Overview and Current Status of Gold-Containing ... - ACS Publications

18

O v e r v i e w and C u r r e n t Status of G o l d - C o n t a i n i n g

Downloaded by NORTH CAROLINA STATE UNIV on May 3, 2015 | http://pubs.acs.org Publication Date: January 26, 1983 | doi: 10.1021/bk-1983-0209.ch018

Antiarthritic D r u g s BLAINE M. SUTTON Smith Kline and French Laboratories, Philadelphia, PA 19101

Auranofin, (2,3,4,6-tetra-O-acetyl-1-thio-βD-glucopyranosato-S)(triethylphosphine)gold is a new compound for treating rheumatoid arthritis (RA). Gold has a long medical history. Gold compounds were first investigated for RA treatment because of the reported relief of joint pain in tubercular patients being treated unsuccessfully with sodium aurothiosulfate. Use of gold therapy and its mechanism of therapeutic benefit have long been controversial. However, clinical studies reported in 1960 confirmed its antiarthritic value. Auranofin has several potential advantages over gold compounds in use today, most important is its route of administration. It is clinically effective when administered orally. Other gold compounds must be given by injection. Auranofin's unique therapeutic properties may be due in part to physical and chemical characteristics which differ markedly from those of currently used agents.

Excellent studies of the interaction of platinum compounds with biologically important small and macromolecular species have been reported both in this volume and elsewhere (1). Consequences of these observations have been associated with proposed modes of antineoplastic action of cis-platinum (II) compounds* The relatively recent discovery of this new class of antineo plastic agents (2) has led to an intensification of research into the therapeutic potential of transition metal compounds. It is surprising that the intensity of scientific zeal directed towards this class of antineoplastic agents has not focused on gold compounds, probably one of the first metals to be used in treatment of 0097-6156/83/0209-0355$06.00/0 © 1983 American Chemical Society In Platinum, Gold, and Other Metal Chemotherapeutic Agents; Lippard, S.; ACS Symposium Series; American Chemical Society: Washington, DC, 1983.

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METAL CHEMOTHERAPEUTIC AGENTS

disease and one that s t i l l holds a prominent p o s i t i o n as a s p e c i f i c therapeutic form f o r treatment of a c t i v e rheumatoid a r t h r i t i s (RA).


History Gold u n l i k e platinum i s an ancient metal and has a long medical h i s t o r y . I t was probably one of the f i r s t to a t t r a c t the a t t e n t i o n of man, because i t i s one of the few that e x i s t e d i n the elemental s t a t e i n nature. Being r e l a t i v e l y i n e r t i t r e t a i n s i t s l u s t e r and does not t a r n i s h on exposure to a i r . Since pure gold was too s o f t to form u s e f u l implements, p r i m i t i v e man valued gold f o r ornamental purposes. The ancient Egyptians obtained t h e i r gold i n a l l u v i a l diggings from the sand and g r a v e l i n s e v e r a l d i s t r i c t s between the N i l e and the Red Sea, the Nubian area. The Rameside papyrus', the o l d e s t map i n the world, l o c a t e s these d i s t r i c t s ( 3 ) . Ornamental gold became a s i g n o f c h i e f t a i n s h i p and remains today as evidence of personal wealth* I t s a c q u i s i t i o n has enslaved unknown numbers of people from ancient to modern times and has motivated unbelievable a c t s of v i o l e n c e and crime: these l i n e s from the Greek w r i t e r Phyoclides ( 4 ) . "Gold and s i l v e r are i n j u r i o u s to mortals: gold i s the source of crime, the plague o f l i f e and r u i n of a l l things* Would be that thou were not such an a t t r a c t i v e scourge: because of these a r i s e r o b b e r i e s , homicide, brothers are maddened against brothers and c h i l d r e n against parents"· The b i o l o g i c a l mystique a t t r i b u t e d to gold i n h i s t o r y equaled and p o s s i b l y surpassed i t s monetary a t t r a c t i o n (5>)* The Egyptian Sun God Ra i n the Pyramid Age was b e l i e v e d to be the procréator o f kings* The l i q u i d of Ra, the gold o f the gods and goddesses, flowed i n t h e i r veins and gave them strength and endurance* Search f o r the golden l i v e r of l i f e was prevalent i n ancient India and P e r s i a * Thus there i s l i t t l e wonder that gold e a s i l y occupied a m a g i c a l l y honored place when i t was considered f o r therapeutic purposes* Older races respected i t s c u r a t i v e power when l a i d upon parts of the body with s u i t a b l e i n c a n t a t i o n s or worn as r i n g s or amulets* I t s golden c o l o r i d e n t i f i e d i t as a remedy f o r jaundice "the Golden Disease" among the Hindus and l a t e r the Greeks, southern Persians and Germans (60. As e a r l y as 2500 BC the Chinese employed gold f o r b i o l o g i c a l b e n e f i t (7)· Ancient Arabic physicians a l s o record i t s b e n e f i t * Gold was revered i n medieval medicine and h e l d an honored place i n pharmacopoeias of those days* P l i n e y describes manifold e f f i c a c i o u s uses of gold i n wounded persons, to ward o f f sorcerous curses; i n ashen form 1

