A Review of Sulfur Containing NanoDrugs™ - Taurox SB™ and Beta LT® - Molecular Activity, Safety, and Efficacy

Floyd Taub, M.D. and Suzin Mayerson, Ph.D.

Background

For over 50 years, low molecular weight thiols and disulfides have been implicated in the control of cell division and growth1, especially of blood and immune cells. The ability of thiols to change from the free thiol form to the bound disulfide form provides proteins the secondary structure necessary for biologic activity. This reversible thiol:disulfide switch is a biologic control mechanism that is highly efficient. It requires low energy input to dramatically change structure and function. Thiols are involved in DNA binding and immune effector mechanism regulation2,3,4. They regulate a variety of cellular enzymes2,5-32 gene expression3,4,5,11,17,23,33-62 and oncogene function63-69. Thiols have been indicated to have immune stimulatory and anticancer properties in animals and they have been used in patients with immune deficiency3,4,70,71. Sulfur containing materials, including garlic, lipoic acid, methylsulfonylmethane (MSM), cysteine and N-acetyl cysteine are frequently used as nutritional supplements. However the activity of these nutritional supplements are limited, and large (gram) amounts are required. Presumably, they supply precursor materials but not the biologically active regulatory molecules.

Two Nanodrugs™ have been developed and tested in experimental animals, pets, and human patients. They are used at microgram or sub-microgram doses. Taurox SB™ is orally available and in pre-clinical studies appeared more potent than the other. Based on its properties, Taurox SB has been developed and proven as a homeopathic remedy. The other, Beta LT®, has been studied in conventional clinical trials. Both appear to modulate the immune system at low doses without toxic side effects. The sections below present the data from studies of Taurox SB and Beta LT.

Taurox SB™ Chemistry

Drs. Knight and Scallen made chemical modifications of beta-alethine (Beta LT®), a small molecule dimer of beta-alanyl cysteamine (see below). In 1994, in Cancer Research, Knight et al. published two synthetic processes beginning with beta alethine that resulted in what was then believed to be a new sulfur-containing compounds. Prior to complete analysis, these compounds were designated "Vitalethine" and the "benzyl derivative of Vitalethine". They were postulated to have a complicated and controversial structures41. Current analytic techniques have resolved the complexity and documented to independent researchers95 and examiners96 that the compound obtained by following the procedure described as synthesis of the "benzyl derivative of Vitalethine" is (3,3'-(dithiodi-2,1-ethanediylamino)bis[N-(3-oxopropyl carbamic acid)]), also known as the zinc slat of carboxybenzoxy-beta-alanyl-taurine. It is a low molecular weight (330) benzyl sulfonic acid (the zinc salt molecular weight is 724). It contains a ring structure on one end, which adds oral activity, and a modified form of the sulfur group on the other. Thus, both ends of the molecule are significantly different than Beta LT. While Beta LT is a chemical combination of cystamine and a derivative of the amino acid beta alanine, Taurox is a chemical combination of taurine and beta alanine. Taurine is a "conditionally essential" nutrient. This amino acid is important in the development and support of brain and retina tissue, and is also an important component of human breast milk and synthetic formulas. Alanine is a non-essential amino acid. The generally accepted structural formula for the product made by Knight's synthesis is shown below in Figure 1.

Figure 1. Taurox SB™ (Taurox™)

Taurox SB™ Biology

The product made by the procedure of Knight et al. was postulated to be an immune modulator and shown to exhibit anti-cancer effects in animals. As a sole agent in vivo it showed potent antitumor effects against melanoma and myeloma models at low doses with negligible toxicity. Taurox synthesized by Hauser[1] was tested in several animal models. Just as the material synthesized by Knight, it showed immune stimulatory activity and extremely potent anti-cancer activity (Table 1).

Table 1. Animal Models of Taurox-SB Activity

[1]Hauser is a contract synthesis organization used by NIH and others for a variety of often difficult synthetic procedures including isolation/synthesis of paclitaxel (and others).

Tom Dunn at the University of Maryland in College Park performed numerous pharmacological experiments on Taurox97. He found Taurox to be a potent immune stimulant for human cells. Dunn concluded that the increase in T-cell calcium flux, which occurred at very low doses, and other immune function increases (see below) induced by Taurox suggested that stimulation of T cells might contribute to Taurox's anti-tumor activity.

His studies using human cells in culture showed that Taurox enhanced components of early T cell activation, including increased intracellular calcium, upregulated expression of the CD69 T cell activation marker and enhanced proliferation of blood peripheral mononuclear (immune) cells in culture98. Tumor necrosis factor alpha (TNF-alpha) and interferon gamma message and protein were also upregulated in the presence of Taurox. This upregulation was seen unless the cells were also exposed to excess levels of exogenous stimulation, in which case a normalization of abnormally high values was seen.

Taurox enhanced granzyme activity in T cells. It also enhanced expression of cell surface TNF-alpha . This arming of lymphocytes was accompanied by a decrease or no change in the amount of secreted TNF-alpha . Secreted TNF-alpha may be associated with systemic toxic effects. The increased presence of surface TNF-alpha, mediated by Taurox, was able to effect killing of HL60 tumor cells in vitro. The in vivo antitumor mechanism of action of Taurox may be through T cell activation in a calcium dependent manner, leading to increased TNF-alpha arming on the surface of the immune cells.

