From Somalia to the INR in Florida, June 1, 2015

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Patient from Somalia with son and Dr. Tobinick at the INR in Boca Raton, June 1, 2015, minutes after treatment.

Patient from Somalia with son and Dr. Tobinick at the INR in Boca Raton, June 1, 2015, minutes after treatment.

From Dunedin, New Zealand to the INR Los Angeles after stroke

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Rapid neurological recovery beginning within minutes, 1.5 years after stroke in a patient from New Zealand. The patient’s wife describes improvement in walking ability, language abilities, sensation, vision, hearing, taste, etc. Video made at the Institute of Neurological Recovery in Los Angeles on June 9, 2014. Treatment with a single dose was on June 2, 2014.

6 July 2014

Dave and Brenda’s story has made the news in New Zealand. The story is published in the Otago Daily Times:

Rising to the challenge of a stroke
By Eileen Goodwin on Sun, 6 Jul 2014

“A Dunedin man thought to be the first New Zealander to undergo innovative stroke treatment in the United States believes it has improved his speech and walking, while reducing fatigue and pain….”

To read the entire story, please click here.

To view the video, please click here.

Disclaimer: Individual results vary, not all patients respond. Continuing maintenance treatment may be necessary to maintain the clinical response. The method utilized for this indication is off-label.  Please see the Terms of Use. Copyright 2014 INR PLLC, all rights reserved. Issued and pending U.S. and foreign patents, including, but not limited to, U.S. 6419944, 6537549, 6982089, 7214658, 7629311, 8119127, 8236306 and 8349323, all assigned to TACT IP, LLC; and Australian patent 758523.

TNF Brain Syndrome

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TNF is an immune signaling molecule. Increasing scientific evidence suggests that excess (pathologic) levels of TNF, if present in the brain, may impair brain function. Physiological levels of TNF are involved in the regulation of normal brain processes, such as the regulation of synaptic function(1-3). In the 1980’s Clark and his colleagues suggested that excess TNF was involved in the pathophysiology of brain dysfunction associated with malaria(4, 5). In 1988, the clinical results of the initial human trials of recombinant TNF for use in oncology gave a further clue to the essential role of TNF in brain physiology, as three of the initial clinical trial participants demonstrated transient focal neurological dysfunction after TNF infusion(6, 7). More than a decade later researchers discovered that TNF levels 25 times normal were present in the cerebrospinal fluid of patients with Alzheimer’s disease(8). INR physicians have published clinical evidence suggesting that excess TNF is a mediator of brain dysfunction in a variety of brain disorders(9-19). The accumulating evidence suggests the existence of a “TNF brain syndrome”, defined as “a shared phenotype of brain dysfunction induced by excess TNF in brain disorders of diverse aetiology.(17)”(20, 21) In 2013-2014, increasing evidence of the favorable effects of TNF inhibitors in ameliorating brain dysfunction or mortality in the clinical setting and in basic science models suggests the validity of such a concept(19, 22-33).

References
1. Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-alpha. Nature. 2006;440(7087):1054-9.
2. Santello M, Volterra A. TNF-alpha in synaptic function: switching gears. Trends Neurosci. 2012;35(10):638-47.
3. Faingold CL. Chapter 7: Network Control Mechanisms: Cellular Inputs, Neuroactive Substances, and Synaptic Changes. In: Faingold CL, Blumenfeld H, editors. Neuronal Networks in Brain Function, CNS Disorders, and Therapeutics: Elsevier; 2014.
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References for TNF Brain Syndrome Post

