Sorafenib alone versus a combination of sorafenib and ninjin'yoeito for the treatment of patients with advanced hepatocellular carcinoma: a retrospective study and pharmacological study in rats

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(1)J .Tr a d.Me d.30,221－228,2013. Me di c a la nd 221 Pha r ma c e u t i c a lSoc i e t y f orWAKANYAKU. Sor af e ni bal onev e r s usac ombi nat i onofs or af e ni b andni nj i n・ yoe i t of ort het r e at me ntofpat i e nt swi t h advanc e dhe pat oc e l l ul arc ar c i noma:ar e t r os pe c t i ve s t udyandphar mac ol ogi c als t udyi nr at s a ) a ) a ) a ) b) Ma s a kiKa i bor i , Mor i hi koI s hi z a ki , Kos ukeMa t s ui , Ma s a nor iKwon, Re iI ma i , c ) Sh i mpe iWa t a na b e , Hi s a yos hiNor i mo t o*c). a) De par t me ntofSur ge r y ,Kans aiMe di c alUni v e r s i t y ;b) De par t me ntofPhar mac y ,Kans aiMe di c alUni v e r s i t yHi r ak at aHos pi t al ,. Shi nmac hi231,Hi r ak at aCi t y ,Os ak a,5731191,J apan.c) KampoRe s e ar c hLabor at or i e s ,Kr ac i ePhar ma,Lt d. ,Kane bomac hi31, .Ac c e pt e dDe c e mbe r10,2013. ) Tak aok aCi t y ,Toy ama9330856J apan.( Re c e i v e dMay15,2013. Abs t r ac t Ar e t r os pe c t i ves t udywa spe r f or me dt oc omp a r et hee f f e c t sofs or a f e ni ba l one( a sac ont r ol )a ndac ombi na t i onof ni nj i n' yoe i t oa nds or a f e ni bont hepr e s e nc eofa na bnor ma la s pa r t a t ea mi not r a ns f e r a s e( AST)l e ve l ,a na bnor ma l a l a ni n et r a ns a mi na s e( ALT)l e ve l ,ora na bnor ma lpl a t e l e tc ount( PLT)i npa t i e nt swi t ha dva nc e dhe pa t oc e l l ul a rc a r c i noma .Thenumbe r so fpa t i e nt swi t ha bnor ma ll e ve l sofAST,ALT,orPLTwe r e7,5,a nd9i nt hec ombi na t i on gr oupa n d8,6,a nd10i nt hec ont r olgr oup,r e s pe c t i ve l y.Thec ombi na t i onofni nj i n' yoe i t oa nds or a f e ni bt e nde dt o r e s ul ti na ni mp r ove dASTl e ve l( P<0 . 1)a ndas i gni f i c a ntde c r e a s ei nt heALTl e ve l( P=0. 048)a f t e r4we e ksof t r e a t me nt ,c omp a r e dwi t ht her e s ul t si nt hec ont r olgr oup.Bot ht heASTa ndALTl e ve l si mpr ove ds i gni f i c a n t l y,c ompa r e dwi t ht hepr e t r e a t me ntva l ue s ,i nt hec ombi na t i ongr oup.Fur t he r mor e ,t hec ha ngei nt hePLTa f t e r12we e ksof t r e a t me ntwa ss i gni f i c a nt( P=0. 0 46) ,t hought h ei mpr ove me nt sbe t we e nt hepr e t r e a t me nta ndp os t t r e a t me ntva l ue s we r enots i gni f i c a nt .Thr oughoutt het r e a t me nt ,t hedos a geofs or a f e ni bwa sma i nt a i ne da ndt het r e a t me ntwa sc ont i nue di nbot ht h ec ont r ola ndc ombi na t i ongr oups ,a ndt hel e ve l soft umorma r ke r swe r ea l s omoni t or e d.Fur t he r mor e , t ove r i f yt he s ef i ndi ngs ,e xpe r i me nt a lr a t st r e a t e dwi t hs or a f e ni ba nd/ orac ombi na t i onofs or a f e ni ba ndni nj i n・ yoe i t o we r eus e dt oe x a mi net hee f f e c toft hec omb i ne dt r e a t me ntonl i ve rf unc t i on.Asar e s ul t ,t her e pe a t e da dmi n i s t r a t i on ofs or a f e ni bl e dt oa ni nc r e a s ei nt heAST,t ot a lbi l i r ubi n( TBI L) ,a nddi r e c tbi l i r ubi n( DBI L)l e ve l s ,a ndt he ywe r e s i g ni f i c a nt l yi mpr ove dbyt hec ombi n e dt r e a t me ntwi t hni nj i n・ yoe i t o.The s er e s ul t ss ugge s tt ha tni nj i n・ yoe i t omi ght beus e f ulf orr e du c i ngt hea dve r s ee f f e c t sofs or a f e ni bt r e a t me nt ,s uc ha sl i ve ri nj ur ya n dPLTr e duc t i ons ,pos s i bl y c ont r i but i ngt ot hes ur vi va lbe ne f i tofs or a f e ni bbyma i nt a i ni ngi t sc ont i nuousa dmi ni s t r a t i on. ug,a dve r s e e f f e c t Ke ywor dsSor a f e ni b,ni nj i n・ yoe i t o,t r a di t i ona lJ a pa ne s eme di c i ne( Ka mpo) ,mol e c ul a rt a r ge tdr r e duc t i on.. I nt r oduc t i on Sor a f e ni bi st hef i r s tor a l l ya c t i vemol e c ul a rt a r ge t dr ug a ga i ns ta dva nc e d he pa t oc e l l ul a rc a r c i noma . *Towhom c or r e s ponde nc es houl db ea ddr e s s e d. e ma i l:h_nor i mot o@phm. kr a c i e . c o. j p. nt l ya s s oc i a t e dwi t ha dHowe ve r ,s or a f e ni bi sf r e que ve r s ee f f e c t s ,s uc ha sl i ve rdys f unc t i on,t hr omboc yt ope ni a , 1) a nda ne mi a ,whe nus e dc l i ni c a l l y, a nddos ei nt e r r upt i onorunde r dos a gec a nl e a dt ot he r a pe ut i cf a i l ur e .On t heot he rha nd,ni nj i n・ yoe i t o,at r a di t i ona lChi ne s e ne s eme di c i ne( r e f e r r e dt oa sKa mpome di c i ne ) ,ha s J a pa be e nus e dt ot r e a tphys i c a le xha us t i on,f a t i gue ,a nor e xi a ,.

