Re-printed from Allergy Research Group
Newsletter February 2004
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In March of 2001, a total of 39 normal volunteers
completed the first homeopathic proving trial for COBAT. COBAT was prepared
according to GMP homeopathic standards by Eric Foxman at Hauser, Inc. It was
diluted via a series of six ten-fold dilution steps with vigorous agitation
(succussion) at each step. The final steps were in 20% EtOH to prevent
microbial growth. COBAT is prepared by the classic homeopathic methods of
dilution and vigorous mixing at each step. COBAT is considered a homeopathic
medicine and has entered that regulatory path. Documentation of COBAT as a
homeopathic medicine has been made by a variety of experts under "Rule of 3" of
"Of all the homeopathic provings I have been
involved with (35 trials) COBAT produced the strongest effects." David Riley,
"The results of the homeopathic proving trial
suggest that it might be involved in a wide variety of immune related
conditions. These should be studied in the future" Floyd Taub, M.D.
proving trial was a double-blind, placebo trial which evaluated 6x and 8x
doses. An apparent physiological effect was observed in 26% of patients given
the placebo. 92% (overall for 6x and 8x) receiving COBAT were identified as
having physiological effects. Dr. Rileys report of the essential
characteristics of Materia Medica (i.e. those symptoms that may be according to
the law of similars, either caused or resolved if previously present) are shown
Essential Characteristics of
Symptoms (by Riley):
- Appetite Abnormalities
- Increasing Energy
- Irritable Bowel Syndrome, Loose stools
- Muscle aches and Pains
- Neurological Problems
Doctor Floyd Taub, M.D.
The Goldilocks Effect
Dr. Floyd Taub, M.D., notes that COBAT shows
adaptogenic activity at the molecular (mRNA) level, as demonstrated by Pontzer,
Dunn and Wormsley. While in un-stimulated inactive cells, it increases
interferon gamma messages, and thereby has antiviral and antitumor effects. In
pharmacologically highly treated cells, it actually dramatically decreased or
eliminated the RNA messages for this key TH1 cytokine. Similarly, while it had
relatively little effect on secretion of TNFa in un-stimulated cells, it
virtually eliminated release from pharmacologically stimulated cells (the
decrease was over 100 fold). This may be the first molecular data showing an
adaptogenic effect. COBAT apparently acts as an immune modulator. It appears to
provide just the right amount - the "Goldilocks" effect - not to much, not too
little - just the right amount.
This balancing of the immune system is further
demonstrated by a lack of stimulation of allergic or autoimmune responses .
While data on autoimmune disease is sparse, virtually none of the persons with
allergies showed an increase. In fact, 60% showed a decrease in allergies
(p.007). In those that responded, the average decrease was 71%.
Most of our patients are fatigued. However, we
typically focus on medical therapy to fight the underlying disease. The use of
COBAT can be very complimentary to alternative (or conventional) therapies and
a major help to patients by relieving much of their fatigue before, during and
after* treatment. COBAT clearly improves quality of life.
*Patients may want to skip COBAT on the day of and day
following major cytotoxic therapies to minimize potential damage to the immune
Dr. David Riley, M.D.
Dr. David Riley,
M.D., stated that his observations during the homeopathic proving trial
indicated this was the most powerful homeopathic agent he had tried in over 35
homeopathic provings that he had performed, based on the magnitude of the
effects in some patients. This double-blind, placebo controlled trial revealed
his clinical sense to be accurate. COBAT-treated persons showed an effect 92%
of the time, while placebo-treated patients showed an effect 26% of the
COBAT Versus Conventional Drug Therapy
Cytokines Regulate Sleep and
by Daniel Rubin, N.D. & Stephen Levine, Ph.D.
Modern day fatigue has gone beyond a mere message or
signal of the need to retire to a bed for the night. It has seeped its way from
a nocturnal sensation into our common daily manner of living. In some
instances, fatigue has become so pervasive that it has become the defining
entity of some patients lives, almost a way of being. In
cases of severe illness, it is the major symptom preventing the patient from
participating in and enjoying many aspects of life. NIH describes fatigue as
one of the three key symptoms of cancer and the worst managed of the three.
