Abstract

In order to evaluate the effect of colloidal metallic gold on cognitive functions, the revised Wechsler Intelligence scales battery of tests (WAIS-R) was administered to 5 subjects aged 15 to 45 years, before, after 4 weeks on nanoparticle gold at 30 mg/day and again 1 to 3 months off the gold preparation. The WAIS-R total scores (I.Q) were calculated by adding the sum of the verbal test scores to the sum of the performance scores. After 4 weeks on nanoparticle gold, there was a 20% increase in I.Q scores with mean + SE of 112.8 + 2.3 pre gold and 137 + 3.8, post gold (p <0.005). Both the performance and verbal test scores contributed equally to this increase in I.Q scores. The effect of the nanoparticle gold persisted in 3 subjects after 1 to 2 month off gold, where as in 2 subjects who took the tests 3 months after stopping the gold, I.Q scores were down to baseline levels.

Introduction

It is generally accepted that intelligence or cognitive functioning is the sum of many mental capacities. For this reason, tests that were developed to measure intelligence quotient (I.Q) comprised a series of subtests evaluating the several dimensions of intelligence. Of the several I.Q tests available, educators have found that the Full Scale I.Q score of the Wechsler intelligence scales (WIS) battery, which is calculated from the sum of the individual scores of 11 tests, (6 verbal and 5 performance tests) is an excellent predictor of academic achievement.1 The revised version of this I.Q test (WAIS-R) has been used extensively to assess the effect of deficiencies and supplementation of specific nutrients2,3 and the effects of sex, race, age and education4-7 on mental performance.

Gold is a precious metal which belongs to the transition group I in the periodic table and exists in nature in two basic forms: metallic gold and gold salts. Metallic gold is non-toxic, used extensively in dentistry and is widely available in colloidal form as a nutritional supplement for human consumption. One of us (GEA) has observed a significant subjective improvement of mental performance in 21 adult subjects after ingestion of a preparation of colloidal metallic gold (Aurasol®) for 3 to 9 months at a daily dosage of 15 mg of gold (unpublished). In order to use an objective and more standardized approach in evaluating the effect of nanoparticle gold on mental performance, the WAIS-R battery of tests7 was performed on 5 subjects (4 females, 1 male) age 15-45 years, before, during and after the ingestion of the same nanoparticle gold preparation at 30 mg/day. The results suggest that nanoparticle gold at 30 mg/day improved significantly the I.Q scores after only one month of administration.

Materials and Methods

Aqueous dispersion of colloidal metallic gold was prepared by a modification of the citrate reduction method of Frens. The concentration of gold in this preparation (Aurasol®) was 30 mg per ounce of fluid. Five subjects were recruited for this study ( 4 females and 1 male) with ages ranging from 15 to 45 years. The subjects were evaluated using the WAIS-R procedure.7 Verbal scores, performance scores and total scores (I.Q) for each subject were calculated. The WAIS-R battery was performed on each subject before gold administration, after ingesting 30 mg of nanoparticle gold daily for one month, and again after being off the gold preparation for 1 to 3 months. The statistical significance of the data was assessed by Student’s paired t test.9

Results

The group of tests called verbal are non-learning and therefore is not influenced significantly by repetition. The performance tests can be learned with repetition, and this should be taken into consideration when evaluating the results displayed in Table I. The mean scores + standard error (SE) were respectively for pre- and post-gold administration: verbal 61.4 + 2.4 and 75.4 + 4.5 (p<0.005); performance 51.4 + 0.83 and 61.6 + 1.9 (p<0.01); total scores (IQ) 112.8 + 2.3 and 137 + 3.8 (p<0.005). Since both the verbal (non-learning and performance (learning) scores contributed equally to the increased values observed in the total IQ scores following nanoparticle gold, the positive effect of nanoparticle gold cannot be attributed solely to learning the correct responses on the second test due to repetition.

