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INR 100 UCLA Medical Plaza, Suites 205-210 Los Angeles, California 90095 (310) 824-6199 Edward Tobinick MD, Medical Director

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The INR has pioneered a revolutionary new approach to Alzheimer's disease

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About the INR

The INR has discovered and pioneered unique therapeutic approaches for a variety of medical disorders with enormous unmet need, including Alzheimer's disease and various forms of neuropathic pain, including sciatica and cervical radiculopathy[1-9].

The pioneering efforts of the INR's medical director, Edward Tobinick MD, have led to the clear identification of a new therapeutic target in Alzheimer's disease. This therapeutic target, an excess of an immune molecule called TNF (tumor necrosis factor), provides a startingly new alternative to the use of drugs designed to directly attack the brain plaques (amyloid) known to be present in the Alzheimer brain. The theory, called the amyloid hypothesis, was that removal of these plaques would result in improvement in Alzheimer's disease; but this has always been a theory in search of proof, which has proven elusive. Pursuit of the amyloid hypothesis has failed to lead to an effective therapeutic compound, despite hundreds of millions of dollars spent. The spectacular failures of therapeutics directed against amyloid, i.e. Alzhemed®, Flurizan®, and AN-1792, the first anti-amyloid vaccine co-developed by Elan® and Wyeth®, have resulted in public questioning of the validity of these approaches. The identification of an alternative to these anti-amyloid agents thus provides a highly promising, and much needed, area for further scientific identification. The INR's work in establishing the validity of this anti-TNF approach in Alzheimer's disease has been seminal.

With respect to inquiries regarding INR presentations at scientific congresses, please note the following. Dr. Edward Tobinick, the medical director of the INR, has presented the INR's scientific studies, including a prospective, multi-author, peer-reviewed six-month pilot study involving perispinal etanercept for Alzheimer's disease, at multiple international scientific conferences, including the following:

The 7th International Alzheimer's Drug Discovery Conference, invited speaker, presented by Dr. Tobinick in New York City, 2006.

The Days of Molecular Medicine Conference, Karolinska Institutet, Stockholm, Sweden, presented by Dr. Tobinick in Stockholm in 2006.

Best Practices in the Continuum of Care: Advances in Alzheimer's Disease Management conference, Little Rock, Arkansas, University of Arkansas Medical Sciences, invited speaker, presented by Dr. Tobinick in Little Rock, April 2008.

International Conference on Alzheimer's Disease 2008 (ICAD 2008), sponsored by the Alzheimer's Association, Chicago, Illinois, the world's "leading forum on dementia research", according to its sponsor, the national Alzheimer's Association, presented by Dr. Tobinick July 30, 2008 in Chicago.

In addition, the plausibility of the rapid clinical improvement documented in the INR's published clinical studies has not only been peer-reviewed by multiple experts reviewing for four different scientific journals, but is also supported and documented by multiple independent observers, including an independent leading scientist who is a journal editor, and multiple additional observers, including board-certified neurologists, a board-certified rheumatologist, and multiple families of patients treated at the INR[1-5]. Fortunately, the scientific basis for this rapid improvement is supported by multiple scientific studies, including multiple peer-reviewed articles, which have documented the ability of TNF to affect communication between neurons ("synaptic effects"), a causal explanation advanced by Dr. Tobinick[1, 2, 5, 10-12]. Indeed, the most recent research documents that TNF can produce synaptic changes in as little as one minute in experimental models[10].

The central role of excess TNF in the pathogenesis of Alzheimer's disease is now supported by multiple scientific studies from academic centers around the world, including genetic, basic science, epidemiologic, and clinical studies[11, 13-33] (reviewed in [2, 5, 6]).

The INR is pleased to offer a new, patented**, off-label, anti-TNF therapeutic alternative for selected patients who have failed to adequately respond to the existing approved Alzheimer drugs. The INR welcomes the inquiries of physicians and scientists who are interested in learning the details of our clinical experience. To this end, in addition to our previous and continuing scientific publications and presentations at leading scientific conferences, the INR has established a physician training program. Please contact the INR for further information.