The key factor initiating action of Taurox may be the change in calcium flux it induces. This is a primary activation signal for immune cells leading to an amplifying cascade of immune stimulation under appropriate conditions. This phenomenon was observed at exceedingly low (nanomolar) doses. Dunn suggested that Taurox may serve to keep the immune systems active in the elderly as it is thought by some that diminished calcium response is a factor in lowered T cell activity in older persons. The action of both Beta LT and Taurox occur at lower doses in vivo than in vitro. The ability of nanomolar doses of (one trillionth of a mole) Taurox to alter calcium flux in vitro is noteworthy.

MicroMedicine™

Low dose medicine, or MicroMedicine, has a long history but is often poorly understood. Low dose medicine is accepted for immunology by both allopathic (standard) and homeopathic schools of medicine. The immune system is known to be exquisitely sensitive; almost microscopic amounts of allergens such as poison ivy, pollens or bee sting toxins cause very significant symptoms in susceptible people. The principle of vaccination is that a small amount of an infectious agent (preferably a weakened agent or a fragment of the agent so that it is no longer infectious) will activate the immune system to prevent future infection. Homeopaths call the principle of vaccination the "Law of Similars" or "like may cure like". Similarly, both allopathic and homeopathic physicians routinely use extremely small amounts of an allergen to desensitize and decrease an abnormal allergic response. Although this aspect of homeopathic medicine is broadly accepted, many allopathic physicians would like to dismiss the law of similars and all of homeopathy. In some cases, this may be justified. Some homeopathic drugs lack effectiveness, and some drugs lack any of the original physical drug material. However, many homeopathic medicines have very significant numbers of molecules, but fewer molecules than allopathic preparations. Some of these have been evaluated by standard double blind trials and found effective99,100,101. Some are commonplace in pharmacies. It may be that those homeopathic preparations that are effective are those that affect the immune system and are thus amplified by accepted immune regulatory cascades of cytokines. Homeopathic preparations given at these moderate doses have proved exceptionally safe in clinical practice. These doses are a small fraction of the doses animal studies indicate are potentially toxic. (In contrast, many prescription and conventional OTC pharmaceuticals are given at doses much closer to the toxic levels.) To date, human experience has shown that any material given sufficiently below the toxic animal dose will also be non-toxic in humans. Modern science supports this experience. For example, environmental toxicologists consider 1/100,000 of a compound's toxic dose to be so safe that it is labeled a "Virtually Safe Dose" and not analyzed for toxicity.

Specific toxicology studies of Taurox suggest that it has an unusually wide margin of safety between the effective dose and the amount of material that can be harmful. Acute toxicology studies conducted by Midlantic Bio-Research on Taurox in adult male and female CD-1 mice suggested a maximally tolerated dose (MTD) of about 133 mg/kg administered a single intravenous bolus102. A similar finding was obtained with rats103. Thus, the toxic dose levels of the compounds appear high (assuming man is like a rat or mouse and not correcting for a different surface-area-to-weight ratio, an injected dose of 9,975 mg (9.9 g) would not be lethal for a 75-kg person). Standard prescription strength of oral homeopathic Taurox dosing is about one billion fold lower than this level (Table 2). Studies of oral Taurox (Product Safety Labs106) found that rats tolerated 2000 mg/kg daily for 14 days without adverse effects. Water intoxication would prevent a person from ingesting sufficient amounts of the preparation to receive even one ten thousandth of the amount of Taurox anticipated to be toxic. In a GLP (FDA-suitable good laboratory practices) study in rats no toxic side effects were observed following either oral or subcutaneous 400 ug/kg doses of Taurox given daily104. During the 14-day post-administration period, the animals all gained the appropriate amount of weight as compared to saline-injected controls and there was no morbidity or mortality. Following euthanasia, there were no abnormal findings in the gross necropsies.

Taurox is prepared by the classic homeopathic methods of dilution and vigorous mixing at each step, and like many homeopathic medicines it stimulates the immune system. As many homeopathic medicines, it has a virtually non-existent toxicity profile; Taurox is labeled as a homeopathic medicine and has entered that regulatory path. In March of 2001, a total of 39 normal volunteers completed the first homeopathic proving trial. Taurox 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 at each step (i.e., homeopathic dilution; see Table 3 for concentrations). The final steps were in 20% ETOH to prevent microbial growth. The typical dose is one drop per day, which is about 1/30 to 1/20 of a milliliter.

Table 2. Taurox Concentrations and Homeopathic Designations

* This maximum concentration (6x) is equal to approximately one million x one million x 27 molecules per drop. (1X to 5X potencies have not been used and are listed for comparison.)

At the projected toxic dose of about 10 grams per full sized adult, 1,000,000 liters of the maximum dose (6X) would be needed to get a toxic dose. Both the ethanol and the water in the preparation would cause toxicity prior to reaching one thousandth of the toxic doses of Taurox.

Taurox SB™ Clinical Studies

The proving study design was double blind, placebo-controlled and evaluated 6x and 8x doses, 1 drop per day. An apparent physiological placebo effect was observed in 26% of patients where placebo was given. In contrast, 92% of those receiving Taurox were identified as having physiologic affects (Figure 2)105. The difference between groups is statistically significant (p<0.001) as measured by several statistical tests, including Chi-squared, Fisher's Exact Test and Exact Cochran Armitage Test. Dr. Riley reported 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 in Table 3.

Figure 2. Results of Double-Blind Placebo-Controlled Proving

An experienced research physician who did not know which patients received the placebo or actual drug was asked to judge if patients had a physiologic response to Taurox. Data clearly indicated physiologic response well in excess of the placebo.

