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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 colloidal 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 patients status improved from totally disabled to full-time
work. Evaluated individually, 9 of 10 patients improved markedly after
24 weeks of colloidal gold at 30 mg/day. Cytokines interleukin-6 (IL-6)
and Tumor necrosis factor (TNFa) were significantly suppressed by the
colloidal 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 colloidal
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 produce
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 colloidal 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 colloidal 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 colloidal 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 the 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 colloidal 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 colloidal 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 colloidal
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 colloidal 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 colloidal 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 colloidal gold at 30 mg/day.
iscussion
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 colloidal
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 colloidal gold while devoid of cytotoxicity and side effects
could make it usefull in other inflammatory and immune complexes diseases.
Tissue levels of colloidal 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 colloidal
gold could be in potentiating the suppressive effect of antioxydants
on free radical formation. The mechanisms of action of colloidal 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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