[Show abstract][Hide abstract] ABSTRACT: Background and purpose:
Knowing characteristic adverse events (AEs) and their incidence among patients participating in acute stroke trials may assist interpretation of future studies. We aimed to develop an online tool to inform stroke trial safety.
We identified relevant AEs from patients within the Virtual International Stroke Trials Archive (VISTA), using receiver operating characteristic principles. We modeled their incidence on patient age, baseline National Institutes of Health Stroke Scale, and comorbidities using binary logistic regression. Models with an R(2) >5% were deemed powerful enough to predict expected AE incidences and were included. The calculator was developed using programs R and Visual Studios.
Forty-eight of the most common AEs were identified and incorporated into the IschAEmic Stroke Calculator. The calculator, publicly available at www.vistacollaboration.org calculates the expected incidence of AEs or groups of AEs in a trial cohort and where possible compares them with the observed incidence.
The IschAEmic Stroke Calculator is an open access resource to support safety interpretation within acute stroke trials. Prediction of AEs with higher likelihood of occurrence may direct preventive clinical measures.
[Show abstract][Hide abstract] ABSTRACT: Meperidine is used for pain control and treatment of shivering. Concerns about neurotoxicity, particularly seizures, have led to efforts limiting meperidine use. We reviewed the body of evidence linking meperidine to seizures. We searched PubMed for the terms meperidine, normeperidine, pethidine, and norpethidine; each was combined with the terms: seizure, epilepsy, epileptogenic, toxicity, overdose, seizure threshold, and convulsion. Articles were assessed for relevance. Semiologies were reviewed to ascertain seizure likelihood. Our search yielded 351 articles, of which 66 were relevant. Of these, 33 had primary clinical data on meperidine-associated seizures, comprising 50 patients. Twenty events were deemed likely to be seizures, 26 indeterminate, and 4 unlikely. Most studies were case reports. Confounding comorbidities were frequent. The evidence base for meperidine-associated seizures in man is scant. Seizure risk associated with meperidine appears to be overstated. The utility of meperidine should continue to be explored, especially for therapeutic hypothermia.
[Show abstract][Hide abstract] ABSTRACT: Intravenous rt-PA was proven safe and effective for acute ischemic stroke in 1995, approved by US FDA in 1996, and endorsed by the American Heart Association, American Academy of Neurology, and National Stroke Association in 1997. The treatment is remarkably cost-effective, despite the high cost of the drug itself and the stroke teams to give it. Community-based practicing neurologists can use t-PA for acute stroke without the need for specialized expertise. The benefit is durable over long-term follow-up and no particular subgroups, such as the elderly or those with very large strokes, should be excluded from treatment. Several additional studies have now confirmed the beneficial effects of thrombolytic therapy for stroke in de novo samples. So why isn't the drug used more? Some troubling mis-understandings in the literature seem persistent and influential among clinicians. Considerable data supports the use of rt-PA for acute ischemic stroke, which should remove remaining doubts.
No preview · Article · May 2015 · Expert Review of Neurotherapeutics
[Show abstract][Hide abstract] ABSTRACT: We review the organizational principles of the cortical vasculature and the underlying patterns of blood flow under normal conditions and in response to occlusion of single vessels. The cortex is sourced by a two-dimensional network of pial arterioles that connects to a three-dimensional network of subsurface microvessels in close proximity to neurons and glia. Blood flow within the surface and subsurface networks is largely insensitive to occlusion of a single vessel within either network. However, the penetrating arterioles that connect the pial network to the subsurface network are bottlenecks to flow; occlusion of even a single penetrating arteriole results in the death of a 500 μm diameter cylinder of cortical tissue despite the potential for collateral flow through microvessels. This pattern of flow is consistent with that calculated from a full reconstruction of the angioarchitecture. Conceptually, collateral flow is insufficient to compensate for the occlusion of a penetrating arteriole because penetrating venules act as shunts of blood through collaterals. Future directions that stem from the analysis of the angioarchitecture concern cellular-level issues, in particular the regulation of blood flow within the subsurface microvascular network, and system-level issues, in particular the role of penetrating arteriole occlusions in human cognitive impairment. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Full-text · Article · Feb 2015 · Microcirculation (New York, N.Y.: 1994)
[Show abstract][Hide abstract] ABSTRACT: Cerebral postischemic reperfusion injury is defined as deterioration of ischemic brain tissue that parallels and antagonizes the benefits of restoring cerebral circulation after therapeutic thrombolysis for acute ischemic stroke. To understand the paradox of injury caused by treatment, we first emphasize the phenomenon in which recanalization of an occluded artery does not lead to tissue reperfusion. Additionally, no-reflow after recanalization may be due to injury of the neurovascular unit, distal microthrombosis, or both, and certainly worsens outcome. We examine the mechanism of molecular and subcellular damage in the neurovascular unit, notably oxidative stress, mitochondrial dysfunction, and apoptosis. At the level of the neurovascular unit, which mediates crosstalk between the damaged brain and systemic responses in blood, we summarize emerging evidence demonstrating that individual cell components play unique and cumulative roles that lead to damage of the blood–brain barrier and neurons. Furthermore, we review the latest developments in establishing a link between the immune system and microvascular dysfunction during ischemic reperfusion. Progress in assessing reperfusion injury has also been made, and we review imaging studies using various magnetic resonance imaging modalities. Lastly, we explore potential treatment approaches, including ischemic preconditioning, postconditioning, pharmacologic agents, and hypothermia.