Under the auspices of the University of Southern California Institutional Review Board further studies were performed. Structured Case studies were done to examine the effects of Taurox on individual patients with some of the indications in Table 3. For select indications additional patients were accrued for Clinical Outcome Studies.

The work of Dunn et al suggested a normalization of pathologic immune function might be seen. The structured case studies suggest that patients with allergies and chronic fatigue benefited from Taurox. Immune system molecules (cytokines) are known to cause fatigue and certain immunoglobulins and immune cells are key in the pathogenesis of allergic symptoms.

Figures 3 through 9 show results of initial Clinical Outcome Studies. Most patients took one drop of 8X daily[2]. The frequency of allergy symptoms in 18 patients reporting at least moderate allergy symptoms at pre-study is shown in Figure 3. More than half the patients reported a significant decrease in allergic symptoms. A number of patients have reported that they were virtually symptom free under conditions (such as perfume or cat exposure) that previously were incapacitating. Other patients had little benefit. While statistical analysis and averaging is of limited relevance to any individual patient, the average patient had a 54% decrease in frequency of allergic symptoms; this was statistically significant (p < 0.007). For those who responded to Taurox, the average decrease in frequency of symptoms was 71% (p=0.0001). A principle of homeopathic medicine, and modern genomics, is that it is often incorrect to assume all patients will respond similarly, and a lack of response in patients with certain characteristics does not decrease the value of a drug for those with characteristics leading to responsiveness.

Figure 3.

Figure 4 shows the amount of fatigue patients reported in terms of the total score on a 12-item questionnaire[3]. This chart reports only those patients with moderate to severe fatigue (those scoring above the midpoint on the fatigue scale at pres-study). This fatigue is believed to be a result of pathologic immune dysregulatory syndromes. All patients, except one, with this level of fatigue reported a decrease in symptoms[4]. Unlike patients with allergies the effect seemed to occur throughout the group. In the initial sample, there was a 44% decrease in symptoms and the decrease was highly statistically significant (p= 0.0005). Results for both allergy and fatigue were similar at different sites (see for example Figure 4).

Figure 4. Decreased Fatigue: Initial Data (Lower scores indicate less fatigue)

Site 1 is on the left graph; all other sites are on the right. Patient numbers are on the right side of each graph. Lower scores indicate less fatigue.

Subsequent data continued to show this pattern. Figure 5 displays this as a bar chart in which data from all patients are stacked. Scores were first converted to a 100 point scale. In the analysis of first and last time point for each person (n=16), the average score decreased from 65 to 33, a 52% mean change. Pre-post differences are statistically significant by paired t-test, p=0.000002. One patient did not report improvement; in that case, only 4 weeks of data were provided and they show that there was no change in fatigue. Figure 6 shows the HCV patients separately; those differences were also significant (p=0.002). Figure 7 shows the average of all patients. Figure 8 shows the average scores of patients who stayed in the study for 22 weeks or more. The effect of Taurox SB appears to continue and increase with greater duration of use.

Figure 5. Decreased Fatigue: All Data	Figure 6. Decreased Fatigue in HCV Patients

Figure 7. Average Fatigue: All Patients	Figure 8. Long Term Reductions in Fatigue

 In the initial group, one patient's fatigue was a result of hepatitis C. This patient, a middle-aged Asian female, is thought to have contracted Hepatitis C (genotype 1) through a blood transfusion in 1984. In mid-1992, she was notified of the HCV antibodies following a rejected blood donation. She did not become symptomatic until late 1992. In 1999, she had received Interferon Alpha Therapy (IFN). IFN caused severe deliberating side effects, severe fatigue, weight loss, low white blood cell counts and depression. It provided only temporary stoppage of viral proliferation (see Figure 9). She entered the Taurox study in late 2001 due to fatigue. She took Taurox at strengths of 6x or 8x over a period of 4 months. Her viral load decreased by about 40% on average (see Figures 9-11) and her overall mood also improved. Test results showed that patient 101 had a maximal viral load decrease of 62%.

Figure 9.

Figure 10. Reduced HCV in Patient 101	Figure 11. Reduced Fatigue in Patient 101

Patient 101 took the 8x dose except where 6x is indicated by the shaded box. The last dose was March 26.

She also reported less fatigue on both doses (Figure 11). The largest decrease in viral count and fatigue occurred on 6x. The previously required daily naps became unnecessary upon initiation of 6x. After she completed the trial and stopped taking Taurox, she frequently required lengthy daily naps. Five additional HCV patients have reported reduced fatigue while on Taurox (see Figure 6).

Taurox-SB™ Summary

Pre-clinical research and initial human testing indicate Taurox has the potential to treat a variety of illnesses. Animal data indicate virtually no toxicity and a statistically significant effect on modulating immune responses, melanoma and myeloma. Tests on human cells detected immune enhancement under conditions of low stimulation and normalization of the immune response under conditions of excess immune stimulation. Initial human clinical trials have evaluated the effects of Taurox on conditions of disregulated immunity (as seen in autoimmunity, allergy, hyper-immunity or fatigue syndrome). The human clinical trial patients presenting with a moderate to high level of pre-study fatigue or allergies reported statistically significant improvement in symptoms.

Beta LT®

In 1994 researchers at the University of New Mexico reported on highly potent biologically active thiols and disulfides that may be immune regulatory compounds. The prototype regulatory disulfide (beta alethine, Beta LT) is an organically synthesized pharmaceutical. It has been shown to be at least one thousand to one million fold more potent than nutritional or other pharmaceutical preparations, virtually non-toxic, and immuno-modulatory72-82. Microgram (one millionth of a gram) doses once every 2 weeks have been associated with cancer shrinkage in human clinical trials83.

