Blog Articles

Tumor necrosis factor alpha antagonism improves neurological recovery in murine intracerebral hemorrhage

August 20, 2013:

A new basic science study from a research group at Duke provides new evidence supporting the rationale of TNF Inhibition following certain forms of stroke. The scientific rationale was discussed more than a decade earlier by Edward Tobinick in U.S. patent 6,419,934, filed September 5, 2000. On August 20, 2013, in the Journal of Neuroinflammation, the study authors  wrote: “Antagonism of pro-inflammatory cytokines by specific antibodies represents a compelling therapeutic strategy to improve neurological outcome in patients after ICH“. (Lei, B., et al., Tumor necrosis factor alpha antagonism improves neurological recovery in murine intracerebral hemorrhage. J Neuroinflammation, 2013. 10(1): p. 103). The background and conclusions of the abstract follow: Background: Intracerebral hemorrhage (ICH) is a devastating stroke subtype characterized by a prominent neuroinflammatory response. Antagonism of pro-inflammatory cytokines by specific antibodies represents a compelling therapeutic strategy to improve neurological outcome in patients after ICH. To test this hypothesis, the tumor necrosis factor alpha (TNF-alpha) antibody CNTO5048 was administered to mice after ICH induction, and histological and functional endpoints were assessed. Conclusions: Post-injury treatment with the TNF-alpha antibody CNTO5048 results in less neuroinflammation and improved functional outcomes in a murine model of ICH. See also: (Tobinick, E., Rapid improvement of chronic stroke deficits after perispinal etanercept: three consecutive cases. CNS Drugs, 2011. 25(2): p. 145-55; and Tobinick, E., et al., Selective TNF Inhibition for Chronic Stroke and Traumatic Brain Injury : An Observational Study Involving 629 Consecutive Patients Treated with Perispinal Etanercept. CNS Drugs, 2012. 26(12): p. 1051-70. Results can vary. Please see the Terms of Use.

 

TNF gene polymorphism is associated with outcome after traumatic brain injury

October 15, 2013: New clinical evidence of the involvement of TNF in the pathogenesis of neurological dysfunction following traumatic brain injury has been published by a research consortium in the UK. The lead author is Ryan J. Waters from Wessex Neurological Centre, University Hospital Southampton NHS Foundation Trust (Cytokine gene polymorphisms and outcome after traumatic brain injury. J Neurotrauma, 2013. 30(20): p. 1710-6). The article abstract includes: “….Cytokines play an important role in mediating the inflammatory response provoked within the central nervous system after TBI. This study was designed to identify associations between cytokine gene polymorphisms and clinical outcome 6 months after head injury. A prospectively identified cohort of patients (n=1096, age range 0-93 years, mean age 37) was used. Clinical outcome at 6 months was assessed using the Glasgow Outcome Scale. In an initial screen of 11 cytokine gene single nucleotide polymorphisms (SNPs) previously associated with disease susceptibility or outcome … TNFA -308 was identified as having a likely association. The TNFA -308 SNP was further evaluated, and a significant association was identified…. These findings are consistent with experimental and clinical data suggesting that neuroinflammation has an impact on clinical outcome after TBI and that tumor necrosis factor alpha plays an important role in this process. (emphasis added). Although results can vary (see the Terms of Use) these findings support the scientific rationale underlying the clinical results reported in  2012 by Edward Tobinick M.D. and his colleagues (Tobinick, E., et al.,CNS Drugs, 2012. 26(12): p. 1051-70).

TNF drives Alzheimer's disease-related neuronal cycle events

October 17, 2013:

Further experimental evidence implicating excess TNF (tumor necrosis factor-alpha) as centrally involved in the pathogenesis of Alzheimer’s disease has published. The article is entitled “Microglial derived tumor necrosis factor-alpha drives Alzheimer’s disease-related neuronal cycle events“.  The new study, from scientists at the Department of Molecular Genetics and Microbiology, University of New Mexico, provides further support for the scientific rationale proposed by Edward Tobinick M.D in 1999 (U.S. patent 6,177,077)  and later elaborated in subsequent publications (for published reviews, please see Edward Tobinick, Tumour necrosis factor modulation for treatment of Alzheimer’s disease: rationale and current evidence. CNS Drugs, 2009. 23(9): p. 713-25; Clark, I.A., L.M. Alleva, and B. Vissel, The roles of TNF in brain dysfunction and disease. Pharmacol Ther, 2010. 128(3): p. 519-48; and Tobinick, E., Current Alzheimer Research, 2012. 9(1): p. 99-109.