Erythropoietin and similar drugs garner a four billion dollar market treating
the subset of this fatigue due to anemia. Patients on dialysis also suffer from
fatigue as do those with HCV, any severe infection, or even the common cold.
The collective knowledge about fatigue has become large enough that the
relationship between biochemistry, infection and fatigue is receiving
attention. Even with such available knowledge, fatigue is increasingly
pervasive in our society.
The combination of cytokines and immune cells is
analogous to the combination of neurotransmitters and brain cells that allow
recognition of an enemy and a response that is not too small nor excessive. In
animals, it is particularly easy to identify a TH1-type pattern composed of
pro inflammatory cytokines especially effective in fighting
viruses and cancer. In CFS, these cytokines may be overactive, especially when
compared to the pathogen which may have been illuminated, or is at least beyond
our ability to clearly identify. Effective control of all types of viruses and
cancer, and most likely CFS, requires an initial TH1 response that is effective
and then a return to a homeostatic state including decreased TH1 and TH2
cytokines and associated antibodies. Unfortunately, effective elimination of
the disease and the return to homeostasis may not occur in CFS, cancer, HCV, or
other chronic viral infections. Selective anergy may occur, and chronic
overstimulation may result in fatigue without fully effective antiviral
Immune-Cytokine Imbalances Similar in Chronic
Fibromyalgia, Gulf War Syndrome and Cancer
Data was presented at the 38th Annual Meeting of AAEM
on immunologic studies of patients with Chronic Fatigue Syndrome (CFS),
Fibromyalgia (FM) and Gulf War Syndrome (GWS) by Aristo Vojandi (ImmunoScience
Laboratory) in 2003. Therein, certain immunological discoveries were mentioned
likening the immunological dysregulation found in patients with CFS, FM and
GWS. Data was reported b from a retrospective study of 2500 patients, mostly
with CFS, some with FM, and some with GWS (this is the largest study of this
nature that we know of), wherein it was stated that chronic fatigue could be
caused by any of a number of stressful events, though mainly viral or other
infectious agents, and various toxic chemicals. And it was concluded that many
different stressors could lead to development of these conditions. The patient
groups exhibited surprising similarities in immune cytokine patterns. Noted was
a general switch from TH1 T cell dominance to a TH2 dominance. Gradually,
interferon gamma and natural killer cell activity and phagocytosis were reduced
. Inflammatory cytokines were also enhanced, leaving patients more prone to
allergy, hypersensitivity and autoimmunity.
These syndromes are similarly characterized by
multi-organ complaints such as achiness, headache, lymph node pain and
gastrointestinal problems. The infection vector for some patients is highly
probable, but also, once a person becomes fatigued for a particular reason and
subsequently becomes less mobile, there is a greater potential for infection.
For instance, it is well known that bedridden patients are extremely prone to
infection, mostly due to lack of mobility. The human body is designed for
mobility inactivity creates stagnation which sets the stage for infectious
organisms to propagate. As infection ensues in the body, the bias towards a TH2
phenotype follows accordingly.
This research suggests that the body adapts to these
kinds of stressors in defined ways, some of which become maladaptive. The
alteration in the immune and cytokine patterns appear to be such an adaptation
- maladaption is common and similar in these three illnesses, and generally in
the fatigue associated with cancer.
Cytokines are small glycoproteins found in
femtomolar and picomolar concentrations in the blood, which when bound to their
receptors in a hormone-like fashion, elicit certain responses. Cytokines are
able to individually elicit such responses but usually work in
groups to achieve a better overall effect. Almost all biological
systems are influenced by cytokines, including the induction of
It appears that the body is trying to protect itself
against overwhelming stress. Figuratively, the body throws a switch, which is
like a light dimmer switch, which then establishes a common
biochemical-immune-endocrine-inflammation and cytokine pattern associated with
lower energy and pain. This affects the hypothalamus/pituitary/adrenal axis,
involving hormonal and autonomic nervous function.
In addition to rectifying the infectious, chemical,
and other stressors which may have precipitated these conditions, it may be
productive to balance the immune and cytokine aberrations directly.
