JURNAL Antihyperalgesic.docx

8/20/2019 JURNAL Antihyperalgesic.docx

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Antihyperalgesic/Antinociceptive Efects o Cetriaxone and Its SynergisticInteractions with Diferent Analgesics in Inammatory Pain in odents

A!S"AC"!ac#gro$nd% "he &'lactam anti(iotic cetriaxone stim$lates gl$tamatetransporter )*"'+ expression and is efective in ne$' ropathic and visceral painmodels, "his st$dy examined the efects o cetriaxone and its interactions withdiferent analgesics -i($proen. celecoxi(. paracetamol. and levetiracetam insomatic and visceral pain models in rodents, 0ethods% "he efects o cetriaxone-intraperitoneally/intraplantarly. analgesics -orally. and their com(inations wereexam' ined in the carrageenan'ind$ced paw inammatory hyperalgesia model inrats -n 1 23+4 and in the acetic acid'ind$ced writhing test in mice -n 1 23+5,

"he type o interaction (etween cetriaxone and analgesics was determined (y

iso(olographic analysis, es$lts% Pretreatment with intraperitoneallyadministered cetriaxone -+53455 mg/#g per day or 6 days prod$ced a sig'ni7cant dose'dependent antihyperalgesia in the somatic inammatory model,Ac$te administration o cetriaxone. via either intraperitoneal -+53455 mg/#g orintraplantar -5,5835,4 mg per paw ro$tes. prod$ced a signi7cant and dose'dependent ($t less e9cacio$s antihyperalgesia, In the visceral pain model.signi7cant dose'dependent antinociception o cetriaxone -483455 mg/#g perday was o(served only ater the 6'day pretreatment, Iso(olographic analysis inthe inammatory hyper' algesia model revealed approximately +5'old red$ctiono doses o (oth dr$gs in all examined com(inations, In the visceral nociception

model. more than 6' and +6'old red$ction o doses o (oth dr$gs was o(servedin com(inations o cetriaxone with i($proen/paracetamol andcelecoxi(/levetiracetam. respectively, Concl$sions% Cetriaxone exertsantihyperalgesia/antinociception in (oth somatic and visceral inammatory pain,Its e9cacy is higher ater a 6'day pretreatment than ater ac$te administration,

"he two'dr$g com(inations o cetriaxone and the nonsteroidalanalgesics/levetiracetam have synergistic interactions in (oth pain models,

"hese res$lts s$ggest that cetriaxone. partic$larly in com(inations withi($proen. celecoxi(. paracetamol. or levetiracetam. may provide $se$lapproach to the clinical treatment o inammation'related pain,

I: inammatory somatic and visceral pain. tiss$e dam' age or inammationsensiti;es peripheral aferents and dorsal horn ne$rons,+ Synaptic inp$t romprimary afer' ents onto second'order ne$rons in the dorsal horn is excit' atory,

"his excitation is mostly mediated (y the release o gl$tamate. which is thema


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extracell$lar space. ($t there is high'a9nity. e9cient. high' capacity gl$tamatetransporter system within the central and peripheral nervo$s systems thatremoves gl$tamate rom the extracell$lar space, "he gl$tamate transporter )*"'+ is distri($ted primarily in astrocytes and plays a cr$cial role in gl$tamateclearance in the synaptic clet in the central

nervo$s system.23? as well as in satellite and Schwann cells in the peripheralnervo$s system,@ A novel strategy to decrease synaptic gl$tamate (y $preg'$lating the gl$tamate transporter )*"'+ might (e efective in mitigatinginlammatory pain,+5 Evidence s$ggests that the &'lactam anti(iotic.cetriaxone. is a potent stim$lator o )*"'+ expression+5 and that it canatten$ate ne$ropathic and visceral pain,+= "here are no data a(o$t its e9cacyin inammatory somatic pain, As there is evidence that inammatory somatic aswell as visceral pain processes are associated not only with gl$tamate ($t alsowith prostaglandins and some other released mediators. com(ination therapy is