In Platinum, Gold, and Other Metal Chemotherapeutic Agents; Lippard, S.; ACS Symposium Series; American Chemical Society: Washington, DC, 1983.


18.

SUTTON

Gold-Containing Antiarthritic Drugs

357

to cure f i s t u l a s and discharges, p u t r i d u l c e r s and sores; b o i l e d i n honey as a purgative l i n i m e n t (50· Gold i n some form has been recommended as a panacea f o r a l l diseases from the 8th Century by Abn Moussa the Wise t o as r e c e n t l y as 1500 AD by Paracelsus ( 7 ) . Homeopathic medicine i n the 18th and 19th century valued the b e n e f i t o f gold therapy ( 8 ) . Hahnemann p r a i s e d the v i r t u e o f g o l d i n homeopathy, published a pharmacodynamic study o f powdered g o l d and i n a s s o c i a t i o n w i t h ten other p h y s i c i a n s experienced and d e s c r i b e d b i z a r r e b i o l o g i c a l responses a f t e r the i n g e s t i o n o f t r i t u r a t e d gold l e a f (aurum f o l i a t i u r a ) . He a l s o reported i n 1879 treatment o f a 55 year o l d women w i t h b a c t e r i a l e n d o c a r d i t i s , n o t i n g improvement i n the heart as w e l l as the j o i n t s , freed o f rheumatism. Robert Koch reported the f i r s t experimental a n t i b a c t e r i a l a c t i v i t y o f gold s a l t s i n 1890 ( 9 ) . He described i n v i t r o a n t i t u b e r c u l a r a c t i v i t y o f gold cyanide at a d i l u t i o n o f 1 t o 2 m i l l i o n , a c o n c e n t r a t i o n much too d i l u t e t o invoke cyanide i o n as the a c t i v e agent. When he l a t e r f a i l e d t o demonstrate a n t i t u b e r c u l a r a c t i v i t y w i t h gold s a l t s i n experimental animals, Koch terminated h i s work w i t h gold compounds. However h i s observations d i d not go unnoticed. D i f f e r e n t p h y s i c i a n s administered i n o r g a n i c gold s a l t s o f t e n i n t r a v e n o u s l y i n l a r g e doses and reported b e n e f i c i a l r e s u l t s i n s k i n t u b e r c u l o s i s , s y p h i l i s (10), lupus v u l g a r i s (11) and pulmonary t u b e r c u l o s i s (12). As one might suspect i n many o f these cases the treatment was probably more t e r m i n a l than the d i s e a s e . The i n t r o d u c t i o n o f g o l d sodium t h i o s u l f a t e (Sanochrysin) by Mollgaard i n 1924 r e k i n d l e d use o f gold compounds f o r t u b e r c u l o s i s therapy (13) and sparked what P. D'Arcy Hart termed the "Gold Decade" (1925-1935) (14). The mystique o f gold therapy again caught the p u b l i c imagination* D i f f e r e n t chemical forms (15) and s m a l l e r dosages reduced f a t a l i t i e s due t o the therapy. However t o x i c i t y and i n c o n c l u s i v e t h e r a p e u t i c b e n e f i t c o n t r i b u t e d t o a d e c l i n e i n the use o f g o l d compounds f o r treatment o f t u b e r c u l o s i s . Although the r e a l value o f gold therapy f o r t u b e r c u l o s i s may never be answered, the c l i n i c a l b e n e f i t , h i s t o r i c a l l y , d i d not outweigh the p e r s i s t e n t r i s k a s s o c i a t e d w i t h i t s t o x i c i t y . Development o f Chrysotherapy f o r Rheumatoid A r t h r i t i s Lande f i r s t used aurothioglucose ( S o l g a n a l , Schering) t o t r e a t non-tuberculosis i n f e c t i o n s (16). He t r e a t e d a group of 39 p a t i e n t s w i t h b a c t e r i a l e n d o c a r d i t i s and v a r i o u s p o o r l y defined diseases i n c l u d i n g rheumatic f e v e r . H i s o b s e r v a t i o n o f the s i g n i f i c a n t l o s s o f j o i n t p a i n i n these p a t i e n t s and recommendations f o r t r i a l s t u d i e s i n chronic a r t h r i t i s l e d J . F o r e s t i e r t o i n v e s t i g a t e the use o f gold



