasm in an in vivo rabbit model of SAH. METHODS: Twenty-four rabbits were assigned to three groups as follows: SAH plus placebo (n = 8), SAH plus deferiprone (n = 8), or control plus placebo (n = 8). Deferiprone was administered to an additional group of three rabbits that were not subjected to SAH. Drug administration was initiated 8 hours after SAH was induced and was repeated at 8-hour intervals. The animals were killed using perfusion-fixation 48 hours after SAH. Cross-sectional areas of basilar artery histological sections were measured by an investigator blinded to the treatment groups. RESULTS: In placebo-treated animals, the average luminal cross-sectional area of the basilar artery was reduced by 54% after SAH compared to controls (i.e., from 0.272 to 0.125 mm2). The vasospastic response after SAH was attenuated significantly in animals treated with deferiprone (0.208 mm2, representing a 24% reduction). CONCLUSION: Previous experimental studies suggested that iron chelation can be effective in attenuating cerebral vasospasm after SAH. Deferiprone is a recently developed iron chelator that has been extensively evaluated for the treatment of patients requiring chronic blood transfusions. The present study demonstrates that deferiprone is effective in attenuating experimental cerebral vasospasm. Because of its stability, lipophilicity, and ability to penetrate the blood-brain barrier, deferiprone represents an attractive candidate for the treatment of cerebral vasospasm.


Asunto(s)
Quelantes del Hierro/uso terapéutico , Ataque Isquémico Transitorio/tratamiento farmacológico , Ataque Isquémico Transitorio/etiología , Piridonas/uso terapéutico , Hemorragia Subaracnoidea/complicaciones , Animales , Arteria Basilar/efectos de los fármacos , Arteria Basilar/patología , Deferiprona , Ataque Isquémico Transitorio/patología , Masculino , Conejos
4.
Neurosurgery ; 49(5): 1205-12; discussion 1212-3, 2001 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11846914

RESUMEN

OBJECTIVE: Eicosanoids have been implicated in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). Leukotrienes, 5-hydroxyperoxyeicosatetraenoic acid, and 5-hydroxyeicosatetraenoic acid are part of this group of substances, resulting from the 5-lipoxygenase activity on arachidonic acid metabolism. This study examined the effects of ABT-761, a new 5-lipoxygenase inhibitor, on cerebral vasospasm in an in vivo rabbit model of SAH. METHODS: A total of 48 rabbits were assigned to one of six groups: SAH + placebo (n = 8), SAH + ABT-761 20 mg/kg (n = 8), SAH + ABT-761 30 mg/kg (n = 8), control + placebo (n = 8), control + ABT-761 20 mg/kg (n = 8), and control + ABT-761 30 mg/kg (n = 8). Drug administration was initiated 30 minutes after induction of SAH and repeated 24 hours later. The animals were killed 48 hours after SAH, using the perfusion-fixation method. The cross sectional areas of basilar artery histological sections were measured by an investigator blinded to the treatment groups of the individual samples. RESULTS: In placebo-treated animals, the average luminal cross sectional area of the basilar artery was reduced by 68% after SAH as compared with controls (P < 0.0001). After SAH, the vasospastic response was attenuated in animals treated with 20 or 30 mg/kg representing a 28 or 35% reduction, respectively (P = 0.0011 and P = 0.0038). CONCLUSION: The results demonstrated that ABT-761 is effective in attenuating experimental cerebral vasospasm, indicating that this new drug represents a potential therapeutic agent for the treatment of vasospasm after SAH.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Hidroxiurea/análogos & derivados , Hidroxiurea/farmacología , Inhibidores de la Lipooxigenasa , Hemorragia Subaracnoidea/patología , Vasoespasmo Intracraneal/patología , Animales , Arteria Basilar/patología , Modelos Animales de Enfermedad , Masculino , Conejos
5.
Neurosurgery ; 43(6): 1409-17; discussion 1417-8, 1998 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-9848855

