Recovery of Homeostasis and Functional Immune System

Positive short term and long term effects with homeopathic growth factors IGF-1, PDGFBB, TGFß, GM-CSF.

Barbara Brewitt, M.Div., Ph.D., Michael Traub, N.D., D.H.A.N.P., Carl Hangee-Bauer, N.D., Lyn Patrick, N.D., Leanna J. Standish, N.D., Ph.D.

Presented at the U.S. and International Conferences on AIDS, Denver, CO, October-December, 1999 andin press AIDS and Alternative Medicine: The Current State of the Science, Harcourt International, editors, L.J. Standish, C. Calabrese and M.L. Galantino.

• Dysregulated Levels of Growth Factors Within the Body Lead to Pathologies
• Homeopathic Growth Factors Meet the Homeopathic Law of Similars and Effectively Treat HIV
• Clinical Study Purpose
• Immune Support
• Metabolic Support
• Discussion

INTRODUCTION

HIV disease and its associated immunodeficiency involve interrelated, immuno-pathogenic and complex mechanisms that severely impair cellular immunity. HIV disease is characterized by high rates of viral replication and mutation with consequential high rates of lymphocyte cell death. Disease progression is characterized by deterioration of immune defense systems within tissues, concomitant with loss of lean body mass, increased inflammation, and increased infections throughout the body. Treatment of opportunistic infections by primary antiviral therapies has not been accompanied by reduction in the prevalence of wasting syndrome.

Healthy immunoregulatory mechanisms include cell-to-cell communication via growth factor signaling. Normally, growth factor signaling regulates cell growth, cell differentiation and cell metabolism throughout the body. During HIV infection the healthy expression of growth factors is dysregulated in ways that enhance viral replication.

Dysregulated Levels of Growth Factors Within the Body Lead to Pathologies

Growth factors are generally present within the body at relatively low concentrations in the nanomolar range, i.e. 10^-9 molar. Growth factors have short half-lives of minutes, due to their powerful and pathological effects at higher than normal concentrations (Raines and Ross 1995). For example, concentrations of 1ug/ml of unbound insulin-like growth factor-1 (IGF-1) suppressed T and B lymphocyte proliferation in vitro (Hunt and Eardley 1986). IGF-1 when injected sub-cutaneously at 10 ug twice daily suppressed Thy-1, 2⁺ T-lymphocytes from entering the spleen of mice (Bergerot et al 1996) which at times, is associated with increased levels of inflammation, as measured by erythrocyte sedimentation rates (ESR) (Higgins 1997). Platelet-derived growth factor (PDGF) when present in excessive concentrations in the body is associated with enlarged lymph nodes. Transforming growth factor-beta (TGFß) at higher than normal concentrations contributes to non-adherence of lymphocytes to lymph nodes, suppression of macrophage function, and can be stimulatory to HIV replication in vitro (Poli et al. 1994). TGFßis found in the peripheral blood mononuclear cells at higher than normal concentrations in HIV infected people (Kekow et al. 1990). Granulocyte-macrophage colony stimulating factor (GM-CSF) when in excess can lead to higher than normal levels of HIV replication in an infected individual (Perno et al. 1996; Poli et al. 1994).

Complex biological systems such as the immune, nervous and hormonal systems often involve complex feedback loops with non-linear dynamics wherein different growth factor concentrations provide totally different regulatory effects. Lymphocytes for example, have IGF-1 receptors (Johnson et al. 1992, Lee et al. 1986, Rosenfeld and Hintz 1980) and nanomolar or lower concentrations suppress HIV replication in macrophages (Germinario et al. 1995) whereas higher than normal concentrations of IGF-1 increase inflammation and suppress lymphocyte proliferation. TGFB has both stimulatory and inhibitory effects on fibroblasts, chondrocytes, and smooth muscle cells at concentrations as low as 10^-9 molar through 10^-12 molar via complex control of autocrine feedback loops of PDGF (Battegay et al. 1990). The complexity of growth factor feedback loops within the body have made it difficult to predict clinical results from pharmacological (large) concentrations of growth factors prescribed for treatment of HIV infection.