o val$e in this context,+.+>3+2 0oreover. when com(inations o s$ita(le dr$gsare $sed. s$(maximal doses can (e applied. with ewer adverse efects andgreater e9cacy,+6.+? :onsteroidal antiinammatory dr$gs and paracetamol are$se$l in the management o (oth somatic and visceral pain, "he anal' gesicefect o nonsteroidal antiinammatory dr$gs has traditionally (een related tothe red$ction o prostaglan' din synthesis. (y inhi(ition o cyclooxygenases-CB' +/4, "he mechanism o analgesic efect o paracetamol is still a matter ode(ate, ecent evidence s$ggests that the red$ction o prostaglandin synthesisca$sed (y the inhi(ition o CB'4 co$ld (e the main mechanism o itsaction,[email protected] $r research gro$p has shown that levetirace' tam. a novel

antiepileptic dr$g. ind$ces antihyperalgesia in the somatic inammatory modelo pain via adrenergic. opioidergic. 8'hydroxytryptaminergic. 'amino($tyric acid-)A!Aergic. and adenosine receptors,4+.44 It seems that levetiracetam isavora(le or coadministration with other dr$gs (eca$se $nli#e otherantiepileptics. it does not ind$ce and is not a high'a9nity s$(strate orcytochrome P'>85 isoorms or gl$c$ronidation en;ymes and th$s it is devoid opharmaco#inetic -meta(olic interactions with other dr$gs,4= "he c$rrent st$dywas $nderta#en to determine the e9cacy o cetriaxone. as well as the types ointeractions -additivity. synergism. or antagonism o cetriaxone with diferentanalgesics -i($proen. celecoxi(. paracetamol. and levetiracetam in somatic andvisceral inammatory pain models in rodents,

0aterials and 0ethods Animals All experiments were approved (y theInstit$tional Animal Care and se Committee o the ac$lty o Pharmacy. ni'versity o !elgrade. !elgrade. Ser(ia. and were carried o$t in compliance withthe :ational Instit$tes o Fealth )$ide or the Care and se o *a(oratoryAnimals,4> Experiments were perormed on male Gistar rats -weighing +?53445g and Swiss Ge(ster mice -weighing 483=5 g o(tained rom the 0ilitary 0edicalAcademy !reeding arm. !elgrade. Ser(ia, "he animals were ho$sed $nder a +4h light/dar# cycle. with ood and water availa(le ad li(it$m, or allmeas$rements. the experimenter was (linded to the treatment gro$p,


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Dr$gs and "heir Administration Cetriaxone -*ongacephH )aleni#a. !elgrade.Ser(ia was dissolved in saline, I($proen -Pharmagen )m(F. ran#' $rt.)ermany. celecoxi( -Cele(rexH P7;er 0an$act$ring De$tschland )m(F.Illertissen. )ermany. paracetamol -PanadolH )laxoSmithline D$ngarvan *td,.D$ngarvan. Ireland. and levetiracetam -eppraH C! Pharma A). !r$' selles.

!elgi$m were s$spended in distilled water, "wo distinct protocols were $sed orcetriaxone adminis' tration, In the pretreatment protocol. cetriaxone was intra'peritoneally administered once daily or 6 consec$tive days. and the experimentswere perormed on day ? -starting 4> h ater the last cetriaxone in


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0odel o isceral :ociception "he writhing test descri(ed previo$sly42.=5 was$sed, 0ice were in


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otarod "est otarod perormance was assessed to eval$ate the efects ocetriaxone and levetiracetam on motor coordination or seda' tion,=8 "he testwas perormed $sing a rotarod apparat$s -"readmill or rats >6655 or "readmillor mice 6255H go !asile. 0ilano. Italy. consisting o a rod rotating at a con'stant speed o +8 rpm,=5.=2 "he animals were trained to drive the rotarod o$r

times a day or 4 days, nly those animals that co$ld stay on the rod or +?5 son two consec$tive trials were $sed in the experiments, Cetriaxone wasadministered in (oth pretreatment and ac$te treatment protocols. and leve'tiracetam was administered only as an ac$te treatment, In the ac$te treatmentprotocols. cetriaxone and levetiracetam were administered =5 or 25 min (eorethe testing. respectively, "he posttreatment latency to remain on the rotating rod-with a +?5 s c$tof was recorded at o$r time points. d$ring 4>5 min,