358


compounds f o r treatment of rheumatoid a r t h r i t i s (17)· Six years l a t e r (1935) F o r e s t i e r reported evidence of the b e n e f i c i a l a c t i o n of gold s a l t s on the e v o l u t i o n of chronic rheumatoid a r t h r i t i s (18). In h i s i n i t i a l s t u d i e s he used sodium aurothiopropanolsulfonate ( A l l o c h r y s i n e ) . Later he used other preparations sodium aurothiomalate (Myochrysine), aurothioglucose (Solganal) and o t h e r s . He recommended that the preparations be administered i n t r a m u s c u l a r l y and noted that c o l l o i d a l g o l d , gold c h l o r i d e and gold cyanide were not useful. Chrysotherapy was not r e a d i l y accepted i n the United S t a t e s . As l a t e as 1934, C e c i l reported that drugs played a r e l a t i v e l y minor r o l e i n treatment of rheumatoid a r t h r i t i s and that h i s experience w i t h gold compounds had never shown s t r i k i n g r e s u l t s (19). The f i r s t report of the s u c c e s s f u l use of gold compounds i n t r e a t i n g a r t h r i t i s induced i n experimental animals was that of Sabin and Warren i n 1940 (20). Intravenous i n j e c t i o n of a pleuropneumonia-like microorganism (Type Β s t r a i n ) w i t h a p a r t i c u l a r a f f i n i t y f o r the j o i n t s of the animals (mice) produced a migratory and progressive p o l y a r t h r i t i s l e a d i n g to a n k y l o s i s i n two to four months. A v a r i e t y of g o l d ( l ) t h i o l a t e s e x h i b i t e d p r o p h y l a c t i c prevention as w e l l as t h e r a p e u t i c r e v e r s a l of the a r t h r i t i c syndrome i n the i n f e c t e d mice. I t was noted that the i n f e c t i o u s agent was c l e a r e d q u i c k l y from the v a s c u l a r system and l o c a l i z e d i n the j o i n t areas. G o l d ( l ) t h i o l a t e s d i d not i n h i b i t growth o f the pleuropneumonia-like microorganism i n v i t r o l e a d i n g the authors to hypothesize an i n v i v o a c t i v a t i o n of the r e t i c u l o e n d o t h e l i a l system as a mechanism whereby the gold s a l t s produced t h e i r e f f e c t s . G o l d ( l l l ) i n the form of sodium t e t r a c h l o r o a u r a t e was somewhat b e n e f i c i a l at a near t o x i c dose l e v e l . C o l l o i d a l g o l d was i n e f f e c t i v e . Freyberg and co-workers l a t e r reproduced t h i s a r t h r i t i c mouse model and demonstrated that the b e n e f i c i a l e f f e c t s of gold c o o r d i n a t i o n compounds r e s i d e d i n the gold c o n t a i n i n g complexes and not i n the t h i o l l i g a n d (21). Sodium aurothiomalate was 100% p r o t e c t i v e when administered i n t r a v e n o u s l y at a dose of 2 or 4 mg/mouse on a l t e r n a t e days u n t i l 9 or 10 i n j e c t i o n s had been given. Sodium thiomalate was i n e f f e c t i v e at doses as h i g h as 15.4 mg administered i n the same regimen. Sodium succinimide aurate, a compound not c o n t a i n i n g a t h i o l l i g a n d was e q u a l l y e f f e c t i v e as sodium aurothiomalate, r a i s i n g f u r t h e r question as to the r o l e of the t h i o l l i g a n d i n the t h e r a p e u t i c response. C o n f l i c t i n g r e p o r t s of the b e n e f i t of chrysotherapy i n rheumatoid a r t h r i t i s motivated S i r Stanley Davidson of the Empire Rheumatism C o u n c i l (Great B r i t a i n ) to p l a n f o r a



18.