RESUMEN

OBJECTIVE: Increasing evidence implicates endothelin (ET)-1 in the pathophysiological development of cerebral vasospasm. This study examined the ability of TBC 11251 (TBC), a new ETA receptor antagonist, to prevent vasospasm in a rabbit model of subarachnoid hemorrhage (SAH). METHODS: Eighty-five New Zealand White rabbits were assigned to 1 of 10 groups. SAH was induced by injecting autologous blood into the cisterna magna. The treatment groups were as follows: 1) control (no SAH), 2) SAH alone, 3) SAH plus vehicle every 12 hours (BID), 4) SAH plus 5 mg/kg TBC BID, 5) SAH plus 10 mg/kg TBC BID, 6) SAH plus 20 mg/kg TBC BID, 7) SAH plus vehicle at 24 and 36 hours after SAH (24/36), 8) SAH plus 5 mg/kg TBC 24/36, 9) SAH plus 10 mg/kg TBC 24/36, and 10) SAH plus 20 mg/kg TBC 24/36. Animals were killed 48 hours after SAH, by perfusion-fixation, and then basilar arteries were histologically prepared and their cross-sectional areas were measured. RESULTS: The mean basilar artery cross-sectional area was constricted from 0.332 mm2 in the control group to 0.131 mm2 in the SAH alone group, 0.132 in the vehicle 24/36 group, and 0.125 in the vehicle BID group. All groups treated with TBC showed an increase in cross-sectional luminal basilar artery area, relative to the vehicle-treated groups. The 5 mg/kg TBC BID group exhibited a mean basilar artery area of 0.217 mm2, and the 10 mg/kg TBC BID group showed a mean basilar artery area of 0.240 mm2; both groups were statistically improved, compared with the vehicle-treated groups (P < 0.05). No side effects were seen, and there were no differences in the mean arterial pressures between drug- and vehicle-treated groups. CONCLUSION: These findings demonstrate that systemic administration of the ETA receptor antagonist TBC significantly attenuates cerebral vasospasm after SAH, thus providing additional support for the role of ET-1 in vasospasm.


Asunto(s)
Antagonistas de los Receptores de Endotelina , Endotelina-1/fisiología , Ataque Isquémico Transitorio/tratamiento farmacológico , Isoxazoles/uso terapéutico , Hemorragia Subaracnoidea/complicaciones , Tiofenos/uso terapéutico , Animales , Arteria Basilar/patología , Señalización del Calcio/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Endotelina-1/antagonistas & inhibidores , Infusiones Intravenosas , Ataque Isquémico Transitorio/etiología , Ataque Isquémico Transitorio/patología , Isoxazoles/administración & dosificación , Masculino , Conejos , Receptor de Endotelina A , Tiofenos/administración & dosificación
6.
J Neurosurg ; 83(3): 516-21, 1995 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-7666231

RESUMEN

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.


Asunto(s)
Péptido Relacionado con Gen de Calcitonina/fisiología , Ataque Isquémico Transitorio/fisiopatología , Hemorragia Subaracnoidea/complicaciones , Análisis de Varianza , Animales , Arteria Basilar/efectos de los fármacos , Arteria Basilar/fisiopatología , Péptido Relacionado con Gen de Calcitonina/farmacología , Colforsina/análisis , AMP Cíclico/análisis , GMP Cíclico/análisis , Relación Dosis-Respuesta a Droga , Técnicas In Vitro , Ataque Isquémico Transitorio/etiología , Contracción Isométrica/efectos de los fármacos , Contracción Isométrica/fisiología , Masculino , Nitroglicerina/farmacología , Potasio/farmacología , Conejos , Serotonina/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología
7.
Neurosurg Focus ; 3(4): ARTICLE, 1997 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-15104411