Statistical Analysis All pharmacological comp$tations were perormed $singPharm PCS -0icro'Comp$ter Specialists. Philadelphia. PA and Pharm "ools Pro

-"he 0cCary )ro$p. Schnec#sville. PA, "he statistical analysis was cond$cted$sing SigmaPlot ++ -Systat Sotware Inc,. ichmond. CA, "he data were nor'mally distri($ted -Shapiro3Gil# test and are presented as the means W SE0,

"ime'co$rse data in the inammatory hyperal' gesia model were analy;ed $singa two'way repeated'meas$res A:A. ollowed (y "$#ey honestly signi7cantdiference test or (etween'gro$p comparisons and comparisons at each timepoint, "wo'way A:A was $sed to compare the pea# efects o each cetriaxonedose that was achieved ater the pretreatment and the ac$te treatment, Datarom the visceral nociception model were analy;ed (y one'way A:A, "$#eyhonestly sig' ni7cant diference test was $sed or post hoc comparisons, Data

rom the rotarod test were analy;ed (y independent sample St$' dent t test, "hediferences (etween ED85 mix and ED85 add were examined (y modi7ed ttest,=+ "he slopes o the KAF3UAC regression lines were compared (y the testor parallelism,== A P val$e less than 5,58 was considered statisticallysigni7cant,

es$lts Efects o Cetriaxone on Somatic Inammatory Fyperalgesia Seven'daypretreatment with intraperitoneally admin' istered cetriaxone -+53455 mg/#gper day prod$ced a dose'dependent red$ction o hyperalgesia -P X 5,55+ (y

two'way repeated'meas$res A:AH 7g, +A, "he maxi' mal efects wereo(served +4534>5 min ater the ind$ction o inammation, "he correspondingED85 W SE0 calc$' lated rom the pea# efect val$es was =+,@2 W +4,54 mg/#gper day -ta(le +, Ac$te treatment with intraperitoneally administered ce'triaxone -+53455 mg/#g also prod$ced a dose'dependent antihyperalgesia -P X5,55+ (y two'way repeated'meas$res A:AH 7g, +!. which pea#ed =55 minater the ind$ction o inammation -4>5 min ater cetriaxone administration,

"he pea# efect prod$ced with each tested dose o cetriax' one in the ac$tetreatment was signi7cantly lower than the pea# efect o the same doseprod$ced ater the 6'day pre' treatment -P X 5,55+ (y two'way A:AH 7g, +C,

Ac$te treatment with intraplantar cetriaxone -5,583 5,4 mg per paw red$cedhyperalgesia in a dose'dependent manner -P X 5,55+ (y two'way repeated'


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meas$res A:AH 7g, 4A, "he efect o cetriaxone was local (eca$se it was noto(served ater the in


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mixt$re, ^ ED85 mix is the experimental ED85 or dr$g mixt$re, ║ P X 5,58(etween ED85 add and ED85 mix -t test indicates a synergistic interaction,=+

)A0!AAAAig, 4, "ime co$rse o the local peripheral antihyperalgesic efects o CE -A,!asal d -plotted at vertical axis was o(tained (eore CE and CA i,pl,administration -denoted (y arrows, Each point represents the mean W SE0, ZZPX 5,5+ compared with control gro$p at each time point -"$#ey honestlysigni7cant diference post hoc test ater two'way repeated'meas$res A:A, -!*og dose3response c$rve or CE local peripheral antihyperalgesia at the time opea# efects, KAF 1 percentage o anti' hyperalgesic activityH CA 1carrageenanH CE 1 cetriaxoneH contra, 1 contralaterallyH d 1 paw press$rediference (etween nonin and are s$m' mari;edin ta(le +, "wo'dr$g com(inations o intraperitoneally adminis' tered cetriaxone-6'day pretreatment with oral analgesics also ca$sed a dose'dependentred$ction o hyperalgesia -P X 5,55+ (y two'way repeated'meas$res A:AH 7g,8, or all o the examined com(inations. the ED85 mix was signi7cantly lowerthan the ED85 add -P X 5,58 (y t test and the interaction index was less than +which indicates a synergistic interaction -7g, 2 and ta(le +, According to theinteraction index val$es. at all o the examined com(i' nations. there was almostthe same degree o potentiation with approximately +5'old red$ction o doses o