It is of interest to note that in two subjects (#1 and #2) who repeated the battery 3 months after stopping nanoparticle gold, the total IQ scores were close to baseline pre-gold levels whereas, in 2 subjects who performed the test 1 month after stopping the gold, (#3 and #5) and in one subject (#4) who did so after 2 months off nanoparticle gold, the total IQ scores were still elevated above baseline, suggesting that the effect of the gold on mental performance has a carry-over of one to two months after stopping the use of this preparation.

Discussion

The WIS battery of tests is an excellent predictor of scholastic performance.1 In fact, according to Lezak,10 the average scores on a WIS battery provide just about as much information as do average scores on a school report card. We have observed a significant increase (20%) of the mean IQ scores in 5 subjects aged 15 to 45 years after only one month on oral colloidal metallic gold at 30 mg/day. This effect persisted for up to 2 months following discontinuation of the gold preparation. To our knowledge, this is the first study evaluating the effect of nanoparticle gold on mental performance. Possible mechanisms of action of the nanoparticle gold preparation are only speculative at this time. However, the potential applications of a non-toxic nanoparticle metal with marked and rapid positive effect on mental performance are without question of great practical value, not only in scholastic performance but also in the workplace.

The encouraging results of this pilot study warrant further evaluation of colloidal metallic gold in a larger number of subjects of different age groups. Testing various amounts of gold would assist in quantifying the response of the IQ tests in terms of cumulative amount of gold ingested in order to investigate a possible dose-response relationship. Using the smallest amount of nanoparticle gold that results in a desirable effect on mental performance and scholastic achievement would keep the cost of such a program as low as possible.

References

1. Lezak, M.D., In: Neuropsychological Assessment. New York, Oxford University Press; 1995:690.
2. Goodwin, J.S., Goodwin, J.M., Garry, P.J. Association between nutritional status and cognitive functioning in a healthy elderly population. J Amer. Med. Assoc., 1983; 249:2917-2921.
3. Southon, S., Wright, A.J., Finglas, P.M., Bailey, A.L., et. al. Dietary intake and micronutrient status of adolescents: effect of vitamin and trace element supplementation on indices of status and performance in tests of verbal and non-verbal intelligence. Br. J. Nutr., 1994; 71:897-918.
4. Kaufman, A.S., McLean, J.E., Reynolds, C.R. Sex, race, residence, region, and education differences on the 11 WAIS-R subtests. J. Clin. Psychology, 1988; 44:231-248.
5. Kaufman, A.S., McLean, J., Reynolds, C. Analysis of WAIS-R factor patterns sex and race. J. Clin. Psychology, 1991; 47:548-557.
6. Kaufman, A.S., Reynolds, C.R., McLean, J.E. Age and WAIS-R intelligence in a national sample of adults in the 20 to 74 year age range: A cross-sectional analysis with educational level controlled. Intelligence, 1989; 13:235-253.
7. Kaufman, A.S. Assessing adolescent and adult intelligence. Boston, Allyn and Bacon Inc.; 1990.
8. Abraham, G.E., Himmel, P.B. Management of Rheumatoid Arthritis: Rationale for the Use of Colloidal Metallic Gold. In Press, J. Nutr. Med., 1997.
9. Huntsberger, D.V., Leaverton, P.E., In: Statistical Inference in the Biomedical Sciences. Boston, Allyn and Bacon Inc.; 1970:135.
10. Lezak, M.D., In: Neuropsychological Assessement. New York, Oxford University Press;1995:691.

Colloidal Gold in the Treatment of Rheumatoid Arthritis (RA)

Peter B. Himmel, Jorge D. Flechas, Guy E. Abraham

Gold salts (aurothiolates), once the primary therapy for active RA has in recent years declined in its use because of apparent lack of long term efficacy, toxic side effects, and delayed onset of action. One of us (GEA) postulated that the active ingredient in aurothiolates is nanoparticle gold generated by in vivo disproportionation with subsequent clustering of monoatomic gold, and that the side effects were due to the aurothiolates themselves and the trivalent cationic gold generated from the disproportionation. If this postulate is valid, one would expect nanoparticle gold to have therapeutic effects in RA and devoid of side effects.