SUTTON


m u l t i c e n t e r , double b l i n d study o f the treatment i n 1938. The Second World War took p r i o r i t y so that the study was not i n i t i a t e d u n t i l 1957. The f i r s t report o f t h i s study i n 1960 s t a t e d that "by a l l c r i t e r i a except r a d i o l o g i c a l , p a t i e n t s w i t h acute rheumatoid a r t h r i t i s t r e a t e d , over a p e r i o d o f f i v e months, w i t h a t o t a l treatment dose o f l g o f sodium aurothiomalate fared b e t t e r than those t r e a t e d w i t h a t o t a l dose o f 0.01g o f the same substance given i n a double b l i n d t r i a l over the same p e r i o d " (22). The f i n a l r e p o r t as recent as 1961 compared the r e s u l t s o f 77 p a t i e n t s t r e a t e d w i t h a f i v e months course o f twenty weekly gold i n j e c t i o n s w i t h 81 c o n t r o l s followed f o r a t o t a l o f 30 months. I n general "gold t r e a t e d p a t i e n t s fared b e t t e r than c o n t r o l s from the t h i r d t o s i x t h month and on the whole up t o month 18, one f u l l year a f t e r completion o f the 5 month course o f treatment. Thereafter gold t r e a t e d p a t i e n t s d e t e r i o r a t e d t o an appreciable extent although they r e t a i n e d some s m a l l advantage over c o n t r o l s a t 30 months". No s i g n i f i c a n t r a d i o l o g i c a l d i f f e r e n c e was found between the gold t r e a t e d and c o n t r o l groups (23). Data from t h i s study supported the e f f i c a c y o f chrysotherapy i n p a t i e n t s w i t h rheumatoid a r t h r i t i s but d i d not d e s c r i b e a dosage regimen that was c o n s i s t e n t w i t h a r e l i a b l e c l i n i c a l response. Current A p p l i c a t i o n s Although the report o f the Empire Rheumatism C o u n c i l e s t a b l i s h e d the b e n e f i t o f gold therapy, i t was o n l y subsequent t o the r i s e and f a l l o f the c o r t i c o s t e r o i d a r t h r i t i c panacea p e r i o d (24) that rheumatology reevaluated gold preparations as major t h e r a p e u t i c m o d a l i t i e s f o r RA (25). Recent s t u d i e s have presented r a d i o l o g i c a l evidence t h a t gold therapy slows and o f t e n terminates the progress o f degenerative j o i n t changes a s s o c i a t e d w i t h the disease process (26). However there i s yet no u n i v e r s a l agreement upon the p a t i e n t p o p u l a t i o n that should r e c e i v e chrysotherapy, the most appropriate time t o i n i t i a t e therapy nor the most appropriate dosage regimen. There a l s o does not appear t o be a c o r r e l a t i o n between blood gold l e v e l s and a t h e r a p e u t i c response. The degree o f a l l o w a b l e s i d e e f f e c t s e v e r i t y f o r continued therapy i s unresolved and the mechanisms o f the a n t i a r t h r i t i c a c t i v i t y o f gold compounds are r e c e i v i n g continued but not n e c e s s a r i l y c o n c l u s i v e a t t e n t i o n . However, i t i s now accepted that b e n e f i t o f gold therapy outweighs the r i s k a s s o c i a t e d w i t h i t s use and that low maintenance therapy i s appropriate i n those p a t i e n t s who have responded t o treatment (27). Since the Report o f the B r i t i s h Rheumatism C o u n c i l , there has been l i t t l e change i n the chemical forms o f gold



360


used to t r e a t RA (sodium aurothiomalate and a u r o t h i o g l u c o s e ) i n the United S t a t e s . However, there have been notable m o d i f i c a t i o n s of the dosage regimens employed w i t h the i n t e n t o f decreasing t o x i c r e a c t i o n s and i n c r e a s i n g t h e r a p e u t i c responses* The present conventional treatment procedure i n v o l v e s an i n i t i a l intramuscular i n j e c t i o n of a gold compound c o n t a i n i n g 10 mg of gold* This i n i t i a l small dose i d e n t i f i e s those p a t i e n t s that might be h y p e r s e n s i t i v e to g o l d therapy and should not continue treatment* Thereafter the dose i s increased stepwise i n the next two to three weeks to 25 mg and 50 mg (based on Au content of the compound). A f t e r a dose l e v e l of compound c o n t a i n i n g 50 mg o f g o l d has been reached, i t i s continued f o r twenty weeks u n t i l a t o t a l of l g of gold has been administered. I f a c l i n i c a l response occurs, weekly dosing i s g r a d u a l l y changed to a maintenance regimen c o n s i s t i n g o f a s i n g l e monthly i n j e c t i o n of compound c o n t a i n i n g 50 mg of gold (28) · Serum gold l e v e l s i n p a t i e n t s on t h i s t h e r a p e u t i c regimen are q u i t e v a r i a b l e reaching 4 to 8 ug/ml a f t e r the i n j e c t i o n and f a l l i n g o f f to 0.75 to 1.25 ug/ml when the gold compounds are administered on a monthly bases. Lorber (29) has claimed that a more enhanced and prolonged c l i n i c a l response can be obtained i f the gold compounds are administered at weekly doses s u f f i c i e n t to m a i n t a i n a steady s t a t e serum gold l e v e l of 3 ug/ml, however, c o r r e l a t i o n of serum gold l e v e l s w i t h c l i n i c a l response has been challenged repeatedly (28). Gold t h i o l a t e s comprise the major c l a s s o f gold compounds used today t o t r e a t RA, sodium aurothiomalate, Myochrisine (I), and a u r o t h i o g l u c o s e , Solganal (£), being the drugs of choice i n the United S t a t e s . The former i s administered as an i n j e c t a b l e aqueous s o l u t i o n and the l a t t e r as an i n j e c t a b l e suspension i n o i l .