The abstract of the new article concludes “….. Together our data suggest a cell-autonomous role of microglia, and identify TNF-alpha as the responsible cytokine, in promoting neuronal CCEs in the pathogenesis of AD”.

This new data joins data published in September 2013 from UCSF implicating excess TNF in the pathogenesis of another form of dementia, semantic variant Primary Progressive Aphasia (PPA). Dr. Tobinick reported the rapid clinical response of a patient with PPA to TNF inhibition in 2008 (Tobinick, E., …..rapid improvement in primary progressive aphasia: identification of a novel, rapidly reversible TNF-mediated pathophysiologic mechanism. Medscape J Med, 2008. 10(6): p. 135). TNF modulation is utilized at the INR off-label. Individual results can vary. Please see the Terms of Use.

Charlie and Cheryll reunite with Dr. Tobinick at the INR Los Angeles July 2013

Charlie and Cheryll at the INR 100 UCLA Medical Plaza Los Angeles July 2013
Charlie and Cheryll at the INR 100 UCLA Medical Plaza Los Angeles July 2013

3 years after filming the 60 Minutes Australia documentary, entitled “A New Shot at Life” Charlie and Cheryll reunite with Dr. Tobinick at the INR in Los Angeles. To view the 60 Minutes documentary, click here or here.

New data points to excess TNF as a potential therapeutic target for certain forms of dementia

On March 30, 2013, new data from the UCSF Memory and Aging Center published pointing to excess TNF as a potential therapeutic target for certain forms of dementia. In particular, elevated TNF levels were observed in the cohort of individuals examined with semantic variant PPA (primary progressive aphasia) (see Miller ZA, Rankin KP, Graff-Radford NR, Takada LT, Sturm VE, Cleveland CM, Criswell LA, Jaeger PA, Stan T, Heggeli KA, et al: TDP-43 frontotemporal lobar degeneration and autoimmune disease. J Neurol Neurosurg Psychiatry 2013).

We note that this UCSF study follows by more than four years the initial report of rapid clinical improvement in an individual with PPA following the off-label use of perispinal etanercept (Tobinick E: Perispinal etanercept produces rapid improvement in primary progressive aphasia: identification of a novel, rapidly reversible TNF-mediated pathophysiologic mechanism. Medscape J Med 2008, 10:135).

Basic Science News: TNF inhibition reduces neurovascular injury after Intracerebral Hemorrhage

TNF-alpha receptor antagonist, R-7050, improves neurological outcomes following intracerebral hemorrhage in mice

Melanie D. King,
Cargill H. Alleyne Jr.,
Krishnan M. Dhandapani
Department of Neurosurgery, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA
Abstract

Intracerebral hemorrhage (ICH), the most common form of hemorrhagic stroke, exhibits the highest acute mortality and the worst long-term prognosis of all stroke subtypes. Unfortunately, treatment options for ICH are lacking due in part to a lack of feasible therapeutic targets. Inflammatory activation is associated with neurological deficits in pre-clinical ICH models and with patient deterioration after clinical ICH. In the present study, we tested the hypothesis that R-7050, a novel cell permeable triazoloquinoxaline inhibitor of the tumor necrosis factor receptor (TNFR) complex, attenuates neurovascular injury after ICH in mice. Up to 2 h post-injury administration of R-7050 significantly reduced blood–brain barrier opening and attenuated edema development at 24 h post-ICH. Neurological outcomes were also improved over the first 3 days after injury. In contrast, R-7050 did not reduce hematoma volume, suggesting the beneficial effects of TNFR inhibition were downstream of clot formation/resolution. These data suggest a potential clinical utility for TNFR antagonists as an adjunct therapy to reduce neurological injury and improve patient outcomes after ICH.