Methods:

10 patients (6 female, 4 male; average age 50 +/- 3.16 (SE) with long standing erosive RA ( 9 of 10 seropositive) were given an oral dose of 30 to 60 mg a day of colloidal gold (Aurasol-tm) for a period of 1 month. Clinical exams were performed weekly and laboratory studies done on weeks 1, 2, 4. Gold toxicity was evaluated by questioning the patient as to pruritus, rashes, oral ulcers, metallic taste, GI disturbance. The blood was checked for a drop in WBC, Hb, platelet count, BUN, creatinine or eosinophil elevation, and urine for proteinuria. Efficacy was evaluated by an 86 Joint Count Index scoring for joint tenderness and swelling: AM stiffness; the Modified Health Assessment Questionnaire (MHAQII) by T. Pincus and an ESR.

Results:

Statistically significant improvement was found on each weekly exam for joint tenderness and swelling beginning with the first week 58.8 to 18.2 (p<0.01) for tenderness; 42.5 to 15.9 (p<0.01) for swelling. Joint swelling reduced further to a value of 13.0 (p<0.001) by week 4. Patients fatigue decreased from 5.32 to 3.35 (p<0.05) over the month and a feeling of satisfaction in one’s ability to do activities was apparent after 1 week, 3.1 to 2.5 (p<0.01) and persisted. No laboratory tests indicative of gold toxicity was noted. One patient reported 2 chancre sores which cleared while in therapy, 8 of 10 patients responded to nanoparticle gold.

Conclusion:

In this pilot study colloidal gold (Aurasol-tm) was found to be rapid acting (within one week) by reducing joint tenderness and swelling, without side effects, improved ones feeling of satisfaction in the ability to perform activities and reduce fatigue in 8 out of 10 patients with long standing erosive RA. The study will continue for one year. More definitive controlled trials should now be undertaken with nanoparticle gold.

Note:

The study has now completed its eighth month with all ten of the original patients still enrolled. The patients continue to do well with no significant side effects noted. This data is being compiled to be submitted for publication.

Management of Rheumatoid Arthritis:
Rationale for the Use of Colloidal Metallic Gold

Guy E. Abraham MD FACN1 and Peter B. Himmel MD2
1Optimox Corporation, Torrance, CA, USA and 2 Himmel Health, Wakefield, RI, USA

In Press – J. Nutr. Med., Vol. 7 – Dec. 1997

• Abstract
• Introduction
• Materials and Methods
• Results
• Discussion
• References

Abstract

Gold salts of monovalent gold (AU I) with a gold-sulfur ligand (aurothiolates) are the only form of gold currently in use for the management of Rheumatoid Arthritis (RA). Aurothiolates have limited success and are associated with a high incidence of side effects. Metallic gold (AUo) is non-toxic and used extensively in dentistry. Monoatomic metallic gold is generated in vivo from AUI salts, during oxydation to AU III. Monoatomic gold tends to form clusters of colloid particles. It is postulated that the active ingredient in aurotherapy is AUo and the side effects are caused by AU III. To test this postulate, 10 RA patients with long standing erosive bone disease not responding to previous treatment, were recruited from a private practice. Clinical and laboratory evaluation were performed prior to oral administration of 30 mg of colloidal metallic gold daily, and thereafter weekly for 4 weeks and monthly for an additional 5 months. There was no clinical or laboratory evidence of toxicity in any of the patients.

The effects of the nanoparticle gold on tenderness and swelling of joints were rapid and dramatic, with a significant decrease in both parameters after the first week, which persisted during the study period. The mean scores for tenderness and swelling were respectively for the pre-and post- 1 week = 58.8 and 18.2 (p<0.01); and 42.5 and 15.9 (p<0.01).