lAu

HO 1

2


18.


New

SUTTON


Developments

The mechanisms whereby g o l d ( l ) compounds a r r e s t progression o f the disease syndrome i n RA are not w e l l understood. L e i b f a r t h and P e r s e l l i n i n a recent review h i g h l i g h t t h i s f a c t (30). They evaluated the a n t i m i c r o b i a l , antiinflammatory, antienzyme and immunosuppressive a c t i v i t i e s r e p o r t e d l y observed w i t h d i f f e r e n t i n j e c t a b l e gold products. Their conclusions favored antiinflammatory and antienzyme a c t i v i t i e s of g o l d ( l ) compounds as being the best documented mechanisms i n v o l v e d i n a r r e s t i n g the progressive c r i p p l i n g processes a s s o c i a t e d w i t h RA (Table I)· I n t e r f e r e n c e w i t h other proposed mediators o f inflammation (macrophage a c t i v a t i o n , r e l e a s e of mast c e l l r e a c t o r s , chemotactic f a c t o r s , p r o s t a g l a n d i n p a r t i c i p a t i o n ) were considered i n need o f f u r t h e r study. We reported p r e v i o u s l y on a s e r i e s of phosphine g o l d c o o r d i n a t i o n compounds that produced a n t i a r t h r i t i c a c t i v i t y i n adjuvant induced a r t h r i t i s i n r a t s when administered by the o r a l route (32). A l l other gold compounds are e f f e c t i v e o n l y when administered p a r e n t e r a l l y . One member from t h i s group, (2,3,4,6-tetra-0-acetyl-l-thio-3-D-glucopyranosato-S_) ( t r i e t h y l p h o s p h i n e ) g o l d , a u r a n o f i n (jj}, e x h i b i t e d potent a c t i v i t y o f t h i s type and i s now undergoing c l i n i c a l t r i a l . CHoOAc

S-Au-P-Et

This compound d i f f e r s from c u r r e n t l y used gold t h i o l a t e s i n that the g o l d ( l ) i n the molecule i s two coordinated through t h i o l and phosphine l i g a n d s . This novel molecular environment appears to endow a u r a n o f i n w i t h p h y s i c a l and b i o l o g i c a l p r o p e r t i e s unique to g o l d compounds i n c u r r e n t t h e r a p e u t i c use. Auranofin e x i s t s as a monomolecular species i n the s o l i d s t a t e and i n s o l u t i o n as determined by x-ray c r y s t a l l o g r a p h i c s t u d i e s and osmometric molecular weight determinations (33, 34). Mossbauer s p e c t r o s c o p i c s t u d i e s confirm both the monovalent s t a t e of gold i n the molecule as w e l l as the monomolecular nature of the compound (35). E a r l i e r Mossbauer Spectroscopic s t u d i e s have shown t h a t there i s a l i n e a r r e l a t i o n s h i p between isomer s h i f t (IS) and quadrupole s p l i t t i n g (QS) f o r two c o o r d i n a t e , monovalent gold compounds which d i f f e r s s i g n i f i c a n t l y from that of t r i v a l e n t gold (36). The p l o t i n Figure 1 l o c a t e s a u r o t h i o l a t e s , aurothioglucose and sodium aurothiomalate i n the lower r e g i o n of that l i n e a r p l o t i n an area where gold i s coordinated to two s u l f u r atoms, i . e . b i s - ( e t h y l e n e t h i o -



human

human s y n o v i a l

human

Elastase

Cathepsin

Collagenase

Reproduced with permission from Ref. 30.