The literature on chronic fatigue does support the
notion that there is some activation in the TH1-driven inflammatory cytokines,
but also, there is an important switch that appears to be a TH2 dominance. This
is in agreement with findings in the Applied Neuropsychology article (Roberto
Patarca - Montero, et al. Applied Neuropsychology, Vol. 8, No.1, 51-54,
Sleep and Cytokine Regulation
Sleep is regulated by neuronal and humoral (soluble)
factors which are dependent on one another. Several humoral sleep-regulatory
substances (SRS) have been identified as follows: For non-rapid eye movement
sleep: a) Interleukin (IL)-1; b) Tumor Necrosis Factor (TNF) (which have been
identified as TH1 cytokines); c) Growth Hormone Releasing Hormone; d)
Prostaglandin D2; e) adenosine; and f) uridine. For SRS-governing rapid eye
movement sleep: Prolactin and VIP (vasoactive intestinal peptide). The humoral
factors IL-1 and TNF appear to bear the most significance in that substances
that inhibit the production or activity of IL-1 or TNF inhibit sleep
altogether. Somnogenic sites for most SRS appear to occupy the ventrolateral
preoptic area of the hypothalamus. However there may be other areas of the
brain that also participate.
A prudent antifatigue strategy would be to manipulate
the SRS in order to promote predictive and restorative, normal sleeping
patterns. Since sleep is regulated by SRS that are measurable, an investigation
into the relationship between the SRS which govern proper sleep and the soluble
factors which may alter their activity is warranted. Three aspects of such BRM
(Biological Response Modification) systems will be discussed as hypotheses for
the causes of fatigue in: a) cancer b) Gulf War Syndrome; and c) Chronic
IL-6: Cancer-Related Fatigue Antagonizes SRS and
Imbalances Immune Function Towards TH2 Dominance
Cancer patients have been shown to have higher
endogenous levels of IL-6 (IL-6 is a TH2-inducing cytokine). I n fact, not only
has elevated IL-6 been positively correlated with cancer patients, but it has
also been shown to play an important role in the progression of some cancers,
and has been correlated with fatigue in cancer patients. So IL-6 has been
touted as a novel target for treatment of cancer patients. It is well known
that cancer patients have a deficient cell-mediated immune response.
The cell-mediated response is characterized by the
presence of CD4+ T lymphocytes, namely TH1 lymphocytes. A certain destiny of a
naïve CD4+ T lymphocyte (TH0) is acquisition of either a TH1 or a TH2
phenotype - a phenomenon mostly dependent upon the endogenous cytokine milieu.
For instance, under the influence of IL-12, TH0 cells will elicit cytokines
peculiar to the TH1 phenotype, thereby inducing a cell-mediated response; under
the influence of other cytokines such as IL-4 or IL-10 TH0 CD4+, lymphocytes
will obtain a TH2 phenotype and elicit an antibody-mediated immune response.
During the activation of a CD4+ cell, locally present IL-6 can induce the
production of IL-4 and therefore, differentiation of a local TH0 t o a TH2
While both responses may be beneficial against
malignant cells, the cell-mediated response, mediated by TH1, is more
appropriate in terms of seeking an immunological-based recovery from cancer.
Tumor-protective blocking antibodies have long been known. In fact, it has been
shown that many cancer patients who were successfully treated using
immunotherapeutic techniques were stuck in a TH2 rut prior to their
treatment. However, after successful immunological treatment, the endogenous
cytokine bias was towards a TH1 phenotype.
IL-6: CFS, FM, GWS, Sleep, Fatigue &
From the data presented, IL-6 (TH2 cytokine)
overproduction may play a very significant role in these cytokine-immunological
imbalances. IL-6 production is stimulated in various ways, and in terms of the
populations of people that have been discussed, the most reasonable production
stimulus for IL-6 appears to be either inflammatory or immunological -both
critical issues for patients with CFS, FMS, GWS and cancer. IL-6 is produced by
a host of immunoreactive cells - phagocytic cells such as dendritic cells and
macrophages, as well as B lymphocytes. Also, IL-6 has a profound effect on the
stress system and is secreted under times of inflammatory stress. Furthermore,
IL-6 activates the hypothalamic-pituitary-adrenal axis. IL-6 may also mediate
some of the effects of stress on immune-cytokine regulation.
