TNFMedicine

The Cerebrospinal Venous System: Anatomy, Physiology, and Clinical Implications.

The cerebrospinal venous system(CSVS), a term coined by me, plays a central role in the vascular circulation of the brain, the spinal cord, and the nerve roots. Detailed knowledge of the CSVS is therefore of consequence when considering therapeutic intervention for diseases involving these structures. The seminal work regarding the anatomy and physiology of the CSVS was done by Oscar Batson, a pioneering professor at the University of Pennsylvania, in the 1940's. Although "Batson's Plexus" has achieved widespread recognition, much of his highly important work never achieved the scientific dissemination it deserved. Perhaps the use of highly potent and selective biologic therapeutics capable of transport via the CSVS (as described in my pending patent applications) will help illuminate the brilliance of Dr. Batson's early discoveries.

Title The Cerebrospinal Venous System: Anatomy, Physiology, and Clinical Implications.
Author(s) Edward Tobinick MD
Institution Assistant Clinical Professor of Medicine
Source MedGenMed 2006; 8(1):53.
Abstract There is substantial anatomical and functional continuity between the veins, venous sinuses, and venous plexuses of the brain and the spine. The term "cerebrospinal venous system" (CSVS) is proposed to emphasize this continuity, which is further enhanced by the general lack of venous valves in this network. The first of the two main divisions of this system, the intracranial veins, includes the cortical veins, the dural sinuses, the cavernous sinuses, and the ophthalmic veins. The second main division, the vertebral venous system (VVS), includes the vertebral venous plexuses which course along the entire length of the spine. The intracranial veins richly anastomose with the VVS in the suboccipital region. Caudally, the CSVS freely communicates with the sacral and pelvic veins and the prostatic venous plexus. The CSVS constitutes a unique, large-capacity, valveless venous network in which flow is bidirectional. The CSVS plays important roles in the regulation of intracranial pressure with changes in posture, and in venous outflow from the brain. In addition, the CSVS provides a direct vascular route for the spread of tumor, infection, or emboli among its different components in either direction.
Language ENG
Pub Type(s) JOURNAL ARTICLE
PubMed ID 16915183

A Guide to this website

This website is meant to be a guide for the reader to the latest scientific information in the medical literature which discusses the role of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha, or simply TNF) in medicine. A particular emphasis is given to the role of TNF in two critical areas, where TNF is centrally involved: the pathogenesis (pathogenesis: the development of disease; more specifically the cellular events and reactions and other pathologic mechanisms occurring in the development of disease) of Alzheimer's Disease and other forms of dementia; and in back pain and sciatica, and other forms of disc-related pain.

In this section, on the top left column of the webpage, are listed the various categories into which the website is divided. By clicking on each of these categories one may see the various dated posts which have been made which fall into this category. Some of the posts made fall into multiple categories, such as "TNF and dementia" and "Key articles"; many will fall into only one category.

When time permits, I will precede the article citation by a brief discussion. This discussion will be in italic type, to distinguish it from the citation itself.

The categories, with a brief explanation of each, are as follows:

1. A guide to this website.
Designed to be read first, this is an introduction and a guide to the website.
2. Author's recent articles.
This includes citations to the peer-reviewed, published articles written by the author of this website within the last few years.
3. Cerebrospinal venous system.
The cerebrospinal venous system plays a key role in the vascular circulation of the brain and the spine. Its importance has historically been underrecognized in general medicine, but it represents a key pathway between the brain and the spine. The CSVS is the subject of a review I wrote which published in the journal Medscape General Medicine in February 2006. link to PubMed abstract.
4. Key articles.
These are the articles which I believe are of highest relevance for this website, and includes links to the PubMed citations, which include the abstract and usually will include a link to the full-text article.
5. Links.
This section includes links to websites which I believe may be useful to the reader seeking further information regarding the role of TNF-alpha and anti-TNF-alpha therapeutics in medicine, or which are otherwise related to the information in this website.
6. Scientific articles citing author's articles.
These are generally peer-reviewed scientific articles or textbooks which have cited one or more of my published articles. By definition, my article has preceeded the citing article in publication date, usually by several years.
7. TNF and Alzheimer's/Dementia.
TNF plays a central role in the pathogenesis of Alzheimer's Disease and other forms of dementia. This category includes an increasing number of scientific articles which provide scientific support for this concept. It now appears that TNF likely contributes to the pathogenesis of Alzheimer's in a variety of ways, not only by initiating and amplifying the inflammatory response, but also by interfering with synaptic transmission, and by its involvement in pathways involving amyloid, glutamate, AMPA and NMDA receptors. The articles in this category will not necessarily be discussed in date order, since I am going to attempt to go back into the literature and discuss previous articles of relevance as time permits.
8. TNF and Back Pain/Sciatica.
9. TNF and off-label use.
10. TNF in general medicine.

