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A Site-Specific, Sustained-Release Drug Delivery System for Aneurysmal Subarachnoid Hemorrhage.

ABSTRACT: Nimodipine is the only drug approved for use by the Food and Drug Administration for improving outcome after aneurysmal subarachnoid hemorrhage (SAH). It has less than optimal efficacy, causes dose-limiting hypotension in a substantial proportion of patients, and is administered enterally 6 times daily. We describe development of site-specific, sustained-release nimodipine microparticles that can be delivered once directly into the subarachnoid space or cerebral ventricles for potential improvement in outcome of patients with aneurysmal SAH. Eight injectable microparticle formulations of nimodipine in poly(DL-lactide-co-glycolide) (PLGA) polymers of varying composition were tested in vitro, and 1 was advanced into preclinical studies and clinical application. Intracisternal or intraventricular injection of nimodipine-PLGA microparticles in rats and beagles demonstrated dose-dependent, sustained concentrations of nimodipine in plasma and cerebrospinal fluid for up to 29 days with minimal toxicity in the brain or systemic tissues at doses <2 mg in rats and 51 mg in beagles, which would be equivalent of up to 612-1200 mg in humans, based on scaling relative to cerebrospinal fluid volumes. Efficacy was tested in the double-hemorrhage dog model of SAH. Nimodipine-PLGA microparticles significantly attenuated angiographic vasospasm. This therapeutic approach shows promise for improving outcome after SAH and may have broader applicability for similar diseases that are confined to body cavities or spaces, are self-limited, and lack effective treatments.

SUBMITTER: Hanggi D

PROVIDER: S-EPMC4824023 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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A Site-Specific, Sustained-Release Drug Delivery System for Aneurysmal Subarachnoid Hemorrhage.

Hänggi Daniel D Etminan Nima N Steiger Hans Jakob HJ Johnson Mark M Peet M Melissa MM Tice Tom T Burton Kevin K Hudson Bruce B Turner Michele M Stella Angela A Heshmati Parissa P Davis Cara C Faleck Herbert J HJ Macdonald R Loch RL

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20160401 2

Nimodipine is the only drug approved for use by the Food and Drug Administration for improving outcome after aneurysmal subarachnoid hemorrhage (SAH). It has less than optimal efficacy, causes dose-limiting hypotension in a substantial proportion of patients, and is administered enterally 6 times daily. We describe development of site-specific, sustained-release nimodipine microparticles that can be delivered once directly into the subarachnoid space or cerebral ventricles for potential improvem ...[more]

PMID: 26935204

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Project description:BackgroundThe primary aim was to determine to what extent continuously monitored neurointensive care unit (neuro-ICU) targets predict cerebral blood flow (CBF) and delivery of oxygen (CDO2) after aneurysmal subarachnoid hemorrhage. The secondary aim was to determine whether CBF and CDO2 were associated with clinical outcome.MethodsIn this observational study, patients with aneurysmal subarachnoid hemorrhage treated at the neuro-ICU in Uppsala, Sweden, from 2012 to 2020 with at least one xenon-enhanced computed tomography (Xe-CT) obtained within the first 14 days post ictus were included. CBF was measured with the Xe-CT and CDO2 was calculated based on CBF and arterial oxygen content. Regional cerebral hypoperfusion was defined as CBF < 20 mL/100 g/min, and poor CDO2 was defined as CDO2 < 3.8 mL O2/100 g/min. Neuro-ICU variables including intracranial pressure (ICP), pressure reactivity index, cerebral perfusion pressure (CPP), optimal CPP, and body temperature were assessed in association with the Xe-CT. The acute phase was divided into early phase (day 1-3) and vasospasm phase (day 4-14).ResultsOf 148 patients, 27 had underwent a Xe-CT only in the early phase, 74 only in the vasospasm phase, and 47 patients in both phases. The patients exhibited cerebral hypoperfusion and poor CDO2 for medians of 15% and 30%, respectively, of the cortical brain areas in each patient. In multiple regressions, higher body temperature was associated with higher CBF and CDO2 in the early phase. In a similar regression for the vasospasm phase, younger age and longer pulse transit time (lower peripheral resistance) correlated with higher CBF and CDO2, whereas lower hematocrit only correlated with higher CBF but not with CDO2. ICP, CPP, and pressure reactivity index exhibited no independent association with CBF and CDO2. R2 of these regressions were below 0.3. Lower CBF and CDO2 in the early phase correlated with poor outcome, but this only held true for CDO2 in multiple regressions.ConclusionsSystemic and cerebral physiological variables exhibited a modest association with CBF and CDO2. Still, cerebral hypoperfusion and low CDO2 were common and low CDO2 was associated with poor outcome. Xe-CT imaging could be useful to help detect secondary brain injury not evident by high ICP and low CPP.