References

1. 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.
2. Tobinick, E.L. and H. Gross, Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration. J Neuroinflammation, 2008. 5: p. 2.
3. 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(6): p. 135.
4. Griffin, W.S., Perispinal etanercept: potential as an Alzheimer therapeutic. J Neuroinflammation, 2008. 5: p. 3.
5. Tobinick, E., Perispinal etanercept for treatment of Alzheimer's disease. Curr Alzheimer Res, 2007. 4(5): p. 550-2.
6. Tobinick, E., H. Gross, A. Weinberger, and H. Cohen, TNF-alpha modulation for treatment of Alzheimer's Disease: A six month pilot study. Alzheimer's & Dementia: The Journal of the Alzheimer's Association, 2006. 2(3): p. S364-S365.
7. Tobinick, E., H. Gross, A. Weinberger, and H. Cohen, TNF Modulation for Treatment of Alzheimer's Disease: A 6-month Pilot Study. Medscape General Medicine: Neurology, 2006. 8(2): p. 25f.
8. 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.
9. Tobinick, E.L. and S. Britschgi-Davoodifar, Perispinal TNF-alpha inhibition for discogenic pain. Swiss Med Wkly, 2003. 133(11-12): p. 170-7.
10. Youn, D.H., H. Wang, and S.J. Jeong, Exogenous tumor necrosis factor-alpha rapidly alters synaptic and sensory transmission in the adult rat spinal cord dorsal horn. J Neurosci Res, 2008.
11. Rowan, M.J., I. Klyubin, Q. Wang, N.W. Hu, and R. Anwyl, Synaptic memory mechanisms: Alzheimer's disease amyloid beta-peptide-induced dysfunction. Biochem Soc Trans, 2007. 35(Pt 5): p. 1219-23.
12. Wang, Y., Modification of synaptic plasticity by TNF and sphingomyelinase: Implications for cognitive impairment in AD, in ICAD 2008: Molecular mechanisms of neurodegeneration; synaptic disruption. 2008: Chicago.
13. Perry, R.T., J.S. Collins, H. Wiener, R. Acton, and R.C. Go, The role of TNF and its receptors in Alzheimer's disease. Neurobiol Aging, 2001. 22(6): p. 873-83.
14. Tarkowski, E., N. Andreasen, A. Tarkowski, and K. Blennow, Intrathecal inflammation precedes development of Alzheimer's disease. J Neurol Neurosurg Psychiatry, 2003. 74(9): p. 1200-5.
15. Laws, S.M., R. Perneczky, S. Wagenpfeil, U. Muller, H. Forstl, R.N. Martins, A. Kurz, and M. Riemenschneider, TNF polymorphisms in Alzheimer disease and functional implications on CSF beta-amyloid levels. Hum Mutat, 2005. 26(1): p. 29-35.
16. Pickering, M., D. Cumiskey, and J.J. O'Connor, Actions of TNF-alpha on glutamatergic synaptic transmission in the central nervous system. Exp Physiol, 2005. 90(5): p. 663-70.
17. Wang, Q., J. Wu, M.J. Rowan, and R. Anwyl, Beta-amyloid inhibition of long-term potentiation is mediated via tumor necrosis factor. Eur J Neurosci, 2005. 22(11): p. 2827-32.
18. Chiarini, A., I. Dal Pra, J.F. Whitfield, and U. Armato, The killing of neurons by beta-amyloid peptides, prions, and pro-inflammatory cytokines. Ital J Anat Embryol, 2006. 111(4): p. 221-46.
19. Ramos, E.M., M.T. Lin, E.B. Larson, I. Maezawa, L.H. Tseng, K.L. Edwards, G.D. Schellenberg, J.A. Hansen, W.A. Kukull, and L.W. Jin, Tumor necrosis factor alpha and interleukin 10 promoter region polymorphisms and risk of late-onset Alzheimer disease. Arch Neurol, 2006. 63(8): p. 1165-9.
20. Csiszar, A., N. Labinskyy, K. Smith, A. Rivera, Z. Orosz, and Z. Ungvari, Vasculoprotective effects of anti-tumor necrosis factor-alpha treatment in aging. Am J Pathol, 2007. 170(1): p. 388-98.
21. Tweedie, D., K. Sambamurti, and N.H. Greig, TNF-alpha Inhibition as a Treatment Strategy for Neurodegenerative Disorders: New Drug Candidates and Targets. Curr Alzheimer Res, 2007. 4(4): p. 375-8.
22. De, A., J.M. Krueger, and S.M. Simasko, Glutamate induces the expression and release of tumor necrosis factor-alpha in cultured hypothalamic cells. Brain Res, 2005. 1053(1-2): p. 54-61.
23. Edwards, M.M. and S.R. Robinson, TNF alpha affects the expression of GFAP and S100B: implications for Alzheimer's disease. J Neural Transm, 2006.
24. Janelsins, M.C., M.A. Mastrangelo, S. Oddo, F.M. LaFerla, H.J. Federoff, and W.J. Bowers, Early correlation of microglial activation with enhanced tumor necrosis factor-alpha and monocyte chemoattractant protein-1 expression specifically within the entorhinal cortex of triple transgenic Alzheimer's disease mice. J Neuroinflammation, 2005. 2: p. 23.
25. Jekabsone, A., P.K. Mander, A. Tickler, M. Sharpe, and G.C. Brown, Fibrillar beta-amyloid peptide Abeta1-40 activates microglial proliferation via stimulating TNF-alpha release and H2O2 derived from NADPH oxidase: a cell culture study. J Neuroinflammation, 2006. 3: p. 24.
26. Medeiros, R., R.D. Prediger, G.F. Passos, P. Pandolfo, F.S. Duarte, J.L. Franco, A.L. Dafre, G. Di Giunta, C.P. Figueiredo, R.N. Takahashi, M.M. Campos, and J.B. Calixto, Connecting TNF-{alpha} Signaling Pathways to iNOS Expression in a Mouse Model of Alzheimer's Disease: Relevance for the Behavioral and Synaptic Deficits Induced by Amyloid {beta} Protein. J Neurosci, 2007. 27(20): p. 5394-5404.
27. Meme, W., C.F. Calvo, N. Froger, P. Ezan, E. Amigou, A. Koulakoff, and C. Giaume, Proinflammatory cytokines released from microglia inhibit gap junctions in astrocytes: potentiation by beta-amyloid. Faseb J, 2006. 20(3): p. 494-6.
28. Mrak, R.E. and W.S. Griffin, Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging, 2005. 26(3): p. 349-54.
29. Ralay Ranaivo, H., J.M. Craft, W. Hu, L. Guo, L.K. Wing, L.J. Van Eldik, and D.M. Watterson, Glia as a therapeutic target: selective suppression of human amyloid-beta-induced upregulation of brain proinflammatory cytokine production attenuates neurodegeneration. J Neurosci, 2006. 26(2): p. 662-70.
30. Takeuchi, H., S. Jin, J. Wang, G. Zhang, J. Kawanokuchi, R. Kuno, Y. Sonobe, T. Mizuno, and A. Suzumura, Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J Biol Chem, 2006. 281(30): p. 21362-8.
31. Tan, Z.S., A.S. Beiser, R.S. Vasan, and e. al., Inflammatory markers and the risk of Alzheimer disease: The Framingham Study. Neurology, 2007. 68(19): p. 1902-1908.
32. Zou, J.Y. and F.T. Crews, TNF alpha potentiates glutamate neurotoxicity by inhibiting glutamate uptake in organotypic brain slice cultures: neuroprotection by NF kappa B inhibition. Brain Res, 2005. 1034(1-2): p. 11-24.
33. Zuliani, G., M. Ranzini, G. Guerra, L. Rossi, M.R. Munari, A. Zurlo, S. Volpato, A.R. Atti, A. Ble, and R. Fellin, Plasma cytokines profile in older subjects with late onset Alzheimer's disease or vascular dementia. J Psychiatr Res, 2006.