(2) 222. Th ec ombi na t i one f f e c t sofs or a f e ni ba ndn i nj i n・ yoe i t oona dva nc e dhe pa t oc e l l ul a rc a r c i noma. a nda ne mi a .Thi sf or mu l ai sa l s oknownt oi mpr ove l i ve rf unc t i on,pl a t e l e tc ount s ,bodi l yf unc t i o nsa nd a ppe t i t ei np a t i e nt swi t hhe pa t i t i sa nd/ orhe p a t i cc i r r ho24) s i s . Pr e vi ous l y,we r e por t e dt ha tni nj i n・ yoe i t oi mpr o ve dt hel i ve rf unc t i ono fpa t i e nt swhoha dbe e n i ve rf unc t i on t r e a t e dwi t hs or a f e ni bwh e nbi oma r ke r sofl we r ec ompa r e db e f or ea nda f t e rt hea dmi ni s t r a t i ono f ni nj i n・ yoe i t o.Na me l y,t hea ddi t i onofn i nj i n・ yoe i t ot o a f e ni bt r e a t me ntr e s ul t e di ns i gni f i c a ntr e ongoi ngs or duc t i onsi nt hea s pa r t a t ea mi not r a ns f e r a s e( AST)l e ve l a twe e k4a ndt h ea l a ni net r a ns a mi na s e( ALT)l e ve la t we e ks4a nd8,c ompa r e dwi t ht hepr e ni nj i n・ y oe i t ot r e a t me ntva l ue s ;f u r t he r mo r e ,t hepl a t e l e tc ount( PLT) l i z e da f t e r12we e ksoft r e a t me ntwi t hni nj i wa snor ma n・ yoe i t oi npa t i e nt sr e c e i v i ngo ngoi ngs or a f e ni bt r e a t 5) me nt . Howe ve r ,t he s er e s ul t swe r enots uf f i c i e ntt ode t e r mi newhe t he rni nj i n・ yoe i t oc a nc l e a r l yr e duc et he a dve r s ee f f e c t sofs or a f e ni bt r e a t me nt ,s uc ha sl i ve ri nj ur ya ndt hr omb oc yt ope ni a . The r e f or e ,i nt hepr e s e nts t udy,wec onduc t e dar e t yr e vi e wi ngc a s e swi t he i t he rl i ve r r os pe c t i ves t udyb dys f unc t i on( ASTa nd/ orALTa sa ni nde x)ort hr ombof e ni b c yt ope ni aa ndc omp a r e dpa t i e nt st r e a t e dwi t hs or a a l one( c ont r olgr oup)a ndt hos et r e a t e dwi t hac o mbi na t i ono fs or a f e ni ba ndni nj i n・ yoe i t o.Mor e ove r ,t ove r i f y lf i ndi ngs ,t hepha r ma c ol ogi c a le f f e c t so f t hec l i ni c a ni n j i n・ yoe i t oons or a f e ni bi nduc e dl i ve ri nj ur ywe r ea l s o e xa mi ne di nr a t s .. que nt l yt r e a t e dwi t hac ombi na t i ono fni nj i n・ yoe i t o( 7. 5 g/ da y;Kr a c i ePha r ma ,Lt d. )a nds or a f e ni bors or a f e ni b wi t houtni nj i n・ yoe i t oa sac ont r olf ore i t he r4or12 r ea s s e s s e d we e ks ;t heAST/ ALTl e ve l sa ndt hePLTwe i na l lt hec a s e s .Ca s e si nwhi c ht hes or a f e ni bt r e a t me nt wa si nt e r r upt e dordi s c ont i nue dwe r enoti nc l ude di nt he ne r a lc ons e ntf ort he i rc l i ni c a li nf or ma t i ont o s t udy.Age beus e di nt hi sme di c a lr e s e a r c ha ndwa sc onduc t e di n a c c or da nc ewi t ht hepr i nc i pl e soft heDe c l a r a t i onof He l s i nki .Thes t udywa sa ppr ove dbyt heLoc a lEt hi c s Commi t t e e ofKa ns a iMe di c a lUni ve r s i t y,Hi r a ka t a Hos pi t a l . me t e r swe r et a bul a t e df ort umorma r ke r s Thepa r a ( AFPa ndPI VKAI I )a ndt hes e r umASTa ndALTl e ve l sa ndPLTdur i ngs or a f e ni bt r e a t me ntwi t ho rwi t hout i n・ yoe i t o.TheAST,ALT,a ndPLT va l ue swe r e ni nj a na l yz e dl oga r i t hmi c a l l y. St a t i s t i c a la na l ys e swe r epe r f or me df ori nt r a -a nd i nt e r gr oup c ompa r i s onsa ti ni t i a lofobs e r v a t i on a s s howi nga bnor ma lva l ueofe a c hpa r a me t e r .I na ddi t i on, ompa r e da f t e r l i ve rf unc t i ona ndt hePLTva l ue swe r ec 4a nd12we e ksofa dmi ni s t r a t i on,r e s pe c t i ve l y,ba s e don 5) St a t i s t i c a ls i g n i f i c a nc e t her e s ul t sofapr e vi ouss t udy. wa sde t e r mi ne dus i ngt heSt ude ntt t e s t ,a ndPva l ue s l e s st ha n0. 05we r er e ga r de da sbe i ngs i gni f i c a nt .. I I .Phar mac ol ogi c als t udy Mat e r i al sandMe t hods. I .Re t r os pe c t i ves t udy Pat i e nt sa ndMe t hods Thi sr e t r os pe c t i ves t udywa sc onduc t e db yr e vi e wi ng t he me di c a lr e c or dsofp a t i e nt swi t ha dva nc e d e tt hec r i t e r i a he pa t oc e l l ul a rc a r c i nomawhodi dnotme f ors ur gi c a lr e s e c t i on;t he s t udy wa sc onduc t e da t Ka ns a iMe di c a lUni ve r s i t yHi r a ka t aHos pi t a l ,J a pa n, y2011a ndf r omJ a nua r y2010t oApr i l f r omApr i lt oJ ul 20 11.Thec r i t e r i af orp a t i e nti nc l us i onwe r ee i t he ra n e l e va t e dAST( >4 0I U/ L)orALT( >35I U/ L)l e ve lora r e duc e d PLT ( <150, 000/ mL) a f t e rt r e a t me nt wi t h ・;Ba ye rSc he r i ngPha r ma ,Os a ka ) s or a f e ni b( ne xa va r f ormo r et ha nf ourwe e ks .Thepa t i e nt swe r es ubs e -. Ani mal s :Ma l eSDr a t s( 6we e ksol dupona r r i va l )we r e obt a i ne df r omSLC,I nc .( Shi z uoka ,J a pa n) .Thea ni ma l s we r egr ouphou s e d( 2r a t s / c a ge )i nat e mpe r a t ur e -a nd humi di t yc o nt r ol l e dr oom wi t ha12hrl i ght / da r kc yc l e t e r ( l i ght sof f ,8: 00PM) ;l a bor a t or yp e l l e tc howa n dwa we r epr ovi de dadl i bi t um.Be f or et hee xpe r i me nt a lpr oc e dur e s ,t her a t swe r ea l l owe dt oa c c l i ma t et ot her oom xpe r i me nt s( a ppr o va lNo. f or1we e k.Al lt hea ni ma le 100095)we r er e vi e we da nda ppr ove dbyt heExp e r i me nt a lAni ma lCa r eCommi t t e eofKr a c i ePha r ma ,Lt d. r i al sandpr e par at i onoft hee xt r ac t :Dr i e d Pl antmat e e xt r a c tpowde rofni nj i n・ yoe i t o( LotNo.09010720)wa s rwa sma nuf a c t ur e di nt he us e di nt hi ss t udy;t hepowde GMPp ha r ma c e ut i c a lf a c t or yofKr a c i ePha r maLt d.The.