Beta-alethine (MW 367) is a small molecule dimer of beta-alanyl cysteamine (see Figure 12), which is a chemical combination of the amino acid (beta-alanine) covalently linked to an amine (cystamine). Beta-alethine has been shown to stimulate the immune system and/or have anticancer effects in diverse types of animals84-88 as well as human cells89. Studies in a variety of model systems are summarized in Table 4.

Table 4. Animal Models of Beta-Alethine Activity

Figure 12. Beta-alethine (Beta LT®)

Beta-alethine is currently showing promising results in tests on people90-94. Wilson H. Miller, Jr., Ph.D., M.D., Head, Clinical Research Unit and Principal Investigator of Beta LT Clinical Trials at McGill University/Jewish General Hospital gave a presentation entitled "Immune Stimulation in Patients with Follicular Lymphoma and Myeloma with Evidence of Tumor Response and No Significant Toxicity"; this was presented at the December 2001 meeting of the American Society of Hematology. During the 90-day study[5], five of nine immuno-competent lymphoma patients had tumor reduction, with several responses eventually exceeding 50% (Figure 13). As seen in Figure 14, one grapefruit-sized tumor shrank over 60%. The other four patients' tumor measurements showed no progression (tumor size unchanged + 10%).

Figure 13. Tumor Reduction in the Beta LT Study

[5] Many patients elected to continue receiving Beta LT after the 90-day trial.

Figure 14. Reduction in Tumor Size as Seen in CT Scan (Beta LT patient #1202)

Baseline	253 Days	337 Days

This immuno-competent group did significantly better (p<0.02) than a comparison group composed of patients with the same disease at the same stage but lacking immune system function thought necessary to respond to Beta LT; the latter group showed progressions or stable disease but no patients with disease shrinkage. There are no reports in the literature that such patients do worse than average lymphoma patients. While it is possible that this comparison group had a prognosis worse than other patients, the course of these patients was similar to historical controls and current clinical experience. About half were stable during the 90-day study, half showed an increase in disease of 10% or more. The particular lymphoma studied (low grade, well differentiated B-cell lymphoma) is a slowly progressive disease. Patients may live 5-10 years having periods of clinical stable disease (usually associated with slow sub-clinical growth) mixed with periods of more rapid growth requiring radiation or chemotherapy. While these therapies generally control the disease temporarily, they ultimately fail, leading to death. Temporary lymphoma shrinkage, thought to be immune system induced, may occur but is rare. There are no reports of any population(s) in which a significant position of the patients have shrinkage of their disease. The observation that 50% of the immuno-competent lymphoma patients treated with Beta LT had shrinkage of disease is thus suggestive of its ability to enhance the immune system's recognition of the lymphoma. Miller et al. also reported Beta LT enhanced recognition of infectious disease agents; half of the patients who were anergic upon study entry developed T-cell responses to various infectious disease antigens.

Beta LT® Summary

Human and animal data indicate in vitro and in vivo immune stimulation and anticancer effects. One third of the persons with low grade lymphoma who were immuno-competent had 50% shrinkage of the cancers, and half had some cancer shrinkage without drug related side effects.

References:

