Reversal of Alzheimer’s disease following perispinal etanercept administration
this work of the past 5 years from Los Angeles beggars belief, that any drug promoting neurotransmission via inhibition of cytokines- TNF alpha can produce immediate and sustained improvement in moderate to severe Alzheimer’s disease- and without significant adverse effect. A Nobel prize for someone. Up to now, no modern designer drug has done any significant good for these patients.
The current patient that Tobinick ea report certainly had severe brain atrophy. In 2006 they reported 15 patients with progressive Alzheimers who showed improvement on 32mg etanerept a week – with improvement in scores of between 10% & 25%, p<.002. This is in contrast to the usual relentless decline over 6 months, to death after an average of 7years.
Enbrel – etanercept – is available and used in RSA for Rheumatoid arthritis. in a recent MIMS the retail price is apparently about R1400 per injection, and according to Dr Tobinick’s report this is given weekly paraspinally at C6/7. It earned Amgen $2.9billion in 2006. Expensive hightech (intraspinal injection) treatment for senile dementia, but apparently strikingly mind-saving.
There are still no controlled trials of etanercept for Alzheimers, so it is speculative as to whether the improvement seen in cases could be placebo effect of the attention, injection and other supplements;
The reports below indicate improvement in psoriasis; ankylosing spondylitis; rheumatoid arthritis; but not heart failure or Sjogren’s syndrome.
It apparently shows the unthinkable, that a drug can within minutes and for at least 6 months partly reverse Alzheimers to a considerable degree even with major brainscan changes – severe diffuse neuronal loss.
However, there are already two reports of leukenephalopathy.
It is striking that there are as yet no reports from other units about such therapy of Alzheimer’s disease.
Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration Journal of Neuroinflammation 2008, 5:2doi:10.1186/1742-2094-5-2 ; 9 January 2008 Edward L Tobinick, Hyman Gross , Department of Neurology, USC School of Medicine, Los Angeles, USA
Substantial basic science and clinical evidence suggests that excess tumor necrosis factor-alpha (TNF-alpha) is centrally involved in the pathogenesis of Alzheimer’s disease. In addition to its pro-inflammatory functions, TNF-alpha has recently been recognized to be a gliotransmitter that regulates synaptic function in neural networks. TNF-alpha has also recently been shown to mediate the disruption in synaptic memory mechanisms, which is caused by beta-amyloid and beta-amyloid oligomers. The efficacy of etanercept, a biologic antagonist of TNF-alpha, delivered by perispinal administration, for treatment of Alzheimer’s disease over a period of six months has been previously reported in a pilot study. This report details rapid cognitive improvement, beginning within minutes, using this same anti-TNF treatment modality, in a patient with late-onset Alzheimer’s disease. Rapid cognitive improvement following perispinal etanercept may be related to amelioration of the effects of excess TNF-alpha on synaptic mechanisms in Alzheimer’s disease and provides a promising area for additional investigation and therapeutic intervention.
RESPONSES from the FACT file:
—– Original Message —–
Sent: Tuesday, March 11, 2008 11:28 PM
Subject: Etanercept, in Alzheimer’s disease responses
A2: Dear Dr,
This is actually a very disturbing study. I have a patient in my clinic now who used the same medication and it induced multiple sclerosis!
Neuroinflammation can be modulated by using phenylbutyrate, IV glutathione, oral PC and IV Lipostabil.
‘In the moment’ there were good responses with this drug but… at what cost for the future of these patients’ health. We have many patients with Alzheimer’s who respond dramatically to our PK Protocol – with natural substances that heal the brain, without side effects.
A3: This etanercept study is interesting more for it’s insight into the possible mechanisms of Alzheimer’s than for it’s therapeutic potential. We all know that the side effects of long term administration of Enbrel include increased susceptibility to infection, lymphomas and other cancers, etc. In addition, the effects on AD were very short-lived and the route of administration impractical to say the least, for the clinical setting. The study does however point to one of the possible mechanisms of the preventive action of curcumin (which also inhibits TNF alpha) and other natural agents. Of course we’ll never see billions of research dollars poured into the study of potential natural preventives and cures for this devastating disease.