(3) 223. J .Tr a d.Me d.( Vol . 30No. 5/ 62 013). e xt r a c tpowde rwa ss us pe nde di nt hedi s t i l l e dwa t e rj us t be f o r eus ea ndwa sa dmi ni s t e r e dor a l l ya tados eof400 mg/ kgbodywe i ght / da y,whi c hc or r e s pondst oha l ft he da i l yc l i ni c a ldos e( 6, 700mg/ da y) .. HPLC pr of i l eofni nj i n・ yoe i t oa l ongwi t hac he mi c a l a na l ys i s .Che mi c a l ma r ke r s ,s uc ha sp a e oni f l or i n, he s pe r i di n,a ndgl yc yr r hi z i ca c i d,we r eus e df orqua l i t y c ont r ol . Hesperidin. Glycyrrhizic acid Hi ghpe r f or manc el i qui dc hr omat o gr aphyanal ys i s Paeoniflorin t o:Ni nj i n・ yoe i t oe xt r a c t( 0. 5 g)wa s ofni nj i n・ yoe i 250 mAU mi xe da nds ha ke nwi t h50%Me OH( 50mL)a ndt hes u200 pe r na t a nt( 5mL)wa ss ubj e c t e dt oah i ghpe r f or ma nc e 150 hr oma t ogr a phy ( HPLC)a na l ys i s .Thet hr e e l i qui dc di me ns i ona lHPLCpr of i l eofni nj i n・ yoe i t owa sobt a i ne d 100 us i ngaShi ma z uLCMS8030l i qui dc hr oma t ogr a phy 50 ma s ss pe c t r ome t e re qui ppe dwi t ha nLC30ADa ndar e 0 ve r s e dpha s ec ol umn( Shi mpa c kXRODSI I I ,2. 0mm 240 280 ×5 0mm,1. 6mm,Col umnt e mpe r a t ur e :40℃)a nd i . d. 320 a nSPDM2 0A de t e c t orwi t hs c a nni ngf orar a ngeof 0 360 5 10 230400nm.Thec ol umnwa se qui l i br a t e dwi t hs ol ve nt 400 nm 15 20 min ndB( 0. 1% f or mi c A( 0. 1% f or mi ca c i di na c e t oni t r i l e )a g.1 3 DHPLC pr of i l eofni nj i n・ yoe i t o.Ea c hofc he mi c a l a c i ds ol ut i on) ,a n dt her a t i oofs ol ve ntAwa si nc r e a s e d Fi ma r ke r( pa e oni f l or i n,he s pe r i di n,gl yc yr r hi z i ca c i d)i nt he by5% ove r16mi n,70% ove r1mi n,a nd5% ove r1 HPLCpr of i l ewa si de nt i f i e db yc ompa r i s onwi t ht her e t e nt i on t i me sa ndUVs pe c t r a( 230―400nm)oft he i rr e f e r e nc es t a nmi n,wi t haf l owr a t ea t0. 5mL/ mi n.. da r ds .. i ve ri nj ur y :Ba s e dont her e s ul t so fapr e t e s t , Ratl s or a f e ni b( Ba t c hNo.J PR1483; ,Ba ye rSc he r i ngPha r ma , Os a ka )a tados eo f200mg/ kg/ da ywa sus e dt oc r e a t ea r a tl i ve r i nj ur y mode l .Br i e f l y,r a t swi t hs or a f e ni bi vi de di nt oac ont r olgr oup i nduc e dl i ve ri nj ur i e swe r ed a ndac ombi na t i ong r oup,wi t ht hel a t t e rgr oupa l s or e c e i vi ng ni nj i n・ yoe i t o( 400 mg / kg)t wo hour sbe f or e ntwi t hs or a f e ni bf ore i ghtda ys .I na ddi t i on,r a t s t r e a t me wi t houts or a f e ni bi nduc e dl i ve ri nj ur i e swe r et r e a t e d ma lgr oup.Bl oodf r ome a c h wi t hdi s t i l l e dwa t e ra sanor a ni ma lwa sc ol l e c t e dt hought hes a phe nousve i nunde r di e t hyle t he ra ne s t he s i aonda ys4,6,a nd8a f t e rt hes t a r t oft hi ss t udy,a ndt hebl oodAST,ALT,t ot a lbi l i r ubi n ( TBI L) ,a nddi r e c tbi l i r ubi n( DBI L)l e ve l swe r eme a s ndPLTv a l ue swe r ea na l yz e d ur e d.TheAST,ALT,a l oga r i t hmi c a l l y.Thee xpe r i me nt a lda t awe r ee xpr e s s e d E. M.St a t i s t i c a ls i gni f i c a nc ewa s a st heme a n ± S. e va l ua t e dus i ngr e pe a t e dme a s ur e sANOVAwi t has i gni f i c a nc el e ve lofP<0. 05.. Re s ul t s sofni nj i n・ yoe i t o:Fi gur e1s howsa3DHPLCanal ys i. Re duc t i oni nadve r s ee f f e c t saf t e rt headdi t i onof e i t ot oongoi ngs or af e ni bt r e at me nti nar e t ni nj i n・ yo r os pe c t i ver e vi e w:Thec ombi na t i ong r oupc ons i s t e do f 8pa t i e nt swi t ha na bnor ma lASTl e ve l ,6pa t i e nt swi t ha n a bnor ma lALTl e ve l ,a nd1 0pa t i e nt swi t ha na bnor ma l PLTva l uea tt hes t a r toft r e a t me ntwi t hni nj i n・ yoe i t o, whe r e a st hec ont r olgr oupc ons i s t e dof7p a t i e nt swi t h a na bnor ma lASTl e ve l ,5pa t i e nt swi t ha na bnor ma l ALTl e ve l ,a nd9pa t i e nt swi t ha na bnor ma lPLTl e ve l t me ntwi t houtni nj i n・ yoe i t o.Ta bl e1 a tt hes t a r toft r e a t a bul a t e st heb a c kgr oundc ha r a c t e r i s t i c soft hepa t i e nt s nj i n・ yoe i t o.The t r e a t e dwi t ha ndt hos et r e a t e dwi t houtni me a npe r i odsofs or a f e ni bt he r a pypr i ort ot hes t a r tof e ks ,40± 30we e ks , t hepr e s e nts t udywe r e42± 30we ± e ksf ort hepa t i e nt swi t ha bnor ma lAST, a nd46 27we ALT,a ndPLTva l ue swhowe r es ubs e que nt l yt r e a t e d 3we e ks ,4. 