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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Judgment is entered in favor of plaintiff TACT IP LLC against defendents Janssen Biotech, Inc. and New York University

August 5, 2013: On August 5, 2013, in the United States District Court for the Eastern District of Virginia, Alexandria Division, judgment in favor of TACT IP, LLC, holding patents of Edward Tobinick, M.D., was entered: " Case No. 1:12cv909 JUDGMENT ORDER Upon consideration of the July 19, 2013 Report and Recommendation of the United States Magistrate Judge designated to conduct a hearing in this matter, no objections having been filed, and upon an independent de novo review of the record, it is hereby ORDERED that the Court adopts as its own the findings of fact and recommendation of the United States Magistrate Judge, as set forth in the June 19, 2013 Report and Recommendation. Accordingly, it is hereby ORDERED that judgment is ENTERED by default in favor of plaintiff TACT IP LLC and against defendants Janssen Biotech, Inc. and New York University....." Edward Tobinick's issued patents, assigned to TACT IP LLC, include, but are not limited to the following U.S. patents: 6419944, 6537549, 6982089, 7214658, 7629311, 8119127, and 8236306. The patents at issue in the entered judgment in favor of TACT IP LLC included those involving epidural administration of etanercept for treatment of symptomatic lumbar disc herniation.

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TNF and Brain Dysfunction

TNF is an immune signaling molecule that initiates and amplifies the inflammatory response in a variety of organ systems. In addition, TNF serves a variety of functions related to the immune modulation of neuronal and brain function. Increasing evidence suggests that excess TNF may be associated with brain dysfunction. Excess TNF may exert its deleterious effects via a variety of mechanisms related to modulation of synaptic transmission and synaptic scaling. Clinical observations by INR physicians over a period of more than a decade have contributed to the understanding of the role of TNF-mediated pathophysiology in a variety of neuroinflammatory disorders.

 
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Scientific Publications

Dr. Tobinick's contributions to the medical literature include co-authorship of a medical textbook and more than 20 scientific articles that have published in peer-reviewed medical and scientific journals. These articles include recent reviews in the journals Expert Review of Neurotherapeutics, CNS Drugs, and Drug Discovery Today, as well as published articles in BMC Neurology, Current Alzheimer Research, and the Journal of Neuroinflammation.

 
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Scientific Recognition

When reporting their scientific results, scientists will discuss and refer to previous publications in their articles. These citations to the scientific literature are an integral part of the scientific process. There have been hundreds of scientific citations to Dr. Tobinick's publications, including in the journals Brain Research, Molecular Pain, Nature Clinical Practice Neurology, Neurobiology of Aging, Neuroscience, Pharmacology and Therapeutics, Spine and F1000 Biology.

 
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