Scientific Articles:
1. Griffin WS. Perispinal etanercept: Potential as an Alzheimer therapeutic. J Neuroinflammation. 2008 Jan 10;5(1):3. [download free full-text PDF].
2. Misra, Ambikanandan; Jogani, Viral; Jinturkar, Kaustubh; Vyas, Tushar. Recent Patents Review on Intranasal Administration for CNS Drug Delivery. Recent Patents on Drug Delivery & Formulation, Volume 2, Number 1, January 2008 , pp. 25-40(16).
3. Zanella, John M. MS; Burright, Eric N. PhD; Hildebrand, Keith DVM, PhD; Hobot, Chris BS; Cox, Mark BS; Christoferson, Laura BS; McKay, William F. MS. Effect of Etanercept, a Tumor Necrosis Factor-Alpha Inhibitor, on Neuropathic Pain in the Rat Chronic Constriction Injury Model. Spine 33(3):227-234, February 1, 2008.
4. Sonya Vasto, Giuseppina Candore, Giovanni Duro, Domenico Lio, Maria Paola Grimaldi, Calogero Caruso. Alzheimer's disease and genetics of inflammation: a pharmacogenomic vision. Pharmacogenomics December 2007, Vol. 8, No. 12, Pages 1735-1745.
5. Tweedie D, Sambamurti K, Greig NH. Drug Design & Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, US. TNF-alpha Inhibition as a Treatment Strategy for Neurodegenerative Disorders: New Drug Candidates and Targets. Curr Alzheimer Res. 2007 Sep;4(4):375-8.
6. Van Eldik, L. J. Thompson, W. L. Ranaivo, H. R. Behanna, H. A. Watterson, D. M. Glia Proinflammatory Cytokine Upregulation as a Therapeutic Target for Neurodegenerative Diseases: Function-Based and Target-Based Discovery Approaches, International Review of Neurobiology 2007, 82:278-297.
7. Uceyler N, Sommer C. Cytokine-induced Pain: Basic Science and Clinical Implications. Reviews in Analgesia 2007;9(2):87-103.
8. Tubbs RS, Hansasuta A, Loukas M, Louis RG, Jr., Shoja MM, Salter EG, et al. The basilar venous plexus. Clin Anat 2007.
9. Saxena AK, Kumar S. Management strategies for pain in breast carcinoma patients: current opinions and future perspectives. Pain Pract 2007;7(2):163-77.
10. Owlia MB, Salimzadeh A, Alishiri G, Haghighi A. Comparison of two doses of corticosteroid in epidural steroid injection for lumbar radicular pain. Singapore Med J 2007;48(3):241-5.
11. Munoz L, Ralay Ranaivo H, Roy SM, Hu W, Craft JM, McNamara LK, et al. A novel p38alpha MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer's disease mouse model. J Neuroinflammation 2007;4(1):21.
12. Hu W, Ranaivo HR, Roy SM, Behanna HA, Wing LK, Munoz L, et al. Development of a novel therapeutic suppressor of brain proinflammatory cytokine up-regulation that attenuates synaptic dysfunction and behavioral deficits. Bioorg Med Chem Lett 2007;17(2):414-8.
13. Le Maitre CL, Hoyland JA, Freemont AJ. Catabolic cytokine expression in degenerate and herniated human intervertebral discs: IL-1beta and TNFalpha expression profile. Arthritis Res Ther. 2007 Aug 9;9(4):R77.
14. Kenneth M. Kulmatycki1, Fakhreddin Jamali. Drug Disease Interactions: Role of Inflammatory Mediators in Pain and Variability in Analgesic Drug Response. J Pharm Pharm Sci, 10 (4): 554-566, 2007.
15. Schäfers, Maria; Sommer, Claudia. Anticytokine therapy in neuropathic pain management. Expert Review of Neurotherapeutics, Volume 7, Number 11, November 2007 , pp. 1613-1627(15).