No preview · Article · Feb 2015 · International Journal of Stroke
[Show abstract][Hide abstract] ABSTRACT: For centuries, physicians believed the brain would tolerate no more than a few minutes of ischemia without suffering permanent cell death. In the 1980s, a series of investigations proved that irreparable damage affects only a portion of the brain tissue so quickly after focal ischemia. Cells in the surrounding region, referred to as the 'ischemic penumbra,' may remain viable for several hours. The elucidation of the penumbra concept-especially the notion that brain regions tolerated prolonged ischemia without permanent death-inspired thoughts about thrombolysis as a possible treatment for stroke. Vascular occlusion results in an immediate drop in cerebral blood flow, cerebral perfusion, and cerebral metabolism within the territory supplied by the occluded artery. The classic model of the penumbra includes a core region where blood flow is too low to allow cell survival, and a surrounding zone where marginal flow allows brain to survive but not function. Cells in the penumbra metabolize slowly, called "idling" to suggest that they are salvageable. In the core, cells die rapidly (within minutes) whereas cells in the penumbra may survive for up to several hours. Restoration of blood flow to this area within an hour or so may salvage the 'viable' cells and diminish the degree of neurological deficits. If reperfusion begins early, penumbral tissue may survive. Neuroprotection targets the penumbra; agents that block the sequence of metabolic events triggered by ischemia might prolong cell survival in the penumbra until such a time as flow is restored. To date, no neuroprotectant has yet entered widespread clinical use.
[Show abstract][Hide abstract] ABSTRACT: Protease activated receptors (PARs) populate neurons and astrocytes in the brain. The serine protease thrombin, which activates PAR-1 during the first hours after stroke, appears to be associated with the cytotoxicity. Thrombin antagonists and PAR-1 inhibitors have been correlated with reduced cell death and behavioral protection after stroke, but no data yet supports a mechanistic link between PAR-1 action and benefit. We sought to establish the essential role of PAR-1 in mediating ischemic damage. Using a short hairpin mRNA packaged with green fluorescent protein in a lentivirus vector, we knocked downPAR-1 in the medial caudate nucleus prior to rat middle cerebral artery occlusion (MCAo) and in rat neurons prior to oxygen-glucose deprivation. We also compared aged PAR-1 knockout mice with aged PAR-3, PAR-4 mice and young wild-type mice in a standard MCAo model. Silencing PAR-1 significantly reduced neurological deficits, reduced endothelial barrier leakage, and decreased neuronal degeneration in vivo during MCAo. PAR-1 knock-down in the ischemic medial caudate allowed cells to survive the ischemic injury; infected cells were negative for TUNEL and c-Fos injury markers. Primary cultured neurons infected with PAR-1 shRNA showed increased neuroprotection during hypoxic/aglycemic conditions with or without added thrombin. The aged PAR-1 knockout mice showed decreased infarction and vascular disruption compared to aged controls or young wild types. We demonstrated an essential role for PAR-1 during ischemia. Silencing or removing PAR-1 significantly protected neurons and astrocytes. Further development of agents that act at PAR-1or its downstream pathways could yield powerful stroke therapy.