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1. Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-alpha. Nature. 2006;440(7087):1054-9.
2. Santello M, Volterra A. TNF-alpha in synaptic function: switching gears. Trends Neurosci. 2012;35(10):638-47.
3. Faingold CL. Chapter 7: Network Control Mechanisms: Cellular Inputs, Neuroactive Substances, and Synaptic Changes. In: Faingold CL, Blumenfeld H, editors. Neuronal Networks in Brain Function, CNS Disorders, and Therapeutics: Elsevier; 2014.
4. Clark IA, Chaudhri G. The balance of useful and harmful effects of TNF, with special reference to malaria. Ann Inst Pasteur Immunol. 1988;139(3):305-6.
5. Clark IA, Rockett KA, Cowden WB. Role of TNF in cerebral malaria. Lancet. 1991;337(8736):302-3.
6. Sherman ML, Spriggs DR, Arthur KA, Imamura K, Frei E, 3rd, Kufe DW. Recombinant human tumor necrosis factor administered as a five-day continuous infusion in cancer patients: phase I toxicity and effects on lipid metabolism. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1988;6(2):344-50.
7. Spriggs DR, Sherman ML, Michie H, Arthur KA, Imamura K, Wilmore D, et al. Recombinant human tumor necrosis factor administered as a 24-hour intravenous infusion. A phase I and pharmacologic study. Journal of the National Cancer Institute. 1988;80(13):1039-44.
8. Tarkowski E, Andreasen N, Tarkowski A, Blennow K. Intrathecal inflammation precedes development of Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2003;74(9):1200-5.
9. Tobinick E, Gross H, Weinberger A, Cohen H. TNF-alpha modulation for treatment of Alzheimer’s disease: a 6-month pilot study. MedGenMed. 2006;8(2):25.
10. Tobinick E. Perispinal etanercept for treatment of Alzheimer’s disease. Curr Alzheimer Res. 2007;4(5):550-2.
11. Tobinick E. Perispinal etanercept produces rapid improvement in primary progressive aphasia: identification of a novel, rapidly reversible TNF-mediated pathophysiologic mechanism. Medscape journal of medicine. 2008;10(6):135.
12. Tobinick EL, Gross H. Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer’s disease. BMC neurology. 2008;8:27.
13. Tobinick EL, Gross H. Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration. Journal of neuroinflammation. 2008;5:2.
14. Tobinick E. Tumour necrosis factor modulation for treatment of Alzheimer’s disease: rationale and current evidence. CNS Drugs. 2009;23(9):713-25.
15. Tobinick E. Perispinal etanercept for neuroinflammatory disorders. Drug Discov Today. 2009;14(3-4):168-77.
16. Tobinick E. Perispinal etanercept: a new therapeutic paradigm in neurology. Expert Rev Neurother. 2010;10(6):985-1002.
17. Tobinick E. Rapid improvement of chronic stroke deficits after perispinal etanercept: three consecutive cases. CNS Drugs. 2011;25(2):145-55.
18. Tobinick E. Deciphering the physiology underlying the rapid clinical effects of perispinal etanercept in Alzheimer’s disease. Curr Alzheimer Res. 2012;9(1):99-109.
19. Tobinick E, Rodriguez-Romanacce H, Levine A, Ignatowski TA, Spengler RN. Immediate neurological recovery following perispinal etanercept years after brain injury. Clinical drug investigation. 2014;34(5):361-6.
20. Clark IA, Alleva LM, Vissel B. The roles of TNF in brain dysfunction and disease. Pharmacol Ther. 2010;128(3):519-48.
21. Clark IA, Vissel B. Treatment implications of the altered cytokine-insulin axis in neurodegenerative disease. Biochem Pharmacol. 2013;86(7):862-71.
22. Ye J, Jiang R, Cui M, Zhu B, Sun L, Wang Y, et al. Etanercept reduces neuroinflammation and lethality in mouse model of Japanese encephalitis. The Journal of infectious diseases. 2014.
23. Ekici MA, Uysal O, Cikriklar HI, Ozbek Z, Turgut Cosan D, Baydemir C, et al. Effect of etanercept and lithium chloride on preventing secondary tissue damage in rats with experimental diffuse severe brain injury. European review for medical and pharmacological sciences. 2014;18(1):10-27.
24. Detrait ER, Danis B, Lamberty Y, Foerch P. Peripheral administration of an anti-TNF-alpha receptor fusion protein counteracts the amyloid induced elevation of hippocampal TNF-alpha levels and memory deficits in mice. Neurochemistry international. 2014.
25. Coelho SC, Bastos-Pereira AL, Fraga D, Chichorro JG, Zampronio AR. Etanercept reduces thermal and mechanical orofacial hyperalgesia following inflammation and neuropathic injury. Eur J Pain. 2014.
26. Works MG, Koenig JB, Sapolsky RM. Soluble TNF receptor 1-secreting ex vivo-derived dendritic cells reduce injury after stroke. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2013.
27. Shi X, Zhou W, Huang H, Zhu H, Zhou P, Zhu H, et al. Inhibition of the inflammatory cytokine tumor necrosis factor-alpha with etanercept provides protection against lethal H1N1 influenza infection in mice. Crit Care. 2013;17(6):R301.
28. Lei B, Dawson HN, Roulhac-Wilson B, Wang H, Laskowitz DT, James ML. Tumor necrosis factor alpha antagonism improves neurological recovery in murine intracerebral hemorrhage. Journal of neuroinflammation. 2013;10(1):103.
29. King MD, Alleyne CH, Jr., Dhandapani KM. TNF-alpha receptor antagonist, R-7050, improves neurological outcomes following intracerebral hemorrhage in mice. Neurosci Lett. 2013;542:92-6.
30. Chio CC, Chang CH, Wang CC, Cheong CU, Chao CM, Cheng BC, et al. Etanercept attenuates traumatic brain injury in rats by reducing early microglial expression of tumor necrosis factor-alpha. BMC Neurosci. 2013;14(1):33.
31. Cheong CU, Chang CP, Chao CM, Cheng BC, Yang CZ, Chio CC. Etanercept attenuates traumatic brain injury in rats by reducing brain TNF- alpha contents and by stimulating newly formed neurogenesis. Mediators Inflamm. 2013;2013:620837.
32. Butterworth RF. The liver-brain axis in liver failure: neuroinflammation and encephalopathy. Nat Rev Gastroenterol Hepatol. 2013;10(9):522-8.
33. Boivin N, Menasria R, Piret J, Rivest S, Boivin G. The combination of valacyclovir with an anti-TNF alpha antibody [etanercept] increases survival rate compared to antiviral therapy alone in a murine model of herpes simplex virus encephalitis. Antiviral research. 2013;100(3):649-53.