1. Guzman Barron, E.S. Thiol groups of biological importance. Adv. Enzymol., 11:201-266, 1951.
2. Abate, C., Patel, L., Rauscher, F.J. III, Curran, T., Redox regulation of Fos and Jun DNA-binding activity in vitro. Science, 249, 1157-1161, 1990.
3. Droge, W., Eck, P.P., Gmunder, H., Mihm, S. Modulation of lymphocyte functions and immune responses by cysteine derivatives. AJM, 91:140S-144S, 1991.
4. Droge, W., Kinscherf, K., Sabine, M., et al. Thiols and the immune system: Effect of N-acetylcysteine on T cell system in human subjects. Methods in Enzymology 1995
5. Ahn, HS, Foster M, Foster, C, Sybertz E, Wells JN. Evidence for essential histidine and cysteine residues in calcium/calmodulin-sensitive cyclic nucleotide phosphodiesterase. Biochemistry, 30(27), 6754-6760 (1991).
6. Bennett, B., Bray, R.C. Further studies on redox related activation and deactivation of E. coli nitrate reductase: a possible physiologically relevant role for the low potential [4Fe 4S] centres. Biochem. Soc. Trans., 22(3), 283S (1994).
7. Bergamini, C.M., Signorini, M., Ferrari, C., Poltronieri, L., Rippa, M. Periodate inactivates muscle glycogen phosphorylase by modifying the enzyme active site. Biochem. Int., 7(3), 353 360 (1983).
8. Chopra, I.J. Sulfhydryl groups and the monodeiodination of thyroxine to triiodothyronine. Science (Washington DC), 199, 904 905 (1978).
9. Booker, S., Licht, S., Broderick, J., Stubbe, J. Coenzyme B12 dependent ribonucleotide reductase: evidence for the participation of five cysteine residues in ribonucleotide reduction. Biochemistry 33(42), 12676 12685 (1994)
10. Gibbs, J.B. Ras C terminal processing enzymes: new drug targets? Cell, 65, 1 4 (1991).
11. Gilbert, H. F. Biological disulfides: the third messenger? J. Biol. Chem., 257, 12086 12091 (1982).
12. Gilbert, L., Smith, J.T. The effect of dietary sulfur on enzymes related to the hexose mono phosphate shunt. Fed. Proc., 38(3 1), 611 (1979).
13. Gitler, C., Londner, M., Mogyoros, M., Kalef, E., Zarmi, B. Thiology methodology to study protein vicinal dithiols, Methods in Enzymology. Biothiols, (1995).
14. Gitler, C., Londner, M., Mogyoros, M., Kalef, E., Zarmi, B. Anal. Biochem. 212, 325 334 (1993).
15. Gruetter, D.Y., Gruetter, C.A., Barry, B.K., Baricos, W.H., Hyman, A.L., Kadowitz, P.J., Ignarro, L.J. Activation of coronary arterial guanylate cyclase by nitric oxide, nitroprusside, and nitrosoguanidine inhibition by calcium, lanthanum, and other cations. Biochem Pharmacol., 29(21), 2943 2950 (1980).
16. Hancock, J.F., Paterson, Hl, and Marshall, C.J. A polybasic domain or palmitoylation is to the CAAX motif to localize p21 to the plasma membrane. Cell, 63, 133 139 (1990).
17. Ignarro, L.J., Gruetter, C.A. Requirement of thiols for activation of coronary arterial guanylate cyclase by glyceryl trinitrate and sodium nitrite: Possible involvement of S nitrosothiols. Biochem. Biophys. Acta., 631(2), 221 231 (1980).
18. Jocelyn, P.C. Biochemistry of the SH Group. London: Academic Press, 1 46, 100 136, 163 278, and 337 349 (1972).
19. Korzekwa, K.R., Trager, W.F., Smith, S.J., Osawa, Y., Gillette, J.R. Theoretical studies on the mechanism of conversion of androgens to estrogens by aromatase. Biochemistry, 30(25), 6155 6162 (1991).
20. Lewis, S.J., Ohta, H., Machado, B., Bates, J.N., Talman, W.T. Microinjection of S nitrosocysteine into the nucleus tractus solitarii decreases arterial pressure and heart rate via activation of soluble guanylate cyclase. Eur. J. Pharmacol., 202(1), 135 136 (1991).
21. Lo, J Y, Smith, L.C., Chan, L. Lipoprotein lipase: Role of intramolecular disulfide bonds in enzyme catalysis. Biochemical and Biophysical Research Communications, 206(1), 266 271 (1995).
22. Mantsala, P., Zalkin, H. Glutamine amidotransferase function: Replacement of the active site cysteine in glutamine phosphoribosylpyrosphosphate amidotransferase by site directed mutagenesis. J. Biol. Chem., 259(22), 14230 14236 (1984).
23. Morre, D.J. Hormone and growth factor stimulated NADH oxidase. J. Bioenerg. Biomembr., 26(4), 421 433 (1994).
24. Namboodiri, M.A., Favilla, J.T., Klein, D.C. Activation of pineal Acetyl Coenzyme A hydrolase by disulfide peptides. J.Biol. Chem., 257(17), 10030 10032 (1982).
25. Noctor, G., Mills, J.D. Thiol modulation of the thylakoid ATPASE lack of oxidation of the enzyme in the presence of a difference in the proton electrochemical potential in vivo and a possible explanation of the physiological requirement for thiol regulation of the enzyme. Biochem. Biophys. Acta, 935(1), 53 60 (1988).
26. Namboodiri, M.A., Weller, J.L., Klein, D.C. Rapid and reversible activation of Acetyl CoA hydrolase in intact pineal cells by disulfide exchange. Biochem. Biophys. Res. Commun., 96(1), 188 195 (1980).
27. Pontremoli, S., Traniello, S., Enser, M., Shapiro, S., and Horecker, B.L. Regulation of fructose diphosphatase activity by disulfide exchange. Biochemistry, 58, 286 293 (1967).
28. Schafer, W.R., Kim, R. Sterne, R., Thorner, J., Kim, S H., and Rine, J. Genetic and humans. Science (Washington, DC), 245, 379 385 (1989).
