8 results on '"Bullock MR"'
Search Results
2. Safety and tolerability of cyclosporin a in severe traumatic brain injury patients: results from a prospective randomized trial.
- Author
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Mazzeo AT, Brophy GM, Gilman CB, Alves OL, Robles JR, Hayes RL, Povlishock JT, and Bullock MR
- Subjects
- Adolescent, Adult, Aged, Anti-Inflammatory Agents administration & dosage, Anti-Inflammatory Agents adverse effects, Anti-Inflammatory Agents pharmacokinetics, Biomarkers, Blood Urea Nitrogen, Brain Injuries mortality, Creatinine blood, Cyclosporine adverse effects, Cyclosporine pharmacokinetics, Double-Blind Method, Drug-Related Side Effects and Adverse Reactions, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors adverse effects, Enzyme Inhibitors pharmacokinetics, Female, Humans, Immunosuppressive Agents administration & dosage, Immunosuppressive Agents adverse effects, Immunosuppressive Agents pharmacokinetics, Kidney drug effects, Leukocyte Count, Male, Middle Aged, Neuroprotective Agents adverse effects, Neuroprotective Agents pharmacokinetics, Placebos, Prospective Studies, Treatment Outcome, Young Adult, Brain Injuries drug therapy, Brain Injuries physiopathology, Cyclosporine administration & dosage, Neuroprotective Agents administration & dosage
- Abstract
Cyclosporin A (CsA) has recently been proposed for use in the early phase after traumatic brain injury (TBI), for its ability to preserve mitochondrial integrity in experimental brain injury models, and thereby provide improved behavioral outcomes as well as significant histological protection. The aim of this prospective, randomized, double-blind, dual-center, placebo-controlled trial was to evaluate the safety, tolerability, and pharmacokinetics of a single intravenous infusion of CsA in patients with severe TBI. Fifty adult severe TBI patients were enrolled over a 22-month period. Within 12 h of the injury patients received 5 mg/kg of CsA infused over 24 h, or placebo. Blood urea nitrogen (BUN), creatinine, hemoglobin, platelets, white blood cell count (WBC), and a hepatic panel were monitored on admission, and at 12, 24, 36, and 48 h, and on days 4 and 7. Potential adverse events (AEs) were also recorded. Neurological outcome was recorded at 3 and 6 months after injury. This study revealed only transient differences in BUN levels at 24 and 48 h and for WBC counts at 24 h between the CsA and placebo patients. These modest differences were not clinically significant in that they did not negatively impact on patient course. Both BUN and creatinine values, markers of renal function, remained within their normal limits over the entire monitoring period. There were no significant differences in other mean laboratory values, or in the incidence of AEs at any other measured time point. Also, no significant difference was demonstrated for neurological outcome. Based on these results, we report a good safety profile of CsA infusion when given at the chosen dose of 5 mg/kg, infused over 24 h, during the early phase after severe head injury in humans, with the aim of neuroprotection.
- Published
- 2009
- Full Text
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3. Perfluorocarbon emulsions improve cognitive recovery after lateral fluid percussion brain injury in rats.
- Author
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Zhou Z, Sun D, Levasseur JE, Merenda A, Hamm RJ, Zhu J, Spiess BD, and Bullock MR
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- Animals, Blood Pressure drug effects, Brain Injuries complications, Brain Injuries physiopathology, Cell Count, Cognition Disorders etiology, Disease Models, Animal, Hippocampus drug effects, Hippocampus injuries, Hippocampus pathology, Male, Maze Learning drug effects, Neurons drug effects, Neurons pathology, Oxygen Consumption drug effects, Oxygen Inhalation Therapy, Rats, Rats, Sprague-Dawley, Recovery of Function drug effects, Wounds, Nonpenetrating, Brain Injuries drug therapy, Cognition Disorders drug therapy, Fluorocarbons therapeutic use, Neuroprotective Agents therapeutic use
- Abstract
Objective: Perfluorocarbon emulsions have been shown to improve outcomes in stroke models. This study examined the effect of Oxycyte, a third-generation perfluorocarbon emulsion (04RD33; Synthetic Blood International, Inc., Costa Mesa, CA) treatment on cognitive recovery and mitochondrial oxygen consumption after a moderate lateral fluid percussion injury (LFPI)., Methods: Adult male Sprague-Dawley rats (Harlan Bioproducts for Science, Indianapolis, IN) were allocated to 4 groups: 1) LFPI treated with a lower dose of Oxycyte (4.5 mL/kg); 2) LFPI with a higher dose of Oxycyte (9.0 mL/kg); 3) LFPI with saline infusion; and 4) sham animals treated with saline. Fifteen minutes after receiving moderate LFPI or sham surgery, animals were infused intravenously with Oxycyte or saline within 30 minutes while breathing 100% O2. Animals breathed 100% O2 continuously for a total of 4 hours after injury. At 11 to 15 days after LFPI, animals were assessed for cognitive deficits using the Morris water maze test. They were sacrificed at Day 15 after injury for histology to assess hippocampal neuronal cell loss. In a parallel study, mitochondrial oxygen consumption values were measured by the Cartesian diver microrespirometer method., Results: We found that injured animals treated with a lower or higher dose of Oxycyte had significant improvement in cognitive function when compared with injured saline-control animals (P < 0.05). Moreover, injured animals that received either dose of Oxycyte had significantly less neuronal cell loss in the hippocampal CA3 region compared with saline-treated animals (P < 0.05). Furthermore, a lower dose of Oxycyte significantly improved mitochondrial oxygen consumption levels (P < 0.05)., Conclusion: The current study demonstrates that Oxycyte can improve cognitive recovery and reduce CA3 neuronal cell loss after traumatic brain injury in rats.