By 24 weeks of gold administration, the mean scores were 10 times lower than pre-treatment levels being respectively 5.4 and 3.3 for tenderness and swelling. As a group, there were significant improvement of functional status after 24 weeks of gold therapy: 3 patients were in clinical remission and one patient’s status improved from totally disabled to full-time work. Evaluated individually, 9 of 10 patients improved markedly after 24-weeks of nanoparticle gold at 30 mg/day. Cytokines interleukin-6 (IL-6) and Tumor necrosis factor (TNFa) were significantly suppressed by the nanoparticle gold with pre- and post-24 week mean values of 270 and 104 (p<0.05) for IL-6; and 207 and 74 (p<0.05) for TNFa. The results of this open trial in 10 patients with long standing erosive RA not responding to previous treatment support the postulate that nanoparticle gold is indeed the active ingredient in aurothiolate therapy, and that the side effects are mainly due to the trivalent gold (AU III) generated by oxydation of AU I. Colloidal metallic gold could become an effective and safte alternative to the aurothiolates in the management of RA patients. Keywords: rheumatoid arthritis, colloidal metallic gold.

Introduction

Aurothiolates have been used in the treatment of rheumatoid arthritis (RA) since their introduction by Forestier in 1929 (1). In a follow-up publication, Forestier reported that the only forms of gold effective in the management of RA were organic compounds containing monovalent cathionic gold (AU I) covently bound to a sulfur moiety (aurothiolates) and given by weekly intramuscular injection to achieve a total cummulative dose of 2.5 to 3 gm (2). He stated that colloidal gold was ineffective, but did not mention the dosage, the form of colloidal gold, whether metallic or cathionic, neither the method of administration. Several subsequent reports by various investigators have confirmed the short-term efficacy of the parenteral forms of aurothiolates in RA (3), but in more recently published clinical studies with the parenteral aurothiolates, several side effects were reported: Pulmonary damage (4-7), myelotoxicity, leukopenia, thrombocytopenia, and anemia (8-12). In a recent longitudinal study of 822 RA patients receiving parenteral aurothiolate therapy over a 5-year period (13), no statistical improvement was observed in two outcome variables evaluated: functional assessment and number of painful joints. In an attempt to minimize the side effects of injectable gold complexes, an oral preparation was introduced in 1976 (14). However, this preparation caused diarrhea/loose stools in 50% of the patients, was less effective than the parenteral forms of aurothiolates and produced the same side effects as the injectable forms of gold salts although to a lesser extent.

Since chemical complexes of monovalent gold readily disproportionate in solution with formation of metallic monoatomic gold and trivalent gold according to the reaction: 3AU+® 2AUo + AU +++ (15), it would be expected that monovalent gold organocomplexes, such as the aurothiolates if administered orally or parenterally, would disproportionate in vivo with formation of metallic monoatomic gold and trivalent gold (AU III). In vivo clustering of metallic gold atoms would eventually form colloidal particles of gold. One of us (GEA) postulated that the active ingredient in aurothiolate therapy is colloidal metallic gold generated by in vivo disproportionation with subsequent clustering of monoatomic metallic gold to form colloidal gold; and that the side effects were due mainly to the trivalent gold (AU III) generated from disproportionation (Fig 1). If this postulate is valid, one would expect colloidal metallic gold to have therapeutic effects in RA and devoid of side effects. Metallic gold is non-toxic, used extensively in dentistry and is widely available in colloidal form as a nutritional supplement for human consumption. The above postulate was tested in 10 patients with long standing erosive RA with minimal to no response to previous treatment. The results obtained support the postulate that colloidal metallic gold is indeed the active ingredient in aurothiolate therapy and offer a more effective and safer alternative to aurothiolate therapy in R.A. patients.

Materials and Methods

A. Colloidal metallic gold:

Aqueous dispersions of colloidal gold (Aurasol®) were prepared by one of us (GEA) at a final concentration of 1000 mg/L, (1000 PPM) by the citrate method of Maclagan (16) and Frens (17), with several proprietary modifications. The sizes of the colloid particles were less than 20 nm in several batches, confirmed by quantitative recovery after passing through a 20 nm filter. Accelerated shelf-life studies proved the stability of the aqueous dispersion for up to 2 years at ambient temperature. The following metals were measured in the aqueous nanoparticle gold dispersion and were undectable at 0.5 PPM (<0.5 mg/L): Antimony, arsenic, barium, beryllium, cadmium, chromium, cobalt, copper, lead, mercury, molybdenum, nickel, selenium, silver, thallium, vanadium, and zinc. Lead levels were measured again in a more sensitive assay and were undetectable at 50 PPB (<0.05 mg/L). Sterilization was achieved by microfiltration through 100 nm pore size and sodium benzoate was used as anti-microbial preservative.