2± 0. 4 wi t hni nj i n・ yoe i t oa nd6. 9± 6. 5we e ksf ort hepa t i e nt swi t ha bnor we e ks ,a nd6 . 7± 5. ma lAST,ALT,a ndPLTva l ue swhowe r es ubs e que nt l y ve l y.Th eme a n t r e a t e dwi t houtni nj i n・ yoe i t o,r e s pe c t i dos eofs or a f e ni ba tt hebe gi nni ng/ e ndi ngoft r e a t me nt wi t horwi t houtni nj i n・ yo e i t owa ske ptwi t hi nar a ngeof nbot hgr oups . 200－400mgi.

(4) 224. Th ec ombi na t i one f f e c t sofs or a f e ni ba ndn i nj i n・ yoe i t oona dva nc e dhe pa t oc e l l ul a rc a r c i noma. Tabl e1 Ba c kgr oundoft hepa t i e nt swi t ha bnor ma lAST,ALT,orPLTl e ve l sus e di nt her e s pe c t i ves t udy Abs t r a c t e dc a s e s( n). Cont r olgr oup ( s or a f e ni ba l one ,n=7/ 5/ 9). Combi na t i ongr oup ( ni nj i n' yoe i t oa nds or a f e ni b,n=8/ 6/ 10). Se x. Ma l e( 7/ 5/ 9) ,Fe ma l e( 0/ 0/ 0). Ma l e( 5/ 3/ 6) ,Fe ma l e( 3/ 3/ 4). Age( ys ,Me a n± SD). 70± 10/ 73± 9/ 66± 14. 69± 7/ 69± 6/ 70± 5. Pe r i odofs or a f e ni bt he r a pybe f or et he s t udya tbe gi nni ng( wks ,Me a n± SD). Dos eo f Sor a f e ni b( mg ). 42± 30/ 40± 30/ 46± 27. Atbe gi nni ng. Af t e r4/ 4/ 12we e ks. Atbe gi nni ng. Af t e r4/ 4/ 1 2we e ks. 100. 0/ 0/ 0. 0/ 0/ 1. 1 / 1/ 1. 0/ 0/ 0. 200. 5/ 4/ 7. 5/ 4/ 4. 4/ 2/ 6. 4/ 2/ 6. 400. 2/ 1/ 2. 2/ 1/ 4. 1 / 1/ 1. 3/ 3/ 3. 0/ 0/ 0. 0 / 0/ 0. 2/ 2/ 2. 1 / 1/ 1. 600. 2257± 98/ 240± 89 257± 98/ 240± 89 313± 196/ 350± 217 325± 149/ 3 6 7± 151 / 244± 88 / 2 78± 120 / 2 90± 179 / 3 00± 141. Me a n± SD Tumorma ke r ( Me a n± SD). 6. 9± 6. 3/ 4. 2± 0. 4/ 6. 7± 5. 5. AFP( ng/ ml ). 54± 95/ 21± 11 / 172± 391. －) */ 42± 59 ( / 1 95± 366. PI VKAI I ( mAU/ ml ). 96± 138/ 127± 155 / 64± 88. －) */ 83± 91 ( / 54± 63. 120± 279 －－ 100± 239/ () */ () */ 53± 129 / 5 4± 124 41± 15 40± 17/ / 41± 34. －) －) ( */ ( */ 26± 11. *:nor e c or d.. Conc e r ni ngt het umo rma r ke r s ,t heAFPa ndPI VKA I Iva l ue swe r enots i gni f i c a nt l ydi f f e r e ntbe t we e nt he xc l ud i ng c ombi na t i ongr ou pa ndt hec on t r olgr oup,e s omemi s s i ngva l ue s ,a tt hebe gi nni ngore ndi n go ft he t r e a t me ntwi t ho rwi t houtni nj i n・ yoe i t o. t udy,8c a s e si nt hec ombi na Att hebe g i nni ngoft hes t i ongr oupa nd7c a s e si nt hec ont r olgr oupha da bnor ma lASTva l ue s ,whi l e6a nd5c a s e sha da bnor ma lALT ombi na t i ona ndc ont r olgr oups ,r e s pe c va l ue si nt hec t i ve l y( Ta bl e s2,3) . Thec ha nge si nt heme a nASTl e ve l sa f t e r4we e k sof. nj i n・ yoe i t owe r e0 . 13± t r e a t me ntwi t horwi t houtni 0. 13I U/ L( f r om 1. 80± 0. 13t o1. 66± 0. 15I U/ L)a nd 15I U/ L( f r om 1. 78± 0. 18I U/ Lt o1 . 78 0. 001± 0. ±0 . l 0I U/ L)i nt hec ombi na t i ona ndc ont r olgr oups ,r e s pe c t i ve l y.Thec ha nge si nt heme a nALTl e ve l swe r e 11I U/ L( f r om 1. 76± 0. 10t o1 . 54± 0. 12 0. 2± 0. 15I U/ L( f r om1. 80± 0. 18t o1. 72 I U/ L)a nd0. 072± 0. ±0 . l 5I U/ L)i nt hec ombi na t i ona ndc ont r olgr oups ,r e s pe c t i ve l y. Compa r e dwi t ht hec ont r olgr oup,t hec ombi na t i on nc yt owa r da ni mpr o ve dAST gr oupe xhi bi t e dat e nde. Tabl e2 Compa r i s onswi t hi na ndbe t we e nt hec ont r ola ndni nj i n・ yoe i t oc omb i na t i ongr oupsi nt he i rASTva l ue sa nda mo untofc ha nge AST. Cont r olgr oup( n=7). Combi na t i ong r oup( n=8). Be t we e ng r oups( pva l ue ). Atbe gi nni ng. 1. 78 ± 0. 18[ 65. 0±30. 7]. 1. 80± 0. 13[ 65. 0 ±19. 0]. n. s .. Af t e r4we e kt r e a t me nt. 1. 78 ± 0. 10[ 61. 4±13. 4]. 1. 66± 0. 15[ 48. 3 ±15. 0]. p<0. 1,n. s .. Δ) AmountofCha nge(. 0. 001± 0. 15[ 3. 57±26. 3]. 0. 13± 0. 13[ 16. 8 ±17. 4]. p<0. 1,n. s. Wi t hi ng r oups( pva l ue ). n. s .. 0. 