* L e w i s et a l . r e c e n t l y r e p o r t e d t h a t sodium a u r o t h i o m a l a t e d a s e and 3 - g l u c o s a m i n i d a s e d e r i v e d f r o m mouse m a c r o p h a g e s

leukocyte

fluid

leukocytes

human s y n o v i a l f l u i d plasma l e u k o c y t e s

failed

to

3

-4

3-glucuroni-

1x10

4x10

4

Cone.

5xl0" -10"

1x10

-3 5x10 -5 5x10

Inh. -3 5x10 -4 2x10

Molar

inhibit

Aurothiosulfate

Aurothiomalate

Aurothiomalate

Aurothiomalate

Aurothiomalate

( 1 χ 1 0 ~ M) (31).

Sodium

Sodium

Sodium

B-Glucuronidase*

$-Glucosaminidase

Sodium

guinea p i g p e r i t o n e a l human s y n o v i a l . f l u i d

macrophage

Sodium

macrophage

Compound

Acid Phosphatase

Enzyme S o u r c e

(30)

Activity

guinea pig peritoneal human s y n o v i a l f l u i d

Enzyme

Enzyme

I

b y G o l d Compounds, i n v i t r o

I n h i b i t i o n of

Table


Η

o w

>

w

w

ι

m

s

w

H >


F/gwre i .

1

3

4

* neii/ sec

P/oi sfowmg relationship between isomer shifts (IS) and quadrupole splitting (QS) for go/d compounds.

2


S



364

u r o n i u m ) g o l d ( l ) c h l o r i d e , e t c . The c l o s e f i t to the two-coordinate l i n e i n d i c a t e s t h a t i n the s o l i d s t a t e these compounds are two-coordinate through two s u l f u r l i g a n d s * In c o n t r a s t a u r a n o f i n i s l o c a t e d i n upper r e g i o n of the p l o t , a l o c a t i o n occupied by monomeric molecular species* These data as w e l l as nmr, EXAFS and g e l f i l t r a t i o n s t u d i e s i n d i c a t e t h a t g o l d t h i o l a t e s , sodium aurothiomalate and a u r o t h i o g l u c o s e , e x i s t i n polymeric s t a t e s (37, 38, 39)* S u i t a b l e c r y s t a l l i n e forms have not been prepared t o i n v e s t i g a t e these molecules by x-ray c r y s t a l l o g r a p h y * In f a c t the s t r u c t u r e of g o l d t h i o l a t e s i s b e t t e r represented by 4 r a t h e r than those s t r u c t u r e s d e s c r i b e d e a r l i e r * Auranofin i s a l i p o p h i l i c , n o n i o n i c compound whereas g o l d t h i o l a t e s i n general are h y d r o p h i l i c (40, 41)* The characteristic physical

2

2 +

R= (SCHCO2CH2CO2) ~" Na , sodium aurothiomalate R SC6H12O5, a u r o t h i o g l u c o s e s

p r o p e r t i e s o f a u r a n o f i n ( l i p o p h i l i c i t y , monomolecular, n o n - i o n i c ) are d i f f e r e n t from those o f g o l d t h i o l a t e s i n c l i n i c a l use and may c o n t r i b u t e t o i t s novel b i o l o g i c a l properties* No exact experimental model of rheumatoid a r t h r i t i s has been developed* However i n numerous b i o l o g i c a l assays designed t o i n t e r p r e t drug e f f e c t on models of or events a s s o c i a t e d w i t h RA, a u r a n o f i n produced d i s t i n c t l y d i f f e r e n t responses than g o l d t h i o l a t e s * Auranofin i n h i b i t e d the development of e x p e r i m e n t a l l y induced adjuvant a r t h r i t i s i n r a t s when administered o r a l l y * Sodium aurothiomalate i n h i b i t e d only when administered i n t r a m u s c u l a r l y (31, 42)* Serum g o l d l e v e l s i n animals t r e a t e d e f f e c t i v e l y w i t h a u r a n o f i n were approximately one t h i r d of those t r e a t e d w i t h sodium aurothiomalate* Kidney r e t e n t i o n of gold i n the sodium aurothiomalate animals was ten o r more times t h a t o f a u r a n o f i n t r e a t e d animals* Thus a u r a n o f i n produced a n t i a r t h r i t i c a c t i v i t y i n t h i s a r t h r i t i c animal model a f t e r o r a l a d m i n i s t r a t i o n a t lower serum concentrations than those r e q u i r e d by sodium aurothiomalate w i t h much l e s s kidney g o l d retention*



