Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial

Gao, Xiao; Wei, Jing; Yan, Wei; Wang, Weimin; Lu, Zhenhui

doi:10.1186/cc6887

Cited by 416 publications

(322 citation statements)

References 31 publications

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“…Patients receiving progesterone had a lower 30-day mortality compared to those receiving placebo treatment (Wright et al, 2005). In a second study of 159 severe TBI patients, progesterone administered at 1.0 mg/kg via intramuscular injection and then repeated every 12 h for 5 consecutive days had lower mortality and a more favorable outcome at 3 and 6 months follow-up time points (Xiao et al, 2008).…”

Section: T He Centers For Disease Control and Preventionmentioning

confidence: 92%

The Effect of Progesterone Dose on Gene Expression after Traumatic Brain Injury

Anderson

Farin

Bammler

et al. 2011

Journal of Neurotrauma

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Microarray-based transcriptional profiling was used to determine the effect of progesterone in the cortical contusion (CCI) model. Gene ontology (GO) analysis then evaluated the effect of dose on relevant biological pathways. Treatment (vehicle, progesterone 10 mg/kg or 20 mg/kg given i.p.) was started 4 h post-injury and administered every 12 h post-injury for up to 72 h, with the last injection 12 hr prior to death for the 24 h and 72 h groups. In the CCI-injured vehicle group compared to non-injured animals, expression of 1,114, 4,229, and 291 distinct genes changed > 1.5-fold ( p < 0.05) at 24 h, 72 h, and 7 days, respectively. At 24 h, the effect of low-dose progesterone on differentially expressed genes was < 20% the effect of higher dose compared to vehicle. GO analysis identified a significant effect of low-and high-dose progesterone treatment compared to vehicle on DNA damage response. At 72 h, high-dose progesterone treatment compared to vehicle affected expression of almost twice as many genes as did low-dose progesterone. Both low-and high-dose progesterone resulted in expression of genes regulating inflammatory response and apoptosis. At 7 days, there was only a modest difference in high-dose progesterone compared to vehicle, with only 14 differentially expressed genes. In contrast, low-dose progesterone resulted in 551 differentially expressed genes compared to vehicle. GO analysis identified genes for the low-dose treatment involved in positive regulation of cell proliferation, innate immune response, positive regulation of anti-apoptosis, and blood vessel remodeling.

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Section: T He Centers For Disease Control and Preventionmentioning

confidence: 92%

The Effect of Progesterone Dose on Gene Expression after Traumatic Brain Injury

Anderson

Farin

Bammler

et al. 2011

Journal of Neurotrauma

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“…The HIT III study targeted a subgroup of the overall population, which only included patients with traumatic subarachnoid hemorrhage. The progesterone study reported by Xiao et al 10 concerned a single-center study. The CRASH trials represented the only "mega trial" conducted in the field of TBI.…”

Section: Clinical Trials In Tbi: Past Experiencementioning

confidence: 99%

“…This is important, for example, because of various trials conducted in mainland China that have shown beneficial effects of decompressive craniectomy, hypothermia, and progesterone. 10,[12][13][14][15] These were all well-designed, high-quality studies. However, it is conceivable that differences may exist in referral policies, potential for selection bias, access to health care, acute and post-acute treatments, and outcome.…”

Section: Clinical Trials In Tbi: Past Experiencementioning

confidence: 99%

Clinical Trials in Traumatic Brain Injury: Past Experience and Current Developments

2010

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Summary:In this article, we review past and current experience in clinical trials of traumatic brain injuries (TBIs), we discuss limitations and challenges, and we summarize current directions. The focus is on severe and moderate TBIs. A systematic literature search of the years from 1980 to 2009 revealed 27 large phase III trials in TBI; we were aware of a further 6 unpublished trials. Analysis of these 33 trials yielded interesting observations:• There was a peak incidence of trial initiations that occurred in the mid-1990s with a sharp decline during the period from 2000 to 2004.• Most trials that reported a significant treatment effect were studies on a therapeutic strategy (e.g., decompressive craniectomy, hypothermia), and these were single-center studies.• Increasingly, studies have been shifting toward the Far East.The currently existing trial registries permit insight into ongoing or recently conducted trials. Compared with the past decade, the number of studies on neuroprotective agents taken forward into efficacy-oriented studies is low. In contrast, the number of studies on therapeutic strategies appears to be increasing again.The disappointing results in trials on neuroprotective agents in TBI have led to a critical reappraisal of clinical trial methodology. This has resulted in recommendations for preclinical workup and has triggered extensive analysis on approaches to improve the design and analysis of clinical trials in TBI. An interagency initiative toward standardization on selection and coding of data elements across the broad spectrum of TBI is ongoing, and will facilitate comparison of research findings across studies and encourage high-quality meta-analysis of individual patient data in the future.

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“…75 In another clinical study in 159 patients with acute severe TBI (initial GCS Ͻ 8), treatment with progesterone significantly improved neurological outcome at 6 months. 76 A phase III clinical study with progesterone in TBI patients is under way (http://www.Clinicaltrials.gov Identifier: NCT00822900).…”

Section: Clinical Studiesmentioning

confidence: 99%

Use of Magnesium in Traumatic Brain Injury

Sen¹,

Gulati

2010

Neurotherapeutics

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Summary: Depletion of magnesium is observed in animal brain and in human blood after brain injury. Treatment with magnesium attenuates the pathological and behavioral changes in rats with brain injury; however, the therapeutic effect of magnesium has not been consistently observed in humans with traumatic brain injury (TBI). Secondary brain insults are observed in patients with brain injury, which adversely affect clinical outcome. Systemic administration studies in rats have shown that magnesium enters the brain; however, inducing hypermagnesemia in humans did not concomitantly increase magnesium levels in the CSF. We hypothesize that the neuroprotective effects of magnesium in TBI patients could be observed by increasing its brain bioavailability with mannitol. Here, we review the role of magnesium in brain injury, preclinical studies in brain injury, clinical safety and efficacy studies in TBI patients, brain bioavailability studies in rat, and pharmacokinetic studies in humans with brain injury. Neurodegeneration after brain injury involves multiple biochemical pathways. Treatment with a single agent has often resulted in poor efficacy at a safe dose or toxicity at a therapeutic dose. A successful neuroprotective therapy needs to be aimed at homeostatic control of these pathways with multiple agents. Other pharmacological agents, such as dexanabinol and progesterone, and physiological interventions, with hypothermia and hyperoxia, have been studied for the treatment of brain injury. Treatment with magnesium and hypothermia has shown favorable outcome in rats with cerebral ischemia. We conclude that coadministration of magnesium and mannitol with pharmacological and physiological agents could be an effective neuroprotective regimen for the treatment of TBI.

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Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial

Cited by 416 publications

References 31 publications

The Effect of Progesterone Dose on Gene Expression after Traumatic Brain Injury

The Effect of Progesterone Dose on Gene Expression after Traumatic Brain Injury

Clinical Trials in Traumatic Brain Injury: Past Experience and Current Developments

Use of Magnesium in Traumatic Brain Injury

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