29. Scheibe, R. Redox modification of stromal enzymes: Variations of a regulatory principle during oxygenic photosynthesis. Biologia Plantarum (Prague), 36(suppl.), S162 (1994).
30. Zhou, Y., Guo, Y.L., Ni, Y.S., Zhang, L.X. Site directed mutagenesis of disulfide linkages in trypsin and its effect on enzyme activity. Shengwu Huaxue Yu Shengwu Wuli Xuebao, 25(4), 355 360 (1993).
31. Ziegler, D.M. Role of reversible oxidation reduction of enzyme thiols disulfides in metabolic regulation. Biochem., 54, 305 329 (1985).
32. Uhlin, U., Eklund, H. Structure of ribonucleotide reductase protein R1. Nature, 370, 533 534 (1994).
33. Anderson, M.T., Staal, F.J.T., Gitler, C., Herzenberg, L.A., Herzenberg, L.A. Separation of oxidant initialized and redox regulated steps in the NF kB signal transduction pathway. Proc. Natl. Acad. Sci. USA 91(24), 11527 11531 (1994).
34. Baeuerle, P.A., Henkel, T. Function and activation of NF kB in the immune system. Annu. Rev. Immunol., 12, 141 179 (1994).
35. Bauskin, A.R., Alkalay, I., Ben Neriah, Y. Redox regulation of a protein tyrosine kinase in the endoplasmic reticulum. Cell, 66(4), 685 696 (1991).
36. Beg, A.A., Baldwin, A.S. The IkB proteins: Multifunctional regulators of Rel/NFkB transcription factors. Gene Dev., 7, 2064 2070 (1993).
37. Benezra, R. An intermolecular disulfide bond stabilizes E2A homodimers and is required for DNA binding at physiological temperatures. Cell, 79, 1057 1067, (1994).
38. elDeib, M.M., Parker, C.D., White, A.A. Activation of intestinal brush border guanylate cyclase by aromatic disulphide compounds. Biochem J., 275(Pt.1), 29 34 (1991).
39. Gilmore, T., Morin, P. The IkB proteins: Members of a multifunctional family. Trends Genet., 9, 427 433 (1993).
40. Hainaut, P., Rolley, N., Davies, M., Milner, J. Modulation by copper of p53 conformation and sequence specific DNA binding: Role for Cu(II) Cu(I) redox mechanism. Oncogene 10(1), 27 32 (1995).
41. Knight, G.D., Laubscher, K.H., Fore, M.L., Clark, D.A., Scallen, T.J. Vitalethine modulates erythropoiesis and neoplasia. Cancer Research, 54, 5623 5635 (1994a).
42. Kopp, E., Ghosh, S. NFkB and Rel proteins in innate immunity. Adv. Immunol., 58, 1 27 (1994).
43. Landgraf, W., Regulla, S. Meyer, H.E., Hofmann, F. Oxidation of cysteines activates cGMP dependent protein kinase. J. Biol. Chem., 266(25), 16305 16311 (1991).
44. Li, W.C., Wang, G.M., Wang, R.R., Spector, A. The redox active components H202 and N acetyl L cysteine regulate expression of C Jun and C Fos in lens systems. Exp. Eye Res., 59(2), 179 190 (1994).
45. Macchi, M., Bornert, J. M., Davidson, I., Kanno, M., Rosales, R., Vigneron, M., Xiao, J. H., Fromental, C., Chambon, P. The SV40 TC II (kB) enhancer binds ubiquitous and cell type specifically inducible nuclear proteins from lymphoid and non lymphoid cell lines. EMBO J., 8, 4215 4227 (1989).
46. Matthews, J.R., Wakasugi, N., Virelizier, J., Yodoi, J., Hay, R.T. Thioredoxin regulates the DNA binding activity of NF kB by reduction of a disulphide bond involving cysteine 62. Nucleic Acids Research, 20, 3821 3830 (1992).
47. Mulsch, A., Mordvintcev, P., Vanin, A.F., Busse, R. The potent vasodilating and guanylyl cyclase activating dinitrosyl Iron (II) complex is stored in a protein bound form in vascular tissue and is released by thiols. FEBS Lett., 294(3), 252 256 (1991).
48. Nabel, G. & Baltimore, D. An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature, 326, 711 713 (1987).
49. Nedved, M.L., Moe, G.R. Cooperative, non specific binding of a zinc finger peptide to DNA. Nucleic Acids Research, 22(22), 4705 4711 (1994).
50. Sambucetti, L.C., Cherrington, J.M., Wilkinson, G.W.G., Mocarski, E.S. NFkB activation of the cytomegalovirus enhancer is mediated by a viral transactivator and by T cell stimulation. EMBO J., 8, 4251 4258 (1989).
51. Schreck, R., Baeuerle, P.A. A role for oxygen radicals as second messengers. Trends in Cell Biology, 1, 39 42 (1991).
52. Schreck, R., Rieber, P., Baeuerle, P.A. EMBO J., 10, 2247 2258 (1991).
53. Sen, R. & Baltimore, D. Multiple nuclear factors interact with the immunoglobulin enhancer sequence. Cell, 46, 705 716 (1986a).
54. Stamler, J.S. Singel, D.J., Loscalzo, J. Biochemistry of nitric oxide and its redox activated forms. Science, 258, 1898 1902 (1992).
55. Summers, M. et al. Protein Science 1, 563 (1992).
56. Tainer, J., Russell, P. Cracking tyrosine phosphatases. Nature, 370, 506 507 (1994).
57. Thompson, J.E., Phillips, R.J., Erjument Bromage, H., Tempst, P., Ghosh, S. IkB B regulates the persistent response in a biphasic activation of NF kB. Cell, 80, 573 582 (1995).
58. Toledano, M.B., Kullik, I., Trinh, F., Baird, P.T., Schneider, T.D., Storz, G. Redox dependent shift of OxyR DNA contacts along an extended DNA binding site: A mechanism for differential promoter selection. Cell, 78, 897 909, (1994).
59. Toledano, M.B. & Leonard, W.J. Modulation of transcription factor NFkB binding activity by oxidation reduction in vitro. Proc. Natl. Acad. Sci USA, 88, 4328 4332 (1991)