Clinical studies of high concentrations of GM-CSF and TGFß administered intravenously at 0.25-4.00 mg/kg/day were predicted to improve the qualitative and quantitative defects in the immune system during HIV infection (Miles 1990, Miles 1991). However, clinical results included unpredictable, as well as adverse events in people, including increased HIV replication, increased p24 antigen levels, chills, and nausea (Poli et al. 1991; Scadden 1990). TGFß is well recognized for its inhibitory action on human lymphocytes (Kehrl et al. 1991). Specifically, high levels of TGFß selectively inhibit CD4⁺ T cell production of IL-2 and inhibit the induction of CD8⁺ CTL activity (Matsushima et al. 1993). Cell-line infection with human T-lymphotrophic virus-I (HTLV-I), a retrovirus similar to HIV, transforms T-lymphocytes to code for and express the PDGF - B chain, whereas uninfected T-lymphocytic and T-lymphoblastoid cell lines do not produce PDGF (Goustin et al. 1990). HTLV I and II-infected T-lymphocyte cell lines also upregulate IGF-1 receptors, suggesting these viruses subvert the growth-control machinery of normal cells for their own replication (Lal et al. 1993).

Homeopathic Growth Factors Meet the Homeopathic Law of Similars and Effectively Treat HIV

Samuel Hahnemann, the founder of homeopathy observed in his patients during the late 18th century, one of the guiding principles of pharmacology, i.e. that a drug directly effects the body and then the body reacts to the drug producing symptoms, which are either healing or adverse (Hahnemann 1982). He was able to separate the two effects through discovering that serial dilutions and agitation of a substance provided some of the positive healing benefits of the substance without the adverse side effects on the body. The fundamental principle of homeopathy is called the Law of Similars which states that if a substance can cause an adverse effect at a high concentration, it can also effectively treat the adverse effect when given in exceedingly low concentrations (even if diluted beyond measurable concentrations) (Bellavite and Signorini 1995). What is not directly stated nor commonly understood from the Law of Similars, but was within Hahnemann’s meaning and has been demonstrated through in vitro experimental testing is that some of the positive effects of a substance are maintained in homeopathic preparations (Brewitt et al. 1999; Benveniste et al. 1991; Davenas et al. 1988).

In studies conducted in Montreal, Canada, IGF-1 concentrations as low as 1.3 x 10^-9 molar inhibited HIV p24 antigen 49% of the time in cultured mononuclear cells (Germinario et al. 1995). Similarly, PDGFBB concentrations in the nanomolar and lower range normally regulate T-cell function, enhancing IL-2 production while decreasing IL-4, IL-5 and IFN-gamma production (Daynes et al. 1991). Finally, Hahnemann stated that the stronger the drug, the more highly diluted it should be to evoke the positive benefits (Hahnemann 1982).

Biomed Comm Inc. research demonstrates three significant attributes of homeopathic growth factors and homeopathic growth hormone:

1. Many of the positive effects of the injectable growth factor or growth hormone are achieved without the negative side effects.
2. There is fulfillment of the Law of Similars by treatment of symptoms in people that match the side effects known to be caused by pharmacological concentrations of the growth factor or growth hormone.
3. Homeopathic growth factors or growth hormone have unique ‘guiding symptoms’ not described by the pharmacological injectable forms.

Clinical Study Purpose

We tested the homeopathic Law of Similars and the hypothesis that positive effects of homeopathic growth factors can reestablish homeostasis and support cellular immunity without stimulating HIV replication by evaluating therapeutic efficacy of homeopathic growth factors in HIV-infected (HIV⁺) people. We selected four growth factors known for their adverse effects in HIV disease at high concentrations while also known for their positive effects on cell and tissue growth at physiological concentrations. Preliminary clinical studies on HIV⁺ subjects using subtle energy delivery of radio frequency signals that simulated homeopathic growth factors demonstrated increases in T-lymphocyte counts (Brewitt 2000).