Access the FACT website: http://promed.gordonresearch.com/factforum/welcome.html
Perispinal etanercept: potential as an Alzheimer therapeutic.
J Neuroinflammation. 2008 Jan 10;5:3. Griffin WS. University of Arkansas for Medical Sciences, Arkansas USA.
Tumor necrosis factor-alpha (TNF) is one of a number of systemic and immunomodulating cytokines that generally act to promote acute-phase reactions but can drive degenerative changes when chronically elevated. Traditional focus on TNF has been directed at these inflammation-related functions. Of particular relevance to intersections between neuroinflammation and neurodegeneration is the ability of TNF to increase expression of interleukin-1 (IL-1), which in turn increases production of the precursors necessary for formation of amyloid plaques, neurofibrillary tangles, and Lewy bodies. More recent data have revealed that TNF, one of the few gliotransmitters, has strikingly acute effects on synaptic physiology. These complex influences on neural health suggest that manipulation of this cytokine might have important impacts on diseases characterized by glial activation, cytokine-mediated neuroinflammation, and synaptic dysfunction. Toward such manipulation in Alzheimer’s disease, a six-month study was conducted with 15 probable-Alzheimer patients who were treated weekly with perispinal injection of Etanercept, an FDA-approved TNF inhibitor that is now widely used for treatment of rheumatoid arthritis and other systemic diseases associated with inflammation. The results demonstrated that perispinal administration of etanercept could provide sustained improvement in cognitive function for Alzheimer patients. Additionally, the authors were impressed by the striking rapidity with which these improvements occurred in the study patients. An example of this rapid improvement is presented in this issue as a case report by Tobinick and Gross. Such rapid gain of function inspires speculation about the role of gliotransmission or other equally rapid synaptic events in the relationship of TNF to Alzheimer-impacted neurophysiology. Because of the inability of large molecules such as etanercept to cross the blood brain barrier following conventional systemic administration, it is likely that the more direct drug delivery system pioneered by Tobinick also contributed to the effectiveness of the treatment. If so, this system could be useful in drug delivery to the brain in other neural disorders, as well as in animal research studies, many of which currently employ delivery strategies that inflict damage to neural cells and thus engender neuroinflammatory responses.
.TNF-alpha modulation for treatment of Alzheimer’s disease: a 6-month pilot study. MedGenMed. 2006 Apr 26;8(2):25 Tobinick E, Gross H, Weinberger A, Cohen H University of California, Los Angeles,
CONTEXT: Current pharmacologic treatments for Alzheimer’s disease (AD) do not prevent long-term clinical deterioration. Tumor necrosis factor (TNF)-alpha, a proinflammatory cytokine, has been implicated in the pathogenesis of AD. OBJECTIVE: To investigate the use of a biologic TNF-alpha inhibitor, etanercept was given by perispinal extrathecal administration for the treatment of AD. METHODS: This was a prospective, single-center, open-label, pilot (proof-of-concept) study, in which 15 patients with mild-to-severe AD were treated for 6 months. We administered etanercept, 25-50 mg, once weekly by perispinal administration. Main outcome measures included the Mini-Mental State Examination (MMSE), the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog), and the Severe Impairment Battery (SIB). RESULTS: The average age of our patient population was 76.7. The mean baseline MMSE was 18.2 (n = 15); the mean baseline ADAS-Cog was 20.8 (n = 11); and the mean baseline SIB was 62.5 (n = 5). There was significant improvement with treatment, as measured by all of the primary efficacy variables, through 6 months: MMSE increased by 2.13 -/+ 2.23, ADAS-Cog improved (decreased) by 5.48 -/+ 5.08, and SIB increased by 16.6 -/+ 14.52. CONCLUSION: An increasing amount of basic science and clinical evidence implicates inflammatory processes and resulting glial activation in the pathogenesis of AD. This small, open-label pilot study suggests that inhibition of the inflammatory cytokine TNF-alpha may hold promise as a potential approach to AD treatment. Further study in randomized, placebo-controlled clinical trials is merited.
TNF-antagonist etanercept induced reversible posterior leukoencephalopathy syndrome.
J Neurol. 2008 Feb 20; Kastrup O, Diener HC.