B. R.A. Patients:

In order to minimize the placebo effect, the 10 worse cases (9 of 10 seropositive) with long standing (7-40 years duration) erosive RA with minimal to no response to previous treatment, were recruited from the private practice of one of us (PBH). Nine of 10 patients received previously aurothiolate therapy without effect and 5 of the 9 experienced side effects of skin rash, stomatitis and proteinuria. The clinical data on these patients are displayed in Table I. Six of the ten patients were totally work-disabled. After informed consent was obtained, the patients underwent complete clinical and laboratory evaluations before and weekly afterward for 4 weeks and monthly for an additional 5 months of oral nanoparticle gold administration. The inflammatory cytokines, tumor necrosis factor a (TNFa) and interleukin-6 (IL-6) were evaluated prior to and 24 weeks following gold administration (Immunoscience Lab, Beverly Hills, CA). Paired data analysis was used for the evaluation of response to nanoparticle gold (18).

Performance parameters were assessed by the method of Pincus, et. al., (19). The severity of swelling and tenderness was assessed for 86 joints, based on the quantitation of Lansbury (20), and the classification described in the Dictionary of Rheumatic Diseases (21). The American Rhematology Association (ARA) functional class by Steinbrocker, et al., (22) was used to evaluate functional status: Class I: Complete functional capacity with ability to carry on all usual duties without handicaps; Class II: Functional capacity adequate to conduct normal activities despite handicap or discomfort or limited mobility of one or more joints; Class III: Functional capacity adequate to perform only few or none of the duties of usual occupation or or self-care; Class IV: Largely or wholly incapacited with patient bed ridden or confined to wheel chair, permitting little or no self-care.

Since preliminary data by one of us (GEA) suggested that amounts up to 15 mg/day of nanoparticle gold was without clinical effect in RA, patients 1 through 5 received 30 mg/day for the first week and 60 mg/day for the second week, whereas patients 6 through 10 received 60mg/day for the first week and 30 mg/day for the second week. Except for one patient, no significant difference was found between these two amounts on the clinical parameters evaluated. The patients were therefore continued on the trial at 30 mg/day for a duration of 24 weeks.

Results

The effects of the colloidal gold (Aurasol®) on tenderness and swelling of joints were rapid and dramatic, with a significant decrease in both parameters after the first week, which persisted during the study period. The mean scores for tenderness and swelling were respectively for the pre- and post- 1 week = 58.8 and 18.2 (p<0.01); and 42.5 and 15.9 (p<0.01). By 24 weeks of gold administration, the mean scores were 10 times lower than pre-treatment levels being respectively 5.4 and 3.3 for tenderness and swelling. Duration of AM joint stiffness (in hours) showed a decreasing trend that reached statistical significance with pre-and post-24 week mean scores of 2.8 and 0.4 respectively (p<0.01).

The mean body weight after 24 weeks on nanoparticle gold was not significantly different from the pre-treatment mean value. As a group, there were significant changes in ARA functional class, and physician’s estimate of disease activity. Pre- and post- 24 week mean values were 2.9 and 2.3 (P<0.05) for ARA functional class; and 3.1 and 1.5 (P<0.01) for physician’s estimate of disease activity. After 24 weeks on nanoparticle gold, 3 patients (#5, #6, #7) were in clinical remission. Work status improved in 3 patients (#3, #5, #6), with the most impressive results in patient #6, who changed from totally disabled to full time work, and ARA class IV to class I. The inflammatory cytokines IL-6 and TNFa were significantly suppressed by the nanoparticle gold with pre- and post-24 week mean values of 270 and 104 (p<0.05) for IL-6; and 207 and 74 (p<0.05) for TNFa.

