STUDIES ON THE TOXICITY OF GOLD COMPOUNDS IN MICE AND RATS

166 Pages·07.315 MB·English

by  DENKO, CHARLES W.

DOCTORAL DISSERTATION SERIES
S i u d i e S on the T o ^ i c i i y ofC-ohL
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CHARLES W. DENKO
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UNIVERSITY,
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DEGREE PUBLICATION NO.
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^ UNIVERSITY MICROFILMS
S ” A N N ARBOR - M I C H I G A N
THE PENNSYLVANIA STATE COLLEGE
The Graduate School
Department of Agricultural and Biological Chemistry
STUDIES ON THE TOXICITY OP GOLD COMPOUNDS
IN MICE AND RATS
A Dissertation
fcy
CHARLES W. DENKD
Submitted in partial fulfillment of the
requirements for the degree of
DOCTOR m PHILOSOPHY
October, 194-3
issor of Physiological Chem
Head of the Department of Agricultural and
Biological Chemistry
TABLE OF CONTENTS
Page
I* INTRODUCTION 1
IX. REVIEW OF LITERATURE 5
A.. Historical Surrey 5
1. Introduction
2. Use of Gold Compounds in Tuberculosis,
Lupus, and Other Diseases of
Tuberculous Nature 5
3» Use of Gold Compounds in Experimental*
and Miscellaneous Diseases 9
4* Use of Gold Compounds in Arthritis 11
B. Synthesis of Gold Compounds 16
C. Toxic Reactions 20
D. Tolerance and Cross Tolerance 23
E* Histopathological Results 25
F. Experimental Mouse Arthritis ... 30
III* PURPOSE OF INVESTIGATION 3&
IV. GENERAL METHODS AND MATERIALS 37
. A. Sources of Gold Compounds 37
B. Preparation of Gold Compounds 3^
C. Determination of Gold in Prepared
Compounds 40
D» Biochemical Methods " 41
E# Bacteriological Methods 43
1, Sources of Cultures and Animals 43
Page
2* Preparation of Media and Cultures 45
V. PRESENTATION OE DATA. 51
A* Preparation of Gold Compounds 51
1* Potassium Ethyl Xanthate or
Potassium Xanthogenate 52
2* Aurothioglycolic acid and Its Salts 53
3« Alpha-aurothio**n**butyr ic Acid 60
4* Auro~n»»propyl Xantha.te 64
5* Auro-i s opropyl Xanthate 66
6a Auro~n~butyl Xanthate 68
7© Auro»isobutyl Xanthate 69
Ba Gold Content of Compounds Prepared as
an Index of Composition and Purity 70
G* Animal Studies 73
1» Studies on Mice 75
a* Toxicity Studies by the
Survival Method 75
b«, The Effect of Type of Carrier
on Toxicity of Aurothi©glucose 76
Co The Effect of pH on the Toxicity
of Aurothioglucose 79
d® The Effect of the Route of
Administration on The Toxicity
of Colloidal Gold 8l
e* Toxicity of Some Prepared Gold
Compounds 83
Page
f® The Eonprotein 2STitrogen
Level of1 the Blood as an
Index of Toxicity of
Aurothiogluc ose 86
g» Tolerance Studies on
Aurothiogluc ose
91
h® Therapeutic Studies
93
2« Bat Studies 96
1* Toxicity Studies
99
a« The Effect of Type of
Carrier on the Toxicity
of Aurothioglucose
99
b® Toxicity of Gold Sodium
Thiasulfate 105
c* Toxicity of Colloidal
Gold and Strontium
Aurothioglycslate 108
d® The Effect of pH on the
Toxicity of Aur o thi ogluc o s e 109
e® Toxicity of Alpha-aur o thi o**
n-butyric Acid 112
to Toxicity of Auroxanthates 118
g* Toxicity of Alpha-
aurothio-n-butyrie Acid
Due to Presence of the
Gold Atom 123
2* Tolerance and Cross Tolerance
Studies
a® Tolerance Development to
Aurothioglucose and Gold
Sodium Thiosulfate 126
b® Development of cross
Tolerance 131
page
3• Hi s t opa th o1ogic al Studies 138
VI* COFCLUSIOITS 143
VXX« SUMMARY 146
ACKNOWLEDGMENTS 148
BIBLIOGRAPHY I49
AUTOBIOGRAPHY 1^9
I. DJTROIKJCTIOIT
with, the momentous discovery of arsphenamine
for treatment of syphilis JShrlich (90), in I909
established the science now known as chemotherapy*
Actually the beginnings of chemotherapy are lost in
ancient times, since various metals, including gold,
were used in treating diseases centuries ago* Also,
in the seventeenth century quinine was introduced as
a specific remedy for malaria (63)* However, j£hrlich®s
discovery, plus the new knowledge of the bacterial