Homeopathic and allopathic concentrations of drugs can be represented on the same sinusoidal curve. The relationship between dose and the physiological response of cells is not linear as many people often think (fig. 1/Old Paradigm). There is an inevitable toxic effect with increasing concentration of any substance. The Food and Drug Administration (FDA) requires pharmaceutical companies to develop drugs that are below an LD-50 concentration, i.e. a lethal dose 50% of the time. In actuality, there are several harmonic concentrations of substances over a log-scale of concentrations that gives the same desired effect without toxicity (fig. 1/Key Concept). Allopathic medicines are often used at high concentrations to suppress (inhibit) unwanted symptoms such as a histamine reaction or heart fibrillation. Homeopathic medicines are used at as low a concentration as possible to increase (stimulate) the body’s energy level, even when the medicine is diluted beyond Avogadro’s number. Both stimulatory and inhibitory effects can be evoked at varied concentrations of the starting substance spread over several log dilutions. Allopathy uses above physiological concentrations not too distant from a toxic reaction and in HIV infection the drugs are designed to inhibit viral replication, which simultaneously has inhibitory effects on normal physiology. Homeopathy uses below physiological concentrations, as distant from the toxic reaction as possible to achieve the desired effects.

Figure 1

Homeopathic growth factors are designed to stimulate the body’s own immune and subtle electromagnetic forces. HIV infection, homeopathic growth factors, and biological actions of electromagnetic forces on cells use some of the same communication pathways, i.e. G-protein dependent pathways. HIV subverts growth factor signaling of normal cells for the purpose of increasing HIV replication, thus it may be possible through the homeopathic Law of Similars that homeopathic growth factors will effectively eliminate HIV’s ability to replicate. Growth factors are ideal for development as homeopathic medicines because they are physiologically active at nanogram or lower concentrations.

The question asked in these studies was: "Will oral administration of a combination of four homeopathic growth factors, IGF-1, PDGFBB, TGF ß1 and GM-CSF, benefit the immune systems of HIV⁺ patients taking only natural therapies without anti-retroviral therapy compared to a similar group taking only natural therapies and a placebo?" Also evaluated was long term benefits of homeopathic growth factors compared to people taking anti-viral and protease inhibitor therapies. Treatment efficacy was determined by measurements of CD4⁺ and CD8⁺ lymphocytes, HIV viral load, lean body mass and ESR.

Objective: Growth factors and cytokines regulate immune function of T-cell activation, division, differentiation and death. However, clinical studies in the 1990’s demonstrated that injecting high concentrations of growth factors into people living with AIDS (PLWAs) resulted in adverse effects such as increased HIV replication, chills, nausea, lost weight and lost lean mass. Additionally, higher than normal concentrations of growth factors in the healthy body resulted in suppression of lymphocyte replication, lymph node swelling non-adherence of lymphocytes to lymph nodes, increased inflammation and inhibited macrophage function; all symptoms similar to HIV infection. The major principle of homeopathy, called the Law of Similars, states that when high concentrations of a substance evoke adverse, dichotomous and complex problems, the same substance may treat these problems or symptoms when given at exceedingly small, homeopathic concentrations. The efficacy of four homeopathic growth factors was evaluated in an original study and re-tested for replication effects in a 2.5 yr follow-up and in a multi-site Phase I/II trial.

Methods: An original, double-blind, placebo, controlled study (DBPCS) (16 wk, n=30) + 2.5 yr open label follow-up (n=26) and a 7-city-multi-site DBPCS (8 wk, n=53), evaluated oral delivery of a combination of four homeopathic growth factors. The growth factors were insulin-like (IGF-1), platelet-derived (PDGFBB), transforming beta-1 (TGFß1, and granulocyte-macrophage colony stimulating factor (GM-CSF). Preparations were serially diluted, hand succussed to 1M, 30C + 1M, 30C + 1M, 200C potencies (equivalent to concentrations of 10^-2000, 10^-60 + 10^-2000, 10^-60 + 10^-2000, 10^-400 molar), respectively. Inclusion criteria for participants were 200-500 CD4⁺ cells/ul in original and 130-570 CD4⁺ cells/ul in the multi-site replication study. Exclusion criteria were antiviral or glucocorticoid therapy for DBPCSs. PLWA ages ranged from 23 to 62 years old with an average 10±1 years of HIV infection. Parameters measured were CD4⁺ and CD8⁺ lymphocyte counts, HIV viral load, lean mass, and total weight.