020*. I U/ L). Loga r i t hmi cva l ue s[ t heor i gi na lva l ue s ]we r ee xpr e s s e dme a n± SD( *:p<0. 05 * *:p<0. 01 （wi t hi ng r oup:Pa i r e dt t e s t ,be t we e ng r oups :St ude nt ・ st t e s t ) we e nt hec ont r ola ndni nj i n・ yoe i t oc ombi na t i ong r oupsi nt he i rALTva l ue sa nda mo untofc ha nge Tabl e3 Comp a r i s onswi t hi na ndbe t Cont r olgr oup( n=5). Comb i na t i ongr oup( n=6). Be t we e ngr oups( pva l ue ). Atbe gi nni ng. ALT. 18[ 66. 8 ±25. 7] 1. 80 ± 0.. 1. 74± 0. 10[ 55. 7 ±13. 8]. n. s .. Af t e r4we e kt r e a t me nt. 15[ 55. 4 ±16. 8] 1. 72 ± 0.. 1. 54± 0. 12[ 35. 7 ±9. 42]. 0. 048*. Δ) AmountofCha nge(. 0. 072± 0. 15[ 11. 4 ±23. 3]. 0. 20± 0. 11[ 20. 0 ±11. 2]. n. s .. Wi t hi ngr oups( pva l ue ). n. s .. 0. 007**. I U/ L). Loga r i t hmi cva l ue s[ t heor i gi na lva l ue s ]we r ee xpr e s s e dme a n± SD( *:p<0. 05 * *:p<0. 01 （wi t hi ng r oup:Pa i r e dt t e s t ,be t we e ng r oups :St ude nt ・ st t e s t ).

(5) 225. J .Tr a d.Me d.( Vol . 30No. 5/ 62 013). Tabl e4 Compa r i s on swi t hi na ndbe t we e nt hec ont r ola ndn i nj i n・ yoe i t oc ombi na t i ongr oupsi nt he i rPTLva l ue sa nda mo untofc ha nge PTL. Cont r olgr oup( n=9). Combi na t i ong r oup( n=10). Be t we e ng r oups( pva l ue ). Atbe gi nni ng. 3. 94 ± 0. 12[ 9. 11±2. 34]. 3. 92± 0. 10[8. 4 4±1. 82]. n. s .. Af t e r12we e kt r e a t me nt. 3. 92 ± 0. 14[ 8. 60±2. 48]. 4. 02± 0. 24[ 11. 9±6. 47]. n. s .. Δ) Amo untofCha nge(. 0. 028± 0. 07[ 0. 51±1. 45]. 0. 10± 0. 17[3. 4 3±5. 43]. 0. 046*. Wi t hi ngr oups( pva l ue ). n. s .. n. s .( <0. 1). Loga r i t hmi cva l ue s[ t heor i gi na lva l ue s ]we r ee xpr e s s e dme a n± SD( a mo unt× 104/ ml ) . *:p<0. 05 **:p<0. 01 （wi t hi ngr oup:Pa i r e dt t e s t ,be t we e ngr oups :St ude nt ・ st t e s t ). 2.5. *. 2.4. p=0.035 p =0. 035. 2.3 2.2 2.1 2.0 4. 6. 8. After administration of sorafenib (day). i n4oft he10c a s e s ,a ndt heva l ue sf or2oft hepa t i e nt s r e c ove r e dt owi t hi nt henor ma lr a nge( i ndi vi dua lda t a dnotc ha ngea ndr e nots hown) .ThePLT va l uedi ma i ne dl owi nt hec ont r olgr oup. Phar mac ol ogi c ale f f e c tofni nj i n・ yoe i t oons or af e ni b:Ass howni nFi gs .2a nd i nduc e dl i ve ri nj ur yi nr at s 3,t hec ons e c ut i veor a la dmi ni s t r a t i onofs or a f e ni b( 200 mg/ kg)t or a t sf or8d a ysr e s ul t e di nl i ve ri nj ur y,a sde mons t r a t e dbyt hes i gni f i c a nti nc r e a s e si nAST,ALT, TBI L,a ndDBI Lt ha twe r eobs e r ve dond a ys4,6,a nd i on,nos i g8,c ompa r e dwi t hanor ma lgr oup.I na ddi t ni f i c a ntdi f f e r e nc e si nt hel oga r i t hmi cva l ue sofAST, t hel oga r i t hmi cva l ue sofALT,TBI L,orDBI Lwe r e r ma l ,c ont r ol ,a ndc omobs e r ve donda y0a mongt heno bi ne dni nj i n・ yoe i t ot r e a t me ntgr oups( AST:2. 21± 0. 03, 2. 16± 0. 03a nd2. 09± 0. 02;ALT:1. 68± 0. 02,1. 70 ± 0 . 01a nd1. 67± 0. 01;TBI L:1. 50± 0. 0 3,1. 38 ± 0 . 03a nd1. 28± 0. 02;a ndDBI L:1. 65± 0. 03, 06a nd1. 50± 0. 02) . 1. 65± 0. Af t e rt r e a t me ntwi t hac ombi na t i onofs or a f e ni ba nd. Logarithmic value of ALT (IU/L). Logarithmic value of AST (IU/L). l e ve l( P<0. 1)a ndas i gni f i c a nt l yr e duc e dALTl e ve l ( P=0. 048)a f t e r4we e kso ft r e a t me nt .Mor e ove r ,t he a c t ua lASTa ndt heALTl e ve l si mpr ove ds i gni f i c a nt l y whe nt heva l ue sobt a i ne dbe f or ea nda f t e rt r e a t me nt wi t hn i nj i n・ yo e i t owe r ec omp a r e d,whe r e a st he yr e olgr oup.Ass howni nTa bl e4, ma i ne dhi ghi nt hec ont r 11a nd1 0c a s e sh a dar e duc e dPLTva l uei nt hec ombi na t i ona ndc ont r o lgr oups ,r e s pe c t i ve l y. r e a t me ntwi t horwi t houtni nj i n・ Af t e r1 2we e ksoft yoe i t o,t hePLTva l ue sc ha nge df r om 3 . 92± 0. 10× 104/ mLbe f or et r e a t me ntwi t hni nj i n・ yoe i t ot o4. 02± Δ= 0. 24× 104/ mLa f t e rt r e a t me ntwi t hni nj i n・ yoe i t o( 4 ± × 17 10/ mL)i nt hec ombi na t i ongr oupa nd 0. 10 0. 12× 104/ mLb e f or et r e a t me ntwi t hout f r om 3. 95± 0. 14× 104/ mLa f t e rt r e a t me nt ni nj i n・ yoe i t ot o3. 