Leukoencephalopathy during administration of etanercept for refractory rheumatoid arthritis Mod Rheumatol. 2007;17(1):72-4 Yamamoto M, ea Sapporo Medical University, Japan.
A 74-year-old Japanese woman was diagnosed with rheumatoid arthritis due to polyarthralgia. She was prescribed various disease-modifying anti-rheumatic drugs, but most of them were discontinued because of side effects or poor effectiveness. She was referred to our hospital in 2004, and etanercept was administered from June 2005. This resulted in rapid improvement of polyarthritis; however, she developed disorientation from February 2006. She was admitted to our hospital because of convulsions and loss of consciousness. She was diagnosed with progressive multifocal leukoencephalopathy on the basis of clinical symptoms and magnetic resonance imaging of the brain. In this significant and important case, leukoencephalopathy occurred during etanercept administration, and we refer to the risk of anti-TNFalpha drugs.
Etanercept and efalizumab treatment for high-need psoriasis. Effects and side effects in a prospective cohort study in outpatient clinical practice.
J Dermatolog Treat. 2007;18(2):76-83.Berends MA, ea. Radboud University Medical Centre, Nijmegen, The Netherlands.
BACKGROUND: Since the beginning of 2005, etanercept and efalizumab are officially registered and reimbursed for the treatment of recalcitrant psoriasis in The Netherlands. OBJECTIVE: The evaluation of the efficacy, safety and adverse events of etanercept and efalizumab treatment in daily practice. METHODS: A prospective cohort study was carried out for patients treated with etanercept or efalizumab between February 2005 and March 2006. RESULTS: Over the past 13 months 45 individuals were treated with etanercept and 17 subjects were treated with efalizumab. The cohort represented a high-need population. At week 12, 82% of the subjects treated with 2 x 50 mg etanercept/week and 71% of the subjects treated with 2 x 25 mg etanercept/week reached a PASI-50. Efficacy of etanercept treatment was comparable to the results of clinical trials. For efalizumab, efficacy in responding patients was also comparable to clinical trial data, but the percentage of dropouts was substantial. During biologic treatment, safety was preserved and mainly mild adverse events were reported. CONCLUSION: Etanercept and efalizumab are effective and safe treatments of psoriasis, even in a high-need population. Etanercept was able to sustain the clinical improvement throughout 24 weeks, whereas efalizumab was not in 47% of subjects.
J Rheumatol. 2006 May;33(5):854-61. Epub 2006 Mar 15.
Etanercept treatment in adults with established rheumatoid arthritis: 7 years of clinical experience.
Moreland LW ea, University of Alabama at Birmingham, USA.
OBJECTIVE: To evaluate safety and efficacy of longterm etanercept treatment in patients with disease modifying antirheumatic drug (DMARD) refractory rheumatoid arthritis (RA). METHODS: Safety results are reported for 714 patients who received etanercept in one of 7 initial trials or a longterm extension. Efficacy results are reported for 581 patients who enrolled in the extension. RESULTS: Of the 714 patients enrolled in the initial trials, 581 (81%) enrolled in the extension, and 388 (54%) patients are continuing to receive etanercept therapy. The longest individual treatment was 8.2 years, with 3139 total patient-years of etanercept exposure. Rates of serious adverse events (overall rate=14.8 events/100 patient-yrs), serious infections (overall rate=4.2 events/100 patient-yrs), cancer (overall rate=1.0 events/100 patient-yrs), and deaths (overall rate=0.7 events/100 patient-yrs) were stable each year, through 8 years of etanercept exposure. For 356 patients who completed 6 years of etanercept treatment, response rates were ACR20=73%, ACR50=52%, ACR70=27%, DAS28 CRP good response=52%, and DAS28 CRP remission=37% of patients. Similar responses occurred in 167 patients who completed Year 7. Doses of concomitant methotrexate or corticosteroids were reduced in many patients who maintained clinical responses. CONCLUSION: The safety profile of etanercept was consistent over time, with rates of adverse events similar to those reported for patients with RA in general. Durable clinical responses were observed in some patients for 7 years or more. The benefit-to-risk ratio for longterm etanercept treatment remains highly favorable.
