RESUMEN
OBJECT: Ibuprofen is an antiinflammatory drug that disrupts leukocyte-endothelial cell interactions by limiting expression of endothelial adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), also known as CD54. The authors hypothesized that ibuprofen could reduce the size of the infarct associated with transient focal ischemia by inhibition of ICAM-1 expression, and they evaluated its effects in rats treated with middle cerebral artery (MCA) occlusion. Ibuprofen treatment was compared with mild systemic hypothermia, which is known to be neuroprotective and is commonly used during neurosurgical procedures. METHODS: The maximum ibuprofen dose (240 mg/kg/day) that could be tolerated with no systemic toxicity was established in the initial experiments. In the efficacy experiment, rats were pretreated with vehicle, ibuprofen, or hypothermia (33 degrees C) prior to 2 hours of MCA occlusion; then their brains were harvested at 24 hours of reperfusion for histological studies. End-ischemic cerebral blood flow (CBF) was evaluated using [14C]iodoantipyrine autoradiography in additional cohorts. Expression of ICAM-1 within ischemic compared with nonischemic caudate nucleus and putamen (striatum) or cortex was evaluated using immunohistochemical studies. Compared with vehicle treatment, ibuprofen produced a 46.2% reduction (p = 0.01) in striatal infarcts, which was comparable to hypothermia (48.7% reduction, p = 0.02). Ibuprofen did not alter end-ischemic CBF in any region studied, and the ibuprofen treatment group had the lowest proportion of animals with marked ICAM-1 staining. CONCLUSIONS: Ibuprofen given in maximum tolerated doses reduces the striatal infarct size after focal cerebral ischemia. The neuroprotective mechanism does not work through preservation of intraischemic CBF and is consistent with inhibition of ICAM-1 expression; however, at the doses used in this study, other effects of ibuprofen on platelet and endothelial function are possible.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Infarto Cerebral/tratamiento farmacológico , Infarto Cerebral/etiología , Cuerpo Estriado/irrigación sanguínea , Ibuprofeno/uso terapéutico , Infarto de la Arteria Cerebral Media/complicaciones , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Encéfalo/irrigación sanguínea , Infarto Cerebral/metabolismo , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Esquema de Medicación , Ibuprofeno/administración & dosificación , Inmunohistoquímica , Molécula 1 de Adhesión Intercelular/metabolismo , Masculino , Ratas , Ratas WistarRESUMEN
BACKGROUND AND PURPOSE: A reduction in the local availability of nitric oxide (NO) may play a role in the etiology of chronic cerebral vasospasm after subarachnoid hemorrhage (SAH). We investigated the toxicity and efficacy of a locally delivered NO donor from a controlled-release polymer in preventing experimental cerebral vasospasm in rats and rabbits, respectively. METHODS: Diethylenetriamine/NO (DETA/NO) was incorporated into controlled release ethylene-vinyl acetate (EVAc) polymers. Twenty-eight rats were used in a dose-escalation toxicity study to establish a maximally tolerated dose of DETA/NO-EVAc polymer. In the efficacy experiment, 20 rabbits were assigned to 4 experimental groups (n=5 per group): sham operation; SAH only; SAH+empty EVAc polymer; and SAH+DETA/NO-EVAc polymer. Treatment was initiated 30 minutes after blood deposition. Basilar artery lumen patency was assessed 72 hours after hemorrhage to evaluate the efficacy of DETA/NO in preventing cerebral vasospasm. RESULTS: In the toxicity study, a dose of 3.4 mg/kg was identified as the LD(20) (dose with 20% mortality during the study period) of this DETA/NO formulation. Brain histology revealed hemorrhage and ischemic changes at the implantation site associated with high concentrations of DETA/NO. In the efficacy study, treatment with DETA/NO-EVAc polymer resulted in a significant decrease in basilar artery vasospasm compared with no treatment (93.0+/-4.9% versus 71.4+/-11.9%; P=0.035) or compared with treatment with blank EVAc polymer (93.0+/-4.9% versus 73.2+/-6.4%; P=0.003). CONCLUSIONS: Local delivery of DETA/NO prevents vasospasm in the rabbit basilar artery. Local delivery of DETA/NO via polymers is a safe and effective strategy for preventing cerebral vasospasm after SAH in this model.