Science News: New pathology study: Inflammation persists for years after a single traumatic brain injury

Brain. 2013 Jan;136(Pt 1):28-42. doi: 10.1093/brain/aws322.
Inflammation and white matter degeneration persist for years after a single traumatic brain injury.

Johnson VE, Stewart JE, Begbie FD, Trojanowski JQ, Smith DH, Stewart W.
Source

Penn Centre for Brain Injury and Repair and Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Abstract

A single traumatic brain injury is associated with an increased risk of dementia and, in a proportion of patients surviving a year or more from injury, the development of hallmark Alzheimer’s disease-like pathologies. However, the pathological processes linking traumatic brain injury and neurodegenerative disease remain poorly understood. Growing evidence supports a role for neuroinflammation in the development of Alzheimer’s disease. In contrast, little is known about the neuroinflammatory response to brain injury and, in particular, its temporal dynamics and any potential role in neurodegeneration. Cases of traumatic brain injury with survivals ranging from 10 h to 47 years post injury (n = 52) and age-matched, uninjured control subjects (n = 44) were selected from the Glasgow Traumatic Brain Injury archive. From these, sections of the corpus callosum and adjacent parasaggital cortex were examined for microglial density and morphology, and for indices of white matter pathology and integrity. With survival of ?3 months from injury, cases withtraumatic brain injury frequently displayed extensive, densely packed, reactive microglia (CR3/43- and/or CD68-immunoreactive), a pathology not seen in control subjects or acutely injured cases. Of particular note, these reactive microglia were present in 28% of cases with survival of >1 year and up to 18 years post-trauma. In cases displaying this inflammatory pathology, evidence of ongoing white matter degradation could also be observed. Moreover, there was a 25% reduction in the corpus callosum thickness with survival >1 year post-injury. These data present striking evidence of persistent inflammation and ongoing white matter degeneration for many years after just a single traumatic brain injury in humans. Future studies to determine whether inflammation occurs in response to or, conversely, promotes white matter degeneration will be important. These findings may provide parallels for studying neurodegenerative disease, withtraumatic brain injury patients serving as a model for longitudinal investigations, in particular with a view to identifying potential therapeutic interventions.

INR on 60 Minutes New Zealand

March 11, 2012

Pleased to report that the featured news story, “A Shot at Life”, was shown tonight on 60 Minutes New Zealand. We welcome correspondence and inquiries from our friends in New Zealand . The story can be seen on the 60 Minutes New Zealand website at the following link:

http://www.tv3.co.nz/Mar-11—A-Shot-At-Life/tabid/2059/articleID/76134/Default.aspx

We thank 60 Minutes Australia and our wonderful patients and their families to making this possible.

Best wishes to all,

The INR staff

60 Minutes Australia lead story on November 6, 2011 features INR's Alzheimer treatment

Pleased to report that the lead story on 60 Minutes Australia tonight (November 6, 2011), in both the Sydney and Melbourne metropolitan areas, is their feature story about our work.

The transcript and full-story can be viewed here:

http://sixtyminutes.ninemsn.com.au/stories/8360210/a-new-shot-at-life.

Many thanks to all our patients, friends, and staff that have helped to make this happen and bring this forward.

Validity of INR's pioneering work re-confirmed

A newly published randomized study from Chiba University in Japan provides robust scientific support for our pioneering work utilizing novel methods of delivery and indications for etanercept. The new study, published ahead-of-print in the leading journal Spine demonstrated the superiority of epidural administration of etanercept over an epidural steroid injection for treatment of sciatica associated with spinal stenosis. This method of treatment was invented at the INR (U.S. patent 6419944, issued to Edward Tobinick M.D.) a decade ago. When the INR first published our work with etanercept for sciatica in 2003 and 2004 there were many who were [incorrectly] skeptical. This new study joins a favorable randomized, placebo-controlled study conducted by the U.S. Army in conjunction with Johns Hopkins researchers published in 2009 after their [uncredited] consultation with us several years before. Pleased that the truth has again been confirmed.