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Studies of the Effect of Metal Containing Drugs on Acute and Chronic Inflammation

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Studies of the Effect of Metal Containing Drugs on Acute and Chronic Inflammation +tL- STUDIES OF THE EFFECT OF METAL GONTAINING DRUGS ON ACUTE AND CHRONIG INFLAMMATION lan Ross Garrett BSc.,Grad.Dip.Med.Tech. A thesis submitted for the Degree of Doctor of PhilosoPhY in the University of Adelaide Department of PathologY The University of Adelaide January 1986 l_ TABLI OF CONTENTS CI-IAPTER 1 REVIEìIÚ OF CURffiI\T LITERAruRT INTrcN,CTIO{ TO I'ETAL IO\ THTRAPIIS A. fSSlruf lnl LfUfrufS. ¡ rr ¡ r. ¡ r. ¡ r ¡ r ¡. ¡. ¡ ¡ ¡ ¡ ¡ ¡ t. ¡..r. ¡ ¡ 1 7. Macroninera7s...... ..... ..... 2 2. MicronineraTs (trace eTenents) 2 3. Toxic elenents...... .......... ........ 4 B. BIO-NffnlS. .. ¡ ¡ . r ¡ r r . r r ¡ r ¡ r r r r . r r r r . ¡ r r r r r . , . 5 7. CTassification .... .... .. ... o. 5 3. Biological factors affecting netaT ion interactions. ............... B C. THr IruvolvrurNT oF Mrrrus IN INFLAT'44ATION. r ¡ r ¡' r ¡ r. 9 1. InfTannatory disease... ......... 10 2 Macrophages, Tynphocytes and inf7annation...... 12 c Macrophages and netaTs. ..... -........ 15 tl- 'l D. BIO-Vffnl TUennplfsr ¡.. r ¡.. r r r r r.. r... ¡. ¡ r. ¡..,... 6 7. Bio-neta1 pharnaco7ogy......................... 16 2. MetaTs in nedicirte . ¡....... .... 17 II . REVITÌd OF GOLD CO',PLIXES A. IrurnOouCrloN..rrrr..rr.¡¡r¡r.r¡¡...rr.I...t''''''' 20 B CHfMtSfnyr. r. r ¡ r. r. ¡.. r. ¡. r !.. rr rr ¡ r r r r. r ¡ ¡ ¡..,... 20 C. Golo(l ) Couplrxrs 21 D. Golo( III ) OovpLEXES 24 f. PHnn¡¡ncoruNETIcs AND DlsrnleurloNl 25 F. Rot-Es oF GOLD oR LIGAND AS THE PHARMACO-ACTIVE SPECIES. ' 28 G. ItbOfS OF ACTION¡.¡..r¡.r..r¡..!¡.¡rrrr.r.¡r.. ....' 29 7. ProteirQS. r. ..... o...... ....... o ...... 29 2. Co17agen.................. """ 37 3. Ce77u7ar functioÍ7.c...r................- .. 32 4. AninaT nodeTs'."' ""' "" 34 5. Interactions with other netaT ions...... .. 36 H. Toxrctrv 36 I. Ct-trurcnl PRncrlcr AND PRosPECTS FOR THE FuruRE'... 38 all III - COPPTR AND INFLAIV}4ATIO\ A. Hlsronrcnl 40 B. Bnrrr ovERVIEw oF INFLAtvlvlATIoN.¡r..r.'rrrr...r¡.r. 4l C. DternnV COPPER STATUS AND EXPERIMENTAL INFLAt"l'lATfOril44 7. ModeLs of acute infTannation-...... ...... 45 2. ModeTs of chronic infTamnation ..."' 46 D CHnruers IN coppER METABoLISM.....r ¡r,r r.r ¡,,...'.. 48 1. r/¡ith acute infTanmation.. ...... 48 2. With chronic infLanmation.. 48 [. Nrt-rNFLApn4AToRY PRoPERTIES oF coPPER PRorEINS... 50 1. CeruToplasnin .......... 50 2. Superoxide disnutase. ..... 53 F. hru-TNFLAI'I'IAToRy PRoPERTIES oF coPPER cot'4PLEXES. 55 1. Copper(II) peptides. ...... 55 2. Copper(I) conpTexes. ... .. ...... 56 3. Copper(I/U)-D-peniciTTanine. 58 4. Other copper(II) conplexes... ..... 60 IV C}IAPTER 2 GOLD THEIìAPY ATID ADJJVANII ARTHRITIS A. Suwnnv 65 B. lt4nffnlrus nfrlO METHODS ..¡r.¡..r¡.¡.¡.¡r.rr...,..,. 67 1. AninaTs. .. 67 2. Adjuvants.. ..... .... o 67 3. Disease outLine ...... .... ...... 68 4. Drug treatments......... ....... 68 (a) GoTd sodiun thionaTate (l'lay and Baker).... 69 (b) Gold sodiun thionaTate (ATdrich)... .. 69 (c) GoTd sodiun thioglucosê.. o . .... ..... - 69 (d) Gold sodiun thiosuTphate.. .... ...... 70 (e) Auranofin. ..... 70 (f) Thiona7ate...... ...... 70 (g) PhenyTnercuric nitrate 70 5. Piasna gold Teve-2s... 71 6. Copper 7eve7s... .. 7 I C. Rrsulrs AND DIScusstoN 72 72 75 76 v Exprnrugrur 4 Ains and out7ine..................... ....... 