[Show abstract][Hide abstract] ABSTRACT: Interventional Management of Stroke (IMS) III is a randomized, parallel arm trial comparing the approach of intravenous tissue plasminogen activator followed by endovascular treatment with intravenous tissue plasminogen activator alone in patients with acute ischemic stroke presenting <3 hours of symptom onset. The trial intended to enroll 900 subjects to ensure adequate statistical power to detect an absolute 10% difference in the percentage of subjects with good outcome, defined as modified Rankin Scale score of 0 to 2 at 3 months. In April 2012, after 656 subjects were randomized, further enrollment was terminated by the National Institute of Neurological Disorders and Stroke based on the prespecified criterion for futility using conditional power <20%.
Conditional power was defined as the likelihood of finding statistical significance at the end of the study, given the accumulated data to date and with the assumption that a minimum hypothesized difference of 10% truly exists between the 2 groups. The evolution of study data leading to futility determination is described, including the interaction between the unblinded study statisticians and the Data and Safety Monitoring Board in the complex deliberation of analysis results.
The futility boundary was crossed at the trial's fourth interim analysis. At this point, based on the conditional power criteria, the Data and Safety Monitoring Board recommended termination of the trial.
Even in spite of prespecified interim analysis boundaries, interim looks at data pose challenges in interpretation and decision making, underscoring the importance of objective stopping criteria.
http://www.clinicaltrials.gov. Unique identifier: NCT00359424.
[Show abstract][Hide abstract] ABSTRACT: We showed previously robust neuroprotection with the thrombin inhibitor argatroban and now sought additional support for its neuroprotective potential.
We used behavioral and histological end points; rigorously blinded the study groups; extended the treatment window to 3 hours after ischemia onset; and used 2 separate models. First, 2-hour filament middle cerebral artery occlusion in 64 male Sprague-Dawley rats was followed by learning and memory testing and quantitative histomorphometry. Randomly assigned treatment was 0.45 mg argatroban, saline, or 0.4 U thrombin. Second, we used the quantal bioassay (n=272) after 2-hour middle cerebral artery occlusion to detect the longest time delay after which therapy failed.
Argatroban powerfully and significantly reversed learning and memory deficits because of focal ischemia compared with saline or thrombin (P<0.03; ANOVA). Argatroban was significantly (P<0.05; t test with Bonferroni) protective when given immediately or after 1, 2, 3, but not 4 hours delay.
We obtained supportive evidence for argatroban protection of the neurovascular unit using behavioral and histological measurements at realistic therapeutic time windows.
[Show abstract][Hide abstract] ABSTRACT: Background and purpose:
Activated Protein C (APC) stimulates multiple cytoprotective pathways via the protease activated receptor-1 (PAR-1) and promotes anticoagulation. 3K3A-APC was designed for preserved activity at PAR-1 with reduced anticoagulation. This Phase 1 trial characterized pharmacokinetics and anticoagulation effects of 3K3A-APC.
Subjects (n=64) were randomly assigned to receive 3K3A-APC (n=4) at 6, 30, 90, 180, 360, 540 or 720 µg/kg or placebo (n=6) and were observed for 24 hr. After safety review additional subjects received drug every 12 hr for 5 doses (n=6 per group) at 90, 180, 360, or 540 µg/kg or placebo (n=8) and were observed for 24 hr.
All subjects returned for safety assessments at 72 hours and 15 days. We found few adverse events in all groups. Systolic blood pressure increased in both active and placebo groups. Moderately severe headache, nausea and vomiting were reported in one of two subjects treated with 720 µg/kg so 540 µg/kg was considered the highest tolerated dose. Mean plasma concentrations increased in proportion to dose. Clearance ranged from 11,693 ± 807 to 18,701 ± 4,797 mL/hr, volume of distribution ranged from 4,873±828 to 6,971 ± 1,169 mL, and elimination half-life ranged from 0.211 ± 0.097 to 0.294 ± 0.054 hours. Elevations in aPTT were minimal.
3K3A-APC was well tolerated at multiple doses as high as 540 µg/kg. These results should be confirmed in stroke patients with relevant co-morbidities. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01660230.
No preview · Article · Dec 2013 · Current pharmaceutical design