Asunto(s)
Donantes de Óxido Nítrico/administración & dosificación , Poliaminas/administración & dosificación , Hemorragia Subaracnoidea/complicaciones , Vasoespasmo Intracraneal/etiología , Vasoespasmo Intracraneal/prevención & control , Animales , Arteria Basilar/efectos de los fármacos , Arteria Basilar/fisiopatología , Encéfalo/irrigación sanguínea , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/cirugía , Cisterna Magna , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/efectos adversos , Preparaciones de Acción Retardada/química , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Implantes de Medicamentos/administración & dosificación , Implantes de Medicamentos/efectos adversos , Implantes de Medicamentos/química , Femenino , Masculino , Dosis Máxima Tolerada , Donantes de Óxido Nítrico/efectos adversos , Donantes de Óxido Nítrico/química , Poliaminas/efectos adversos , Poliaminas/química , Polivinilos/administración & dosificación , Polivinilos/efectos adversos , Polivinilos/química , Conejos , Ratas , Ratas Endogámicas F344 , Hemorragia Subaracnoidea/fisiopatología , Tasa de Supervivencia , Resultado del Tratamiento , Vasoespasmo Intracraneal/fisiopatologíaRESUMEN
OBJECTIVE: Hydrocephalus requiring shunt placement is a common complication after aneurysmal subarachnoid hemorrhage (aSAH). Previous investigations suggest that fenestration of the lamina terminalis during microsurgery for aSAH may be associated with a reduced rate of shunt-dependent hydrocephalus. We report a retrospective analysis correlating fenestration of the lamina terminalis with decreased shunt-dependent hydrocephalus after aSAH. METHODS: During the past decade, 582 patients were admitted to our institution with aSAH. We compared the rate of shunting in patients operated on by a neurosurgeon ("index neurosurgeon") who routinely fenestrated the lamina terminalis (>98% of his patients) with that in patients managed by 14 other neurosurgeons who rarely fenestrated the lamina terminalis (<5% of their patients) and by 6 interventional neuroradiologists. The total cohort was subdivided into two groups on the basis of surgical approach and microsurgical access to the lamina terminalis. Group A included frontosphenotemporal craniotomies, an approach in which the lamina terminalis is accessible, and Group B included other approaches in which the lamina terminalis is not accessible. Shunting rates of the index neurosurgeon and those of the other practitioners were compared within Groups A and B. Shunting rates were compared by logistic regression and multivariable analysis. This study design isolates the effect of fenestrating the lamina terminalis on the incidence of shunt-dependent hydrocephalus. RESULTS: In Group A, the index neurosurgeon had a significantly lower rate of shunting, 2.3%, versus 12.6% for other practitioners (P = 0.011; odds ratio, 0.15). In Group B, in which the approach did not allow microsurgical fenestration of the lamina terminalis, there was no difference (P = 0.789) in the rate of shunting between the index neurosurgeon (10.0%) and other practitioners (13.2%). CONCLUSION: Fenestration of the lamina terminalis appears to be associated with a decreased incidence of shunt-dependent hydrocephalus of more than 80% after aSAH. This straightforward microsurgical maneuver should be performed whenever possible during aneurysm surgery.
Asunto(s)
Derivaciones del Líquido Cefalorraquídeo , Hidrocefalia/prevención & control , Hipotálamo/cirugía , Aneurisma Intracraneal/cirugía , Microcirugia , Hemorragia Subaracnoidea/cirugía , Enfermedad Aguda , Adulto , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Hidrocefalia/epidemiología , Hidrocefalia/fisiopatología , Hidrocefalia/cirugía , Incidencia , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
PURPOSE: An alternative strategy for the treatment of intractable seizures may be to administer anticonvulsants directly into the brain near the site of a seizure focus using controlled-release polymers. We describe the pharmacokinetics of a phenytoin-ethylene-vinyl acetate (EVAc) controlled-release polymer and report the reduction of seizures in a cobalt-induced rat model of epilepsy with the intracerebral delivery of phenytoin using surgically implanted polymers. METHODS: In the pharmacokinetics study, the drug release rate of 50%-loaded phenytoin-EVAc polymers (n=3) was determined in vitro over 15 weeks initially and then several months later (over a 2-week period after 1 year of in vivo release). In the efficacy study, 85 rats underwent implantation of skull-mounted cortical electrodes for electrocorticography (ECoG) and then underwent application of cobalt chloride to the cerebral cortex for the induction of seizures. Rats in the treatment group (n=9) underwent surgical implantation of phenytoin-EVAc polymers and rats in the control group (n=10) underwent implantation of empty EVAc polymers. In the morbidity study, the potential histologic pathology of the intracerebral delivery of increasing doses of phenytoin from the polymer (10, 20, 30, and 50% loading) was assessed. RESULTS: Phenytoin was released in vitro from EVAc polymers in a controlled fashion with an initial release of 0.20% of the total loaded dose per week and a continued release of 0.70% of the total loaded dose per week after 365 days of implantation in the brain. The intracerebral controlled-release of phenytoin resulted in a statistically significant reduction in seizure activity in the treatment group as evidenced by lower Racine scores. The four groups of rats (n=5 per group) that underwent intracerebral implantation of 10, 20, 30, or 50%-loaded phenytoin-EVAc polymers displayed expected average weight gain and normal behavior over 365 days. One rat in the 50% group, however, died 354 days after polymer implantation for undetermined reasons. CONCLUSIONS: The intracerebral delivery of phenytoin using an EVAc polymer, which will release this drug for a calculated period of 3.5 years, resulted in a significant reduction in seizures in a rat model of cobalt-induced epilepsy by both behavioral and ECoG criteria. In rats, the long-term interstitial delivery of phenytoin in the brain was not associated with any deleterious effects.