The therapeutic potential of TNF inhibition in stroke models

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April 2014

In 2014, accumulating evidence implicates inflammatory mechanisms in the pathogenesis of cerebral injury induced by stroke. Increasing scientific evidence supports the therapeutic potential of the inhibition of the immune signaling molecule, TNF, in stroke models.

References

1. Siniscalchi, A., L. Gallelli, G. Malferrari, D. Pirritano, R. Serra, E. Santangelo, and G. De Sarro, Cerebral stroke injury: the role of cytokines and brain inflammation. J Basic Clin Physiol Pharmacol, 2014.

2. Lei, B., H.N. Dawson, B. Roulhac-Wilson, H. Wang, D.T. Laskowitz, and M.L. James, Tumor necrosis factor alpha antagonism improves neurological recovery in murine intracerebral hemorrhage. J Neuroinflammation, 2013. 10(1): p. 103. (Free full-text PDF, click here).

3. King, M.D., C.H. Alleyne, Jr., and K.M. Dhandapani, TNF-alpha receptor antagonist, R-7050, improves neurological outcomes following intracerebral hemorrhage in mice. Neurosci Lett, 2013. 542: p. 92-6.

4. Works, M.G., J.B. Koenig, and R.M. Sapolsky, Soluble TNF receptor 1-secreting ex vivo-derived dendritic cells reduce injury after stroke. J Cereb Blood Flow Metab, 2013.

Scientific evidence supporting the potential of etanercept to favorably intervene in brain disorders of diverse etiology continues to accrue

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Of great interest, independent scientists from around the world continue to provide scientific evidence supporting the potential of etanercept to favorably intervene in brain disorders of diverse etiology:

1.         Ye, J., R. Jiang, M. Cui, B. Zhu, L. Sun, Y. Wang, A. Zohaib, Q. Dong, X. Ruan, Y. Song, W. He, H. Chen, and S. Cao, Etanercept reduces neuroinflammation and lethality in mouse model of Japanese encephalitis. J Infect Dis, 2014.

2.         Warrington, J.D., H; Ryan, M; Granger, J, The role of TNF alpha in placental ischemia-induced cerebrovascular abnormalities (1084.6). The FASEB Journal, 2014. 28 no. 1 Supplement 1084.6.

3.         Tobinick, E., H. Rodriguez-Romanacce, A. Levine, T.A. Ignatowski, and R.N. Spengler, Immediate Neurological Recovery Following Perispinal Etanercept Years After Brain Injury. Clin Drug Investig, 2014.

4.         Ekici, M.A., O. Uysal, H.I. Cikriklar, Z. Ozbek, D. Turgut Cosan, C. Baydemir, B. Kazanci, and D. Hafizoglu, Effect of etanercept and lithium chloride on preventing secondary tissue damage in rats with experimental diffuse severe brain injury. Eur Rev Med Pharmacol Sci, 2014. 18(1): p. 10-27.

5.         Chio, C.C., C.H. Chang, C.C. Wang, C.U. Cheong, C.M. Chao, B.C. Cheng, C.Z. Yang, and C.P. Chang, Etanercept attenuates traumatic brain injury in rats by reducing early microglial expression of tumor necrosis factor-alpha. BMC Neurosci, 2013. 14: p. 33.