- Published
- 2008
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4. The effect of the selective NMDA receptor antagonist traxoprodil in the treatment of traumatic brain injury.
- Author
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Yurkewicz L, Weaver J, Bullock MR, and Marshall LF
- Subjects
- Adolescent, Adult, Aged, Brain Injuries mortality, Excitatory Amino Acid Antagonists blood, Female, Glasgow Outcome Scale, Humans, Male, Middle Aged, Neuroprotective Agents blood, Piperidines blood, Recovery of Function, Survival Analysis, Survival Rate, Treatment Outcome, Brain Injuries drug therapy, Excitatory Amino Acid Antagonists therapeutic use, Neuroprotective Agents therapeutic use, Piperidines therapeutic use, Receptors, N-Methyl-D-Aspartate antagonists & inhibitors
- Abstract
Traumatic brain injury (TBI) remains a major public health problem, and there is a great medical need for a pharmacological treatment that could improve long-term outcome. The excitatory neurotransmitter, glutamate, has been implicated in processes leading to neurodegeneration. Traxoprodil (CP-101,606) is a novel and potent glutamate receptor antagonist that is highly selective for the NR2B subunit of the NMDA receptor; it has been shown to be neuroprotective in animal models of brain injury and ischemia. A randomized, double-blind, placebo-controlled study was therefore conducted to assess the efficacy and safety of a 72-h infusion of traxoprodil compared to placebo in subjects with computed tomography scan evidence of severe TBI (GCS 4-8). A total of 404 males and non-pregnant females, aged 16-70, were treated within 8 h of injury. At baseline, subjects were stratified by motor score severity. The results showed that a greater proportion of the traxoprodil-treated subjects had a favorable outcome on the dichotomized Glasgow Outcome Scale (dGOS) at 6 months (delta 5.5%, OR 1.3, p = 0.21, 95% CI:[0.85, 2.06]) and at last visit (delta 7.5%, OR 1.47, p = 0.07, 95% CI:[0.97, 2.25]). The mortality rate with traxoprodil treatment was 7% less than with placebo treatment (OR 1.45, p = 0.08, 95% CI:[0.96, 2.18]). Differences between treatment groups were more pronounced in the severest subset (delta 11.8% for the dGOS at last visit and delta 16.6% for mortality). Traxoprodil was well tolerated. Although these results are intriguing, no definitive claim of efficacy can be made for traxoprodil for the treatment of severe TBI.
- Published
- 2005
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5. Intraventricular infusion of the neurotrophic protein S100B improves cognitive recovery after fluid percussion injury in the rat.
- Author
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Kleindienst A, Harvey HB, Rice AC, Müller C, Hamm RJ, Gaab MR, and Bullock MR
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- Animals, Brain Injuries blood, Injections, Intraventricular, Male, Maze Learning drug effects, Nerve Growth Factors blood, Phosphopyruvate Hydratase blood, Rats, Rats, Sprague-Dawley, Recovery of Function, S100 Calcium Binding Protein beta Subunit, S100 Proteins blood, Brain Injuries drug therapy, Cognition drug effects, Nerve Growth Factors administration & dosage, Neuroprotective Agents therapeutic use, S100 Proteins administration & dosage
- Abstract
Elevated serum S100B levels have been shown to be a predictor of poor outcome after traumatic brain injury (TBI). Experimental data, on the other hand, demonstrate a neuroprotective and neurotrophic effect of this calcium-binding protein. The purpose of this study was to examine the role of increased S100B levels on functional outcome after TBI. Following lateral fluid percussion or sham injury in male Sprague Dawley rats (n = 56), we infused S100B (50 ng/h) or vehicle into the cerebrospinal fluid of the ipsilateral ventricle for 7 days using an osmotic mini-pump. Assessment of cognitive performance by the Morris water maze on days 30-34 after injury revealed an improved performance of injured animals after S100B infusion (p < 0.05), when compared to vehicle infusion. Blood samples for analysis of clinical markers of brain damage, S100B and neuron specific enolase, taken at 30 min, 3 h, 4 h, 2 days, or 5 days showed a typical peak 3 h after injury (p < 0.01), and higher serum levels correlated significantly with an impaired cognitive recovery (p < 0.01). The correlation of higher serum S100B levels with poor water maze performance may result from injury induced opening of the blood-brain barrier, allowing the passage of S100B into serum. Thus while higher serum levels of S100B seem to reflect the degree of blood-brain barrier opening and severity of injury, a beneficial effect of intraventricular S100B administration on long-term functional recovery after TBI has been demonstrated for the first time. The exact mechanism by which S100B exerts its neuroprotective or neurotrophic influence remains unknown and needs to be elucidated by further investigation.
