Perispinal etanercept stroke trial design: PESTO and beyond.

Introduction: Perispinal etanercept (PSE) is an innovative treatment designed to improve stroke recovery by addressing chronic post-stroke neuroinflammation. Basic science evidence, randomized clinical trial (RCT) evidence and 14 years of favorable clinical experience support the use of PSE to treat chronic stroke. This article provides guidance for the design of future PSE RCTs in accordance with current FDA recommendations.

Rapid improvement in severe long COVID following perispinal etanercept.

Background: This study aimed to describe the neurological improvements in a patient with severe long COVID brain dysfunction following perispinal etanercept administration. Perispinal administration of etanercept, a novel method designed to enhance its brain delivery via carriage in the cerebrospinal venous system, has previously been shown to reduce chronic neurological dysfunction after stroke. Etanercept is a recombinant biologic that is capable of ameliorating two components of neuroinflammation: microglial activation and the excess bioactivity of tumor necrosis factor (TNF), a proinflammatory cytokine that is a key neuromodulator in the brain.

Perispinal injection of a TNF blocker directed to the brain of rats alleviates the sensory and affective components of chronic constriction injury-induced neuropathic pain.

Neuropathic pain is chronic pain that follows nerve injury, mediated in the brain by elevated levels of the inflammatory protein tumor necrosis factor-alpha (TNF). We have shown that peripheral nerve injury increases TNF in the hippocampus/pain perception region, which regulates neuropathic pain symptoms. In this study we assessed pain sensation and perception subsequent to specific targeting of brain-TNF (via TNF antibody) administered through a novel subcutaneous perispinal route.

Perispinal Delivery of CNS Drugs.

Perispinal injection is a novel emerging method of drug delivery to the central nervous system (CNS). Physiological barriers prevent macromolecules from efficiently penetrating into the CNS after systemic administration. Perispinal injection is designed to use the cerebrospinal venous system (CSVS) to enhance delivery of drugs to the CNS.

Perispinal etanercept for post-stroke neurological and cognitive dysfunction: scientific rationale and current evidence.

There is increasing recognition of the involvement of the immune signaling molecule, tumor necrosis factor (TNF), in the pathophysiology of stroke and chronic brain dysfunction. TNF plays an important role both in modulating synaptic function and in the pathogenesis of neuropathic pain. Etanercept is a recombinant therapeutic that neutralizes pathologic levels of TNF.

Immediate neurological recovery following perispinal etanercept years after brain injury.

Positron emission tomographic brain imaging and pathological examination have revealed that a chronic, intracerebral neuroinflammatory response lasting for years after a single brain injury may occur in humans. Evidence suggests the immune signaling molecule, tumor necrosis factor (TNF), is centrally involved in this pathology through its modulation of microglial activation, role in synaptic dysfunction, and induction of depressive symptoms and neuropathic pain. Etanercept is a recombinant TNF receptor fusion protein and potent TNF inhibitor that has been found to reduce microglial activation and neuropathic pain in multiple experimental models.

Selective TNF inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients treated with perispinal etanercept.

Background: Brain injury from stroke and traumatic brain injury (TBI) may result in a persistent neuroinflammatory response in the injury penumbra. This response may include microglial activation and excess levels of tumour necrosis factor (TNF). Previous experimental data suggest that etanercept, a selective TNF inhibitor, has the ability to ameliorate microglial activation and modulate the adverse synaptic effects of excess TNF.

Deciphering the physiology underlying the rapid clinical effects of perispinal etanercept in Alzheimer's disease.

Excess tumor necrosis factor (TNF) plays a pivotal role in the pathogenesis of Alzheimer's disease(AD). Clinical improvement following perispinal administration of etanercept in patients with Alzheimer's disease and other forms of dementia and brain dysfunction is characteristically evident within minutes. The rapidity and constellation of the clinical effects across multiple domains (cognition, mood, memory, motor function, and attention) suggest they are mediated by non-synaptic signaling mechanisms previously unrecognized for etanercept.

Rapid improvement of chronic stroke deficits after perispinal etanercept: three consecutive cases.

Background: Thrombolytic therapy reduces stroke size and disability by reperfusion and salvage of ischaemic penumbra. Emerging evidence suggests that retrieved penumbra may be the site of ongoing inflammatory pathology that includes extensive microglial activation. Microglial activation may be associated with excessive levels of tumour necrosis factor (TNF) and resultant neurotoxicity.

Perispinal etanercept: a new therapeutic paradigm in neurology.

Etanercept is a potent antagonist of TNF, a pleotropic immune signaling molecule that is also a pivotal regulator of synaptic function. Excess TNF is centrally involved in the pathogenesis of a variety of inflammatory neurological disorders, including Alzheimer's disease, sciatica, traumatic brain injury and spinal cord injury. Perispinal etanercept produces rapid improvement in both Alzheimer's disease and sciatica and in other forms of disc-related pain.