Arthritis Rheum. 2005 Jan;52(1):49-60.Presentation and analysis of data on radiographic outcome in clinical trials: experience from the TEMPO study. van der Heijde D, ea University Hospital, Maastricht, The Netherlands.
OBJECTIVE: To evaluate different methods of presentation and analysis of radiographic data in a rheumatoid arthritis (RA) randomized controlled trial. METHODS: A double-blind randomized controlled trial including 682 patients with active RA who were treated with methotrexate, etanercept, or a combination of the 2 drugs was used for this study. Probability plots of the change from baseline to year 1 were produced to visualize progression, and were compared with usual descriptive statistics. The primary analysis of the trial (based on annualized actual mean change from baseline in total Sharp score at 1 year, using linear imputation) was challenged using various ways of handling missing information with alternative imputation methods, and by various statistical analyses including analysis of covariance (ANCOVA) and mixed model analysis on both raw and log-transformed data. RESULTS: Probability plots provided detailed insight into the differentiated treatment effects between the 3 arms of this study. As adjuncts to formal hypothesis testing, these plots were more useful for presenting data than were summary descriptive statistics or use of preset cutoff points to define lack of progression. Additional analyses presented here support the results obtained with the per-protocol analysis that showed an advantage of the combination treatment compared with the monotherapy arms and for etanercept versus methotrexate alone. Various ways of handling missing information confirmed the robustness of the results. In addition, both ANCOVA and mixed model analyses on raw and on log-transformed data produced similar results. CONCLUSION: We suggest a panel of alternative analysis methods and alternative ways of handling missing information to verify that the radiographic results reported in an randomized controlled trial are not influenced by technical factors, such as interpolation, handling of missing data, and choice of statistical tests.
Rheumatology (Oxford). 2005 Mar;44(3):342-8.
Long-term efficacy and safety of etanercept after readministration in patients with active ankylosing spondylitis. Brandt J, Medical University Berlin, Germany.
OBJECTIVES: Treatment of ankylosing spondylitis (AS) with the tumour necrosis factor alpha (TNF-alpha) receptor fusion protein etanercept has shown efficacy in patients with active disease in randomized controlled trials (RCTs) for limited periods. The objective of the study was to assess the long-term efficacy and safety of etanercept over 1 yr, including discontinuation and readministration. METHODS: In this 54-week open observational study, 26 AS patients received 25 mg etanercept subcutaneously twice weekly after several months of discontinuation following a 6-month RCT with the same agent. All patients who developed high disease activity after cessation of etanercept, defined as a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) > or = 4 and pain > or = 4 on a numerical rating scale, entered the study. Standard assessment tools, such as the Bath Ankylosing Spondylitis functional index (BASFI), were used. An intention-to-treat (ITT) and a completer analysis were performed. The results were compared with the baseline values of the open study. RESULTS: Out of the initial 30 patients, 26 (87%) were eligible for the open extension study after a mean of about 27 weeks. At week 54, 23/26 patients (88%) were still on treatment with etanercept. The ITT analysis showed that 58% (95% confidence interval 39-74%) of the patients achieved a 50% improvement of BASDAI at week 54. According to the Assessments in Ankylosing Spondylitis working group criteria, 8/26 patients (31%) were in partial remission at week 54. Function, metrology and quality of life improved significantly. Only one patient had a serious adverse event that resulted in discontinuation. CONCLUSIONS: This study shows that treatment with etanercept is efficacious and safe after readministration over 1 yr in patients with active AS not taking DMARDs or steroids.
Eur J Heart Fail. 2001 Jun;3(3):381-7.
Clinical Trials Update: CAPRICORN, COPERNICUS, MIRACLE, STAF, RITZ-2, RECOVER and RENAISSANCE and cachexia and cholesterol in heart failure. Highlights of the Scientific Sessions of the American College of Cardiology, 2001.
Louis A ea University of Hull, UK. This is a synopsis of presentations made at the American College of Cardiology (ACC) in 2001 summarising recent research developments relating to heart failure. Clinical studies of particular interest to physicians with an interest in heart failure and its prevention are reviewed. The RENAISSANCE and RECOVER outcome studies of etanercept, a tumour necrosis factor (TNF) receptor analogue that blocks the effect of TNF, were stopped because of lack of evidence of benefit shortly after the ACC.