92± 0. Δ=0. 028± 0. 07× 104/ mL)i n wi t houtni nj i n・ yoe i t o( t hec ont r olgr oup.Thus ,t hec ha ngei nt hePLTl e ve l wa ss i gni f i c a nt l yl a r ge ri nt hec ombi na t i ongr oup( P= nt hea c t ua lpr e t r e a t me nt 0. 046) .Al t hought hec ha ngei a ndp os t t r e a t me ntPLTva l ue swa snots i gni f i c a nti nt he c ombi na t i ong r ou p,t hePLTva l ueha dc l e a r l yi mpr ove d. 2.4 n.s. 2.2. 2.0. 1.8. 1.6 4. 6. 8. After administration of sorafenib (day). 䂔 Normal; 䂾 Control; 䃂 Ninjin’yoeito Mean 㫧 S.E.M (n=6~8), *: p<0.05, n.s.: not significant (repeated measure ANOVA). Fi g.2 Thec ha nge sofASTa ndALTa f t e rni nj i n・ yoe i t ot r e a t me nti ns or a f e ni bi nduc e dl i ve ri nj ur yo fr a t s.

(6) Th ec ombi na t i one f f e c t sofs or a f e ni ba ndn i nj i n・ yoe i t oona dva nc e dhe pa t oc e l l ul a rc a r c i noma. -0.6 -0.8. *. -1.0 p=0.022 p =0. 022 -1.2 -1.4 -1.6. 4. 6. 8. After administration of sorafenib (day). Logarithmic value of D-Bil (mg/dL). Logarithmic value of T-Bil (mg/dL). 226. -1.2 -1.3. * -1.4. p=0. 016 p=0.016. -1.5 -1.6 -1.7 -1.8 4. 6. 8. After administration of sorafenib (day). 䂔 Normal; 䂾 Control; 䃂 Ninjin’yoeito Mean 㫧 S.E.M (n=6~8), *: p<0.05, n.s.: not significant (repeated measure ANOVA). Fi g.3 Thec ha nge sofTBI La ndDBI La f t e rni nj i n・ yoe i t ot r e a t me nti ns or a f e ni bi nduc e dl i ve ri nj ur yofr a t s. ni nj i n・ yoe i t oa tados eof400mg/ kg,t heASTl e ve li mpr ove ds i gni f i c a n t l y,c ompa r e dwi t ht hec ont r ol( P= 0. 035) .Fi gur e2s howst ha tt hec ha nge si nt heASTa t 04,2. 39± 0 . 04,a nd e a c ht i mepoi ntwe r e2. 37± 0. 06I U/ Li nt h ec ombi na t i ongr oup,a nd2. 43 2. 39± 0. ±0 ± ± . 06I U/ L,2. 45 0. 06I U/ L,a nd2. 45 0. 05I U/ L i nt hec ont r olgr oup.Al t hought heALT l e ve l swe r e 08 l owe ri nt hec ombi na t i ong r oupo ve rt i me( 2. 16± 0. 0 8I U/ L,a nd2. 24± 0. 07I U/ L)c omI U/ L,2. 21± 0. 05I U/ L, pa r e dwi t ht hos ei nt hec ont r olgr oup( 2. 19± 0. 08I U/ L,a nd2. 30± 0. 08I U/ L) ,t hedi f f e r e nc e 2. 25± 0. be t we e nt het wog r oupswa snots i gni f i c a nt . I na ddi t i on,bot ht heTBI La ndt h eDBI Lwe r es i gni f i e t t e ri nt hec omb i na t i ong r oup,c omp a r e dwi t h c a nt l yb t hec ont r olgr oup( P=0. 022a ndP=0. 016,r e s pe c 0 5,0. 90 t i ve l y) .Thedi f f e r e nc e si nTBI L( 0. 97± 0. ±0 . 04,a n d0. 94± 0. 04mg/ dLvs .0. 87± 0. 0 3,0. 82 ±0 . 03,0. 78± 0. 02)a ndDBI L( 1. 37± 0. 02,1. 35 ±0 . 03,a n d1. 39± 0. 05mg/ dLvs .1. 30± 0. 0 2,1. 26 ±0 . 03,a nd1. 29± 0. 02mg/ dL)be t we e nt hec ombi na t i ona ndc ont r olgr oupsa te a c ht i mep oi nta r es howni n Fi g.3.. Di s c us s i on 5) I napr e vi ouss t udy, ni nj i n・ yoe i t owa ss hownt o c a us eas i gni f i c a nti mpr ove me nti nt heAST,ALT,a nd PLTl e ve l sofpa t i e nt s( n=12)wi t ha dva nc e dhe pa t oc e u l a rc a r c i nomawhoha dunde r gonepr e vi oust r e a t me nt l l. wi t hs or a f e ni bf or4,4/ 8,a nd1 2we e ks ,r e s pe c t i ve l y, f or et hea dmi ni s t r a t i on c ompa r e dwi t ht heout c ome sbe ofni nj i n・ yoe i t of or12we e ks .I nt hepr e s e nts t u dy,ar e t r os pe c t i ves t udywa spe r f or me dt of ur t he ri n ve s t i ga t e t heout c ome sbe t we e nt r e a t me ntwi t hs or a f e ni ba l one a nd t r e a t me ntwi t h ac ombi na t i on ofs or a f e ni ba nd ni nj i n・ yoe i t o. i bwa sma i nt a i ne dt hr oughout Thedos eofs or a f e n t r e a t me nti nbot ht hes or a f e ni ba l onea ndt hec ombi na t i ono fs or a f e ni ba ndn i nj i n・ yoe i t og r oups .Al t hougha l e a rs t a t i s t i c a ldi f f e r e nc ewa sdi f f i c ul tt ode t e c tbe c a us e c oft her e l a t i ve l ys ma l lnumbe rofc a s e si nc l ude di nt hi s de nc yt owa r da ni mpr ove me nti nt heAST s t udy,at e n ( P<0. 