- Published
- 2004
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6. Critical appraisal of neuroprotection trials in head injury: what have we learned?
- Author
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Tolias CM and Bullock MR
- Subjects
- Animals, Clinical Trials as Topic, Humans, Research Design, Craniocerebral Trauma drug therapy, Neuroprotective Agents therapeutic use
- Abstract
To date, despite very encouraging preclinical results, almost all phase II/III clinical neuroprotection trials in traumatic brain injury (TBI) have failed to show any consistent improvement in outcome for TBI patients. To understand the reasons behind such developments we need to review and evaluate the evolution of trial design as a result of our changing understanding of the pathophysiology of brain cell death and progress of translational research from the laboratory bench to the bedside. This paper attempts to critically appraise these neuroprotection trials, rationalize the paucity of effectiveness, review any recent developments in the field, and try to draw some conclusions on how to move forward.
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- 2004
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7. Lactate administration attenuates cognitive deficits following traumatic brain injury.
- Author
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Rice AC, Zsoldos R, Chen T, Wilson MS, Alessandri B, Hamm RJ, and Bullock MR
- Subjects
- Animals, Brain Chemistry drug effects, Brain Chemistry physiology, Brain Injuries metabolism, Brain Injuries physiopathology, Cell Death drug effects, Cell Death physiology, Cognition Disorders etiology, Cognition Disorders physiopathology, Energy Metabolism drug effects, Energy Metabolism physiology, Hippocampus pathology, Hippocampus physiopathology, Homeostasis drug effects, Homeostasis physiology, Lactic Acid metabolism, Male, Maze Learning physiology, Nerve Degeneration drug therapy, Nerve Degeneration etiology, Nerve Degeneration prevention & control, Neurons metabolism, Neurons pathology, Neuroprotective Agents metabolism, Rats, Rats, Sprague-Dawley, Brain Injuries drug therapy, Cognition Disorders drug therapy, Hippocampus drug effects, Lactic Acid pharmacology, Maze Learning drug effects, Neurons drug effects, Neuroprotective Agents pharmacology
- Abstract
Moderately head injured patients often suffer long term neurological sequelae. There is no therapy for brain trauma and current treatments aim only to minimize secondary damage. These secondary effects are often triggered by the inability to re-establish ionic homeostasis after injury, due to large energy demands. Recent reports have demonstrated that neurons are capable of utilizing lactate as an energy source, thus this report examines the usefulness of lactate administration in the attenuation of behavioural deficits following a moderate brain injury. Lactate infusion (i.v.) was started 30 min after lateral fluid percussion injury and continued for 3 h. Cognitive deficits were determined using the Morris water maze. Lactate infused injured animals demonstrated significantly less cognitive deficits than saline infused injured animals. Thus, lactate infusion attenuated the cognitive deficits normally observed in this model, and therefore may provide moderately head injured patients with a treatment to help ameliorate the sequelae.
- Published
- 2002
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8. Current status of neuroprotection trials for traumatic brain injury: lessons from animal models and clinical studies.
- Author
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Bullock MR, Lyeth BG, and Muizelaar JP
- Subjects
- Animals, Clinical Trials as Topic, Disease Models, Animal, Humans, Brain Injuries drug therapy, Neuroprotective Agents therapeutic use
- Abstract
Laboratory studies have identified numerous potential therapeutic interventions that might have clinical application for the treatment of human traumatic brain injury. Many of these therapies have progressed into human clinical trials in severe traumatic brain injury. Numerous trials have been completed, and many others have been prematurely terminated or are currently in various phases of testing. The results of the completed Phase III trials have been generally disappointing, compared with the expectations produced by the successes of these interventions in animal laboratory studies. In this review, we summarize the current status of human traumatic brain injury clinical trials, as well as the animal laboratory studies that led to some of these trials. We summarize criteria for conducting clinical trials in severe traumatic brain injury, with suggestions for future improvements. We also attempt to identify factors that might contribute to the discrepancies between animal and human trials, and we propose recommendations that could help investigators avoid certain pitfalls in future clinical trials in traumatic brain injury.
- Published
- 1999
- Full Text
- View/download PDF
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