Randomized, placebo-controlled, double-blind clinical trial confirms the efficacy of perispinal etanercept


Perispinal Etanercept RCT 2019

Gold Coast, Australia (January 3, 2020): The results of a randomized, placebo-controlled, double-blind clinical  trial of perispinal etanercept were published today, confirming the efficacy and remarkable results of perispinal etanercept in a cohort of stroke survivors with relentless, intractable daily pain after stroke. The individuals were treated an average of about 4 years after stroke and each reported constant daily pain after their stroke that had failed to adequately respond to all previous forms of treatment. They received two doses of perispinal etanercept, each two weeks apart, with the control group receiving two doses of saline administered perispinally. The control group had no change in their daily pain, but the etanercept group had a significant reduction in pain, measured at 30 days, with 30% of the etanercept patients showing near complete pain abatement after the first etanercept treatment. The study concludes: “Perispinal etanercept can provide significant and ongoing benefits for the chronic post-stroke management of pain and greater shoulder flexion by the paretic arm. Effects are rapid and highly significant, supporting direct action on brain function.”

The clinical trial results published on January 3, 2020 in the journal  Expert Opinion on Investigational Drugs. Learn More.

February 4, 2013 article in Massachusetts newspaper discusses new stroke treatment


February 4, 2012 article in The Recorder, Greenfield, Massachusetts:


New treatment gives stroke victim hope

Recorder/Paul Franz<br /><br /><br /><br /><br /><br /><br /><br />
Rodney Krug, 91, of Bernardston at the Bernardston Senior Center.Recorder/Paul Franz Rodney Krug, 91, of Bernardston at the Bernardston Senior Center.

Sunday, February 3, 2013
(Published in print: Monday, February 4, 2013)
For the full article, please go to:http://www.recorder.com/home/4088414-95/krug-treatment-stroke-able

From Dunedin, New Zealand to the Institute of Neurological Recovery in Los Angeles


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 published in the Otago Daily Times: “Rising to the challenge of a stroke” by Eileen Goodwin on Sunday, July 6, 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 2018 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.

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


Of great interest, independent scientists from around the world continue to provide scientific evidence in basic science models, in addition to the INR’s published clinical studies, 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.


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


  • 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:


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.


On October 26, 2012, the peer-reviewed INR scientific article, detailing nearly two years of clinical results utilizing the patented new off-label treatment developed at the INR for chronic neurological impairment following stroke or traumatic brain injury, published. The full-text of the article is available at this link: http://www.ncbi.nlm.nih.gov/pubmed/23100196 .

CNS Drugs. 2012 Oct 26. [Epub ahead of print]

Selective TNF Inhibition for Chronic Stroke and Traumatic Brain Injury : An Observational Study Involving 629 Consecutive Patients Treated with Perispinal Etanercept. Tobinick EKim NMReyzin GRodriguez-Romanacce HDepuy V.

Institute of Neurological Recovery, 100 UCLA Medical Plaza, Suites 205-210, Los Angeles, CA, 90095, USA, nrimed@gmail.com.


BACKGROUND: Brain injury from stroke and traumatic brain injury (TBI) may result in a persistent neuroinflammatory response in the injury penumbra. This response may include microglial activation and excess levels of tumour necrosis factor (TNF). Previous experimental data suggest that etanercept, a selective TNF inhibitor, has the ability to ameliorate microglial activation and modulate the adverse synaptic effects of excess TNF. Perispinal administration may enhance etanercept delivery across the blood-CSF barrier.

OBJECTIVE: The objective of this study was to systematically examine the clinical response following perispinal administration of etanercept in a cohort of patients with chronic neurological dysfunction after stroke and TBI.

METHODS: After approval by an independent external institutional review board (IRB), a chart review of all patients with chronic neurological dysfunction following stroke or TBI who were treated open-label with perispinal etanercept (PSE) from November 1, 2010 to July 14, 2012 at a group medical practice was performed.

RESULTS: The treated cohort included 629 consecutive patients. Charts of 617 patients following stroke and 12 patients following TBI were reviewed. The mean age of the stroke patients was 65.8 years ± 13.15 (range 13-97). The mean interval between treatment with PSE and stroke was 42.0 ± 57.84 months (range 0.5-419); for TBI the mean interval was 115.2 ± 160.22 months (range 4-537). Statistically significant improvements in motor impairment, spasticity, sensory impairment, cognition, psychological/behavioural function, aphasia and pain were noted in the stroke group, with a wide variety of additional clinical improvements noted in individuals, such as reductions in pseudobulbar affect and urinary incontinence. Improvements in multiple domains were typical. Significant improvement was noted irrespective of the length of time before treatment was initiated; there was evidence of a strong treatment effect even in the subgroup of patients treated more than 10 years after stroke and TBI. In the TBI cohort, motor impairment and spasticity were statistically significantly reduced.

DISCUSSION: Irrespective of the methodological limitations, the present results provide clinical evidence that stroke and TBI may lead to a persistent and ongoing neuroinflammatory response in the brain that is amenable to therapeutic intervention by selective inhibition of TNF, even years after the acute injury.

CONCLUSION: Excess TNF contributes to chronic neurological, neuropsychiatric and clinical impairment after stroke and TBI. Perispinal administration of etanercept produces clinical improvement in patients with chronic neurological dysfunction following stroke and TBI. The therapeutic window extends beyond a decade after stroke and TBI. Randomized clinical trials will be necessary to further quantify and characterize the clinical response. PMID: 23100196

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

  • Department of Neurosurgery, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA


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 VEStewart JEBegbie FDTrojanowski JQSmith DHStewart W.


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


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.

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).

Charlie and Cheryll at the INR Los Angeles July 2013


Charlie and Cheryll Giles with Dr. Tobinick at the INR 100 UCLA Medical Plaza July 11, 2013

Charlie and Cheryll Giles with Dr. Tobinick at the INR 100 UCLA Medical Plaza July 11, 2013

Three years after the original filming of “A New Shot at Life” by 60 Minutes Australia.

To view the documentary, please go to the original 60 Minutes Australia feature, available here.

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