origin of disease established by Pasteur, was responsible
for much research activity seeking to develop chemical
agents for the control and eradication of microbial
diseases of mankind. The term chemotherapy has become
associated with the treatment of infectious diseases by
the introduction into the body of specific drugs or
chemicals»
In 193? Dom&gk (22) demonstrated that Prontosil,
a derivative of sulfanilamide would cure streptococcal
infections. In 1908 G-elmo (35) had reported the
synthesis of sulfanilamide, para-aminobenzenesulfonamide,
as a dyestuff intermediate. Domagkts discovery has
called the attention of the scientific world to the
curative properties of the sulfa drugs which are now
revolutionizing the practice of medicine* Extensive
research has now prodticed about 2500 derivatives of
sulfanilamide, which are commonly known as sulfonamides
(63)* Many of these are more therapeutically active
than sulfanilamide and are now used in the treatment of
wounds , pneumonia, a variety of animal ailments,
intestinal infections, erysipelas, scarlet fever,
tonsiliti3, gonorrhea, mastoiditis, osteomyelitis,
puerperal fever and peritonitis (19)•
Sulfonamides have contributed greatly to the
control of infection. The toxicity of the sulfonamides
is in general very low in comparison to their potency?
nevertheless, these very helpful chemotherapeutic agents
have their limitations. Recently hope has been held out
that man may eventually develop chemotherapeutic agents
having little or no toxicity.
At present there is much interest in the surprising
anti-bacterial action of metabolic products of
microorganisms. Important new discoveries in this field
were made by Fleming (29) in 1929 when he found penicillin,
a metabolic product of the green mold Penicillium notatum,
3
to be bacteriostatic to gonococci, pneumo­
cocci, staphylococci and streptococci* In view
of the usefulness of penicillin at present in war
wounds, much energy is being devoted to its study by
pharmaceutical manufacturers in this country*
The work of Dubos (24) of the Rockefeller
Institute for Medical Research, led to the isolation
of two bacterial products, gramicidin and tyrocidin,
active against Gram-positive and Gram-negative bacteria
respectively* Flavicin, an antibacterial substance
produced by Aspergillus flavus, was announced by Bush
and Goth (14) in 1943 to be active against the Gram-
positive cocci, Corynebacterium diphtheriae, Bacillus
anthracis, Staphylococcus albus and Brucella abortus *
Little is known of the chemical nature of flavicin;
however, it is thought to be unlike penicillin, tyrocidin
and gramicidin which appear to be protein or polypeptide
in nature. Extensive studies are now being conducted
to determine the exact chemical constitution of these
microorganismic products in order to manufacture them
synthetically*
Viricidal agents are also being studied with
great interest. Andrews, King and van den Bnde (5)
have studied the effect of about twenty different classes
of compounds on influenza A, lymphogranuloma venereum
and vaccinia.
Although the stupendous success of sulfa drugs and
the promising future of microorganismic products has
overshadowed all other chemotherapeutic agents, much work
has been done with entirely different compounds* One
type of lesser publicized compounds consists of those
remedies containing gold now being widely applied in the
treatment of tuberculosis, lupus and rheumatoid arthritis.
The greatest obstacle to the widespread use of
gold remedies is the toxic reactions which so often
follow. However, the great hope of improvement and cure
which gold compounds hold for many sufferers makes their
use of pertinent significance. Thus the work in this
thesis was undertaken mainly to synthesize and study
experimentally the toxicity of several gold compounds
which might prove to be therapeutically useful.