It appears then, that IL-6 plays a central role in the
generation and perpetuation of fatigue. Accordingly, a systemic diminution of
IL-6 would be a pragmatic therapeutic goal. However, such elegant modulation of
the endogenous cytokine milieu has historically been difficult and complicated,
and previously un-achievable. Antibodies to IL-6 have not had clinical success
However, research on a new compound - carbobenzoxy
beta-alanyltaurine or COBAT suggests it may play a critical role in
normalizing some of the abnormal immune-cytokine biochemistry that we have
described. COBAT has been the subject of multiple cell cultures in both animal
and human studies, and a pattern of IL-6 down-regulation, as well as a
balancing of other TH2 mediators , appears consistently throughout these works,
highlighted as follows:
1) in vitro: Tom Dunn of the University of
Maryland, College Park, performed numerous pharmacological experiments on
COBAT. He found COBAT to be a potent immune stimulant for human cells. The
highlight of this study was that COBAT amplified the expression of cell surface
TNF without a concomitant increase in circulating TNF (soluble or circulating
TNF can produce inflammatory symptoms) so that the increase in membrane or cell
surface TNF may help as an active factor in sleep, without increasing
inflammatory symptoms. Also, COBAT caused an increase in interferon -gamma
(IFN-gamma) expression and secretion. According to the IL-6 hypothesis
presented herein, two issues hold true: a) IL-6 acts as a negative regulator of
TNF, thus an increase in its expression would signal a decrease in IL-6 levels
and; b) IFN-gamma is a stereotypical TH1 cytokine. The mere presence of
IFN-gamma signifies a TH1 dominance.
2) Animal study: A University of New Mexico
study tested the efficacy of COBAT in a Myeloma NS-1 model. The results
demonstrate a dose-dependent response: a) increased survival of the animals
with up to 100% tumor- free (100 pg/kg, i.p.) and; b) 66%-75% survival at other
doses (100 fg/kg to 10 ng/kg, both i.p.). IL-6 is the most important growth
factor for human multiple myeloma and several investigations have supported
this notion. Thus, the central theme holds true here: improvement in the status
of animals affected with myeloma would follow a decrease or complete abatement
of circulating IL-6.
3) Human Study: COBAT moderated immune
function, appeared to be adaptogenic, and produced physiological changes in
patients during a blinded homeopathic proving trial, with a 92% response rate
in treated patients and a 26% response rate in controls. In a subsequent
University of S o u t h e rn California IRB study on fatigue in patients whose
fatigue was believed to be a result of pathologic immune dysregulation, all
patients but one reported a decrease in symptoms. All these effects were highly
We believe that IL-6 plays a central role in the
physiological aberrations which contribute to or lead to advanced fatigue
states and immunological dysfunctions. Fatigue is enigmatic it seems to be born
from such a variety of sources that its treatment has been equally as
enigmatic. COBAT appears to represent a revolution in the management of fatigue
potentially via a down-regulation of IL-6 levels and other Type 2 cytokines.
Regardless of the IL-6 hypothesis, the clinical observation of reduced fatigue
and apparently enhanced immune function is striking. It should be noted that
the effects may begin immediately, but progressively increase for months. A
therapeutic trial should be one month. Patients who do not respond to a low
dose within 3-4 weeks should be switched to the stronger dose containing more
molecules. A striking lack of side effects is note-worthy as well.
References available on request.
Daniel Rubin, N.D.
In addition to his
private consulting practice, in which he specializes in I m m u n o l o g y,
Oncology and Integrative Medicine, Dr. Rubin is the Medical Consultant in
Oncology and Internal Medicine to the Naturopathic Physicians Board of Medical
Examiners in the State of Arizona; Associate Clinical Professor of Naturopathic
Medicine at Southwest College of Naturopathic Medicine; Assistant Editor of
Integrative Cancer Therapies; Researcher for the Block Center for Integrative
Medicine. In addition, Dr. Rubin frequently lectures nationally and
internationally, and his work has been featured in numerous scientific
Website: www. rubinmedical.com
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