88 Results...................o.' " .. "" .. .. """" 91 Discussiol?. ¡ o.................. o ' ' ' " ' ' ' ' " " " " 92 ExpgnrNErur 5 Ains and out7ine........... o.... .... '. " " " 94 Resufts...................." " " " .. " " o "" "' 98 99 Discussioll .. o ¡.................. ' " " " " " ' ' " " Exprnrurrur 6 Ains and out7ine...................."""""" 101 Resu7ts... ............." ' " " " " ' 104 Discussion. o. .. .' .' "''''''''''' 106 109 112 114 vl_ Coruclusrorus 125 CIIAPTER 3 GOLD THENAPY AIID I4ACRIPIIAGT FI}ICTIO{ A, Suwnnv 137 B. lt4RrrntRls AND METHoES 1n 140 140 140 141 142 143 143 145 145 vl_r [xprnrNrrur 10 Ains and out7ine...... ..... 146 Resu-l ts... .......... 148 Discussion.... ..... ..... 149 152 154 154 156 158 158 CoruClus I oNS . ' r r r . r . ¡ . r ¡ . ¡ r ¡ ¡ r . ¡ ¡ . r . r r ¡ r r r ! r . r r 1 60 CI-IAPTER 4 IruvrsrtonrtoN oF THE BIoLoGIcAL AcrlvlrY 0F ooPPER COT'4PLEXES PARTICULARLY COPPER.PENICILLAMINE IN ANIMALS A. Suwnnv 163 B. lt4Rrrnrnls AND METHoDS 165 7. The preparation of copper conpTexes . 165 2. The irritancy of copper conplexes 165 3. Effect on Tiver netaboTisn by copper conplexes 766 VIII 4. Anti-infTamnatory assays..... ....-....... 166 (a) Carrageenan Paw Oedenâc. o. ........... 166 (b) fBC inpregnated sponge .......... 166 (c) Adjuvant induced arthritis....... 167 5, Copper distribution study............... 168 (a) Radiochenica7............................. 168 (b) BioTogicaT .......... ............ 168 (c) Ana7ytica7..... .......... ....... 169 C. Rrsulrs AND DIScusstoN 170 178 180 181 ax Expenrverur 16 Ains and out7ine..... ... o.. o............ " " " ' e 183 Resufts....... ¡ ....... " " " " 185 185 Discussiofl . o o o....... ... o.. i o....... " ". " " t t ' Expenruerur 17 Ains and out7ine................o..............' 187 Resufts......... o............ o.... " ' " ' " " ' " ' 189 Discussiofl ....... o... ........ .......... " " " .. ' 189 Expgnrurrr¡r 1B Ains and out7ine...................... 191 ResufÈs.. ........ .... ........ ... o " .. " " " " " ' 193 Discussiorl. .'''''''' I'''' 195 Corucluslol'ls 198 211 x TABLTS TneLe 1 3 TnsLr 2 7 Tnale 3 22 TnsLe 4 30 Tnalr 5 33 TnsLr 6 35 TneLr 7 43 TneLr B 64 TnaLr 9 73 TneLr 10 t9 TnsLr 11 83 Tnalr 12 B4 TneLr 13 B9 TneLr 14 90 TnsLr 15 95 TnsLe 16 96 TneLr 17 97 TnsLE 18 102 Tnelr 19 103 TneLr 20 119 TneLr 21 120 TnsLr 22 130 TneLr 23 171 TneLr 24 175 :(I r r ¡ . ¡ . I r I I I ¡ TnsLr 25 a . t. ¡ l ¡ r ¡ ¡ r r ¡ r . I . I I I ' ' ' ' ' 179 Tnelr 26 179 . I I t I . I . I ¡ ¡ I t ¡ ¡ ¡ ¡ Tnaur 27 . t . ¡ r t ¡ t r l r a . ¡ a I t . I a ' ' ' 184 I I ¡ r t I ¡ I I Tnale 28. ¡ ¡ . r . ¡ r . t a ¡ ¡ . I I . I I ¡ . I I I ¡ I ' 188 ?0 Tnalr L) a a.r a a a ¡ ¡r a r r ¡ ta ¡ l a l a¡ I I I r a ¡ t I ¡ r ¡' I ¡ ¡.' I I 192 TneLr 30 193 Tnalr 31 200 FIqJRES Frounr 1 14 Frounr 2 52 Frounr 3 57 a a t ! r . a I a I I I I r ¡ ¡ I r ¡ ¡ ¡ I t I Frounr 4. a a a ¡ r r ¡ a t r r r r a ¡ r ' 60 Freunr 5 74 ¡ l r I ¡ ¡ I t r l a l I r r l a ¡ ¡ l a r l t t I l ! 110 Fr ounr 0a a t a r a a ! r t ' ' ' Froune 7 111 Frounr I 144 0 ¡ r r ¡ I ¡ I ¡ I Froune )l l l a a ¡ a ¡ r a a a ¡ I ¡ ¡ a t a l a l i a a ¡ r I I ¡ ¡ ' 1M r r I r .. r ¡ . ¡ r I t l .. ¡ 147 Frounr 10. t t r r ¡ r. ¡ r a ¡ ¡ l. t I a. " ' ' Freunr 11 147 . ! . t . ¡ I t r r I ¡ I t ¡ 153 Fr ounr 12... r ¡ r | ¡ . r | . t t I . ¡ ¡ t ¡ ' ' Frounr 13 157 Frounr 14 157 xl_J. $T4{ARY Metal ions are involved in the functional acLivity of enzymes and ce1ls of the inflammatory response. The effecL of these in controlling or regulaLing inflammation has