Results: Figure 2 shows that in the original 4-month study DBPCS, CD4⁺ and CD8⁺ lymphocyte counts were stable on treatment from entry through exit (338 ± 28 to 351 ± 28 CD4⁺ cells/ul and 960 ± 132 to 1030 ± 217 CD8⁺ cells/ul.) In contrast, the CD4⁺ and CD8⁺ counts in the placebo group significantly dropped approximately 85 cells/ul and approximately 254 cells/ul, respectively (p<0.03). In 2-month multi-site testing for replication (rep), stable trends on treatment were documented (CD4⁺ counts were 343 ± 21 to 344 ± 28 CD4⁺ cells/ul on treatment vs declines from 339 ± 26 to 300 ± 25 CD4⁺ cells/ul on placebo). CD8⁺ cells were also stable on treatment with declines on placebo in the multi-site replication testing. HIV viral load continually declined (-0.7 log over 52 wks, p<0.01 and -0.3 log over 8 wks) on treatment vs. placebo in multi-site, P<0.02. There was no (0%) hospitalization during 2.5 yrs follow-up on homeopathic growth factors versus 25% and 40% hospitalizations due to opportunistic infections or disease-related infections on antiviral therapy or on only natural supplements without growth factors.

Immune Support

Original, Replication and Follow-up Studies

CD4⁺ and CD8⁺ lymphocyte counts remained stable throughout forty weeks of follow-up observation in the original study group participants who voluntarily broke into three groups:

1. those who selectively began antiviral, protease inhibitor therapies (antivirals),
2. those who remained on homeopathic growth factors and
3. those who selected their favorite natural therapy of acupuncture, Chinese herbs or vitamin/mineral/botanical supplements (fig. 3).

Follow-up observations demonstrated no statistical differences between homeopathic growth factor treatment and antiviral treatment compared to disease progression on natural therapy (fig. 4).

Figure 2

Figure 3. Original DBPCT and Open-label Study

Figure 4

HIV viral load trends decreased on treatment (Squares) in three separate small studies with people who had medium and high viral loads at study entry (fig. 5). The longer participants used homeopathic growth factors, the more statistically significant the decrease in viral load, i.e. a statistically significant 0.7 log decrease after twelve months (P<0.01). In contrast, trends in HIV viral load increased in both placebo (triangles) groups tested. During the 33-month post entry follow-up period, HIV viral load was found to be no different between the homeopathic growth factor group and the antiviral group (fig. 6)

Figure 5

Figure 6

Metabolic Support

Figure 7

Figure 8 & 9

NO DISEASE PROGRESSION

Homeopathic Growth Factor Protocol

Long-term follow-up for hospitalization was:
0% Homeopathic Growth Factors
25% Antivirals
40% Natural Therapies

Figure 10

Figure 11

Discussion

There is widespread use of alternative therapies with and without supplemental anti-retroviral therapy among HIV⁺ persons (Anderson et al. 1993). It is critical that alternative medicine practitioners develop, evaluate, and design effective protocols for their patients. Numerous clinical studies have shown a general downward trend in those HIV⁺ persons using only natural therapies (Brewitt 1998, Standish et al. 1992). In light of the fact that the incidence of wasting syndrome is on the rise and there are new complications from HAART therapies, it is essential that non-toxic, affordable, and effective natural therapies be developed (Carr et al. 1998, Griffin et al. 1998).

The purpose of these clinical studies was two fold: a) test the homeopathic Law of Similars and b) evaluate the therapeutic efficacy of four orally administered homeopathic growth factors, IGF-1, PDGFBB. TGF ß1 , and GM-CSF in HIV⁺ patients choosing to use only natural therapies without anti-retroviral therapy. Additionally, we evaluated the long term stability of the immune system in participants who had used homeopathic growth factors for two and one-half years. Results were compared to participants who had switched to using anti-retroviral therapy or natural therapy without homeopathic growth factors.

