clazosentan and Nervous-System-Diseases

Predictors of outcome after aneurysmal subarachnoid hemorrhage have been determined previously through hypothesis-driven methods that often exclude putative covariates and require a priori knowledge of potential confounders. Here, we apply a data-driven approach, principal component analysis, to identify baseline patient phenotypes that may predict neurological outcomes.. Principal component analysis was performed on 120 subjects enrolled in a prospective randomized trial of clazosentan for the prevention of angiographic vasospasm. Correlation matrices were created using a combination of Pearson, polyserial, and polychoric regressions among 46 variables. Scores of significant components (with eigenvalues>1) were included in multivariate logistic regression models with incidence of severe angiographic vasospasm, delayed ischemic neurological deficit, and long-term outcome as outcomes of interest.. Sixteen significant principal components accounting for 74.6% of the variance were identified. A single component dominated by the patients' initial hemodynamic status, World Federation of Neurosurgical Societies score, neurological injury, and initial neutrophil/leukocyte counts was significantly associated with poor outcome. Two additional components were associated with angiographic vasospasm, of which one was also associated with delayed ischemic neurological deficit. The first was dominated by the aneurysm-securing procedure, subarachnoid clot clearance, and intracerebral hemorrhage, whereas the second had high contributions from markers of anemia and albumin levels.. Principal component analysis, a data-driven approach, identified patient phenotypes that are associated with worse neurological outcomes. Such data reduction methods may provide a better approximation of unique patient phenotypes and may inform clinical care as well as patient recruitment into clinical trials.. http://www.clinicaltrials.gov. Unique identifier: NCT00111085.

Topics: Brain Ischemia; Cerebral Angiography; Dioxanes; Double-Blind Method; Female; Humans; Intracranial Hemorrhages; Male; Middle Aged; Nervous System Diseases; Phenotype; Principal Component Analysis; Prospective Studies; Pyridines; Pyrimidines; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Tomography, X-Ray Computed; Treatment Outcome; Vasospasm, Intracranial

Early identification of patients at risk of angiographic vasospasm after aneurysmal subarachnoid hemorrhage (SAH) may mitigate its sequelae. One mechanism that may contribute to angiographic vasospasm is increased central sympathetic activity, which is also thought to cause electrocardiographic (ECG) changes after SAH. Here, we perform the first study to determine the association between ECG changes and angiographic vasospasm after SAH.. Exploratory analysis was performed on 413 patients from CONSCIOUS-1, a prospective randomized trial of clazosentan for the prevention of angiographic vasospasm. ECGs were obtained within 24 hours of aneurysm rupture and during the vasospasm risk period. Angiographic vasospasm was assessed using catheter angiography at baseline and 7 to 11 days after SAH. Multivariate logistic regression was used to identify significant associations.. The most prevalent finding on ECG both immediately following SAH and during the vasospasm risk period was QT prolongation (42% and 25%, respectively). A prolonged QT interval and tachycardia on the baseline ECG were associated with angiographic vasospasm (OR, 1.86; 95% CI, 1.00-3.45; and OR, 10.83; 95% CI, 1.17-100.50, respectively). QT prolongation on ECG during the vasospasm risk period was also associated with angiographic vasospasm (OR, 3.53; 95% CI, 1.67-7.39). No ECG findings were associated with delayed ischemic neurological deficit, but tachycardia and ST changes were associated with worse clinical outcome.. QT prolongation and tachycardia on ECG were independently associated with angiographic vasospasm after aneurysmal SAH on multivariate analysis.. URL: http://clinicaltrials.gov. Unique Identifier: NCT00111085.

Topics: Adult; Aged; Aneurysm, Ruptured; Brain Ischemia; Cerebral Angiography; Databases, Factual; Dioxanes; Electrocardiography; Female; Humans; Logistic Models; Male; Middle Aged; Multivariate Analysis; Myocardial Stunning; Nervous System Diseases; Potassium; Predictive Value of Tests; Prognosis; Prospective Studies; Pyridines; Pyrimidines; Risk Factors; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Treatment Outcome; Vasospasm, Intracranial

Endothelin-1 (ET-1) is involved on the development of cerebral edema in acute ischemic stroke. As edema is a therapeutic target in cerebral ischemia, our aim was to study the effect of antagonists for ET-1 receptors (Clazosentan® and BQ-788, specific antagonists for receptors A and B, respectively) on the development of edema, infarct volume and sensorial-motor deficits in rats subjected to ischemia by occlusion of the middle cerebral artery (MCAO). We used Wistar rats (280-320 g) submitted to ischemia by intraluminal transient (90 min) MCAO. After ischemia, rats were randomized into 4 groups (n = 6) treated with; 1) control group (saline), 2) Clazosentan® group (10 mg/kg iv), 3) BQ-788 group (3 mg/kg iv), and 4) combined treatment (Clazosentan® 10 mg/kg plus BQ-788 3 mg/kg iv). We observed that rats treated with Clazosentan® showed a reduction of edema, measured by MRI, at 72 h (hours) and at day 7 (both p < 0.0001), and a decrease in the serum levels of ET-1 at 72 h (p < 0.0001) and at day 7 (p = 0.009). The combined treatment also induced a reduction of edema at 24 h (p = 0.004), 72 h (p < 0.0001) and at day 7 (p < 0.0001), a reduction on infarct volume, measured by MRI, at 24 and 72 h, and at day 7 (all p < 0.01), and a better sensorimotor recovery at 24 and 72 h, and at day 7 (all p < 0.01). Moreover, Clazosentan® induced a decrease in AQP4 expression, while BQ-788 induced an increase in AQP9 expression. These results suggest that antagonists for ET-1 receptors may be a good therapeutic target for cerebral ischemia.

Topics: Animals; Aquaporins; Blotting, Western; Brain Edema; Brain Ischemia; Dioxanes; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Evoked Potentials, Somatosensory; Image Processing, Computer-Assisted; Infarction, Middle Cerebral Artery; Magnetic Resonance Imaging; Male; Nervous System Diseases; Neuroprotective Agents; Oligopeptides; Piperidines; Pyridines; Pyrimidines; Rats; Rats, Wistar; Stroke; Sulfonamides; Tetrazoles