60. Wagner, J., Mutus, B. Transient activation of calcineurin during thiol modification. Second Messengers Phosphoproteins, 13(4), 199 215 (1991).
61. Witte, M.M., Dickson, R.C. Cysteine residues in the zinc finger and amino acids adjacent to the finger are necessary for DNA binding by the LAC9 regulatory protein of kluyveromyces lactis. Mol. Cell Biol., 8(9), 3726 3733 (1988).
62. Xanthoudakis, S., Curran, T. EMBO J., 22, 653 665 (1992).
63. Bryant, H.U., Holaday, J.W., Bernto, E.W. Cysteamine produces dose related bidirectional immunomodulatory effects in mice. J. Pharmacol., 249, 424 429 (1989).
64. Delneste Y., Jeannin P., Potier L., Romero P., Bonnefoy J.Y.. N acetyl L cysteine exhibits antitumoral activity by increasing tumor necrosis factor alpha dependent T cell cytotoxicity. Blood 90, 1124 1132 (1997).
65. Kalebic, T. Kinter, A., Poli, G., Anderson, M.E., Meister, A., Fauci, A.S. Suppression of human immunodeficiency virus expression in chronically infected monocytic cells by glutathione, glutathione ester, and N acetylcysteine. Proc. Natl. Acad. Sci., 88, 986 990 (1991).
66. Marquardt, H., Sapozink, M.D., and Zedeck, M.S. Inhibition by cysteamine HCI of oncogenesis induced by 7,12 dimethylbenz(a)anthracene without affecting toxicity. Cancer Res., 34, 3387 3390 (1974).
67. Oliver, R. Flow cytometry technique for assessing effects of N acetylcysteine on apoptosis and cell viability of human immunodeficiency virus infected lymphocytes. Methods in Enzymology 251, 270 278 (1995).
68. Roederer, M., Staal, F.J.T., Raju, P.A., Ela, S.W., Herzenberg, L.A., Herzenberg, L..A. Cytokine stimulated human immunodeficiency virus replication is inhibited by N acetyl L cysteine. Proc. Natl. Acad. Sci., 87, 4884 4888 (1990).
69. Tatsuta, M., Iishi, H., Yamamura, H., Baba, M., Mikuni, T., and Taniguchi, H. Inhibitory effect of prolonged administration of cysteamine on experimental carcinogenesis in rat stomach induced by N methyl N nitro N nitrosoguanidine. Int. J. Cancer, 41, 423 426 (1988).
70. Beloqui O, Prieto J, Suarez M, Gil B, Qian CH, Garcia N, Civeira MP. N-acetyl cyteine enhances the response to interferon-alpha in chronic hepatitis C: a pilot study. J Interferon Res 1993; 13:279-82.
71. Neri S, Ierna D, Antoci S, Campanile E, D'Amico RA, Noto R. Association of alpha-interferon and acetyl cysteine in patients with chronic C hepatitis. Panminerva Med 2000 Sep;42(3):187-92.
72. Taub, F., Mayerson, S., Dunn, T., Mokyr, M., Pier, G., Schuman, R., Fichtner, I. BETATHINE™: A new low molecular weight non-toxic immune stimulant. Presented at the 10th NCI-EORTC Symposium on New Drugs in Cancer Therapy, Amsterdam, Netherlands, June 1998.
73. Taub, F., Mayerson, S., Dunn, T., Mokyr, M., Pier, G., Schuman, R., Fichtner, I. BETATHINE™: A new low molecular weight non-toxic immune stimulant. Presented at the 10th NCI-EORTC Symposium on New Drugs in Cancer Therapy, Amsterdam, Netherlands, June 1998.
74. Taub, F., Mayerson, S., Fichtner, I. BETATHINE™: A non-toxic small molecule immune therapeutic with anti-breast cancer activity. Presented at the UCLA Symposium on Breast and Prostate Cancer, Keystone, Colorado, February 1998.
75. Taub, F. Beta-alethine (Beta LT™): A low molecular weight cytokine inducer with anti-cancer properties and low toxicity in mice and man? Review of data to date. Presented at the Cancer Immunosurveillance 1999 International Symposium, New York, New York, 1999.
76. Taub, F. Review of Beta LT immunomodulation in lab studies and patients with follicular B cell lymphoma: Initial phase I/II results. Presented at the Comprehensive Cancer Care 2000, Arlington, VA, June 2000.
77. Taub, F., Manos, K., Mayerson, S. A review of animal models and human clinical trial data supportive of beta-alethine (BT) immune therapy for minimal residual disease (MRD). Presented at the 15th Annual Scientific Meeting of the Society for Biological Therapy, Seattle, WA October 2000.
78. Taub, F., Mayerson, S., Dunn, T., Mokyr, M., Pier, G., Schuman, R., Fichtner, I. BETATHINE™: A new low molecular weight non-toxic immune stimulant. Presented at the 10th NCI-EORTC Symposium on New Drugs in Cancer Therapy, Amsterdam, Netherlands, June 1998.
79. Taub, F., Mayerson, S., Fichtner, I. BETATHINE™: A non-toxic small molecule immune therapeutic with anti-breast cancer activity. Presented at the UCLA Symposium on Breast and Prostate Cancer, Keystone, Colorado, February 1998.
80. Taub, F. Beta-alethine (Beta LT™): A low molecular weight cytokine inducer with anti-cancer properties and low toxicity in mice and man? Review of data to date. Presented at the Cancer Immunosurveillance 1999 International Symposium, New York, New York, 1999.
81. Taub, F. Review of Beta LT immunomodulation in lab studies and patients with follicular B cell lymphoma: Initial phase I/II results. Presented at the Comprehensive Cancer Care 2000, Arlington, VA, June 2000.