16. van Marum, R.J., Current and future therapy in Alzheimer's disease. Fundam Clin Pharmacol, 2008. 22(3): p. 265-74.
17. Schwab, C. and P.L. McGeer, Inflammatory aspects of Alzheimer disease and other neurodegenerative disorders. J Alzheimers Dis, 2008. 13(4): p. 359-69.
18. Maczurek, A., K. Shanmugam, and G. Munch, Inflammation and the redox-sensitive AGE-RAGE pathway as a therapeutic target in Alzheimer's disease. Ann N Y Acad Sci, 2008. 1126: p. 147-51.
19. Berbaum, K., K. Shanmugam, G. Stuchbury, F. Wiede, H. Korner, and G. Munch, Induction of novel cytokines and chemokines by advanced glycation endproducts determined with a cytometric bead array. Cytokine, 2008. 41(3): p. 198-203.

Hardcover/ Bound Texts:
1. Neuroinflammation in Neuronal Death and Repair, Volume 82 (International Review of Neurobiology.) G. Bagetta, editor (Hardcover - Jul 16, 2007) Amsterdam ; Boston : Elsevier Academic Press ©2007. ISBN: 9780123739896 0123739896.
2. Interactions Between Neurons and Glia in Aging and Disease by Joao Malva, Ana Cristina Rego, Rodrigo Cunha, and Catarina Oliveira (Eds.) (Hardcover - Aug 22, 2007). 2007, Approx. 535 p., Hardcover ISBN: 978-0-387-70829-4 New York ; London : Springer, 2007.
3. Cytokines in the Genesis and Treatment of Cancer (Cancer Drug Discovery and Development) by Michael A. Caligiuri and Michael T. Lotze (Hardcover - April 20, 2007) Totowa, N.J. : Humana Press ©2007. ISBN: 9780896038202 0896038203 9781597454551 1597454559.
4. Chapter 10: Anti-TNF-alpha antibody and cancer cachexia, The ASCRS Textbook of Colon and Rectal Surgery by J.M. Church, J. Garcia-Aguilar, P.L. Roberts, and T.J. Saclarides; New York : Springer ©2007. ISBN: 9780387248462 0387248463.
5. Spinal Reconstruction: Clinical Examples of Applied Basic Science, Biomechanics and Engineering by Kai-Uwe Lewandrowski, Michael J. Yaszemski, Iain Kalfas, and Paul Park (Hardcover - Feb 12, 2007) New York : Informa Healthcare ©2007. ISBN: 9780849398155 0849398150.
6. Olesen J, Jensen T. From Basic Pain Mechanisms to Headache. Oxford University Press 2007.
7. Neuroimmunology: The Immune System and Alzheimers, in the 2007 Progress Report on Brain Research, Dana Alliance for Brain Initiatives, Dana Press, New York ©2007.

Perispinal etanercept for Alzheimer's disease and other forms of dementia (the Tobinick Method™) is a patented, off-label treatment method developed at the INR.