clazosentan and Brain-Injuries

There is a correlation between poor neuropsychological outcome and focal regions of atrophy in patients with subarachnoid hemorrhage (SAH). No study has investigated the impact of global brain atrophy on outcome after SAH. In other neurological disorders, such as multiple sclerosis, a correlation has been found between global atrophy and outcome. This analysis of patients entered into a randomized clinical trial of clazosentan in patients with SAH (CONSCIOUS-1) investigated the relationship between global cerebral atrophy, clinical factors, and outcome.The 413 patients in the CONSCIOUS-1 study underwent cranial computed tomography (CT) on admission and 6 weeks after SAH. After patients with large clip/coil artefacts and those with infarctions on CT were excluded, 97 patients remained and had voxel-based volumetric measurements of the baseline and 6-week CT scans. The percentage difference in volume between times was taken and analysed against clinical variables. Relationships were modeled using univariate and multivariate analysis.Age, female gender, and higher body temperature during the patient's stay in the intensive care unit were significantly correlated with brain atrophy. Greater brain atrophy significantly correlated with poor outcome (modified Rankin scale), more severe neurological deficits on the National Institute of Health Stroke Scale (NIHSS), and poorer health status (EQ-5D).

Topics: Adult; Analysis of Variance; Atrophy; Body Weight; Brain Injuries; Cerebral Cortex; Dioxanes; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pyridines; Pyrimidines; Statistics, Nonparametric; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Time Factors; Tomography, X-Ray Computed; Trauma Severity Indices; Treatment Outcome

The purpose of this study was to test the efficacy of a novel endothelin receptor A antagonist on blood flow and behavioral outcome given 30 minutes following traumatic brain injury.. Male Sprague-Dawley rats (400-450 g) were used in this study. All animals were scanned for initial blood flow using arterial spin labeling magnetic resonance imaging (n = 72 total). Half were subjected to traumatic brain injury using a weight acceleration impact device (n = 36 total). Sham operated animals were used as control (n = 36 total). Thirty minutes following traumatic brain injury, animals were given one intravenous injection of vehicle (0·9% saline) or 1·0 mg/kg clazosentan, a novel endothelin receptor A antagonist, for a total of four groups. At 4, 24, and 48 hours post-traumatic brain injury, blood flow determination continued. On the second day post-traumatic brain injury/sham operation, behavioral testing commenced using a radial arm maze to assess cognitive function.. Our results indicate that 1·0 mg/kg clazosentan was effective in ameliorating hypoperfusion seen after traumatic brain injury. Saline had no effect. Furthermore, clazosentan treatment was effective in significantly improving behavioral outcome following traumatic brain injury.. Collectively, these results indicate that clazosentan, given at 30 minutes post-traumatic brain injury, is effective in improving outcome following injury.

Topics: Animals; Behavior, Animal; Brain Injuries; Cerebrovascular Circulation; Cerebrovascular Disorders; Cognition Disorders; Dioxanes; Disease Models, Animal; Endothelin A Receptor Antagonists; Male; Maze Learning; Pyridines; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Sulfonamides; Tetrazoles; Vasodilator Agents

Endothelin-1 (ET-1) is a 21 amino acid peptide that has been closely linked to cerebral vasospasm and more recently to oxidative stress after traumatic brain injury. In this study, we have examined the effects of the endothelin receptor subtype A antagonist, Ro 61-1790, on acute cortical neuronal injury and delayed neuronal death in the cerebellum after mild traumatic brain injury. Rats were administered Ro 61-1790 or vehicle for 24 h after injury and euthanized at 1 day, 3 days, or 7 days. Heat shock protein70 (HSP70), a marker of neuronal stress/injury, was immunolocalized in the cortex. Induction of heme oxygenase-1 (HO-1) and enhanced immunoexpression of the complement C3bi receptor, both of which are indicators of cerebellar glial reactivity, and Purkinje cell loss were evaluated in the cerebellum. There was maximal induction of HSP70 in cortical neurons at 24 h postinjury in all animals. Drug treated animals showed significantly fewer HSP70 labeled cortical neurons at this time point. There were fewer reactive glia in the cerebellum of drug treated animals as compared to vehicle controls at 3 days postinjury. However, at 7 days postinjury glial reactivity and Purkinje cell loss were similar in both groups. These findings demonstrate that Ro 61-1790, when administered for the first 24 h postinjury, limits acute neuronal injury in the cortex, transiently influences glial reactivity in the cerebellum, and does not attenuate delayed Purkinje cell death. The latter finding may reflect the duration of infusion of the drug.

Topics: Animals; Antibodies, Monoclonal; Brain Injuries; Cell Count; Cell Death; Cerebral Cortex; Dioxanes; Endothelin Receptor Antagonists; Endothelin-1; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; HSP70 Heat-Shock Proteins; Macrophage-1 Antigen; Male; Microglia; Nerve Degeneration; Purkinje Cells; Pyridines; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptors, Endothelin; Sulfonamides; Tetrazoles