Institute of Neurological Recovery Blog

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INR News and Links

For further information regarding the INR, please see the following sources, accessible by clicking on the links below:

 

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Griffith University initiates a randomized, double-blind clinical trial using a TNF inhibitor for Alzheimer’s disease

December 18, 2013 (Gold Coast, Australia): Today Griffith University, on their Alzheimer’s trial website, announced that the Griffith University Alzheimer’s Study has recently been granted full approval by the Human Research Ethics Committee as the first randomized double blind clinical trial to test perispinal etanercept  for dementia in Australian patients. More information here, on the Griffith website. The INR congratulates Griffith University and its scientists and physicians for their diligence and outstanding efforts that have enabled the initiation of this new study. The approval and initiation of this new study represents independent scientific support for the scientific rationale underlying this treatment approach that was invented and pioneered at the INR in Los Angeles.

 

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Study provides new evidence for the efficacy of a TNF inhibitor for relief of persistent sciatica

November 1, 2013: A new randomized study published in the November 1, 2013 issue of the journal Spine (Freeman, B.J., et al., Randomized, Double-blind, Placebo-Controlled, Trial of Transforaminal Epidural Etanercept for the Treatment of Symptomatic Lumbar Disc Herniation. Spine (Phila Pa 1976), 2013. 38(23): p. 1986-94) provides new evidence for the efficacy of a TNF inhibitor for relief of persistent sciatica associated with lumbar disc herniation. Etanercept is a potent anti-inflammatory drug that is a selective blocker of an immune signaling molecule called TNF. Local perilesional methods of administration of etanercept, including epidural injection for treating sciatica associated with lumbar disc herniation were invented by Edward Tobinick M.D. more than a decade earlier (U.S. patent 6,419,944; 6,537,549; and others).

The new Spine study now constitutes the third published favorable clinical trial providing randomized, controlled trial (RCT) data of the efficacy of etanercept for treating sciatica. Dr. Tobinick was the first to publish human data reporting the effectiveness of etanercept for this indication in 2003, with a larger study published in 2004 (Tobinick, E. and S. Davoodifar, Efficacy of etanercept delivered by perispinal administration for chronic back and/or neck disc-related pain: a study of clinical observations in 143 patients. Curr Med Res Opin, 2004. 20(7): p. 1075-85).

Individual results can vary. See the Terms of Use.  Intractable disc-related low back and neck pain are important medical problems with significant unmet medical need.

 

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Four randomized controlled clinical trials support the efficacy of a TNF inhibitor for disc-related pain

November 4, 2013:

U.S. patent 6,419,944 (inventor Edward Tobinick M.D., filed April 5, 2001) contained the first clinical report of rapid improvement in disc-related pain following the administration of perispinal etanercept. Now, more than a decade later, there are four favorable clinical trials that provide randomized, controlled trial (RCT) data supporting the efficacy of etanercept for treating disc-related pain. In 2013, data from two of these RCTs have been presented: the Nov 1 study by Freeman published in Spine; and the study conducted at Chiba University in Japan(Sainoh, T., et al., Intradiscal Administration of Tumor Necrosis Factor-Alpha Inhibitor, Etanercept, Clinically Improves Intractable Discogenic Low Back Pain: A Prospective Randomized Study, in International Society for the Study of the Lumbar Spine 40th Annual Meeting, May 2013). In 2012 the RCT by Ohtori reported positive etanercept data (Ohtori, S., et al., Epidural administration of spinal nerves with the tumor necrosis factor-alpha inhibitor, etanercept, compared with dexamethasone for treatment of sciatica in patients with lumbar spinal stenosis: a prospective randomized study. Spine (Phila Pa 1976), 2012. 37(6): p. 439-44). In 2009 the RCT performed at Walter Reed Army Medical Center provided favorable efficacy and human and animal safety data (Cohen, S.P., et al., Randomized, double-blind, placebo-controlled, dose-response, and preclinical safety study of transforaminal epidural etanercept for the treatment of sciatica. Anesthesiology, 2009. 110(5): p. 1116-26).

 

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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.

 

 

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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).

 

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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.

 

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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.

 

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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).

 

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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.