The concepts of self-defense and self-recovery are central to the Law of Similars principle of homeopathy (VanWyk and Wiegant 1997; Jacobs and Moskowitz 1996). Since restoration of cellular immunity and reestablishment of homeostasis are central issues in HIV disease, a homeopathic approach seemed logical as a possible non-toxic, affordable and effective approach. Clinical studies of the past had injected high levels of growth factors into HIV⁺ patients with the hope of repairing the damaged cell-signaling component of the immune system (Miles 1992, Miles 1991). Injections of high dose growth factors however were met with unwanted side effects, including increased HIV replication, loss of lean mass, loss of body weight and general fatigue (Lee et al. 1996; Poli et al. 1991; Scadden 1990). The Law of Similars states that if a high concentration of a substance causes a problem, then it will effectively treat that same problem when given back at exceedingly small homeopathic concentrations. A subtle energy approach of simulating signals of homeopathic growth factors via radio frequencies predicted that oral delivery of homeopathic growth factors would be effective in support of the immune system without stimulating HIV replication (Brewitt 1998). We found that, as predicted, a combination of four homeopathic growth factors were effective in reestablishing some homeostasis and functional cell immunity to people with HIV disease. These positive clinical effects were seen in two double blind, placebo controlled and two open label studies. Neither long term nor short-term effects from homeopathic growth factors were associated with any adverse negative reactions from the subjects.

Although the sample size in each of the individual studies was small, taken together the positive results demonstrate that the Law of Similars applies to homeopathic growth factors. We found significant, positive and reproducible metabolic and immunological effects from the combination of homeopathic growth factors. The statistically significant treatment effects were the following:1) stabilized or increased CD4 counts on treatment vs losses on placebo; 2) increased percentage of treatment group returned to ideal body weight compared to none in the placebo group; 3) stabilized lean body mass on treatment versus significant losses on placebo; and 4) decreasing HIV viral loads on treatment compared to increasing viral loads on placebo.

The longer a person remained on treatment the more statistically significant the decline in HIV viral load. There were no signs of viral resistance or viral mutation such as commonly occurs with mono- or multiple combination anti-retroviral therapy (Cohen 1997). Homeopathic treatment over the long term slowed disease progression and the need for hospitalizations compared to the use of natural therapies without homeopathic growth factors or the use of anti-retroviral therapies.

We found that CD4⁺ and CD8⁺ lymphocytes were highly correlated, regardless of treatment or placebo, demonstrating that immune cell communication is tightly regulated. This finding is similar to the observation that the absolute change in CD4 cells correlated significantly with absolute changes in CD8⁺CD28⁺ cells in HIV infected people (Burgisser et al. 1998). Analyses of significant immune subset markers may in the future help clinicians better understand immune communication and activation during chronic viral infection. Measures of naïve CD45RA⁺ lymphocytes may be one subset of CD4⁺ and CD8⁺ cells that best characterizes functional immunity (Ginaldi et al 1997). Statistically significant increases in CD4⁺-CD45RA⁺ naïve lymphocytes in the treatment group (data not shown) support the conclusion that homeopathic growth factors stimulated functional cell mediated immunity.

CD4⁺ T-cell counts are accepted measures of HIV disease progression to AIDS with the measures of HIV viral load indicative of the speed of progression (Daar 1998; O’Brien et al. 1996). A treatment effect can be observed within a matter of days since HIV particles and CD4 cell counts rapidly turnover during the disease process (Daar 1998). A great amount of immune stability occurred in the treatment groups. The treatment periods of 2- and 4-months were sufficient to determine treatment efficacy. The natural medicines used by the people in our studies consisted largely of spiritual practices, vitamin C, vitamin B12 , garlic, zinc, unspecified Chinese herbs, acupuncture and beta-carotene.

Our goal was to improve cell-mediated immunity in HIV infected individuals without stimulating viral replication. The viral load trended downward in all of the study groups using homeopathic growth factors, in contrast to the upward trends observed in the two placebo groups tested and in long term follow-up of persons using only natural therapies. It was surprising to find that people who had used homeopathic growth factors over the course of 2.5 years had HIV viral loads equally low as the viral loads of people using antiviral therapy.

We conclude that oral administration of homeopathic growth factors provide positive clinical, metabolic and immunological outcomes in HIV⁺ patients taking only natural therapies. This approach was designed to stimulate immune self-defense without stimulation of HIV replication and to support self-healing and metabolic stability. Homeopathic growth factors offer a cost-effective option to HIV-infected people whose economic resources or treatment options do not include antiviral therapy.