RESUMEN

Cerebral vasospasm is a major complication of subarachnoid hemorrhage (SAH) after the rupture of an intracranial aneurysm. Although the cause of cerebral vasospasm has not been fully established, several lines of evidence suggest that the vasoconstrictor peptide endothelin (ET) may play a crucial role. In the present study the potential of TBC 11251 (TBC), a newly developed ET(A) receptor antagonist, to prevent and/or reverse cerebral vasospasm was examined in a well-established rabbit model of SAH. Sixty-five New Zealand White rabbits were assigned to one of six groups. Experimental SAH was induced in rabbits comprising five of the groups by injecting autologous arterial blood into the cisterna magna. The treatment groups were as follows: 1) control (no SAH); 2) SAH only; 3) SAH + placebo at 24 and 36 hours (24/36); 4) SAH + TBC (24/36); 5) SAH + placebo twice daily (BID); and 6) SAH + TBC BID. All drug-treated animals received an intravenous dosage of 5 mg/kg TBC. After 48 hours, the animals were killed by intracardiac perfusion with fixative. The brainstems were removed and the basilar arteries (BAs) were prepared for histological examination. The cross-sectional area of each BA was measured using computer-assisted videomicroscopy by an investigator blind to the group from which it came. A one-way analysis of variance and paired group mean comparisons with the post-hoc Fisher least significant difference test were used for analysis of BA diameters and physiological parameters. The model provided reliable vasospasm, with the mean BA cross-sectional area constricting from 0.388 mm2 in the control group to 0.106 mm2 (27.4% of control) in the SAH only group. Treatment with TBC (24/36) after SAH (reversal protocol) produced a mean BA area of 0.175 mm2 (44.2% of control) which, although larger than the placebo group value of 0.135 mm2 (39.9% of control), was not statistically significant. However, treatment with TBC BID (prevention protocol) produced a mean BA area of 0.303 mm2 (78.1% of control) compared with the placebo BID value of 0.134 mm2 (34.6% of control); this effect was statistically significant (p < 0.01). There were no side effects noted and no differences in the mean arterial pressures between drug and placebo groups. These findings demonstrate that systemic administration of the ET(A) receptor antagonist TBC significantly attenuates cerebral vasospasm after SAH when given as a preventative therapy, and they provide additional support for the role of ET in the establishment of vasospasm.

8.
Stroke ; 29(9): 1930-5; discussion 1935-6, 1998 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-9731621

RESUMEN

BACKGROUND AND PURPOSE: Inflammatory responses have been implicated in the elaboration of several forms of central nervous system injury, including cerebral vasospasm after subarachnoid hemorrhage (SAH). A critical event participating in such responses is the recruitment of circulating leukocytes into the inflammatory site. Two of the key adhesion molecules responsible for the attachment of leukocytes to endothelial cells are intercellular adhesion molecule-1 (ICAM-1) and the common beta chain of the integrin superfamily (CD18). This study examined the effects of monoclonal antibodies on ICAM-1 and the effects of CD18 on cerebral vasospasm after SAH. METHODS: A rabbit model of SAH was utilized to test the influence of intracisternally administered antibodies to ICAM-1 and CD18 on cerebral vasospasm. Antibodies were administered alone or in combination, and the cross-sectional area of basilar arteries was assessed histologically on day 2 post-SAH. RESULTS: Treatment with antibodies to ICAM-1 or CD18 inhibited vasospasm by 22% and 27%, respectively. When administered together, the attenuation of vasospasm increased to 56%. All of these effects achieved statistical significance. CONCLUSIONS: These findings provide the first evidence that the severity of cerebral vasospasm can be attenuated using monoclonal antibodies against ICAM-1 and CD18. The results reinforce the concept that cell-mediated inflammation plays an important role in cerebral vasospasm after SAH and suggest that therapeutic targeting of cellular adhesion molecules can be of benefit in treating cerebral vasospasm.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Antígenos CD18/inmunología , Molécula 1 de Adhesión Intercelular/inmunología , Hemorragia Subaracnoidea/terapia , Vasoconstricción/inmunología , Animales , Arteria Basilar/química , Arteria Basilar/fisiología , Análisis de los Gases de la Sangre , Citocinas/fisiología , Modelos Animales de Enfermedad , Inmunoterapia , Ataque Isquémico Transitorio/etiología , Ataque Isquémico Transitorio/terapia , Masculino , Conejos , Hemorragia Subaracnoidea/complicaciones
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