A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury

Marshall, Lawrence F.; Maas, Andrew I. R.; Marshall, Sharon Bowers; Bricolo, Albino; Fearnside, Michael R.; Iannotti, Fausto; Klauber, Melville R.; Lagarrigue, J; Lobato, R.D.; Persson, Lennart; Pickard, John D.; Piek, J.; Servadei, Franco; Wellis, G.; Morris, Gabrielle F.; Means, Eugene D.; Musch, B

doi:10.3171/jns.1998.89.4.0519

Cited by 316 publications

(137 citation statements)

References 11 publications

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“…113 The free radical scavenger tirilazad mesylate also failed to show any benefit over placebo in a randomized controlled trial of adults with severe and moderate TBI with the exception of males presenting with a subarachnoid hemorrhage. 114 In this group, tirilazad mesylate treatment significantly reduced mortality at six months post-injury. Dexanabinol, a synthetic cannabinoid with antioxidant, anti-inflammatory, and antiglutamatergic properties, has also undergone phase II testing in severe TBI patients.…”

Section: Oxidative Damagementioning

confidence: 99%

Traumatic injury to the immature brain: Inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets

Potts

Koh

Whetstone

et al. 2006

NeuroRX

137

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Summary: Traumatic brain injury (TBI) is the leading cause of morbidity and mortality among children and both clinical and experimental data reveal that the immature brain is unique in its response and vulnerability to TBI compared to the adult brain. Current therapies for pediatric TBI focus on physiologic derangements and are based primarily on adult data. However, it is now evident that secondary biochemical perturbations play an important role in the pathobiology of pediatric TBI and may provide specific therapeutic targets for the treatment of the head-injured child. In this review, we discuss three specific components of the secondary pathogenesis of pediatric TBIinflammation, oxidative injury, and iron-induced damage -and potential therapeutic strategies associated with each. The inflammatory response in the immature brain is more robust than in the adult and characterized by greater disruption of the blood-brain barrier and elaboration of cytokines. The immature brain also has a muted response to oxidative stress compared to the adult due to inadequate expression of certain antioxidant molecules. In addition, the developing brain is less able to detoxify free iron after TBI-induced hemorrhage and cell death. These processes thus provide potential therapeutic targets that may be tailored to pediatric TBI, including anti-inflammatory agents such as minocycline, antioxidants such as glutathione peroxidase, and the iron chelator deferoxamine.

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Section: Oxidative Damagementioning

confidence: 99%

Traumatic injury to the immature brain: Inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets

Potts

Koh

Whetstone

et al. 2006

NeuroRX

137

View full text Add to dashboard Cite

show abstract

“…In trials performed under EFIC in the traumatic brain injury (TBI) population, the rate of missing endpoint data has been as high as 14%. [9][10][11][12][13] In a recently published analysis of alternative statistical modeling strategies for missing data in a TBI trial, the authors reported missing outcome data in 15% of treated patients attributed to denied consent or loss to follow-up. 14 For trials where hospital discharge outcome data are the primary endpoints, and these data exist in a patient's medical record as part of routine documentation of clinical care, investigators and IRBs are left with a challenging question: should informed consent be required for collection of hospital outcomes data that exist as part of routine clinical care?…”

Section: Discussionmentioning

confidence: 99%

The Association of Health Status and Providing Consent to Continued Participation in an Out‐of‐hospital Cardiac Arrest Trial Performed Under Exception From Informed Consent

Salzman

Frascone

Burkhart

et al. 2015

Academic Emergency Medicine

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Objectives: Emergency medical research performed under federal regulation 21 § CFR 50.24 provides a means to protect human subjects and investigate novel time-sensitive treatments. Although prospective individual consent is not required for studies conducted under this regulation, consent from a legally authorized representative (LAR) or the patient at the earliest feasible opportunity is required to obtain short-and long-term outcome data. The objective of this study was to determine which demographic, cardiac arrest, and patient outcome characteristics predicted the likelihood of obtaining informed consent following enrollment under exception from informed consent in a multicenter cardiac arrest study. Methods:This investigation was an analysis of data collected during a multisite, randomized, controlled, out-of-hospital cardiac arrest clinical trial performed under 21 § CFR 50.24. Research personnel attempted to obtain informed consent from LARs and subjects for medical records review of primary outcome data, as well as consent for neurologic outcome assessments up to 1 year post-cardiac arrest. Hospital discharge and neurologic status were obtained from public records and/or medical records up until the time consent was formally denied, in accordance with federal regulations and guidance. Local institutional review boards also allowed medical records review for cases where consent was neither obtained nor declined despite multiple consent attempts. Patient demographic, cardiac arrest, and clinical outcome characteristics were analyzed in univariate multinomial regression models, with consent status (obtained, denied, neither obtained nor denied) as the dependent variable. A multivariate multinomial logistic regression was then performed. An exploratory secondary analysis following the same process was performed after assigning patients who neither consented nor declined to the declined consent group.Results: Among a total study population of 1,655 cardiac arrest subjects, 457 were transported and had consent attempted (27.6%). The survival status and neurologic function at the time of hospital discharge were known in 440 of 457 (96%) subjects. In the multivariate analysis, initial rhythm of ventricular fibrillation/ventricular tachycardia (VF/VT) and survival with good neurologic outcome were strong predictors of obtaining consent (odds ratio [OR] = 3.15, 95% confidence interval [CI] = 1.73 to 5.75;

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“…155,156 In a randomized, controlled trial, adults with moderate to severe TBI treated with tirilazad mesylate failed to show any benefit when compared with placebo. 157 …”

Section: Other Chronic Brain Disordersmentioning

confidence: 99%

Iron in Chronic Brain Disorders: Imaging and Neurotherapeutic Implications

et al. 2007

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Summary:Iron is important for brain oxygen transport, electron transfer, neurotransmitter synthesis, and myelin production. Though iron deposition has been observed in the brain with normal aging, increased iron has also been shown in many chronic neurological disorders including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. In vitro studies have demonstrated that excessive iron can lead to free radical production, which can promote neurotoxicity. However, the link between observed iron deposition and pathological processes underlying various diseases of the brain is not well understood. It is not known whether excessive in vivo iron directly contributes to tissue damage or is solely an epiphenomenon. In this article, we focus on the imaging of brain iron and the underlying physiology and metabolism relating to iron deposition. We conclude with a discussion of the potential implications of iron-related toxicity to neurotherapeutic development.

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A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury

Cited by 316 publications

References 11 publications

Traumatic injury to the immature brain: Inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets

Traumatic injury to the immature brain: Inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets

The Association of Health Status and Providing Consent to Continued Participation in an Out‐of‐hospital Cardiac Arrest Trial Performed Under Exception From Informed Consent

Iron in Chronic Brain Disorders: Imaging and Neurotherapeutic Implications

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