(oth dr$gs when the dr$gs were applied in com(ination compared with thedoses that prod$ced the same level o efect ater indi' vid$al administration,


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Analysis o the D$ration o the Efects o Cetriaxone. Analgesics. andCetriaxone3Analgesic Com(inations in a 0odel o Somatic InammatoryFyperalgesia Slope o the KAF3UAC regression line or cetriaxone -6'daypretreatment was greater than the slope or each analgesic -P X 5,58 (y test orparallelismH ta(le =, "his

)A0!A

"a(le 4, Parameters o Iso(olographic Analysis or Cetriaxone3AnalgesicsCom(inations in a 0odel o isceral :ociception

Z ED85 is the efective dose that prod$ces 85K antinociceptive activity, \Interaction index. 1 ED85 CE"IAB:E C0!I:ED GI"F A:A*)ESIC/ ED85CE"IAB:E )IE: A*:E V ED85 A:A*)ESIC C0!I:ED GI"FCE"IAB:E/ED85 A:A*)ESIC )IE: A*:E, al$es near + indicate additiveinteraction. val$es Y+ imply an antagonistic interaction. and val$es X+ indicate

a synergistic interaction,=4 ] ED85 add is the theoretical additive ED85 or dr$gmixt$re, ^ ED85 mix is the experi' mental ED85 or dr$g mixt$re, ║ P X 5,58(etween ED85 add and ED85 mix -t test indicates a synergistic interaction,

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ig, >, *og dose3response c$rves or antihyperalgesia ind$ced (y I!. CE*. PA.and *E in a model o somat' ic inammatory hyperalgesia in rats at the time opea# e' ects, Each point represents the mean W SE0 o(tained in 2'@ animals,

KAF 1 percentage o antihyperalgesic activityH CE* 1 celecoxi(H I! 1i($proenH *E 1 levetiracetamH PA 1 paracetamol,

res$lt indicates that the efects prod$ced (y individ$ally administeredcetriaxone lasted longer than the efects pro' d$ced (y individ$ally administeredanalgesics, "he slopes or all two'dr$g com(inations o cetriaxone were not di'erent rom the slope or cetriaxone per se -P Y 5,58 (y test or parallelismHta(le =, "his indicates that the d$ration o the efects o cetriaxone was$nchanged when it was applied alone and when it was applied with analgesics,

Fowever. the slopes or cetriaxone3i($proen and cetriaxone3celecoxi(com(inations were greater than the slopes or the corre' sponding analgesicswhen applied individ$ally -P X 5,58 (y test or parallelismH ta(le =, "hisindicates that the actions o i($proen and celecoxi( were longer when com(inedwith cetriaxone, "he high correlation coeicients o the KAF3 UAC line or allo the treatments indicate that the d$ra' tions o the efects were dosedependent -ta(le =,

Interactions (etween Cetriaxone and Analgesics in a isceral :ociception 0odelral i($proen -+4,83+55 mg/#g. celecoxi( -=,683=5 mg/#g. paracetamol -83

+85 mg/#g. and levetiracetam -+348 mg/#g ca$sed a dose'dependentred$ction o writhes ind$ced (y acetic acid -P X 5,55+ (y one'way A:A. not


