ProTECT: A Randomized Clinical Trial of Progesterone for Acute Traumatic Brain Injury

Wright, David W.; Kellermann, Arthur L.; Hertzberg, Vicki; Clark, Pamela; Frankel, Michael; Goldstein, Felicia C.; Salomone, Jeffrey P.; Dent, Louise; Harris, Odette A.; Ander, Douglas S.; Lowery, Douglas W.; Patel, Manish; Denson, Donald D.; Gordon, Angelita B.; Wald, Marlena M.; Gupta, Sanjay; Hoffman, Stuart W.; Stein, Donald G.

doi:10.1016/j.annemergmed.2006.07.932

Cited by 526 publications

(420 citation statements)

References 60 publications

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“…Also, moderate to good clinical outcome with improved GOS-E scores were observed in patients with moderate TBI (initial GCS 9 -12), but no differences were observed between progesterone treatment and placebo groups for patients with severe TBI. 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: 95%

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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Section: Clinical Studiesmentioning

confidence: 95%

Use of Magnesium in Traumatic Brain Injury

Sen¹,

Gulati

2010

Neurotherapeutics

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“…In addition to the neuroprotective effects in experimental TBI, clinical studies suggest that pharmacological dosing of progesterone can improve neurological outcomes after TBI. 48 However, progesterone effects on other hormones and/or aromatase activity have not been conducted. Further, the role of estradiol treatment in the TBI population is still unknown.…”

Section: Garringer Et Almentioning

confidence: 99%

Impact of Aromatase Genetic Variation on Hormone Levels and Global Outcome after Severe TBI

Garringer

Niyonkuru

McCullough

et al. 2013

Journal of Neurotrauma

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Although experimental traumatic brain injury (TBI) studies support estradiol as a neuroprotectant and potent stimulator of neuroplasticity, clinical studies suggest a negative association between endogenous estradiol profiles and mortality/poor outcomes. However, no studies have evaluated associations with cerebral spinal fluid (CSF) hormone profiles and aromatase gene (cytochrome P450 [CYP]19A1) variability on clinical TBI outcomes. We evaluated 110 adults with severe TBI. Average and daily estradiol, testosterone, and estradiol/testosterone ratios (E2:T) were measured using CSF and serum samples and compared to healthy controls. Eighteen tagging and four functional single-nucleotide polymorphisms (SNPs) for CYP19A1 were genotyped and compared to hormones, acute mortality, and Glasgow Outcome Scale (GOS) scores 6 months post-TBI. TBI subjects had lower CSF estradiol over time versus controls. CSF testosterone was initially high, but declined over time. E2/T ratios were initially low, compared to controls, but rose over time. Higher mean E2/T ratio in bivariate analysis was associated with lower mortality ( p = 0.019) and better GOS-6 scores ( p = 0.030). rs2470152 influenced CSF E2/T ratio and also serum and CSF testosterone ( p £ 0.05 all comparisons). Multiple-risk SNPs rs2470152, rs4646, and rs2470144 were associated with worse GOS-6 scores ( p £ 0.05, all comparisons), and those with > 1 risk SNP variant had a higher risk for poor outcome, compared with those with £ 1 risk variant. TBI results in low CSF estradiol and dynamic CSF testosterone and E2/T ratio. In contrast to clinical serum hormone studies, higher CSF E2/T ratio was associated with better outcome. Further, genetic variation in CYP19A1 influences both hormone dynamics and outcome post-TBI.

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“…26 Preliminary clinical data obtained with the use of various progesterone formulations and routes of delivery, combined with experimental data showing adequate brain penetration, provided initial support for a neuroprotective role of progesterone in TBI. The initial PROTECT trial 13 recruited 100 patients from a single site who had a GCS score of 4 to 12. Treatment was initiated within 11 hours after injury, with a 72-hour treatment duration, and was associated with a reduction in the rate of death from any cause, as compared with placebo (13.0% vs. 30.4%; relative risk, 0.43; 95% CI, 0.18 to 0.99).…”

Section: Adverse Eventsmentioning

confidence: 99%

“…12 In addition, two phase 2 randomized, controlled clinical trials with progesterone showed a clinical benefit. 13,14 On the basis of these collective data, two phase 3 trials were initiated at around the same time: the Study of a Neuroprotective Agent, Progesterone, in Severe Traumatic Brain Injury (SYNAPSE) and the Progesterone for the Treatment of Traumatic Brain Injury (PROTECT III) trial. 15 SYNAPSE, a trial sponsored by BHR Pharma, was designed to investigate the clinical effectiveness of progesterone, provided in a 6% soybeanoil emulsion as a ready-to-use formulation, under well-controlled conditions.…”

mentioning

confidence: 99%