82. Taub, F., Manos, K., Mayerson, S. A review of animal models and human clinical trial data supportive of beta-alethine (BT) immune therapy for minimal residual disease (MRD). Presented at the 15th Annual Scientific Meeting of the Society for Biological Therapy, Seattle, WA October 2000.
83. Miller, W.H. Jr., Roy, J., Feldman, B., Belch, A., McQuillan, A., Mayerson, S., Caplan, S., Shustik, C., Roy, D. and Taub, F. Beta-Alethine Phase I/II Data: Immune Stimulation in Patients with Follicular Lymphoma and Myeloma with Evidence of Tumor Response and no Significant Toxicity. Presented at the 43rd Annual Meeting of the American Society for Hematology, December, 2001.
84. Taub, F., Mayerson, S., Dunn, T., Mokyr, M., Pier, G., Schuman, R., Fichtner, I. BETATHINE™: A new low molecular weight non-toxic immune stimulant. Presented at the 10th NCI-EORTC Symposium on New Drugs in Cancer Therapy, Amsterdam, Netherlands, June 1998.
85. Taub, F., Mayerson, S., Fichtner, I. BETATHINE™: A non-toxic small molecule immune therapeutic with anti-breast cancer activity. Presented at the UCLA Symposium on Breast and Prostate Cancer, Keystone, Colorado, February 1998.
86. Taub, F. Beta-alethine (Beta LT™): A low molecular weight cytokine inducer with anti-cancer properties and low toxicity in mice and man? Review of data to date. Presented at the Cancer Immunosurveillance 1999 International Symposium, New York, New York, 1999.
87. Taub, F. Review of Beta LT immunomodulation in lab studies and patients with follicular B cell lymphoma: Initial phase I/II results. Presented at the Comprehensive Cancer Care 2000, Arlington, VA, June 2000.
88. Taub, F., Manos, K., Mayerson, S. A review of animal models and human clinical trial data supportive of beta-alethine (BT) immune therapy for minimal residual disease (MRD). Presented at the 15th Annual Scientific Meeting of the Society for Biological Therapy, Seattle, WA October 2000.
89. Dunn, T.M., Wormsley, S., Taub, F.E., Pontzer, C.H. Increased T cell cytotoxicity by BETATHINE™: Induced upregulation of TNF . International Journal of Immunopharmacology (2000) 22, 213-227.
90. Miller, W., Caplan, S., Shustik, C., McQuillan, A., Sicilia, F, Batist, G., Mayerson, S., Taub, F. Toxicity and biological effects of beta-alethine - Report of the first Phase I/II study. Presented at the VII International Multiple Myeloma Workshop, Stockholm, Sweden, September 1999.
91. Taub, F., Mayerson, S., McQuillan, A., Caplan, S., Shustik, C., Miller, W. Phase I/II evaluation of Beta LT™ as an antilymphoma agent and enhancer of DTH in lymphoma patients. Presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, Washington, D.C., November 1999.
92. Miller, W.H., Caplan, S., Shustik, C., McQuillan, A., Sicilia, F., Mayerson, S., Taub, F. Beta-alethine immunomodulation in follicular B cell lymphoma and multiple myeloma: Initial Phase I/II results. Blood Suppl., Part II, Nov. 15, 1999, p.264b.
93. Miller, W.H. Jr., Caplan, S., Shustik, C., McQuillan, A., Sicilia, F., Mayerson, S., Taub, F. Beta-alethine: TNF alpha, Antitumor Effects and Delayed Type Hypersensitivy in Follicular B-Cell Lymphoma. Oral presentation at the ISH 2000 (28th International Congress) Toronto, Ontario, August 2000.
94. Miller, W.H. Jr., Caplan, S., Shustik, C., McQuillan, S., Sicilia, F., Mayerson, S.,Taub, F. T cells exhibit increased TNF alpha and delayed type hypersensitivity responses are restored in patients with B cell malignancies following administration of beta-alethine. Presented at the 11th NCI-EORTC-AACR Symposium on New Drugs in Cancer Therapy (Amsterdam, The Netherlands), 2000.
95. United States District Court, District Of New Mexico, Findings Of Fact And Conclusions Of Law (No. CIV 99-577 JC/WWD) [Final order dated September 10, 2001.]
96. Knight et al. United States Patent: 6,096,536. University of New Mexico, Filed: June 5, 1995.
97. Dunn, T.M. Immunostimulatory Effects of Taurox SB™, Thesis, University of Maryland Department of Pharmacology and Experimental Therapeutics, 2000.
98. Ibid.
99. Lussignoli, S, Bertani, S, Metelmann, H, Bellavite, P, Conforti, A. Effect of Traumeel S, a homeopathic formulation, on blood-induced inflammation in rats. Complement. Ther. Medicine, 1999, Dec; 7(14):225-30.
100. Oberbaum, M, Yaniv, I, Ben-Gal, Y, Stein, J, Ben-Zvi, N, Freedman, LS, Branski, D. A randomized, controlled clinical trial of the homeopathic medication TRAUMEEL S in the treatment of chemotherapy-induced stomatitis in children undergoing stem cell transplantation. Cancer, 2001, Aug 1; 92(3):684-90.
101. Hirt M, Nobel S, Barron E. Zinc nasal gel for the treatment of common cold symptoms: a double-blind, placebo-controlled trial. Ear Nose Throat J. 2000 Oct;79(10):778-80, 782.
102. Midlantic Bio-Research, MBR study 34-02, 1995, unpublished data.
103. Midlantic Bio-Research, MBR study 34-01, 1995, unpublished data.
104. Dovetail Technologies, Inc. (2001). Draft Report. Assessment of Toxicity of Taurox. Study No. R-98-63.
105. Riley, D., Homeopathic proving, unpublished data.
106. Product Safety Labs (2001). 14-Day Repeat dose Oral Toxicity Study in Rats. Study number 10564.

Home