Therapeutic potential of cytokine and chemokine antagonists in cancer therapy

This excellent 2006 review from the group at Centocor discusses the therapeutic potential of biologic TNF-alpha antagonists for the treatment of patients with cancer. The article cites and discusses my 2003 article reporting a therapeutic response in two patients with cancer metastases to the spine, which was the first report in the literature of this nature. (see Edward Tobinick MD, Targeted etanercept for treatment-refractory pain due to bone metastasis: two case reports. [Case Reports, Journal Article] Clinical Therapeutics 2003 Aug; 25(8) :2279-88).

Therapeutic potential of cytokine and chemokine antagonists in cancer therapy.
Yan L,
Anderson GM,
DeWitte M,
Nakada MT.
Centocor R&D Inc., 145 King of Prussia Road, Radnor, PA 19087, USA.
A new paradigm is becoming widely accepted, that chronic inflammation, driven in part by chemokines and cytokines at the site of a tumour, may facilitate tumour progression instead of promoting anti-tumour immunity. Tumours and activated stromal cells secrete pro-inflammatory chemokines and cytokines that act either directly or indirectly through stimulation of the vascular endothelium to recruit leukocytes to the tumour. After activation, these tumour-associated leukocytes release angiogenic factors, mitogens, proteolytic enzymes, and chemotactic factors, recruiting more inflammatory cells and stimulating angiogenesis to sustain tumour growth and facilitate tumour metastasis. Breaking this cycle by inhibiting targets such as cytokines, chemokines and other inflammatory mediators, either alone, or more realistically, in combination with other therapies, such as anti-angiogenic or cytotoxic agents, may provide highly efficacious therapeutic regimens for the treatment of malignancies. This article reviews anti-cytokine and anti-chemokine therapies being pursued in cancer, and discusses in more detail anti-tumour necrosis factor-alpha (TNF) approaches.
Eur J Cancer. 2006 Apr;42(6):793-802. Epub 2006 Mar 9
PMID: 16524718 [PubMed - indexed for MEDLINE]

Editorial: cytokine inhibition for treatment of Alzheimer's disease

This editorial, by a well-respected expert on the mechanisms of molecular inflammation in Alzheimer's disease, was commissioned to discuss our pilot study, which was the first article in the medical literature to report the use of perispinal administration of a biologic TNF antagonist for Alzheimer's:
Edward Tobinick MD, Hyman Gross MD, Alan Weinberger MD, and Hart Cohen, MD,
TNF-alpha Modulation for Treatment of Alzheimer's Disease: A 6-Month Pilot Study. [Journal Article]
MedGenMed 2006; 8(2):25.

Title Editorial: Cytokine inhibition for treatment of Alzheimer's disease.
Author(s) Rosenberg PB 
Institution Assistant Professor of Psychiatry and Behavioral Sciences, Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Source MedGenMed 2006; 8(2) :24.
Language eng
Pub Type(s) Journal Article
PubMed ID 16926763

The role of neuroinflammation in neuropathic pain: mechanisms and therapeutic targets

This article, an excellent review, whose lead author is Robert Myers, MD, editor of the Journal of the Peripheral Nervous System and a leading researcher into the role of TNF-alpha and neuroinflammation, cited our article:
Edward Tobinick MD and Susan Davoodifar MD,
Efficacy of etanercept delivered by perispinal administration for chronic back and/or neck disc-related pain: a study of clinical observations in 143 patients. [Case Reports, Journal Article]
Curr Med Res Opin 2004 Jul; 20(7) :1075-85.

