Homeopathic Proving

Re-printed from Allergy Research Group Newsletter February 2004

See Additional Newsletter Articles on (Taurox SB™ 6X Enhanced) - COBAT

Article Index

Trials
Methods
Commentary, Dr Floyd Taub M.D.
COBAT vs. Conventional Medicine
Cytokines

Homeopathic Proving Trial

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 the FDA.

"Of all the homeopathic provings I have been involved with (35 trials) COBAT produced the strongest effects." David Riley, M.D.

"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.

Methods

The homeopathic 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. Riley’s 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 here:

HP Methods

Materia Medica
Essential Characteristics of Symptoms (by Riley):

Allergies
Appetite Abnormalities
Colds
Coughs
Headaches
Increasing Energy
Irritable Bowel Syndrome, Loose stools
Muscle aches and Pains
Neurological Problems
PMS
Viruses

Commentary from 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 system.

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 time.

COBAT Versus Conventional Drug Therapy for CFS

Cytokines Regulate Sleep and Fatigue
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 responses.

Immune-Cytokine Imbalances Similar in Chronic Fatigue Syndrome,
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 sleep.

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, 2001).

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 Fatigue Syndrome.

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 phenotype.

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 & COBAT

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 to date.

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 statistically significant.

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 publications.
Phone: 480-250-6757
Website: www. rubinmedical.com

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