6.         Cheong, C.U., C.P. Chang, C.M. Chao, B.C. Cheng, C.Z. Yang, and C.C. Chio, Etanercept attenuates traumatic brain injury in rats by reducing brain TNF- alpha contents and by stimulating newly formed neurogenesis. Mediators Inflamm, 2013. 2013: p. 620837.

7.         Boivin, N., R. Menasria, J. Piret, S. Rivest, and G. Boivin, The Combination of Valacyclovir with an Anti-TNF Alpha Antibody [etanercept] Increases Survival Rate Compared to Antiviral Therapy Alone in a Murine Model of Herpes Simplex Virus Encephalitis. Antiviral Res, 2013.

8.         Tobinick, E., N.M. Kim, G. Reyzin, H. Rodriguez-Romanacce, and V. DePuy, 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.

9.         Tobinick, E., Deciphering the Physiology Underlying the Rapid Clinical Effects of Perispinal Etanercept in Alzheimer’s Disease. Curr Alzheimer Res, 2012. 9(1): p. 99-109.

10.       McAfoose, J., L. Kulic, T. Welt, C. Spani, R. Derungs, A. Pfister, and R. Nitsch, Effects of anti-TNF Therapy on Amyloid Pathology and Neuroinflammation in 12-month old ARCA-beta Transgenic Mice. Alzheimer’s and Dementia, 2012. 8(4): p. P394.

11.       Desjardins, P., T. Du, W. Jiang, L. Peng, and R.F. Butterworth, Pathogenesis of hepatic encephalopathy and brain edema in acute liver failure: role of glutamine redefined. Neurochem Int, 2012. 60(7): p. 690-6.

12.       Tobinick, E., Rapid improvement of chronic stroke deficits after perispinal etanercept: three consecutive cases. CNS Drugs, 2011. 25(2): p. 145-55.

13.       Tobinick, E., Perispinal etanercept: a new therapeutic paradigm in neurology. Expert Rev Neurother, 2010. 10(6): p. 985-1002.

14.       Chio, C.C., J.W. Lin, M.W. Chang, C.C. Wang, J.R. Kuo, C.Z. Yang, and C.P. Chang, Therapeutic evaluation of etanercept in a model of traumatic brain injury. J Neurochem, 2010. 115(4): p. 921-9.

15.       Aden, U., G. Favrais, F. Plaisant, M. Winerdal, U. Felderhoff-Mueser, J. Lampa, V. Lelievre, and P. Gressens, Systemic inflammation sensitizes the neonatal brain to excitotoxicity through a pro-/anti-inflammatory imbalance: key role of TNFalpha pathway and protection by etanercept. Brain Behav Immun, 2010. 24(5): p. 747-58.

16.       Tobinick, E., Perispinal etanercept for neuroinflammatory disorders. Drug Discov Today, 2009. 14(3-4): p. 168-77.

17.       Tobinick, E., Tumour necrosis factor modulation for treatment of Alzheimer’s disease: rationale and current evidence. CNS Drugs, 2009. 23(9): p. 713-25.

18.       Tobinick, E.L. and H. Gross, Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration. J Neuroinflammation, 2008. 5: p. 2.

19.       Tobinick, E.L. and H. Gross, Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer’s disease. BMC Neurol, 2008. 8: p. 27.

20.       Tobinick, E., H. Gross, A. Weinberger, and H. Cohen, TNF-alpha modulation for treatment of Alzheimer’s disease: a 6-month pilot study. MedGenMed, 2006. 8(2): p. 25.

 

Multiple Citing Scientific Publications in 2014

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Multiple scientific publications in 2014 have cited scientific publications of Edward Tobinick MD, including articles in the fields of stroke, dementia, synaptic function, and pain:

1.         Bae, W.C. and K. Masuda, Chapter 25: Enhancing Disc Repair by Growth Factors and Other Modalities, in The Intervertebral Disc, I.M. Shapiro and M.V. Risbud, Editors. 2014, Springer-Verlag: Wien.

2.         Bastos, L.F. and M.M. Coelho, Drug repositioning: playing dirty to kill pain. CNS Drugs, 2014. 28(1): p. 45-61.

3.         Clark, I.A. and B. Vissel, Inflammation-sleep interface in brain disease: TNF, insulin, orexin. J Neuroinflammation, 2014. 11(1): p. 51.

4.         Faingold, C.L., Chapter 7: Network Control Mechanisms: Cellular Inputs, Neuroactive Substances, and Synaptic Changes, in Neuronal Networks in Brain Function, CNS Disorders, and Therapeutics, C.L. Faingold and H. Blumenfeld, Editors. 2014, Elsevier.