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shown, "he corresponding log dose3response c$rves are shown in 7g, 6. and theED85 val$es are s$mmari;ed in ta(le 4, "wo'dr$g com(inations ointraperitoneally adminis' tered cetriaxone -6'day pretreatment with oralanalge' sics also red$ced nociception in a dose'dependent manner -P X 5,55+(y one'way A:AH 7g, ?, Iso(olographic anal' ysis revealed synergistic

interactions or all o the examined com(inations -ta(le 4 and 7g, @, Interactionindex val$es indicated a diferent degree o potentiation with the ollow' ingran#% cetriaxone3celecoxi( 1 cetriaxone3levetiracetam Y cetriaxone3i($proen1 cetriaxone3paracetamol, A more than +6'old red$ction o doses o (oth dr$gsin the ce' triaxone3celecoxi( and cetriaxone3levetiracetam com(ina' tions anda more than seven'old red$ction o doses in the cetriaxone3i($proen andcetriaxone3paracetamol com(i' nations are o(served when compared with thecorrespond' ing doses ater individ$al administration,

Efects o Cetriaxone and *evetiracetam in a otarod "est Intraperitoneallyadministered cetriaxone either ater 6'day pretreatment -455 mg/#g per day oran ac$te treatment -455 mg/#g did not in$ence the rotarod perormance in(oth rats and mice -P Y 5,58 (y St$dent t test. not shown, ral levetiracetam-455 mg/#g was also witho$t signi7cant efect in (oth species -P Y 5,58 (ySt$dent t test. not shown, Disc$ssion Antihyperalgesic/Antinociceptive Efects o Cetriaxone in Somatic and isceral Inammatory Pain 0odels "he c$rrent st$dyshows that the administration o cetri' axone or 6 days ca$sed a signi7cant anddose'dependent red$ction o carrageenan'ind$ced mechanical hyperalgesia inrats and acetic acid'ind$ced nociception in mice, $r res$lts widen the 7ndings

(y *in et al,.+=.=6 F$ et al,.++ and _ang et al,=? who o(served that cetriaxone.in preventive 6'day administration. is efective not only in chronic ne$' ropathicand visceral pain ($t also in somatic inammatory pain, "he animal model ocarrageenan'ind$ced hyperalge' sia. as a model o somatic pain. mimics clinicalinamma' tory conditions,=@ $r st$dy shows or the 7rst time that the ac$tetreatment with cetriaxone in the same dose range prod$ces a signi7cant anddose'dependent antihyperalge' sic efect which is signi7cantly lower than thatprod$ced (y 6'day treatments with all doses, As cetriaxone did not prod$ce asigni7cant impairment o motor perormance in the rotarod test in rats and miceat the highest $sed doses. it wo$ld appear that the

antihyperalgesic/antinociceptive efects o cetriaxone were not d$e to motorimpairment or sedation, "he c$rrent st$dy also demonstrates a modest e9' cacyo cetriaxone as a local peripheral antihyperalgesic dr$g in the carrageenan'ind$ced pain inammatory model, "here is no literat$re data regardingcetriaxoneNs local peripheral antinociceptive e9cacy, "he local nat$re o thisaction was veri7ed (y the a(sence o efect o cetriaxone ater it was in5 times lower thanwith the lowest efective systemic dose -+5 mg/#g, "his 7nding s$ggests thatwhen cetriaxone is given systemically -either as an ac$te dose or a 6'day

pretreatment. it achieves efective concentrations at the periphery, It also points


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to the contri' ($tion o a peripheral antihyperalgesic efect to the net efect osystemically administered cetriaxone,

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ig, 8, "ime co$rse o the antihyperalgesic efects o CE V I! -A. CE V CE*-!. CE V PA -C. and CE V *E -D com' (inations, !asal d -plotted atvertical axis was o(tained (eore dr$gs administration and the ind$ction oinammation (y an i,pl, in= andperipheral@ nervo$s systems, !eca$se cetriaxone prod$ced analgesic activity in

the paw press$re test ater sys' temic and local peripheral application. it co$ld(e s$ggested that the red$ction o intrasynaptic gl$tamate in the spinal cord and


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peripheral sensory terminals wo$ld contri($te to the anti' hyperalgesic efect ocetriaxone in somatic inammatory pain,