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Gold i n the blood f o l l o w i n g the a d m i n i s t r a t i o n of sodium aurothiomalate i s a s s o c i a t e d p r i m a r i l y w i t h p r o t e i n s i n the serum. In c o n t r a s t gold from o r a l a d m i n i s t r a t i o n o f a u r a n o f i n i s e q u a l l y d i s t r i b u t e d between the c e l l u l a r components and serum p r o t e i n s o f the blood during the 24-48 h r . p e r i o d a f t e r a d m i n i s t r a t i o n . A f t e r seventy hours a u r a n o f i n gold i s a l s o l o c a l i z e d i n the serum p r o t e i n s (43). The b i o l o g i c a l s i g n i f i c a n c e o f the property has not been i n t e r p r e t e d . Tissue damage present i n RA i s a t t r i b u t e d i n part t o a c t i o n of l y t i c lysosomal enzymes released by phagocytic c e l l s i n inflammed t i s s u e . Auranofin i n h i b i t s the r e l e a s e o f lysosomal enzymes from phagocytizing leukocytes a t micromolar concentrations (1-10 uM) (44, 45). I t d i d not produce leukocyte c y t o t o x i c i t y nor i n h i b i t i o n o f c e l l f r e e lysosomal enzyme a c t i v i t y at these e f f e c t i v e c o n c e n t r a t i o n s . Sodium aurothiomalate, aurothioglucose and sodium a u r o t h i o s u l f a t e d i d not e x h i b i t t h i s potent a c t i v i t y . The e t i o l o g y and pathogenesis o f RA are unknown, however both humoral and c e l l mediated immune responsiveness are thought to p l a y a r o l e i n the pathogenesis o f chronic inflammation (46, 47). Auranofin has been shown to suppress humoral immunity (antibody production) i n assay systems i n which sodium aurothiomalate was e i t h e r i n e f f e c t i v e o r s t i m u l a t e d antibody production (48). In other s t u d i e s both a u r a n o f i n and sodium aurothiomalate were shown to be capable of s t i m u l a t i n g l o w - l e v e l delayed h y p e r s e n s i t i v i t y i n mice but o n l y a u r a n o f i n was capable o f r e s t o r i n g iramunosuppressed (methotrexate) c e l l mediated immunity (49). These c o n t r a s t i n g immunopharmacological p r o p e r t i e s o f a u r a n o f i n , suppression o f humoral immunity and enhancement of c e l l mediated immunity, appear i d e a l l y s u i t e d to c o r r e c t immunological abnormalites observed i n RA (hyperactive humoral immunity, suppressed c e l l mediated immunity). U n l i k e the t r a n s i t i o n elements, copper and i r o n , which are normal body c o n s t i u e n t s , gold does not have a w e l l defined t r a n s p o r t , storage or enzyme f u n c t i o n w i t h i n the body. Gold t h i o l a t e compounds used c l i n i c a l l y to t r e a t RA have l i m i t i n g s i d e e f f e c t l i a b i l i t y , i . e . m i l d d e r m a t i t i s , p r o t e i n u r e a , nephrosis, e x f o l i a t i v e d e r m a t i t i s , leukopenia, thrombocytopenia. Auranofin, f i r s t studied c l i n i c a l l y by F i n k e l s t e i n (50) and B e r g l o f (51), i s now undergoing extensive c l i n i c a l e v a l u a t i o n . The r e s u l t s o f i t s use i n treatment o f 1200 RA p a t i e n t s f o r periods up to 3 years have been reported t o the Food and Drug A d m i n i s t r a t i o n . Both symptomatic and s e r o l o g i c a l improvement was seen i n p a t i e n t s a f t e r s i x months treatment. A dose o f 6mg/day o f drug was observed to be safe and e f f e c t i v e . Side e f f e c t s r e q u i r i n g