Tumour necrosis factor modulation for treatment of Alzheimer's disease: rationale and current evidence.

Tumour necrosis factor (TNF), a key regulator of varied physiological mechanisms in multiple organ systems, is an immune signalling molecule produced by glia, neurons, macrophages and other immune cells. In the brain, among other functions, TNF serves as a gliotransmitter, secreted by glial cells that envelope and surround synapses, which regulates synaptic communication between neurons. The role of TNF as a gliotransmitter may help explain the profound synaptic effects of TNF that have been demonstrated in the hippocampus, in the spinal cord and in a variety of experimental models.

WITHDRAWN: PET Imaging Reveals that Etanercept Crosses the Blood-Cerebrospinal Fluid but not the Blood-Brain Barrier: Implications for Alzheimer's Disease.

Ahead of Print article withdrawn by publisher.

The value of drug repositioning in the current pharmaceutical market.

Drug repositioning is the process of developing new indications for existing drugs or biologics. Increasing interest in drug repositioning has occurred due to sustained high failure rates and costs involved in attempts to bring new drugs to market. It has been estimated that it may cost more than USD 800 million to develop a new drug de novo.

Rapid intracerebroventricular delivery of Cu-DOTA-etanercept after peripheral administration demonstrated by PET imaging.

Background: The cytokines interleukin-1 and tumor necrosis factor (TNF), and the cytokine blocker interleukin-1 receptor antagonist, all have been demonstrated to enter the cerebrospinal fluid (CSF) following peripheral administration. Recent reports of rapid clinical improvement in patients with Alzheimer's disease and related forms of dementia following perispinal administration of etanercept, a TNF antagonist, suggest that etanercept also has the ability to reach the brain CSF. To investigate, etanercept was labeled with a positron emitter to enable visualization of its intracranial distribution following peripheral administration by PET in an animal model.

Perispinal etanercept for neuroinflammatory disorders.

Excess TNF is centrally involved in the pathogenesis of a variety of neuroinflammatory disorders, including Alzheimer's disease, other forms of dementia, intervertebral disc-related pain, and related disorders. TNF causes neuronal dysfunction, regulates synaptic mechanisms, and mediates amyloid-induced disruption of molecular mechanisms involved in memory. Perispinal administration of etanercept, a potent anti-TNF fusion protein, is a treatment modality whose rapid clinical effects may be related to modulation of these TNF-related mechanisms, particularly the role of TNF as a gliotransmitter capable of regulating synaptic transmission.

Perispinal etanercept produces rapid improvement in primary progressive aphasia: identification of a novel, rapidly reversible TNF-mediated pathophysiologic mechanism.

Primary progressive aphasia (PPA) is an uncommon form of progressive dementia for which there exists no established treatment. The underlying pathology may be that of either frontotemporal dementia or Alzheimer's disease. Increasing evidence suggests that excess tumor necrosis factor (TNF) may play a central role in Alzheimer's disease.

Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer's disease.

Background: Recent clinical studies point to rapid and sustained clinical, cognitive, and behavioral improvement in both Alzheimer's disease and primary progressive aphasia following weekly perispinal administration of etanercept, a TNF-alpha inhibitor that acts by blocking the binding of this cytokine to its receptors. This outcome is concordant with recent basic science studies suggesting that TNF-alpha functions in vivo as a gliotransmitter that regulates synaptic function in the brain. We hypothesized that perispinal etanercept had the potential to improve verbal function in Alzheimer's disease, so we included several standarized measures of verbal ability to evaluate language skills in a clinical trial of perispinal etanercept for Alzheimer's disease.

Perispinal etanercept for treatment of Alzheimer's disease.

Background: Increasing basic science and clinical evidence implicates inflammatory processes and resulting glial activation in the pathogenesis of Alzheimer's Disease. Excess TNF-alpha, a cytokine with pleotropic effects in the CNS, has been suggested to be involved in the pathogenesis of AD. In addition to its pro-inflammatory effects, TNF-alpha affects synaptic transmission; and glutamate, NMDA, and amyloid pathways.

Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration.

Substantial basic science and clinical evidence suggests that excess tumor necrosis factor-alpha (TNF-alpha) is centrally involved in the pathogenesis of Alzheimer's disease. In addition to its pro-inflammatory functions, TNF-alpha has recently been recognized to be a gliotransmitter that regulates synaptic function in neural networks. TNF-alpha has also recently been shown to mediate the disruption in synaptic memory mechanisms, which is caused by beta-amyloid and beta-amyloid oligomers.