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"a(le =, Parameters o the D$ration o Action o Cetriaxone. Analgesics. and "heir Com(inations in a 0odel o Inammatory Fyperalgesia

Z Slope o the KAF3UAC regression line is the relative meas$re o the d$rationo the dr$g/dr$g com(ination efect,42.46.=> \ Correlation coe9' cient o theKAF3UAC regression line, ] P X 5,58H comparing with the slope or cetriaxone.test or parallelism, ^ P X 5,58H comparing with the slope or analgesic alone. testor parallelism, KAF 1 percentage o antihyperalgesic activityH UAC 1diference (etween area $nder the time3d c$rve or control and each dose o

dr$g/ dr$g com(ination gro$psH d 1 paw press$re diference (etween nonin' 8.>2 Amin et al,+6 o(served that a +'wee# treatment with cetriaxonesigni7cantly atten$ates these cyto#ines in the spinal cord, Several previo$s st$d'ies have descri(ed the synergistic interaction o inamma' tory cyto#ines andgl$tamate in ne$ronal sensiti;ation,+6.>2 "hereore. cetriaxone might prod$ceantihyperalgesic/ antinociceptive efects ater 6 days o systemic administra' tionat least (y decreasing cyto#ine levels, "his co$ld also explain the o(servedantihyperalgesia ater ac$te systemic administration o cetriaxone, Fowever.the synergistic interactions o inammatory cyto#ines and gl$tamate and the

o(servation that cetriaxone red$ces intrasynaptic gl$tamate thro$gh increasedtranscription o the )*"'+ gene+5 -ho$rs and days are needed or its $ll efectco$ld explain the signi7cantly lower antihyperalgesia/antinoci' ception ater anac$te systemic administration o cetriax' one than that ater its systemicadministration or 6 days in (oth models, "here is evidence that (oth somaticand visceral compo' nents. as well as inammation. contri($te to many #inds opostoperative pain,>6.>? "he availa(le data s$ggest that ce' triaxone co$ld alsowor# as an ad


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prod$ced signi7cant antihyperalgesic efects ater (oth ac$te and 6'dayadministration as well as the lowest dose that prod$ced a signi7cantantinociceptive efect ater 6 day administration are compara(le with the doses$sed in s$rgical prophylaxis -+34 g/day. intram$sc$lar/intraveno$s and in severeinec' tions -43> g/day. intram$sc$lar/intraveno$s in h$mans,

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ig, 6, *og dose3response c$rves or antinociception ind$ced (y I!. CE*. PA.and *E in a visceral nociception model in mice, Each point represents the meanW SE0 o(tained in 23+5 animals, KA: 1 percentage o antinociceptive activityHCE* 1 celecoxi(H I! 1 i($proenH *E 1 levetiracetamH PA 1 paracetamol,

Efects o "wo'dr$g Com(inations o Cetriaxone and Diferent Analgesics in

Somatic and isceral Inammatory Pain $r res$lts reveal that cetriaxone exertsa synergistic interac' tion with i($proen. celecoxi(. paracetamol. orlevetiracetam in red$cing carrageenan'ind$ced mechanical hyperalgesia in ratsand acetic acid'ind$ced writhing in mice, Synergistic pharma' codynamicinteractions co$ld (e ascri(ed to the activation o diferent complementarypathways o the o(served actions,>@ "he inammation and in


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interactions (etween cetriaxone and i($proen. celecoxi(. paracetamol. orlevetiracetam co$ld (e explained (y the involvement o m$ltiple diferent targetsand sites in their antihyperalgesic/antinociceptive efects in these inammatorypain models, "he pharmaco#inetic interactions (etween cetriaxone and theexamined analgesics were not within the scope o o$r wor#, Fowever. they

cannot (e excl$ded in the com' (inations o cetriaxone with i($proen andcelecoxi( that displayed prolonged actions, A prolongation o the efect o dr$gcom(ination is li#ely to (e expected in the case o phar' maco#inetic interactionwhich wo$ld res$lt in potentiation o pharmacological efects, "h$s. it seems thatthere co$ld (e more than one possi(le mechanism which co$ld explain thesynergism o(served (etween cetriaxone and i($proen/ celecoxi(, "hisprolongation o the dr$gNs efects. in addition to their potentiation. co$ld (e(ene7cial in the potential clinical $se o these com(inations, A pharmaco#ineticinter' action (etween cetriaxone and paracetamol/levetiracetam appears to (eless li#ely -$nchanged d$ration o efect,