been the subject of considerable interest. This is particularly so for metal ion therapies such as Au(I) complexes which have been used to LreaL chronic unresolving inflammatory disorders such as rheumatoid arLhritis. One of the most perplexing problems of chrysotherapy is exactly how gold elicits its therapeutic activity and induces an apparent remíssion of the inflammatory disease process. The use of the adjuvant i_nduced polyarthritis in rats has 1ed to some interesting although ambivalent findings of the effects of go1d. These findings may reflect, however the variable use and the limitations of this animal model of inflammation. The second chapter describes investigations concerned with the in vivo biological effects of gold compounds on the adjuvant induced polyarthritis model of inflammation in various rat sLrains. The aims of this work were to (i) to investigate the antiarthritic activity of GST in adjuvant arthrítis in rals and to establish the effect of varying the rouLes of administration and differing the tine of administration, (ii) to investigate the comparative antiarthritic efficacy of a number of gold cornplexes, (iii) Lo deLermine the antiarthritic activity of GST and AF in adjuvant polyarthritis using differing rat strains using differing adjuvants ' to standardise the assay and to clarify why previous work has such ambivalent findíngs xl_ l_ l_ using gold salts, (iv) to investigaLe the effect of GST therapy on endogenous copper distribution. Previous experimental studies have indicated a number of biological effects of monovalent gold complexes on macrophages, although Lheir mechanism of action in suppressing or remitting arthritis is not c1ear. The third chapter describes the effect of gold salts on tlio aspects of macrophage functions that have not been widely studied, Fc receptor binding activity (FcBA) and the production of'Or- radicals by a PMA stimulus. The effects of chrysotherapy on the presentation of Fc receptors on the cell surface of adherent macrophages and '02 radical producLion by macrophages from both adjuvantised and non-adjuvantised rats treated with and without gold sodium LhiomalaLe has been studied. Moreover the effect of GST on monocytes ín vitro has been sLudied, and the possibility Lhat gold may mediate some of its antiarthritic activíties Lhrough its effects on Fc receptor expressi-on has been considered. Some copper complexes have been shown to possess anti-inflammatory properties. However' many that have been categorised as anti-inflammatory also demonstrate irritant properLies. The fourth chapLer is concerned with the investigation of the biological activity of copper complexes with particular reference to the complex of copper and D-penicillamine [Cu(I)U Cu(II)U (D-penicillamine)121 Cf5- which has been shown to have substantial superoxide dismutating activity as well as antiulcerogenic activity. The aims of this study were (i) Lo determine the relative irritancy of a number of copper complexes; (ii) to study the effect of administration of these complexes on the liver meLabolism of xLv pentobarbitone measured by induced sleep times; (iii) to investigate the comparative anti-inflammatory activity of these complexes against a number of standard animal models of inflammation including carrageenan pa\¡/ oedema, TBC impregnated sponge irnplanLs and adjuvant induced arthritis in rats; and (iv) to study the relative biodistribution of the mixed valency copper-penicillamine complex.
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