366



discontinuance of therapy have been minimal, about 10%· The most prevalent of these were m i l d d i a r r h e a and s k i n rash* The m a j o r i t y of p a t i e n t s showing these symptoms continued treatment without f u r t h e r c o m p l i c a t i o n s * Data c o l l e c t e d t o date i n d i c a t e that a u r a n o f i n i s a safe and e f f e c t i v e form o f chrysotherapy f o r treatment of RA. I t has s e v e r a l p o t e n t i a l advantages: o r a l dose form, no p a i n from i n j e c t i o n , no n i t r i t o i d r e a c t i o n , p o t e n t i a l low t i s s u e accumulation o f gold (52). Future A p p l i c a t i o n s As a r e s u l t of a u r a n o f i n , chrysotherapy promises to f i n d a new p o s i t i o n i n the treatment of RA* Continued research i n t o i t s mechanism of a c t i o n i s necessary* Development o f more e f f e c t i v e gold agents should be the o b j e c t of continued a t t e n t i o n which w i l l r e q u i r e extensive comparative l a b o r a t o r y and c l i n i c a l study w i t h heavy research investment* Metal c o n t a i n i n g compounds are a t t r a c t i n g i n c r e a s i n g a t t e n t i o n as a n t i n e o p l a s t i c agents* Cisplatin i s e s t a b l i s h e d as u s e f u l therapy f o r treatment of t e s t i c u l a r and o v a r i a n tumors, although a s s o c i a t e d severe s i d e e f f e c t s l i m i t the doses that may be given to p a t i e n t s * Work i s underway to develop l e s s t o x i c , e q u a l l y e f f i c a c i o u s agents (53)* Palladium ( I I ) complexes r e c e n t l y have been reported to e x h i b i t a n t i n e o p l a s t i c p o t e n t i a l i n i n v i t r o s t u d i e s , i n v i v o a c t i v i t y has not been reported (54, 55)* Simon et a l observed i n v i t r o i n h i b i t i o n of DNA synthesis and a n t i p r o l i f e r a t i v e a c t i v i t y w i t h a u r a n o f i n (56, 57)· In l i g h t of the low l e v e l of s e r i o u s s i d e e f f e c t s observed i n c l i n i c a l s t u d i e s , these authors speculated on i t s a n t i n e o p l a s t i c p o t e n t i a l * Other workers have observed i n h i b i t i o n of lymphocyte DNA synthesis w i t h a u r a n o f i n , however t h e i r data i n d i c a t e that the i n h i b i t i o n was a r e s u l t of i n t e r f e r e n c e w i t h membrane transport a c t i v i t y r a t h e r than d i r e c t a c t i o n on DNA synthesis (58)* Simon et a l a l s o reported antitumor a c t i v i t y w i t h a u r a n o f i n u s i n g mouse lymphocytic leukemia P388 (59)* Studies c a r r i e d out at the Southern Research I n s t i t u t e i n d i c a t e d t h a t a u r a n o f i n at maximum non-toxic doses e x h i b i t e d minimal a c t i v i t y i n the P388 system and that continued treatment f a i l e d to reduce the tumor burden or prolong animal s u r v i v a l time* In c o n t r a s t c i s p l a t i n both reduced tumor burden and prolonged animal s u r v i v a l (60). Although a u r a n o f i n , i t s e l f , does not appear to have potent a n t i n e o p l a s t i c a c t i v i t y , r e s u l t s obtained are encouraging. I n v e s t i g a t i o n of the a n t i n e o p l a s t i c a c t i v i t y of other g o l d ( l ) as w e l l as g o l d ( l l l ) compounds appears j u s t i f i e d . G o I d ( i l l ) compounds may be more a t t r a c t i v e i n l i g h t of the s i m i l a r s t r u c t u r a l c h a r a c t e r i s t i c s o f


18.

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367

gold(lll), platinum(ll) and palladiumillj coordination compounds.

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53. Cleare, M.J. Platinum Metals Rev. 1982, 26, 33. 54. Newkome, G.R.; Kawato, T.; Kohli, D.K.; Puckett, W.E.; Oliver, B.D.; Chiari, G.; Fronczek, F.R.; Deutsch, W.A. J. Am. Chem. Soc. 1981, 103, 3423. 55. Graff, G.M. Chem. Week 1982, 130, 35. 56. Simon, T.M.; Kunishima, D.H.; Vibert, G.J.; Lorber Α., J. Rheumatol. 1979, 6 (S5), 91. 57. Simon, T.M.; Kunishima, D.H.; Vibert, G.J.; Lorber, A. Cancer 1979, 44, 1975. 58. Finkelstein, A . E . ; Burrone, O.R.; Walz, D.T.; Misher, A. J. Rheumatol. 1977, 4, 245. 59. Simon, T.M.; Kunishima, D.H.; Vibert, G.J.; Lorber, A. Cancer Res. 1981, 41, 94. 60. Shabel, F . ; Laster, R.; Corbett, T. personal communication. RECEIVED October 4, 1982


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