Title The role of neuroinflammation in neuropathic pain: mechanisms and therapeutic targets.
Author(s) Myers RR, Campana WM, Shubayev VI 
Institution Department of Anesthesiology (0629), University of California-San Diego, La Jolla, CA 92093-0629, USA. rmyers@ucsd.edu
Source Drug Discov Today 2006 Jan; 11(1-2) :8-20.
MeSH Animals
Cytokines
Humans
Neuralgia
Neurogenic Inflammation
Peripheral Nerves
Abstract Neuroinflammation is a proinflammatory cytokine-mediated process that can be provoked by systemic tissue injury but it is most often associated with direct injury to the nervous system. It involves neural-immune interactions that activate immune cells, glial cells and neurons and can lead to the debilitating pain state known as neuropathic pain. It occurs most commonly with injury to peripheral nerves and involves axonal injury with Wallerian degeneration mediated by hematogenous macrophages. Therapy is problematic but new trials with anti-cytokine agents, cytokine receptor antibodies, cytokine-signaling inhibitors, and glial and neuron stabilizers provide hope for future success in treating neuropathic pain.
Language eng
Pub Type(s) Journal Article
Review
PubMed ID 16478686

Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2006

This article, representing the official consensus statement of a group of 143 rheumatologists and bioscientists chosen from 21 countries, cited our article:
Edward Tobinick MD and Susan Davoodifar MD
Efficacy of etanercept delivered by perispinal administration for chronic back and/or neck disc-related pain: a study of clinical observations in 143 patients. [Case Reports, Journal Article]
Curr Med Res Opin 2004 Jul; 20(7) :1075-85.

Title Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2006.
Author(s) Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR, Emery P, Keystone EC, Schiff MH, van Riel PL, Weinblatt ME, Weisman MH 
Institution David Geffen School of Medicine, UCLA - RM 32-59, 1000 Veteran Avenue, Los Angeles, CA 90025, USA. defurst@mednet.ucla.edu.
Source Ann Rheum Dis 2006 Nov.:iii2-iii15.
Language eng
Pub Type(s) Journal Article
PubMed ID 17038465

Pathophysiology of disk-related low back pain and sciatica. II. Evidence supporting treatment with TNF-alpha antagonists

This article, from a group in France which has professed no experience with perispinal administration of TNF-antagonists for disc-related pain, is less notable for its conclusion than for its positive discussion of the scientific evidence supporting a central role of TNF in the pathogenesis of disc-related pain.

Title Pathophysiology of disk-related low back pain and sciatica. II. Evidence supporting treatment with TNF-alpha antagonists.
Author(s) Mulleman D, Mammou S, Griffoul I, Watier H, Goupille P 
Institution François Rabelais de Tours University, EA 3853 Immuno-Pharmaco-genetics of Therapeutic Antibodies (IPGA), France.
Source Joint Bone Spine 2006 May; 73(3) :270-7.
Abstract Strong evidence suggests that TNF-alpha may be among the chemical factors involved in disk-related sciatica. TNF-alpha is involved in the genesis of nerve pain in animal models and may promote pain-signal production from nerve roots previously subjected to mechanical deformation. In animal experiments, TNF-alpha has been identified in nucleus pulposus and Schwann cells. Local production of endogenous TNF-alpha may occur early in the pathogenic process. Exposure to exogenous TNF-alpha induces electrophysiological, histological, and behavioral changes similar to those seen after exposure to nucleus pulposus, and these changes are more severe when mechanical compression is applied concomitantly. TNF-alpha antagonists diminish or abolish abnormalities in animal models. Other cytokines may be involved also, as suggested by the potent inhibitory effects of compounds such as doxycycline. Two open-label studies in humans suggest dramatic efficacy of TNF-alpha antagonists in alleviating disk-related sciatica. In contrast, the results of the only controlled study available to date do not support a therapeutic effect of TNF-alpha antagonists. Thus, whether TNF-alpha antagonist therapy is warranted in patients with disk-related sciatica remains an open question, and further randomized controlled studies are needed.
Language eng
Pub Type(s) Journal Article
PubMed ID 16046171

The Craniospinal Venous System

Imitation (and in this case what appears to be just short of outright plagurism) is said to be the sincerest form of flattery. I was, however, pleased inasmuch as this new article will result in further dissemination of my concepts to the medical community abroad. It should be noted that there is indeed a citation to my original article (which had published six months prior to this European Neurology article) contained within this clearly derivative work, and the citation is as follows:
Edward Tobinick MD,
The Cerebrospinal Venous System: Anatomy, Physiology, and Clinical Implications. [JOURNAL ARTICLE]
MedGenMed 2006 February 22; 8(1):53.