5.         Ferreira, S.T., J.R. Clarke, T.R. Bomfim, and F.G. De Felice, Inflammation, defective insulin signaling, and neuronal dysfunction in Alzheimer’s disease. Alzheimers Dement, 2014. 10(1S): p. S76-S83.

6.         Gisondi, P., F. Sala, F. Alessandrini, V. Avesani, G. Zoccatelli, A. Beltramello, G. Moretto, G. Gambina, and G. Girolomoni, Mild cognitive impairment in patients with moderate to severe chronic plaque psoriasis. Dermatology, 2014. 228(1): p. 78-85.

7.         Griessenauer, C.J., J. Raborn, P. Foreman, M.M. Shoja, M. Loukas, and R.S. Tubbs, Venous Drainage of the Spine and Spinal Cord: A Comprehensive Review of its History, Embryology, Anatomy, Physiology, and Pathology. Clinical Anatomy, 2014. epub.

8.         Najem, D., M. Bamji-Mirza, N. Chang, Q.Y. Liu, and W. Zhang, Insulin resistance, neuroinflammation, and Alzheimer’s disease. Rev Neurosci, 2014.

9.         Ohtori, S., G. Inoue, M. Miyagi, and K. Takahashi, Pathomechanisms of discogenic low back pain in humans and animal models. Spine J, 2014.

10.       Sem, D.S., Repurposing – Finding New Uses for Old (and Patented) Drugs: Bridging the “Valley of Death,” to Translate Academic Research Into New Medicines. Marquette Intellectual Property Law Review, 2014. 18(1): p. 139-166.

11.       Siniscalchi, A., L. Gallelli, G. Malferrari, D. Pirritano, R. Serra, E. Santangelo, and G. De Sarro, Cerebral stroke injury: the role of cytokines and brain inflammation. J Basic Clin Physiol Pharmacol, 2014.

12.       Starke, R.M., D.M. Raper, D. Ding, N. Chalouhi, G.K. Owens, D.M. Hasan, R. Medel, and A.S. Dumont, Tumor Necrosis Factor-alpha Modulates Cerebral Aneurysm Formation and Rupture. Transl Stroke Res, 2014. 5(2): p. 269-77.

13.       Trager, U., R. Andre, N. Lahiri, A. Magnusson-Lind, A. Weiss, S. Grueninger, C. McKinnon, E. Sirinathsinghji, S. Kahlon, E.L. Pfister, R. Moser, H. Hummerich, M. Antoniou, G.P. Bates, R. Luthi-Carter, M.W. Lowdell, M. Bjorkqvist, G.R. Ostroff, N. Aronin, and S.J. Tabrizi, HTT-lowering reverses Huntington’s disease immune dysfunction caused by NFkappaB pathway dysregulation. Brain, 2014. 137(Pt 3): p. 819-33.

14.       Tronel, C., G. Page, S. Bodard, S. Chalon, and D. Antier, The specific PKR inhibitor C16 prevents apoptosis and IL-1beta production in an acute excitotoxic rat model with a neuroinflammatory component. Neurochem Int, 2014. 64: p. 73-83.

15.       Winkelstein, B.A., K.D. Allen, and L.A. Setton, Chapter 19: Intervertebral Disc Herniation: Pathophysiology and Emerging Therapies, in The Intervertebral Disc, I.M. Shapiro and M.V. Risbud, Editors. 2014, Springer-Verlag: Wien, Austria.

New study provides further evidence of the central role of TNF in stroke pathophysiology

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  • A new study, published 14 March 2014, provides further evidence of the central role of TNF in stroke pathobiology:
  • “The abstract begins: “Stroke is a major cause of death worldwide and the leading cause of permanent disability. Although reperfusion is currently used as treatment, the restoration of blood flow following ischaemia elicits a profound inflammatory response mediated by proinflammatory cytokines such as tumour necrosis factor (TNF), exacerbating tissue damage and worsening the outcomes for stroke patients…..”
  • “Our study is in good agreement with other studies pointing to a key role of microglial TNF in early-phase inflammation in the CNS.”

Low, et al., PI3K-delta inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model, Nature Communications 5, Article number: 3450 doi:10.1038/ncomms4450  Published 14 March 2014.

The full-text and abstract of the study are available at this link:

http://www.nature.com/ncomms/2014/140314/ncomms4450/full/ncomms4450.html

See also: (Tobinick, E., Rapid improvement of chronic stroke deficits after [treatment with a biologic TNF inhibitor]: 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 a biological TNF inhibitior]. CNS Drugs, 2012. 26(12): p. 1051-70. Results can vary. Please see the Terms of Use.

INR News and Links

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

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

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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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