Project description:ImportanceCerebral vasospasm largely contributes to a devastating outcome after aneurysmal subarachnoid hemorrhage (aSAH), with limited therapeutic options.ObjectiveTo investigate the safety and efficacy of localized nicardipine release implants positioned around the basal cerebral vasculature at risk for developing proximal vasospasm after aSAH.Design, setting, and participantsThis single-masked randomized clinical trial with a 52-week follow-up was performed between April 5, 2020, and January 23, 2023, at 6 academic neurovascular centers in Germany and Austria. Consecutive patients with World Federation of Neurological Surgeons grade 3 or 4 aSAH due to a ruptured anterior circulation aneurysm requiring microsurgical aneurysm repair participated.InterventionDuring aneurysm repair, patients were randomized 1:1 to intraoperatively receive 10 implants at 4 mg of nicardipine each plus standard of care (implant group) or aneurysm repair alone plus standard of care (control group).Main outcome and measuresThe primary end point was the incidence of moderate to severe cerebral angiographic vasospasm (aVS) between days 7 and 9 after aneurysm rupture as determined by digital subtraction angiography.ResultsOf 41 patients, 20 were randomized to the control group (mean [SD] age, 54.9 [9.1] years; 17 female [85%]) and 21 to the implant group (mean [SD] age, 53.6 [11.9] years; 14 female [67%]). A total of 39 patients were included in the primary efficacy analysis. In the control group, 11 of 19 patients (58%) developed moderate or severe aVS compared with 4 of 20 patients (20%) in the implant group (P = .02). This outcome was paralleled by a lower clinical need for vasospasm rescue therapy in the implant group (2 of 20 patients [10%]) compared with the control group (11 of 19 patients [58%]; P = .002). Between days 13 and 15 after aneurysm rupture, new cerebral infarcts were noted in 6 of 19 patients (32%) in the control group and in 2 of 20 patients (10%) in the implant group (P = .13). At 52 weeks, favorable outcomes were noted in 12 of 18 patients (67%) in the control group and 16 of 19 patients (84%) in the implant group (P = .27). The adverse event rate did not differ between groups.Conclusions and relevanceThese findings show that placing nicardipine release implants during microsurgical aneurysm repair can provide safe and effective prevention of moderate to severe aVS after aSAH. A phase 3 clinical trial to investigate the effect of nicardipine implants on clinical outcome may be warranted.Trial registrationClinicalTrials.gov Identifier: NCT04269408.

Project description:Background: Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating hemorrhagic stroke with high disability and mortality. Neuroinflammation and the immunological response after aSAH are complex pathophysiological processes that have not yet been fully elucidated. Therefore, attention should be paid to exploring the inflammation-related genes involved in the systemic response to the rupture of intracranial aneurysms. Methods: The datasets of gene transcriptomes were downloaded from the Gene Expression Omnibus database. We constructed a gene co-expression network to identify cluster genes associated with aSAH and screened out differentially expressed genes (DEGs). The common gene was subsequently applied to identify hub genes by protein-protein interaction analysis and screen signature genes by machine learning algorithms. CMap analysis was implemented to identify potential small-molecule compounds. Meanwhile, Cibersort and ssGSEA were used to evaluate the immune cell composition, and GSEA reveals signal biological pathways. Results: We identified 602 DEGs from the GSE36791. The neutrophil-related module associated with aSAH was screened by weighted gene co-expression network analysis (WGCNA) and functional enrichment analysis. Several small molecular compounds were predicted based on neutrophil-related genes. MAPK14, ITGAM, TLR4, and FCGR1A have been identified as crucial genes involved in the peripheral immune activation related to neutrophils. Six significant genes (CST7, HSP90AB1, PADI4, PLBD1, RAB32, and SLAMF6) were identified as signature biomarkers by performing the LASSO analysis and SVM algorithms. The constructed machine learning model appears to be robust by receiver-operating characteristic curve analysis. The immune feature analysis demonstrated that neutrophils were upregulated post-aSAH and PADI4 was positively correlated with neutrophils. The NETs pathway was significantly upregulated in aSAH. Conclusion: We identified core regulatory genes influencing the transcription profiles of circulating neutrophils after the rupture of intracranial aneurysms using bioinformatics analysis and machine learning algorithms. This study provides new insight into the mechanism of peripheral immune response and inflammation after aSAH.

Dataset Information

A Site-Specific, Sustained-Release Drug Delivery System for Aneurysmal Subarachnoid Hemorrhage.

Publications

A Site-Specific, Sustained-Release Drug Delivery System for Aneurysmal Subarachnoid Hemorrhage.

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