Title The Craniospinal Venous System.
Author(s) Pearce JM 
Institution Emeritus Consultant Neurologist, Department of Neurology, Hull Royal Infirmary, Hull, UK.
Source Eur Neurol 2006 Sep 8; 56(2) :136-138.
Abstract The valveless craniospinal venous system consists of veins and plexuses that communicate freely and whose flow is bidirectional. It comprises (1) the intracranial-cortical veins, dural sinuses, cavernous sinuses and ophthalmic veins, and (2) the vertebral venous plexuses, which freely anastomose with the intracranial venous system. The vertebral venous plexuses anastamose with the sacral, pelvic and prostatic venous plexus. It is clinically important since it provides a route for the spread of tumours, infection or emboli. This route may go unrecognised. Copyright (c) 2006 S. Karger AG, Basel.
Language ENG
Pub Type(s) JOURNAL ARTICLE
PubMed ID 16960456

Long-lasting neuropathic pain induced by brachial plexus injury in mice: Role triggered by the pro-inflammatory cytokine, tumour necrosis factor alpha

Title Long-lasting neuropathic pain induced by brachial plexus injury in mice: Role triggered by the pro-inflammatory cytokine, tumour necrosis factor alpha.
Author(s) Quintão NL, Balz D, Santos AR, Campos MM, Calixto JB 
Institution Department of Pharmacology, Centre of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, 88049-900 Florianópolis, SC, Brazil.
Source Neuropharmacology 2006 Apr; 50(5) :614-20.
MeSH Animals
Brachial Plexus Neuropathies
Comparative Study
Female
Hyperalgesia
Mice
Mice, Inbred C57BL
Mice, Knockout
Neuralgia
Pain Measurement
Pain Threshold
Reaction Time
Research Support, Non-U.S. Gov't
Time Factors
Tumor Necrosis Factor-alpha
Abstract Brachial plexus avulsion (BPA) resulted in a marked and long-lasting mechanical hypernociception (up to 80 days) in comparison to a sham-operated group, as assessed by Von Frey filaments, in both Swiss and C57/BL6 mice. In the tail-flick test, both Swiss and C57/BL6 mice submitted to BPA showed a significant thermal hypernociception, which persisted for 10 days. Both mechanical and thermal hypernociception following BPA were abolished in tumour necrosis factor alpha (TNFalpha) p55 receptor knockout mice. Moreover, the mechanical hypernociception caused by BPA was inhibited by the local application of the anti-TNFalpha (10 and 100 ng/site) antibody at the time of the surgery or by the intravenous administration (100 microg/kg) of this antibody at the time of the surgery or 4 days after the BPA. A similar inhibition of the mechanical hypernociception was observed when treating mice with the TNFalpha synthesis inhibitor thalidomide (50 mg/kg, s.c.), either at the time of the surgery or 4 days after. The results suggest that the persistent thermal, and especially the persistent mechanical, hypernociception observed following BPA in mice is largely dependent on the generation of TNFalpha. Based on these results, it is possible to suggest that therapeutic strategies for blocking TNFalpha could represent a valuable approach for the treatment of persistent neuropathic pain.
Language eng
Pub Type(s) Journal Article
PubMed ID 16386767

A review of antibody therapeutics and antibody-related technologies for oncology

Title A review of antibody therapeutics and antibody-related technologies for oncology.
Author(s) Scallon BJ, Snyder LA, Mark Anderson G, Chen Q, Yan L, Weiner LM, Nakada MT 
Institution Centocor, Malvern, PA 19355 Fox Chase Cancer Center.
Source J Immunother 2006 Jul-Aug; 29(4) :351-64.
Language eng
Pub Type(s) Journal Article
PubMed ID 16799330