There was no clinical or laboratory evidence of toxicity in the patients. Specifically, no change was observed in subsets of white blood cells and platelets in the RA patients, supporting the absence of cytotoxicity from nanoparticle gold. There was no significant change in hemoglobin, hematocrit, liver function tests, BUN, serum creatinine and urinalysis in the RA patients and the levels of these parameters remained within normal limits during the study period. Clinically, there were no reports or signs of skin rashes, stomatitis, gastrointestinal disturbances, vasomotor reactions, myalgias, arthralgias, pruritus, headache or metallic taste. Evaluated individually, 9 of 10 patients improved markedly after 24 weeks of nanoparticle gold at 30 mg/day.

Discussion

In studies performed in vitro (23) and in vivo (24), administered metallic colloidal gold particles are ultimately sequestered within lysosomes of phagocytes, visible under electron microscopy (EM). After administration of aurothiolates to RA patients, gold particles visible under EM selectively accumulate in the lysosomes of synovial cells and macrophages (25). It is believed that stabilization of lysosomes by these gold particles plays a role in their therapeutic actions (26). Electron probe x-ray analysis of lysosomes revealed that the form of gold present in lysosomes obtained from patients receiving aurothiolates is devoid of sulfur atoms and therefore cannot be in the form of aurothiolates (26). Since disproportionation of aurothiolates generate monoatomic metallic gold with a diameter of 0.28 nm, a size below the resolution of EM, the only way the gold particles in the lysosomes could be visible under EM is by clustering of metallic monoatomic gold to form colloidal gold particles. These results are consistent with the postulate that the gold in lysosomes is in the form of colloid particles of metallic gold. Therefore, the argument that colloidal metallic gold is the active ingredient from aurotherapy seems very plausible.

The results of this open trial in 10 patients with long standing erosive RA not responding to previous treatment support the postulate that nanoparticle gold is indeed the active ingredient in aurothiolate therapy, and that the side effects are mainly due to the trivalent gold (AU III) generated by in vivo disproportionation. Common sense would favor the active ingredient in its pure state over a precursor that generates both the active form and another form causing side effects. The most prevalent side effects of aurotherapy are skin rash and diarrhea. Trivalent gold cause contact dermatitis and skin rash (27). The diarrheogenic action of aurothiolates can be explained by their ability to stimulate intestinal secretion in vitro, an effect shared by trivalent gold (28). Aurothiolates cause adverse immune reactions in up to one third of RA patients (29-31). Some of these side effects can be reproduced in susceptible mouse strains following long-term exposure to the aurothiolates: increased serum levels of IgM, IgG and IgE formation, of IgG antinuclear antibodies, and granular IgG deposits along the glomerular basement membrane (32-34). T-lymphocytes from susceptible mice fail to be sensitized to the aurothiolates but mount a secondary response to Au (III) salts, suggesting the adverse immune reactions to the aurothiolates are elicited by T cell sensitization to Au (III) formed in vivo through oxidation of Au (I) (35).

A placebo effect in these RA patients is very unlikely since their favorable clinical response was associated with the concurrent suppression of the inflammatory cytokines TNFa and IL-6. The powerfull anti-inflammatory properties of nanoparticle gold while devoid of cytotoxicity and side effects could make it usefull in other inflammatory and immune complexes diseases. Tissue levels of nanoparticle gold in the therapeutic ranges could be achieved rapidly with increased dosages without the risks of complications reported for the aurothiolates. Colloidal metallic gold could become an effective and safe alternative to the aurothiolates in the management of R.A. patients.

Since colloidal metallic gold catalyzes electron-transfer in oxydation reduction reactions (36), one possible mechanism of action of nanoparticle gold could be in potentiating the suppressive effect of antioxydants on free radical formation. The mechanisms of action of nanoparticle gold however remain speculative at this time, and we are currently investigating such mechanisms in animal models. Acknowlegement: The authors wish to thank Ralf Albrecht for usefull discussions, and Pat Kellum for skillfull secretarial assistance.

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