1)a ndas i gni f i c a nti mpr ove me nti nt heATLl e ve l swe r eobs e r ve di nt hec ombi ne dt r e a t me ntgr oup.I n a c t ,8c a s e si nt hec ombi na t i ongr oupa nd7c a s e si nt he f c ont r olgr oupha da bnor ma lASTva l ue s ,a nd6c a s e si n t hec ombi na t i ongr oupa nd5c a s e si nt hec ont r olgr oup ha da bnor ma lALTva l ue s . Ther e s ul t ss ugge s tt ha tt hel i ve ri nj ur i e si nt heni ove de nnj i n・ yoe i t oc ombi na t i ongr oupc oul dbei mpr t i r e l y.Ne ve r t he l e s s ,nos i gni f i c a ntdi f f e r e nc e swe r eobs e r ve di nt he i ra mountofc ha nget ha tt her e a s onc oul d but e dt ot hede vi a t i onsoft he m,be c a us et he y bec ont r i we r ec ha nge dl a r ge l ywi t houtar e gul a rdi r e c t i one ve ni f ys or a f e ni b,but i nt hec ont r olgr oup.I na ddi t i on,notonl a l s ol ongt e r ml i ve rdi s or de r s ,i nc l udi ngi mmunol ogi c a l e nt swi t ha di n j ur y,c a nc ont r i but et ol i ve ri nj ur yi np a t i va nc e dhe pa t oc e l l ul a rc a r c i noma ,a l t hought h er e s ul t s s howe dt ha tni nj i n・ yoe i t oi mpr ove dt hel i ve rf unc t i ons.

(7) J .Tr a d.Me d.( Vol . 30No. 5/ 62 013). ofpa t i e nt swhowe r er e c e i vi ngs or a f e ni bt r e a t me nt . I nt hea ni ma le xpe r i me nt ,ni nj i n・ yoe i t or e duc e dt he l i ve ri nj ur yi nduc e db ys or a f e ni bi nr a t s ,a l t hought he e f f e c twa sr e l a t i v e l ywe a k.Ni nj i n・ yoe i t oh a sbe e nr e por t e dt oi mpr ovet heASTa ndALTl e ve l sofpa t i e nt s 2, 3) a lhe pa t i t i s a ndt os uppr e s sa ut oi mmu nei nwi t hvi r f l a mma t i ona ndhe pa t i cf i br os i svi aapha r ma c ol ogi c a l s , me c ha ni s mi nvol v i ngt hei nhi bi t i ono fc yt ot oxi cf a c t or 6) The s ef a c t smi ghte xpl a i nwhy s uc ha sn i t r i coxi de . ni nj i n・ yoe i t or e duc e dl i ve rdys f unc t i o ni npa t i e nt sr e c e i vi ngs or a f e ni bt r e a t me nt . es pe c i f i cb i oma r ke rof Ge ne r a l l y,ALTi samor l i ve rda ma get ha nAST,a nds i gni f i c a nt l ye l e va t e dAST l e ve l sa r eof t e nf oundi npa t i e nt swi t hhe a r tf a i l ur e .Of ot e ,ni nj i n・ yoe i t oc a us e das i gni f i c a nti mp r ove me nti n n t heASTl e ve l ,r a t he rt ha nt heALTl e ve li nt hea ni ma l e xpe r i me nt ,s ugge s t i ngt ha ts or a f e ni bmi ghtc a us eda ma get oo r ga nsot he rt ha nt hel i ve r ,s uc ha st hehe a r tor ki dne y.I no urpr e t e s t ,howe ve r ,nos i gni f i c a nthi s t ol ogi c a ld a ma ge wa s obs e r ve di nr a t st r e a t e d wi t h s or a f e ni b,e ve nwhe ns or a f e ni bwa sa dmi ni s t e r e da ta ots hown) .On dos eof400mg/ kgf ore i ghtda ys( da t an t heot he rha nd,t hec l i ni c a ls t udys ugge s t e dt ha tt hei mpr ove me nti nALTwa ss upe r i ort ot ha tofASTa f t e r n・ yoe i t o.The r e f or e ,f ur t he rs t udy t r e a t me ntwi t hn i nj i us i ngat umor be a r i nga ni ma lmode li sne c e s s a r yt o l i t yof c l a r i f ys or a f e ni bi nduc e dl i ve rda ma gea ndt hea bi ni nj i n・ yoe i t ot oc onf e rpr ot e c t i ona ga i ns tl i ve rda ma ge . Ni nep a t i e nt si nt hec ont r olgr oupa nd10p a t i e nt s da bnor ma lPLT v a l ue s . i nt hec omb i na t i ongr oupha Al t hought henumbe rofpa t i e nt swi t ha na bnor ma lPLT va l uewa sl a r ge rt ha nt henumbe rofpa t i e nt swi t hl i ve r f unc t i on,no s i gni f i c a ntd i f f e r e nc e wa sobs e r ve d dys be t we e nt h ec ont r ola ndc omb i na t i ongr oupswhe nt he a us eoft he a bs ol ut ePLT va l ue swe r ec omp a r e db e c l a r geva r i a t i oni nPLTl e ve l s .I nc ont r a s t ,t hePLTva l ue wa ss i gni f i c a nt l yi nc r e a s e di nt hec ombi na t i ongr oup ft r e a t me nt .Thedi f f e r e nc ei nt hes t a t i s a f t e r12we e kso t i c a ls i gni f i c a nc ema ybei nt e r pr e t e da si ndi c a t i ngt ha t t si ns ome ,butnota l l ,c a s e s . ni nj i n・ yo e i t oha sc l e a re f f e c I nf a c t ,ni nj i n・ yoe i t or e por t e dl yi mp r ove st her e duc t i oni nPLT v a l ue st ha ti sa s s oc i a t e dwi t hl i ve r 4) i sa nde xe r t si t spha r ma c ol ogi c a la c t i onbyp r oc i r r hos mot i nghe ma t opoi e t i cf unc t i ons ,i nc l udi ngpl a t e l e tf or 6) e s ul t