Journal of neurotrauma
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Journal of neurotrauma · Dec 2005
Randomized Controlled Trial Multicenter StudyA single dose, three-arm, placebo-controlled, phase I study of the bradykinin B2 receptor antagonist Anatibant (LF16-0687Ms) in patients with severe traumatic brain injury.
Traumatic brain injury (TBI) mortality and morbidity remains a public health challenge. Because experimental studies support an important role of bradykinin (BK) in the neurological deterioration that follows TBI, a double-blind, randomized, placebo-controlled study of Anatibant (LF16- 0687Ms), a selective and potent antagonist of the BK B(2) receptor, was conducted in severe (Glasgow Coma Scale [GCS] < 8) TBI patients (n = 25) at six sites in the United States. At 8-12 h after injury (9.9 +/- 2.8 h), patients received a single subcutaneous injection of Anatibant (3.75 mg or 22.5 mg, n = 10 each) or placebo (n = 5). ⋯ Anatibant, administered as single subcutaneous injections of 3.75 g and 22.5 mg, was well tolerated in severe TBI patients with no unexpected clinical adverse events or biological abnormalities observed. Interestingly, plasma and CSF levels of BK1-5 were significantly and markedly increased after trauma (e.g., 34,700 +/- 35,300 fmol/mL in plasma vs. 34.9 +/- 5.6 fmol/mL previously reported for normal volunteers), supporting the use of Anatibant as a treatment of secondary brain damage. To address this issue, a dose-response trial that would investigate the effects of Anatibant on the incidence of raised ICP and on functional outcome in severe TBI patients is needed.
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Journal of neurotrauma · Dec 2005
Comparative StudyMethylprednisolone causes minimal improvement after spinal cord injury in rats, contrasting with benefits of an anti-integrin treatment.
Spinal cord injury (SCI) leads to complex secondary events that expand and exacerbate the injury. Methylprednisolone (MP) has been considered a standard of care for acute SCI. The purpose of this study was to test the effects of MP, in severe and more moderate severe clip-compression models of SCI, on the measures of neurological function and lesion sparing that we used previously to assess a highly effective anti-inflammatory therapy, a monoclonal antibody (mAb) to the CD11d integrin. ⋯ The poor neurological outcome after MP treatment may relate to the long-lasting reduction in hematogenous monocyte/macrophages within the injury site that it causes and to the prolongation of a neutrophil presence. These findings demonstrate that the non-selective and enduring effects of immunosuppressive therapy with MP not only fail to improve neurological outcomes, but also can block the beneficial actions of selective therapies such as the anti-CD11d mAb. Combination treatments that cause intense immunosuppression should be viewed with caution.
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Journal of neurotrauma · Dec 2005
Electrical stimulation of the vagus nerve enhances cognitive and motor recovery following moderate fluid percussion injury in the rat.
Intermittent, chronically delivered electrical stimulation of the vagus nerve (VNS) is an FDA-approved procedure for the treatment of refractory complex/partial epilepsy in humans. Stimulation of the vagus has also been shown to enhance memory storage processes in laboratory rats and human subjects. Recent evidence suggests that some of these effects of VNS may be due to the activation of neurons in the nucleus locus coeruleus resulting in the release of norepinephrine (NE) throughout the neuraxis. ⋯ Despite these behavioral effects, neurohistological examination did not reveal significant differences in lesion extent, density of fluorojade positive neurons, reactive astrocytes or numbers of spared neurons in the CA3 subarea of the hippocampus, at least at the one time point studied 15 days post-injury. These results support the idea that vagus nerve stimulation enhances the neural plasticity that underlies recovery of function following brain damage and provides indirect support for the hypothesis that enhanced NE release may mediate the effect. Importantly, since VNS facilitated both the rate of recovery and the extent of motor and cognitive recovery, these findings suggest that electrical stimulation of the vagus nerve may prove to be an effective non-pharmacological treatment for traumatic brain injury.