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ig, ?, Antinociceptive efects o CE V I! -A. CE V CE* -!. CE V PA -C.and CE V *E -D com(inations, Analgesics were administered p,o, 88 min(eore the acetic acid -i,p,, CE was administered i,p, as 6'day pretreatment,Dr$gs were ad' ministered at 7xed'dose ractions o their respective ED85 -+/+21 5,5248. +/? 1 5,+48. +/> 1 5,48. and +/4 1 5,8, Each col$mn represents themean W SE0 n$m(er o writhes, ZP X 5,58. ZZP X 5,5+ compared with controlgro$p -"$#ey honestly signi7cant diference post hoc test ater one'way A:A,CE 1 cetriaxoneH CE* 1 celecoxi(H ED85 1 efective dose that prod$ces 85K o

the antinociceptive efectH I! 1 i($proenH i,p, 1 intraperitonealH *E 1levetiracetamH PA 1 paracetamolH p,o, 1 oral,

ig, @, Iso(olograms or CE V I! -A. CE V CE* -!. CE V PA -C. and CE V*E -D com(inations in the visceral nocicep' tion model in mice, "he ED85val$es or each dr$g are plotted at the axes, "he straight line connecting theeach ED85 val$e is the theoretical additive line. and the point in this line is theED85 add, "here is a signi7cant diference -P X 5,58H t test (etween the ED85add and the ED85 mix in each iso(ologram indicating a synergistic dr$ginteraction or all o the examined com(inations, CE* 1 celecoxi(H CE 1

cetriaxoneH ED85 1 efective dose that prod$ces 85K o the antinociceptiveefectH ED85 add 1 theoretical additive ED85H ED85 mix 1 experimental ED85or dr$g mixt$reH I! 1 i($proenH *E 1 levetiracetamH PA 1 paracetamol,

"he occ$rrence o side efects with all o these com(ina' tions is less li#ely(eca$se the doses o the individ$al com' ponents are mar#edly lower, Also.(eca$se the components have diferent side efects. the addition/potentiation otheir individ$al efects is not expected, In concl$sion. the ma


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analgesics -i($proen. celecoxi(. paracetamol. levetiracetam and is s$perior tomonotherapy or (oth somatic and visceral inammatory pain, $r res$ltss$ggest that cetriaxone. par' tic$larly in com(ination with certain analgesics.may provide a $se$l approach to the clinical treatment o inammation' relatedpain,

Ac#nowledgments "he a$thors than# onald "allarida. Ph,D, -Department oPharmacology. "emple niversity School o 0edicine. Phila' delphia.Pennsylvania. or his help$l advice concerning the experimental design andanalysis o the type o interac' tion (etween the dr$gs that were applied incom(ination, "his wor# was s$pported (y the 0inistry o Ed$cation. Science and

"echnological Development o the ep$(lic o Ser(ia -!elgrade. Ser(ia. )rantno, +685>8,

Competing Interests "he a$thors declare no competing interests,

Correspondence Address correspondence to Dr, Stepanovi'Petrovi% Depart'ment o Pharmacology. ac$lty o Pharmacy. niversity o !elgrade. o85. P! +>2. ++44+ !elgrade. Ser' (ia, raca((re$net,rs, Inormation onp$rchasing reprints may (e o$nd at www,anesthesiology,org or on the mast'head page at the (eginning o this iss$e, AnES"hESIl)yNs ar' ticles are madereely accessi(le to all readers. or personal $se only. 2 months rom the coverdate o the iss$e,

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JURNAL Antihyperalgesic.docx