Acta neurochirurgica. Supplement
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Acta Neurochir. Suppl. · Jan 2015
ReviewIntrathecal application of the nimodipine slow-release microparticle system eg-1962 for prevention of delayed cerebral ischemia and improvement of outcome after aneurysmal subarachnoid hemorrhage.
The effective reduction of delayed cerebral ischemia (DCI), a main contributor for poor outcome following aneurysmal subarachnoid hemorrhage (SAH), remains challenging. Previous clinical trials on systemic pharmaceutical treatment of SAH mostly failed to improve outcome, probably because of insensitive pharmaceutical targets and outcome measures, small sample size, insufficient subarachnoid drug concentrations and also detrimental, systemic effects of the experimental treatment per se. Interestingly, in studies that are more recent, intrathecal administration of nicardipine pellets following surgical aneurysm repair was suggested to have a beneficial effect on DCI and neurological outcome. ⋯ Because of the favorable results of the preclinical data on DCI and neurological outcome in the absence of neurotoxicity or systemic side effects, we are initiating clinical trials. The PROMISE (Prolonged Release nimOdipine MIcro particles after Subarachnoid hemorrhage) trial is designed as an unblinded, nonrandomized, single-center, single-dose, dose-escalation safety and tolerability phase 1 study in patients surgically treated for aSAH and will investigate the effect of intracisternal EG-1962 administration. The NEWTON (Nimodipine microparticles to Enhance recovery While reducing TOxicity after subarachNoid hemorrhage) trial is a phase 1/2a multicenter, controlled, randomized, open-label, dose-escalation, safety, tolerability, and pharmacokinetic study comparing EG-1962 and nimodipine in patients with aneurysmal SAH.
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Acta Neurochir. Suppl. · Jan 2015
ReviewNeurovascular events after subarachnoid hemorrhage: focusing on subcellular organelles.
Subarachnoid hemorrhage (SAH) is a devastating condition with high morbidity and mortality rates due to the lack of effective therapy. Early brain injury (EBI) and cerebral vasospasm (CVS) are the two most important pathophysiological mechanisms for brain injury and poor outcomes for patients with SAH. CVS has traditionally been considered the sole cause of delayed ischemic neurological deficits after SAH. ⋯ The dysfunction of subcellular organelles, such as endoplasmic reticulum stress, mitochondrial failure, and autophagy-lysosomal system activation, has developed during EBI and delayed brain injury after SAH. To our knowledge, there is a lack of review articles addressing the direction of organelle dysfunction after SAH. In this review, we discuss the roles of organelle dysfunction in the pathogenesis of SAH and present the opportunity to develop novel therapeutic strategies of SAH via modulating the functions of organelles.
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Acta Neurochir. Suppl. · Jan 2015
ReviewPerioperative measures to improve outcome after subarachnoid hemorrhage-revisiting the concept of secondary brain injury.
Progress in the management of aneurysmal subarachnoid hemorrhage (SAH) is reflected most clearly in a continuously decreasing case fatality rate over the last decades. The purpose of the present review is to identify the relevant factors responsible for this progress and to outline future possibilities of improvement. Although data on intracerebral hemorrhage and ischemic stroke are less homogeneous, the respective data suggest that reduction of case fatalities could also be achieved with these types of stroke. ⋯ Further efforts to limit vasospasm should therefore be made, and the most promising drugs, calcium antagonists, deserve further development. Because, with various drugs, systemic side effects counteracted the local beneficial effect, future efforts should focus on topical administration of drugs instead of systemic administration. Furthermore, efforts for a better understanding of the variations of the calcium channels and the interplay between the different types of calcium channels should be made.