so ft hi ss t udy,whi c hc ont a i ne d ma t i on. Ther ac ont r olgr oup,v e r i f i e dt hepha r ma c ol ogi c a le f f e c tof. 227. ni nj i n・ yoe i t o. I mpo r t a nt l y,ac ons t a ntdos eofs or a f e ni bi sne e de d t ot r e a tpa t i e nt swi t hl i ve rc a nc e r .A s ur ve yof1 85 1) r e ve a l e dt ha tt r e a t me ntwi t hs or a f e ni bwa sdi s c a s e s c ont i nue d be c a us eofpr ogr e s s i on o fdi s e a s e( 63%) , a dve r s ee f f e c t s( 22%) ,orn of ur t he rt r e a t me nta f t e r s or a f e ni bdos ei nt e r r upt i on( 60%) .Adve r s ee f f e c t sa r i s i ngf r om l i ve rf unc t i onf a i l ur ea ndar e duc t i oni npl a t e r epa r t i c ul a ra t t e nt i onbe c a us et he ya r ee a s i l y l e t sr e qui c a us e dbyc ompl i c a t i onsofl i ve ri nj ur yi npa t i e n t swi t h nf a c t ,ac ons i de r a bl yhi gh he pa t oc e l l ul a rc a r c i noma .I i nc i de nc eofl i ve ri nj ur y,a si ndi c a t e dbya ni n c r e a s ei n t heASTl e ve l( 70%) ,ALTl e ve l( 70%) ,a ndTBI Ll e ve l ( 53%)a ndad e c r e a s ei nt hePLTva l ue( 56%) ,wa sr e por t e dbyapr e vi ouss t udygr oup. Ta ke nt oge t he r ,t hef i ndi ngsoft hepr e s e nts t udy ha tt hea ddi t i onofni nj i n・ yoe i t oc oul de na bl e s ugge s tt t hec ont i nuousa dmi ni s t r a t i onofs or a f e ni bbys u ppr e s s i ngl i ve rf unc t i onf a i l ur ea ndpl a t e l e tr e duc t i ons . Atpr e s e nt ,s or a f e ni bi st heonl ye f f e c t i vet he r a py f orpa t i e nt swi t ha dva nc e dh e pa t oc e l l ul a rc a r c i noma . Sor a f e ni bf unc t i onsbybl oc ki ngc e l lpr ol i f e r a t i ona sa mul t i ki na s ei nhi bi t or .A nove lme c ha ni s mi n whi c h e l l ul a rc a r c i noma b y s or a f e ni ba c t sa ga i ns the pa t oc i nduc i ngc e l lde a t hi nama nne rt ha ti sde pe nde nton r e a c t i veoxyge ns pe c i e spr oduc t i onha sr e c e nt l ybe e n 7) r e f or e ,wes pe c ul a t et ha tt hi sr e a c t i ve r e por t e d. The oxyge ns pe c i e spr oduc t i onma yl e a dt onor ma lc e l lda mpa t opr ot e c t i ve a gei nt hel i ve r .Ont heot he rha nd,t hehe e f f e c t sofni nj i n・ yoe i t oa r eknownt oa r i s enotonl yf r om 8, 9) i t sc ompone nt s ,s uc ha sl i c or i c e , f r uc t usSc hi s a ndr a e 10) 11, 12) 13) t r uspe e l s , a ndPa na xgi ns e ng, but Chi ne ns i s , Ci a l s of r omi t sc he mi c a lc ons t i t ue nt s ,i nc l udi nggl yc yr r hi z i c a c i d,g s c hi z a ndr i n,he s pe r i di na nd gi ns e nos i deRg3, 1417) ndRh ,whi c hpos s e s sa nt i oxi da nta c t i vi t i e s . Rh 1a 2 Ba s e dont he s ef a c t s ,mul t i pl ec ompos i t i onc ompone nt s a nd/ ora c t i vec ons t i t ue nt sofni nj i n・ yoe i t oma ya ddi t i ve l y ors yne r gi s t i c a l l yc ont r i but et oa ni mpr ove me nti nl i ve r f unc t i on.. Ac knowl e dgme nt s Thea ut hor sa r egr a t e f ult oMi s sRumiUc hi ba ya s hi a ndDr .Aki r aOkonogif ora s s i s t a nc ei npe r f or mi ngt he a c t sofni nj i n・ yoe i t o. 3DHPLCa na l ys i soft hee xt r.

(8) 228. Th ec ombi na t i one f f e c t sofs or a f e ni ba ndn i nj i n・ yoe i t oona dva nc e dhe pa t oc e l l ul a rc a r c i noma. Di s c l os ur es t at e me nt. 8) Fuj i t a ,H. ,Sa ku r a i ,T. ,Toyos hi ma ,S. :St udi e sont he Re gul a t i onbyDr ugsAga i ns tExp e r i me nt a lHe pa t i t i s( 1,. Thec l i ni c a la nda ni ma ls t udi e swe r ec o nduc t e da t Ka ns a iMe di c a lUni ve r s i t ya ndKr a c i ePha r ma ,Lt d. ,r e ef undi ngs our c e s .Noc o mpe t i ng s pe c t i ve l y,wi t hs e pa r a t f i na nc i a li nt e r e s t se xi s t .. 2,3)TheThe r a pe ut i c a lEf f e c t so fGl yc yr r hi z i ni cAc i d, DLMe t hi oni ne ,The i rCompl e xa nd Ta bl e t sAga i ns t Ac ut eI nj ur yI nduc e dbyCa r bont e t r a c hl or i deorDGa l a c t os a mi ne .Phar mac ome t r i c s ,16,6376 4 5,1978; i de m.i bi d. ,647657,1978;i de m.i bi d. ,6596 69,1978. 9) Shi ba ya ma ,Y. :Pr e ve nt i onofhe pa t ot oxi cr e s pons e st o. 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